Pediatrics

Common opd cases

 Pediatrics
Common OPD Cases

• Pediatric Community Acquired Pneumonia

o PCAP Guidelines
• Upper Respiratory Tract Infection
• Acute Gastroenteritis
• Asthma
o GINA Guidelines
• Allergic Rhinitis
o ARIA Guidelines

Source: Nelson Textbook of Pediatrics 20th Edition

2088 Part XIX ◆ Respiratory System
Environmental Factors
Exposure to smoke appears to be a strong factor in the development
Goodpasture disease. Whether smoking alters the ultrastructure of the
basement membrane or exogenous particles or noxious substances in
smoke alter the type IV collagen is unknown. Smokers are more likely
to develop pulmonary hemorrhage than non-smokers who have Good-
pasture disease. Other injuries to the alveoli from infection, hydrocar-
bon inhalation, or cocaine inhalation have been reported as associated
events prior to development of Goodpasture disease.
Clinical Manifestations
The majority of patients present with many days or weeks of cough,
dyspnea, fatigue, and sometimes hemoptysis. Young children tend to
swallow small amounts of blood from hemoptysis and may present
with vomiting blood. Occasionally, the hemoptysis is large and resul-
tant anemia is a consequence of large quantities of blood loss. Renal
compromise is found with abnormal renal function tests. Younger
patients tend to present with both the pulmonary and renal syndrome
concurrently. Adults are less likely to develop pulmonary disease.
Laboratory
Serologic detection of anti-GBM antibodies are positive in more than
90% of patients with Goodpasture disease. A complete blood count will
show anemia that is normocytic and normochromic as seen in chronic
inflammatory disease. Urinalysis may reveal hematuria and protein-
uria and blood tests demonstrate renal compromise with elevated
blood urea nitrogen and creatinine.
Studies for pANCA (antimyeloperoxidase ANCA) should also be
performed and are positive in approximately 25-30% of patients con-
currently with anti-GBM antibodies. Clinical disease may be more
difficult to treat and the presence of these antibodies may herald a more
severe form of disease.
Chest Radiography
Chest radiography in Goodpasture disease will often show widely scat-
tered patches of pulmonary infiltrates. If these infiltrates are in the
periphery of the lung, they may be difficult to distinguish from the
eosinophilic lung diseases. Interstitial patterns of thickening may be
found as well. HRCT is usually not performed in this disease as the
constellation of pulmonary hemorrhage, renal compromise, and posi-
tive serologic tests with anti-GBM antibodies detected often preclude
the need for this test.
Pulmonary Function Testing
Pulmonary spirometry often reveals a restrictive defect with reduction
in forced vital capacity and forced expiratory volume at 1-second.
DLCO is a valuable test when pulmonary hemorrhage is a strong
consideration. The intent of this test is to measure the ability of the
lung to transfer inhaled gas to the red blood cell in the pulmonary
capillary bed. This takes advantage of the hemoglobin’s high affinity to
bind carbon monoxide. It was once thought that reduction of DLCO
was a measure of reduced surface area of the alveoli. Current data sug-
gests that it directly correlates with the volume of blood in the pulmo-
nary capillary bed. In pulmonary hemorrhage syndromes, blood in the
alveoli plus the blood in the capillary bed increase the DLCO signifi-
cantly and should alert the clinician to the possibility of pulmonary
hemorrhage.
Bronchoscopy and Bronchoalveolar Lavage
Pulmonary abnormalities can often be best assessed by a bronchoscopy
with BAL. The visual presence of blood on inspection as well as BAL
will be obvious. Infections must be ruled out in many cases, and this
technique adds significant value. BAL cell count will show hemosid-
erin-laden macrophage that have engulfed and broken down the red
blood cells, leaving iron in these cells.
Lung Biopsy
Lung biopsy in patients with active disease reveals capillaritis from
neutrophils, hemosiderin-laden macrophages, type II pneumocyte
hyperplasia, and interstitial thickening at the level of the alveolus.
Staining for IgG and complement is found by immunofluorescence in
along the basement membrane in a linear pattern. This antibody depo-
sition pattern led to the investigation of endogenous antigens in the
basement membrane.
Treatment
More than half of patients with Goodpasture disease who forego treat-
ment die within 2 yr from either respiratory failure, renal failure, or
both. After a diagnosis is made, therapy with corticosteroids (e.g.,
prednisone, 1 mg/kg/day) coupled with oral cyclophosphamide
(2.5 mg/kg/day) is begun. The addition of daily plasmapheresis for
2 wks may accelerate improvement. Cyclophosphamide may be dis-
continued after 2-3 mo. Steroids are often weaned over a 6-9 mo
period. Survival is affected by the need for ongoing dialysis. Patients
who do not require persistent dialysis have a survival rate at 1 yr of
80% or more.
Bibliography is available at Expert Consult.
Chapter 400
Community-Acquired
Pneumonia
Matthew S. Kelly and Thomas J. Sandora
EPIDEMIOLOGY
Pneumonia, defined as inflammation of the lung parenchyma, is the
leading cause of death globally among children younger than age 5 yr,
accounting for an estimated 1.2 million (18% total) deaths annually
(Fig. 400-1). The incidence of pneumonia is more than 10-fold higher
(0.29 episodes vs 0.03 episodes), and the number of childhood-related
deaths from pneumonia ≈2,000 fold higher, in developing than in
developed countries (Table 400-1). Fifteen countries account for more
than three-fourths of all pediatric deaths from pneumonia.
In the United States from 1939-1996, pneumonia mortality in chil-
dren declined by 97%; in 1970, pneumonia accounted for 9% of all
deaths of children younger than age 5 yr compared to 2% in 2007. It
is probable that this decline results from the introduction of antibiotics,
vaccines, and the expansion of medical insurance coverage for chil-
dren. Haemophilus influenzae type b (see Chapter 194) was an impor-
tant cause of bacterial pneumonia in young children but became
uncommon with the routine use of effective vaccines, while measles
vaccine greatly reduced the incidence of measles-related pneumonia
deaths in developing countries. Improved access to healthcare in rural
areas of developing countries and the introduction of pneumococcal
conjugate vaccines (see Chapter 182) were also important contributors
to the further reductions in pneumonia-related deaths achieved over
the past decade.
ETIOLOGY
Although most cases of pneumonia are caused by microorganisms,
noninfectious causes include aspiration (of food or gastric acid, foreign
bodies, hydrocarbons, and lipoid substances), hypersensitivity reac-
tions, and drug- or radiation-induced pneumonitis. The cause of pneu-
monia in an individual patient is often difficult to determine because
direct culture of lung tissue is invasive and rarely performed. Cultures
performed on specimens in children obtained from the upper respira-
tory tract or sputum typically do not accurately reflect the cause of
lower respiratory tract infection. With the use of molecular diagnostic
testing, a bacterial or viral cause of pneumonia can be identified in
 Chapter 400 ◆ Community-Acquired Pneumonia 2089

40-80% of children with community-acquired pneumonia. Streptococ- Salmonella (see Chapter 198), Escherichia coli (see Chapter 200), and
cus pneumoniae (pneumococcus) is the most common bacterial patho- Pneumocystis jiroveci (see Chapter 244) must be considered. The inci-
gen in children 3 wk to 4 yr of age, whereas Mycoplasma pneumoniae dence of pneumonia caused by H. influenzae or S. pneumoniae has
and Chlamydophila pneumoniae are the most frequent bacterial patho- been significantly reduced in areas where routine immunization has
gens in children age 5 yr and older. In addition to pneumococcus, been implemented.
other bacterial causes of pneumonia in previously healthy children in Viral pathogens are a prominent cause of lower respiratory tract
the United States include group A streptococcus (Streptococcus pyo- infections in infants and children older than 1 mo but younger than
genes) and Staphylococcus aureus (see Chapter 181.1 and Table 400-2). 5 yr of age. Viruses can be detected in 40-80% of children with pneu-
S. aureus pneumonia often complicates an illness caused by influenza monia using molecular diagnostic methods. Of the respiratory viruses,
viruses. respiratory syncytial virus (RSV) (see Chapter 260) and rhinoviruses
S. pneumoniae, H. influenzae, and S. aureus are the major causes of are the most commonly identified pathogens, especially in children
hospitalization and death from bacterial pneumonia among children younger than 2 yr of age. However, the role of rhinoviruses in severe
in developing countries, although in children with HIV infection, lower respiratory tract infection remains poorly defined as these
Mycobacterium tuberculosis (see Chapter 215), atypical mycobacteria, viruses are frequently detected in infections with 2 or more pathogens
and among asymptomatic children. Other common viruses causing
Pneumonia pneumonia include influenza virus (see Chapter 258), parainfluenza
Other 18%
(postneonatal) 14% viruses, adenoviruses, enteroviruses, and human metapneumovirus.
Infection with more than 1 respiratory virus occurs in up to 20% of
Pneumonia cases. The age of the patient may help identify possible pathogens
Pneumonia
18%
(neonatal) 4% (Table 400-3).
Measles 1% Lower respiratory tract viral infections are much more common in
Meningitis 2% Other postneonatal the fall and winter in both the northern and southern hemispheres in
35%
AIDS 2%
Diarrhea
relation to the seasonal epidemics of respiratory viral infection that
Diarrhea (postneonatal) 10% occur each year. The typical pattern of these epidemics usually begins
Injuries 5% 11%
in the fall, when parainfluenza infections appear and most often mani-
Diarrhea fest as croup. Later in winter, RSV, human metapneumovirus, and
Malaria 7%
(neonatal) 1% influenza viruses cause widespread infection, including upper respira-
tory tract infections, bronchiolitis, and pneumonia. RSV is particularly
Other neonatal
35%
severe among infants and young children, whereas influenza virus
Other 2% Preterm birth causes disease and excess hospitalization for acute respiratory illness
Tetanus 1% complications 14%
Congenital in all age groups. Knowledge of the prevailing viral epidemic may lead
abnormalities 4% to a presumptive initial diagnosis.
Sepsis and
meningitis 5%
Intrapartum-related Immunization status is relevant because children fully immunized
events 9%
against H. influenzae type b and S. pneumoniae are less likely to be
Figure 400-1 Pneumonia is the leading killer of children worldwide, infected with these pathogens. Children who are immunosuppressed
as shown by this illustration of global distribution of cause-specific or who have an underlying illness may be at risk for specific patho-
mortality among children younger than age 5 yr in 2010. Pneumonia gens, such as Pseudomonas spp. in patients with cystic fibrosis (see
causes 18% of all under-5 deaths. Values may not sum to 100% because Chapter 403).
of rounding. (From Black RE, Allen LH, Bhutta ZA, et al: Maternal and
child undernutrition: global and regional exposures and health conse-
quences. Lancet 371:243–260, 2008; and Liu L, Johnson HL, Cousens PATHOGENESIS
S, et al. Global, regional, and national causes of child mortality: an The lower respiratory tract is normally kept sterile by physiologic
updated systematic analysis for 2010 with time trends since 2000. defense mechanisms, including mucociliary clearance, the properties
Lancet 379:2151–2161, 2012, Fig. 2.) of normal secretions such as secretory immunoglobulin (Ig) A, and

Table 400-1 Incidence of Pneumonia Cases and Pneumonia Deaths Among Children Younger Than Age 5 Yr,
by UNICEF Region, 2004*
NUMBER OF CHILDREN NUMBER OF INCIDENCE OF
YOUNGER THAN 5 YR CHILDHOOD PNEUMONIA CASES TOTAL NUMBER OF
OF AGE (IN PNEUMONIA DEATHS (EPISODES PER PNEUMONIA EPISODES
UNICEF REGIONS THOUSANDS) (IN THOUSANDS) CHILD PER YEAR) (IN THOUSANDS)
South Asia 169,300 702 0.36 61,300
Sub-Saharan Africa 117,300 1,022 0.30 35,200
Middle East and North Africa 43,400 82 0.26 11,300
East Asia and Pacific 146,400 158 0.24 34,500
Latin America and Caribbean 56,500 50 0.22 12,200
Central and Eastern Europe 26,400 29 0.09 2,400
and the Commonwealth of
Independent States
Developing countries 533,000 2,039 0.29 154,500
Industrialized countries 54,200 1 0.03 1,600
World 613,600 2,044 0.26 158,500
*Regional estimates in Columns 2, 3, and 5 do not add up to the world total because of rounding.
From Wardlaw T, Salama P, White Johansson E: Pneumonia: the leading killer of children, Lancet 368:1048–1050, 2006.
2090 Part XIX ◆ Respiratory System
Table 400-2 Causes of Infectious Pneumonia
BACTERIAL
Common
Streptococcus pneumoniae
Group B streptococci
Group A streptococci
Mycoplasma pneumoniae*
Chlamydophila pneumoniae*
Chlamydia trachomatis
Mixed anaerobes
Gram-negative enterics
Uncommon
Haemophilus influenzae type b
Staphylococcus aureus
Moraxella catarrhalis
Neisseria meningitidis
Francisella tularensis
Nocardia species
Chlamydophila psittaci*
Yersinia pestis
Legionella species*
Coxiella burnetii*
VIRAL
Common
Respiratory syncytial virus
Parainfluenza types 1-3
Influenzas A, B
Adenovirus
Human metapneumovirus
Uncommon
Rhinovirus
Enterovirus
Herpes simplex
Cytomegalovirus
Measles
Varicella
Hantavirus
Coronavirus (severe acute
respiratory syndrome, Middle
East respiratory syndrome
[MERS])
FUNGAL
Histoplasma capsulatum
Blastomyces dermatitidis
Coccidioides immitis
Cryptococcus neoformans
Aspergillus species
Mucormycosis
Pneumocystis jiroveci
RICKETTSIAL
Rickettsia rickettsiae
MYCOBACTERIAL
Mycobacterium tuberculosis
Mycobacterium avium complex
PARASITIC
Various parasites (e.g., Ascaris,
Strongyloides species)
*Atypical pneumonia syndrome; may have extrapulmonary manifestations,
low-grade fever, patchy diffuse infiltrates, poor response to β-lactam antibiotics,
and negative sputum Gram stain.
From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric
diagnosis & therapy, ed 2, Philadelphia, 2004, Elsevier, p. 29.
Consolidation, empyema
Neonates
Empyema
Adolescents; summer-fall
epidemics
Adolescents
Infants
Aspiration pneumonia
Nosocomial pneumonia
Unimmunized
Pneumatoceles, empyema; infants
Animal, tick, fly contact;
bioterrorism
Immunosuppressed persons
Bird contact (especially parakeets)
Plague; rat contact; bioterrorism
Exposure to contaminated water;
nosocomial
Q fever; animal (goat, sheep,
cattle) exposure
Bronchiolitis
Croup
High fever; winter months
Can be severe; often occurs
between January and April
Similar to respiratory syncytial
virus
Rhinorrhea
Neonates
Neonates
Infants, immunosuppressed
persons
Rash, coryza, conjunctivitis
Adolescents or unimmunized
Southwestern United States,
rodents
Asia, Arabian peninsula
Ohio/Mississippi River valley;
bird, bat contact
Ohio/Mississippi River valley
Southwest United States
Bird contact
Immunosuppressed persons;
nodular lung infection
Immunosuppressed persons
Immunosuppressed, steroids
Tick bite
Travel to endemic region;
exposure to high-risk persons
Immunosuppressed persons
Eosinophilic pneumonia
Table 400-3 Etiologic Agents Grouped by Age of the
Patient
FREQUENT PATHOGENS
AGE GROUP (IN ORDER OF FREQUENCY)
Neonates Group B streptococcus, Escherichia coli, other
(<3 wk) Gram-negative bacilli, Streptococcus
pneumoniae, Haemophilus influenzae (type b,*
nontypeable)
3 wk-3 mo Respiratory syncytial virus, other respiratory viruses
(rhinoviruses, parainfluenza viruses, influenza
viruses, adenovirus), S. pneumoniae, H. influenzae
(type b,* nontypeable); if patient is afebrile,
consider Chlamydia trachomatis
4 mo-4 yr Respiratory syncytial virus, other respiratory viruses
(rhinoviruses, parainfluenza viruses, influenza
viruses, adenovirus), S. pneumoniae, H. influenzae
(type b,* nontypeable), Mycoplasma pneumoniae,
group A streptococcus
≥5 yr M. pneumoniae, S. pneumoniae, Chlamydophila
pneumoniae, H. influenzae (type b,* nontypeable),
influenza viruses, adenovirus, other respiratory
viruses, Legionella pneumophila
*H. influenzae type b is uncommon with routine H. influenzae type b
immunization.
Adapted from Kliegman RM, Marcdante KJ, Jenson HJ, et al: Nelson
essentials of pediatrics, ed 5, Philadelphia, 2006, Elsevier, p. 504.
clearing of the airway by coughing. Immunologic defense mechanisms
of the lung that limit invasion by pathogenic organisms include mac-
rophages that are present in alveoli and bronchioles, secretory IgA, and
other immunoglobulins. Trauma, anesthesia, and aspiration increase
the risk of pulmonary infection.
Viral pneumonia usually results from spread of infection along the
airways, accompanied by direct injury of the respiratory epithelium,
which results in airway obstruction from swelling, abnormal secre-
tions, and cellular debris. The small caliber of airways in young infants
makes such patients particularly susceptible to severe infection. Atel-
ectasis, interstitial edema, and ventilation–perfusion mismatch causing
significant hypoxemia often accompany airway obstruction. Viral
infection of the respiratory tract can also predispose to secondary
bacterial infection by disturbing normal host defense mechanisms,
altering secretions, and modifying the bacterial flora.
Bacterial pneumonia most often occurs when respiratory tract
organisms colonize the trachea and subsequently gain access to the
lungs, but pneumonia may also result from direct seeding of lung tissue
after bacteremia. When bacterial infection is established in the lung
parenchyma, the pathologic process varies according to the invading
organism. M. pneumoniae (see Chapter 223) attaches to the respiratory
epithelium, inhibits ciliary action, and leads to cellular destruction and
an inflammatory response in the submucosa. As the infection pro-
gresses, sloughed cellular debris, inflammatory cells, and mucus cause
airway obstruction, with spread of infection occurring along the bron-
chial tree, as it does in viral pneumonia.
S. pneumoniae produces local edema that aids in the proliferation of
organisms and their spread into adjacent portions of lung, often result-
ing in the characteristic focal lobar involvement.
Group A streptococcus infection of the lower respiratory tract
results in more diffuse infection with interstitial pneumonia. The
pathology includes necrosis of tracheobronchial mucosa; formation of
large amounts of exudate, edema, and local hemorrhage, with exten-
sion into the interalveolar septa; and involvement of lymphatic vessels
and the increased likelihood of pleural involvement.
S. aureus pneumonia manifests in confluent bronchopneumonia,
which is often unilateral and characterized by the presence of extensive
areas of hemorrhagic necrosis and irregular areas of cavitation of the
lung parenchyma, resulting in pneumatoceles, empyema, or, at times,
bronchopulmonary fistulas.
 Chapter 400 ◆ Community-Acquired Pneumonia 2091

Table 400-4 Differential Diagnosis of Recurrent

Pneumonia
HEREDITARY DISORDERS
Cystic fibrosis
Sickle cell disease
DISORDERS OF IMMUNITY
HIV/AIDS
Bruton agammaglobulinemia
Selective immunoglobulin G subclass deficiencies
Common variable immunodeficiency syndrome
Severe combined immunodeficiency syndrome
Chronic granulomatous disease
Hyperimmunoglobulin E syndromes
Leukocyte adhesion defect
DISORDERS OF CILIA A
Immotile cilia syndrome
Kartagener syndrome
ANATOMIC DISORDERS
Pulmonary sequestration
Lobar emphysema
Gastroesophageal reflux
Foreign body
Tracheoesophageal fistula (H type)
Bronchiectasis
Aspiration (oropharyngeal incoordination)
Aberrant bronchus
From Kliegman RM, Marcdante KJ, Jenson HJ, et al: Nelson essentials of
pediatrics, ed 5, Philadelphia, 2006, Elsevier, p. 507.

Recurrent pneumonia is defined as 2 or more episodes in a single

year or 3 or more episodes ever, with radiographic clearing between
occurrences. An underlying disorder should be considered if a child
experiences recurrent pneumonia (Table 400-4).
CLINICAL MANIFESTATIONS
Pneumonia is frequently preceded by several days of symptoms of an
upper respiratory tract infection, typically rhinitis and cough. In viral
pneumonia, fever is usually present but temperatures are generally
lower than in bacterial pneumonia. Tachypnea is the most consistent
clinical manifestation of pneumonia. Increased work of breathing
accompanied by intercostal, subcostal, and suprasternal retractions,
nasal flaring, and use of accessory muscles is common. Severe infection
may be accompanied by cyanosis and lethargy, especially in infants.
Auscultation of the chest may reveal crackles and wheezing, but it is
often difficult to localize the source of these adventitious sounds in
very young children with hyperresonant chests. It is often not possible
to distinguish viral pneumonia clinically from disease caused by Myco-
plasma and other bacterial pathogens.
Bacterial pneumonia in adults and older children typically begins
suddenly with high fever, cough, and chest pain. Other symptoms that
may be seen include drowsiness with intermittent periods of restless-
ness; rapid respirations; anxiety; and, occasionally, delirium. In many
children, splinting on the affected side to minimize pleuritic pain and
improve ventilation is noted; such children may lie on one side with
the knees drawn up to the chest.
Physical findings depend on the stage of pneumonia. Early in the
course of illness, diminished breath sounds, scattered crackles, and
rhonchi are commonly heard over the affected lung field. With the
development of increasing consolidation or complications of pneumo-
nia such as pleural effusion or empyema, dullness on percussion is
noted and breath sounds may be diminished. A lag in respiratory
excursion often occurs on the affected side. Abdominal distention may
be prominent because of gastric dilation from swallowed air or ileus.
Abdominal pain is common in lower-lobe pneumonia. The liver may
seem enlarged because of downward displacement of the diaphragm
secondary to hyperinflation of the lungs or superimposed congestive
heart failure.
B
Figure 400-2 A, Radiographic findings characteristic of respiratory
syncytial virus pneumonia in a 6 mo old infant with rapid respirations
and fever. Anteroposterior radiograph of the chest shows hyperexpan-
sion of the lungs with bilateral fine air space disease and streaks of
density, indicating the presence of both pneumonia and atelectasis. An
endotracheal tube is in place. B, One day later, the anteroposterior
radiograph of the chest shows increased bilateral pneumonia.
Symptoms described in adults with pneumococcal pneumonia may
be noted in older children but are rarely observed in infants and young
children, in whom the clinical pattern is considerably more variable.
In infants, there may be a prodrome of upper respiratory tract infec-
tion and diminished appetite, leading to the abrupt onset of fever,
restlessness, apprehension, and respiratory distress. These infants
appear ill, with respiratory distress manifested as grunting; nasal
flaring; retractions of the supraclavicular, intercostal, and subcostal
areas; tachypnea; tachycardia; air hunger; and often cyanosis. Results
of physical examination may be misleading, particularly in young
infants, with meager findings disproportionate to the degree of tachy-
pnea. Some infants with bacterial pneumonia may have associated
gastrointestinal disturbances characterized by vomiting, anorexia,
diarrhea, and abdominal distention secondary to a paralytic ileus.
Rapid progression of symptoms is characteristic in the most severe
cases of bacterial pneumonia.
DIAGNOSIS
An infiltrate on chest radiograph (posteroanterior and lateral views)
supports the diagnosis of pneumonia; the film may also indicate a
complication such as a pleural effusion or empyema. Viral pneumonia
is usually characterized by hyperinflation with bilateral interstitial infil-
trates and peribronchial cuffing (Fig. 400-2). Confluent lobar consoli-
dation is typically seen with pneumococcal pneumonia (Fig. 400-3).
The radiographic appearance alone is not diagnostic, and other clinical
features must be considered. Repeat chest radiographs are not required
for proof of cure for patients with uncomplicated pneumonia. Some
2092 Part XIX ◆ Respiratory System
A B
Figure 400-3 Radiographic findings characteristic of pneumococcal pneumonia in a 14 yr old boy with cough and fever. Posteroanterior
(A) and lateral (B) chest radiographs reveal consolidation in the right lower lobe, strongly suggesting bacterial pneumonia.
experts suggest that a chest radiograph may not be necessary for older
children with suspected pneumonia (cough, fever, localized crackles,
or decreased breath sounds) who are well enough to be managed as
outpatients.
Point-of-care use of portable or handheld ultrasonography is highly
sensitive and specific in diagnosing pneumonia in children by deter-
mining lung consolidations and air bronchograms or effusions.
The peripheral white blood cell (WBC) count can be useful in dif-
ferentiating viral from bacterial pneumonia. In viral pneumonia, the
WBC count can be normal or elevated but is usually not higher than
20,000/mm3, with a lymphocyte predominance. Bacterial pneumonia
is often associated with an elevated WBC count, in the range of 15,000-
40,000/mm3, and a predominance of granulocytes. A large pleural
effusion, lobar consolidation, and a high fever at the onset of the illness
are also suggestive of a bacterial etiology. Atypical pneumonia caused
by C. pneumoniae or M. pneumoniae is difficult to distinguish from
pneumococcal pneumonia on the basis of radiographic and laboratory
findings, and although pneumococcal pneumonia is associated with a
higher WBC count, erythrocyte sedimentation rate, procalcitonin, and
C-reactive protein level, there is considerable overlap, particularly with
adenoviruses and enteroviruses.
The definitive diagnosis of a viral infection rests on the isolation of
a virus or detection of the viral genome or antigen in respiratory tract
secretions. Reliable DNA or RNA tests for the rapid detection of many
respiratory pathogens, such as mycoplasma, pertussis, and viruses,
including RSV, parainfluenza, influenza, and adenoviruses, are avail-
able and accurate. Serologic techniques can also be used to diagnose a
recent respiratory viral infection but generally require testing of acute
and convalescent serum samples for a rise in antibodies to a specific
viral agent. This diagnostic technique is laborious, slow, and not gener-
ally clinically useful because the infection usually resolves by the time
it is confirmed serologically. Serologic testing may be valuable as an
epidemiologic tool to define the incidence and prevalence of the
various respiratory viral pathogens. Patient peripheral cell gene expres-
sion patterns determined by microarray reverse transcription poly-
merase chain reaction is an emerging technology that may help
differentiate viral from bacterial causes of pneumonia.
The definitive diagnosis of a bacterial infection requires isolation of
an organism from the blood, pleural fluid, or lung. Culture of sputum
is of little value in the diagnosis of pneumonia in young children, while
percutaneous lung aspiration is invasive and not routinely performed.
Blood culture results are positive in only 10% of children with pneu-
mococcal pneumonia and are not recommended for nontoxic appear-
ing children treated as an outpatient. Blood cultures are recommended
for those who fail to improve or have clinical deterioration, in those
Table 400-5 Factors Suggesting Need for
Hospitalization of Children with
Pneumonia
Age <6 mo
Sickle cell anemia with acute chest syndrome
Multiple lobe involvement
Immunocompromised state
Toxic appearance
Moderate to severe respiratory distress
Requirement for supplemental oxygen
Complicated pneumonia*
Dehydration
Vomiting or inability to tolerate oral fluids or medications
No response to appropriate oral antibiotic therapy
Social factors (e.g., inability of caregivers to administer medications
at home or follow-up appropriately)
*Pleural effusion, empyema, abscess, bronchopleural fistula, necrotizing
pneumonia, acute respiratory distress syndrome, extrapulmonary infection
(meningitis, arthritis, pericarditis, osteomyelitis, endocarditis), hemolytic uremic
syndrome, sepsis.
Adapted from Baltimore RS: Pneumonia. In Jenson HB, Baltimore RS, editors:
Pediatric infectious diseases: principles and practice, Philadelphia, 2002, WB
Saunders, p. 801.
with complicated pneumonia (Table 400-5) and those requiring hos-
pitalization. Cold agglutinins at titers >1 : 64 are found in the blood in
≈50% of patients with M. pneumoniae infections. Cold agglutinin find-
ings are nonspecific because other pathogens such as influenza viruses
may also cause increases. Acute infection caused by M. pneumoniae
can be diagnosed on the basis of a positive polymerase chain reaction
test result or seroconversion in an IgG assay. Serologic evidence, such
as the antistreptolysin O titer, may be useful in the diagnosis of group
A streptococcal pneumonia.
TREATMENT
Treatment of suspected bacterial pneumonia is based on the presump-
tive cause and the age and clinical appearance of the child. For mildly
ill children who do not require hospitalization, amoxicillin is recom-
mended. With the emergence of penicillin-resistant pneumococci,
high doses of amoxicillin (80-90 mg/kg/24 hr) should be prescribed
unless local data indicate a low prevalence of resistance. Therapeutic
alternatives include cefuroxime axetil and amoxicillin/clavulanate. For
school-age children and in children in whom infection with M. pneu-
moniae or C. pneumoniae is suggested, a macrolide antibiotic such as
 Chapter 400 ◆ Community-Acquired Pneumonia 2093

azithromycin is an appropriate choice. In adolescents, a respiratory

fluoroquinolone (levofloxacin, moxifloxacin) may be considered as an
alternative. Despite substantial gains over the past decade, in develop-
ing countries only ≈60% of children with symptoms of pneumonia
(≈50% in sub-Saharan Africa) are taken to an appropriate caregiver,
and less than one-third receive antibiotics. The World Health Organi-
zation and other international groups have developed systems to train
mothers and local healthcare providers in the recognition and treat-
ment of pneumonia.
The empiric treatment of suspected bacterial pneumonia in a hos-
pitalized child requires an approach based on the clinical manifesta-
tions at the time of presentation. In areas without substantial high-level
penicillin resistance among S. pneumoniae, children who are fully
immunized against H. influenzae type b and S. pneumoniae and are not
severely ill should receive ampicillin or penicillin G. For children who
do not meet these criteria, ceftriaxone or cefotaxime should be used.
If clinical features suggest staphylococcal pneumonia (pneumatoceles,
empyema), initial antimicrobial therapy should also include vancomy-
cin or clindamycin.
If viral pneumonia is suspected, it is reasonable to withhold antibi-
otic therapy, especially for those patients who are mildly ill, have clini-
cal evidence suggesting viral infection, and are in no respiratory
distress. However, up to 30% of patients with known viral infection,
particularly influenza viruses, may have coexisting bacterial pathogens.
Therefore, if the decision is made to withhold antibiotic therapy on the
Figure 400-4 Pneumococcal empyema on the chest radiography of
basis of presumptive diagnosis of a viral infection, deterioration in a 3 yr old child who has had upper respiratory symptoms and fever
clinical status should signal the possibility of superimposed bacterial for 3 days. A pleural fluid collection can be seen on the right side. The
infection, and antibiotic therapy should be initiated. patient had a positive pleural tap and blood culture result for pneumo-
Table 400-5 notes the indications for admission to a hospital. The cocci. The child recovered completely within 3 wk. (From Kuhn JP,
optimal duration of antibiotic treatment for pneumonia has not been Slovis TL, Haller JO (eds): Caffrey’s pediatric diagnostic imaging,
well-established in controlled studies. However, antibiotics should gen- ed 10, Philadelphia, 2004, Mosby, p. 1002.)
erally be continued until the patient has been afebrile for 72 hr, and
the total duration should not be less than 10 days (or 5 days if azithro-
mycin is used). Shorter courses (5-7 days) may also be effective, par-
ticularly for children managed on an outpatient basis, but further study COMPLICATIONS
is needed. Available data do not support prolonged courses of treat- Complications of pneumonia (see Table 400-5) are usually the result
ment for uncomplicated pneumonia. In developing countries, oral zinc of direct spread of bacterial infection within the thoracic cavity (pleural
(10 mg/day for <12 mo, 20 mg/day for ≥12 mo) reduces mortality effusion, empyema, and pericarditis) or bacteremia and hematologic
among children with clinically defined severe pneumonia. spread (Fig. 400-4). Meningitis, suppurative arthritis, and osteomyelitis
are rare complications of hematologic spread of pneumococcal or
PROGNOSIS H. influenzae type b infection.
Typically, patients with uncomplicated community-acquired bacterial S. aureus, S. pneumoniae, and S. pyogenes are the most common
pneumonia show response to therapy, with improvement in clinical causes of parapneumonic effusions and empyema (Table 400-6). None-
symptoms (fever, cough, tachypnea, chest pain), within 48-96 hr of theless many effusions that complicate bacterial pneumonia are sterile.
initiation of antibiotics. Radiographic evidence of improvement lags Universal 16S ribosomal RNA gene polymerase chain reaction identi-
substantially behind clinical improvement. A number of possibilities fies the bacterial genome and can determine the bacterial etiology of
must be considered when a patient does not improve with appropriate the effusion if the culture is negative. The treatment of empyema is
antibiotic therapy: (1) complications, such as empyema (see Table 400- based on the stage (exudative, fibrinopurulent, organizing). Imaging
5); (2) bacterial resistance; (3) nonbacterial etiologies such as viruses studies including ultrasonography and CT are helpful in determining
or fungi and aspiration of foreign bodies or food; (4) bronchial obstruc- the stage of empyema. The mainstays of therapy include antibiotic
tion from endobronchial lesions, foreign body, or mucous plugs; (5) therapy and drainage with tube thoracostomy. Additional effective
preexisting diseases such as immunodeficiencies, ciliary dyskinesia, approaches include the use of intrapleural fibrinolytic therapy (uroki-
cystic fibrosis, pulmonary sequestration, or congenital pulmonary nase, streptokinase, tissue plasminogen activator) and selected video-
airway malformation, formerly called cystic adenomatoid malforma- assisted thoracoscopy to debride or lyse adhesions and drain loculated
tion; and (6) other noninfectious causes (including bronchiolitis areas of pus. Early diagnosis and intervention, particularly with fibri-
obliterans, hypersensitivity pneumonitis, eosinophilic pneumonia, nolysis or less often video-assisted thoracoscopy, may obviate the need
aspiration, and granulomatosis with polyangiitis, formerly called for thoracotomy and open debridement. Fibrinolysis is more cost-
Wegener granulomatosis). A repeat chest radiograph is the first step in effective than video-assisted thoracoscopy.
determining the reason for delay in response to treatment. Bronchoal-
veolar lavage may be indicated in children with respiratory failure; PREVENTION
high-resolution CT scans may better identify complications or an ana- Some evidence exists to suggest that vaccination has reduced the inci-
tomic reason for a poor response to therapy. dence of pneumonia hospitalizations. The annual rate of all-cause
Mortality from community-acquired pneumonia in developed pneumonia hospitalization among children younger than 2 yr of age
nations is rare, and most children with pneumonia do not experience in the United States during the period 1997-1999 was 12.5 per 1,000
long-term pulmonary sequelae. Some data suggest that up to 45% of children. In February 2000, the 7-valent pneumococcal conjugate
children have symptoms of asthma 5 yr after hospitalization for pneu- vaccine (PCV7) was licensed and recommended. In 2006, the pneu-
monia; this finding may reflect either undiagnosed asthma at the time monia hospitalization rate in this age group was 8.1 per 1,000 children,
of presentation or a propensity for development of asthma after a 35% decrease from the prevaccine rate. Although these data do not
pneumonia. establish that PCV7 directly reduced pneumonia hospitalization rates,
2094 Part XIX ◆ Respiratory System

Table 400-6 Differentiation of Pleural Fluid

TRANSUDATE EMPYEMA
Appearance Clear Cloudy or purulent
Cell count (per mm3) <1,000 Often >50,000 (cell count has limited predictive value)
Cell type Lymphocytes, monocytes Polymorphonuclear leukocytes (neutrophils)
Lactate dehydrogenase <200 U/L More than two-thirds upper limit of normal for serum lactate
dehydrogenase (LDH)
Pleural fluid : serum LDH ratio <0.6 >0.6
Protein >3 g Unusual Common
Pleural fluid : serum protein ratio <0.5 >0.5
Glucose* Normal Low (<40 mg/dL)
pH* Normal (7.40-7.60) <7.10
Gram stain Negative Occasionally positive (less than one-third of cases)
Cholesterol >55 mg/dL
Pleural cholesterol : serum <0.3 >0.3
cholesterol ratio
*Low glucose or pH may be seen in malignant effusion, tuberculosis, esophageal rupture, pancreatitis (positive pleural amylase), and rheumatologic diseases (e.g.,
systemic lupus erythematosus).
From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis & therapy, ed 2, Philadelphia, 2004, Elsevier, p. 30.

they do suggest that vaccination has resulted in a sustained benefit in

preventing hospitalization for young children with pneumonia. Table 401-1 Conditions That Predispose to
In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) Bronchiectasis in Children
was licensed in the United States; it may prevent even more cases of PROXIMAL AIRWAY NARROWING
pneumococcal disease not covered by the PCV7 vaccine. Airway wall compression (i.e., vascular ring, adenopathy impinging
The expansion of influenza vaccine recommendations to include all on airways)
children >6 mo of age in 2010 might be expected to affect pneumonia Airway intraluminal obstruction (e.g., inhaled foreign body,
hospitalization rates in a similar fashion, and ongoing surveillance is granulation tissue)
warranted. Airway stenosis and malacia
AIRWAY INJURY
Bibliography is available at Expert Consult. Bronchiolitis obliterans (e.g., postviral, after lung transplantation)
Recurrent pneumonitis or pneumonia (e.g., pneumococcal
pneumonia, aspiration pneumonia)
ALTERED PULMONARY HOST DEFENSES
Cystic fibrosis
Ciliary dyskinesia
Chapter 401 Impaired cough (e.g., neuromuscular weakness conditions)
ALTERED IMMUNE STATES
Bronchiectasis Primary abnormalities (e.g., hypogammaglobulinemia)
Secondary abnormalities (e.g., HIV infection, immunosuppressive
agents)
Oren J. Lakser
OTHER
Allergic bronchopulmonary aspergillosis
Plastic bronchitis
Bronchiectasis is characterized by irreversible abnormal dilation and
anatomic distortion of the bronchial tree and represents a common end From Redding GJ: Bronchiectasis in children, Pediatr Clin North Am 56:157–171,
stage of a many nonspecific and unrelated antecedent events. Its inci- 2009, Box 1, p. 158.
dence has been decreasing overall in industrialized countries, but it
persists as a problem in lower and middle income countries and among
some ethnic groups in industrialized nations. Females are afflicted
more frequently than males. Williams-Campbell syndrome, in which there is an absence of
annular bronchial cartilage, and Marnier-Kuhn syndrome (congenital
PATHOPHYSIOLOGY AND PATHOGENESIS tracheobronchomegaly), in which there is a connective tissue disorder.
In industrialized nations, cystic fibrosis (see Chapter 403) is the most Other disease entities associated with bronchiectasis are right middle
common cause of clinically significant bronchiectasis. Other condi- lobe syndrome (chronic extrinsic compression of right middle lobe
tions associated with bronchiectasis include primary ciliary dyskinesia bronchus by hilar lymph nodes) and yellow nail syndrome (pleural
(see Chapter 404), foreign-body aspiration (see Chapter 387), aspira- effusion, lymphedema, discolored nails).
tion of gastric contents, immune deficiency syndromes (especially Three basic mechanisms are involved in the pathogenesis of bron-
humoral immunity), and infection, especially pertussis, measles, and chiectasis. Obstruction can occur because of tumor, foreign body,
tuberculosis (Table 401-1). Bronchiectasis can also be congenital, as in impacted mucus because of poor mucociliary clearance, external
CLINICAL QUESTION 1. WHO SHALL BE CONSIDERED AS HAVING COMMUNITY-ACQUIRED
PNEUMONIA?
1. The presence of pneumonia may be considered even without a chest radiograph in a patient presenting with
cough and/or respiratory difficulty [Recommendation Grade D] plus any of the following predictors of
radiographic pneumonia:
1.1. At the Emergency Room as the site-of-care,
1.1.1. tachypnea as defined by World Health Organization [WHO] in a patient aged 3 months to 5 years
[Recommendation Grade B]; or
1.1.2. fever at any age [Recommendation Grade B]; or
1.1.3. oxygen saturation less than or equal to 92% at room air at any age [Recommendation Grade B] in
the absence of any co-existing illness (neurologic, musculoskeletal, or cardiac condition) that
may potentially affect oxygenation [Recommendation Grade D].
1.2. At the Out-Patient Clinic as the site-of-care,
1.2.1. tachypnea as defined by World Health Organization [WHO] in a patient aged 3 months to
5 years [Recommendation Grade D]; or
1.2.2. fever at any age [Recommendation Grade D].
2. The presence of pneumonia should be determined using a chest radiograph in a patient presenting with
2.1. cough and/or respiratory difficulty [Recommendation Grade D] in the following situations:
2.1.1. Presence of dehydration aged 3 months to 5 years [Recommendation Grade B].
2.1.2. Presence of severe malnutrition aged less than 7 years [Recommendation Grade B].
2.2. high grade fever and leukocytosis aged 3 to 24 months without respiratory symptoms
[Recommendation Grade C].

Clinical Question 2. WHO WILL REQUIRE ADMISSION?

a
1. Revised risk classification for pneumonia-related mortality [Recommendation Grade D]
CLASSIFICATION PROVIDED BY
Philippine Academy of Pediatric Pulmonologists pCAP A or B pCAP C pCAP D
Philippine Health Insurance Corp --- Pneumonia I Pneumonia II
World Health Organization Nonsevere Severe Very severe
b
VARIABLES
Clinical
c
1. Dehydration None Mild Moderate Severe
d
2. Malnutrition None Moderate Severe
3. Pallor None Present Present
4. Respiratory rate
e
3 to12 months >50/min to <60/min >60/min to <70 >70/min
e
1 to 5 years >40/min to <50/min >50/min >50/min
> 5 years >30/min to <35/min >35/min >35/min
5. Signs of respiratory failure
a. Retraction None IC/subcostal Supraclavicular/IC/SC
b. Head bobbing None Present Present
c. Cyanosis None Present Present
d. Grunting None None Present
e. Apnea None None Present
f. Sensorium None Irritable Lethargic/stuporous/comatose
f
Diagnostic aid at site-of-care
1. Chest x ray findings of any of the following:
effusion; abscess; air leak or lobar consolidation None Present Present
2. Oxygen saturation at room air using pulse oximetry 95% <95% <95%
ACTION PLAN
1. Site-of-care Outpatient Admit to ward Admit to a critical care facility
2. Follow-up End of treatment
a
In order to classify to a higher risk category, at least 2 variables (clinical and diagnostic aid) should be present. In the absence of a
diagnostic aid variable, clinical variables will suffice.
b
Risk factors for mortality based on evidence and/or expert opinion among members of the 2012 PAPP Task Force on pCAP.
c
Weight for Height [WFH] SD score < -2 moderate; SD score < -3 severe. WHO management of severe malnutrition: a manual for
physicians and other health workers. Geneva. World Health Organization 1999
d
Grading of dehydration adapted from Nelson’s Textbook of Pediatrics: MILD [thirsty, normal or increased pulse rate, decreased urine
output and normal physical examination]; MODERATE [tachycardia, little or no urine output, irritable/lethargic, sunken eyes
and fontanel, decreased tears, dry mucus membranes, mild tenting of the skin, delayed capillary refill, cool and
pale]; SEVERE [rapid and weak pulse, decreased blood pressure, no urine output, very sunken eyes and fontanel, no tears,
parched mucous membranes, tenting of the skin, very delayed capillary refill, cold and mottled]
e
World Health Organization age specific-criteria for tachypnea for children under 5 years old.
f
Chest x ray and pulse oximetry are desirable variables but not necessary as determinants of admission at site-of-care.
2. Patients under 5 years old [Recommendation Grade B] and more than 5 years old [Recommendation Grade D]
who are classified as pCAP C but whose chest x-ray is without any of the following: effusion, lung
abscess, air leak or multilobar consolidation, and whose oxygen saturation is > 95% at room air
can be managed initially on an outpatient basis.
12
Clinical Question 3. WHAT DIAGNOSTIC AIDS ARE INITIALLY REQUESTED FOR A PATIENT CLASSIFIED
AS EITHER pCAP A or pCAP B BEING MANAGED IN AN AMBULATORY SETTING?
1. Chest x-ray may be requested to rule out pneumonia-related complications or pulmonary conditions simulating
pneumonia [Recommendation Grade D].
1.1. It should not be routinely requested to predict end-of-treatment clinical outcome
[Recommendation Grade A].
2. Chest x-ray, complete blood count, C-reactive protein, erythrocyte sedimentation rate, procalcitonin, or
blood culture should not be routinely requested to determine appropriateness of antibiotic usage
[Recommendation Grade D].

Clinical Question 4. WHAT DIAGNOSTIC AIDS ARE INITIALLY REQUESTED FOR A PATIENT CLASSIFIED
AS EITHER pCAP C or pCAP D BEING MANAGED IN A HOSPITAL SETTING?
1. For pCAP C,
1.1. The following ancillary/diagnostic procedures should be done.
1.1.1. to determine etiology:
1.1.1.1. Gram stain and/or culture and sensitivity of pleural fluid when available
[Recommendation Grade D]
1.1.2. to assess gas exchange:
1.1.2.1. Oxygen saturation using pulse oximetry [Recommendation Grade D]
1.1.2.2. Arterial blood gas [Recommendation Grade D]
1.2. The following ancillary/diagnostic procedures may be done
1.2.1. to confirm clinical suspicion of multilobar consolidation, lung abscess, pleural effusion,
pneumothorax or pneumomediastinum:
1.2.1.1. Chest x-ray PA-lateral
1.2.2. to determine appropriateness of antibiotic usage:
1.2.2.1. C-reactive protein (CRP) [Recommendation Grade A]
1.2.2.2. Procalcitonin (PCT) [Recommendation Grade B]
1.2.2.3. Chest x-ray PA-lateral [Recommendation Grade C]
1.2.2.4. White Blood Cell (WBC) count [Recommendation Grade D]
1.2.2.5. Gram stain of sputum or nasopharyngeal aspirate [Recommendation Grade D]
1.2.3. to determine etiology
1.2.3.1. Sputum culture and sensitivity [Recommendation Grade C]
1.2.3.2. Blood culture and sensitivity [Recommendation Grade C]
1.2.4. to predict clinical outcome:
1.2.4.1. Chest x-ray PA-lateral [Recommendation Grade B]
1.2.4.2. Pulse oximetry [Recommendation Grade B]
1.2.5. to determine the presence of tuberculosis if clinically suspected:
1.2.5.1. Mantoux test (PPD 5-TU) [Recommendation Grade D]
1.2.5.2. Sputum smear for aid fast bacilli
1.2.6. to determine metabolic derangement:
1.2.6.1. Serum electrolytes [Recommendation Grade C]
1.2.6.2. Serum glucose [Recommendation Grade C]
2. For pCAP D, a referral to a specialist should be done [Recommendation Grade D].

Clinical Question 5. WHEN IS ANTIBIOTIC RECOMMENDED?

1. For pCAP A or B, an antibiotic may be administered if a patient is
1.1. beyond 2 years of age [Recommendation Grade D]; or
1.2. with high grade fever without wheeze [Recommendation Grade D].
2. For pCAP C, an antibiotic
2.1. should be administered if alveolar consolidation on chest x-ray is present [Recommendation Grade C].
2.2. may be administered if a patient is with any of the following:
2.2.1. Elevated serum C-reactive protein [CRP] [Recommendation Grade A]
2.2.2. Elevated serum procalcitonin level [PCT] [Recommendation Grade B]
2.2.3. Elevated white cell count [Recommendation Grade D].
2.2.4. High grade fever without wheeze [Recommendation Grade D].
2.2.5. Beyond 2 years of age [Recommendation Grade D].
3. For pCAP D, a specialist should be consulted [Recommendation Grade D].

13
Clinical Question 6. WHAT EMPIRIC TREATMENT SHOULD BE ADMINISTERED IF A BACTERIAL
ETIOLOGY IS STRONGLY CONSIDERED?
1. For a patient who has been classified as pCAP A or B without previous antibiotic,
1.1. amoxicillin [40-50 mg/kg/day, maximum dose of 1500 mg/day in 3 divided doses for at most 7 days] is
the drug of choice [Recommendation Grade B].
1.1.1. Amoxicillin may be given for a minimum of 3 days [Recommendation Grade A].
1.1.2. Amoxicillin may be given in 2 divided doses for a minimum of 5 days
[Recommendation Grade B].
1.2. azithromycin [10 mg/kg/day OD for 3 days or 10mg/kg/day at day 1 then 5 mg/kg/day for days 2 to 5,
maximum dose of 500mg/day], or clarithromycin [15 mg/kg/day, maximum dose of 1000 mg/day
in 2 divided doses for 7 days] may be given to those patients with known hypersensitivity to
amoxicillin [Recommendation Grade D].
2. For a patient who has been classified as pCAP C, without previous antibiotic,
2.1. requiring hospitalization and
2.1.1. has completed the primary immunization against Haemophilus influenza type b,
penicillin G [100,000 units/kg/day in 4 divided doses] administered as monotherapy is
the drug of choice [Recommendation Grade B].
2.1.2. has not completed the primary immunization or immunization status unknown
against Haemophilus influenza type b, ampicillin [100 mg/kg/day in 4 divided doses]
administered as monotherapy is the drug of choice [Recommendation Grade B].
2.1.3. above15 years of age [Recommendation Grade D], a parenteral non-antipseudomonal
β-lactam (β-lactam/β-lactamase inhibitor combination (BLIC), cephalosporin or
carbapenem] + extended macrolide [azithromycin or chlarithromycin], or a parenteral
non-antipseudomonal β-lactam [β-lactam/ β-lactamase inhibitor combination (BLIC],
cephalosporin or carbapenem] + respiratory fluoroquinolones [levofloxacin or
moxifloxacin] administered as combination therapy may be given
[Recommendation Grade A].
2.2. and who can tolerate oral feeding and does not require oxygen support, amoxicillin
[40-50 mg/kg/day, maximum dose of 1500 mg/day in 3 divided doses for at most 7 days] may be given
on an outpatient basis [Recommendation Grade B].
3. For a patient classified as pCAP C who is severely malnourished or suspected to have methicillin-resistant
Staphylococcus aureus, or classified as pCAP D, referral to a specialist is highly recommended
[Recommendation Grade D].
4. For a patient who has been established to have Mycobacterium tuberculosis infection or disease,
antituberculous drugs should be started [Recommendation Grade D].

Clinical Question 7. WHAT TREATMENT SHOULD BE INITIALLY GIVEN IF A VIRAL ETIOLOGY IS

STRONGLY CONSIDERED?
1. Oseltamivir (30 mg twice a day for ≤15 kg body weight, 45 mg twice a day for >15-23 kg, 60 mg twice a day
for >23-40 kg, and 75 mg twice a day for >40 kg) remains to be the drug of choice for laboratory
confirmed [Recommendation Grade A], or clinically suspected [Recommendation Grade D] cases of
influenza.
2. The use of immunomodulators for the treatment of viral pneumonia is not recommended
[Recommendation Grade D].
3. Ancillary treatment as provided in Clinical Question 11 may be given [Recommendation Grade D].

Clinical Question 8. WHEN CAN A PATIENT BE CONSIDERED AS RESPONDING TO THE CURRENT

ANTIBIOTIC?
1. Decrease in respiratory signs and/or defervescense within 72 hours after initiation of antibiotic are predictors of
favorable response [Recommendation Grade D].
2. If clinically responding, further diagnostic aids to assess response such as chest x-ray, C-reactive protein and
complete blood count should not be routinely requested [Recommendation Grade D]

Clinical Question 9. WHAT SHOULD BE DONE IF A PATIENT IS NOT RESPONDING TO CURRENT

ANTIBIOTIC THERAPY?
1. If an outpatient classified as either pCAP A or pCAP B is not responding to the current antibiotic within 72
hours, consider any of the following [Recommendation Grade D]:
1.1. Other diagnosis.
1.1.1. Coexisting illness.
1.1.2. Conditions simulating pneumonia.
1.2. Other etiologic agents for which C-reactive protein, chest x-ray or complete blood count may be used to
determine the nature of the pathogen.
1.2.1. May add an oral macrolide if atypical organism is highly considered.
1.2.2. May change to another antibiotic if microbial resistance is highly considered.

14
2. If an inpatient classified as pCAP C is not responding to the current antibiotic within 72 hours, consider any of
the following [Recommendation Grade D]:
2.1. Other diagnosis:
2.1.1. Coexisting illness.
2.1.2. Conditions simulating pneumonia.
2.2. Consider other etiologic agents for which C-reactive protein, chest x-ray or complete blood count may be
used to determine the nature of the pathogen.
2.2.1. May add an oral macrolide if atypical organism is highly considered.
2.2.2. May change to another antibiotic if microbial resistance is highly considered.
2.3 . May refer to a specialist.
3. If an inpatient classified as pCAP D is not responding to the current antibiotic within 72 hours, immediate
consultation with a specialist should be done [Recommendation Grade D].

Clinical Question 10. WHEN CAN SWITCH THERAPY IN BACTERIAL PNEUMONIA BE STARTED?
1. For pCAP C,
1.1. switch from intravenous antibiotic administration to oral form 3 days after initiation of current antibiotic is
recommended in a patient who should fulfill all of the following [Recommendation Grade D]:
1.1.1. Responsive to current antibiotic therapy as defined in Clinical Question 8.
1.1.2. Tolerance to feeding and without vomiting or diarrhea.
1.1.3. Without any current pulmonary (effusion/empyema; abscess; air leak, lobar consolidation,
necrotizing pneumonia) or extrapulmonary complications; and
1.1.4. Without oxygen support.
1.2. switch therapy from three [3] days of parenteral ampicillin to
1.2.1. amoxicillin [40-50 mg/kg/day for 4 days] [Recommendation Grade B].
2. For pCAP D, referal to a specialist should be considered [Recommendation Grade D].

Clinical Question 11. WHAT ANCILLARY TREATMENT CAN BE GIVEN?

1. For pCAP A or B,
1.1. cough preparation [Recommendation Grade A], elemental zinc [Recommendation Grade B],
vitamin A [Recommendation Grade D], vitamin D [Recommendation Grade D],
probiotic [Recommendation Grade D] and chest physiotherapy [Recommendation Grade D]
should not be routinely given during the course of illness.
1.2. a bronchodilator may be administered in the presence of wheezing [Recommendation Grade D].
2. For pCAP C,
2.1. oxygen and hydration should be administered whenever applicable [Recommendation Grade D].
2.1.1. Oxygen delivery through nasal catheter is as effective as using nasal prong
[Recommendation Grade A].
2.2. a bronchodilator may be administered only in the presence of wheezing. [Recommendation Grade D].
2.2.1. Steroid may be added to a bronchodilator [Recommendation Grade B].
2.3. a probiotic may be administered [Recommendation Grade B].
2.4. cough preparation, elemental zinc, vitamin A, vitamin D and chest physiotherapy should not be
routinely given during the course of illness [Recommendation Grade A].
3. For pCAP D, referal to a specialist should be considered [Recommendation Grade D].

Clinical Question 12. HOW CAN PNEUMONIA BE PREVENTED?

1. The following should be given to prevent pneumonia:
1.1. Vaccine against
1.1.1. Streptococcus pneumonia (conjugate type) [Recommendation Grade A].
1.1.2. Influenza [Recommendation Grade A].
1.1.3. Diphtheria, Pertussis, Rubeola, Varicella, Haemophilus Influenzae type b
[Recommendation Grade A].
1.2. Micronutrient.
1.2.1. Elemental zinc for ages 2 to 59 months to be given for 4 to 6 months
[Recommendation Grade A].
2. The following may be given to prevent pneumonia:
2.1. Micronutrient.
2.1.1. Vitamin D3 supplementation [Recommendation Grade B].
3. The following should not be given to prevent pneumonia:
3.1. Micronutrient
3.1.1. Vitamin A [Recommendation Grade A].

15

Figure 378-2 A typical CT image of an isolated antrochoanal polyp
on the left side. (From Basak S, Karaman CZ, Akdilli A, et al: Surgical
approaches to antrochoanal polyps in children, Int J Pediatr Otorhino-
laryngol 46:197–205, 1998.)
making this diagnosis. Prolonged presence of ethmoidal polyps in a
child can widen the bridge of the nose and erode adjacent osseous
structures. Tumors of the nose cause more local destruction and distor-
tion of the anatomy. CT scan of the midface is key to diagnosis and
planning for surgical treatment (Fig. 378-2).
TREATMENT
Local or systemic decongestants are not usually effective in shrinking
the polyps, although they may provide symptomatic relief from the
associated mucosal edema. Intranasal steroid sprays, and sometimes
systemic steroids, can provide some shrinkage of nasal polyps with
symptomatic relief and have proved useful in children with CF and
adults with nasal polyps. Topical nasal steroid therapy, fluticasone,
mometasone, and budesonide appears to result in nasal symptom
improvement. Doxycycline (200 mg on the 1st day followed by 100 mg
daily) has a significant effect on the size of nasal polyps, nasal symptoms,
and mucosal and systemic markers of inflammation. Polyps should be
removed surgically if complete obstruction, uncontrolled rhinorrhea,
or deformity of the nose appears. If the underlying pathogenic mecha-
nism cannot be eliminated (such as CF), the polyps may soon return.
Functional endoscopic sinus surgery provides more complete polyp
removal and treatment of other associated nasal disease; in some cases,
this has reduced the need for frequent surgeries. Nasal steroid sprays
should also be started preventively, once postsurgical healing occurs.
Antrochoanal polyps do not respond to medical measures and must
be removed surgically. Because these types of polyps are not associated
with any underlying disease process, the recurrence rate is much less
than for other types of polyps.
Bibliography is available at Expert Consult.
Chapter 379
The Common Cold
E. Kathryn Miller and John V. Williams
The common cold is an acute viral infection of the upper respira-
tory tract in which the symptoms of rhinorrhea and nasal obstruction
are prominent. Systemic symptoms and signs such as headache,
myalgia, and fever are absent or mild. The common cold is frequently
referred to as infectious rhinitis but may also include self-limited
Chapter 379 ◆ The Common Cold 2011
involvement of the sinus mucosa and is more correctly termed
rhinosinusitis.
ETIOLOGY
The most common pathogens associated with the common cold are
the more than 200 types of human rhinoviruses (see Chapter 263), but
the syndrome can be caused by many different virus families (Table
379-1). Rhinoviruses are associated with more than 50% of colds in
adults and children. In young children, other viral etiologies of the
common cold include respiratory syncytial virus (RSV; see Chapter
260), human metapneumovirus (see Chapter 261), parainfluenza
viruses (see Chapter 259), and adenoviruses (see Chapter 262).
Common cold symptoms may also be caused by influenza viruses,
nonpolio enteroviruses, and human coronaviruses. Many viruses that
cause rhinitis are also associated with other symptoms and signs such
as cough, wheezing, and fever.
EPIDEMIOLOGY
Colds occur year-round, but the incidence is greatest from the early
fall until the late spring, reflecting the seasonal prevalence of the viral
pathogens associated with cold symptoms. In the northern hemi-
sphere, the highest incidence of rhinovirus infection occurs in the early
fall (August-October) and in the late spring (April-May). The seasonal
incidence for parainfluenza viruses usually peaks in the late fall and
late spring and is highest between December and April for RSVs,
influenza viruses, human metapneumoviruses, and coronaviruses.
Adenoviruses are detected at a low prevalence throughout the cold
season, and enteroviruses may also be detected during summer months
or throughout the year.
Young children have an average of 6-8 colds per year, but 10-15% of
children have at least 12 infections per year. The incidence of illness
decreases with age, with 2-3 illnesses per year by adulthood. The inci-
dence of infection is primarily a function of exposure to the virus.
Children in out-of-home daycare centers during the 1st yr of life have
50% more colds than children cared for only at home. The difference
in the incidence of illness between these groups of children decreases
as the length of time spent in daycare increases, although the incidence
of illness remains higher in the daycare group through at least the 1st
3 yr of life. When they begin primary school, children who attended
daycare have less frequent colds than those who did not. Mannose-
binding lectin deficiency with impaired innate immunity may be asso-
ciated with an increased incidence of colds in children.
PATHOGENESIS
Viruses that cause the common cold are spread by 3 mechanisms:
direct hand contact (self-inoculation of one’s own nasal mucosa or
conjunctivae after touching a contaminated person or object), inhala-
tion of small-particle aerosols that are airborne from coughing, or
deposition of large-particle aerosols that are expelled during a sneeze
and land on nasal or conjunctival mucosa. Although the different
common cold pathogens could be spread by any of these mechanisms,
some routes of transmission appear to be more efficient than others for
particular viruses. Studies of rhinoviruses and RSV indicate that direct
contact is an efficient mechanism of transmission of these viruses,
although transmission by large-particle aerosols can also occur. By
contrast, influenza viruses and coronaviruses appear to be most effi-
ciently spread by small-particle aerosols.
The respiratory viruses have evolved different mechanisms to avoid
host defenses. Infections with rhinoviruses and adenoviruses result in
the development of serotype-specific protective immunity. Repeated
infections with these pathogens occur because there are a large number
of distinct serotypes of each virus. Influenza viruses have the ability to
change the antigens presented on the surface of the virus and thus
behave as though there were multiple viral serotypes. The interaction
of coronaviruses (see Chapter 264) with host immunity is not well
defined, but it appears that multiple distinct strains of coronaviruses
are capable of inducing at least short-term protective immunity. There
are 4 types of parainfluenza viruses and 2 antigenic subgroups of RSV.
In addition to antigenic diversity, many of these viruses are able to
2012 Part XIX ◆ Respiratory System

Table 379-1 Pathogens Associated with the Common Cold

RELATIVE
ASSOCIATION PATHOGEN FREQUENCY* OTHER COMMON SYMPTOMS AND SIGNS
Agents primarily associated with Human rhinoviruses Frequent Wheezing/bronchiolitis
the common cold Coronaviruses Occasional
Agents primarily associated with Respiratory syncytial viruses Occasional Bronchiolitis in children <2 yr of age
other clinical syndromes that also Human metapneumovirus Occasional Pneumonia and bronchiolitis
cause common cold symptoms Influenza viruses Uncommon Influenza, pneumonia, croup
Parainfluenza viruses Uncommon Croup, bronchiolitis
Adenoviruses Uncommon Pharyngoconjunctival fever (palpebral conjunctivitis,
watery eye discharge, pharyngeal erythema)
Enteroviruses Uncommon Herpangina (fever and ulcerated papules on posterior
Coxsackievirus A oropharynx
Other nonpolio enteroviruses Aseptic meningitis
*Relative frequency of colds caused by the agent.

reinfect the upper airway because mucosal immunoglobulin A induced

by previous infection is short-lived, and the brief incubation period of Table 379-2 Conditions That Can Mimic
these viruses allows the establishment of infection before immune the Common Cold
memory responses. Although reinfection is not completely prevented CONDITION DIFFERENTIATING FEATURES
by the adaptive host response to these viruses, the severity of illness is
moderated by preexisting immunity. Allergic rhinitis Prominent itching and sneezing, nasal
Viral infection of the nasal epithelium can be associated with eosinophils
destruction of the epithelial lining, as with influenza viruses and ade- Vasomotor rhinitis May be triggered by irritants, weather
noviruses, or there can be no apparent histologic damage, as with changes, spicy foods, etc.
rhinoviruses and RSV. Regardless of the histopathologic findings, Rhinitis medicamentosa History of nasal decongestant use
infection of the nasal epithelium is associated with an acute inflamma-
tory response characterized by release of a variety of inflammatory Foreign body Unilateral, foul-smelling secretions
cytokines and infiltration of the mucosa by inflammatory cells. This Bloody nasal secretions
acute inflammatory response appears to be partially or largely respon- Sinusitis Presence of fever, headache or facial
sible for many of the symptoms associated with the common cold. pain, or periorbital edema or
Viral shedding of most respiratory viruses peaks 3-5 days after inocula- persistence of rhinorrhea or cough for
tion, often coinciding with symptom onset; low levels of viral shedding longer than 14 days
may persist for up to 2 wk in the otherwise healthy host. Inflammation Streptococcosis Mucopurulent nasal discharge that
can obstruct the sinus ostia or eustachian tube, predisposing to bacte- excoriates the nares
rial sinusitis or otitis media.
Pertussis Onset of persistent or severe paroxysmal
The host immune system is responsible for most cold symptoms,
cough
rather than direct damage to the respiratory tract. Infected cells release
cytokines, such as interleukin-8, that attract polymorphonuclear cells Congenital syphilis Persistent rhinorrhea with onset in the 1st
into the nasal submucosa and epithelium. Rhinoviruses also increase 3 mo of life
vascular permeability in the nasal submucosa, releasing albumin and
bradykinin, which may contribute to symptoms.

CLINICAL MANIFESTATIONS
Symptoms of the common cold vary by age and virus. In infants, fever
and nasal discharge may predominate. Fever is uncommon in older
children and adults. The onset of common cold symptoms typically
occurs 1-3 days after viral infection. The first symptom noted is often
sore or scratchy throat, followed closely by nasal obstruction and rhi-
norrhea. The sore throat usually resolves quickly and, by the 2nd and
3rd day of illness, nasal symptoms predominate. Cough is associated
with two-thirds of colds in children and usually begins after the onset
of nasal symptoms. Cough may persist for an additional 1-2 wk after
resolution of other symptoms. Influenza viruses, RSVs, human meta-
pneumoviruses, and adenoviruses are more likely than rhinoviruses or
coronaviruses to be associated with fever and other constitutional
symptoms. Other symptoms of a cold may include headache, hoarse-
ness, irritability, difficulty sleeping, or decreased appetite. Vomiting
and diarrhea are uncommon. The usual cold persists for approximately
1 wk, although 10% last for 2 wk.
The physical findings of the common cold are limited to the upper
respiratory tract. Increased nasal secretion is usually obvious; a change
in the color or consistency of the secretions is common during the
course of the illness and does not indicate sinusitis or bacterial super-
infection but may indicate accumulation of polymorphonuclear cells.
Examination of the nasal cavity might reveal swollen, erythematous
nasal turbinates, although this finding is nonspecific and of limited
diagnostic value. Abnormal middle ear pressure is common during the
course of a cold. Anterior cervical lymphadenopathy or conjunctival
injection may also be noted on exam.
DIAGNOSIS
The most important task of the physician caring for a patient with a
cold is to exclude other conditions that are potentially more serious or
treatable. The differential diagnosis of the common cold includes non-
infectious disorders as well as other upper respiratory tract infections
(Table 379-2).
LABORATORY FINDINGS
Routine laboratory studies are not helpful for the diagnosis and man-
agement of the common cold. A nasal smear for eosinophils may be
useful if allergic rhinitis is suspected (see Chapter 143). A predomi-
nance of polymorphonuclear cells in the nasal secretions is character-
istic of uncomplicated colds and does not indicate bacterial
superinfection. Self-limited radiographic abnormalities of the parana-
sal sinuses are common during an uncomplicated cold; imaging is not
indicated for most children with simple rhinitis.
The viral pathogens associated with the common cold can be
detected by polymerase chain reaction, culture, antigen detection, or

serologic methods. These studies are generally not indicated in patients
with colds because a specific etiologic diagnosis is useful only when
treatment with an antiviral agent is contemplated, such as for influenza
viruses. Bacterial cultures or antigen detection are useful only when
group A streptococcus (see Chapter 183) or Bordetella pertussis (see
Chapter 197) is suspected. The isolation of other bacterial pathogens
from nasopharyngeal specimens is not an indication of bacterial nasal
infection and is not a specific predictor of the etiologic agent in
sinusitis.
TREATMENT
The management of the common cold consists primarily of supportive
care and anticipatory guidance as recommended by American Academy
of Pediatrics and United Kingdom National Institute for Health and
Clinical Excellence guidelines.
Antiviral Treatment
Specific antiviral therapy is not available for rhinovirus infections.
Ribavirin, which is approved for treatment of severe RSV infections,
has no role in the treatment of the common cold. The neuraminidase
inhibitors oseltamivir and zanamivir have a modest effect on the dura-
tion of symptoms associated with influenza viral infections in children.
Oseltamivir also reduces the frequency of influenza-associated otitis
media. The difficulty of distinguishing influenza from other common
cold pathogens and the necessity that therapy be started early in the
illness (within 48 hr of onset of symptoms) to be beneficial are practi-
cal limitations to the use of these agents for mild upper respiratory
tract infections. Antibacterial therapy is of no benefit in the treatment
of the common cold and should be avoided to minimize possible
adverse effects and the development of antibiotic resistance.
Supportive Care and Symptomatic Treatment
Supportive interventions are frequently recommended by providers.
Maintaining adequate oral hydration may help to thin secretions and
soothe respiratory mucosa. The common home remedy of ingesting
warm fluids may soothe mucosa, increase nasal mucous flow, or loosen
respiratory secretions. Topical nasal saline may temporarily remove
secretions, and saline nasal irrigation may reduce symptoms. Cool,
humidified air has not been well studied but may loosen nasal secre-
tions; however, cool-mist humidifiers and vaporizers must be cleaned
after each use. The World Health Organization suggests that neither
steam nor cool-mist therapy be used in treatment of a cold.
The use of oral nonprescription therapies (often containing antihis-
tamines, antitussives, and decongestants) for cold symptoms in chil-
dren is controversial. Although some of these medications are effective
in adults, no study demonstrates a significant effect in children, and
there may be serious side effects. Young children cannot participate in
the assessment of symptom severity, so studies of these treatments in
children have generally been based on observations by parents or other
observers, a method that is likely to be insensitive for detection of
treatment effects. As a result of the lack of direct evidence for effective-
ness and the potential for unwanted side effects, the American Academy
of Pediatrics recommends that nonprescription cough and cold prod-
ucts not be used for infants and children younger than 6 yr of age. A
decision whether to use these medications in older children must con-
sider the likelihood of clinical benefit compared with the potential
adverse effects of these drugs. The prominent or most bothersome
symptoms of colds vary in the course of the illness. If symptomatic
treatments are used, it is reasonable to target therapy to specific bother-
some symptoms and care should be taken to ensure that caregivers
understand the intended effect and can determine the proper dosage
of the medications.
Zinc, given as oral lozenges to previously healthy patients, reduces
the duration but not the severity of symptoms of a common cold if
begun within 24 hr of symptoms. The function of the rhinovirus 3C
protease, an essential enzyme for rhinovirus replication, is inhibited by
zinc, but there has been no evidence of an antiviral effect of zinc in
vivo. The effect of zinc on symptoms has been inconsistent, with some
studies reporting dramatic treatment effects (in adults), whereas other
Chapter 379 ◆ The Common Cold 2013
studies find no benefit. Side effects are common and include decreased
taste, bad taste, and nausea.
Fever
Fever is not usually associated with an uncomplicated common cold,
and antipyretic treatment is generally not indicated.
Nasal Obstruction
Either topical or oral adrenergic agents may be used as nasal decon-
gestants in older children and adults. Effective topical adrenergic
agents such as xylometazoline, oxymetazoline, or phenylephrine are
available as either intranasal drops or nasal sprays. Reduced-strength
formulations of these medications are available for use in younger
children, although they are not recommended for use in children
younger than 6 yr old. Systemic absorption of the imidazolines (oxy-
metazoline, xylometazoline) has very rarely been associated with
bradycardia, hypotension, and coma. Prolonged use of the topical
adrenergic agents should be avoided to prevent the development of
rhinitis medicamentosa, an apparent rebound effect that causes the
sensation of nasal obstruction when the drug is discontinued. The oral
adrenergic agents are less effective than the topical preparations and
are occasionally associated with systemic effects such as central nervous
system stimulation, hypertension, and palpitations. Aromatic vapors
(such as menthol) for external rub may improve perception of nasal
patency, but do not affect spirometry.
Saline nose drops (wash, irrigation) can improve nasal symptoms
and may be used in all age groups.
Rhinorrhea
The first-generation antihistamines may reduce rhinorrhea by 25-30%.
The effect of the antihistamines on rhinorrhea appears to be related to
the anticholinergic rather than the antihistaminic properties of these
drugs, and therefore the second-generation or “nonsedating” antihis-
tamines have no effect on common cold symptoms. The major adverse
effects associated with the use of the antihistamines are sedation or
paradoxical hyperactivity. Overdose may be associated with respira-
tory depression or hallucinations. Rhinorrhea may also be treated with
ipratropium bromide, a topical anticholinergic agent. This drug pro-
duces an effect comparable to the antihistamines but is not associated
with sedation. The most common side effects of ipratropium are nasal
irritation and bleeding.
Sore Throat
The sore throat associated with colds is generally not severe, but treat-
ment with mild analgesics is occasionally indicated, particularly if
there is associated myalgia or headache. The use of acetaminophen
during rhinovirus infection is associated with suppression of neutral-
izing antibody responses, but this observation has no apparent clinical
significance. Aspirin should not be given to children with respiratory
infections because of the risk of Reye syndrome in children with influ-
enza (see Chapter 361). Nonsteroidal antiinflammatory drugs are
somewhat effective in relieving discomfort caused by a cold, but there
is no clear evidence of their effect on respiratory symptoms. The
balance of harm and benefits must be considered when using nonste-
roidal antiinflammatory drugs for colds.
Cough
Cough suppression is generally not necessary in patients with colds.
Cough in some patients appears to be from upper respiratory tract
irritation associated with postnasal drip. Cough in these patients is
most prominent during the time of greatest nasal symptoms, and treat-
ment with a first-generation antihistamine may be helpful. Cough loz-
enges or hard candy may be temporarily effective and are unlikely to
be harmful in children for whom they do not pose risk of aspiration
(older than age 6 yr). Honey (5-10 mL in children ≥1 year old) has a
modest effect on relieving nocturnal cough and is unlikely to be
harmful in children older than 1 yr of age. Honey should be avoided
in children younger than 1 yr of age because of the risk for botulism
(see Chapter 210).
2014 Part XIX ◆ Respiratory System
In some patients, cough may be a result of virus-induced reactive
airways disease. These patients can have cough that persists for days
to weeks after the acute illness and might benefit from bronchodilator
or other therapy. Codeine or dextromethorphan hydrobromide has no
effect on cough from colds and has potential enhanced toxicity. Expec-
torants such as guaifenesin are not effective antitussive agents. The
combination of camphor, menthol, and eucalyptus oils may relieve
nocturnal cough, but studies of their effectiveness are limited.
Ineffective Treatments
Vitamin C, guaifenesin, and inhalation of warm, humidified air are no
more effective than placebo for the treatment of cold symptoms.
Echinacea is a popular herbal treatment for the common cold.
Although echinacea extracts have biologic effects, echinacea is not
effective as a common cold treatment. The lack of standardization of
commercial products containing echinacea also presents a formidable
obstacle to the rational evaluation or use of this therapy.
There is no evidence that the common cold or persistent acute puru-
lent rhinitis of less than 10 days in duration benefits from antibiotics.
In fact, there is evidence that antibiotics cause significant adverse
effects when given for acute purulent rhinitis.
COMPLICATIONS
The most common complication of a cold is acute otitis media (AOM;
see Chapter 640), which may be indicated by new-onset fever and
earache after the 1st few days of cold symptoms. AOM is reported in
5-30% of children who have a cold, with the higher incidence occur-
ring in young infants and in children cared for in a group daycare
setting. Symptomatic treatment has no effect on the development of
AOM, but treatment with oseltamivir might reduce the incidence of
AOM in patients with influenza.
Sinusitis is another complication of the common cold (see Chapter
380). Self-limited sinus inflammation is a part of the pathophysiology
of the common cold, but 0.5-2% of viral upper respiratory tract infec-
tions in adults, and 5-13% in children, are complicated by acute bacte-
rial sinusitis. The differentiation of common cold symptoms from
-
bacterial sinusitis may be difficult. The diagnosis of bacterial sinusitis
should be considered if rhinorrhea or daytime cough persists without
9
improvement for at least 10-14 days, if symptoms worsen over time, or
if signs of more severe sinus involvement such as fever, facial pain, or
9
facial swelling develop. There is no evidence that symptomatic treat-
ment of the common cold alters the frequency of development of
i r
bacterial sinusitis. Bacterial pneumonia is an uncommon complication
of the common cold.
h
Exacerbation of asthma is a relatively uncommon but potentially
serious complication of colds. The majority of asthma exacerbations in
ta
children are associated with the common cold. There is no evidence
that treatment of common cold symptoms prevents this complication;
however, studies are underway in patients with underlying asthma to
determine effectiveness of preventive or acute treatment at the onset
of upper respiratory tract infection symptoms.
Although not a complication, another important consequence of the
common cold is the inappropriate use of antibiotics for these illnesses
and the associated contribution to the problem of increasing antibiotic
resistance of pathogenic respiratory bacteria, as well as adverse effects
from antibiotics.
PREVENTION
Chemoprophylaxis or immunoprophylaxis is generally not available
for the common cold. Immunization or chemoprophylaxis against
influenza can prevent colds caused by this pathogen; influenza is
responsible for only a small proportion of all colds. Palivizumab is
recommended to prevent RSV lower respiratory infection in high-risk
infants but does not prevent upper respiratory infections from this
virus. Vitamin C, garlic, or echinacea do not prevent the common cold.
Vitamin C prophylaxis may shorten the duration of cold symptoms.
Vitamin D deficiency is associated with increased risk of viral respira-
tory tract infection in some studies, nonetheless, vitamin D prophy-
laxis does not reduce incidence or severity of the common cold in
adults; studies in children are lacking. Zinc sulfate taken for a minimum
of 5 mo may reduce the rate of cold development. However, because
of duration of use and adverse effects of bad taste and nausea, this is
not a recommended prevention modality in children.
Hand-to-hand transmission of rhinoviruses followed by self-
inoculation may be prevented by frequent hand washing and avoiding
touching one’s mouth, nose, and eyes. Some studies report the use of
alcohol-based hand sanitizers and virucidal hand treatments were
associated with decreased transmission. In the experimental setting,
virucidal disinfectants or virucidal-impregnated tissues also reduce
transmission of cold viruses; under natural conditions none of these
interventions prevents common colds.
Bibliography is available at Expert Consult.
G
Chapter 380
Sinusitis
V R
Diane E. Pappas and J. Owen Hendley
d
Sinusitis is a common illness of childhood and adolescence. There are
ti e
2 types of acute sinusitis: viral and bacterial, with significant acute and
chronic morbidity as well as the potential for serious complications.
The common cold produces a viral, self-limited rhinosinusitis (see
Chapter 379). Approximately 0.5-2% of viral upper respiratory tract
n
infections in children and adolescents are complicated by acute symp-
tomatic bacterial sinusitis. Some children with underlying predispos-
U
ing conditions have chronic sinus disease that does not appear to be
infectious. The means for appropriate diagnosis and optimal treatment
of sinusitis remain controversial.
Typically the ethmoidal and maxillary sinuses are present at birth,
but only the ethmoidal sinuses are pneumatized. The maxillary sinuses
are not pneumatized until 4 yr of age. The sphenoidal sinuses are
present by 5 yr of age, whereas the frontal sinuses begin development
at age 7-8 yr and are not completely developed until adolescence. The
ostia draining the sinuses are narrow (1-3 mm) and drain into the
ostiomeatal complex in the middle meatus. The paranasal sinuses are
normally sterile, maintained by the mucociliary clearance system.
ETIOLOGY
The bacterial pathogens causing acute bacterial sinusitis in children
and adolescents include Streptococcus pneumoniae (~30%; see Chapter
182), nontypeable Haemophilus influenzae (~20%; see Chapter 194),
and Moraxella catarrhalis (~20%; see Chapter 196). Approximately
50% of H. influenzae and 100% of M. catarrhalis are β-lactamase posi-
tive. Approximately 25% of S. pneumoniae may be penicillin resistant.
Staphylococcus aureus, other streptococci, and anaerobes are uncom-
mon causes of acute bacterial sinusitis in children. Although S. aureus
(see Chapter 181.1) is an uncommon pathogen for acute sinusitis
in children, the increasing prevalence of methicillin-resistant S. aureus
is a significant concern. H. influenzae, α- and β-hemolytic strepto-
cocci, M. catarrhalis, S. pneumoniae, and coagulase-negative staphy-
lococci are commonly recovered from children with chronic sinus
disease.
EPIDEMIOLOGY
Acute bacterial sinusitis can occur at any age. Predisposing conditions
include viral upper respiratory tract infections (associated with out-
of-home daycare or a school-age sibling), allergic rhinitis, and ciga-
rette smoke exposure. Children with immune deficiencies particularly
of antibody production (immunoglobulin IgG, IgG subclasses,
IgA; see Chapter 124), cystic fibrosis (see Chapter 403), ciliary dys-
function (see Chapter 404), abnormalities of phagocyte function,
 EAR, NOSE, & THROAT
evaluation, and any child with hearing loss should be referred
to an otolaryngologist for further workup and treatment. In
addition to the infants who fall into the high-risk categories
for SNHL as outlined earlier, hearing should be tested in
children with a history of developmental delay, bacterial
meningitis, ototoxic medication exposure, neurodegenerative
disorders, or a history of infection such as mumps or measles.
Children with bacterial meningitis should be referred imme-
diately to an otolaryngologist, as cochlear ossification can
occur, necessitating urgent cochlear implantation. Even if
a newborn screening was passed, all infants who fall into a
high-risk category for progressive or delayed-onset hearing
loss should receive ongoing audiologic monitoring for 3
years and at appropriate intervals thereafter to avoid a missed
diagnosis.
Prevention
Appropriate care may treat or prevent conditions causing
hearing deficits. Aminoglycosides and diuretics, particularly
in combination, are potentially ototoxic and should be used
judiciously and monitored carefully. Given the association
of a certain mitochondrial gene defect and aminoglycoside
ototoxicity, use should be avoided, if possible, in patients
with a family history of aminoglycoside-related hearing loss.
Reduction of repeated exposure to loud noises may prevent
high-frequency hearing loss associated with acoustic trauma.
Any patient with sudden-onset SNHL should be seen by
an otolaryngologist immediately, as in some cases, steroid
therapy may reverse the loss if initiated right away.
Management of Hearing Loss
Children with hearing loss should be referred to an otolar-
yngologist for etiologic workup which may include radio-
graphic imaging and/or laboratory tests. Workup is directed
by each individual patient’s history, examination, and audio-
logic results. As discussed previously, hearing loss may be an
isolated abnormality or may be part of a larger syndrome.
Within the past couple of years, comprehensive genetic
testing for syndromic and nonsyndromic hearing loss using
next-generation sequencing technology has become widely
available to the public.
The importance of early intervention for receptive and
expressive development is well-established. The manage-
ment of hearing loss depends on the type and severity of
impairment. Conductive hearing loss is typically correctable
by addressing the point in sound transmission at which
efficiency is compromised. For example, hearing loss due
to chronic effusions usually normalizes once the fluid has
cleared, whether by natural means or by the placement of
tympanostomy tubes. As of yet, SNHL is not reversible,
although cochlear hair cell regeneration is an area of active
research. Most sensorineural loss is managed with amplifica-
tion. Cochlear implantation is an option for some children
! 515
with severe-profound loss, and at the time of this writing, is
FDA-approved down to the age of 12 months. Unlike hear-
ing aids, cochlear implants do not amplify sound but directly
stimulate the cochlea with electrical impulses. Children with
hearing loss should receive ongoing audiologic monitoring.
Web Resources
Smith RJH, Shearer AE, Hildebrand MS, Van Camp G: Deafness
and hereditary hearing loss overview. Last update January
3, 2013. http://www.ncbi.nlm.nih.gov/books/NBK1434/.
Accessed January 11, 2014.
http://www.asha.org/public/hearing/Prevalence-and-Incidence-
of-Hearing-Loss-in-Children/. Accessed January 11, 2014.
http://www.infanthearing.org/screening/. Accessed January 11,
2014.
" THE NOSE & PARANASAL SINUSES
ACUTE VIRAL RHINITIS (COMMON COLD;
SEE ALSO CHAPTER 38)
The common cold (viral upper respiratory infection) is the
most common pediatric infectious disease, and the incidence
is higher in early childhood than in any other period of life.
Children younger than 5 years typically have 6–12 colds per
year. Approximately 30%–40% of these are caused by rhino-
viruses. Other culprits include adenoviruses, coronaviruses,
enteroviruses, influenza and parainfluenza viruses, and
respiratory syncytial virus.
ESSENTIALS OF DIAGNOSIS
# Clear or mucoid rhinorrhea, nasal congestion, sore
throat.
# Possible fever, particularly in younger children (under
5–6 years).
# Symptoms resolve by 7–10 days.
# Differential Diagnosis
Rhinosinusitis (acute or chronic), allergic rhinitis, nonaller-
gic rhinitis, influenza, pneumonia, gastroesophageal reflux
disease, asthma, and bronchitis.
# Clinical Findings
The patient usually experiences a sudden onset of clear or
mucoid rhinorrhea, nasal congestion, sneezing, and sore
throat. Cough or fever may develop. Although fever is usually
not a prominent feature in older children and adults, in
 516 ! CHAPTER 18

the first 5 or 6 years of life it can be as high as 40.6°C
without superinfection. The nose, throat, and TMs may
appear red and inflamed. The average duration of symptoms
is about 1 week. Nasal secretions tend to become thicker and
more purulent after day 2 of infection due to shedding of
epithelial cells and influx of neutrophils. This discoloration
should not be assumed to be a sign of bacterial rhinosinus-
itis, unless it persists beyond 10–14 days, by which time
the patient should be experiencing significant symptomatic
improvement. A mild cough may persist for 2–3 weeks fol-
lowing resolution of other symptoms.
" Treatment
Treatment for the common cold is symptomatic (Figure 18–5).
Because colds are vial infections, antibiotics will not cure or
shorten their length. Acetaminophen or ibuprofen can be help-
ful for fever and pain. Humidification may provide relief for
congestion and cough. Nasal saline drops and bulb suctioning
may be used for an infant or child unable to blow his or her nose.
Available scientific data suggest that over-the-counter
cold and cough medications are generally not effective in
children. These medications may be associated with serious
adverse effects, and it is recommended that they not be used
in children under the age of 4 years. Antihistamines have not
proven effective in relieving cold symptoms; in rhinoviral
colds, increased levels of histamine are not observed. Oral
decongestants have been found to provide some symp-
tomatic relief in adults but have not been well-studied in
children. Cough suppression at night is the number one goal
of many parents; however, studies have shown that antitus-
sives, antihistamines, antihistamine-decongestant combina-
tions and antitussive-bronchodilator combinations are no
more effective than placebo. Use of narcotic antitussives is
discouraged, as these have been associated with severe respi-
ratory depression.
Education and reassurance may be the most important
“therapy” for the common cold. Parents should be informed
about the expected nature and duration of symptoms, effi-
cacy and potential side effects of medications, and the signs

Acute nasal congestion and rhinosinusitis

Assess presentation

≤ 10 days duration ≥ 10–14 days duration Any duration, with focal signs
without improvement (periorbital edema, sinus tenderness,
or severe headache)

Upper respiratory Bacterial sinusitis

tract infection likely
(viral infection)

Mild symptoms 4Fvere symptoms or

immunosuppressed
r
1ain medication host
r
)VNJEJGied air
r
4aline nose drops • β-BDUBNBTF
FJSTUMJOF
BOUJCJPUJD
r
$ough suppressants stable antibiotic
for 10 days
(see Figure 186) (see Figure 18)
• $onsider imaging and
evaluation for
complications
1oor response after ≥ 3 days

4FDPOEMJOF
BOUJCJPUJc

▲ Figure 18–5. Algorithm for acute nasal congestion and rhinosinusitis.

 EAR, NOSE, & THROAT
! 517

Patient between the ages of 1 and 21

years presents with persistent or
severe upper respiratory tract infection.

2
Primary care clinician
performs physical
examination.

3 4 5
Are symptoms Is child in
Yes Yes Go to box 15.
mild to moderate? day care?

No No
14 6
7
Has the patient
Severe symptoms.
been on recent
Yes Go to box 15.
antimicrobial
15 treatment?
Physician prescribes:
Amoxicillin/clavulanate No 9
(high dose) 8 Physician prescribes:
Cefuroxime Cefuroxime
Cefpodoxime Are there allergies Cefpodoxime
Cefdinir Yes
to penicillin? Cefdinir
A Azithromycin
No Clarithromycin C
16 17 10
Is patient Clinician provides Physician prescribes
cured or Yes appropriate usual high-dose
improved? follow-up. amoxicillin. AB

No No 11 12
18a 18b
Physician prescribes Patient referred for sinus Is patient Clinician provides
Yes
IV therapy with imaging and sinus cured? appropriate follow-up.
cefotaxime or ceftriaxone. aspiration.
No
13
19
20
Is patient Go to box 15.
cured or Yes Go to box 17.
improved?
A. High-dose amoxicillin = 90 mg/kg/d in 2 divided doses
No High-dose amoxicillin/clavulanate = 90 mg/kg/d amoxicillin;
21 6.4 mg/kg/d clavulanate in two divided doses.
B. Usual-dose amoxicillin = 45 mg/kg/d in 2 divided doses.
Go to box 18b.
C. Most patients with allergy to penicillin will tolerate
cepholosporins. If allergy manifests as anaphylaxis,
22 macrolides should be prescribed instead of cephalosporins:
1. Cefuroxime, 30 mg/kg/d in 2 divided doses.
Subsequent modifications
of antibiotic treatment should 2. Cefpodixime, 10 mg/kg/d once daily.
be based on Gram stain 3. Cefdinir, 14 mg/kg/d once daily.
and culture results. 4. Azithromycin, 10 mg/kg on day 1; 5 mg/kg x 4 days in
single daily dose.
5. Clarithromycin, 15 mg/kg/d in 2 divided doses.

▲ Figure 18–6. Management of children with uncomplicated acute bacterial rhinosinusitis (ABRS). (Reproduced, with
permission, from the American Academy of Pediatrics: Clinical practice guidelines: management of sinusitis. Pediatrics
2001;108:798.)
 518 ! CHAPTER 18
and symptoms of complications of the common cold, such
as bacterial rhinosinusitis, bronchiolitis, or pneumonia.
Arroll B, Kenealy T: Are antibiotics effective for acute purulent
rhinitis? Systematic review and meta-analysis of placebo con-
trolled randomized trials. BMJ 2006;333(7562):279. Epub 2006
July 21. [PMID: 16861253].
Smith SM, Schroeder K, Fahey T: Over-the-counter medications
for acute cough in children and adults in ambulatory set-
tings. Cochrane Database Syst Rev 2008;(1):CD001831 [PMID:
18253996].
Taverner D, Latte J: Nasal decongestants for the common cold.
Cochrane Database Syst Rev 2007;(1):CD001953 [PMID:
17253470].
Web Resources
U.S. Food and Drug Administration: Using over-the-counter
cough and cold products in children. Posted Oct 22, 2008.
http://www.fda.gov/ForConsumers/ConsumerUpdates/
ucm048515.htm. Accessed January 11, 2014.
RHINOSINUSITIS
The use of the term rhinosinusitis has replaced sinus-
itis. Rhinosinusitis acknowledges that the nasal and sinus
mucosa are involved in similar and concurrent inflamma-
tory processes.
1. Acute Bacterial Rhinosinusitis
Acute bacterial rhinosinusitis (ABRS) is a bacterial infection
of the paranasal sinuses which lasts less than 30 days and in
which the symptoms resolve completely. It is almost always
preceded by a viral upper respiratory infection (cold). Other
predisposing conditions include allergies and trauma. The
diagnosis of ABRS is made when a child with a cold does
not improve by 10–14 days or worsens after 5–7 days.
The maxillary and ethmoid sinuses are most commonly
involved. These sinuses are present at birth. The sphenoid
sinuses typically form by the age of 5 years, and the frontal
sinuses by age 7–8 years. Frontal sinusitis is unusual before
age 10 years.
ESSENTIALS OF DIAGNOSIS
" Upper respiratory infection symptoms are present 10 or
more days beyond onset, or symptoms worsen within
10 days after an initial period of improvement.
" Symptoms may include nasal congestion, nasal drain-
age, postnasal drainage, facial pain, headache, and
fever.
" Symptoms resolve completely within 30 days.
" Pathogenesis
Situations which lead to inflammation of sinonasal mucosa
and obstruction of sinus drainage pathways underlie the devel-
opment of rhinosinusitis. A combination of anatomic, muco-
sal, microbial, and immune pathogenic factors are believed to
be involved. Both viral and bacterial infections play integral
roles in the pathogenesis. Viral upper respiratory infections
may cause sinus mucosal injury and swelling, resulting in
osteomeatal obstruction, loss of ciliary activity, and mucus
hypersecretion. The bacterial pathogens that commonly cause
acute rhinosinusitis are S pneumoniae, H influenzae (nontype-
able), M catarrhalis, and β-hemolytic streptococci.
" Clinical Findings
The onset of symptoms in ABRS may be gradual or sudden,
and may commonly include nasal drainage, nasal congestion,
facial pressure or pain, postnasal drainage, hyposmia or anos-
mia, fever, cough, fatigue, maxillary dental pain, and ear pres-
sure or fullness. The physical examination is rarely helpful in
making the diagnosis, as the findings are essentially the same
as those in a child with an uncomplicated cold. Occasionally,
sinuses may be tender to percussion, but this is typically seen
only in older children and is of questionable reliability.
In complicated or immunocompromised patients, sinus
aspiration and culture by an otolaryngologist should be
considered for diagnostic purposes and to facilitate culture-
directed antibiotic therapy. Gram stain or culture of nasal
discharge does not necessarily correlate with cultures of
sinus aspirates. If the patient is hospitalized because of
rhinosinusitis-related complications, blood cultures should
also be obtained.
Imaging of the sinuses during acute illness is not indi-
cated except when evaluating for possible complications, or
for patients with persistent symptoms which do not respond
to medical therapy. As with the physical examination, the
radiographic findings of ABRS, such as sinus opacification,
fluid, and mucosal thickening, are indistinguishable from
those seen in the common cold.
" Complications
Complications of ABRS occur when infection spreads to
adjacent structures—the overlying tissues, the eye, or the
brain. S aureus (including methicillin-resistant S aureus
[MRSA]) is frequently implicated in complicated ABRS, as
well as Streptococcus anginosus (milleri), which has been
found to be a particularly virulent organism.
Orbital complications are the most common, arising from
the ethmoid sinuses. These complications usually begin as a
preseptal cellulitis, but can progress to postseptal cellulitis,
subperiosteal abscess, orbital abscess, and cavernous sinus
thrombosis. Associated signs and symptoms include eyelid
 EAR, NOSE, & THROAT
edema, restricted extraocular movements, proptosis, chemo-
sis, and altered visual acuity (see Chapter 15).
The most common complication of frontal sinusitis is
osteitis of the frontal bone, also known as Pott’s puffy tumor.
Intracranial extension of infection can lead to meningitis
and to epidural, subdural, and brain abscesses. Frequently,
children with complicated rhinosinusitis have no prior his-
tory of sinus infection.
" Treatment
For children who are not improving by 10 days, or who have
more severe symptoms, with fever of at least 39°C and puru-
lent nasal drainage for at least 3–4 consecutive days, antibi-
otic therapy is recommended. Although some discrepancy
exists, antibiotics are generally thought to decrease duration
and severity of symptoms.
To minimize the number of children who receive anti-
microbial therapy for uncomplicated viral upper respiratory
infections, and to help combat antibiotic resistance, the
American Academy of Pediatrics in 2001 issued guidelines
for treatment. This algorithm is presented in Figure 18-6.
Key decision points include severity of disease and risk
factors for resistant organisms
For patients with mild-moderate symptoms, who are not
in day care, and have not been on recent antibiotic therapy,
high-dose amoxicillin is considered first-line therapy. For
those with severe symptoms, in day care, or who were on anti-
biotics within the past 1–3 months, high-dose amoxicillin–
clavulanate is recommended as first-line therapy. Cefuroxime,
cefpodoxime, and cefdinir are recommended for patients with
a non–type I hypersensitivity to penicillin. Macrolides should
be reserved for patients with an anaphylactic reaction to peni-
cillin. Other options for these patients include clindamycin
or trimethoprim–sulfamethoxazole. However, it should be
remembered that clindamycin is not effective against gram-
negative organisms such as H influenzae.
Failure to improve after 48–72 hours suggests a resistant
organism or potential complication. Second-line therapies
should be initiated at this point, or, if the patient is already
on amoxicillin–clavulanate or cephalosporin, intravenous
antibiotic therapy should be considered. Imaging and refer-
ral for sinus aspiration should be strongly considered as well.
Patients who are toxic, or who have evidence of invasive
infection or CNS complications, should be hospitalized
immediately. Intravenous therapy with nafcillin or clindamy-
cin plus a third-generation cephalosporin such as cefotaxime
should be initiated until culture results become available.
Decongestants, antihistamines, and nasal saline irriga-
tions are frequently used in acute rhinosinusitis to promote
drainage. To date, there is no evidence-based data sup-
porting their efficacy, and concern has been raised about
potential adverse effects related to impaired ciliary function,
decreased blood flow to the mucosa, and reduced diffusion
! 519
of antibiotic into the sinuses with the use of decongestants.
Topical nasal decongestants, such as oxymetazoline or
phenylephrine sprays, should not be used for more than
3 days due to risk of rebound edema. Patients with underlying
allergic rhinitis may benefit from intranasal cromolyn or
corticosteroid nasal spray.
Principi N, Esposito S: New insights into pediatric rhinosinus-
itis. Pediatr Allergy Immunol 2007;18 (Suppl 18):7–9 [PMID:
17767598].
Shaikh N, Wald ER, Pi M: Decongestants, antihistamines and
nasal irrigation for acute sinusitis in children. Cochrane
Database Syst Rev 2012;9:CD007909. doi: 10.1002/14651858.
CD007909.pub3 [PMID: 22972113].
2. Recurrent or Chronic Rhinosinusitis
Recurrent rhinosinusitis occurs when episodes of ABRS
clear with antibiotic therapy but recur with each or most
upper respiratory infections. Chronic rhinosinusitis (CRS)
is diagnosed when the child has not cleared the infection in
the expected time but has not developed acute complications.
Both symptoms and physical findings are required to support
the diagnosis, and CT scan may be a useful adjuvant in making
the diagnosis. Although recent meta-analysis evaluations have
resulted in recommendations for ABRS, there is a paucity of
data for the treatment of recurrent or chronic rhinosinusitis.
Important factors to consider include allergies, anatomic
variations, and disorders in host immunity. Mucosal inflam-
mation leading to obstruction is most commonly caused by
allergic rhinitis and occasionally by nonallergic rhinitis. There
is a great deal of evidence that allergic rhinitis, rhinosinusitis,
and asthma are all manifestations of a systemic inflammatory
response. Gastroesophageal reflux has also been implicated in
CRS. Less commonly, CRS is caused by anatomic variations,
such as septal deviation, polyp, or foreign body.
Allergic nasal polyps are unusual in children younger than
10 years and should prompt a workup for cystic fibrosis. In
cases of chronic or recurrent pyogenic pansinusitis, poor host
resistance (eg, an immune defect, primary ciliary dyskinesia,
or cystic fibrosis)—though rare—must be ruled out by immu-
noglobulin studies, electron microscopy studies of respiratory
cilia, nasal nitric oxide measurements if available, a sweat
chloride test, and genetic testing (see Chapters 18 and 31).
Anaerobic and staphylococcal organisms are often responsi-
ble for CRS. Evaluation by an allergist and an otolaryngologist
may be useful in determining the underlying causes.
" Treatment
A. Medical Therapy
Antibiotic therapy is similar to that used for ABRS, but the
duration is longer, typically 3–4 weeks. Antimicrobial choice
should include drugs effective against staphylococcal organ-
isms. Nasal saline irrigations and intranasal steroid sprays
 520 ! CHAPTER 18
have been shown to be helpful in the reduction of symptoms
of CRS.
B. Surgical Therapy
The mainstay of treatment for pediatric CRS is medical man-
agement, with appropriate antibiotic therapy and treatment
of comorbid conditions such as allergic rhinitis and asthma.
Only a small percentage of children will warrant surgical
management.
1. Antral lavage—Antral lavage, generally regarded as a
diagnostic procedure, may have some therapeutic value. An
aspirate or a sample from the maxillary sinus is retrieved
under anesthesia. The maxillary sinus is then irrigated. In
the very young child, this may be the only procedure per-
formed.
2. Adenoidectomy—Adenoidectomy is thought to be effec-
tive in 50%–75% of children with CRS. The adenoids serve
as a reservoir of pathogenic bacteria and may also interfere
with mucociliary clearance and drainage. Biofilms have
been reported in the adenoids of children with CRS, and
may explain the resistance of these infections to standard
antibiotic therapy.
3. Balloon catheter dilation—This procedure opens up
the maxillary sinuses without removal of tissue to promote
drainage. Preliminary studies indicate that this may be effec-
tive in children who have failed adenoidectomy.
4. Endoscopic sinus surgery—Endoscopic sinus surgery
in children was controversial because of concerns regard-
ing facial growth. However, recent studies have not sup-
ported this concern. Endoscopic sinus surgery is reported
to be effective in over 80% of cases, and may be indicated if
adenoidectomy or balloon dilation is not effective.
5. External drainage—External drainage procedures are
reserved for complications arising from ethmoid and frontal
sinusitis.
Harvey R, Hannan SA, Badia L, Scadding G: Nasal saline irriga-
tions for the symptoms of chronic rhinosinusitis. Cochrane
Database Syst Rev 2007;3:CD006394. doi: 10.1002/14651858.
CD006394.pub2 [PMID: 17636843].
Makary CA, Ramadan HH: The role of sinus surgery in children.
Laryngoscope 2013 Jan 29. [Epub ahead of print] [PMID:
23361382].
Snidvongs K, Kalish L, Sacks R, Craig JC, Harvey RJ: Topical
steroid for chronic rhinosinusitis without polyps. Cochrane
Database Syst Rev 2011:CD009274. doi: 10.1002/14651858.
CD009274 [PMID: 21833974].
CHOANAL ATRESIA
Choanal atresia occurs in approximately 1 in 7000 live
births. The female-male ratio is 2:1, as is the unilateral-
bilateral ratio. Bilateral atresia results in severe respiratory
distress at birth and requires immediate placement of an oral
airway or intubation, and otolaryngology consultation for
surgical treatment. Unilateral atresia usually appears later
as a unilateral chronic nasal discharge that may be mistaken
for CRS. Diagnosis may be suspected if a 6-Fr catheter can-
not be passed through the nose and is confirmed by axial CT
scan. Approximately 50% of patients with bilateral choanal
atresia have CHARGE association (Coloboma, Heart dis-
ease, Atresia of the choanae, Retarded growth and retarded
development or CNS anomalies, Genital hypoplasia, and Ear
anomalies or deafness) (see Chapter 35) or other congenital
anomalies.
RECURRENT RHINITIS
Recurrent rhinitis is frequently seen in the office practice
of pediatrics. The child is brought in with the chief com-
plaint of having “one cold after another,” “constant colds,”
or “always being sick.” Approximately two-thirds of these
children have recurrent colds; the rest have either allergic
rhinitis or recurrent rhinosinusitis.
1. Allergic Rhinitis
Allergic rhinitis is a chronic disorder of the upper airway
which is induced by IgE-mediated inflammation secondary
to allergen exposure. It is more common in children than in
adults and affects up to 40% of children in the United States.
It significantly affects quality of life, interfering with physical
and social activities, concentration, school performance, and
sleep. Allergic rhinitis can contribute to the development
of rhinosinusitis, otitis media, and asthma. Symptoms may
include nasal congestion, sneezing, rhinorrhea, and itchy
nose, palate, throat, and eyes. On physical examination the
nasal turbinates are swollen and may be red or pale pink-
purple. Several classes of medications have proven effective
in treating allergic rhinitis symptoms, including intranasal
corticosteroids, oral and intranasal antihistamines, leukot-
riene antagonists, and decongestants. Ipratropium nasal
spray may also be used as an adjunctive therapy. Nasal
saline rinses are helpful to wash away allergens. Recent stud-
ies have indicated that use of intranasal steroid sprays may
not only decrease the impairment caused by allergic rhinitis
symptoms, but also help prevent progression to more severe
disease and decrease the risk of related comorbidities such as
asthma and sleep-disordered breathing.
2. Nonallergic Rhinitis
Nonallergic rhinitis also causes rhinorrhea and nasal conges-
tion, but does not seem to involve an immunologic reaction.
Its mechanism is not well understood. Triggers can include
sudden changes in environmental temperature, air pollution,
and other irritants such as tobacco smoke. Medications can
also be associated with nonallergic rhinitis. Nasal decongestant
 EAR, NOSE, & THROAT
sprays, when used for long periods of time can cause rhinitis
medicamentosa, which is a rebound nasal congestion which
can be very difficult to treat. Oral decongestants, nasal cortico-
steroids, antihistamines, and ipratropium spray have all been
shown to offer symptomatic relief.
Rachelefsky G, Farrar JR: A control model to evaluate phar-
macotherapy for allergic rhinitis in children. JAMA Pediatr
2013;167(4):380–386 [PMID: 23440263].
Web Resources
American Academy of Allergy, Asthma, and Immunology:
Rhinitis. http://www.aaaai.org/conditions-and-treatments/
allergies/rhinitis.aspx. Accessed January 11, 2014.
EPISTAXIS
The nose is an extremely vascular structure. In most cases,
epistaxis (nosebleed) arises from the anterior portion of
the nasal septum (Kiesselbach area). It is often due to dry-
ness, vigorous nose rubbing, nose blowing, or nose picking.
Examination of the anterior septum usually reveals a red,
raw surface with fresh clots or old crusts. Presence of telangi-
ectasias, hemangiomas, or varicosities should also be noted.
If a patient has been using a nasal corticosteroid spray, check
the patient’s technique to make sure he or she is not direct-
ing the spray toward the septum. If proper technique does
not reduce the nosebleeds, the spray should be discontinued.
In fewer than 5% of cases, epistaxis is caused by a bleed-
ing disorder such as von Willebrand disease. A hematologic
workup is warranted if any of the following is present: fam-
ily history of a bleeding disorder; medical history of easy
bleeding, particularly with circumcision or dental extraction;
spontaneous bleeding at any site; bleeding that lasts for more
than 30 minutes or blood that will not clot with direct pres-
sure by the physician; onset before age 2 years; or a drop in
hematocrit due to epistaxis. High blood pressure may rarely
predispose to prolonged nosebleeds in children.
A nasopharyngeal angiofibroma may manifest as
recurrent epistaxis. Adolescent boys are affected almost
exclusively. CT scan with contrast of the nasal cavity and
nasopharynx is diagnostic.
" Treatment
The patient should sit up and lean forward so as not to
swallow the blood. Swallowed blood may cause nausea and
hematemesis. The nasal cavity should be cleared of clots by
gentle blowing. The soft part of the nose below the nasal
bones is pinched and held firmly enough to prevent arte-
rial blood flow, with pressure over the bleeding site (anterior
septum) being maintained for 5 minutes by the clock. For per-
sistent bleeding, a one-time only application of oxymetazoline
into the nasal cavity may be helpful. If bleeding continues, the
! 521
bleeding site needs to be visualized. A small piece of gela-
tin sponge (Gelfoam) or collagen sponge (Surgicel) can be
inserted over the bleeding site and held in place.
Friability of the nasal vessels is often due to dryness and
can be decreased by increasing nasal moisture. This can be
accomplished by daily application of a water-based oint-
ment to the nose. A pea-sized amount of ointment is placed
just inside the nose and spread by gently squeezing the
nostrils. Twice-daily nasal saline irrigation and humidifier
use may also be helpful. Aspirin and ibuprofen should be
avoided, as should nose picking and vigorous nose blowing.
Otolaryngology referral is indicated for refractory cases.
Cautery of the nasal vessels is reserved for treatment failures.
NASAL INFECTION
A nasal furuncle is an infection of a hair follicle in the
anterior nares. Hair plucking or nose picking can provide a
route of entry. The most common organism is S aureus. A
furuncle presents as an exquisitely tender, firm, red lump
in the anterior nares. Treatment includes dicloxacillin or
cephalexin orally for 5 days to prevent spread. The lesion
should be gently incised and drained as soon as it points
with a sterile needle. Topical antibiotic ointment may be of
additional value. Because this lesion is in the drainage area
of the cavernous sinus, the patient should be followed closely
until healing is complete. Parents should be advised never
to pick or squeeze a furuncle in this location—and neither
should the physician. Associated cellulitis or spread requires
hospitalization for administration of intravenous antibiotics.
A nasal septal abscess usually follows nasal trauma or
a nasal furuncle. Examination reveals fluctuant gray septal
swelling, which is usually bilateral. The possible complica-
tions are the same as for nasal septal hematoma (see follow-
ing discussion). In addition, spread of the infection to the
CNS is possible. Treatment consists of immediate hospital-
ization, incision and drainage by an otolaryngologist, and
antibiotic therapy.
NASAL TRAUMA
Newborn infants rarely present with subluxation of the
quadrangular cartilage of the septum. In this disorder, the
top of the nose deviates to one side, the inferior septal border
deviates to the other side, the columella leans, and the nasal
tip is unstable. This disorder must be distinguished from the
more common transient flattening of the nose caused by the
birth process. In the past, physicians were encouraged to
reduce all subluxations in the nursery. Otolaryngologists are
more likely to perform the reduction under anesthesia for
more difficult cases.
After nasal trauma, it is essential to examine the inside of
the nose in order to rule out hematoma of the nasal septum,
as these can cause septal necrosis, leading to permanent
nasal deformity. This diagnosis is confirmed by the abrupt
 EAR, NOSE, & THROAT
3. Thrush (See also Chapter 41)
Oral candidiasis mainly affects infants and occasionally
older children in a debilitated state. Candida albicans is a
saprophyte that normally is not invasive unless the mouth
is abraded or the patient is immunocompromised. The
use of broad-spectrum antibiotics and systemic or inhaled
corticosteroids may be contributing factors. Symptoms
include oral pain and refusal of feedings. Lesions consist
of white curdlike plaques, predominantly on the buccal
mucosa, which cannot be washed away after a feeding.
Another less common variation of oral candidal infection
is erythematous candidiasis, which produces erythematous
patches on the palate and dorsum of the tongue. This con-
dition is associated primarily with patients who are taking
broad-spectrum antibiotics or corticosteroids, or are human
immunodeficiency virus (HIV) positive.
Treatment consists of nystatin oral suspension. Large
plaques may be removed with a moistened cotton swab,
and the nystatin may be applied to the lesions with a swab.
Patients who do not respond to oral therapy or are immu-
nocompromised may require systemic antifungal agents.
Parents should be advised to replace any items, such as a
pacifier, that may have become contaminated with Candida.
4. Traumatic Oral Ulcers
Mechanical trauma most commonly occurs on the buc-
cal mucosa secondary to biting by the molars. Thermal
trauma, from very hot foods, can also cause ulcerative lesions.
Chemical ulcers can be produced by mucosal contact with
aspirin or other caustic agents. Oral ulcers can also occur with
leukemia or on a recurrent basis with cyclic neutropenia.
PHARYNGITIS
Figure 18–7 is an algorithm for the management of a sore
throat.
1. Acute Viral Pharyngitis
Over 90% of sore throats and fever in children are due to
viral infections. The findings seldom point toward any
particular viral agent, but four types of viral pharyngitis are
sufficiently distinctive to warrant discussion below.
" Clinical Findings
A. Infectious Mononucleosis
Findings include exudative tonsillitis, generalized cervical
adenitis, and fever, usually in patients older than 5 years. A
palpable spleen or axillary adenopathy increases the likeli-
hood of the diagnosis. The presence of more than 10% atypi-
cal lymphocytes on a peripheral blood smear or a positive
! 523
mononucleosis spot test supports the diagnosis, although
these tests are often falsely negative in children younger than
age 5 years. Epstein-Barr virus serology showing an elevated
IgM-capsid antibody is definitive. Amoxicillin is contraindi-
cated in patients suspected of having mononucleosis because
the drug often precipitates a rash.
B. Herpangina
Herpangina ulcers are classically 3 mm in size, surrounded
by a halo, and are found on the anterior tonsillar pillars, soft
palate, and uvula; the anterior mouth and tonsils are spared.
Herpangina is caused by the coxsackie A group of viruses.
Enteroviral polymerase chain reaction testing is widely
available, but not typically indicated, as herpangina is a self-
limited illness.
C. Hand, Foot, and Mouth Disease
This entity is caused by several enteroviruses, one of which
(enterovirus 71) can rarely cause encephalitis. Ulcers occur
anywhere in the mouth. Vesicles, pustules, or papules may
be found on the palms, soles, interdigital areas, and but-
tocks. In younger children lesions may be seen on the distal
extremities and even the face.
D. Pharyngoconjunctival Fever
This disorder is caused by an adenovirus and often is
epidemic. Exudative tonsillitis, conjunctivitis, lymphade-
nopathy, and fever are the main findings. Treatment is
symptomatic.
2. Acute Bacterial Pharyngitis
ESSENTIALS OF DIAGNOSIS
" Sore throat.
" At least one of the following:
" Cervical lymphadenopathy (lymph nodes tender or
> 2 cm)
" Tonsillar exudates
" Positive group A β-hemolytic streptococcus culture
" Fever greater than 38.3°C
" Differential Diagnosis
Viral pharyngitis, infectious mononucleosis, bacterial phar-
yngitis other than streptococcal, diphtheria, and peritonsillar
abscess.
Approximately 20%–30% of children with pharyngitis
have a group A streptococcal infection. It is most common in
 524 ! CHAPTER 18

Pharyngitis

Assess degree of illness

Mild to moderate Severe (see below)

Afebrile with upper Child febrile or tender cervical nodes

respiratory tract or tonsillar exudates or S pyogenes exposure
infection or family history of rheumatic fever

Symptomatic Rapid strep test

care

Negative Positive

Send throat culture

Penicillin VK 50–70 mg/kg/d in 3 divided
doses; benzathine penicillin 600,000 units IM
if < 27 kg, 1.2 million units if > 27 kg, single
Negative Positive dose; for penicillin-allergic patients use
azithromycin

Cure Failure or relapse in < 1 wk

Repeat throat culture and consider

Severe pharyngitis serologic testing for mononucleosis

ENT consult
Mononucleosis Persistent
test positive group A Streptococcus
Unilateral swelling Bilateral swelling of Airway compromised
of tonsils tonsils and airway problems Counsel about Clindamycin for 10 d
during sleep contact sports
Urgent ENT
assessment
Drain surgically
if abscess or 1. Throat culture and rapid test
treat 2. Mononucleosis diagnostic tests
intravenously if (CBC, Monospot, EBV-IgM)
cellulitis

Admit for observation

▲ Figure 18–7. Algorithm for pharyngitis. CBC, complete blood count; EBV, Epstein-Barr virus; ENT, ear, nose, and throat.
 EAR, NOSE, & THROAT
! 525

children between 5 and 15 years of age in the winter or early
spring. Less common causes of bacterial pharyngitis include
Mycoplasma pneumoniae, Chlamydia pneumoniae, groups C
and G streptococci, and Arcanobacterium hemolyticum. Of
the five, M pneumoniae is by far the most common and may
cause over one-third of all pharyngitis cases in adolescents
and adults.
" Clinical Findings
Sudden onset of sore throat, fever, tender cervical adenopa-
thy, palatal petechiae, a beefy-red uvula, and a tonsillar exu-
date suggest streptococcal infection. Other symptoms may
include headache, stomachache, nausea, and vomiting. The
only way to make a definitive diagnosis is by throat culture
or rapid antigen test. Rapid antigen tests are very specific,
but have a sensitivity of only 85%–95%. Therefore, a posi-
tive test indicates S pyogenes infection, but a negative result
requires confirmation by performing a culture. Diagnosis is
important because untreated streptococcal pharyngitis can
result in acute rheumatic fever, glomerulonephritis, and
suppurative complications (eg, cervical adenitis, peritonsil-
lar abscess, otitis media, cellulitis, and septicemia). The
presence of conjunctivitis, cough, hoarseness, symptoms of
upper respiratory infection, anterior stomatitis, ulcerative
lesions, viral rash, and diarrhea should raise suspicion of a
viral etiology.
Occasionally, a child with group A streptococcal infec-
tion develops scarlet fever within 24–48 hours after the
onset of symptoms. Scarlet fever is a diffuse, finely papular,
erythematous eruption producing a bright red discoloration
of the skin, which blanches on pressure. The rash is more
intense in the skin creases. The tongue has a strawberry
appearance.
A controversial but possible complication of streptococ-
cal infections is pediatric autoimmune neuropsychiatric dis-
orders associated with Streptococcus (PANDAS). PANDAS
is a relatively newly recognized condition. It describes a
subset of pediatric patients who experience a sudden onset
of obsessive-compulsive disorder and/or tics, or worsening
of such symptoms in children who previously had these, fol-
lowing a strep infection.
" Treatment
Suspected or proven group A streptococcal infection should
be treated with penicillin (oral or intramuscular) or amox-
icillin as outlined in Table 18–4. For patients allergic
to penicillin, alternative treatments include cephalexin,
azithromycin, and clindamycin.
Repeat culture after treatment is not recommended and
is indicated only for those who remain symptomatic, have
a recurrence of symptoms, or have had rheumatic fever.
Of note, children who have had rheumatic fever are at a

Table 18–4. Treatment of group A streptococcal pharyngitis.a

Treatment of Acute Group A Strep Pharyngitis

Antibiotic Dose Notes

Penicillin Penicillin V 250 mg 2–3 times per day for 10 d if <%*^Z.(##`Z EXf\fgTaVXgbcXa\V\__\aT`bk\V\__\aTaWY\efg
2–3 times per day for 10 d if >%*^Z ZXaXeTg\baVXc[T_bfcbe\af[TfabgUXXaeXcbegXW!8TV[
Benzathine penicillin)#####ha\gf<@f\aZ_XWbfX\Y<%*^Z. \fXdhT__lXYYXVg\iX\YVb`c_\TaVX\fTffheXW!
$!%`\__\baha\gf<@f\aZ_XWbfX\Y>%*^Z

Amoxicillin 50 mg/kg/d once daily for 10 d (max 1200 mg)

Cephalexin 25–50 mg/kg/d in 2 divided doses for 10 d

Clindamycin 20 mg/kg/d in 3 divided doses for 10 d Rare resistance reported in US

Azithromycin 12 mg/kg once daily for 5 d (max 500 mg/d) Some resistance reported in US

Eradication of carrier state

Clindamycin 20 mg/kg/d in 3 divided doses for 10 d @bfgXYYXVg\iX

Cephalexin 25–50 mg/kg/d in 2 divided doses for 10 d Also effective

Penicillin + rifampin FXXTUbiXcXa\V\__\aWbfXf.e\YT`c\a%#`Z"^Z"Wgj\VXWT\_lYbe

final 4 days
a
Tetracyclines, sulfonamides (including trimethoprim-sulfamethoxazole), and quinolones should not be used for treating GAS infections.
Table reproduced and adapted, courtesy of Todd J: Update on group A streptococcal pharyngitis. Contagious Comments, Children’s Hospital
Colorado, 2013; XXVIII(1).
 526 ! CHAPTER 18
high risk of recurrence if future group A strep infections
are inadequately treated. In this group of patients, long-
term antibiotic prophylaxis is recommended, sometimes
life-long in patients with residual rheumatic heart disease.
(See Chapter 20.)
In general, the carrier state is harmless, self-limited
(2–6 months), and not contagious. An attempt to eradicate
the carrier state is warranted only if the patient or another
family member has frequent streptococcal infections, or if a
family member or patient has a history of rheumatic fever
or glomerulonephritis. If eradication is chosen, a course of
clindamycin for 10 days or rifampin for 5 days should be used.
In the past, daily penicillin prophylaxis was occasion-
ally recommended; however, because of concerns about
the development of drug resistance, tonsillectomy is now
preferred for patients with recurrent streptococcal tonsillitis.
Baugh RF et al; American Academy of Otolaryngology-Head and
Neck Surgery Foundation: Clinical practice guideline: tonsil-
lectomy in children. Otolaryngol Head Neck Surg 2011 Jan;144
(1 Suppl):S1–S30 [PMID: 21493257].
Wessels MR: Clinical practice. Streptococcal pharyngitis. New
Engl J Med 2011;364(7):648–655 [PMID: 21323542].
Web Resources
National Institute of Mental Health PANDAS information: http://
intramural.nimh.nih.gov/pdn/web.htm. Accessed January 11,
2014.
PERITONSILLAR CELLULITIS OR ABSCESS
(QUINSY)
ESSENTIALS OF DIAGNOSIS
" Severe sore throat.
" Unilateral tonsillar swelling.
" Deviation of the uvula.
" Trismus (limited mouth opening).
Tonsillar infection occasionally penetrates the tonsillar
capsule, spreading to the surrounding tissues, causing peri-
tonsillar cellulitis. If untreated, necrosis occurs and a peri-
tonsillar abscess forms. The most common pathogen is
β-hemolytic streptococcus, but others include group D
streptococcus, S pneumoniae, and anaerobes.
The patient complains of a severe sore throat even before
the physical findings become marked. A high fever is usu-
ally present, and the process is almost always unilateral. The
tonsil bulges medially, and the anterior tonsillar pillar is
prominent. The soft palate and uvula on the involved side
are edematous and displaced toward the uninvolved side.
As the infection progresses, trismus, ear pain, dysphagia,
and drooling may occur. The most serious complication of
untreated peritonsillar abscess is a lateral pharyngeal abscess.
It is often difficult to differentiate peritonsillar cellulitis
from abscess. In some children, it is possible to aspirate
the peritonsillar space to diagnose and treat an abscess.
However, it is reasonable to admit a child for 12–24 hours of
intravenous antimicrobial therapy, because aggressive treat-
ment of cellulitis can usually prevent suppuration. Therapy
with a penicillin or clindamycin is appropriate. Failure to
respond to therapy during the first 12–24 hours indicates a
high probability of abscess formation. An otolaryngologist
should be consulted for incision and drainage or for aspira-
tion under local or general anesthesia.
Recurrent peritonsillar abscesses are so uncommon (7%)
that routine tonsillectomy for a single incident is not indicated
unless other tonsillectomy indications exist. Hospitalized
patients can be discharged on oral antibiotics when fever has
resolved for 24 hours and dysphagia has improved.
RETROPHARYNGEAL ABSCESS
Retropharyngeal lymph nodes, which drain the adenoids,
nasopharynx, and paranasal sinuses, can become infected,
commonly due to β-hemolytic streptococci and S aureus.
If this pyogenic adenitis goes untreated, a retropharyngeal
abscess forms. This occurs most commonly during the
first 2 years of life. After this age, the most common cause
of retropharyngeal abscess is superinfection of a penetrating
injury of the posterior wall of the oropharynx.
The diagnosis of retropharyngeal abscess should be
strongly suspected in a child with fever, respiratory symp-
toms, and neck hyperextension. Dysphagia, drooling, dys-
pnea, and gurgling respirations are also found. Prominent
swelling on one side of the posterior pharyngeal wall is
characteristic. Swelling usually stops at the midline because a
medial raphe divides the prevertebral space. On lateral neck
x-ray, the retropharyngeal tissues are wider than the C4 ver-
tebral body. But plain films are not specific; a CT scan with
contrast is more helpful.
Although a retropharyngeal abscess is a surgical emer-
gency, frequently it cannot be distinguished from retropha-
ryngeal adenitis. Immediate hospitalization and intravenous
antimicrobial therapy with a semisynthetic penicillin or
clindamycin is the first step for most cases. Immediate surgi-
cal drainage is required when a definite abscess is seen radio-
graphically or when the airway is compromised. In most
instances, a period of 12–24 hours of antimicrobial therapy
will help differentiate the two entities. In the child with
adenitis, fever will decrease and oral intake will increase. A
child with retropharyngeal abscess will not improve and may
continue to deteriorate. A surgeon should incise and drain
the abscess under general anesthesia to prevent its extension.
1854 Part XVIII ◆ The Digestive System
life activities. Consequently, there has been a shift in efforts to improve
long-term outcomes and quality of life.
Bibliography is available at Expert Consult.
Chapter 340
Acute Gastroenteritis in
Children
Zulfiqar Ahmed Bhutta
The term gastroenteritis denotes infections of the gastrointestinal tract
caused by bacterial, viral, or parasitic pathogens (Tables 340-1 to 340-
3). Many of these infections are foodborne illnesses. The most common
manifestations are diarrhea and vomiting, which can also be associated
with systemic features such as abdominal pain and fever. The term
gastroenteritis captures the bulk of infectious cases of diarrhea. The
term diarrheal disorders is more commonly used to denote infectious
diarrhea in public health settings, although several noninfectious
causes of gastrointestinal illness with vomiting and/or diarrhea are well
recognized (Table 340-4).
EPIDEMIOLOGY OF CHILDHOOD DIARRHEA
Diarrheal disorders in childhood account for a large proportion (9%)
of childhood deaths, with an estimated 0.71 million deaths per year
globally, making it the second most common cause of child deaths
worldwide. Almost 1.731 billion episodes of diarrhea occurred in
2010 in children younger than 5 yr of age in developing countries, with
more than 80% of the episodes occurring in Africa and South Asia
(50.5% and 32.5%, respectively) and 36 million of the total episodes
progress to severe episodes. Global mortality may be declining rapidly,
but the overall incidence of diarrhea has only declined from 3.4 to
approximately 2.9 episodes per child-year in the past 2 decades, and
it is estimated to account for 23 million childhood disability-adjusted
life years.
The decline in diarrheal mortality, despite the lack of significant
changes in incidence, is the result of preventive rotavirus vaccination
and improved case management of diarrhea, as well as improved nutri-
tion of infants and children. These interventions have included wide-
spread home- and hospital-based oral rehydration therapy and
improved nutritional management of children with diarrhea.
In addition to the risk of mortality, persistently high rates of diar-
rhea, especially prolonged and persistent diarrhea among young chil-
dren may be associated with long-term adverse outcomes. Diarrheal
illnesses, especially early and repeated episodes among young children
can be associated with malnutrition, micronutrient deficiencies, and
significant deficits in psychomotor and cognitive development.
ETIOLOGY OF DIARRHEA
Gastroenteritis is the result of infection acquired through the fecal–oral
route or by ingestion of contaminated food or water. Gastroenteritis is
associated with poverty, poor environmental hygiene, and develop-
ment indices. Enteropathogens that are infectious in a small inoculum
(Shigella, enterohemorrhagic Escherichia coli, Campylobacter jejuni,
noroviruses, rotavirus, Giardia lamblia, Cryptosporidium parvum, Ent-
amoeba histolytica) can be transmitted by person-to-person contact,
whereas others, such as cholera, are generally a consequence of con-
tamination of food or water supply (see Tables 340-1 to 340-3).
In the United States, rotavirus and the noroviruses (small round
viruses such as Norwalk-like virus and caliciviruses) are the most
common viral agents, followed by sapoviruses, enteric adenoviruses,
and astroviruses (see Table 340-2). Foodborne outbreaks in the United
States are mostly caused by norovirus, accounting for 58% of all epi-
sodes, and by bacterial causes, which are most commonly Salmonella,
Clostridium perfringens, Campylobacter, and Staphylococcus aureus,
followed much less often by E. coli, Clostridium botulinum, Shigella,
Cryptosporidium, Yersinia, Listeria, Vibrio, and Cyclospora species, in
that order. Food sources include poultry, leafy vegetables, beef, fruits
and nuts, vine-stalk vegetables, and many other foods.
Direct person-to-person contact outbreaks of gastroenteritis are
usually caused by norovirus and Shigella species. Unknown agents are
seen in 30-40%; other pathogens include Salmonella, rotavirus, Giardia,
Cryptosporidium, Clostridium difficile, and C. jejuni.
The exact etiologic fractions of diarrhea among children in develop-
ing countries are a subject of much research, and our knowledge of the
various pathogens that cause moderate to severe childhood diarrhea
has grown considerably (Fig. 340-1; Table 340-5). There are indications
that rates of hospitalization and deaths caused by Shigella infections,
especially Shigella dysenteriae type 1, the most severe form of shigel-
losis, may be declining; however, it accounts for nearly 28,000 deaths
annually. Enteropathogenic E. coli is responsible for 79,000 and entero-
toxigenic E. coli (ETEC) may be responsible for 42,000 deaths annually
among children younger than 5 yr. Rotavirus infections (the most
common identifiable viral cause of gastroenteritis in all children)
account for 197,000 deaths annually or 28% of all deaths caused by
diarrhea among children younger than 5 yr of age.
PATHOGENESIS OF INFECTIOUS DIARRHEA
Pathogenesis and severity of bacterial disease depend on whether
organisms have preformed toxins (S. aureus, Bacillus cereus), produce
secretory (cholera, E. coli, Salmonella, Shigella) or cytotoxic (Shigella,
S. aureus, Vibrio parahaemolyticus, C. difficile, E. coli, C. jejuni) toxins,
or are invasive, and on whether they replicate in food. Enteropathogens
can lead to either an inflammatory or noninflammatory response in
the intestinal mucosa (Table 340-6).
Enteropathogens elicit noninflammatory diarrhea through entero-
toxin production by some bacteria, destruction of villus (surface) cells
by viruses, adherence by parasites, and adherence and/or translocation
by bacteria. Inflammatory diarrhea is usually caused by bacteria that
directly invade the intestine or produce cytotoxins with consequent
fluid, protein, and cells (erythrocytes, leukocytes) that enter the intes-
tinal lumen. Some enteropathogens possess more than 1 virulence
property. Some viruses, such as rotavirus, target the microvillus tips of
the enterocytes and can enter the cells by direct invasion or calcium-
dependent endocytosis. This can result in villus shortening and loss of
enterocyte absorptive surface through cell shortening and loss of
microvilli (Fig. 340-2).
Most bacterial pathogens elaborate enterotoxins; the rotavirus
protein NSP4 acts as a viral enterotoxin. Bacterial enterotoxins can
selectively activate enterocyte intracellular signal transduction and can
also affect cytoskeletal rearrangements with subsequent alterations in
the water and electrolyte fluxes across enterocytes. In toxigenic diar-
rhea, enterotoxin produced by Vibrio cholerae, increased mucosal
levels of cyclic adenosine monophosphate, inhibit electroneutral NaCl
absorption but have no effect on glucose-stimulated Na+ absorption.
In inflammatory diarrhea (e.g., Shigella spp. or Salmonella spp.) there
is extensive histologic damage, resulting in altered cell morphology and
reduced glucose-stimulated Na+ and electroneutral NaCl absorption.
The role of 1 or more cytokines in this inflammatory response is criti-
cal. In secretory cells from crypts, Cl secretion is minimal in normal
subjects and is activated by cyclic adenosine monophosphate in toxi-
genic and inflammatory diarrhea (Fig. 340-3).
ETEC colonizes and adheres to enterocytes of the small bowel via
its surface fimbriae (pili) and induces hypersecretion of fluids and
electrolytes into the small intestine through 1 of 2 toxins: the heat-
labile enterotoxin or the heat-stable enterotoxin. Heat-labile entero-
toxin is structurally similar to the V. cholerae toxin, and activates
adenylate cyclase, resulting in an increase in intracellular cyclic gua-
nosine monophosphate (Fig. 340-4). In contrast, Shigella spp. cause
Text continued on p. 1864
Table 340-1 Foodborne Bacterial Illnesses
INCUBATION SIGNS AND DURATION OF
ETIOLOGY PERIOD SYMPTOMS ILLNESS ASSOCIATED FOODS LABORATORY TESTING TREATMENT
Bacillus anthracis 2 days to weeks Nausea, vomiting, Weeks Insufficiently cooked Blood Penicillin is first choice for naturally
malaise, bloody contaminated meat acquired GI anthrax but use beta
diarrhea, acute lactams with high index of
abdominal pain suspicion for resistance
Ciprofloxacin is second option
Bacillus cereus 1-6 hr Sudden onset of severe 24 hr Improperly refrigerated Normally a clinical diagnosis Supportive care
(preformed nausea and vomiting cooked or fried rice, meats Clinical laboratories do not
enterotoxin) Diarrhea may be routinely identify this
present organism
If indicated, send stool and
food specimens to reference
laboratory for culture and
toxin identification
Bacillus cereus 10-16 hr Abdominal cramps, 24-48 hr Meats, stews, gravies, vanilla Testing not necessary, Supportive care
(diarrheal toxin) watery diarrhea, sauce self-limiting
nausea Consider testing food and
stool for toxin in outbreaks
Brucella abortus, 7-21 days Fever, chills, sweating, Weeks Raw milk, goat cheese made Blood culture and positive Acute: Rifampin and doxycycline
Brucella melitensis, weakness, headache, from unpasteurized milk, serology daily for ≥6 wk
and Brucella suis muscle and joint pain, contaminated meats Infections with complications
diarrhea, bloody require combination therapy with
stools during acute rifampin, tetracycline, and an
phase aminoglycoside
Campylobacter jejuni 2-5 days Diarrhea, cramps, fever, 2-10 days Raw and undercooked Routine stool culture; Supportive care
and vomiting; poultry, unpasteurized milk, Campylobacter requires For severe cases, antibiotics, such
diarrhea may be contaminated water special media and incubation as azithromycin and quinolones,
bloody at 42°C (107.6°F) to grow may be indicated early in the
diarrheal disease
Guillain-Barré syndrome can be a
sequela
Clostridium 12-72 hr Vomiting, diarrhea, Variable (days to Home-canned foods with a Stool, serum, and food can be Supportive care
botulinum: children blurred vision, months) low acid content, improperly tested for toxin Botulism antitoxin is helpful if
and adults diplopia, dysphagia, Can be canned commercial foods, Stool and food can also be given early in the course of the
(preformed toxin) descending muscle complicated by home-canned or fermented cultured for the organism illness. Antitoxin for children and
weakness respiratory fish, herb-infused oils, baked These tests can be performed adults is available through CDC
failure and potatoes in aluminium foil, at some state health Contact the state health
death cheese sauce, bottled department laboratories and department. The 24-hr number
garlic, foods held warm for CDC for CDC is (800) 232-4636
extended periods (e.g., in a (800-CDC-INFO)
warm oven)
Clostridium 3-30 days In infants <12 mo, Variable Honey, home-canned Stool, serum, and food can be Supportive care
botulinum: infants lethargy, weakness, vegetables and fruits, corn tested for toxin Botulinum antitoxin for infants can
poor feeding, syrup Stool and food can also be be obtained from the Infant
constipation, cultured for the organism Botulism Prevention Program,
hypotonia, poor head These tests can be performed Health and Human Services,
control, poor gag and at some state health California (510-540-2646)
sucking reflex department laboratories and
CDC
Chapter 340 ◆ Acute Gastroenteritis in Children 1855

Continued
Table 340-1 Foodborne Bacterial Illnesses—cont’d
INCUBATION SIGNS AND DURATION OF
ETIOLOGY PERIOD SYMPTOMS ILLNESS ASSOCIATED FOODS LABORATORY TESTING TREATMENT
Clostridium 8-16 hr Watery diarrhea, 24-48 hr Meats, poultry, gravy, dried or Stools can be tested for Supportive care
perfringens toxin nausea, abdominal precooked foods, time- enterotoxin and cultured for Antibiotics not indicated
cramps; fever is rare and/or temperature-abused organism
food Because Clostridium
perfringens can normally be
1856 Part XVIII ◆ The Digestive System

found in stool, quantitative

cultures must be done: A
count of at least 106 C.
perfringens spores per gram
of stool within 48 hr of when
illness began is required to
diagnose infection
Enterohemorrhagic 1-8 days Severe diarrhea that is 5-10 days Undercooked beef especially Stool culture; E. coli O157:H7 Supportive care, monitor renal
Escherichia coli often bloody, hamburger, unpasteurized requires special media to function, hemoglobin, and
(EHEC) including E. abdominal pain and milk and juice, raw fruits and grow. If E. coli O157:H7 is platelets closely. E. coli O157:H7
coli O157:H7 and vomiting vegetables (e.g., sprouts), suspected, specific testing infection is also associated with
other Shiga Usually, little or no salami (rarely), contaminated must be requested. Shiga hemolytic uremic syndrome
toxin–producing E. fever is present water toxin testing may be done (HUS), which can cause lifelong
coli (STEC) More common in using commercial kits; complications
children <4 yr old positive isolates should be Studies indicate that antibiotics
forwarded to public health might promote the development
laboratories for confirmation of HUS. Antidiarrheal agents like
and serotyping Imodium may also increase the
risk of developing HUS
Enterotoxigenic E. 1-3 days Watery diarrhea, 3 to >7 days Water or food contaminated Stool culture Supportive care
coli (ETEC) abdominal cramps, with human feces ETEC requires special Antibiotics are rarely needed
some vomiting laboratory techniques for except in severe cases
identification that may not Recommended antibiotics include
be widely available; quinolones although these are
consequently, physicians rarely required unless there is
may make the diagnosis severe infection and should be
based on a patient’s history administered early. Antimotility
and symptoms medications should be avoided
If ETEC is suspected, must by persons with high fevers or
alert microbiology laboratory bloody diarrhea, and should be
that is testing the specimen discontinued if diarrhea
symptoms persist more than
48 hr. Bismuth subsalicylate
compounds (e.g., Pepto-Bismol)
can help reduce the number of
bowel movements
Listeria 9-48 hr for GI Fever, muscle aches, Variable Fresh soft cheeses, Blood or cerebrospinal fluid Supportive care and antibiotics;
monocytogenes symptoms, and nausea or unpasteurized milk, cultures. Selective intravenous ampicillin, penicillin
2-6 wk for diarrhea inadequately pasteurized enrichment media improve G, or TMP-SMX is recommended
invasive Pregnant women might milk, ready-to-eat deli rates of isolation from for invasive disease
disease have mild flu-like meats, hot dogs contaminated specimens
illness, and infection Asymptomatic fecal carriage
can lead to occurs; therefore, stool
premature delivery or culture usually not helpful
stillbirth Antibody to listeriolysin O may
Elderly or be helpful to identify
immunocompromised outbreak retrospectively
patients can have
bacteremia or
meningitis
At birth and Infants infected from Higher dosages of ampicillin
infancy mother at risk for recommended for neonatal
sepsis or meningitis sepsis or meningitis
Salmonella spp. 1-3 days Diarrhea, fever, 4-7 days Contaminated eggs, poultry, Routine stool cultures Supportive care
abdominal cramps, unpasteurized milk or juice, Other than for S. typhi and
vomiting cheese, contaminated raw S. paratyphi, antibiotics are not
S. typhi and S. fruits and vegetables (alfalfa indicated unless there is
paratyphi produce sprouts, melons) extraintestinal spread, or the risk
typhoid with insidious S. typhi epidemics are often of extraintestinal spread of the
onset characterized related to fecal infection
by fever, headache, contamination of water Consider ampicillin, third-
constipation, malaise, supplies or street-vended generation cephalosporins, or
chills, and myalgia; foods quinolones if indicated
diarrhea is A vaccine exists for S. typhi but is
uncommon, and not completely effective.
vomiting is not Washing hands and avoiding
usually severe suspicious foods is equally useful
at preventing disease as
vaccination
Shigella spp. 24-48 hr Abdominal cramps, 4-7 days Food or water contaminated Routine stool cultures Supportive care. Antibiotics are
fever, diarrhea with human fecal material recommended for severe
Stools might contain Usually person-to-person disease, bloody diarrhea, or
blood and mucus spread, fecal–oral compromised immune systems.
transmission Resistance to traditional first-line
Ready-to-eat foods touched drugs like ampicillin and
by infected food workers, TMP-SMX is common. When
e.g., raw vegetables, salads, susceptibility is unknown or when
sandwiches an ampicillin- or TMP-SMX–
resistant strain is isolated,
choices for therapy include
fluoroquinolones, ceftriaxone,
and azithromycin. Antidiarrheal
agents such as Imodium or
Lomotil can worsen the illness
and should be avoided
Staphylococcus 1-6 hr Sudden onset of severe 24-48 hr Unrefrigerated or improperly Normally a clinical diagnosis Supportive care
aureus (preformed nausea and vomiting refrigerated meats, potato Stool, vomitus, and food can
enterotoxin) Abdominal cramps and egg salads, cream be tested for toxin and
Diarrhea and fever may pastries cultured if indicated
be present
Continued
Chapter 340 ◆ Acute Gastroenteritis in Children 1857
 Table 340-1 Foodborne Bacterial Illnesses—cont’d
INCUBATION SIGNS AND DURATION OF
ETIOLOGY PERIOD SYMPTOMS ILLNESS ASSOCIATED FOODS LABORATORY TESTING TREATMENT
Vibrio cholerae 24-72 hr Profuse watery diarrhea 3-7 days Contaminated water, fish, Stool culture Supportive care with aggressive
(toxin) and vomiting, which Causes life- shellfish, street-vended food V. cholerae requires special oral and intravenous rehydration
can lead to severe threatening typically from Latin America media to grow: Cary-Blair Doxycycline is recommended as
dehydration and dehydration or Asia media is ideal for transport, first-line treatment for adults,
death within hours and the selective thiosulfate– whereas azithromycin is
citrate–bile salts agar (TCBS) recommended as first-line
is ideal for isolation and treatment for children and
identification. ; if V. cholerae pregnant women. Ciprofloxacin
is suspected, must request and doxycycline recommended
specific testing. as second-line drugs for children
Commercially available rapid
test kits (e.g., Crystal VC
dipstick) are useful in
epidemic settings but do not
test susceptibility or subtype
so should not be used for
1858 Part XVIII ◆ The Digestive System

routine diagnosis
Vibrio 2-48 hr Watery diarrhea, 2-5 days Undercooked or raw seafood, Stool cultures. V. Supportive care
parahaemolyticus abdominal cramps, such as fish, shellfish parahaemolyticus requires There is no evidence that
nausea, vomiting special media (TCBS agar) to antibiotic treatment decreases
grow; must request specific the severity or the length of the
testing illness. Antibiotics are
recommended in severe or
prolonged cases: tetracycline or
ciprofloxacin can be used
Vibrio vulnificus 1-7 days Vomiting, diarrhea, 2-8 days Undercooked or raw shellfish, Stool, wound, or blood Supportive care and antibiotics:
abdominal pain, especially oysters, other cultures doxycycline, and a third-
bacteremia, and contaminated seafood, and V. vulnificus requires special generation cephalosporin such
wound infections open wounds exposed to media (TCBS agar) to grow; as ceftazidime is recommended
More common and seawater if V. vulnificus is suspected,
potentially fatal in the must request specific testing
immunocompromised
or in patients with
chronic liver disease
(presenting with
septic shock and
hemorrhagic bullous
skin lesions)
Yersinia 24-48 hr Appendicitis-like 1-3 wk, usually Undercooked pork, Stool, vomitus, or blood Supportive care
enterocolitica symptoms (diarrhea self-limiting unpasteurized milk, tofu, culture, throat, lymph nodes, If septicemia or other invasive
and Yersinia and vomiting, fever, contaminated water joint fluid, urine, and bile disease occurs, antibiotic therapy
pseudotuberculosis abdominal pain) Infection has occurred in Yersinia requires special media with aminoglycosides,
occur primarily in infants whose caregivers to grow; must request doxycycline, TMP-SMX, or
older children and handled chitterlings specific testing fluoroquinolones may be useful
young adults Serology is available in
Might have a research and reference
scarlatiniform laboratories
rash or erythema
nodosum with Y.
pseudotuberculosis
CDC, Centers for Disease Control and Prevention; GI, gastrointestinal; TMP-SMX, trimethoprim-sulfamethoxazole.
From Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses, MMWR 53(RR-4):1-33, 2004.
 Table 340-2 Foodborne Viral Illnesses
INCUBATION SIGNS AND DURATION
ETIOLOGY PERIOD SYMPTOMS OF ILLNESS ASSOCIATED FOODS LABORATORY TESTING TREATMENT
Hepatitis A 28 days average Diarrhea, dark urine, Variable, Shellfish harvested from Increase in ALT, bilirubin Supportive care
(15-50 days) jaundice, and flu-like 2 wk-3 mo contaminated waters, raw Positive IgM and anti–hepatitis A antibodies Prevention with immunization

ta
symptoms, i.e., fever, produce, contaminated (vaccine available for persons
headache, nausea, drinking water, uncooked 1 year and older)

h
and abdominal pain foods, and cooked foods

i
that are not reheated after

r
contact with infected food
handler

9
Caliciviruses 12-48 hr Nausea, vomiting, 12-60 hr Shellfish, fecally Routine RT-PCR. RT-PCR assays are the Supportive care such as
(including abdominal cramping, contaminated foods, preferred laboratory method for detecting rehydration. Avoid giving

9
noroviruses and diarrhea, fever, ready-to-eat foods touched norovirus. Conventional RT-PCR followed antimotility agents to
sapoviruses) myalgia, and some by infected food workers by sequence analysis of the RT-PCR children younger than 3 yr
headache (salads, sandwiches, ice, products is used for norovirus genotyping. old. However, these agents

-
Diarrhea is more cookies, fruit) Rapid commercial assays, such as enzyme may be helpful in older
prevalent in adults immunoassays (EIAs), have poor sensitivity children and adults,
and vomiting is more and are not recommended for establishing particularly when used along
prevalent in children diagnosis with rehydration treatment

U
Prolonged Clinical diagnosis, negative bacterial cultures Good hygiene
asymptomatic Stool is negative for WBCs

n
excretion possible
Rotavirus (groups 1-3 days Vomiting, watery 4-8 days Fecally contaminated foods Diagnosis may be made by rapid antigen Supportive care
A-C) diarrhea, low-grade Ready-to-eat foods touched detection of rotavirus in stool specimens. Severe diarrhea can require
fever
Temporary lactose
intolerance can occur
(salads, fruits)
ti e
by infected food workers fluid and electrolyte
replacement
d
Infants and children,
elderly, and
V
immunocompromised
are especially
vulnerable
R

Other viral agents 10-70 hr Nausea, vomiting, 2-9 days Fecally contaminated foods Identification of the virus in early acute stool Supportive care, usually mild,
(astroviruses, diarrhea, malaise, Ready-to-eat foods touched samples self-limiting
G

adenoviruses, abdominal pain, by infected food workers Serology Good hygiene

parvoviruses) headache, fever Some shellfish Commercial ELISA kits are available for
adenoviruses and astroviruses
ALT, alanine aminotransferase; ELISA, enzyme-linked immunosorbent assay; IgM, immunoglobulin M; RT-PCR, reverse transcriptase polymerase chain reaction; WBCs, white blood cells.
From Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses. MMWR 53(RR-4):1-33, 2004.
Chapter 340 ◆ Acute Gastroenteritis in Children 1859
Table 340-3 Foodborne Parasitic Illnesses
INCUBATION SIGNS AND DURATION OF
ETIOLOGY PERIOD SYMPTOMS ILLNESS ASSOCIATED FOODS LABORATORY TESTING TREATMENT
Angiostrongylus 1 wk-≥1 mo Severe headaches, Several weeks to Raw or undercooked No readily available blood tests. Supportive care. There is no specific
cantonensis nausea, vomiting, neck several months intermediate hosts (e.g., History is major guide to treatment. Repeat lumbar punctures
1860 Part XVIII ◆ The Digestive System

stiffness, paresthesias, snails or slugs), infected diagnosis. Examination of CSF and use of corticosteroid therapy
hyperesthesias, paratenic (transport) for elevated pressure, protein, may be used for more severely ill
seizures, and other hosts (e.g., crabs, leukocytes, and eosinophils; patients
neurologic freshwater shrimp), fresh serologic testing using ELISA
abnormalities produce contaminated to detect antibodies to
with intermediate or Angiostrongylus cantonensis
transport hosts
Cryptosporidium 2-10 days Diarrhea (usually May be remitting Any uncooked food or Request specific examination of Supportive care, self-limited
watery), stomach and relapsing food contaminated by the stool for Cryptosporidium. If severe, nitazoxanide can be
cramps, upset over weeks to an ill food handler after Most often, stool specimens prescribed for all patients 1 yr of age
stomach, slight fever months cooking; drinking water are examined microscopically or older
using different techniques
(e.g., acid-fast staining, direct
fluorescent antibody [DFA],
and/or enzyme immunoassays
for detection of
Cryptosporidium sp. antigens)
May need to examine water or
food
Cyclospora 1-14 days, usually Diarrhea (usually May be remitting Various types of fresh Request specific examination of TMP-SMX for 7 days
cayetanensis at ≥1 wk watery), loss of and relapsing produce (imported the stool for Cyclospora
appetite, substantial over weeks to berries, lettuce) May need to examine water or
loss of weight, months food
stomach cramps,
nausea, vomiting,
fatigue
Entamoeba 2-3 days–1-4 wk Diarrhea (often bloody), May be protracted Any uncooked food or Examination of fresh stool for For asymptomatic infections,
histolytica frequent bowel (several weeks to food contaminated by cysts and parasites; may need paromomycin and iodoquinol are the
movements, lower several months) an ill food handler after at least 3 samples drugs of choice. For symptomatic
abdominal pain cooking; drinking water Serology for long-term infections intestinal disease or extraintestinal
infections (e.g., hepatic abscess), the
drugs of choice are metronidazole
and tinidazole, immediately followed
by treatment with paromomycin or
iodoquinol
 Giardia lamblia 1-2 wk Diarrhea, stomach
cramps, gas, weight
loss
Toxoplasma 5-23 days Generally asymptomatic, Months
gondii 20% develop cervical
lymphadenopathy
and/or a flu-like illness
In immunocompromised
patients: CNS disease,
myocarditis, or
pneumonitis is often
seen
ta
h
i
r
9
Toxoplasma In infants at birth Treatment of the Months
gondii mother can reduce
9
(congenital severity and/or
infection) incidence of
congenital infection
Most infected infants
have few symptoms at
birth; later, they
generally develop
signs of congenital
toxoplasmosis (mental
retardation, severely
impaired eyesight,
cerebral palsy,
seizures), unless the
infection is treated
Trichinella 1-2 days for Acute: nausea, diarrhea, Months
spiralis initial vomiting, fatigue,
symptoms; fever, abdominal
others begin discomfort followed
2-8 wk after by muscle soreness,
infection weakness, and
occasional cardiac and
neurologic
complications
CNS, central nervous system; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; IgA, immunoglobulin A; IgM, immunoglobulin M; PCR, polymerase chain reaction; TMP-SMX,
trimethoprim-sulfamethoxazole.
From Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses. MMWR 53(RR-4):1-33, 2004.
Days to weeks Any uncooked food or Examination of stool for ova and
food contaminated by parasites; may need at least 3
an ill food handler after samples
cooking; drinking water
Accidental ingestion of The diagnosis of toxoplasmosis
contaminated is typically made by serologic
substances (e.g., soil testing. however, IgM
contaminated with cat antibodies can persist for
feces on fruits and 6-18 mo and thus do not
vegetables), raw or necessarily indicate recent
partially cooked meat infection
(especially pork, lamb, PCR of bodily fluids
and venison) Diagnosis can also be made by
isolation of parasites from
blood or other body fluids;
observation of parasites in
patient specimens via
microscopy or histology
Detection of organisms is rare
Passed from mother (who Isolation of T. gondii from
acquired acute infection placenta, umbilical cord, or
during pregnancy) to infant blood; PCR of white
child blood cells, CSF, or amniotic
fluid, or IgM and IgA serology,
-
performed by a reference
laboratory
U
n
ti e
Raw or undercooked Positive serology or
d
contaminated meat, demonstration of larvae via
usually pork or wild muscle biopsy; increase in
V
game meat (e.g., bear eosinophils
or moose)
R
G
Metronidazole, tinidazole, or
nitazoxanide. Alternatives to these
medications include paromomycin,
quinacrine, and furazolidone
Asymptomatic healthy, but infected,
persons do not require treatment
Spiramycin or pyrimethamine plus
sulfadiazine may be used for
pregnant women
Pyrimethamine plus sulfadiazine may
be used for immunocompromised
persons, in specific cases
Pyrimethamine plus sulfadiazine (with
or without steroids) may be given for
ocular disease when indicated
Folinic acid is given with
pyrimethamine plus sulfadiazine to
counteract bone marrow suppression
Supportive care plus mebendazole
or albendazole. In addition to
antiparasitic medication, treatment
with steroids is sometimes required
in more severe cases
Chapter 340 ◆ Acute Gastroenteritis in Children 1861
Table 340-4 Foodborne Noninfectious Illnesses
INCUBATION DURATION OF LABORATORY
ETIOLOGY PERIOD SIGNS AND SYMPTOMS ILLNESS ASSOCIATED FOODS TESTING TREATMENT
Antimony 5 min–8 hr usually Vomiting, metallic taste Usually self- Metallic container Identification of Supportive care
<1 hr limited metal in beverage
or food
Arsenic Few hours Vomiting, colic, diarrhea Several days Contaminated food Urine Gastric lavage, BAL
Can cause (dimercaprol)
eosinophilia
Cadmium 5 min–8 hr usually Nausea, vomiting, myalgia, increase in Usually self- Seafood, oysters, clams, Identification of Supportive care
<1 hr salivation, stomach pain limited lobster, grains, peanuts metal in food
1862 Part XVIII ◆ The Digestive System

Ciguatera fish 2-6 hr GI: abdominal pain, nausea, vomiting, Days to weeks to A variety of large reef fish: Radioassay for toxin Supportive care, IV
poisoning diarrhea months grouper, red snapper, in fish or a mannitol
(ciguatera toxin) amberjack, and barracuda consistent history Children more
(most common) vulnerable
3 hr Neurologic: paresthesias, reversal of
hot or cold, pain, weakness
2-5 days Cardiovascular: bradycardia,
hypotension, increase in T-wave
abnormalities
Copper 5 min–8 hr usually Nausea, vomiting, blue or green Usually self- Metallic container Identification of Supportive care
<1 hr vomitus limited metal in beverage
or food
Mercury 1 wk or longer Numbness, weakness of legs, spastic May be protracted Fish exposed to organic Analysis of blood, Supportive care
paralysis, impaired vision, blindness, mercury, grains treated hair
coma with mercury fungicides
Pregnant women and the developing
fetus are especially vulnerable
Mushroom toxins, <2 hr Vomiting, diarrhea, confusion, visual Self-limited Wild mushrooms (cooking Typical syndrome Supportive care
short-acting disturbance, salivation, diaphoresis, might not destroy these and mushroom
(muscimol, hallucinations, disulfiram-like toxins) identified or
muscarine, reaction, confusion, visual demonstration of
psilocybin, disturbance the toxin
Coprinus
atramentaria,
ibotenic acid)
Mushroom toxins, 4-8 hr diarrhea; Diarrhea, abdominal cramps, leading Often fatal Mushrooms Typical syndrome Supportive care,
long-acting 24-48 hr liver to hepatic and renal failure and mushroom life-threatening, may
(amanitin) failure identified and/or need life support
demonstration of
the toxin
Nitrite poisoning 1-2 hr Nausea, vomiting, cyanosis, headache, Usually self- Cured meats, any Analysis of the food, Supportive care,
dizziness, weakness, loss of limited contaminated foods, blood methylene blue
consciousness, chocolate-brown spinach exposed to
blood excessive nitrification
 Pesticides Few minutes to Nausea, vomiting, abdominal cramps, Usually self- Any contaminated food Analysis of the food, Atropine; 2-PAM
(organophosphates few hours diarrhea, headache, nervousness, limited blood (pralidoxime) is used
or carbamates) blurred vision, twitching, convulsions, when atropine is not
salivation, meiosis able to control
symptoms; rarely
necessary in
carbamate poisoning
Puffer fish <30 min Paresthesias, vomiting, diarrhea, Death usually in Puffer fish Detection of Life-threatening, may
(tetrodotoxin) abdominal pain, ascending paralysis, 4-6 hr tetrodotoxin in fish need respiratory
respiratory failure support
Scombroid 1 min-3 hr Flushing, rash, burning sensation of 3-6 hr Fish: bluefin, tuna, skipjack, Demonstration of Supportive care,
(histamine) skin, mouth and throat, dizziness, mackerel, marlin, escolar, histamine in food antihistamines

ta
urticaria, paresthesias and mahi mahi or clinical diagnosis
Shellfish toxins Diarrheic shellfish Nausea, vomiting, diarrhea, and hr to 2-3 days A variety of shellfish, Detection of the Supportive care,

h
(diarrheic, poisoning: abdominal pain accompanied by primarily mussels, oysters, toxin in shellfish; generally self-limiting

i
neurotoxic, 30 min-2 hr chills, headache, and fever scallops, and shellfish from high-pressure

r
amnesic) the Florida coast and the liquid
Gulf of Mexico chromatography

9
Neurotoxic Tingling and numbness of lips, tongue,
shellfish and throat, muscular aches, dizziness,
poisoning: few reversal of the sensations of hot and

9
minutes to hours cold, diarrhea, and vomiting
Amnesic shellfish Vomiting, diarrhea, abdominal pain Elderly are especially

-
poisoning: and neurologic problems such as sensitive to amnesic
24-48 hr confusion, memory loss, shellfish poisoning
disorientation, seizure, coma

U
Shellfish toxins 30 min-3 hr Diarrhea, nausea, vomiting leading to Days Scallops, mussels, clams, Detection of toxin in Life-threatening, may
(paralytic shellfish paresthesias of mouth and lips, cockles food or water need respiratory
poisoning) weakness, dysphasia, dysphonia, where fish are support

n
respiratory paralysis located; high-
pressure liquid
chromatography
Sodium fluoride Few minutes to
2 hr
Salty or soapy taste, numbness of
mouth, vomiting, diarrhea, dilated limited
ti e
Usually self- Dry foods (e.g., dry milk,
flour, baking powder, cake
Testing of vomitus or
gastric washings
Supportive care
d
pupils, spasms, pallor, shock, mixes) contaminated with Analysis of the food
collapse NaF-containing insecticides
and rodenticides
V

Thallium Few hours Nausea, vomiting, diarrhea, painful Several days Contaminated food Urine, hair Supportive care
paresthesias, motor polyneuropathy,
R

hair loss
Tin 5 min-8 hr usually Nausea, vomiting, diarrhea Usually self- Metallic container Analysis of the food Supportive care
<1 hr limited
G

Vomitoxin Few minutes to Nausea, headache, abdominal pain, Usually self- Grains such as wheat, corn, Analysis of the food Supportive care
3 hr vomiting limited barley
Zinc Few hours Stomach cramps, nausea, vomiting, Usually self- Metallic container Analysis of the food, Supportive care
diarrhea, myalgias limited blood and feces,
saliva or urine
BAL, bronchoalveolar lavage; GI, gastrointestinal.
From Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses, MMWR 53(RR-4):1-33, 2004.
Chapter 340 ◆ Acute Gastroenteritis in Children 1863
1864 Part XVIII ◆ The Digestive System

Figure 340-1 Attributable incidence of pathogen-specific moderate-to-severe diarrhea per 100 child-yr by age stratum, all sites combined. The
bars show the incidence rates and the error bars show the 95% confidence intervals. (From Kotloff KL, Nataro JP, Blackwelder WC, et al. Burden
and aetiology of diarrhoeal disease in infants and young children in developing countries [the Global Enteric Multicenter Study, GEMS]: a prospec-
tive, case-control study. Lancet 382(9888):209–222, 2013, Fig. 4.)

gastroenteritis via a superficial invasion of colonic mucosa, which
they invade through M cells located over Peyer patches. After phago-
cytosis, a series of events occurs, including apoptosis of macrophages,
multiplication and spread of bacteria into adjacent cells, release of
inflammatory mediators (interleukin-1 and -8), transmigration of neu-
trophils into the lumen of the colon, neutrophil necrosis and degranu-
lation, further breach of the epithelial barrier, and mucosal destruction
(Fig. 340-5).
RISK FACTORS FOR GASTROENTERITIS
In developed countries, episodes of infectious diarrhea can occur
through seasonal exposure to organisms such as rotavirus, or exposure
to pathogens in settings of close contact (e.g., daycare centers). Major
risks include environmental contamination and increased exposure to
enteropathogens. Additional risks include young age, immunodefi-
ciency, measles, malnutrition, and lack of exclusive or predominant
breastfeeding. Malnutrition increases the risk of diarrhea and associ-
ated mortality, and moderate to severe stunting increases the odds of
diarrhea-associated mortality. The fraction of such infectious diarrhea
deaths that are attributable to nutritional deficiencies varies with the
prevalence of deficiencies; the highest attributable fractions are in sub-
Saharan Africa, south Asia, and Andean Latin America. The risks are
particularly higher with micronutrient malnutrition; in children with
vitamin A deficiency, and accounts for 157,000 deaths from diarrhea,
measles, and malaria. Zinc deficiency is estimated to cause 116,000
deaths from diarrhea and pneumonia. Table 340-7 summarizes some
of the key risk factors associated with childhood diarrhea globally.
The majority of cases of diarrhea resolve within the 1st wk of the
illness. A smaller proportion of diarrheal illnesses fail to resolve and
persist for longer than 2 wk. Persistent diarrhea is defined as episodes
that began acutely but last for 14 or more days. Such episodes account
for 3-19% of all diarrheal episodes in children younger than 5 yr of age
and up to 50% of all diarrhea-related deaths; persistent diarrhea has a
case fatality rate of 60%. Many children (especially infants and tod-
dlers) in developing countries have frequent episodes of acute diarrhea.
Although few individual episodes persist beyond 14 days, frequent
episodes of acute diarrhea, as well as prolonged diarrhea (lasting
between 7-13 days of age), can result in nutritional compromise and
can predispose these children to develop persistent diarrhea, protein-
calorie malnutrition, and secondary infections.
CLINICAL MANIFESTATION OF DIARRHEA
Most of the clinical manifestations and clinical syndromes of diarrhea
are related to the infecting pathogen and the dose or inoculum (see
Tables 340-1 to 340-3). Additional manifestations depend on the devel-
opment of complications (e.g., dehydration and electrolyte imbalance)
 Chapter 340 ◆ Acute Gastroenteritis in Children 1865

Table 340-5 Weighted Annual Incidence (Per 100 Child-Years) of Moderate-to-Severe Diarrhea Attributable to a Specific
Pathogen, with 95% Confidence Interval, By Age Stratum and Country
AGE
GROUP PATHOGEN GAMBIA MALI MOZAMBIQUE KENYA INDIA BANGLADESH PAKISTAN
<12 mo VIRUSES
Rotavirus 3.2 (1.7-4.6) 8.4 (3.5-13.3) 3.5 (1.5-5.4) 10.1 (5.4-14.8) 25.4 (14.7-36.2) 2.1 (1.0-3.2) 5.5 (2.6-8.5)
Norovirus GII 1.2 (0.4-2.0) – – – – – –
Adenovirus 40/41 0.3 (0.1-0.6) 0.7 (0.1-1.3) 0.3 (0.0-0.5) – 3.7 (1.6-5.9) 0.5 (0.2-0.8) 0.5 (0.1-0.8)
BACTERIA
ST-ETEC (ST-only 0.7 (0.1-1.2) 1.4 (0.3-2.5) – 3.6 (1.4-5.8) 2.8 (0.9-4.8) 0.2 (0.0-0.4) 1.7 (0.6-2.8)
or LT/ST)
Shigella 0.5 (0.2-0.9) – – 2.3 (0.8-3.8) 1.9 (0.4-3.3) 1.7 (0.8-2.6) 1.9 (0.8-2.9)
Aeromonas – – – – – 1.2 (0.3-2.2) 2.8 (1.0-4.5)
Campylobacter – – – – – 1.1 (0.1-2.2) 1.7(0.0-3.3)
jejuni
Typical EPEC – – – 2.7 (0.6-4.7) – – –
Nontyphoidal – – – – – 0.5 (0.2-0.9) –
Salmonella

G
Vibrio cholerae – – – – – – 0.8 (0.2-1.3)
O1

R
PROTOZOA
Cryptosporidium 1.6 (0.7-2.4) 5.4 (2.1-8.8) 1.8 (0.7-3.0) 4.6 (2.0-7.2) 11.1 (5.4-16.9) 0.7 (0.2-1.2) 1.4 (0.1-2.6)
Entamoeba – – – – – 0.5 (0.0-0.9) –

V
histolytica
12-23 mo VIRUSES

d
Rotavirus 3.3 (1.3-5.2) 4.1 (1.0-7.1) – 3.0 (1.6-4.3) 12.4 (7.1-17.7) 3.0 (1.1-4.9) 1.6 (0.6-2.7)
Norovirus GII 1.7 (0.5-2.8) – – – 2.3 (0.4-4.2) – –

ti e
Adenovirus 40/41 0.4 (0.0-0.8) – – – 2.2 (0.9-3.4) – 0.4 (0.0-0.7)
BACTERIA
ST-ETEC (ST-only 1.5 (0.3-2.8) 0.8 (0.0-1.7) 0.7 (0.2-1.2) 1.5 (0.6-2.5) 2.8 (1.1-4.6) 0.9 (0.2-1.7)
or LT/ST)

n
EAEC – – – – – 1.6 (0.0-3.2) –
Shigella 2.5 (0.9-4.1) 0.8 (0.0-1.6) 0.5 (0.1-0.9) 1.0 (0.3-1.8) 3.5 (1.7-5.4) 8.5 (3.3-13.7) 2.1 (0.7-3.4)
Aeromonas – – – – – 1.9 (0.2-3.7) 1.6 (0.2-2.9)

U
Campylobacter – – – – – – –
jejuni

-
Typical EPEC – – – 0.8 (0.0-1.5) – – –
Nontyphoidal – – – 0.7 (0.1-1.4) – – –
Salmonella

9
Vibrio cholerae – – – – 1.6 (0.6-2.7) 0.2 (0.0-0.5) 1.3 (0.4-2.1)
O1
PROTOZOA

9
Cryptosporidium 1.5 (0.4-2.5) 1.6 (0.0-3.3) – 2.0 (0.9-3.0) 4.1 (1.2-6.9) – 1.4 (0.4-2.4)

r
Entamoeba – – – – – – –

i
histolytica

h
24–59 mo VIRUSES
Rotavirus 0.4 (0.1-0.6) 0.4 (0.0-3.2) – 0.3 (0.1-0.4) 3.5 (0.0-7.1) – –
Norovirus GII 0.3 (0.0-0.5) – – – – – –

ta
Sapovirus – – – – 0.8 (0.0-1.8) – –
Adenovirus 40/41 – – – – – – –
BACTERIA
ST-ETEC (ST-only 0.3 (0.0-0.5) – – 0.4 (0.1-0.6) 1.5 (0.0-3.1) – 0.1 (0.0-0.3)
or LT/ST)
EAEC – – – – – – –
Shigella 0.4 (0.1-0.7) 0.3 (0.0-2.9) 0.4 (0.0-0.9) 0.7 (0.4-1.1) 2.9 (0.0-5.9) 3.1 (0.0-6.3) 0.2 (0.0-0.4)
Aeromonas – – – – – 0.8 (0.0-1.8) 0.5 (0.2-0.9)
Campylobacter – – – – 2.4 (0.0-5.0) – 0.4 (0.0-0.7)
jejuni
Typical EPEC – – – – – – –
Nontyphoidal – – – 0.3 (0.1-0.5) – – –
Salmonella
Vibrio cholerae – – 0.2 (0.0-0.5) – 1.8 (0.0-3.8) 0.1 (0.0-0.3) –
O1
PROTOZOA
Cryptosporidium – – – 0.2 (0.0-0.4) – – –
Entamoeba – 0.3 (0.0-2.7) – – – – –
histolytica
EAEC, enteroadherent Escherichia coli; EPEC, enteropathogenic Escherichia coli; ETEC, enterotoxigenic Escherichia coli; LT, heat-labile; ST, heat stable.
1866 Part XVIII ◆ The Digestive System

Table 340-6 Comparison of 3 Types of Enteric Infection

TYPE OF INFECTION
PARAMETER I II III
Mechanism Noninflammatory (enterotoxin or Inflammatory (invasion, cytotoxin) Penetrating
adherence/superficial invasion)
Location Proximal small bowel Colon Distal small bowel
Illness Watery diarrhea Dysentery Enteric fever
Stool examination No fecal leukocytes Fecal polymorphonuclear Fecal mononuclear leukocytes
Mild or no ↑ lactoferrin leukocytes
↑↑ Lactoferrin
Examples Vibrio cholerae Shigella Salmonella typhi
Escherichia coli (ETEC, LT, ST) E. coli (EIEC, EHEC) Yersinia enterocolitica
Clostridium perfringens Salmonella enteritidis ?Campylobacter fetus
Bacillus cereus Vibrio parahaemolyticus
Staphylococcus aureus Clostridium difficile
Also†: Campylobacter jejuni
Giardia lamblia Entamoeba histolytica*
Rotavirus
Norwalk-like viruses
Cryptosporidium parvum
E. coli (EPEC, EAEC)
Microsporidia
Cyclospora cayetanensis
*Although amebic dysentery involves tissue inflammation, the leukocytes are characteristically pyknotic or absent, having been destroyed by the virulent amebae.
†
Although not typically enterotoxic, these pathogens alter bowel physiology via adherence, superficial cell entry, cytokine induction, or toxins that inhibit cell
function.
EAEC, enteroaggregative E. coli; EHEC, enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli; EPEC, enteropathogenic E. coli; ETEC, enterotoxigenic E. coli;
LT, heat-labile; ST, heat-stable.
From Mandell GL, Bennett JE, Dolin R, editors: Principles and practices of infectious diseases, ed 7, Philadelphia, 2010, Churchill Livingstone.

NSP4 STa
EAST1
Guanylin
Para-cellular ↑ Cl! ↓ Zinc Uroguanylin
↑ Ca2! disrupts
water flow secretion
Rota- cytoskeleton Increased
Baterial from CFTR
virus Cl secretion
toxins CT Yersinia spp.
(Cholera, LT
E. coli)
Replication
Disrupts
G
PLC TJ GC-C
M
YoPs

IP3
NSP4 PK
↑ Ca2! from cGMP
ER stores cAMP
↑ Ca2! from
ER stores

Crypt cell
Enterocyte
Adenylate
Directly or via cyclase
NSP4 ENS activation
Figure 340-3 Mechanism of cholera toxin. (Adapted from Thapar M,
Figure 340-2 Pathogenesis of rotavirus infection and diarrhea. ENS, Sanderson IR: Diarrhoea in children: an interface between developing
enteric nervous system; ER, endoplasmic reticulum; PLC, phospholi- and developed countries, Lancet 363:641–653, 2004; and Montes M,
pase C; TJ, tight junction. (Adapted from Ramig RF: Pathogenesis of DuPont HL: Enteritis, enterocolitis and infectious diarrhea syndromes.
intestinal and systemic rotavirus infection, J Virol 78:10213–10220, In Cohen J, Powderly WG, Opal SM, et al, editors: Infectious diseases,
2004.) ed 2, London, 2004, Mosby, pp. 31–52.)
 Chapter 340 ◆ Acute Gastroenteritis in Children 1867

Toxigenic Inflammatory

Lumen of
small
intestine Glucose Glucose Glucose
Na! Na! Na!
cAMP
Glucose Glucose Glucose

Na! Na! Na!

Na! Na! Na!
Na! Na! Na! Na! Na! Na!
H! H! H! H! H! H!
cAMP
HCO3" HCO3" HCO3" HCO3" HCO3" HCO3"

Cl" Cl" Cl" Cl" Cl" Cl"

Inflammatory
cell

Villus Lumen of
small intestine

R G
V
Crypt

d
ti e
Cl" 2Cl" cAMP Cl" 2Cl" Cl" 2Cl"
K! K! K! K! K! K!
Na! Na! Na! Na! Na! Na!

n
Cl" Cl"

A B

- U
Figure 340-4 Movement of Na and Cl in the small intestine. A, Movement in normal subjects. Na+ is absorbed by 2 different mechanisms in
+ −

absorptive cells from villi: glucose-stimulated absorption and electroneutral absorption (which represents the coupling of Na+/H+ and Cl−/HCO3−
exchanges). B, Movement during diarrhea caused by a toxin and inflammation. (From Petri WA, Miller M, Binder HJ, et al: Enteric infections,

9
diarrhea and their impact on function and development, J Clin Invest 118:1277–1290, 2008.)

i r 9
h Shigella bacilli

ta M cell
Epithelial barrier
damage and more
Shigella enter

Colon
enterocyte

Neutrophils
IL-8, attraction and
other transmigration
mediators
Cell-cell and
basolateral
invasion Macrophage to
undergo apoptosis
Figure 340-5 Pathogenesis of Shigella infection and diarrhea. IL-8, Interleukin-8. (Adapted from Opal SM, Keusch GT: Host responses to infec-
tion. In Cohen J, Powderly WG, Opal SM, et al, editors: Infectious diseases, ed 2, London, 2004, Mosby, pp. 31–52.)
1868 Part XVIII ◆ The Digestive System

Table 340-7 Proven Risk Factors with Direct Biologic Links to Diarrhea: Relative Risks (RR) or Odds Ratios (OR) and 95%
Confidence Intervals
DIARRHEA
MORBIDITY MORTALITY
Lack of exclusive breastfeeding (0-5 mo) RR = 2.65 (1.72-4.07) compared to not RR = 10.52 (2.79-39.6) compared to not breastfed
breastfed infants infants
No breastfeeding (6-23 mo) RR = 1.32 (1.06-1.63) RR = 2.18 (1.14-4.16)
Underweight (<−2 WAZ) RR = 1.23 (1.12-1.35)
−2 to <−1 WAZ OR = 2.1 (1.6
−3 to <−2 WAZ OR = 3.4 (2.7
<−3 WAZ OR = 9.5 (5.5
Stunted
−2 to <−1 HAZ OR = 1.2 (0.9
−3 to <−2 HAZ OR = 1.6 (1.1
<−3 HAZ OR = 4.6 (2.7
Wasted
−2 to <−1 WHZ OR = 1.2 (0.7
−3 to <−2 WHZ OR = 2.9 (1.8
<−3 WHZ OR = 6.3 (2.7
Vitamin A deficiency Inconsistent evidence RR = 1.47 (1.25-175)
Zinc deficiency RR = 0.87 (0.81-0.94) RR = 0.82 (0.64-1.05)
Crowding (>8 persons/kitchen)
Indoor air pollution
Unwashed hands RR = 0.58 (0.49–0.69) Risk relationship suggested but studies of poor
methodologic quality
Poor water quality RR = 0.73 (0.53-1.01) Inconsistent evidence Relationship suggested but few studies of sufficient
from blinded studies quality
Inappropriate excreta disposal Limited evidence suggests risk relationship
HAZ, height-for-age Z-score; WAZ, weight-for-age Z score; WHZ, weight-for-height Z-score.
Adapted from Walker CL, Rudan I, Liu L, et al: Global burden of childhood pneumonia and diarrhoea. Lancet 381:1405–1416, 2013.

and the nature of the infecting pathogen (Table 340-8). Usually the
ingestion of preformed toxins (e.g., those of S. aureus) is associated
with the rapid onset of nausea and vomiting within 6 hr, with possible
fever, abdominal cramps, and diarrhea within 8-72 hr. Watery diarrhea
and abdominal cramps after an 8-16 hr incubation period are associ-
ated with enterotoxin-producing C. perfringens and B. cereus. Abdomi-
nal cramps and watery diarrhea after a 16-48 hr incubation period can
be associated with noroviruses, several enterotoxin-producing bacte-
ria, Cryptosporidium, and Cyclospora, and also have been a notable
feature of influenza virus H1N1 infections. Several organisms, includ-
ing Salmonella, Shigella, C. jejuni, Yersinia enterocolitica, enteroinvasive
or hemorrhagic (Shigatoxin-producing) E. coli, and V. parahaemolyti-
cus, produce diarrhea that can contain blood as well as fecal leukocytes
in association with abdominal cramps, tenesmus, and fever; these fea-
tures suggest bacterial dysentery and fever (Table 340-8). Bloody diar-
rhea and abdominal cramps after a 72-120 hr incubation period are
associated with infections from Shigella and also Shigatoxin-producing
E. coli, such as E. coli O157:H7. Organisms associated with dysentery
or hemorrhagic diarrhea can also cause watery diarrhea alone without
fever or that precedes a more complicated course that results in
dysentery.
Although many of the manifestations of acute gastroenteritis in chil-
dren are nonspecific, some clinical features can help identify major
categories of diarrhea and allow rapid triage for antibiotic or specific
dietary therapy (see Tables 340-1 to 340-4). There is considerable
overlap in the symptomatology. The positive predictive values for the
features of dysentery are very poor; the negative predictability for
bacterial pathogens is much better in the absence of signs of dysentery.
If warranted and if facilities and resources permit, the etiology can be
verified by appropriate laboratory testing.
COMPLICATIONS
Most of the complications associated with gastroenteritis are related to
delays in diagnosis and delays in the institution of appropriate therapy.
Without early and appropriate rehydration, many children with acute
diarrhea would develop dehydration with associated complications
(see Chapter 57). These can be life-threatening in infants and young
children. Inappropriate therapy can lead to prolongation of the diar-
rheal episodes, with consequent malnutrition and complications such
as secondary infections and micronutrient deficiencies (iron, zinc,
vitamin A). In developing countries and HIV-infected populations,
associated bacteremias are well-recognized complications in malnour-
ished children with diarrhea.
Specific pathogens are associated with extraintestinal manifestations
and complications. These are not pathognomonic of the infection, nor
do they always occur in close temporal association with the diarrheal
episode (Table 340-9).
DIAGNOSIS
The diagnosis of gastroenteritis is based on clinical recognition, an
evaluation of its severity by rapid assessment and by confirmation by
appropriate laboratory investigations, if indicated.

Table 340-8 Differential Diagnosis of Acute Dysentery
and Inflammatory Enterocolitis
SPECIFIC INFECTIOUS PROCESSES
Bacillary dysentery (Shigella dysenteriae, Shigella flexneri, Shigella
sonnei, Shigella boydii; invasive Escherichia coli)
Campylobacteriosis (Campylobacter jejuni)
Amebic dysentery (Entamoeba histolytica)
Ciliary dysentery (Balantidium coli)
Bilharzial dysentery (Schistosoma japonicum, Schistosoma mansoni)
Other parasitic infections (Trichinella spiralis)
Vibriosis (Vibrio parahaemolyticus)
Salmonellosis (Salmonella typhimurium)
Typhoid fever (Salmonella typhi)
Enteric fever (Salmonella choleraesuis, Salmonella paratyphi)
Yersiniosis (Yersinia enterocolitica)
Spirillar dysentery (Spirillum spp.)
PROCTITIS
Gonococcal (Neisseria gonorrhoeae)
Herpetic (herpes simplex virus)
Chlamydial (Chlamydia trachomatis)
Syphilitic (Treponema pallidum)
OTHER SYNDROMES
Necrotizing enterocolitis of the newborn
Enteritis necroticans
Pseudomembranous enterocolitis (Clostridium difficile)
Typhlitis
CHRONIC INFLAMMATORY PROCESSES
Enteropathogenic and enteroaggregative E. coli
Gastrointestinal tuberculosis
Gastrointestinal mycosis
Parasitic enteritis
SYNDROMES WITHOUT KNOWN INFECTIOUS CAUSE
Idiopathic ulcerative colitis
Crohn disease
Radiation enteritis
Ischemic colitis
Allergic enteritis
From Mandell GL, Bennett JE, Dolin R, editors: Principles and practices of
infectious diseases, ed 7, Philadelphia, 2010, Churchill Livingstone.
Clinical Evaluation of Diarrhea
The most common manifestations of gastrointestinal tract infection in
children are diarrhea, abdominal cramps, and vomiting. Systemic
manifestations are varied and associated with a variety of causes. The
evaluation of a child with acute diarrhea includes:
◆ Assessing the degree of dehydration and acidosis and provide
rapid resuscitation and rehydration with oral or intravenous fluids
as required (Tables 340-10 and 340-11).
◆ Obtaining appropriate contact, travel, or exposure history. This
includes information on exposure to contacts with similar
symptoms, intake of contaminated foods or water, child-care
center attendance, recent travel of patient or contact with a person
who traveled to a diarrhea-endemic area, and use of antimicrobial
agents.
◆ Clinically determining the etiology of diarrhea for institution of
prompt antibiotic therapy, if indicated.
Although nausea and vomiting are nonspecific symptoms, they indi-
cate infection in the upper intestine. Fever suggests an inflammatory
process but also occurs as a result of dehydration or coinfection (e.g.,
urinary tract infection, otitis media). Fever is common in patients with
inflammatory diarrhea. Severe abdominal pain and tenesmus indicate
involvement of the large intestine and rectum. Features such as nausea
and vomiting and absent or low-grade fever with mild to moderate
periumbilical pain and watery diarrhea indicate small intestine involve-
ment and also reduce the likelihood of a serious bacterial infection.
This clinical approach to the diagnosis and management of diarrhea
in young children is a critical component of the Integrated Manage-
Chapter 340 ◆ Acute Gastroenteritis in Children 1869
ment of Childhood Illnesses package that is being implemented in
developing countries that have a high burden of diarrhea mortality
(Figs. 340-6 and 340-7).
Stool Examination
Microscopic examination of the stool and cultures can yield important
information on the etiology of diarrhea. Stool specimens could be
examined for mucus, blood, and leukocytes. Fecal leukocytes indicate
bacterial invasion of colonic mucosa, although some patients with
shigellosis have minimal leukocytes at an early stage of infection, as do
patients infected with Shigatoxin-producing E. coli and E. histolytica.
Recent advances in rapid molecular methods of diagnosis for bacterial
and parasitic infections have made the role of traditional microscopy
less important; however, this is still a useful test in developing coun-
tries. XTAG GPP is an FDA-approved gastrointestinal pathogen panel
using multiplexed nucleic acid technology that detects Campylobacter,
C. difficile, toxin A/B, E. coli 0157, enterotoxigenic E. coli, Salmonella,
Shigella, Shiga-like toxin E. coli, norovirus, rotavirus A, Giardia, and
Cryptosporidium. Stool cultures should be obtained as early in the
course of disease as possible from children with bloody diarrhea in
whom stool microscopy indicates fecal leukocytes, in outbreaks with
suspected hemolytic-uremic syndrome, and in immunosuppressed
children with diarrhea. Stool specimens for culture need to be trans-
ported and plated quickly; if the latter is not quickly available, speci-
mens might need to be transported in special transport media. The
yield and diagnosis of bacterial diarrhea is improved by using molecu-
lar diagnostic procedures such as real-time polymerase chain reaction.
In most previously healthy children with uncomplicated watery diar-
rhea, no laboratory evaluation is needed except for epidemiologic
purposes.
TREATMENT
The broad principles of management of acute gastroenteritis in
children include oral rehydration therapy, enteral feeding and diet
selection, zinc supplementation, and additional therapies such as
probiotics.
Oral Rehydration Therapy
Children, especially infants, are more susceptible than adults to dehy-
dration because of the greater basal fluid and electrolyte requirements
per kg and because they are dependent on others to meet these
demands. Dehydration must be evaluated rapidly and corrected in
4-6 hr according to the degree of dehydration and estimated daily
requirements. A small minority of children, especially those in shock
or unable to tolerate oral fluids, require initial intravenous rehydration,
but oral rehydration is the preferred mode of rehydration and replace-
ment of ongoing losses (see Tables 340-8 and 340-9). Risks associated
with severe dehydration that might necessitate intravenous resuscita-
tion include: age <6 mo; prematurity; chronic illness; fever >38°C
(100.4°F) if younger than 3 mo or >39°C (102.2°F) if 3-36 mo of age;
bloody diarrhea; persistent emesis; poor urine output; sunken eyes;
and a depressed level of consciousness. The low-osmolality World
Health Organization (WHO) oral rehydration solution (ORS) contain-
ing 75 mEq of sodium, 64 mEq of chloride, 20 mEq of potassium, and
75 mmol of glucose per liter, with total osmolarity of 245 mOsm/L, is
now the global standard of care and more effective than home fluids,
including decarbonated soda beverages, fruit juices, and tea. These are
not suitable for rehydration or maintenance therapy because they have
inappropriately high osmolalities and low sodium concentrations.
Figure 340-7 and Tables 340-10 and 340-11 outline a clinical evaluation
plan and management strategy for children with moderate to severe
diarrhea. Oral rehydration should be given to infants and children
slowly, especially if they have emesis. It can be given initially by a
dropper, teaspoon, or syringe, beginning with as little as 5 mL at a time.
The volume is increased as tolerated. Replacement for emesis or stool
losses is noted in Table 340-11. Oral rehydration can also be given by
a nasogastric tube if needed; this is not the usual route.
Limitations to oral rehydration therapy include shock, an ileus,
intussusception, carbohydrate intolerance (rare), severe emesis, and
1870 Part XVIII ◆ The Digestive System

Table 340-9 Extraintestinal Manifestations of Enteric Infections

MANIFESTATION
Focal infections from systemic spread of
bacterial pathogens, including
vulvovaginitis, urinary tract infection,
endocarditis, osteomyelitis, meningitis,
pneumonia, hepatitis, peritonitis,
chorioamnionitis, soft-tissue infection,
and septic thrombophlebitis
Reactive arthritis
Guillain-Barré syndrome
Glomerulonephritis
Immunoglobulin A (IgA) nephropathy
Erythema nodosum
Hemolytic uremic syndrome
Hemolytic anemia
From Centers for Disease Control and Prevention: Managing acute gastroenteritis among children, MMWR Recomm Rep 53:1–33, 2004.
ASSOCIATED ENTERIC PATHOGEN(S)
All major pathogens can cause such
direct extraintestinal infections,
including Salmonella, Shigella, Yersinia,
Campylobacter, Clostridium difficile
Salmonella, Shigella, Yersinia,
Campylobacter, Cryptosporidium,
C. difficile
Campylobacter
Shigella, Campylobacter, Yersinia
Campylobacter
Yersinia, Campylobacter, Salmonella
Shigella dysenteriae 1, Escherichia coli
O157:H7, others
Campylobacter, Yersinia
ONSET AND PROGNOSIS
Onset usually during the acute infection but can occur
subsequently
Prognosis depends on infection site
Typically occurs 1-3 wk after infection
Relapses after reinfection can develop in 15-50% of
people, but most children recover fully within 2-6 mo
after the first symptoms appear
Usually occurs a few weeks after the original infection
Prognosis is good although 15-20% may have sequelae
Can be of sudden onset in acute, referring to a sudden
attack of inflammation, or chronic, which comes on
gradually
In most cases, the kidneys heal with time
Characterized by recurrent episodes of blood in the
urine, this condition results from deposits of the
protein IgA in the glomeruli. IgA nephropathy can
progress for years with no noticeable symptoms
Men seem more likely to develop this disorder than
women
Although painful, is usually benign and more commonly
seen in adolescents
Resolves with 4-6 wk
Sudden onset, short-term renal failure
In severe cases, renal failure requires several sessions
of dialysis to take over the kidney function, but most
children recover without permanent damage to their
health
Relatively rare complication and can have a chronic
course

Table 340-10 Symptoms Associated with Dehydration

MINIMAL OR NO MILD TO MODERATE
DEHYDRATION DEHYDRATION SEVERE DEHYDRATION
SYMPTOM (<3% LOSS OF BODY WEIGHT) (3-9% LOSS OF BODY WEIGHT) (>9% LOSS OF BODY WEIGHT)
Mental status Well; alert Normal, fatigued or restless, irritable Apathetic, lethargic, unconscious
Thirst Drinks normally; might refuse Thirsty; eager to drink Drinks poorly; unable to drink
liquids
Heart rate Normal Normal to increased Tachycardia, with bradycardia in
most severe cases
Quality of pulses Normal Normal to decreased Weak, thready, or impalpable
Breathing Normal Normal; fast Deep
Eyes Normal Slightly sunken Deeply sunken
Tears Present Decreased Absent
Mouth and tongue Moist Dry Parched
Skinfold Instant recoil Recoil in <2 sec Recoil in >2 sec
Capillary refill Normal Prolonged Prolonged; minimal
Extremities Warm Cool Cold; mottled; cyanotic
Urine output Normal to decreased Decreased Minimal
Adapted from Duggan C, Santosham M, Glass RI: The management of acute diarrhea in children: oral rehydration, maintenance, and nutritional therapy, MMWR
Recomm Rep 41(RR-16):1–20, 1992; and World Health Organization: The treatment of diarrhoea: a manual for physicians and other senior health workers, Geneva,
1995, World Health Organization; Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses, MMWR 53(RR-4):1-33, 2004.
 Chapter 340 ◆ Acute Gastroenteritis in Children 1871

high stool output (>10 mL/kg/hr). Ondansetron (oral mucosal absorp-
tion preparation) reduces the incidence of emesis, thus permitting
more effective oral rehydration and is well established in emergency
management of acute gastroenteritis in developed countries.
Enteral Feeding and Diet Selection
Continued enteral feeding in diarrhea aids in recovery from the
episode, and a continued age-appropriate diet after rehydration is the
norm. Although intestinal brush-border surface and luminal enzymes
can be affected in children with prolonged diarrhea, there is evidence
that satisfactory carbohydrate, protein, and fat absorption can take
place on a variety of diets. Once rehydration is complete, food should
be reintroduced while oral rehydration is continued to replace ongoing
losses from emesis or stools and for maintenance. Breastfeeding or
nondiluted regular formula should be resumed as soon as possible.
Foods with complex carbohydrates (rice, wheat, potatoes, bread, and
cereals), lean meats, yogurt, fruits, and vegetables are also tolerated.
Fatty foods or foods high in simple sugars (juices, carbonated sodas)

Table 340-11 Summary of Treatment Based on Degree of Dehydration

DEGREE OF DEHYDRATION REHYDRATION THERAPY REPLACEMENT OF LOSSES NUTRITION
Minimal or no dehydration Not applicable <10 kg body weight: 60-120 mL ORS Continue breastfeeding or
for each diarrheal stool or vomiting resume age-appropriate
episode >10 kg body weight: normal diet after initial
120-240 mL ORS for each diarrheal hydration, including adequate
stool or vomiting episode caloric intake for maintenance*
Mild to moderate dehydration ORS, 50-100 mL/kg body weight Same Same
over 3-4 hr
Severe dehydration Lactated Ringer solution or normal Same; if unable to drink, administer Same
saline in 20 mL/kg body weight through nasogastric tube or
IV until perfusion and mental administer 5% dextrose in normal
status improve; then administer saline with 20 mEq/L potassium
100 mL/kg body weight ORS chloride IV
over 4 hr or 5% dextrose normal
saline IV at twice maintenance
fluid rates
*Overly restricted diets should be avoided during acute diarrheal episodes. Breastfed infants should continue to nurse ad libitum even during acute rehydration.
Infants too weak to eat can be given milk or formula through a nasogastric tube. Lactose-containing formulas are usually well tolerated. If lactose malabsorption
appears clinically substantial, lactose-free formulas can be used. Complex carbohydrates, fresh fruits, lean meats, yogurt, and vegetables are all recommended.
Carbonated drinks or commercial juices with a high concentration of simple carbohydrates should be avoided.
ORS, oral rehydration solution.
From Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses, MMWR 53(RR-4):1-33, 2004.

Two of the following signs: • If child has no other severe classification:

Does the child have diarrhea? -Give fluid for severe dehydration (Plan C).
• Lethargic or unconscious OR
If yes, ask: Look and feel: • Sunken eyes If child also has another severe classification:
• Not able to drink or drinking Severe - Refer URGENTLY to hospital with mother
• For how long? Look at the child’s general poorly dehydration giving frequent sips of ORS on the way.
condition. • Skin pinch goes back very Advise the mother to continue breastfeeding.
• Is there blood
Is the child: slowly.
in the stool?
Lethargic or unconscious? • If child is two years or older and there is cholera
Restless and irritable? in your area, give antibiotic for cholera.

Look for sunken eyes.
Offer the child fluid. Is the child:
Not able to drink or drinking poorly?
Drinking eagerly, thirsty?
Pinch the skin of the abdomen.
Does it go back:
Very slowly (longer than 2
seconds)?
Slowly?
Two of the following signs:
For dehydration
• Restless irritable
• Sunken eyes
• Drinks eagerly, thirsty
• Skin pinch goes back slowly.
Classify
diarrhea Not enough signs to classify
as some or severe
dehydration
• Give fluid and food for some dehydration (Plan B).
If child also has a severe classification:
Some - Refer URGENTLY to hospital with mother
dehydration giving frequent sips of ORS on the way.
Advise the mother to continue breastfeeding.
• Advise mother when to return immediately.
• Follow-up in 2 days if not improving.
• Give fluid and food to treat diarrhea at home (Plan A).
No
• Advise mother when to return immediately.
dehydration
• Follow-up in 2 days if not improving.

• Dehydration present Severe • Treat dehydration before referral unless the child has
persistent another severe classification.
diarrhea • Refer to hospital.
And if diarrhea
14 days or more • No dehydration • Advise the mother on feeding a child who has
PERSISTENT DIARRHEA.
Persistent
• Give multivitamin, mineral supplement for two weeks
diarrhea
• Advise mother when to return immediately
• Follow-up in 5 days.

• Blood in the stool • Treat for 5 days with an oral antibiotic

And if blood Dysentery recommended for Shigella.
in stool • Advise mother when to return immediately
• Follow-up in 5 days.

Figure 340-6 Integrated Management of Childhood Illnesses (IMCI) protocol for the recognition and management of diarrhea in developing
countries. ORS, Oral rehydration solution.
1872 Part XVIII ◆ The Digestive System

Persistent diarrhea
(diarrhea !14 days with malnutrition)

Assessment, resuscitation, and early stabilization

SUSPECTED Intravenous and/or oral rehydration (hypo-osmolar ORS)
SEVERE Treat electrolyte imbalance
DEHYDRATION Screen and treat associated systemic infections

Continued breastfeeding
Reduced lactose load by
• Milk-cereal (usually rice-based) diet or
• Replacement of milk with yogurt
Micronutrient supplementation (zinc, vitamin A, folate)

Recovery Continued or recurrent diarrhea

Poor weight gain

Follow-up for growth Reinvestigate for infections

Second-line dietary therapy (comminuted chicken or elemental diets)
Continued diarrhea and dehydration

Refer URGENTLY to Reinvestigate to exclude intractable diarrhea of infancy

hospital for IV or NG Intravenous hyperalimentation plus
treatment Slow or continuous enteral alimentation

DANGER SIGNS, COUGH

DIARRHEA

ASSESS AND CLASSIFY

Figure 340-7 Management of persistent diarrhea. IV, Intravenous; NG, nasogastric tube; ORS, oral rehydration solution.

should be avoided. The usual energy density of any diet used for the
therapy of diarrhea should be around 1 kcal/g, aiming to provide an
energy intake of a minimum of 100 kcal/kg/day and a protein intake
of 2-3 g/kg/day. In selected circumstances when adequate intake of
energy-dense food is problematic, the addition of amylase to the diet
through germination techniques can also be helpful.
With the exception of acute lactose intolerance in a small subgroup,
most children with diarrhea are able to tolerate milk and lactose-
containing diets. Withdrawal of milk and replacement with specialized
(and expensive) lactose-free formulations are unnecessary. Although
children with persistent diarrhea are not lactose intolerant, administra-
tion of a lactose load exceeding 5 g/kg/day may be associated with
higher purging rates and treatment failure. Alternative strategies for
reducing the lactose load while feeding malnourished children who
have prolonged diarrhea include addition of milk to cereals and
replacement of milk with fermented milk products such as yogurt.
Rarely, when dietary intolerance precludes the administration of
cow’s milk–based formulations or whole milk it may be necessary to
administer specialized milk-free diets such as a comminuted or blend-
erized chicken-based diet or an elemental formulation. Although
effective in some settings, the latter are unaffordable in most develop-
ing countries. In addition to rice-lentil formulations, the addition of
green banana or pectin to the diet has also been shown to be effective
in the treatment of persistent diarrhea. Figure 340-7 gives an
algorithm for managing children with prolonged diarrhea in develop-
ing countries.
Among children in low- and middle-income countries, where the
dual burden of diarrhea and malnutrition is greatest and where access
to proprietary formulas and specialized ingredients is limited, the use
of locally available age-appropriate foods should be promoted for the
majority of acute diarrhea cases. Lactose intolerance is an important
complication in some cases, but even among those children for whom
lactose avoidance may be necessary, nutritionally complete diets com-
prised of locally available ingredients can be used at least as effectively
as commercial preparations or specialized ingredients. These same
conclusions may also apply to the dietary management of children with
persistent diarrhea, but the evidence remains limited.
Zinc Supplementation
Zinc supplementation in children with diarrhea in developing coun-
tries leads to reduced duration and severity of diarrhea and could
potentially prevent a large proportion of cases from recurring. Zinc
administration for diarrhea management can significantly reduce all-
cause mortality by 46% and hospital admission by 23%. In addition to
improving diarrhea recovery rates, administration of zinc in commu-
nity settings leads to increased use of ORS and reduction in the inap-
propriate use of antimicrobials. All children older than 6 mo of age
with acute diarrhea in at-risk areas should receive oral zinc (20 mg/

day) in some form for 10-14 days during and continued after diarrhea.
The role of zinc in well nourished, zinc replete populations in devel-
oped countries is less certain.
Additional Therapies
The use of probiotic nonpathogenic bacteria for prevention and therapy
of diarrhea has been successful in some settings although the evidence
is inconclusive to recommend their use in all settings. In addition to
restoring beneficial intestinal flora, probiotics can enhance host protec-
tive immunity such as downregulation of proinflammatory cytokines
and upregulation of anti inflammatory cytokines. A variety of organ-
isms (Lactobacillus, Bifidobacterium) have a good safety record; therapy
has not been standardized and the most effective (and safe) organism
has not been identified. Saccharomyces boulardii is effective in
antibiotic-associated and in C. difficile diarrhea, and there is some
evidence that it might prevent diarrhea in daycare centers. Lactobacil-
lus rhamnosus GG is associated with reduced diarrheal duration and
severity, which reduction is more evident in cases of childhood rota-
virus diarrhea.
Antimotility agents (loperamide) are contraindicated in children
with dysentery and probably have no role in the management of acute
watery diarrhea in otherwise healthy children. Similarly, antiemetic
agents, such as the phenothiazines, are of little value and are associated
with potentially serious side effects (lethargy, dystonia, malignant
hyperpyrexia). Nonetheless, ondansetron is an effective and less-toxic
antiemetic agent and as indicated previously, is a useful adjunct to the
treatment of vomiting in ambulatory settings with reduced risk of
intravenous fluid requirements and hospitalization. Because persistent
vomiting can limit oral rehydration therapy, a single sublingual dose
of an oral dissolvable tablet of ondansetron (4 mg 4-11 yr and 8 mg
for children older than 11 yr [generally 0.2 mg/kg]) may be given.
However, most children do not require specific antiemetic therapy;
careful oral rehydration therapy is usually sufficient.
Racecadotril, an enkephalins inhibitor, has inconsistently been
shown to reduce stool output in patients with diarrhea. Experience
with this drug in children is limited, and for the average child with
acute diarrhea it may be unnecessary.
Antibiotic Therapy
Timely antibiotic therapy in select cases of diarrhea related to bacterial
infections can reduce the duration and severity of illness and prevent
complications (Table 340-12). Although these agents are important to
use in specific cases, their widespread and indiscriminate use leads to
the development of antimicrobial resistance. Nitazoxanide, an antiin-
fective agent, is effective in the treatment of a wide variety of patho-
gens, including C. parvum, G. lamblia, E. histolytica, Blastocystis
hominis, C. difficile, and rotavirus.
PREVENTION
In many developed countries, diarrhea caused by pathogens such as
C. botulinum, E. coli O157:H7, Salmonella, Shigella, V. cholerae,
Cryptosporidium, and Cyclospora is a notifiable disease and, thus,
contact tracing and source identification is important in preventing
outbreaks.
Many developing countries struggle with huge disease burdens of
diarrhea where a wider approach to diarrhea prevention may be
required. Preventive strategies may be of relevance to both developed
and developing countries.
Promotion of Exclusive Breastfeeding
Exclusive breastfeeding (administration of no other fluids or foods for
the 1st 6 mo of life) is not common, especially in many developed
countries. Exclusive breastfeeding protects very young infants from
diarrheal disease through the promotion of passive immunity and
through reduction in the intake of potentially contaminated food
and water. Breast milk contains all the nutrients needed in early
infancy, and when continued during diarrhea, it also diminishes the
adverse impact on nutritional status. Exclusive breastfeeding for the
1st 6 mo of life is widely regarded as one of the most effective
Chapter 340 ◆ Acute Gastroenteritis in Children 1873
interventions to reduce the risk of premature childhood mortality and
the potential to prevent 12% of all deaths of children younger than
5 yr of age.
Improved Complementary Feeding Practices
There is a strong inverse association between appropriate, safe comple-
mentary feeding and mortality in children age 6-11 mo; malnutrition
is an independent risk for the frequency and severity of diarrheal
illness. Complementary foods should be introduced at 6 mo of age, and
breastfeeding should continue for up to 2 yr. Complementary foods in
developing countries are generally poor in quality and often are heavily
contaminated, thus predisposing to diarrhea. Contamination of com-
plementary foods can be potentially reduced through caregivers’ edu-
cation and improving home food storage. Improved vitamin A status
has been shown to reduce the frequency of severe diarrhea. Vitamin A
supplementation reduces all-cause childhood mortality by 25% (95%
confidence interval [CI], 12-36%) and diarrhea-specific mortality by
30% (95% CI, 14-42%).
Rotavirus Immunization
Most infants acquire rotavirus diarrhea early in life; an effective rota-
virus vaccine would have a major effect on reducing diarrhea mortality
in developing countries. In 1998, a quadrivalent Rhesus rotavirus-
derived vaccine was licensed in the United States but subsequently
withdrawn because of an increased risk of intussusception. Subsequent
development and testing of newer rotavirus vaccines have led to their
introduction in most developed countries and approval by the WHO
in 2009 for widespread use in developing countries. It is now clear
that the introduction of these vaccines is associated with a significant
reduction in severe diarrhea and associated mortality.
The institution of large-scale rotavirus vaccination programs has led
to major reduction in the burden of disease and associated mortality.
In an evaluation of large-scale rotavirus vaccine introduction, coverage
rate of 74% was achieved in infants younger than 12 mo of age, with
41% reduction (95% CI, 36-47%) in diarrhea-related mortality. In an
evaluation of the vaccine in Africa, overall protective efficacy against
rotavirus gastroenteritis ranged from 49-61%, with 30% protective effi-
cacy against all-cause severe gastroenteritis in infancy. Vaccine (live
virus) associated rotavirus infection has been reported in children with
severe combined immunodeficiency disease, but the vaccine has been
shown to be safe in HIV-infected populations.
Other vaccines that could potentially reduce the burden of severe
diarrhea and mortality in young children are vaccines against cholera,
Shigella, and ETEC. Preventive use of cholera vaccines in endemic
countries can reduce the risk of developing cholera by 52% (95% CI,
36-65%).
Improved Water and Sanitary Facilities and
Promotion of Personal and Domestic Hygiene
Much of the reduction in diarrhea prevalence in the developed world
is the result of improvement in standards of hygiene, sanitation, and
water supply. Strikingly, an estimated 88% of all diarrheal deaths
worldwide can be attributed to unsafe water, inadequate sanitation, and
poor hygiene. Improving water quality can reduce the risk of diarrhea
by 17%, whereas hand washing with soap and safe excreta disposal
reduce the risk of diarrhea by 48% and 36%, respectively. Behavioral
change strategies through promotion of handwashing indicate that
handwashing promotion and access to soap reduces the burden of
diarrhea in developing countries.
Improved Case Management of Diarrhea
Improved management of diarrhea through prompt identification and
appropriate therapy significantly reduces diarrhea duration, its nutri-
tional penalty, and risk of death in childhood. Improved management
of acute diarrhea is a key factor in reducing the burden of prolonged
episodes and persistent diarrhea. The WHO/UNICEF recommenda-
tions to use low-osmolality ORS and zinc supplementation for the
management of diarrhea, coupled with selective and appropriate use
of antibiotics, have the potential to reduce the number of diarrheal
1874 Part XVIII ◆ The Digestive System

Table 340-12 Antibiotic Therapy for Infectious Diarrhea

ORGANISM
Shigella (severe dysentery
and EIEC dysentery)
EPEC, ETEC, EIEC
Salmonella
Aeromonas/Plesiomonas
Yersinia spp.
Campylobacter jejuni
Clostridium difficile
Entamoeba histolytica
Giardia lamblia
Cryptosporidium spp.
Isospora spp.
Cyclospora spp.
Blastocystis hominis
EIEC, Enteroinvasive Escherichia coli; EPEC, enteropathogenic E. coli; ETEC, enterotoxigenic E. coli; GI, gastrointestinal; max, maximum; SMX, sulfamethoxazole;
TMP, trimethoprim.
DRUG OF CHOICE
Ciprofloxacin, ampicillin, ceftriaxone, azithromycin, or
TMP-SMX
Most strains are resistant to several antibiotics
TMP-SMX or ciprofloxacin
No antibiotics for uncomplicated gastroenteritis in
normal hosts caused by nontyphoidal species
Treatment indicated in infants younger than 3 mo,
and patients with malignancy, chronic GI disease,
severe colitis hemoglobinopathies, or HIV infection,
and other immunocompromised patients
Most strains are resistant to multiple antibiotics
TMP-SMX
Ciprofloxacin
Antibiotics are not usually required for diarrhea
Deferoxamine therapy should be withheld for severe
infections or associated bacteremia
Treat sepsis as for immunocompromised hosts, using
combination therapy with parenteral doxycycline,
aminoglycoside, TMP-SMX, or fluoroquinolone
Erythromycin or azithromycin
Metronidazole (first line)
Discontinue initiating antibiotic
Vancomycin (second line)
Metronidazole followed by iodoquinol or
paromomycin
Furazolidone or metronidazole or albendazole or
quinacrine
Nitazoxanide PO treatment may not be needed in
normal hosts
In immunocompromised, PO immunoglobulin +
aggressively treat HIV, etc.
TMP-SMX
TMP/SMX
Metronidazole or iodoquinol
DOSAGE AND DURATION OF TREATMENT
Ceftriaxone 50-100 mg/kg/day IV or IM, qd or bid × 7 days
Ciprofloxacin 20-30 mg/kg/day PO bid × 7-10 days
Ampicillin PO, IV 50-100 mg/kg/day qid × 7 days
TMP 10 mg/kg/day and SMX 50 mg/kg/day bid × 5 days
Ciprofloxacin PO 20-30 mg/kg/day qid for 5-10 days
See treatment of Shigella
TMP 10 mg/kg/day and SMX 50 mg/kg/day bid for 5 days
Ciprofloxacin PO 20-30 mg/kg/day divided bid × 7-10 days
Erythromycin PO 50 mg/kg/day divided tid × 5 days
Azithromycin PO 5-10 mg/kg/day qid × 5 days
PO 30 mg/kg/day divided qid × 5 days; max 2 g
PO 40 mg/kg/day qid × 7 days, max 125 mg
Metronidazole PO 30-40 mg/kg/day tid × 7-10 days
Iodoquinol PO 30-40 mg/kg/day tid × 20 days
Paromomycin PO 25-35 mg/kg/day tid × 7 days
Furazolidone PO 25 mg/kg/day qid × 5-7 days
Metronidazole PO 30-40 mg/kg/day tid × 7 days
Albendazole PO 200 mg bid × 10 days
Children 1-3 yr: 100 mg bid × 3 days
Children 4-11 yr: 200 mg bid
PO TMP 5 mg/kg/day and SMX 25 mg/kg/day, bid × 7-10
days
PO TMP 5 mg/kg/day and SMX 25 mg/kg/day bid × 7
days
Metronidazole PO 30-40 mg/kg/day tid × 7-10 days
Iodoquinol PO 40 mg/kg/day tid × 20 days

deaths among children through Community Case Management and
Integrated Management of Childhood Illnesses.
Community-based interventions to diagnose and treat childhood
diarrhea through community health workers leads to a significant rise
in care seeking behaviors for diarrhea and are associated with signifi-
cantly increased use of ORS and zinc at household level as well as
reduction in the unnecessary use of antibiotics for diarrhea by 75%.
Bibliography is available at Expert Consult.
340.1 Traveler’s Diarrhea
Zulfiqar Ahmed Bhutta
Traveler’s diarrhea is a common complication of visitors to developing
countries and is caused by a variety of pathogens, in part depending
on the season and the region visited (see Table 340-12). Traveler’s diar-
rhea has a high attack rate among travelers from higher-income coun-
tries visiting, during the summer, countries in a warmer climate that
have a high prevalence of indigenous infectious diarrhea. Traveler’s
diarrhea can manifest with watery diarrhea or as dysentery. Without
treatment, 90% will have resolved within a week and 98% within a
month of onset. Some individuals develop more severe diarrhea and
become dehydrated or unwell and may experience systemic complica-
tions that warrant further attention. Most cases of traveler’s diarrhea
resolve spontaneously and a simple stool culture may be the only
investigation required. For those individuals with ongoing symptoms,
further tests should be requested depending on the history and clinical
presentation.
TREATMENT
Traveler’s diarrhea is often self-limiting but requires particular atten-
tion to avoid dehydration. For infants and children, rehydration, as

discussed in Chapter 340, is appropriate, followed by a standard diet.
Adolescents and adults should increase their intake of electrolyte-rich
fluids. Kaolin-pectin, anticholinergic agents, Lactobacillus, and bismuth
salicylate have not been effective therapies. Loperamide, an antimotil-
ity and antisecretory agent, reduces the number of stools in older
children with watery diarrhea and improves outcomes when used in
combination with antibiotics in traveler’s diarrhea. However, loper-
amide should be used with great caution or not at all in febrile or toxic
patients with dysentery and in those with bloody diarrhea.
Antibiotics, with or without loperamide, can also reduce the number
of unformed stools. Short-duration (3 days) therapy with fluoroquino-
lones, trimethoprim-sulfamethoxazole, azithromycin, or rifaximin is
effective; the choice of antibiotic depends on the age of the patient, the
potential organism, and the organism’s local resistance patterns.
However, antibiotics often have a negative risk-benefit ratio when
weighing potential side effects vs treatment need for a short-lasting and
self-limiting disease such as traveler’s diarrhea. Azithromycin has
several advantages over other antibiotics. It is taken only once
(1,000 mg), the rate of antimicrobial resistance is low, and it has a good
safety profile. Furthermore, in contrast to rifaximin, it can be used in
severe cases of diarrhea with fever or bloody stools and can even be
administered in children. Optionally, azithromycin can be combined
with antimotility medications such as loperamide. Travelers should be
reminded that diarrhea can be a symptom of other severe diseases,
such as malaria. Therefore, if diarrhea persists or additional symptoms
such as fever occur, travelers should seek medical advice. For up-to-
date information on local pathogens and resistant patterns, see
www.cdc.gov/travel.
PREVENTION
Travelers should drink bottled or canned beverages or boiled water.
They should avoid ice, salads, and fruit they did not peel them-
selves. Food should be eaten hot, if possible. Raw or poorly cooked
seafood is a risk, as is eating in a restaurant rather than a private
home. Swimming pools and other recreational water sites can also be
contaminated.
Chemoprophylaxis is not routinely recommended for previously
healthy children or adults. Nonetheless, travelers should bring azithro-
mycin (younger than 16 yr of age) or ciprofloxacin (older than 16 yr
of age) and begin antimicrobial therapy if diarrhea develops.
Bibliography is available at Expert Consult.
Chapter 341
Chronic Diarrhea
Alfredo Guarino, David Branski, and
Harland S. Winter
DEFINITION AND EPIDEMIOLOGY
Chronic diarrhea is defined as stool volume of more than 10 g/kg/day
in toddlers/infants and greater than 200 g/day in older children that
lasts for 14 days or more. In practice, this usually means having loose
or watery stools more than 3 times a day. Awakening at night to pass
stool is often a sign of an organic cause of diarrhea. The epidemiology
has 2 distinct patterns. In developing countries, chronic diarrhea is, in
many cases, the result of an intestinal infection that persists longer than
expected. This syndrome is often defined as protracted diarrhea, but
there is no clear distinction between protracted and chronic diarrhea.
In countries with higher socioeconomic conditions, chronic diarrhea
is less frequent and the etiology often varies with age. The outcome of
diarrhea depends on the cause and ranges from benign, self-limited
Chapter 341 ◆ Chronic Diarrhea 1875
Osmotic Secretory
Water
Water
Stool volume: Moderately increased Very large
Response to fasting: Diarrhea stops Diarrhea continues
Stool osmolality: Normal to increased Normal
Ion gap: ! 100 mOsm/kg " 100 mOsm/kg
Figure 341-1 Pathways of osmotic and secretory diarrhea. Osmotic
diarrhea is caused by functional or structural damage of intestinal epi-
thelium. Nonabsorbed osmotically active solutes drive water into the
lumen. Stool osmolality and ion gap are generally increased. Diarrhea
stops in children when not eating. In secretory diarrhea, ions are
actively pumped into the intestine by the action of exogenous and
endogenous secretagogues. Usually there is no intestinal damage.
Osmolality and ion gap are within normal levels. Large volumes of
stools are lost independent of food ingestion.
conditions, such as toddler’s diarrhea, to severe congenital diseases,
such as microvillus inclusion disease, that may lead to progressive
intestinal failure.
PATHOPHYSIOLOGY
The mechanisms of diarrhea are generally divided into secretory and
osmotic, but often diarrhea is a combination of both mechanisms. In
addition, inflammation and motility disorders may contribute to diar-
rhea. Secretory diarrhea is usually associated with large volumes of
watery stools and persists when oral feeding is withdrawn. Osmotic
diarrhea is dependent on oral feeding, and stool volumes are usually
not as massive as in secretory diarrhea (Fig. 341-1).
Secretory diarrhea is characterized by active electrolyte and water
fluxes toward the intestinal lumen, resulting from either the inhibition
of neutral NaCl absorption in villous enterocytes or an increase in
electrogenic chloride secretion in secretory crypt cells as a result of the
opening of the cystic fibrosis transmembrane regulator (CFTR) chlo-
ride channel or both. The result is more secretion from the crypts than
absorption in the villous that persists during fasting. The other com-
ponents of the enterocyte ion secretory machinery are (1) the Na-K
2Cl cotransporter for the electroneutral chloride entrance into the
enterocyte; (2) the Na-K pump, which decreases the intracellular Na+
concentration, determining the driving gradient for further Na+ influx;
and (3) the K+ selective channel, that enables K+, once it has entered
the cell together with Na+, to return to the extracellular fluid.
Electrogenic secretion is induced by an increase of intracellular con-
centration of cyclic adenosine monophosphate, cyclic guanosine
monophosphate, or calcium in response to microbial enterotoxins, or
to endogenous endocrine or nonendocrine moieties, including inflam-
matory cytokines. Another mechanism of secretory diarrhea is the
inhibition of the electroneutral NaCl-coupled pathway that involves
the Na+/H+ and the Cl−/HCO3− exchangers. Defects in the genes of the
Na+/H+ and the Cl−/HCO3− exchangers are responsible for congenital
Na+ and Cl− diarrhea, respectively.
Osmotic diarrhea is caused by nonabsorbed nutrients in the intes-
tinal lumen as a result of 1 or more of the following mechanisms: (1)
intestinal damage (e.g., enteric infection); (2) reduced absorptive
surface area (e.g., active celiac disease); (3) defective digestive enzyme
or nutrient carrier (e.g., lactase deficiency); (4) decreased intestinal
transit time (e.g., functional diarrhea); and (5) nutrient overload,
exceeding the digestive capacity (e.g., overfeeding, sorbitol in fruit
juice). Whatever the mechanism, the osmotic force generated by non-
absorbed solutes drives water into the intestinal lumen. A very common
1088 Part XV ◆ Allergic Disorders
or a month. Because allergen extracts gradually lose potency, the first
dose from a fresh replacement vial of maintenance allergen extract is
reduced by 25-75% and is then increased in increments weekly until
the usual maintenance dose is reached. The recommended length for
a course of allergen immunotherapy is 3-5 yr. Insect VIT may be con-
tinued indefinitely in patients with a history of life-threatening ana-
phylaxis. Patients who have not shown improvement after 1 year of
receiving maintenance doses of an appropriate allergen extract are
unlikely to benefit, and allergen immunotherapy should be discontin-
ued. Most patients enjoy a sustained improvement after allergen
immunotherapy whereas others experience a gradual return of symp-
toms. Those who experience a relapse would be expected to respond
upon resuming immunotherapy.
Rush immunotherapy is the administration of multiple injections
either in a single day or over several days in an attempt to reach main-
tenance dose more rapidly. The risk of adverse reactions, including
systemic reactions, is higher than with traditional allergen immuno-
therapy schedules. Patients to undergo rush immunotherapy are often
pretreated with antihistamines and corticosteroids. Children are at
even greater risk for adverse reactions with rush immunotherapy; thus
the benefits and risks should be fully considered. Preadministration of
omalizumab (anti-IgE therapy) reduces the incidence of systemic reac-
tions associated with the use of this form of immunotherapy.
Although allergen immunotherapy is regarded as safe, the potential
for anaphylaxis always exists when patients are injected with extracts
containing allergens to which they are sensitized. Allergen immuno-
therapy should be offered in only medical settings where a physician
with access to emergency equipment and medications required for the
treatment of anaphylaxis is available (see Chapter 149). Allergen injec-
tions should never be given at home or by untrained personnel. The
patient should remain in the office for 30 min after the injection
because most reactions to allergen immunotherapy begin within this
time frame. Fatal anaphylaxis triggered by allergen immunotherapy,
although rare, is estimated to occur at an incidence of 1 per 2 million
injections. The risk of an adverse reaction is increased by dosage errors
and the use of rush immunotherapy schedules. Particular caution is
warranted when injections from a new vial are given. Patients with
exquisite sensitivity or unstable asthma and those experiencing exac-
erbations of allergic rhinitis or asthma are also at increased risk for
adverse reactions to allergen immunotherapy. Precautions to reduce
significant adverse reactions include using standardized extracts,
having extract vials personalized for each patient, allowing only trained
personnel to administer injections, paying careful attention to detail
when giving injections, ensuring beforehand that the patient is medi-
cally stable, having appropriate medications and equipment available,
and requiring the patient to remain in the office for 30 min after each
injection. Checking peak flow or spirometry before an injection is
advisable for some asthmatic patients. It is also prudent to advise
patients to carry self-injectable epinephrine for 24 hr following each
injection. While uncommon, delayed systemic reactions have been
reported following immunotherapy injections.
Other approaches to immunotherapy are under investigation; they
include chemical or genetic manipulation of the allergen and linking
of the principle allergenic moiety of a relevant allergen to a highly
active adjuvant, such as an immunostimulatory sequence mimicking
patterns of bacterial DNA.
Local nasal immunotherapy is administered by having the patient
spray allergen solutions into the nose at scheduled intervals. Although
symptom amelioration has been noted, a lack of a significant sys-
temic immunologic response has decreased interest in pursuing
this form of therapy. SLIT involves the sublingual administration of
high-dose allergen, which is then swallowed. SLIT is now FDA-
approved for a limited number of pollens, and its use is expected to
increase given its favorable safety profile and convenience of
administration.
Efficacy
The positive impact of allergen immunotherapy on seasonal or peren-
nial allergic rhinitis or rhinoconjunctivitis is well documented. In
regard to the treatment of allergic rhinitis, birch, mountain cedar,
grass, ragweed, and Cladosporium are allergens for which allergen
immunotherapy has been effective. Effectiveness of allergen immuno-
therapy with other allergens commonly used for the treatment of aller-
gic rhinitis is inconclusive. Most of the controlled trials examining the
effects of allergen immunotherapy on seasonal or perennial allergic
asthma also report favorable results. A meta-analysis of 20 trials exam-
ining the effects of allergen immunotherapy on allergic asthma revealed
a significant increase in the odds for improvement after treatment
along with fewer symptoms, improved pulmonary functions, less need
for medication, and a reduction in bronchial hyperreactivity. The most
convincing data for the benefit of allergen immunotherapy in the treat-
ment of allergic asthma are available for birch, mountain cedar, grass,
ragweed, and dust mite with less conclusive but suggestive data avail-
able for Cladosporium, Alternaria, and cat allergens. Studies examining
the effects of allergen immunotherapy in the treatment of patients with
allergic rhinitis and allergic asthma have documented increases in
circulating allergen-specific IgG and decreases in allergen-specific IgE
after treatment. Reductions in sensitivity to administered allergens
have been demonstrated in nasal and bronchial challenges. These
studies have often shown that the late-phase response after allergen
challenge is ablated or significantly reduced. The protective benefit as
well as the safety of VIT in patients with sensitivity to Hymenoptera
venoms has also been well documented in several large studies. The
efficacy of allergen immunotherapy for the treatment of urticaria and
latex allergy has not been documented. Dust mite allergen immuno-
therapy may be helpful in patients with atopic dermatitis. Studies using
OIT, involving the oral administration of gradually increasing doses of
a food allergen under close medical observation followed by a pro-
longed maintenance phase of daily fixed-dose food allergen adminis-
tration at home, has been shown to desensitize patients but has not yet
proven to induce tolerance. Although still under investigation, OIT
and perhaps SLIT are promising therapeutic approaches to the treat-
ment of food allergy in the future.
Bibliography is available at Expert Consult.
Chapter 143
Allergic Rhinitis
Henry Milgrom and Scott H. Sicherer
Allergic rhinitis (AR) is an inflammatory disorder of the nasal mucosa
marked by nasal congestion, rhinorrhea, and itching, often accompa-
nied by sneezing and conjunctival inflammation. Its recognition as
a major chronic respiratory disease of children rests largely on its
high prevalence, detrimental effects on quality of life and school per-
formance, and comorbidities. Children with AR often have related
conjunctivitis, sinusitis, otitis media, serous otitis, hypertrophic tonsils
and adenoids, and eczema. Childhood AR is associated with a 3-fold
increase in risk for asthma at an older age. Over the past 50 yr an
upsurge in AR has been observed throughout the world, particularly
in areas where its prevalence previously had been low. In prosperous
societies, 20-40% of children suffer from AR. The symptoms may
appear in infancy; with the diagnosis generally established by the time
the child reaches age 6 yr. The prevalence peaks late in childhood.
Risk factors include family history of atopy and serum immuno-
globulin (Ig) E higher than 100 IU/mL before age 6 yr. Early life
exposures and/or their absence have a profound influence on the
development of the allergic phenotype. The risk increases in children
whose mothers smoke heavily, even before delivery and especially
before the infants are 1 yr old, and those with heavy exposure to indoor
allergens. A critical period exists early in infancy when the genetically
susceptible individual is at greatest risk of sensitization. Delivery by

cesarean section is associated with AR and atopy in children with a
parental history of asthma or allergies. This association may be
explained by the lack of exposure to maternal vaginal/fecal flora during
delivery. Children between 2 and 3 yr old who have elevated anticock-
roach and antimouse IgE are at increased risk of wheezing, AR, and
atopic dermatitis. The occurrence of 3 or more episodes of rhinorrhea
in the first year of life is associated with AR at age 7 yr. Intriguingly,
the exposure to dogs, cats, and endotoxin early in childhood protects
against the development of atopy. Prolonged breastfeeding is beneficial,
but it does not need to be exclusive There is also a decreased risk of
asthma, AR, and atopic sensitization with early introduction to wheat,
rye, oats, barley, fish and eggs.
ETIOLOGY AND CLASSIFICATION
Two factors necessary for expression of AR are sensitivity to an allergen
and the presence of the allergen in the environment. AR classification
as seasonal or perennial is giving way to the designations intermittent
and persistent. The 2 sets of terms are based on different suppositions,
but inhalant allergens are the main cause of all forms of AR irrespective
of terminology. AR may also be categorized as mild-intermittent,
moderate-severe intermittent, mild-persistent, and moderate-
severe persistent (Fig. 143-1). The symptoms of intermittent AR occur
on <4 days per week or for <4 consecutive weeks. In persistent AR
symptoms occur on >4 days per week and/or for >4 consecutive weeks.
The symptoms are considered mild when they are not troublesome, the
sleep is normal, there is no impairment in daily activities, and no
incapacity at work or school. Severe symptoms result in sleep distur-
bance, and impairment in daily activities and school (Fig. 143-1).
In temperate climates, airborne pollen responsible for exacerbation
of intermittent AR appear in distinct phases: trees pollinate in the
spring, grasses in the early summer, and weeds in the late summer. In
temperate climates, mold spores persist outdoors only in the summer,
but in warm climates throughout the year. Symptoms of intermittent
AR typically cease with the appearance of frost. Knowledge of the time
of occurrence of symptoms, of the regional patterns of pollination and
mold sporulation, and of the patient’s specific IgE is necessary for the
recognition of the cause of intermittent AR. Persistent AR is most often
associated with the indoor allergens: house dust mites, animal danders,
mice, and cockroaches. Cat and dog allergies are of major importance
in the United States. The allergens from saliva and sebaceous secretions
may remain airborne for a prolonged time. The ubiquitous major cat
allergen, Fel d 1, may be carried on cat owners’ clothing into such “cat-
free” settings as schools and hospitals.
Intermittent symptoms Persistent symptoms
• !4 days/week • "4 days a week
• or !4 weeks at a time • and/or " 4 weeks at a time
Mild Moderate-to-severe
• Normal sleep One or more items
• Normal daily activities
• Abnormal sleep
• Normal work and school • Impairment of daily activities,
• No troublesome symptoms sport and leisure
• Difficulties caused at school
or work
• Troublesome symptoms
Figure 143-1 ARIA classification of allergic rhinitis. Every box can be
subclassified further into seasonal or perennial on the basis of timing
of symptoms or when causative and allergen therapeutic factors are
considered. For example, a UK patient with grass pollen allergy might
have moderate-to-severe persistent seasonal rhinitis in June and July
and be suitable for specific allergen immunotherapy. (From Scadding
GK, Durham SR, Mirakian R, et al: BASCI guidelines for the manage-
ment of allergic and non-allergic rhinitis. Clin Exp Allergy 38:19-42,
2008 [Fig 2, p. 22].)
Chapter 143 ◆ Allergic Rhinitis 1089
PATHOGENESIS
The exposure of an atopic host to an allergen leads to specific IgE
production. The clinical reactions on reexposure to the allergen have
been designated as early-phase and late-phase allergic responses.
Bridging of the IgE molecules on the surface of mast cells by allergen
initiates early-phase allergic response, characterized by degranulation
of mast cells and release of preformed and newly generated inflamma-
tory mediators including histamine, prostaglandin 2, and the cysteinyl
leukotrienes. Late-phase allergic response appears 4-8 hr following
allergen exposure. Inflammatory cells, including basophils, eosino-
phils, neutrophils, mast cells, and mononuclear cells, infiltrate the nasal
mucosa. Eosinophils release proinflammatory mediators, including
cysteinyl leukotrienes, cationic proteins, eosinophil peroxidase, and
major basic protein, and serve as a source of interleukin (IL)-3, IL-5,
granulocyte-macrophage colony-stimulating factor, and IL-13.
Repeated intranasal introduction of allergens causes “priming”—a
more brisk response even with a lesser provocation. Over the course
of an allergy season a multifold increase in submucosal mast cells takes
place. These cells, once thought to have a role exclusively in the early-
phase allergic response, have an important function in sustaining
chronic allergic disease. Allergens, autoantigens, and components of
superimposed infectious agents activate the immune system.
CLINICAL MANIFESTATIONS
Symptoms of AR may be ignored or mistakenly attributed to a respira-
tory infection. Older children blow their noses, but younger children
tend to sniff and snort. Nasal itching brings on grimacing, twitching,
and picking of the nose that may result in epistaxis. Children with AR
often perform the allergic salute, an upward rubbing of the nose with
an open palm or extended index finger. This maneuver relieves itching
and briefly unblocks the nasal airway. It also gives rise to the nasal
crease, a horizontal skin fold over the bridge of the nose. The diagnosis
of AR is based on symptoms in the absence of an upper respiratory
tract infection and structural abnormalities. Typical complaints include
intermittent nasal congestion, itching, sneezing, clear rhinorrhea, and
conjunctival irritation. Symptoms increase with greater exposure to the
responsible allergen. The patients may lose their sense of smell and
taste. Some experience headaches, wheezing, and coughing. Nasal con-
gestion is often more severe at night, causing mouth breathing and
snoring, interfering with sleep, and arousing irritability.
Signs on physical exam include abnormalities of facial development,
dental malocclusion, and the “allergic gape” or continuous open-
mouth breathing, chapped lips, “allergic shiners” (dark circles under
the eyes), and the transverse nasal crease. Conjunctival edema, itching,
tearing, and hyperemia are frequent findings. A nasal exam performed
with a source of light and a speculum may reveal clear nasal secretions;
edematous, boggy, and bluish mucus membranes with little or no
erythema; and swollen turbinates that may block the nasal airway. It
may be necessary to use a topical decongestant to perform an adequate
examination. Thick, purulent nasal secretions indicate the presence of
infection.
DIFFERENTIAL DIAGNOSIS
Evaluation of AR calls for a thorough history, including details of the
patient’s environment and diet and family history of allergic conditions
such as eczema, asthma, and AR, physical examination, and laboratory
evaluation. The history and laboratory findings provide clues to the
provoking factors. Symptoms that include sneezing, rhinorrhea, nasal
itching, and congestion and the laboratory findings of elevated IgE,
specific IgE antibodies, and positive allergy skin test results typify AR.
Intermittent AR differs from persistent AR by history and skin test
results. Nonallergic rhinitides cause sporadic symptoms. Their causes
are often unknown. Nonallergic inflammatory rhinitis with eosino-
phils imitates AR in presentation and response to treatment, but
without elevated IgE antibodies. Vasomotor rhinitis is characterized by
excessive responsiveness of the nasal mucosa to physical stimuli. Other
nonallergic conditions, such as infectious rhinitis; structural problems,
including nasal polyps and septal deviation; rhinitis medicamentosa
(caused by the overuse of topical vasoconstrictors); hormonal rhinitis
1090 Part XV ◆ Allergic Disorders

asthma (asthma, sinusitis with nasal polyposis, and aspirin sensitivity)

Table 143-1 Causes of Nonallergic Rhinitis often responds poorly to therapy. Patients who undergo repeated
Structural/mechanical factors: endoscopic surgery derive diminishing benefit with each successive
• Deviated septum/septal wall anomalies procedure.
• Hypertrophic turbinates Rhinitis that coexists with asthma may be taken too lightly or com-
• Adenoidal hypertrophy pletely overlooked. Up to 78% of patients with asthma have AR, and
• Foreign bodies 38% of patients with AR have asthma. Aggravation of AR coincides
Nasal tumors: with exacerbation of asthma, and treatment of nasal inflammation
• Benign reduces bronchospasm, asthma-related emergency department visits,
• Malignant and hospitalizations. Postnasal drip associated with AR commonly
• Choanal atresia
causes persistent or recurrent cough. Eustachian tube obstruction and
Infectious:
• Acute middle ear effusion are frequent complications. Chronic allergic
• Chronic inflammation causes hypertrophy of adenoids and tonsils that may be
Inflammatory/immunologic: associated with eustachian tube obstruction, serous effusion, otitis
• Granulomatosis with polyangiitis media, and obstructive sleep apnea. AR is linked to snoring in children.
• Sarcoidosis The association between rhinitis and sleep abnormalities and subse-
• Midline granuloma quent daytime fatigue is well documented.
• Systemic lupus erythematosus The Pediatric Rhinoconjunctivitis Quality of Life Questionnaire
• Sjögren syndrome (PRQLQ) is suitable for children 6-12 yr old, and the Adolescent Rhi-
• Nasal polyposis
noconjunctivitis Quality of Life Questionnaire (ARQLQ) is appropri-
Physiologic:
• Ciliary dyskinesia syndrome ate for patients 12-17 yr of age. Children with rhinitis have anxiety and
• Atrophic rhinitis physical, social, and emotional issues that affect learning and the ability
Hormonally induced: to integrate with peers. The disorder contributes to headaches and
• Hypothyroidism fatigue, limits daily activities, and interferes with sleep. There is evi-
• Pregnancy dence of impaired cognitive functioning and learning that may be
• Oral contraceptives exacerbated by the adverse effects of sedating medications. Rhinitis is
• Menstrual cycle an important cause of lost school attendance, resulting in more than 2
• Exercise million days of absence in the United States annually.
• Atrophic
Drug induced:
• Rhinitis medicamentosa LABORATORY FINDINGS
• Oral contraceptives Epicutaneous skin tests provide the best method for detection of
• Antihypertensive therapy allergen-specific IgE (positive predictive value of 48.7% for the epide-
• Aspirin miologic diagnosis of AR). They are inexpensive and sensitive, and the
• Nonsteroidal antiinflammatory drugs risks and discomfort are minimal. Responses to seasonal respiratory
Reflex induced: allergens are rare before 2 seasons of exposure, and children <1 yr
• Gustatory rhinitis seldom display positive skin test responses to these allergens. To avoid
• Chemical or irritant induced false-negative results, montelukast should be withheld for 1 day, most
• Posture reflexes
sedating antihistamine preparations for 3-4 days, and nonsedating
• Nasal cycle
• Environmental factors: antihistamines for 5-7 days. Serum immunoassays for specific IgE to
• Odors allergens provide a suitable alternative (positive predictive value 43.5%)
• Temperature for patients with dermatographism or extensive dermatitis, those
• Weather/barometric pressure taking medications that interfere with mast cell degranulation, others
• Occupational at high risk for anaphylaxis, and some who cannot cooperate with the
• Nonallergic rhinitis with eosinophilia syndrome procedure. Presence of eosinophils in nasal smear supports the diag-
• Perennial nonallergic rhinitis (vasomotor rhinitis) nosis of AR, and of neutrophils infectious rhinitis. Eosinophilia and
• Emotional factors measurements of total serum IgE concentrations have relatively low
From Leung DYM, Sampson HA, Geha RS, et al: Pediatric allergy principles and sensitivity.
practice, St. Louis, 2003, Mosby, p. 290.
TREATMENT
Safe and effective prevention and/or relief of symptoms are the current
associated with pregnancy or hypothyroidism; neoplasms; vasculitides; goals of treatment. Specific measures to limit indoor allergen exposure
and granulomatous disorders may mimic AR (Table 143-1, Fig. 143-2). may reduce the risk of sensitization and symptoms of allergic respira-
Occupational risks for rhinitis include exposure to allergens (grain tory disease. Sealing the patient’s mattress, pillow, and covers in
dust, insects, latex, enzymes) and irritants (wood dust, paint, solvents, allergen-proof encasings reduces the exposure to mite allergen. Bed
smoke, cold air). linen and blankets should be washed every week in hot water (>54.4°C
[130°F]). The only effective measure for avoiding animal allergens in
COMPLICATIONS the home is the removal of the pet. Avoidance of pollen and outdoor
AR is frequently associated with complications and comorbid condi- molds can be accomplished by staying in a controlled environment.
tions. Children with AR experience frustration over their appearance. Air conditioning allows for keeping windows and doors closed, reduc-
Allergic conjunctivitis, characterized by itching, redness and swelling ing the pollen exposure. High-efficiency particulate air filters lower the
of the conjunctivae, has been reported in at least 20% of the popula- counts of airborne mold spores.
tion and in more the 70% of patients with AR, most frequently in older Oral antihistamines help reduce sneezing, rhinorrhea and ocular
children and young adults. The 2 conditions share pathophysiologic symptoms. Administered as needed they provide acceptable treatment
mechanisms and epidemiologic characteristics (see Chapter 147). for mild-intermittent disease. Antihistamines have been classified as
Chronic sinusitis is a common complication of AR, sometimes associ- first generation (relatively sedating) or second generation (relatively
ated with purulent infection, but most patients have negative bacterial nonsedating). Antihistamines usually are administered by mouth, but
cultures despite marked mucosal thickening, and sinus opacification. they are also available for topical ophthalmic and intranasal use. Both
The inflammatory process is characterized by marked eosinophilia. first- and second-generation antihistamines are available as nonpre-
Allergens, possibly fungal, are the inciting agents. The sinusitis of triad scription drugs. Second-generation antihistamines are preferred
 Chapter 143 ◆ Allergic Rhinitis 1091

Rhinitis

Positive skin-prick Negative skin-prick

test and/or nasal test and nasal
allergen challenge allergen challenge

Allergic Non-allergic

Occupational
(allergic and non-allergic)

Infective Non-infective

Acute rhinosinusitis Chronic rhinosinusitis

Exclude predisposing
causes
• Cystic fibrosis
• Primary ciliary dyskinesia
• Immunodeficiency
• Immunopathology
• Polyps

Non-allergic rhinitis Immunopathologic Structural abnormalities Hormonal Drug-induced Others

with eosinophilia findings
Consider aspirin, • Churg-Strauss syndrome
entopy (local nasal IgE) • Wegener granulomatosis
• Sarcoidosis
• Relapsing polychondritis
• Systematic lupus
erythematosus
• Deviated septum • Pregnancy • Oral contraceptive • Non-infective,
• Nasal valve dysfunction • Menstrual cycle • Rhinitis medicamentosa non-allergic rhinitis
• Nasal polyps • Puberty • Antihypertensives Neurogenic (gustatory,
• Foreign body • Hormone • Cocaine abuse emotional, cold-air
• Adenoidal hypertrophy replacement • Aspirin or NSAID induced)
• Choanal atresia therapy • Atrophic
• Cerebral fluid leak • Acromegaly • Gastro-esophageal
• Nasal or CNS tumors • Hypothyroidism reflux
• Idiopathic

Figure 143-2 Diagnostic algorithm for rhinitis. Nasal allergen challenge is a research procedure and is not undertaken routinely. Causes likely
to be seen in children are highlighted in italics. NSAID, nonsteroidal antiinflammatory drug. (From Greiner AN, Hellings PW, Rotiroti G, Scadding
GK: Allergic rhinitis. Lancet 378:2112-2120, 2011 [Fig. 3, p. 2116].)

because they cause less sedation. Preparations containing pseudo-
ephedrine, typically in combination with other agents, are used for
relief of nasal and sinus congestion and pressure and other symptoms
such as rhinorrhea, sneezing, lacrimation, itching eyes, oronasopha-
ryngeal itching, and cough. Pseudoephedrine is available without pre-
scription (generally in fixed combination with other agents such as
first-generation antihistamines: brompheniramine, chlorpheniramine,
triprolidine; second-generation antihistamines: desloratadine, fexofen-
adine, loratadine; antipyretics: acetaminophen, ibuprofen; antitussives:
guaifenesin, dextromethorphan; anticholinergic: methscopolamine).
Pseudoephedrine is an oral vasoconstrictor disfavored for causing irri-
tability and insomnia and for its association with infant mortality.
Because younger children (2-3 yr of age) are at increased risk of over-
dosage and toxicity, some manufacturers of oral nonprescription cough
and cold preparations have voluntarily revised their product labeling
to warn against the use of preparations containing pseudoephedrine
for children younger than 4 yr. Pseudoephedrine is misused as a start-
ing material for the synthesis of methamphetamine and methcathi-
none. Oral agents for treatment of AR are shown in Tables 143-2, 143-3,
and 143-4.
The anticholinergic nasal spray ipratropium bromide is effective for
the treatment of serous rhinorrhea (Table 143-5). Intranasal decon-
gestants (oxymetazoline and phenylephrine) should be used for less
than 5 days, not to be repeated more than once a month in order to
avoid rebound nasal congestion. Sodium cromoglycate (available as
nonprescription drug) is effective but requires frequent administra-
tion, q4h. Leukotriene-modifying agents have a modest effect on rhi-
norrhea and nasal blockage (see Chapter 144 for additional indications
and side effects). Nasal saline irrigation is a good adjunctive option
with all other treatments of AR. Patients with more persistent, severe
symptoms require intranasal corticosteroids, the most effective therapy
for AR, a treatment that may be beneficial also for concomitant aller-
gic conjunctivitis (Table 143-6). These agents reduce the symptoms of
AR with eosinophilic inflammation, but not those of rhinitis associ-
ated with neutrophils or free of inflammation. Beclomethasone, tri-
amcinolone, and flunisolide are absorbed from the gastrointestinal
tract, as well as from the respiratory tract; budesonide, fluticasone,
mometasone, and ciclesonide offer greater topical activity with lower
systemic exposure. More severely affected patients may benefit from
simultaneous treatment with oral antihistamines and intranasal
corticosteroids.
Allergy immunotherapy is an effective treatment for AR and allergic
conjunctivitis. In addition to reducing symptoms, it may change the
course of allergic disease and induce allergen-specific immune toler-
ance. Immunotherapy administered by subcutaneous injection should
be considered for children in whom IgE-mediated allergic symptoms
cannot be adequately controlled by avoidance and medication, espe-
cially in the presence of comorbid conditions. Sublingual immuno-
therapy has been used successfully in Europe and South America.
Sublingual immunotherapy is considered investigational in the United
States, and there are no extracts for sublingual administration licensed
by the FDA. Omalizumab (anti-IgE antibody) given subcutaneously
has a dose-dependent effect on seasonal AR; its role compared with
standard therapy has yet to be determined.
Typically, treatment of AR with oral antihistamines and inhaled
corticosteroids provides sufficient relief for most cases of coexisting
allergic conjunctivitis. If it fails, additional therapies directed primarily
to allergic conjunctivitis may be added (see Chapter 147). Intranasal
corticosteroids are of some value for the treatment of ocular symptoms,
but ophthalmic corticosteroids remain the most potent pharmacologic
agents for ocular allergy. They carry the risk of adverse effects, such as
delayed wound healing, secondary infection, elevated intraocular
1092 Part XV ◆ Allergic Disorders

Table 143-2 Oral Allergic Rhinitis Treatments (Prescription, Examples)

SECOND-GENERATION ANTIHISTAMINES
GENERIC/BRAND STRENGTH FORMULATIONS DOSING
Desloratadine
Clarinex Reditabs* 2.5 mg, 5 mg Orally disintegrating tablet Children 6-11 mo of age: 1 mg once daily
Clarinex Tablets 5 mg Tabs Children 12 mo-5 yr of age: 1.25 mg once daily
Clarinex Syrup 0.5 mg/mL Syrup Children 6-11 yr of age: 2.5 mg once daily
Adults and adolescents ≥12 yr of age: 5 mg once daily
Levocetirizine dihydrochloride
Xyzal Oral Solution 0.5 mg/mL Solution 6 mo-5 yr: max 1.25 mg once daily in the P.M.
6-11 yr: max 2.5 mg once daily in the P.M.
LEUKOTRIENE ANTAGONIST
Montelukast
Singulair 10 mg Tablets 6 mo-5 yr: 4 mg daily
Singulair Chewables* 4 mg, 5 mg Chewable tablets 6-14 yr: 5 mg daily
Singulair Oral Granules 4 mg/packet Oral granules >14 yr: 10 mg daily
*Contains phenylalanine.
Dosing recommendations taken in part from Arcara K, Tschudy M for the Johns Hopkins Hospital: The Harriet Lane Handbook, ed 19. Philadelphia, 2012 Mosby.

Table 143-3 Oral Allergic Rhinitis Treatments (Nonprescription, Examples)

FIRST-GENERATION H1 ANTAGONISTS
GENERIC/BRAND STRENGTH FORMULATIONS DOSING
Chlorpheniramine maleate
Chlor-Trimeton 4 mg Tablets 2-5 yr: 1 mg every 4-6 hr (maximum 6 mg/day)
Chlor-Trimeton Syrup 2 mg/5 mL Syrup 6-11 yr: 2 mg every 4-6 hr (maximum 12 mg/day)
>12 yr 4 mg every 4-6 hr (maximum 24 mg/day)
SECOND-GENERATION H1 ANTAGONISTS
Cetirizine
Children’s Zyrtec Allergy Syrup 1 mg/mL Syrup 6-12 mo: 2.5 mg once daily
Children’s Zyrtec 5 mg, 10 mg Chewable tablets 12-23 mo: initial: 2.5 mg once daily; dosage may
Chewable be increased to 2.5 mg twice daily
Zyrtec tablets 5 mg, 10 mg Tablets 2-5 yr: 2.5 mg/day; may be increased to a
maximum of 5 mg/day given either as a single
dose or divided into 2 doses
Zyrtec Liquid Gels 10 mg Liquid-filled gels ≥6 yr: 5-10 mg/day as a single dose or divided
into 2 doses
Fexofenadine HCl
Children’s Allegra 30 mg Tablet
Children’s Allegra ODT* 30 mg Orally disintegrating tablets 6 mo-<2 yr: 15 mg (2.5 mL) every 12 hr
Children’s Allegra Oral 30 mg/5 mL Suspension >2-11 yr: 30 mg every 12 hr
Suspension
Allegra Tabs 30, 60, 180 mg Tablet >12 yr-adult: 60 mg every 12 hr; 180 mg once
daily
Loratadine
Alavert ODT* 10 mg Orally disintegrating tablets 2-5 yr: 5 mg once daily.
10 mg Tablets >6 yr: 10 mg once daily or 5 mg twice daily
10 mg Liquid-filled caps
5 mg Chewable tablets
1 mg/mL Syrup
*Contains phenylalanine.
Dosing recommendations taken in part from Arcara K, Tschudy M for the Johns Hopkins Hospital: The Harriet Lane Handbook, ed 19, Philadelphia, 2012, Mosby.

Table 143-4 Combined Antihistamine + Sympathomimetic (Examples)

GENERIC STRENGTH FORMULATIONS DOSING
Chlorpheniramine maleate 4 mg Tablets >12 yr: 1 tablet every 4 hr not to exceed
Phenylephrine HCl 10 mg 6 tablets per day
Sudafed Sinus & Allergy
Cetirizine + pseudoephedrine 5 mg cetirizine + 120 mg Extended release tablet >12 yr: 1 tablet every 12 hr
Zyrtec-D 12 hour pseudoephedrine
Dosing recommendations taken in part from Arcara K, Tschudy M for the Johns Hopkins Hospital: The Harriet Lane Handbook, ed 19, Philadelphia, 2012, Mosby.
 Chapter 143 ◆ Allergic Rhinitis 1093

Table 143-5 Miscellaneous Intranasal Sprays

INDICATIONS (I), MECHANISM(s) OF
DRUG ACTION (M), AND DOSING
Ipratropium bromide: I: Symptomatic relief of rhinorrhea
M: Anticholinergic
Atrovent nasal spray (0.06%) Colds (symptomatic relief of rhinorrhea):
5-12 yr: 2 sprays in each nostril 3 times/day
≥12 yr and adults: 2 sprays in each nostril 3-4
times/day
Azelastine: I: Treatment of rhinorrhea, sneezing, and
nasal pruritus
M: Antagonism of histamine H1-receptor
Astelin 6-12 yr: 1 spray bid
>12 yr: 1-2 sprays bid
Cromolyn sodium: I: AR.
M: Inhibition of mast cell degranulation
NasalCrom >2 yr: 1 spray tid-qid; max ×6 /day
Oxymetazoline: I: Symptomatic relief of nasal mucosal
congestion
M: Adrenergic agonist, vasoconstricting agent
Afrin, Nostrilla 0.05% solution: instill 2-3 sprays into each
nostril twice daily; therapy should not
exceed 3 days
Phenylephrine: I: Symptomatic relief of nasal mucosal
congestion
M: Adrenergic, vasoconstricting agent
Neo-Synephrine 2-6 yr: 1 drop every 2-4 hr of 0.125% solution
as needed. Note: Therapy should not
exceed 3 continuous days
6-12 yr: 1-2 sprays or 1-2 drops every 4 hr of
0.25% solution as needed. Note: Therapy
should not exceed 3 continuous days
>12 yr: 1-2 sprays or 1-2 drops every 4 hr of
0.25% to 0.5% solution as needed; 1%
solution may be used in adults with extreme
nasal congestion. Note: Therapy should not
exceed 3 continuous days
COMMENTS, CAUTIONS, ADVERSE
EVENTS, AND MONITORING
Atrovent inhalation aerosol is contraindicated
in patients with hypersensitivity to soy
lecithin
Safety and efficacy of use beyond 4 days in
patients with the common cold have not
been established
Adverse effects: Epistaxis, nasal dryness,
nausea
May cause drowsiness
Adverse effects: Headache, somnolence,
bitter taste
Not effective immediately; requires frequent
administration
Excessive dosage may cause profound central
nervous system (CNS) depression
Use in excess of 3 days may result in severe
rebound nasal congestion
Do not repeat more than once a month
Use with caution in patients with
hyperthyroidism, heart disease,
hypertension, and diabetes
Adverse effects: Hypertension, palpitations,
reflex bradycardia, nervousness, dizziness,
insomnia, headache, CNS depression,
convulsions, hallucinations, nausea,
vomiting, mydriasis, elevated intraocular
pressure, blurred vision
Use in excess of 3 days may result in severe
rebound nasal congestion
Do not repeat more than once a month
0.16% and 0.125% solutions are not
commercially available
Adverse effects: Reflex bradycardia,
excitability, headache, anxiety, and dizziness

Table 143-6 Intranasal Inhaled Corticosteroids

INDICATIONS (I), MECHANISM(s) OF
DRUG ACTION (M), AND DOSING
Beclomethasone: I: AR
M: Antiinflammatory, immune modulator
Beconase AQ (42 μg/spray) 6-12 yr: 1 spray in each nostril bid; may increase
Qnasl (80 μg/spray) if needed to 2 sprays in each nostril bid
>12 yr: 1 or 2 sprays in each nostril bid
Flunisolide 6-14 yr: 1 spray each nostril 3 times daily or 2
sprays in each nostril twice daily; not to
exceed 4 sprays/day in each nostril
≥15 yr: 2 sprays each nostril twice daily
(morning and evening); may increase to 2
sprays 3 times daily; maximum dose: 8 sprays/
day in each nostril (400 μg/day)
COMMENTS, CAUTIONS, ADVERSE EVENTS, AND
MONITORING
Shake container before use; blow nose; occlude 1
nostril, administer dose to the other nostril
Adverse effects: Burning and irritation of nasal mucosa,
epistaxis
Monitor growth
Shake container before use; blow nose; occlude 1
nostril, administer dose to the other nostril
Adverse effects: Burning and irritation of nasal mucosa,
epistaxis
Monitor growth
Continued
1094 Part XV ◆ Allergic Disorders
Table 143-6 Intranasal Inhaled Corticosteroids—cont’d
DRUG
Triamcinolone
Nasacort AQ (55 μg/spray)
Fluticasone propionate (available
as a generic preparation):
Flonase (50 μg/spray)
Fluticasone furoate:
Veramyst (27.5 μg/spray)
Mometasone:
Nasonex (50 μg/spray)
ta
Budesonide:
Rhinocort Aqua (32 μg/spray)
Ciclesonide:
Omnaris
Zetonna (50 μg/spray)
Azelastine/fluticasone (137 μg
azelastine/50 μg fluticasone)
Dymista
INDICATIONS (I), MECHANISM(s) OF
ACTION (M), AND DOSING
I: AR
M: Antiinflammatory, immune modulator
2-6 yr; 1 spray in each nostril qd
6-12 yr: 1-2 sprays in each nostril qd
≥12 yr: 2 sprays in each nostril qd
I: AR
M: Antiinflammatory, immune modulator
≥4 yr: 1-2 sprays in each nostril qd
2-12 yr:
Initial dose: 1 spray (27.5 μg/spray) per nostril
once daily (55 μg/day)
Patients who do not show adequate response
may use 2 sprays per nostril once daily
(110 μg/day)
Once symptoms are controlled, dosage may be
ti e
reduced to 55 μg once daily
Total daily dosage should not exceed 2 sprays
in each nostril (110 μg)/day
≥12 yr and adolescents:
n
Initial dose: 2 sprays (27.5 μg/spray) per nostril
once daily (110 μg/day)
Once symptoms are controlled, dosage may be
U
reduced to 1 spray per nostril once daily
(55 μg/day)
Total daily dosage should not exceed 2 sprays
-
in each nostril (110 μg)/day
I: AR
9
M: Antiinflammatory, immune modulator
2-12 yr: 1 spray in each nostril qd
9
>12 yr: 2 sprays in each nostril qd
r
i
h
I: AR
M: Antiinflammatory, immune modulator
6-12 yr: 2 sprays in each nostril qd
>12 yr: up to 4 sprays in each nostril qd
(maximum dose)
I: AR
M: Antiinflammatory, immune modulator
2-12 yr: 1-2 sprays in each nostril qd
>12 yr: 2 sprays in each nostril qd
>12 yr: 1 spray in each nostril bid
COMMENTS, CAUTIONS, ADVERSE EVENTS, AND
MONITORING
Shake container before use; blow nose; occlude 1
nostril, administer dose to the other nostril
Adverse effects: Burning and irritation of nasal mucosa,
epistaxis
Monitor growth
Shake container before use; blow nose; occlude 1
nostril, administer dose to the other nostril
Ritonavir significantly increases fluticasone serum
concentrations and may result in systemic
corticosteroid effects
Use fluticasone with caution in patients receiving
ketoconazole or other potent cytochrome P450 3A4
isoenzyme inhibitor
Adverse effects: Burning and irritation of nasal mucosa,
epistaxis
G
Monitor growth
R
V
d
Mometasone and its major metabolites are
undetectable in plasma after nasal administration of
recommended doses
Preventive treatment of seasonal AR should begin
2-4 wk prior to pollen season
Shake container before use; blow nose; occlude 1
nostril, administer dose to the other nostril
Adverse effects: Burning and irritation of nasal mucosa,
epistaxis
Monitor growth
Shake container before use; blow nose; occlude 1
nostril, administer dose to the other nostril
Adverse effects: Burning and irritation of nasal mucosa,
epistaxis
Monitor growth
Prior to initial use, gently shake, then prime the pump
by actuating 8 times
If the product is not used for 4 consecutive days,
gently shake and reprime with 1 spray or until a fine
mist appears
Shake bottle gently before using. Blow nose to clear
nostrils. Keep head tilted downward when spraying.
Insert applicator tip 14 to 12 inch into nostril, keeping
bottle upright, and close off the other nostril. Breathe
in through nose. While inhaling, press pump to
release spray
 Chapter 144 ◆ Childhood Asthma 1095

pressure, and formation of cataracts. These agents are only suited for
the treatment of allergic conjunctivitis that does not respond to the
medications discussed above. Sound practice calls for the assistance of
an ophthalmologist.
Environment Biological and
PROGNOSIS • Allergens Genetic Risk
Therapy with nonsedating antihistamines and topical corticoste- • Infections Age • Immune
• Microbes • Lung
roids, when taken faithfully, significantly improves health-related • Pollutants
quality-of-life measures in patients. The reported rates of remission • Repair
• Stress
among children are between 10% and 23%. Pharmacotherapy that will
target cells and cytokines involved in inflammation and treat allergy
as a systemic process is on the horizon, and more selective targeting of
drugs based on the development of specific biomarkers and genetic
profiling may soon be realized.
Innate and Adaptive Immune Development
Bibliography is available at Expert Consult. (Atopy)

• Respiratory viral
Lower infections
Airways • Aeroallergens
Injury • ETS
• Pollutants/toxicants
Chapter 144
Childhood Asthma Aberrant
• Persistent inflammation
• AHR
• Remodeling
Andrew H. Liu, Ronina A. Covar, Repair • Airways growth and
differentiation
Joseph D. Spahn, and Scott H. Sicherer

Asthma is a chronic inflammatory condition of the lung airways result-
ing in episodic airflow obstruction. This chronic inflammation height-
ens the twitchiness of the airways—airways hyperresponsiveness
(AHR)—to provocative exposures. Asthma management is aimed at
reducing airways inflammation by minimizing proinflammatory envi-
ronmental exposures, using daily controller antiinflammatory medica-
tions, and controlling comorbid conditions that can worsen asthma.
Less inflammation typically leads to better asthma control, with fewer
exacerbations and decreased need for quick-reliever asthma medica-
tions. Nevertheless, exacerbations can still occur. Early intervention
with systemic corticosteroids greatly reduces the severity of such epi-
sodes. Advances in asthma management and, especially, pharmaco-
therapy enable all but the uncommon child with difficult asthma to live
normally.
ETIOLOGY
Although the cause of childhood asthma has not been determined, a
combination of environmental exposures and inherent biologic and
genetic susceptibilities has been implicated (Fig. 144-1). In the suscep-
tible host, immune responses to common airways exposures (e.g.,
respiratory viruses, allergens, tobacco smoke, air pollutants) can
stimulate prolonged, pathogenic inflammation and aberrant repair of
injured airways tissues. Lung dysfunction (AHR, reduced airflow) and
airway remodeling develop. These pathogenic processes in the growing
lung during early life adversely affect airways growth and differentia-
tion, leading to altered airways at mature ages. Once asthma has devel-
oped, ongoing inflammatory exposures appear to worsen it, driving
disease persistence and increasing the risk of severe exacerbations.
Genetics
To date, more than 100 genetic loci have been linked to asthma, although
relatively few have consistently been linked to asthma in different study
cohorts. Replicating variants include genetic loci containing proaller-
gic, proinflammatory genes. Because epigenetic marks are heritable, are
responsive to environmental exposures, and can result in rapid and
persistent changes in gene expression it is conceivable that epigenetic
modification of genes play a role in the transmission of asthma.
ASTHMA
Figure 144-1 Etiology and pathogenesis of asthma. A combination
of environmental and genetic factors in early life shape how the immune
system develops and responds to ubiquitous environmental exposures.
Respiratory microbes, inhaled allergens, and toxins that can injure the
lower airways target the disease process to the lungs. Aberrant immune
and repair responses to airways injury underlie persistent disease.
AHR, airways hyperresponsiveness; ETS, environmental tobacco smoke.
Environment
Recurrent wheezing episodes in early childhood are associated with
common respiratory viruses, especially common cold rhinoviruses,
and also respiratory syncytial virus, influenza virus, adenovirus, para-
influenza virus, and human metapneumovirus. This association implies
that host features affecting immunologic host defense, inflammation,
and the extent of airways injury from ubiquitous viral pathogens
underlie susceptibility to recurrent wheezing in early childhood. Other
airways exposures can also exacerbate ongoing airways inflammation,
increase disease severity, and drive asthma persistence. Home allergen
exposures in sensitized individuals can initiate airways inflammation
and hypersensitivity to other irritant exposures, and are strongly linked
to disease severity and persistence. Consequently, eliminating the
offending allergen(s) can lead to resolution of asthma symptoms
and can sometimes cure asthma. Environmental tobacco smoke and
common air pollutants can aggravate airways inflammation and
increase asthma severity. Cold, dry air, hyperventilation from physical
play or exercise, and strong odors can trigger bronchoconstriction.
Although many exposures that trigger and aggravate asthma are well
recognized, the causal environmental features underlying the develop-
ment of host susceptibilities to the various common airway exposures
are not well defined.
EPIDEMIOLOGY
Asthma is a common chronic disease, causing considerable morbidity.
In 2011, more than 10 million children (14% of U.S. children) had ever
been diagnosed with asthma, with 70% of this group reporting current
asthma. Male gender and living in poverty are demographic risk factors
for having childhood asthma in the U.S. Fifteen percent of boys
1096 Part XV ◆ Allergic Disorders
compared to 13% of girls have had asthma; and 18% of all children
living in poor families (incomes less than $25,000 per year), compared
to 12% of children in families not classified as poor, have had asthma.
Childhood asthma is among the most common causes of childhood
emergency department visits, hospitalizations, and missed school days.
In the United States in 2006, childhood asthma accounted for 593,000
emergency department visits, 155,000 hospitalizations, and 167 deaths.
A disparity in asthma outcomes links high rates of asthma hospitaliza-
tion and death with poverty, ethnic minorities, and urban living. In the
past 2 decades, black children have had 2-7 times more emergency
department visits, hospitalizations, and deaths as a result of asthma
than nonblack children. Although current asthma prevalence is higher
in black than in nonblack U.S. children (in 2011, 16.5% vs 8.1% for
white and 9.8% for Latino children), prevalence differences cannot
fully account for this disparity in asthma outcomes.
Worldwide, childhood asthma appears to be increasing in preva-
lence, despite considerable improvements in our management and
pharmacopeia to treat asthma. Numerous studies conducted in differ-
ent countries have reported an increase in asthma prevalence of
approximately 50% per decade. Globally, childhood asthma prevalence
varies widely in different locales. A study of childhood asthma preva-
lence in 233 centers in 97 countries (International Study of Asthma
and Allergies in Childhood, Phase 3) found a wide range in the preva-
lence of current wheeze in 6-7 yr (2.4-37.6%) and 13-14 yr old children
(0.8-32.6%). Asthma prevalence correlated well with reported allergic
rhinoconjunctivitis and atopic eczema prevalence. Childhood asthma
seems more prevalent in modern metropolitan locales and more afflu-
ent nations, and is strongly linked with other allergic conditions. In
contrast, children living in rural areas of developing countries and
farming communities with domestic animals are less likely to experi-
ence asthma and allergy.
Approximately 80% of all asthmatic patients report disease onset
prior to 6 yr of age. However, of all young children who experience
recurrent wheezing, only a minority go on to have persistent asthma
in later childhood. Early childhood risk factors for persistent asthma
have been identified (Table 144-1) and have been described as major
(parent asthma, eczema, inhalant allergen sensitization) and minor
(allergic rhinitis, wheezing apart from colds, ≥4% peripheral blood
eosinophils, food allergen sensitization) risk factors. Allergy in young
children with recurrent cough and/or wheeze is the strongest identifi-
able factor for the persistence of childhood asthma.
Types of Childhood Asthma
There are 2 common types of childhood asthma based on different
natural courses: (1) recurrent wheezing in early childhood, primarily
triggered by common respiratory viral infections, usually resolves
during the preschool/lower school years; and (2) chronic asthma
associated with allergy that persists into later childhood and often
adulthood (Table 144-2). School-age children with mild-moderate per-
sistent asthma generally improve as teenagers, with some (~40%)
Table 144-1 Early Childhood Risk Factors
for Persistent Asthma
Parental asthma
Allergy:
• Atopic dermatitis (eczema)
• Allergic rhinitis
• Food allergy
• Inhalant allergen sensitization
• Food allergen sensitization
Severe lower respiratory tract infection:
• Pneumonia
• Bronchiolitis requiring hospitalization
Wheezing apart from colds
Male gender
Low birthweight
Environmental tobacco smoke exposure
Reduced lung function at birth
developing intermittent disease. Milder disease is more likely to remit.
Inhaled corticosteroid controller therapy for children with persistent
asthma does not alter the likelihood of outgrowing asthma in later
childhood; however, because children with asthma generally improve
with age, their need for controller therapy subsequently lessens and
often resolves. Progressive decline in lung function can be a feature of
severe, persistent disease.
Asthma is also classified by disease severity (e.g., intermittent or
persistent [mild, moderate, or severe]) or control (e.g., well, not well,
or very poorly controlled), especially for asthma management pur-
poses. Because most children with asthma can be well controlled with
conventional management guidelines, children with asthma can also
be characterized according to treatment response and medication
requirements as being: (1) easy-to-treat: well controlled with low
Table 144-2 Asthma Patterns in Childhood, Based on
Natural History and Asthma Management
TRANSIENT NONATOPIC WHEEZING
Common in early preschool years
Recurrent cough/wheeze, primarily triggered by common
respiratory viral infections
Usually resolves during the preschool and lower school years,
without increased risk for asthma in later life
Reduced airflow at birth, suggestive of relatively narrow airways.
AHR near birth. Improves by school age
PERSISTENT ATOPY-ASSOCIATED ASTHMA
Begins in early preschool years
Associated with atopy in early preschool years:
• Clinical (e.g., atopic dermatitis in infancy, allergic rhinitis, food
allergy)
• Biologic (e.g., early inhalant allergen sensitization, increased
serum immunoglobulin E, increased blood eosinophils)
• Highest risk for persistence into later childhood and adulthood
Lung function abnormalities:
• Those with onset before 3 yr of age acquire reduced airflow by
school age
• Those with later onset of symptoms, or with later onset of
allergen sensitization, are less likely to experience airflow
limitation in childhood
ASTHMA WITH DECLINING LUNG FUNCTION
Children with asthma with progressive increase in airflow limitation
Associated with hyperinflation in childhood, male gender
ASTHMA MANAGEMENT TYPES
(From national and international asthma management guidelines)
SEVERITY CLASSIFICATION*
• Intrinsic disease severity while not on asthma medications
Intermittent
Persistent:
• Mild
• Moderate
• Severe
CONTROL CLASSIFICATION*
• Clinical assessment while asthma being managed and treated
Well controlled
Not well controlled
Very poorly controlled
MANAGEMENT PATTERNS
• Easy-to-treat: well controlled with low levels of daily controller
therapy
• Difficult-to-treat: well controlled with multiple and/or high levels
of controller therapies
• Exacerbators: despite being well controlled, continue to have
severe exacerbations
• Refractory: continue to have poorly controlled asthma despite
multiple and high levels of controller therapies
*From National Asthma Education and Prevention Program’s Expert Panel
Report 3 (EPR3): Guideline for the diagnosis and management of asthma.
NIH Publication No. 07-4051. Bethesda, MD, 2007, U.S. Department of Health
and Human Services; National Institutes of Health, National Heart, Lung,
and Blood Institute; National Asthma Education and Prevention Program.
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.
AHR, airways hyperresponsiveness.
 Chapter 144 ◆ Childhood Asthma 1097

levels of controller therapy; (2) difficult-to-treat: well controlled with
multiple and/or high levels of controller therapies; (3) exacerbators:
despite being well controlled, continue to have severe exacerbations;
and (4) refractory asthma: continue to have poorly controlled asthma
despite multiple and high levels of controller therapies (Table 144-2).
Different airways pathologic processes, causing airways inflammation,
AHR, and airways congestion and blockage, are believed to underlie
these different types of asthma.
PATHOGENESIS
Airflow obstruction in asthma is the result of numerous pathologic
processes. In the small airways, airflow is regulated by smooth muscle
encircling the airway lumen; bronchoconstriction of these bronchiolar
muscular bands restricts or blocks airflow. A cellular inflammatory
infiltrate and exudates distinguished by eosinophils, but also including
other inflammatory cell types (neutrophils, monocytes, lymphocytes,
mast cells, basophils), can fill and obstruct the airways and induce
epithelial damage and desquamation into the airways lumen. Helper
AHR, edema, basement membrane thickening, subepithelial collagen
deposition, smooth muscle and mucous gland hypertrophy, and mucus
hypersecretion—all processes that contribute to airflow obstruction.
CLINICAL MANIFESTATIONS AND DIAGNOSIS
Intermittent dry coughing and expiratory wheezing are the most
common chronic symptoms of asthma. Older children and adults
report associated shortness of breath and chest congestion and tight-
ness; younger children are more likely to report intermittent, nonfocal
chest pain. Respiratory symptoms can be worse at night, associated
with sleep, especially during prolonged exacerbations triggered by
respiratory infections or inhalant allergens. Daytime symptoms, often
linked with physical activities (exercise-induced) or play, are reported
with greatest frequency in children. Other asthma symptoms in chil-
dren can be subtle and nonspecific, including self-imposed limitation
of physical activities, general fatigue (possibly resulting from sleep
disturbance), and difficulty keeping up with peers in physical activities.
Asking about previous experience with asthma medications (broncho-

G
T lymphocytes and other immune cells that produce proallergic, dilators) may provide a history of symptomatic improvement with
proinflammatory cytokines (interleukin [IL]-4, IL-5, IL-13), and treatment that supports the diagnosis of asthma. Lack of improvement
chemokines (eotaxins) mediate this inflammatory process. Pathogenic with bronchodilator and corticosteroid therapy is inconsistent with

R
immune responses and inflammation may also result from a breach in underlying asthma and should prompt more vigorous consideration of
normal immune regulatory processes (such as regulatory T lympho- asthma-masquerading conditions.

V
cytes that produce IL-10 and transforming growth factor-β) that Asthma symptoms can be triggered by numerous common events
dampen effector immunity and inflammation when they are no longer or exposures: physical exertion and hyperventilation (laughing), cold

d
needed. Hypersensitivity or susceptibility to a variety of provocative or dry air, and airways irritants (see Table 144-3). Exposures that
exposures or triggers (Table 144-3) can lead to airways inflammation, induce airways inflammation, such as infections with common respira-

ti e
tory pathogens (rhinovirus, respiratory syncytial virus, metapneumo-
virus, parainfluenza virus, influenza virus, adenovirus, Mycoplasma
pneumoniae, Chlamydia pneumoniae), and inhaled allergens in sensi-
Table 144-3 Asthma Triggers tized children, also increase AHR to dry cold air and irritant exposures.

n
An environmental history is essential for optimal asthma management
Common viral infections of the respiratory tract
Aeroallergens in sensitized asthmatic patients
(see Chapter 141).

U
The presence of risk factors, such as a history of other allergic condi-
INDOOR ALLERGENS tions (allergic rhinitis, allergic conjunctivitis, atopic dermatitis, food
• Animal dander allergies), parental asthma, and/or symptoms apart from colds, sup-

-
• Dust mites ports the diagnosis of asthma. During routine clinic visits, children
• Cockroaches with asthma commonly present without abnormal signs, emphasizing
• Molds

9
the importance of the medical history in diagnosing asthma. Some may
SEASONAL AEROALLERGENS exhibit a dry, persistent cough. The chest findings are often normal.

9
• Pollens (trees, grasses, weeds) Deeper breaths can sometimes elicit otherwise undetectable wheezing.
• Seasonal molds In clinic, quick resolution (within 10 min) or convincing improvement

i r
AIR POLLUTANTS in symptoms and signs of asthma with administration of a short-acting
• Environmental tobacco smoke inhaled β-agonist (SABA; e.g., albuterol) is supportive of the diagnosis

h
• Ozone of asthma.
• Nitrogen dioxide During asthma exacerbations, expiratory wheezing and a prolonged

ta
• Sulfur dioxide exhalation phase can usually be appreciated by auscultation. Decreased
• Particulate matter breath sounds in some of the lung fields, commonly the right lower
• Wood- or coal-burning smoke
posterior lobe, are consistent with regional hypoventilation caused by
• Mycotoxins
• Endotoxin airways obstruction. Rhonchi and crackles (or rales) can sometimes be
• Dust heard, resulting from excess mucus production and inflammatory
exudate in the airways. The combination of segmental crackles and
STRONG OR NOXIOUS ODORS OR FUMES poor breath sounds can indicate lung segmental atelectasis that is dif-
• Perfumes, hairsprays
ficult to distinguish from bronchial pneumonia and can complicate
• Cleaning agents
acute asthma management. In severe exacerbations, the greater extent
OCCUPATIONAL EXPOSURES of airways obstruction causes labored breathing and respiratory
• Farm and barn exposures distress, which manifests as inspiratory and expiratory wheezing,
• Formaldehydes, cedar, paint fumes increased prolongation of exhalation, poor air entry, suprasternal and
Cold dry air intercostal retractions, nasal flaring, and accessory respiratory muscle
Exercise
Crying, laughter, hyperventilation
use. In extremis, airflow may be so limited that wheezing cannot be
heard (Table 144-4).
COMORBID CONDITIONS
• Rhinitis DIFFERENTIAL DIAGNOSIS
• Sinusitis Many childhood respiratory conditions can present with symptoms
• Gastroesophageal reflux
and signs similar to those of asthma (Table 144-5). Besides asthma,
DRUGS other common causes of chronic, intermittent coughing include gas-
• Aspirin and other nonsteroidal antiinflammatory drugs troesophageal reflux (GER) and rhinosinusitis. Both GER and chronic
• β-Blocking agents sinusitis can be challenging to diagnose in children. Often, GER is
• Sulfiting agents clinically silent in children, and children with chronic sinusitis do not
• Tartrazine
report sinusitis-specific symptoms, such as localized sinus pressure and
1098 Part XV ◆ Allergic Disorders

Table 144-4 Formal Evaluation of Asthma Exacerbation Severity in the Urgent or Emergency Care Setting*
SUBSET: RESPIRATORY
MILD MODERATE SEVERE ARREST IMMINENT
SYMPTOMS
Breathlessness While walking While at rest (infant—softer, While at rest (infant—
shorter cry, difficulty stops feeding)
feeding)
Can lie down Prefers sitting Sits upright
Talks in Sentences Phrases Words
Alertness May be agitated Usually agitated Usually agitated Drowsy or confused
SIGNS
Respiratory rate† Increased Increased Often >30 breaths/min
Use of accessory muscles; Usually not Commonly Usually Paradoxical thoracoabdominal
suprasternal retractions movement
Wheeze Moderate; often only Loud; throughout exhalation Usually loud; throughout Absence of wheeze
end-expiratory inhalation and exhalation
Pulse rate (beats/min)‡ <100 100-120 >120 Bradycardia
Pulsus paradoxus Absent May be present Often present Absence suggests respiratory
<10 mm Hg 10-25 mm Hg >25 mm Hg (adult) muscle fatigue
20-40 mm Hg (child)
FUNCTIONAL ASSESSMENT
Peak expiratory flow ≥70% Approx. 40-69% or response <40% <25%§
(value predicted or lasts <2 hr
personal best)
Pao2 (breathing air) Normal (test not usually ≥60 mm Hg (test not usually <60 mm Hg; possible
necessary) necessary) cyanosis
and/or
PCO2 <42 mm Hg (test not <42 mm Hg (test not usually ≥42 mm Hg; possible
usually necessary) necessary) respiratory failure
SaO2 (breathing air) at sea >95% (test not usually 90-95% (test not usually <90%
level necessary) necessary)
Hypercapnia (hypoventilation) develops more readily in young children than in adults and adolescents
*Notes:
• The presence of several parameters, but not necessarily all, indicates the general classification of the exacerbation.
• Many of these parameters have not been systematically studied, especially as they correlate with each other. Thus, they serve only as general guides.
• The emotional impact of asthma symptoms on the patient and family is variable but must be recognized and addressed and can affect approaches to treatment
and follow-up.
†
Normal breathing rates in awake children by age: <2 mo, <60 breaths/min; 2-12 mo, <50 breaths/min; 1-5 yr, <40 breaths/min; 6-8 yr, <30 breaths/min.
‡
Normal pulse rates in children by age: 2-12 mo, <160 beats/min; 1-2 yr, <120 beats/min; 2-8 yr, <110 beats/min.
§
Peak expiratory flow testing may not be needed in very severe attacks.
Modified from EPR–3. Expert panel report 3: guidelines for the diagnosis and management of asthma, NIH Publication No. 07-4051, Bethesda, MD, 2007, U.S.
Department of Health and Human Services; National Institutes of Health, National Heart, Lung, and Blood Institute; National Asthma Education and Prevention
Program. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.

tenderness. In addition, both GER and rhinosinusitis are often comor-
bid with childhood asthma and, if not specifically treated, may make
asthma difficult to manage.
In early life, chronic coughing and wheezing can indicate recurrent
aspiration, tracheobronchomalacia, a congenital anatomic abnormality
of the airways, foreign-body aspiration, cystic fibrosis, or bronchopul-
monary dysplasia.
In older children and adolescents, vocal cord dysfunction (VCD)
can manifest as intermittent daytime wheezing (Table 144-6). In this
condition, the vocal cords involuntarily close inappropriately during
inspiration and sometimes exhalation, producing shortness of breath,
coughing, throat tightness, and often audible laryngeal wheezing and/
or stridor. In most cases of VCD, spirometric lung function testing
reveals “truncated” and inconsistent inspiratory and expiratory flow-
volume loops, a pattern that differs from the reproducible pattern of
airflow limitation in asthma that improves with bronchodilators. VCD
can coexist with asthma. Flexible rhinolaryngoscopy in the patient
with symptomatic VCD can reveal paradoxical vocal cord movements
with anatomically normal vocal cords. This condition can be well
managed with specialized speech therapy training in the relaxation and
control of vocal cord movement. Furthermore, treatment of underlying
causes of vocal cord irritability (e.g., high GER/aspiration, allergic
rhinitis, rhinosinusitis, asthma) can improve VCD. During acute VCD
exacerbations, in addition to relaxation breathing techniques in con-
junction with inhalation of heliox (a mixture of 70% helium and 30%
oxygen) can relieve vocal cord spasm and VCD symptoms.
Exercise-induced laryngeal obstruction must be considered in
children with a presumptive diagnosis of exercise-induced asthma.
The diagnosis is confirmed by continuous video laryngoscopy during
exercise.
In some locales, hypersensitivity pneumonitis (farming communi-
ties, homes of bird owners), pulmonary parasitic infestations (rural
areas of developing countries), or tuberculosis may be common causes
of chronic coughing and/or wheezing. Rare asthma-masquerading
conditions in childhood include bronchiolitis obliterans, interstitial
lung diseases, primary ciliary dyskinesias, humoral immune deficien-
cies, allergic bronchopulmonary mycoses, congestive heart failure,
mass lesions in or compressing the larynx, trachea, or bronchi, and
coughing and/or wheezing that is an adverse effect of medication.
Chronic pulmonary diseases often produce clubbing, but clubbing is a
very unusual finding in childhood asthma.
LABORATORY FINDINGS
Lung function tests can help to confirm the diagnosis of asthma and
to determine disease severity.
Pulmonary Function Testing
Forced expiratory airflow measures are helpful in diagnosing and
monitoring asthma and in assessing efficacy of therapy. Lung function
testing is particularly helpful in children with asthma who are poor
perceivers of airflow obstruction or when physical signs of asthma do
not occur until airflow obstruction is severe.
 Chapter 144 ◆ Childhood Asthma 1099

Table 144-5 Differential Diagnosis of Childhood Table 144-7 Lung Function Abnormalities in Asthma
Asthma
Spirometry (in clinic):
UPPER RESPIRATORY TRACT CONDITIONS • Airflow limitation:
Allergic rhinitis* • Low FEV1 (relative to percentage of predicted norms)
Chronic rhinitis* • FEV1:FVC ratio <0.80
Sinusitis* Bronchodilator response (to inhaled β-agonist):
Adenoidal or tonsillar hypertrophy • Improvement in FEV1 ≥12% and ≥200 mL*
Nasal foreign body Exercise challenge:
• Worsening in FEV1 ≥15%*
MIDDLE RESPIRATORY TRACT CONDITIONS Daily peak flow or FEV1 monitoring: day to day and/or A.M.-to-P.M.
Laryngotracheobronchomalacia* variation ≥20%*
Laryngotracheobronchitis (e.g., pertussis)*
Laryngeal web, cyst, or stenosis *Main criteria consistent with asthma.
Exercise-induced laryngeal obstruction FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity.
Vocal cord dysfunction*
Vocal cord paralysis
Tracheoesophageal fistula
Vascular ring, sling, or external mass compressing on the airway
(e.g., tumor)

G
Foreign body aspiration* Many asthma guidelines promote spirometric measures of airflow
Chronic bronchitis from environmental tobacco smoke exposure* and lung volumes during forced expiratory maneuvers as standard
Toxic inhalations for asthma assessment. Spirometry is a helpful objective measure of

R
airflow limitation (Fig. 144-2). Spirometry is an essential assessment
LOWER RESPIRATORY TRACT CONDITIONS
Bronchopulmonary dysplasia (chronic lung disease of preterm
tool in children who are at risk for severe asthma exacerbations and

V
infants) those who have poor perception of asthma symptoms. Knowledgeable
Viral bronchiolitis* personnel are needed to perform and interpret findings of spirometry

d
Gastroesophageal reflux* tests. Valid spirometric measures depend on a patient’s ability to prop-
Causes of bronchiectasis: erly perform a full, forceful, and prolonged expiratory maneuver,

ti e
Cystic fibrosis usually feasible in children >6 yr of age (with some younger excep-
Immune deficiency tions). Reproducible spirometric efforts are an indicator of test validity;
Allergic bronchopulmonary mycoses (e.g., aspergillosis) i.e., the FEV1 (forced expiratory volume in 1 sec) should be reproduc-
Chronic aspiration ible within 5% on 3 measurements, and the highest value taken as the

n
Immotile cilia syndrome, primary ciliary dyskinesia
Bronchiolitis obliterans
reported measure effort of the 3 is used. This standard utilization of
Interstitial lung diseases the highest of 3 reproducible efforts is indicative of the effort depen-

U
Hypersensitivity pneumonitis dence of reliable spirometric testing.
Pulmonary eosinophilia, Churg-Strauss vasculitis In asthma, airways blockage results in reduced airflow with forced
exhalation (see Fig. 144-2). Because asthmatic patients typically have

-
Pulmonary hemosiderosis
Tuberculosis hyperinflated lungs, FEV1 can be simply adjusted for full expiratory
Pneumonia lung volume—the forced vital capacity (FVC)—with an FEV1:FVC
Pulmonary edema (e.g., congestive heart failure)

9
ratio. Generally, an FEV1:FVC ratio <0.80 indicates significant airflow
Medications associated with chronic cough: obstruction (Table 144-7). Normative values for FEV1 have been deter-
Acetylcholinesterase inhibitors

9
β-Adrenergic antagonists
mined for children on the basis of height, gender, and ethnicity. Abnor-
mally low FEV1 as a percentage of predicted norms is 1 of 6 criteria

r
Angiotensin-converting enzyme inhibitors

i
used to determine asthma severity and control in asthma management
*More common asthma masqueraders. guidelines sponsored by the U.S. National Institutes of Health (NIH)

h
and the Global Initiative for Asthma (GINA).
Such measures of airflow alone are not diagnostic of asthma, because

ta
numerous other conditions can cause airflow reduction. Bronchodila-
tor response to an inhaled β-agonist (e.g., albuterol) is greater in asth-
matic patients than nonasthmatic persons; an improvement in FEV1
≥12% or >200 mL is consistent with asthma. Bronchoprovocation
Table 144-6 Similarities and Differences Between Vocal challenges can be helpful in diagnosing asthma and optimizing asthma
Cord Dysfunction and Asthma management. Asthmatic airways are hyperresponsive and therefore
more sensitive to inhaled methacholine, mannitol, and cold or dry air.
VOCAL CORD DYSFUNCTION ASTHMA The degree of AHR to these exposures correlates to some extent with
Extrathoracic Intrathoracic asthma severity and airways inflammation. Although bronchoprovoca-
tion challenges are carefully dosed and monitored in an investigational
Rare (?never) hypoxemia + Hypoxemia
setting, their use is rarely practical in general practice. Exercise chal-
No hypercapnia/acidosis + Hypercapnia/acidosis lenges (aerobic exertion or “running” for 6-8 min) can help to identify
Normal expiratory spirometry Reduced expiratory flow children with exercise-induced bronchospasm. Although the airflow
response of nonasthmatic persons to exercise is to increase functional
Abnormal inspiratory loop (in some) Normal inspiratory loop lung volumes and improve FEV1 slightly (5-10%), exercise often pro-
Start/stop abruptly; few symptoms Persistent symptoms vokes airflow obstruction in persons with inadequately treated asthma.
between episodes Accordingly, in asthmatic patients, FEV1 typically decreases during or
Frequent emergency department/office Frequent emergency
after exercise by >15% (see Table 144-7). The onset of exercise-induced
visits department/office visits bronchospasm is usually within 15 min after a vigorous exercise chal-
lenge and can spontaneously resolve within 30-60 min. Studies of exer-
Multiple medications Multiple medications cise challenges in school-age children typically identify an additional
From Noyes BE, Kemp JS: Vocal cord dysfunction in children. Paediat Respir 5-10% with exercise-induced bronchospasm and previously unrecog-
Rev 8:155–163, 2007 (Table 2, p. 159). nized asthma. There are 2 caveats regarding exercise challenges: first,
1100 Part XV ◆ Allergic Disorders

Peak flow
6

FVC
FEV1
Subject 1
4
4
Flow (L/sec)

A Expiratory flow
B volume loop

Volume (L)
C 3
2
D
Subject 2
2
E

0 1
100 50 0

1 2 3 4 5 6 7
!2 Time (sec)
Inspiratory flow
volume loop Subject 1: A non-asthmatic child
FEV1 " 3.4 (100% of predicted)
FVC " 3.8 (100% of predicted)
Vital capacity (%)
!4 FEV1/FVC " 0.86

Subject 2: An asthmatic child

FEV1 " 2.1 (62% of predicted)
FVC " 3.7 (97% of predicted)
!6 FEV1/FVC " 0.57
A B
Figure 144-2 Spirometry. A, Spirometric flow-volume loops. A is an expiratory flow-volume loop of a nonasthmatic person without airflow limita-
tion. B through E are expiratory flow-volume loops in asthmatic patients with increasing degrees of airflow limitation (B is mild; E is severe). Note
the “scooped” or concave appearance of the asthmatic expiratory flow-volume loops; with increasing obstruction, there is greater “scooping.”
B, Spirometric volume-time curves. Subject 1 is a nonasthmatic person; subject 2 is an asthmatic patient. Note how the FEV1 and FVC lung volumes
are obtained. The FEV1 is the volume of air exhaled in the 1st sec of a forced expiratory effort. The FVC is the total volume of air exhaled during
a forced expiratory effort, or forced vital capacity. Note that subject 2’s FEV1 and FEV1:FVC ratio are smaller than subject 1’s, demonstrating airflow
limitation. Also, subject 2’s FVC is very close to what is expected.

treadmill challenges in the clinic are not completely reliable and can
miss exertional asthma that can be demonstrated on the playing field;
and second, exercise challenges can induce severe exacerbations in
at-risk patients. Careful patient selection for exercise challenges and
preparedness for severe asthma exacerbations are required.
Measuring exhaled nitric oxide (FENO), a marker of airway inflam-
mation in allergy-associated asthma, may possibly help adjust antiin-
flammatory management and confirm the diagnosis of asthma.
Peak expiratory flow (PEF) monitoring devices provide simple and
inexpensive home-use tools to measure airflow and can be helpful in
a number of circumstances (Fig. 144-3). Similarly to spirometry in
clinics, poor perceivers of asthma can benefit by monitoring PEFs at
home to assess their airflow as an indicator of asthma control or prob-
lems. PEF devices vary in the ability to detect airflow obstruction: they
are generally less sensitive and reliable than spirometry to detect
airflow obstruction such that, in some patients, PEF values decline only
when airflow obstruction is severe. Therefore, PEF monitoring should
be started by measuring morning and evening PEFs (best of 3 attempts)
for several weeks for patients to practice the technique, to determine
diurnal variation and a “personal best,” and to correlate PEF values
with symptoms (and ideally spirometry). Diurnal variation in PEF
>20% is consistent with asthma (see Fig. 144-3 and Table 144-7).
Radiology
The findings of chest radiographs (posteroanterior and lateral views)
in children with asthma often appear to be normal, aside from subtle
and nonspecific findings of hyperinflation (e.g., flattening of the dia-
phragms) and peribronchial thickening (Fig. 144-4). Chest radio-
graphs can help identify abnormalities that are hallmarks of asthma
masqueraders (aspiration pneumonitis, hyperlucent lung fields in
bronchiolitis obliterans) and complications during asthma exacerba-
tions (atelectasis, pneumomediastinum, pneumothorax). Some lung
abnormalities can be better appreciated with high-resolution, thin-
section chest CT scans. Bronchiectasis, which is sometimes difficult to
appreciate on chest radiograph but is clearly seen on CT scan, impli-
cates an asthma masquerader such as cystic fibrosis, allergic broncho-
pulmonary mycoses (aspergillosis), ciliary dyskinesias, or immune
deficiencies.
Other tests, such as allergy testing to assess sensitization to inhalant
allergens, help with the management and prognosis of asthma. In a
comprehensive U.S. study of 5-12 yr old asthmatic children (Child-
hood Asthma Management Program [CAMP]), 88% of the subjects
had inhalant allergen sensitization according to results of allergy prick
skin testing.
TREATMENT
The NIH-sponsored National Asthma Education and Prevention Pro-
gram’s Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and
Management of Asthma 2007 is available online (www.nhlbi.nih.gov/
guidelines/asthma/asthgdln.htm). Similar guidelines From the Global
Strategy for Asthma Management and Prevention, GINA 2012, are
also available online (www.ginaasthma.org). The key components to
optimal asthma management are specified (Fig. 144-5). Management
of asthma should have the following components: (1) assessment and
monitoring of disease activity; (2) education to enhance patient and
family knowledge and skills for self-management; (3) identification
and management of precipitating factors and comorbid conditions that
worsen asthma; and (4) appropriate selection of medications to address
the patient’s needs. The long-term goal of asthma management is
attainment of optimal asthma control.

250 Green zone ("80%)
200
PEF (L/min)
150
Yellow zone (50-80%)
100
50 Red zone (#50%)
0 evaluated by spirometry in children 5 yr and older. Risk refers to the
2 4 6 8 10 12 14 16 18
A Days
250 Green zone ("80%)
200
PEF (L/min)
150
Yellow zone (50-80%)
100
1 ! Prednisone initiated
50 Red zone (#50%) 2 ! Prednisone discontinued
1 2
0 thermore, with respect to risk assessment, besides considering severity
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 31
B Days
Figure 144-3 An example of the role of peak flow monitoring in
childhood asthma. A, PEFs performed and recorded twice daily, in
the morning (A.M.) and evening (P.M.), over 1 mo in an asthmatic child.
This child’s “personal best” PEF value is 220 L/min; therefore, the
green zone (>80-100% of best) is 175-220 L/min; the yellow zone
(50-80%) is 110-175 L/min; and the red zone (<50%) is <110 L/min.
Note that this child’s P.M. PEF values are almost always in the green
zone, whereas his A.M. PEFs are often in the yellow or red zone. This
pattern illustrates the typical diurnal A.M.-to-P.M. variation of inade-
r
quately controlled asthma. B, PEFs performed twice daily, in the
i
morning (A.M.) and evening (P.M.), over 1 mo in an asthmatic child in
whom an asthma exacerbation developed from a viral respiratory tract
infection. Note that the child’s PEF values were initially in the green
h
zone. A viral respiratory tract infection led to asthma worsening, with
a decline in PEF to the yellow zone that continued to worsen until
ta
PEF values were in the red zone. At that point, a 4-day prednisone
course was administered, followed by improvement in PEF back to
the green zone.
Component 1: Regular Assessment
and Monitoring
Regular assessment and monitoring are based on the concepts of
asthma severity, asthma control, and responsiveness to therapy.
Asthma severity is the intrinsic intensity of disease, and assessment is
generally most accurate in patients not receiving controller therapy.
Hence, assessing asthma severity directs the initial level of therapy. The
2 general categories are intermittent asthma and persistent asthma,
the latter being further subdivided into mild, moderate, and severe.
In contrast, asthma control refers to the degree to which symptoms,
ongoing functional impairments, and risk of adverse events are mini-
mized, and goals of therapy are met. In children receiving controller
therapy, assessment of asthma control is important in adjusting therapy
and is categorized in 3 levels: well-controlled, not well-controlled, and
very poorly controlled. Responsiveness to therapy is the ease or dif-
ficulty with which asthma control is attained by treatment.
Chapter 144 ◆ Childhood Asthma 1101
Classification of asthma severity and control is based on the
domains of impairment and risk. These domains may not correlate
with each other and may respond differently to treatment. In some
children with asthma, day-to-day impairment is well controlled, but
the risk of severe exacerbations remains. The NIH guidelines have
distinct criteria for 3 childhood age groups—0-4 yr, 5-11 yr, and
≥12 yr—for the evaluation of both severity (Table 144-8) and control
(Table 144-9). The level of asthma severity or control is based on the
most severe impairment or risk category. In assessing asthma severity,
impairment consists of an assessment of the patient’s recent symptom
AM PEF
frequency (daytime and nighttime, with subtle differences in numeric
PM PEF cutoffs between the 3 age groups), SABA usage for quick relief, ability
to engage in normal or desired activities, and airflow compromise
20 22 24 26 28 30 likelihood of developing severe asthma exacerbations. Of note, in the
absence of frequent symptoms, persistent asthma should be consid-
ered, and therefore long-term controller therapy should be initiated
AM PEF for infants or children who have risk factors for asthma (see earlier)
G
PM PEF and 4 or more episodes of wheezing over the past year that lasted
longer than 1 day and affected sleep, or 2 or more exacerbations in
6 mo requiring systemic corticosteroids.
R
Asthma management can be optimized through regular clinic visits
every 2-6 wk until good asthma control is achieved. For children
V
already on controller medication therapy, management is tailored to
the child’s level of control. The NIH guidelines provide tables for evalu-
d
ating asthma control for the 3 age groups (see Table 144-9). In evalu-
ation of asthma control, as in severity assessment, impairment includes
ti e
an assessment of the patient’s symptom frequency (daytime and night-
time), SABA usage for quick relief, ability to engage in normal or
desired activities, and, for older children, airflow measurements. Fur-
n
and frequency of exacerbations requiring systemic corticosteroids,
tracking of lung growth in older children and monitoring adverse
U
effects of medications is also warranted. The degree of impairment and
presence of risk are used to determine the patient’s level of asthma
control as well-controlled, not well-controlled, or very poorly con-
-
trolled. Children with well-controlled asthma have daytime symptoms
≤2 days/wk and need a rescue bronchodilator ≤2 days/wk; an FEV1 of
9
>80% of predicted (and an FEV1:FVC ratio >80% for children 5-11 yr
of age); no interference with normal activity; and <2 exacerbations in
9
the past year. The impairment criteria vary slightly depending on age
group: there are different thresholds in the frequency of nighttime
awakenings; addition of FEV1:FVC ratio criteria for children 5-11 yr
old and addition of validated impairment questionnaires (e.g., Asthma
Control Test [ACT] for ages ≥12 yr, Childhood ACT for ages 4-11 yr).
Children whose status does not meet all of the criteria defining well-
controlled asthma are determined to have either not-well-controlled
or very poorly controlled asthma, which is determined by the single
criterion with the poorest rating.
Two to 4 asthma checkups per year are recommended for reassessing
and maintaining good asthma control. Lung function testing (spirom-
etry) is recommended at least annually and more often if asthma is
poorly perceived, inadequately controlled and/or lung function is
abnormally low. PEF monitoring at home can be helpful in the assess-
ment of asthmatic children with poor symptom perception, other
causes of chronic coughing in addition to asthma, moderate to severe
asthma, or a history of severe asthma exacerbations. PEF monitoring
is feasible in children as young as 4 yr who are able to master this skill.
Use of a stoplight zone system tailored to each child’s “personal best”
PEF values can optimize effectiveness and interest (see Fig 144-3): The
green zone (80-100% of personal best) indicates good control; the
yellow zone (50-80%) indicates less-than-optimal control and neces-
sitates increased awareness and treatment; the red zone (<50%) indi-
cates poor control and greater likelihood of an exacerbation, requiring
immediate intervention. In actuality, these ranges are approximate and
may need to be adjusted for many asthmatic children by raising the
ranges that indicate inadequate control (in the yellow zone, 70-90%).
Once-daily PEF monitoring is preferable in the morning when peak
flows are typically lower.
1102 Part XV ◆ Allergic Disorders
A B
Figure 144-4 A 4-year-old boy with asthma. Frontal (A) and lateral (B) radiographs show pulmonary hyperinflation and minimal peribronchial
thickening. No asthmatic complication is apparent.
Recurrent/chronic cough, wheeze, dyspnea
• Symptoms
• Exacerbations
Diagnosis • Risk factors (Tables 144-1, -2)
• Triggers (Table 144-3)
• Lung function (Figs. 144-2, -3; Table 144-7)
• Differential dx. (Table 144-5)
Asthma
Management
• Assessment and • Assess severity (Table 144-8)
monitoring • Monitor control (Table 144-9)
• Med adverse effects (Table 144-15)
• Education • Key elements (Table 144-10)
• Contol environmental factors • Environmental controls (Table 144-11)
and co-morbid conditions • Co-morbidities (Table 144-11)
• Medications • Long-term controllers (Tables 144-12
to 144-14)
• Quick relievers (Table 144-12)
• Exacerbations • Management (Table 144-16)
• High-risk features (Table 144-17)
• Home action plan
Optimal goal: Well-controlled asthma
• Reduce impairment • Prevent chronic symptoms
• Prevent sleep disturbance
• Infrequent SABA need
• Maintain (near) normal lung function
• Maintain normal activity
• Reduce risk • Prevent exacerbations
• Minimize ER visits/hospitalizations
• Prevent reduced lung growth
• No (minimal) adverse effects of therapy
Figure 144-5 The key elements to optimal asthma management.
SABA, short-acting β-agonist.
Component 2: Patient Education
Specific educational elements in the clinical care of children with
asthma are believed to make an important difference in home manage-
ment and in adherence of families to an optimal plan of care and
eventually impacting patient outcomes (Table 144-10). Every visit pres-
ents an important opportunity to educate the child and family, allow-
ing them to become knowledgeable partners in asthma management,
because optimal management depends on their daily assessments and
implementation of any management plan. Effective communications
take into account sociocultural and ethnic factors of children and their
families, provide an open forum for concerns about asthma and its
treatment to be raised and addressed, and include patients and families
as active participants in the development of treatment goals and selec-
tion of medications. Self-management skills should be reevaluated
regularly (e.g., inhaler medication technique).
During initial patient visits, a basic understanding of the pathogen-
esis of asthma (chronic inflammation and AHR underlying a clinically
intermittent presentation) can help children with asthma and their
parents understand the importance of recommendations aimed at
reducing airways inflammation to achieve and maintain good asthma
control. It is helpful to specify the expectations of good asthma control
resulting from optimal asthma management (see Fig. 144-5). Address-
ing concerns about potential adverse effects of asthma pharmaco-
therapeutic agents, especially their risks relative to their benefits, is
essential in achieving long-term adherence with asthma pharmaco-
therapy and environmental control measures.
Children with asthma and their families, particularly patients with
moderate or severe persistent or poorly controlled asthma and patients
who have had severe exacerbations, benefit from a written asthma man-
agement plan. This plan has 2 main components: (1) a daily “routine”
management plan describing regular asthma medication use and other
measures to keep asthma under good control; and (2) an action plan
to manage worsening asthma, describing indicators of impending
exacerbations, identifying what medications to take, and specifying
when and how to contact the regular physician and/or obtain urgent/
emergency medical care.
Regular follow-up visits are recommended to help to maintain
optimal asthma control. In addition to determining disease control
level and revising daily and exacerbation management plans accord-
ingly, follow-up visits are important teaching opportunities to encour-
age open communication of concerns with asthma management
recommendations (e.g., daily administration of controller medica-
tions). Reassessing patients’ and parents’ understanding of the role of
different medications in asthma management and control, and their
technique in using inhaled medications, can be insightful and can help
guide teaching to improve adherence to a management plan that might
not have been adequately or properly implemented.
ADHERENCE
Asthma is a chronic condition that is usually best managed with daily
controller medication. However, symptoms wax and wane, severe exac-
erbations are infrequent, and when asthma is asymptomatic, a natural
tendency is to reduce or discontinue daily controller therapies. As such,
adherence to a daily controller regimen is commonly suboptimal;
 Chapter 144 ◆ Childhood Asthma 1103

Table 144-8 Assessing Asthma Severity and Initiating Treatment for Patients Who Are Not Currently Taking Long-Term
Control Medications*
CLASSIFICATION OF ASTHMA SEVERITY
PERSISTENT
Intermittent Mild Moderate Severe
COMPONENTS OF SEVERITY
Impairment
Daytime symptoms ≤2 days/wk >2 days/wk but not daily Daily Throughout the day
Nighttime awakenings:
Age 0-4 yr 0 1-2×/mo 3-4×/mo >1×/wk
Age ≥5 yr ≤2×/mo 3-4×/mo >1×/wk but not nightly Often 7×/wk
Short-acting β2-agonist use ≤2 days/wk >2 days/wk but not daily, Daily Several times per day
for symptoms (not for and not more than 1×
prevention of exercise- on any day
induced bronchospasm)
Interference with normal None Minor limitation Some limitation Extreme limitation
activity
Lung function:
FEV1 % predicted, age ≥5 yr Normal FEV1 between ≥80% predicted 60-80% predicted <60% predicted
exacerbations
>80% predicted
FEV1:FVC ratio†:
Age 5-11 yr >85% >80% 75-80% <75%
Age ≥12 yr Normal Normal Reduced 5% Reduced >5%
Risk
Exacerbations requiring
systemic corticosteroids:
Age 0-4 yr 0-1/yr (see notes) ≥2 exacerbations in 6 mo requiring systemic corticosteroids or
≥4 wheezing episodes/yr lasting >1 day and risk factors for persistent asthma
Age ≥ 5 yr 0-1/yr (see notes) ≥2/yr (see notes) ≥2/yr (see notes) ≥2/yr (see notes)
Consider severity and interval since last exacerbation.
Frequency and severity may fluctuate over time for patients in any severity category.
Relative annual risk of exacerbations may be related to FEV1.
RECOMMENDED STEP FOR INITIATING THERAPY
All ages Step 1 Step 2
Age 0-4 yr Step 3 Step 3
Age 5-11 yr Step 3, medium-dose ICS
Step 3, medium-dose ICS
option option
or
Step 4
Age ≥12 yr Consider a short course of Consider a short course of
systemic corticosteroids systemic corticosteroids
In 2-6 wk, evaluate level of asthma control that is achieved and adjust therapy accordingly. If no clear benefit
is observed within 4-6 wk, consider adjusting therapy or alternative diagnoses.
*Notes:
• The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs.
• Level of severity is determined by both impairment and risk. Assess impairment domain by patient’s/caregiver’s recall of previous 2-4 wk. Symptom assessment for
longer periods should reflect a global assessment, such as inquiring whether a patient’s asthma is better or worse since the last visit. Assign severity to the most
severe category in which any feature occurs.
• At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. For treatment purposes, patients who
had ≥2 exacerbations requiring oral systemic corticosteroids in the past 6 mo, or ≥4 wheezing episodes in the past year, and who have risk factors for persistent
asthma may be considered the same as patients who have persistent asthma, even in the absence of impairment levels consistent with persistent asthma.
†Normal FEV1:FVC: 8-19 yr, 85%; 20-39 yr, 80%.
FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; ICS, inhaled corticosteroids.
Adapted from the National Asthma Education and Prevention Program: Expert Panel Report 3 (EPR 3): Guidelines for the diagnosis and management of asthma—
summary report 2007, J Allergy Clin Immunol 120(Suppl):S94–S138, 2007.

inhaled corticosteroids (ICSs) are underused 60% of the time. In one
study, children with asthma who required an oral corticosteroid course
for an asthma exacerbation had used their daily controller ICS 15% of
the time. Misconceptions about controller medication time to onset,
efficacy, and safety often underlie poor adherence and can be addressed
by asking about such concerns at each visit.
Component 3: Control of Factors Contributing
to Asthma Severity
Controllable factors that can worsen asthma can be generally grouped
as (1) environmental exposures and (2) comorbid conditions
(Table 144-11).
Eliminating and Reducing Problematic
Environmental Exposures
The majority of children with asthma have an allergic component to their
disease; steps should be taken to investigate and minimize allergen expo-
sures in sensitized asthmatic patients. The medical history should
address potential allergen triggers (see below), but often patients have
chronic symptoms and cannot identify potential triggers. Therefore,
allergy testing should be considered for at least those with persistent
asthma. For asthmatic patients who are allergic to allergens in their
homes, reducing or eliminating these home allergen exposures can
decrease asthma symptoms, medication requirements, AHR, severe
exacerbations, and disease persistence. Common home allergen
1104 Part XV ◆ Allergic Disorders

Table 144-9 Assessing Asthma Control and Adjusting Therapy in Children*

CLASSIFICATION OF ASTHMA CONTROL
Well-Controlled Not Well-Controlled Very Poorly Controlled
COMPONENTS OF CONTROL
Impairment
Symptoms ≤2 days/wk but not more than >2 days/wk or multiple times on Throughout the day
once on each day ≤2 days/wk
Nighttime awakenings:
Age 0-4 yr ≤1×/mo >1×/mo >1×/wk
Age 5-11 yr ≤1×/mo ≥2×/mo ≥2×/wk
Age ≥12 yr ≤2×/mo 1-3×/wk ≥4×/wk
Short-acting β2-agonist use for ≤2 days/wk >2 days/wk Several times per day
symptoms (not for exercise-
induced bronchospasm
pretreatment)
Interference with normal activity None Some limitation Extremely limited
Lung function:
Age 5-11 yr:
FEV1 (% predicted or peak flow) >80% predicted or personal best 60-80% predicted or personal best <60% predicted or personal best
FEV1/FVC: >80% 75-80% <75%
Age ≥ 12 yr:
FEV1 (% predicted or peak flow) >80% predicted or personal best 60-80% predicted or personal best <60% predicted or personal best
Validated questionnaires†:
Age ≥ 12 yr:
ATAQ 0 1-2 3-4
ACQ ≤0.75 ≤1.5 N/A
ACT ≥20 16-19 ≤15
Risk
Exacerbations requiring systemic
corticosteroids:
Age 0-4 yr 0-1/yr 2-3/yr >3/yr
Age ≥5 yr 0-1/yr ≥2/yr (see notes)
Consider severity and interval since last exacerbation.
Treatment-related adverse effects Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of
intensity does not correlate to specific levels of control but should be considered in the overall
assessment of risk.
Reduction in lung growth or Evaluation requires long-term follow-up care.
progressive loss of lung function
RECOMMENDED ACTION FOR TREATMENT
Maintain current step. Step up‡ (1 step) and reevaluate in Consider short course of oral
Regular follow-up every 1-6 mo 2-6 wk. corticosteroids.
to maintain control. If no clear benefit in 4-6 wk, Step up§ (1-2 steps) and
Consider step down if well- consider alternative diagnoses reevaluate in 2 wk.
controlled for at least 3 mo. or adjusting therapy. If no clear benefit in 4-6 wk,
For side effects, consider consider alternative diagnoses
alternative options. or adjusting therapy.
For side effects, consider
alternative options.
*Notes:
• The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.
• The level of control is based on the most severe impairment or risk category. Assess impairment domain by caregiver’s recall of previous 2-4 wk. Symptom
assessment for longer periods should reflect a global assessment such as inquiring whether the patient’s asthma is better or worse since the last visit.
• At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense
exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or intensive care unit admission) indicate poorer disease control. For treatment purposes,
patients who had ≥2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled
asthma, even in the absence of impairment levels consistent with not-well-controlled asthma.
†
Validated questionnaires for the impairment domain (the questionnaires do not assess lung function or the risk domain) and definition of minimal important
difference (MID) for each:
• ATAQ, Asthma Therapy Assessment Questionnaire; MID = 1.0
• ACQ, Asthma Control Questionnaire; MID = 0.5
• ACT, Asthma Control Test; MID not determined
‡
ACQ values of 0.76-1.40 are indeterminate regarding well-controlled asthma.
§
Before step-up therapy: (a) review adherence to medications, inhaler technique, and environmental control; (b) if alternative treatment option was used in a step,
discontinue it and use preferred treatment for that step.
FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity.
Adapted from the National Asthma Education and Prevention Program: Expert Panel Report 3 (EPR 3): Guidelines for the diagnosis and management of asthma—
summary report 2007, J Allergy Clin Immunol 120(Suppl):S94–S138, 2007.

Table 144-10 Key Elements of Productive Clinic Visits
for Asthma
Specify goals of asthma management
Explain basic facts about asthma:
• Contrast normal vs asthmatic airways
• Link airways inflammation, “twitchiness,” and bronchoconstriction
• Long-term-control and quick-relief medications
• Address concerns about potential adverse effects of asthma
pharmacotherapy
Teach, demonstrate, and have patient show proper technique for:
• Inhaled medication use (spacer use with metered-dose inhaler)
• Peak flow measures
Investigate and manage factors that contribute to asthma severity:
• Environmental exposures
• Comorbid conditions
Create written 2-part asthma management plan:
• Daily management
• Action plan for asthma exacerbations
Regular follow-up visits:
• Twice yearly (more often if asthma not well-controlled)
• Monitor lung function annually
Table 144-11 Control of Factors Contributing to
Asthma Severity
ELIMINATE OR REDUCE PROBLEMATIC ENVIRONMENTAL
EXPOSURES:
Environmental tobacco smoke elimination or reduction in home
and automobiles
Allergen exposure elimination or reduction in sensitized asthmatic
patients:
• Animal danders: pets (cats, dogs, rodents, birds)
• Pests (mice, rats)
• Dust mites
• Cockroaches
• Molds
Other airway irritants:
• Wood- or coal-burning smoke
• Strong chemical odors and perfumes (e.g., household cleaners)
• Dusts
TREAT COMORBID CONDITIONS:
• Rhinitis
• Sinusitis
• Gastroesophageal reflux
exposures include furred or feathered animals as pets (cats, dogs,
rodents, birds) or as pests (mice, rats), and occult indoor allergens,
such as dust mites, cockroaches, and molds. Although some sensitized
children may report an increase in asthma symptoms on exposure to
the allergen source, improvement from allergen avoidance may not
become apparent without a sustained period of days to weeks away
from the offending exposure. Tobacco, wood and coal smoke, dusts,
strong odors, and noxious air pollutants can all aggravate asthma.
These airways irritants should be eliminated from or reduced in the
homes and automobiles used by children with asthma. School class-
rooms and daycare settings can also be sites of environmental expo-
sures that worsen asthma. Eliminating or minimizing these exposures
(e.g., furred or feathered pets in classrooms of sensitized children with
asthma) can reduce asthma symptoms, disease severity, and the
amount of medication needed to achieve good asthma control. Annual
influenza vaccination continues to be recommended for all children
with asthma, although influenza is not responsible for the large major-
ity of virus-induced asthma exacerbations experienced by children.
Chapter 144 ◆ Childhood Asthma 1105
Aspirin-exacerbated respiratory disease, formerly called aspirin-
induced asthma, is also associated with chronic eosinophilic rhinitis
and nasal polyposis. Inhibition of cyclooxygenase by aspirin and
other nonsteroidal antiinflammatory drugs (including cyclooxygenase
[COX]-2 inhibiting agents) is thought to be the primary mechanism,
which leads to exacerbations of disease, predominantly in patients with
moderate to severe persistent asthma. Acetaminophen, a weak COX-1
inhibitor, is safe in low doses, but may produce symptoms if high doses
are taken. The incidence is between 5% and 10% of predominantly
adolescents with asthma; it is rare in children <10 yr of age. Following
ingestion of the drug, symptoms may appear between 30 and 120 min
and include profuse rhinorrhea, nasal congestion, and tearing, accom-
panied by bronchospasm. Vocal cord spasm and an anaphylactic-like
reaction are rare complications. Aspirin and related drugs should be
avoided in these patients; an alternative approach is aspirin desensitiza-
tion by an allergist.
Treating Comorbid Conditions
Rhinitis, sinusitis, and GER often accompany asthma and worsen
disease severity. They can also mimic asthma symptoms and lead to
misclassification of asthma severity and control. Indeed, these condi-
tions with asthma are the most common causes of chronic coughing.
Effective management of these comorbid conditions may improve
asthma symptoms and disease severity, such that less asthma medica-
tion is needed to achieve good asthma control.
GER is observed in 43% of children with persistent asthma. GER
may worsen asthma through 2 postulated mechanisms: (1) aspiration
of refluxed gastric contents (micro- or macro-aspiration); and (2)
vagally mediated reflex bronchospasm. Occult GER should be sus-
pected in individuals with difficult-to-control asthma, especially
patients who have prominent asthma symptoms while eating or sleep-
ing (in a horizontal position) or who prop themselves up in bed to
reduce nocturnal symptoms. GER can be demonstrated by reflux of
barium into the esophagus during a barium swallow procedure or by
esophageal probe monitoring. Because radiographic studies lack suf-
ficient sensitivity and specificity, extended esophageal monitoring is
the method of choice for diagnosing GER. If significant GER is noted,
reflux precautions should be instituted (no food 2 hr before bedtime,
head of the bed elevated 6 in, avoidance of caffeinated foods and bever-
ages) and medications such as proton pump inhibitors (omeprazole,
lansoprazole) or H2-receptor antagonists (cimetidine, ranitidine)
administered for 8-12 wk. Proton pump inhibition did not improve
asthma control in a study of children with persistent, poorly controlled
asthma and GER.
Rhinitis is usually comorbid with asthma, detected in ≈90% of
children with asthma. Rhinitis can be seasonal and/or perennial,
with allergic and nonallergic components. Rhinitis complicates and
worsens asthma via numerous direct and indirect mechanisms. Nasal
breathing may improve asthma and reduce exercise-induced broncho-
spasm by humidifying and warming inspired air and filtering out
allergens and irritants that can trigger asthma and worsen airway
inflammation. Reduction of nasal congestion and obstruction can
help the nose to perform these humidifying, warming, and filtering
functions. In asthmatic patients, improvement in rhinitis is also asso-
ciated with improvement in AHR, lower airways inflammation,
asthma symptoms, and asthma medication use. Optimal rhinitis man-
agement in children is similar to asthma management in regard to the
importance of interventions to reduce nasal inflammation (see
Chapter 143).
Radiographic evidence for sinus disease is common in patients with
asthma. There is usually significant improvement in asthma control in
patients diagnosed and treated for sinus disease. A coronal, “screening”
or “limited” CT scan of the sinuses is the gold standard test for sinus
disease and can be helpful if recurrent sinusitis has been suspected and
repeatedly treated without such evidence. In comparison, sinus X-rays
are inaccurate. If the patient with asthma has clinical and radiographic
evidence for sinusitis, topical therapy to include nasal saline irriga-
tions, intranasal corticosteroids, and a 2-3–wk course of antibiotics
should be considered.
1106 Part XV ◆ Allergic Disorders

Component 4: Principles of Asthma
Pharmacotherapy
The current version of NIH asthma guidelines (2007) provides treat-
ment recommendations that vary by age groups and are based on
current evidence (Table 144-12). The goals of therapy are to achieve a
well-controlled state by reducing the components of both impairment
(e.g., preventing chronic and troublesome symptoms, allowing infre-
quent need of quick-reliever medications, maintaining “normal” lung
function, maintaining normal activity levels including physical activity
and school attendance, meeting families’ expectations and satisfaction

Table 144-12 Stepwise Approach for Managing Asthma in Children*

INTERMITTENT
AGE THERAPY† ASTHMA PERSISTENT ASTHMA: DAILY MEDICATION

STEP UP if needed (first check inhaler

STEP DOWN if possible (and asthma is well ASSESS technique, adherence, environmental control,
controlled at least 3 months) CONTROL and comorbid condition)

Step 1 Step 2 Step 3 Step 4 Step 5 Step 6

0-4 yr Preferred SABA prn Low-dose ICS Medium-dose ICS Medium-dose ICS High-dose ICS + High-dose ICS +
+ either either either
LABA LABA LABA
or or or
LTRA LTRA LTRA
and
Oral corticosteroid
Alternative Cromolyn or
montelukast
5-11 yr Preferred SABA prn Low-dose ICS Either low-dose ICS Medium-dose ICS High-dose ICS + High-dose ICS +
± LABA, LTRA, or + LABA LABA LABA
theophylline and
or Oral corticosteroid
Medium-dose ICS
Alternative Cromolyn, LTRA, Medium-dose ICS High-dose ICS + High-dose ICS +
nedocromil, or + either either either
theophylline LTRA LTRA LTRA
or or or
Theophylline Theophylline Theophylline and
Oral corticosteroid
≥12 yr Preferred SABA prn Low-dose ICS Low-dose ICS + Medium-dose ICS High-dose ICS + High-dose ICS +
LABA + LABA LABA LABA + oral
or and corticosteroid
Medium-dose ICS Consider and
omalizumab Consider omalizumab
for patients for patients with
with allergies allergies
Alternative Cromolyn, LTRA, Low-dose ICS Medium-dose
nedocromil, or + LTRA, ICS + LTRA,
theophylline theophylline, theophylline, or
or zileuton zileuton
Each step: Patient education, environmental control, and management of comorbidities.
Age ≥5 yr: Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma.
QUICK-RELIEF MEDICATION FOR ALL PATIENTS
SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-min intervals as
needed. Short course of oral systemic corticosteroids may be needed.
Caution: Use of SABA >2 days/wk for symptom relief (not prevention of exercise-induced bronchospasm) generally indicates
inadequate control and the need to step up treatment.
For ages 0-4 yr: With viral respiratory infection: SABA q4-6h up to 24 hr (longer with physician consult). Consider short course of
systemic corticosteroids if exacerbation is severe or patient has history of previous severe exacerbations.
*Notes:
• The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.
• If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before stepping up.
• If clear benefit is not observed within 4-6 wk and patient/family medication technique and adherence are satisfactory, consider adjusting therapy or alternative
diagnosis.
• Studies on children age 0-4 yr are limited. The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient
needs.
• Clinicians who administer immunotherapy or omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur.
• Theophylline is a less desirable alternative because of the need to monitor serum concentration levels.
• Zileuton is less desirable alternative because of limited studies as adjunctive therapy and the need to monitor liver function.
†
Alphabetical order is used when more than 1 treatment option is listed within either preferred or alternative therapy.
ICS, inhaled corticosteroid; LABA, inhaled long-acting β2-agonist; LTRA, leukotriene receptor antagonist; prn, as needed; SABA, inhaled short-acting β2-agonist.
Adapted from the National Asthma Education and Prevention Program: Expert Panel Report 3 (EPR 3): Guidelines for the diagnosis and management of asthma—
summary report 2007, J Allergy Clin Immunol 120(Suppl):S94–S138, 2007.

with asthma care) and risk (e.g., preventing recurrent exacerbations,
reduced lung growth, and medications’ adverse effects). The recom-
mendations for initial therapy are based on assessment of asthma
severity. For patients who are already using controller therapy, modi-
fication of treatment is based on assessment of asthma control and
responsiveness to therapy. A major objective of this approach is to
identify and treat all “persistent” and inadequately controlled asthma
with antiinflammatory controller medication. Daily controller therapy
is not recommended for children with “intermittent asthma.” Manage-
ment of intermittent asthma is simply the use of a SABA as needed for
symptoms and for pretreatment in those with exercise-induced broncho-
spasm (Step 1 therapy; see Table 144-12).
The preferred treatment for all patients with persistent asthma is daily
ICS therapy, as monotherapy or in combination with adjunctive therapy.
The type(s) and amount(s) of daily controller medications to be used
are determined by the asthma severity and control rating. Alternative
medications for Step 2 therapy include a leukotriene receptor antago-
nist (montelukast), nonsteroidal antiinflammatory agents (cromolyn
and nedocromil), and theophylline (for youths). For young children
(≤4 yr) with moderate or severe persistent asthma, medium-dose ICS
monotherapy is recommended (Step 3); combination therapy is recom-
mended only as a Step 4 treatment for uncontrolled asthma.
Along with medium-dose ICSs, combination therapy with an ICS
plus any of the following adjunctive therapies (depending on age
group) is recommended as Steps 3 and 4 treatment for moderate
persistent asthma, or as step-up therapy for uncontrolled persistent
asthma: long-acting inhaled β2-agonists (LABAs), leukotriene-
modifying agents, chromones, and theophylline. In a study of children
with uncontrolled asthma while on low-dose ICS, the addition of
LABA provided more improvement than either adding a leukotriene
receptor antagonist (LTRA) or increasing ICS dosage. However, some
children had a good response to ICS or LTRA, justifying them as
step-up controller therapy options.
Children with severe persistent asthma (treatment Steps 5 and 6)
should receive high-dose ICS and LABA. Long-term administration of
oral corticosteroids as controller therapy can be effective, but is rarely
needed with the availability of potent ICS and LABA combination
formulations in single devices. In addition, omalizumab can be used
in children ≥12 yr old with severe allergic asthma. A rescue course of
systemic corticosteroids may be necessary at any step. For children age
≥5 yr with allergic asthma requiring Steps 2-4 care, allergen immuno-
therapy can be considered.
“Step-Up, Step-Down” Approach
The NIH guidelines emphasize initiating higher-level controller
therapy at the outset to establish prompt control, with measures to
“step down” therapy once good asthma control is achieved. Initially,
airflow limitation and the pathology of asthma may limit the delivery
and efficacy of ICS such that stepping up to higher doses and/or com-
bination therapy may be needed to gain asthma control. Furthermore,
ICS requires weeks to months of daily administration for optimal effi-
cacy to occur. Combination pharmacotherapy can achieve relatively
immediate improvement while also providing daily ICS to improve
long-term control and reduce exacerbation risk.
Asthma therapy can be stepped down after good asthma control has
been achieved and ICS has had time to achieve optimal efficacy. By
determining the lowest number or dose of daily controller medica-
tions that can maintain good control, the potential for medication
adverse effects is reduced. If a child has had well-controlled asthma
for at least 3 mo, the guidelines suggest decreasing the dose or number
of the child’s controller medication(s) to establish the minimum
required medications to maintain well-controlled asthma. Regular
follow-up is still emphasized because the variability of asthma’s course
is well recognized. In contrast, if a child has not-well-controlled
asthma, the therapy level should be increased by 1 step and close
monitoring is recommended. For a child with very poorly controlled
asthma, the recommendations are that treatment go up 2 steps and/
or a short course of oral corticosteroid therapy be given, with evalua-
tion within 2 wk. As step-up therapy is being considered at any point,
Chapter 144 ◆ Childhood Asthma 1107
it is important to check inhaler technique and adherence, implement
environmental control measures, and identify and treat comorbid
conditions.
Referral to Asthma Specialist
Referral to an asthma specialist for consultation or co-management is
recommended if there are difficulties in achieving or maintaining
control. For children younger than 4 yr, referral is recommended for
moderate persistent asthma or if the patient requires at least Step 3
care, and should be considered if the patient requires Step 2 care. For
children 5 yr of age and older, consultation with a specialist is recom-
mended if the patient requires Step 4 care or higher, and should be
considered if Step 3 is required. Referral is also recommended if aller-
gen immunotherapy or anti–immunoglobulin (Ig) E therapy is being
considered.
Long-Term Controller Medications
All levels of persistent asthma should be treated with daily medications
to improve long-term control (see Table 144-12). Such medications
include ICSs, LABAs, leukotriene modifiers, nonsteroidal antiinflam-
matory agents, and sustained-release theophylline. An anti-IgE prepa-
ration, omalizumab (Xolair), is approved by the FDA for use as an
add-on therapy in children ≥12 yr who have moderate to severe aller-
gic asthma that is difficult to control. Corticosteroids are the most
potent and most effective medications used to treat both the acute
(administered systemically) and chronic (administered by inhalation)
manifestations of asthma. They are available in inhaled, oral, and par-
enteral forms (Tables 144-13 and 144-14).
Inhaled Corticosteroids
The NIH guidelines recommend daily ICS therapy as the treatment of
choice for all patients with persistent asthma (see Table 144-12). ICS
therapy improves lung function as well as reduces asthma symptoms,
AHR, and use of “rescue” medications; most importantly, it reduces
urgent care visits, hospitalizations, and prednisone use for asthma
exacerbations by approximately 50%. ICS therapy may lower the risk
of death attributable to asthma. It can achieve all of the goals of asthma
management and, as a result, is viewed as first-line treatment for per-
sistent asthma.
Six ICSs are approved for use in children by the FDA, and the NIH
guidelines provide an equivalence classification (see Table 144-14),
although direct comparisons of efficacy and safety outcomes in chil-
dren are lacking. ICSs are available in metered-dose inhalers (MDIs),
in dry powder inhalers (DPIs), or in suspension for nebulization. Fluti-
casone propionate, mometasone furoate, ciclesonide, and, to a lesser
extent, budesonide are considered “second-generation” ICSs, in that
they have greater antiinflammatory potency and diminished systemic
bioavailability for potential adverse effects, owing to extensive first-
pass hepatic metabolism. The selection of the initial ICS dose is based
on the determination of disease severity. A fraction of the initial ICS
dose is often sufficient to maintain good control after this goal has been
achieved.
Although ICS therapy has been widely used in adults with persistent
asthma, its application in children has lagged because of concerns
about the potential for adverse effects with long-term use. Generally,
clinically significant adverse effects that occur with long-term systemic
corticosteroid therapy have not been seen or have only very rarely been
reported in children receiving ICSs in recommended doses. The risk
of adverse effects from ICS therapy is related to the dose and frequency
with which ICSs are given (Table 144-15). High doses (≥1,000 μg/day
in children) and frequent administration (4 times/day) are more
likely to have local and systemic adverse effects. Children who receive
maintenance therapy with higher ICS doses are also likely to require
systemic corticosteroid courses for asthma exacerbations, further
increasing the risk of corticosteroid adverse effects.
The most commonly encountered adverse effects of ICSs are local:
oral candidiasis (thrush) and dysphonia (hoarse voice). Thrush results
from propellant-induced mucosal irritation and local immunosuppres-
sion. Dysphonia occurs from vocal cord myopathy. These effects are
1108 Part XV ◆ Allergic Disorders

Table 144-13 Usual Dosages for Long-Term Control Medications

Medication
INHALED CORTICOSTEROIDS (see Table 144-13)
Methylprednisolone:
2, 4, 8, 16, 32 mg tablets
Prednisolone:
5 mg tablets; 5 mg/5 mL,
15 mg/5 mL
Prednisone:
1, 2.5, 5, 10, 20, 50 mg tablets; 5 mg/
mL, 5 mg/5 mL
Fluticasone/salmeterol:
DPI: 100, 250, or 500 mg/50 mg
HFA: 45 μg/21 μg, 115 μg/21 μg,
230 μg/21 μg
Budesonide/formoterol:
HFA: 80 μg/4.5 μg, 160 μg/4.5 μg
Mometasone/formoterol
HFA: 100 μg/5 μg, 200 μg/5 μg
Cromolyn:
Nebulizer 20 mg/ampule
Leukotriene receptor antagonists:
Montelukast:
4 or 5 mg chewable tablet
4 mg granule packets
10 mg tablet
Zafirlukast:
10- or 20-mg tablet
5-Lipoxygenase inhibitor:
Zileuton CR: 600-mg tablet
Theophylline:
Liquids, sustained-release tablets,
and capsules
Immunomodulators:
Omalizumab (anti-IgE):
Subcutaneous injection,
150 mg/1.2 mL after reconstitution
with 1.4 mL sterile water for
injection
bid, Twice a day; DPI, dry powder inhaler; HFA, hydrofluoroalkane Ig, immunoglobulin; MDI, metered-dose inhaler; q, every; qhs, every night; qid, 4 times a day;
qod, every other day; SC, subcutaneous.
0-4 yr
• 0.25-2 mg/kg daily in single
dose in A.M. or qod as
needed for control
• Short-course “burst”:
1-2 mg/kg/day; maximum
30 mg/day for 3-10 days
NA
NA
1 ampule qid; NA <2 yr of age
4 mg qhs (1-5 yr of age)
NA
NA
Starting dose 10 mg/kg/day;
usual max:
• <1 yr of age: 0.2 (age in wk)
+ 5 = mg/kg/day
• >1 yr of age: 16 mg/kg/day
NA
AGE
5-11 yr ≥12 yr
• 0.25-2 mg/kg daily in single • 7.5-60 mg daily in a single dose
dose in A.M. or qod as in A.M. or qod as needed for
needed for control control
• Short-course “burst”: 1-2 mg/ • Short-course “burst” to achieve
kg/day; maximum 60 mg/day control: 40-60 mg/day as single
for 3-10 days or 2 divided doses for 3-10
days
1 inhalation bid; dose depends 1 inhalation bid; dose depends
on level of severity or control on level of severity or control
2 inhalations bid; dose depends
on level of severity or control
2 inhalations bid; dose depends
on level of severity or control
2 inhalations bid; dose depends
on level of severity or control
1 ampule qid 1 ampule qid
5 mg qhs (6-14 yr) 10 mg qhs
10 mg bid (7-11 yr) 40 mg daily (20 mg tablet bid)
NA 1,200 mg twice daily (give 2
tablets bid)
Starting dose 10 mg/kg/day; Starting dose 10 mg/kg/day up to
usual maximum: 16 mg/kg/day 300 mg maximum; usual
maximum 800 mg/day
NA 150-375 mg SC q 2-4 wk,
depending on body weight and
pretreatment serum IgE level

dose-dependent and are most common in individuals receiving high-
dose ICS and/or oral corticosteroid therapy. The incidence of these
local effects can be greatly minimized by using a spacer with an MDI
ICS, because spacers reduce oropharyngeal deposition of the drug and
propellant. Mouth rinsing using a “swish and spit” technique after ICS
use is also recommended.
The potential for growth suppression and osteoporosis with long-
term ICS use has been a concern. In the long-term, prospective NIH-
sponsored CAMP study of children with mild to moderate asthma,
after ≈4.3 yr of ICS therapy and 5 yr after the trial, there was a signifi-
cant 1.7 cm decrease in height in girls, but not in boys. There was also
a slight dose-dependent effect of ICS therapy on bone mineral accretion
in boys, but not girls. A greater effect on bone mineral accretion was
observed with increasing numbers of courses of oral corticosteroid
burst therapy for asthma, as well as an increase in risk for osteopenia,
again limited to boys. Although this study cannot predict a significant
effect of ICS therapy in childhood on osteoporosis in later adulthood,
improved asthma control with ICS therapy may result in a need for
fewer courses of oral corticosteroid burst therapy over time. These
findings were with use of budesonide at doses of about 400 μg/day;
higher ICS doses, especially of agents with increased potency, have a
greater potential for adverse effects. Hence, corticosteroid adverse
effects screening and osteoporosis prevention measures are recom-
mended for patients receiving higher ICS doses, as these patients are
also likely to require systemic courses for exacerbations (see Table
144-15).
Systemic Corticosteroids
ICS therapy has allowed the large majority of children with asthma to
maintain good disease control without maintenance oral corticosteroid
therapy. Oral corticosteroids are used primarily to treat asthma exac-
erbations and, rarely, in patients with severe disease who remain symp-
tomatic despite optimal use of other asthma medications. In these
severely asthmatic patients, every attempt should be made to exclude
any comorbid conditions and to keep the oral corticosteroid dose at
≤20 mg qod. Doses exceeding this amount are associated with numer-
ous adverse effects (see Chapter 577). To determine the need for con-
tinued oral corticosteroid therapy, tapering of the oral corticosteroid
 Chapter 144 ◆ Childhood Asthma 1109

Table 144-14 Estimated Comparative Inhaled Corticosteroid Doses

LOW DAILY DOSE BY AGE MEDIUM DAILY DOSE BY AGE HIGH DAILY DOSE BY AGE
Drug 0-4 yr 5-11 yr ≥12 yr 0-4 yr 5-11 yr ≥12 yr 0-4 yr 5-11 yr ≥12 yr
Beclomethasone NA 80-160 μg 80-240 μg NA >160-320 μg >240-480 μg NA >320 μg >480 μg
HFA, 40 or
80 μg/puff
Budesonide DPI 90, NA 180-400 μg 180-600 μg NA >400-800 μg >600-1200 μg NA >800 μg >1200 μg
180, or 200 μg/
inhalation
Budesonide inhaled 0.25-0.5 mg 0.5 mg NA >0.5-1.0 mg 1.0 mg NA >1.0 mg 2.0 mg NA
suspension for
nebulization, 0.25,
0.5, and 1.0 mg
dose
Flunisolide, NA 500-750 μg 500-1000 μg NA 1000-1250 μg >1000-2000 μg NA >1250 μg >2000 μg
250 μg/puff
Flunisolide HFA, NA 160 μg 320 μg NA 320 μg >320-640 μg NA ≥640 μg >640 μg
80 μg/puff
Fluticasone HFA/ 176 μg 88-176 μg 88-264 μg >176-352 μg >176-352 μg >264-440 μg >352 μg >352 μg >440 μg
MDI: 44, 110, or
220 μg/puff
Fluticasone DPI, 50, NA 100-200 μg 100-300 μg NA >200-400 μg >300-500 μg NA >400 μg >500 μg
100, or 250 μg/
inhalation
Mometasone DPI, NA NA 220 μg NA NA 440 μg NA NA >440 μg
110 μg and
220 μg/inhalation
Triamcinolone NA 300-600 μg 300-750 μg NA >600-900 μg >750-1500 μg NA >900 μg >1500 μg
acetonide,
75 μg/puff
DPI, dry powder inhaler; HFA, hydrofluoroalkane; MDI, metered-dose inhaler; NA, not approved and no data available for this age group.
Adapted, from the National Asthma Education and Prevention Program: Expert Panel Report 3 (EPR 3): guidelines for the diagnosis and management of asthma—
summary report 2007, J Allergy Clin Immunol 120(Suppl):S94–S138, 2007.

Table 144-15 Risk Assessment for Corticosteroid Adverse Effects

CONDITIONS
Low risk (≤1 risk factor*)
Low- to medium-dose ICS (see Table 144-11)
Medium risk (If >1 risk factor,* consider evaluating as high
risk)
High-dose ICS (see Table 144-11)
At least 4 courses oral corticosteroid/yr
High risk Chronic systemic corticosteroids (>7.5 mg
daily or equivalent for >1 mo)
≥ 7 oral corticosteroid burst treatments/year
Very-high-dose ICS (e.g., fluticasone
propionate ≥800 μg/day)
*Risk factors for osteoporosis: Presence of other chronic illness(es), medications (corticosteroids, anticonvulsants, heparin, diuretics), low body weight, family history of
osteoporosis, significant fracture history disproportionate to trauma, recurrent falls, impaired vision, low dietary calcium and vitamin D intake, and lifestyle factors
(decreased physical activity, smoking, and alcohol intake).
DEXA, dual-energy x-ray absorptiometry; ICS, inhaled corticosteroid; TSH, thyroid-stimulating hormone.
RECOMMENDATIONS
• Monitor blood pressure and weight with each physician visit
• Measure height annually (stadiometry); monitor periodically for declining
growth rate and pubertal developmental delay
• Encourage regular physical exercise
• Ensure adequate dietary calcium and vitamin D with additional supplements
for daily calcium if needed
• Avoid smoking and alcohol
• Ensure TSH status if patient has history of thyroid abnormality
As above, plus:
• Yearly ophthalmologic evaluations to monitor for cataracts or glaucoma
• Baseline bone densitometry (DEXA scan)
• Consider patient at increased risk for adrenal insufficiency, especially with
physiologic stressors (e.g., surgery, accident, significant illness)
As above, plus:
• DEXA scan: if DEXA Z score ≤1.0, recommend close monitoring (every 12 mo)
• Consider referral to a bone or endocrine specialist
• Bone age assessment
• Complete blood count
• Serum calcium, phosphorus, alkaline phosphatase determinations
• Urine calcium and creatinine measurements
• Measurements of testosterone in males, estradiol in amenorrheic
premenopausal women, vitamin D (25-OH and 1,25-OH vitamin D),
parathyroid hormone, and osteocalcin
• Urine telopeptides for those receiving long-term systemic or frequent oral
corticosteroid treatment
• Assume adrenal insufficiency for physiologic stressors (e.g., surgery, accident,
significant illness)
1110 Part XV ◆ Allergic Disorders
dose (over several weeks to months) should be considered, with close
monitoring of the patient’s symptoms and lung function.
When administered orally, prednisone, prednisolone, and methyl-
prednisolone are rapidly and completely absorbed, with peak plasma
concentrations occurring within 1-2 hr. Prednisone is an inactive
prodrug that requires biotransformation via first-pass hepatic metabo-
lism to prednisolone, its active form. Corticosteroids are metabolized
in the liver into inactive compounds, with the rate of metabolism
influenced by drug interactions and disease states. Anticonvulsants
(phenytoin, phenobarbital, carbamazepine) increase the metabolism of
prednisolone, methylprednisolone, and dexamethasone, with methyl-
prednisolone most significantly affected. Rifampin also enhances the
clearance of corticosteroids and can result in diminished therapeutic
effect. Other medications (ketoconazole, oral contraceptives) can
significantly delay corticosteroid metabolism. Macrolide antibiotics
(erythromycin, clarithromycin, troleandomycin) delay the clearance of
only methylprednisolone.
Children who require long-term oral corticosteroid therapy are at
risk for development of associated adverse effects over time. Essentially
all major organ systems can be adversely affected by long-term oral
corticosteroid therapy (see Chapter 577). Some of these effects occur
immediately (metabolic effects). Others can develop insidiously over
several months to years (growth suppression, osteoporosis, cataracts).
Most adverse effects occur in a cumulative dose- and duration-
dependent manner. Children who require routine or frequent short
courses of oral corticosteroids, especially with concurrent high-dose
ICSs, should receive corticosteroid adverse effects screening (see Table
144-15) and osteoporosis preventive measures (see Chapter 707).
Long-Acting Inhaled β-Agonists
LABAs (salmeterol, formoterol) are considered to be daily controller
medications, not intended for use as rescue medication for acute
asthma symptoms or exacerbations, nor as monotherapy for persis-
tent asthma. Controller formulations that combine an ICS with a
LABA (fluticasone/salmeterol, budesonide/formoterol, mometasone/
formoterol) are available and recommended, in lieu of separate inhaler
delivery devices. Salmeterol has a prolonged onset of action, with
maximal bronchodilation approximately 1 hr after administration,
whereas formoterol has an onset of action within 5-10 min. Both medi-
cations have a prolonged duration of effect, at least 12 hr. Given their
long duration of action, they are well suited for patients with nocturnal
asthma and for individuals who require frequent SABA use during the
day to prevent exercise-induced bronchospasm. Their major role is as
an add-on agent in patients whose asthma is suboptimally controlled
with ICS therapy alone. For those patients, the addition of a LABA to
ICS therapy is superior to doubling the dose of ICS, especially on day
and nocturnal symptoms. Of note, the FDA requires all LABA-
containing medications to be labeled with a warning of an increase in
severe asthma episodes associated with these agents. Some studies have
reported a higher number of asthma-related deaths among patients
receiving LABA therapy in addition to their usual asthma care than in
patients not receiving LABAs. This notice reinforces the appropriate use
of LABAs in the management of asthma. Specifically, LABA products
should not be initiated as first-line or sole asthma therapy without the
concomitant use of an ICS, used with worsening wheezing, or used for
acute control of bronchospasm. LABAs should be stopped once asthma
control is achieved, and the asthma should be maintained with the use
of an asthma controller agent (ICS). Fixed-dose preparations (with an
ICS) are recommended to ensure compliance with these guidelines.
Leukotriene-Modifying Agents
Leukotrienes are potent proinflammatory mediators that can induce
bronchospasm, mucus secretion, and airways edema. Two classes of
leukotriene modifiers have been developed: inhibitors of leukotriene
synthesis and LTRAs. Zileuton, the only leukotriene synthesis inhibi-
tor, is not approved for use in children <12 yr of age. Because zileuton
can result in elevated liver function enzyme values in 2-4% of patients,
and interacts with medications metabolized via the cytochrome P450
system, it is rarely prescribed for children with asthma.
LTRAs have bronchodilator and targeted antiinflammatory proper-
ties and reduce exercise-, aspirin-, and allergen-induced bronchocon-
striction. LTRAs are recommended as alternative treatment for mild
persistent asthma and as add-on medication with ICS for moderate
persistent asthma. Two LTRAs are FDA-approved for use in children:
montelukast and zafirlukast. Both medications improve asthma symp-
toms, decrease the need for rescue β-agonist use, and improve lung
function. Montelukast is FDA-approved for use in children ≥1 yr of
age and is administered once daily. Zafirlukast is FDA-approved for
use in children ≥5 yr of age and is administered twice daily. Although
incompletely studied in children with asthma, LTRAs appear to be less
effective than ICSs in patients with mild persistent asthma. In general,
ICSs improve lung function by 5-15%, whereas LTRAs improve lung
function by 2-7.5%. LTRAs are not thought to have significant adverse
effects, although case reports described a Churg-Strauss–like vasculitis
(pulmonary infiltrates, eosinophilia, cardiomyopathy) in adults with
corticosteroid-dependent asthma treated with LTRAs. It remains to
be determined whether these patients have a primary eosinophilic
vasculitis masquerading as asthma, which was “unmasked” as the oral
corticosteroid dose was tapered, or whether the disease is a very rare
adverse effect of LTRA. Montelukast has rarely been associated with
mood changes and suicidality.
Nonsteroidal Antiinflammatory Agents
Cromolyn and nedocromil are nonsteroidal antiinflammatory agents
that can inhibit allergen-induced asthmatic responses and reduce
exercise-induced bronchospasm. Both drugs are considered alternative
antiinflammatory drugs for children with mild persistent asthma.
Although largely devoid of adverse effects, these medications must be
administered frequently (2-4 times/day) and are not nearly as effective
daily controller medications as ICSs and leukotriene-modifying agents.
Because they inhibit exercise-induced bronchospasm, they can be used
in place of SABAs, especially in children who develop unwanted
adverse effects with β-agonist therapy (tremor and elevated heart rate).
Cromolyn and nedocromil can also be used in addition to a SABA in
a combination pretreatment for exercise-induced bronchospasm in
patients who continue to experience symptoms with use of SABA
pretreatment alone. Nedocromil has been taken off the market and
cromolyn is only available in a solution for nebulization.
Theophylline
In addition to its bronchodilator effects, theophylline has antiinflam-
matory properties as a phosphodiesterase inhibitor, although the
extent of its clinical relevance has not been clearly established. When
used long-term, theophylline can reduce asthma symptoms and the
need for rescue SABA use. Although it is considered an alternative
monotherapy controller agent for older children and adults with mild
persistent asthma, it is no longer considered a first-line agent for
young children, in whom there is significant variability in the absorp-
tion and metabolism of different theophylline preparations, necessi-
tating frequent dose monitoring (drug blood levels) and adjustments.
Because theophylline may have some corticosteroid-sparing effects
in individuals with oral corticosteroid–dependent asthma, it is still
sometimes used in this group of asthmatic children. Theophylline
has a narrow therapeutic window; therefore, when it is used, serum
theophylline levels need to be routinely monitored, especially if
the patient has a viral illness associated with a fever or is started
on a medication known to delay theophylline clearance, such as a
macrolide antibiotic, cimetidine, an oral antifungal agent, an oral
contraceptive, a leukotriene synthesis inhibitor, or ciprofloxacin. The-
ophylline overdosage and elevated theophylline levels have been
associated with headaches, vomiting, cardiac arrhythmias, seizures,
and death.
Anti–Immunoglobulin E (Omalizumab)
Omalizumab is a humanized monoclonal antibody that binds IgE,
thereby preventing its binding to the high-affinity IgE receptor and
blocking IgE-mediated allergic responses and inflammation. Because
it is unable to bind IgE that is already bound to high-affinity IgE
 Chapter 144 ◆ Childhood Asthma 1111

receptors, the risk of anaphylaxis via direct IgE cross linking by the
drug is circumvented. It is FDA-approved for patients >12 yr old with
moderate to severe asthma, documented hypersensitivity to a peren-
nial aeroallergen, and inadequate disease control with inhaled and/or
oral corticosteroids. Omalizumab is given every 2-4 wk subcutane-
ously, the dosage based on body weight and serum IgE levels. Asth-
matic patients receiving omalizumab have fewer asthma exacerbations
and symptoms while able to reduce their ICS and/or oral corticosteroid
doses. This agent is generally well tolerated, although local injection
site reactions can occur. Hypersensitivity reactions (including anaphy-
laxis) and malignancies have been very rarely associated with omali-
zumab use. The FDA requires packaging of omalizumab to contain a
black box warning of potentially serious and life-threatening anaphy-
lactic reactions with omalizumab treatment. On the basis of reports
from approximately 39,500 patients, anaphylaxis following omali-
zumab treatment occurred in at least 0.1% of treated people. Although
most of these reactions occurred within 2 hr of omalizumab injection,
there are reports of serious delayed reactions 2-24 hr or even longer
after injections. Anaphylaxis occurred after any omalizumab dose
(including the first dose). Omalizumab-treated patients should be
observed in the facility for an extended period after the drug is given,
and medical providers who administer the injection should be pre-
pared to manage life-threatening anaphylactic reactions. Patients who
receive omalizumab should be fully informed about the signs and
symptoms of anaphylaxis, their chance of development of delayed ana-
phylaxis following each injection, and how to treat it, including the use
of autoinjectable epinephrine.
Mepolizumab, an anti–IL-5 antibody, has been shown to improve
asthma control, reduce prednisone dose and lower sputum and blood
eosinophil events in adults with prednisone-dependent asthma who
also had sputum eosinophils. Dupilumab, an anti–IL-4 receptor anti-
body and another monoclonal antibody against IL-13, have also shown
promise in adult studies.
Quick-Reliever Medications
Quick-reliever or “rescue” medications (SABAs, inhaled anticholiner-
gics, and short-course systemic corticosteroids) are used in the man-
agement of acute asthma symptoms (Table 144-16).

Table 144-16 Management of Asthma Exacerbation (Status Asthmaticus)

RISK ASSESSMENT ON ADMISSION
Focused history
Clinical assessment
Risk factors for asthma morbidity and death
TREATMENT
Drug and Trade Name
Oxygen (mask or nasal cannula)
Inhaled short-acting β-agonists:
Albuterol nebulizer solution (5 mg/mL
concentrate; 2.5 mg/3 mL,
1.25 mg/3 mL, 0.63 mg/3 mL)
Albuterol MDI (90 μg/puff)
Levalbuterol (Xopenex) nebulizer
solution (1.25 mg/0.5 mL concentrate;
0.31 mg/3 mL, 0.63 mg/3 mL,
1.25 mg/3 mL)
Systemic corticosteroids:
• Onset of current exacerbation
• Frequency and severity of daytime and nighttime symptoms and activity limitation
• Frequency of rescue bronchodilator use
• Current medications and allergies
• Potential triggers
• History of systemic steroid courses, emergency department visits, hospitalization, intubation,
or life-threatening episodes
• Physical examination findings: vital signs, breathlessness, air movement, use of accessory
muscles, retractions, anxiety level, alteration in mental status
• Pulse oximetry
• Lung function (defer in patients with moderate to severe distress or history of labile disease)
See Table 144-17
Mechanisms of Action and Dosing Cautions and Adverse Effects
Treats hypoxia • Monitor pulse oximetry to maintain O2
saturation >92%
• Cardiorespiratory monitoring
Bronchodilator • During exacerbations, frequent or continuous
doses can cause pulmonary vasodilation,
! ! mismatch, and hypoxemia
V/Q
• Adverse effects: palpitations, tachycardia,
arrhythmias, tremor, hypoxemia
Nebulizer: 0.15 mg/kg (minimum: 2.5 mg) as • Nebulizer: when giving concentrated forms,
often as every 20 min for 3 doses as needed, dilute with saline to 3 mL total nebulized
then 0.15-0.3 mg/kg up to 10 mg every 1-4 hr volume
as needed, or up to 0.5 mg/kg/hr by
continuous nebulization
2-8 puffs up to every 20 min for 3 doses as • For MDI: use spacer/holding chamber
needed, then every 1-4 hr as needed
0.075 mg/kg (minimum: 1.25 mg) every 20 min • Levalbuterol 0.63 mg is equivalent to
for 3 doses, then 0.075-0.15 mg/kg up to 5 mg 1.25 mg of standard albuterol for both
every 1-4 hr as needed, or 0.25 mg/kg/hr by efficacy and side effects
continuous nebulization
Antiinflammatory • If patient has been exposed to chickenpox
or measles, consider passive immunoglobulin
prophylaxis; also, risk of complications with
herpes simplex and tuberculosis
• For daily dosing, 8 A.M. administration
minimizes adrenal suppression
• Children may benefit from dosage tapering if
course exceeds 7 days
• Adverse effects monitoring: Frequent
therapy bursts risk numerous corticosteroid
adverse effects (see Chapter 578); see Table
144-15 for adverse effects screening
recommendations
Continued
1112 Part XV ◆ Allergic Disorders

Table 144-16 Management of Asthma Exacerbation (Status Asthmaticus)—cont’d

Prednisone: 1, 2.5, 5, 10, 20, 50 mg tablets
Methylprednisolone (Medrol): 2, 4, 8, 16,
24, 32 mg tablets
Prednisolone: 5 mg tablets; 5 mg/5 mL
and 15 mg/5 mL solution
Depo-Medrol (IM); Solu-Medrol (IV)
Anticholinergics:
Ipratropium:
Atrovent (nebulizer solution
0.5 mg/2.5 mL; MDI 18 μg/inhalation)
Ipratropium with albuterol:
DuoNeb nebulizer solution (0.5 mg
ipratropium + 2.5 mg albuterol/3 mL
vial)
Injectable sympathomimetic epinephrine:
Adrenalin 1 mg/mL (1 : 1000)
EpiPen autoinjection device (0.3 mg;
EpiPen Jr 0.15 mg)
Terbutaline:
Brethine 1 mg/mL
RISK ASSESSMENT FOR DISCHARGE
Medical stability
Home supervision
Asthma education
IM, intramuscular; MDI, metered-dose inhaler; PEF, peak expiratory flow; SABA, short-acting β-agonist; SC, subcutaneous; V/Q,
0.5-1 mg/kg every 6-12 hr for 48 hr, then
1-2 mg/kg/day bid (maximum: 60 mg/day)
Short-course “burst” for exacerbation: 1-2 mg/
kg/day qd or bid for 3-7 days
Mucolytic/bronchodilator • Should not be used as first-line therapy;
added to β2-agonist therapy
Nebulizer: 0.5 mg q6-8h (tid-qid) as needed
MDI: 2 puffs qid
1 vial by nebulizer qid • Nebulizer: may mix ipratropium with
albuterol
Bronchodilator • For extreme circumstances (e.g., impending
respiratory failure despite high-dose inhaled
SABA, respiratory failure)
SC or IM: 0.01 mg/kg (max dose 0.5 mg); may
repeat after 15-30 min
• Terbutaline is β-agonist–selective relative to
epinephrine
• Monitoring with continuous infusion:
cardiorespiratory monitor, pulse oximetry,
blood pressure, serum potassium
• Adverse effects: tremor, tachycardia,
palpitations, arrhythmia, hypertension,
headaches, nervousness, nausea, vomiting,
hypoxemia
Continuous IV infusion (terbutaline only):
2-10 μg/kg loading dose, followed by
0.1-0.4 μg/kg/min
Titrate in 0.1-0.2 μg/kg/min increments every
30 min, depending on clinical response
Discharge to home if there has been sustained
improvement in symptoms and bronchodilator
treatments are at least 3 hr apart, physical
findings are normal, PEF >70% of predicted or
personal best, and oxygen saturation >92%
when breathing room air
Capability to administer intervention and to
observe and respond appropriately to clinical
deterioration
See Table 144-9
! ! ventilation–perfusion.

Short-Acting Inhaled β-Agonists Anticholinergic Agents

Given their rapid onset of action, effectiveness, and 4-6 hr duration of
action, SABAs (albuterol, levalbuterol, terbutaline, pirbuterol) are the
drugs of choice for acute asthma symptoms (“rescue” medication) and
for preventing exercise-induced bronchospasm. β-Agonists cause
bronchodilation by inducing airway smooth muscle relaxation, reduc-
ing vascular permeability and airways edema, and improving muco-
ciliary clearance. Levalbuterol, or the r-isomer of albuterol, is associated
with less tachycardia and tremor, which can be bothersome to
some asthmatic patients. Overuse of β-agonists is associated with an
increased risk of death or near-death episodes from asthma. This is a
major concern for some patients with asthma who rely on the frequent
use of SABAs as a “quick fix” for their asthma, rather than using con-
troller medications in a preventive manner. It is helpful to monitor the
frequency of SABA use, in that use of at least 1 MDI/mo or at least
3 MDIs/year (200 inhalations/MDI) indicates inadequate asthma
control and necessitates improving other aspects of asthma therapy
and management.
As bronchodilators, the anticholinergic agents (ipratropium bromide)
are less potent than the β-agonists. Inhaled ipratropium is used pri-
marily in the treatment of acute severe asthma. When used in combi-
nation with albuterol, ipratropium can improve lung function and
reduce the rate of hospitalization in children who present to the emer-
gency department with acute asthma. Ipratropium is the anticholiner-
gic formulation of choice for children because it has few central
nervous system adverse effects and it is available in both MDI and
nebulizer formulations. Although widely used in children with asthma
exacerbations of all ages, it is approved by the FDA for use in children
>12 yr of age. A long-acting inhaled anticholinergic agent, tiotropium,
is gaining interest as a potential add-on controller therapy (i.e., in
addition to ICS with or without LABA) for adults with asthma.
Delivery Devices and Inhalation Technique
Inhaled medications are delivered in aerosolized form in a MDI, as
a DPI formulation, or in a suspension or solution form delivered via a

nebulizer. In the past, MDIs, which require coordination and use of a
spacer device, have dominated the market. MDIs are now using hydro-
fluoroalkane propellant for its ozone-friendly properties, rather than
chlorofluorocarbon. Spacer devices, recommended for the administra-
tion of all MDI medications, are simple and inexpensive tools that: (1)
decrease the coordination required to use MDIs, especially in young
children; (2) improve the delivery of inhaled drug to the lower airways;
and (3) minimize the risk of propellant-mediated adverse effects
(thrush). Optimal inhalation technique for each puff of MDI-delivered
medication is a slow (5 sec) inhalation, then a 5-10 sec breathhold. No
waiting time between puffs of medication is needed. Young, preschool-
age children cannot perform this inhalation technique. MDI medica-
tions can also be delivered with a spacer and mask, using a different
technique: Each puff is administered with regular breathing for about
30 sec or 5-10 breaths, a tight seal must be maintained, and talking,
coughing, or crying will blow the medication out of the spacer. This
technique will not deliver as much medication per puff as the optimal
MDI technique used by older children and adults.
DPI devices (e.g., Diskus, Flexhaler Autohaler, Twisthaler, Aerolizer)
are popular because of their simplicity of use, albeit adequate inspira-
tory flow is needed. They are breath-actuated (the drug comes out only
as it is breathed in) and spacers are not needed. Mouth rinsing is rec-
ommended after ICS use to rinse out ICS deposited on the oral mucosa
and reduce the swallowed ICS and the risk of thrush.
Nebulizers have been the mainstay of aerosol treatment for infants
and young children. An advantage of using nebulizers is the simple
technique required of relaxed breathing. The preferential nasal breath-
ing, small airways, low tidal volume, and high respiratory rate of
infants markedly increase the difficulty of inhaled drug therapy target-
ing the lung airways. Disadvantages of nebulizers include need for a
power source, inconvenience in that treatments take about 5 min,
expense, and potential for bacterial contamination.
Asthma Exacerbations and Their Management
Asthma exacerbations are acute or subacute episodes of progressively
worsening symptoms and airflow obstruction. Airflow obstruction
during exacerbations can become extensive, resulting in life-threatening
respiratory insufficiency. Often, asthma exacerbations worsen during
sleep (between midnight and 8 a.m.), when airways inflammation and
hyperresponsiveness are at their peak. Importantly, SABAs, which are
first-line therapy for asthma symptoms and exacerbations, increase
pulmonary blood flow through obstructed, unoxygenated areas
of the lungs with increasing dosage and frequency. When airways
obstruction is not resolved with SABA use, ventilation–perfusion mis-
matching can cause significant hypoxemia, which can perpetuate bron-
choconstriction and further worsen the condition. Severe, progressive
asthma exacerbations need to be managed in a medical setting, with
administration of supplemental oxygen as first-line therapy and close
monitoring for potential worsening. Complications that can occur
during severe exacerbations include atelectasis and air leaks in the
chest (pneumomediastinum, pneumothorax).
A severe exacerbation of asthma that does not improve with stan-
dard therapy is termed status asthmaticus. Immediate management
of an asthma exacerbation involves a rapid evaluation of the severity
of obstruction and assessment of risk for further clinical deterioration
(see Tables 144-15 and 144-16). For most patients, exacerbations
improve with frequent bronchodilator treatments and a course of
systemic (oral or intravenous) corticosteroid. However, the optimal
management of a child with an asthma exacerbation should include a
more comprehensive assessment of the events leading up to the exac-
erbation and the underlying disease severity. Indeed, the frequency and
severity of asthma exacerbations help define the severity of a patient’s
asthma. Whereas most children who experience life-threatening
asthma episodes have moderate to severe asthma by other criteria,
some children with asthma appear to have mild disease except when
they suffer severe, even near-fatal exacerbations. The biologic, envi-
ronmental, economic, and psychosocial risk factors associated with
asthma morbidity and death can further guide this assessment
(Table 144-17).
Chapter 144 ◆ Childhood Asthma 1113
Table 144-17 Risk Factors for Asthma Morbidity and
Mortality
BIOLOGIC
Previous severe asthma exacerbation (intensive care unit admission,
intubation for asthma)
Sudden asphyxia episodes (respiratory failure, arrest)
Two or more hospitalizations for asthma in past year
Three or more emergency department visits for asthma in past year
Increasing and large diurnal variation in peak flows
Use of >2 canisters of short-acting β-agonists per month
Poor response to systemic corticosteroid therapy
Male gender
Low birthweight
Nonwhite (especially black) ethnicity
Sensitivity to Alternaria
ENVIRONMENTAL
Allergen exposure
Environmental tobacco smoke exposure
Air pollution exposure
Urban environment
ECONOMIC AND PSYCHOSOCIAL
Poverty
Crowding
Mother <20 yr old
Mother with less than high school education
Inadequate medical care:
Inaccessible
Unaffordable
No regular medical care (only emergency)
Lack of written asthma action plan
No care sought for chronic asthma symptoms
Delay in care of asthma exacerbations
Inadequate hospital care for asthma exacerbation
Psychopathology in the parent or child
Poor perception of asthma symptoms or severity
Alcohol or substance abuse
Asthma exacerbations characteristically vary among individuals but
tend to be similar in the same patient. Severe asthma exacerbations,
resulting in respiratory distress, hypoxia, hospitalization, and/or respi-
ratory failure, are the best predictors of future life-threatening exacer-
bations or a fatal asthma episode. In addition to distinguishing such
high-risk children, some experience exacerbations that come on over
days, with airflow obstruction resulting from progressive inflamma-
tion, epithelial sloughing, and cast impaction of small airways. When
such a process is extreme, respiratory failure as a result of fatigue can
ensue, necessitating mechanical ventilation for numerous days. In con-
trast, some children experience abrupt-onset exacerbations that may
result from extreme AHR and physiologic susceptibility to airways
closure. Such exacerbations, when extreme, are asphyxial in nature,
often occur outside medical settings, are initially associated with very
high arterial partial pressure of carbon dioxide (Pco2) levels, and tend
to require only brief periods of supportive ventilation. Recognizing the
characteristic differences in asthma exacerbations is important for
optimizing their early management.
Home Management of Asthma Exacerbations
Families of all children with asthma should have a written action plan
to guide their recognition and management of exacerbations, along
with the necessary medications and tools to manage them. Early rec-
ognition of asthma exacerbations in order to intensify treatment early
can often prevent further worsening and keep exacerbations from
becoming severe. A written home action plan can reduce the risk of
asthma death by 70%. The NIH guidelines recommend immediate
treatment with “rescue” medication (inhaled SABA, up to 3 treatments
in 1 hr). A good response is characterized by resolution of symptoms
within 1 hr, no further symptoms over the next 4 hr, and improvement
in PEF value to at least 80% of personal best. The child’s physician
1114 Part XV ◆ Allergic Disorders
should be contacted for follow-up, especially if bronchodilators are
required repeatedly over the next 24-48 hr. If the child has an incom-
plete response to initial treatment with rescue medication (persistent
symptoms and/or a PEF value <80% of personal best), a short course
of oral corticosteroid therapy (prednisone 1-2 mg/kg/day [not to
exceed 60 mg/day] for 4 days), in addition to inhaled β-agonist therapy,
should be instituted. The physician should also be contacted for further
instructions. Immediate medical attention should be sought for severe
exacerbations, persistent signs of respiratory distress, lack of expected
response or sustained improvement after initial treatment, further
deterioration, or high-risk factors for asthma morbidity or mortality
(previous history of severe exacerbations). For patients with severe
asthma and/or a history of life-threatening episodes, especially if
abrupt-onset in nature, providing an epinephrine autoinjector and,
possibly, portable oxygen at home should be considered. Use of either
of these extreme measures for home management of asthma exacerba-
tions would be an indication to call 911 for emergency support
services.
Emergency Department Management
of Asthma Exacerbations
In the emergency department, the primary goals of asthma manage-
ment include correction of hypoxemia, rapid improvement of airflow
obstruction, and prevention of progression or recurrence of symptoms.
Interventions are based on clinical severity on arrival, response to
initial therapy, and presence of risk factors that are associated with
asthma morbidity and mortality (see Table 144-17). Indications of a
severe exacerbation include breathlessness, dyspnea, retractions, acces-
sory muscle use, tachypnea or labored breathing, cyanosis, mental
status changes, a silent chest with poor air exchange, and severe airflow
limitation (PEF or FEV1 value <50% of personal best or predicted
values). Initial treatment includes supplemental oxygen, inhaled
β-agonist therapy every 20 min for 1 hr, and, if necessary, systemic
corticosteroids given either orally or intravenously (see Table 144-16).
Inhaled ipratropium may be added to the β-agonist treatment if no
significant response is seen with the first inhaled β-agonist treatment.
An intramuscular injection of epinephrine or other β-agonist may be
administered in severe cases. Oxygen should be administered and con-
tinued for at least 20 min after SABA administration to compensate
for possible ventilation-perfusion abnormalities caused by SABAs.
Close monitoring of clinical status, hydration, and oxygenation are
essential elements of immediate management. A poor response to
intensified treatment in the 1st hr suggests that the exacerbation will
not remit quickly. The patient may be discharged to home if there is
sustained improvement in symptoms, normal physical findings, PEF
>70% of predicted or personal best, an oxygen saturation >92% while
the patient is breathing room air for 4 hr. Discharge medications
include administration of an inhaled β-agonist up to every 3-4 hr plus
a 3-7 day course of an oral corticosteroid. Optimizing controller
therapy before discharge is also recommended. The addition of ICS to
a course of oral corticosteroid in the emergency department setting
reduces the risk of exacerbation recurrence over the subsequent month.
Hospital Management of Asthma Exacerbations
For patients with moderate to severe exacerbations that do not ade-
quately improve within 1-2 hr of intensive treatment, observation and/
or admission to the hospital, at least overnight, is likely to be needed.
Other indications for hospital admission include high-risk features for
asthma morbidity or death (see Table 144-17). Admission to an inten-
sive care unit is indicated for patients with severe respiratory distress,
poor response to therapy, and concern for potential respiratory failure
and arrest.
Supplemental oxygen, frequent or continuous administration of an
inhaled bronchodilator, and systemic corticosteroid therapy are the
conventional interventions for children admitted to the hospital for
status asthmaticus (see Table 144-16). Supplemental oxygen is admin-
istered because many children hospitalized with acute asthma have or
eventually have hypoxemia, especially at night and with increasing
SABA administration. SABAs can be delivered frequently (every
20 min to 1 hr) or continuously (at 5-15 mg/hr). When administered
continuously, significant systemic absorption of β-agonist occurs and,
as a result, continuous nebulization can obviate the need for intrave-
nous β-agonist therapy. Adverse effects of frequently administered
β-agonist therapy include tremor, irritability, tachycardia, and hypoka-
lemia. Patients requiring frequent or continuous nebulized β-agonist
therapy should have ongoing cardiac monitoring. Because frequent
β-agonist therapy can cause ventilation–perfusion mismatch and
hypoxemia, oximetry is also indicated. Inhaled ipratropium bromide
is often added to albuterol every 6 hr if patients do not show a remark-
able improvement, although there is little evidence to support its use
in hospitalized children receiving aggressive inhaled β-agonist therapy
and systemic corticosteroids. In addition to its potential to provide a
synergistic effect with a β-agonist agent in relieving severe broncho-
spasm, ipratropium bromide may be beneficial in patients who have
mucous hypersecretion or are receiving β-blockers.
Short-course systemic corticosteroid therapy is recommended for
use in moderate to severe asthma exacerbations to hasten recovery and
prevent recurrence of symptoms. Corticosteroids are effective as single
doses administered in the emergency department, short courses in the
clinic setting, and both oral and intravenous formulations in hospital-
ized children. Studies in children hospitalized with acute asthma have
found corticosteroids administered orally to be as effective as intrave-
nous corticosteroids. Accordingly, oral corticosteroid therapy can often
be used, although children with sustained respiratory distress who are
unable to tolerate oral preparations or liquids are obvious candidates
for intravenous corticosteroid therapy.
Patients with persistent severe dyspnea and high-flow oxygen
requirements require additional evaluations, such as complete blood
cell counts, measurements of arterial blood gases and serum electro-
lytes, and chest radiograph, to monitor for respiratory insufficiency,
comorbidities, infection, and/or dehydration. Hydration status moni-
toring is especially important in infants and young children, whose
increased respiratory rate (insensible losses) and decreased oral intake
put them at higher risk for dehydration. Further complicating this situ-
ation is the association of increased antidiuretic hormone secretion
with status asthmaticus. Administration of fluids at or slightly below
maintenance fluid requirements is recommended. Chest physical
therapy, incentive spirometry, and mucolytics are not recommended
during the early acute period of asthma exacerbations as they can
trigger severe bronchoconstriction.
Despite intensive therapy, some asthmatic children remain critically
ill and at risk for respiratory failure, intubation, and mechanical ventila-
tion. Complications (air leaks) related to asthma exacerbations increase
with intubation and assisted ventilation; every effort should be made
to relieve bronchospasm and prevent respiratory failure. Several thera-
pies, including parenterally administered epinephrine, β-agonists,
methylxanthines, magnesium sulfate (25-75 mg/kg, maximum dose
2.5 g, given intravenously over 20 min), and inhaled heliox (helium
and oxygen mixture) have demonstrated some benefit as adjunctive
therapies in patients with severe status asthmaticus. Administration of
either methylxanthine or magnesium sulfate requires monitoring of
serum levels and cardiovascular status. Parenteral (subcutaneous,
intramuscular, or intravenous) epinephrine or terbutaline sulfate may
be effective in patients with life-threatening obstruction that is not
responding to high doses of inhaled β-agonists, because in such
patients, inhaled medication may not reach the lower airway.
Rarely, a severe asthma exacerbation in a child results in respiratory
failure, and intubation and mechanical ventilation become necessary.
Mechanical ventilation in severe asthma exacerbations requires the
careful balance of enough pressure to overcome airways obstruction
while reducing hyperinflation, air trapping, and the likelihood of baro-
trauma (pneumothorax, pneumomediastinum) (see Chapter 411). To
minimize the likelihood of such complications, mechanical ventilation
should be anticipated, and asthmatic children at risk for the develop-
ment of respiratory failure should be managed in a pediatric ICU.
Elective tracheal intubation with rapid-induction sedatives and para-
lytic agents is safer than emergency intubation. Mechanical ventilation
aims to achieve adequate oxygenation while tolerating mild to

moderate hypercapnia (Pco2 50-70 mm Hg) to minimize barotrauma.
Volume-cycled ventilators, using short inspiratory and long expiratory
times, 10-15 mL/kg tidal volume, 8-15 breaths/min, peak pressures
<60 cm H2O, and without positive end-expiratory pressure are starting
mechanical ventilation parameters that can achieve these goals. As
measures to relieve mucous plugs, chest percussion and airways lavage
are not recommended because they can induce further bronchospasm.
One must consider the nature of asthma exacerbations leading to respi-
ratory failure; those of rapid or abrupt onset tend to resolve quickly
(hours to 2 days), whereas those that progress gradually to respiratory
failure can require days to weeks of mechanical ventilation. Such pro-
longed cases are further complicated by muscle atrophy and, when
combined with corticosteroid-induced myopathy, can lead to severe
muscle weakness requiring prolonged rehabilitation. This myopathy
should not be confused with the rare occurrence of an asthma-
associated flaccid paralysis (Hopkins syndrome), which is of unknown
etiology but prolongs the intensive care stay.
In children, management of severe exacerbations in medical centers
is usually successful, even when extreme measures are required. Con-
sequently, asthma deaths in children rarely occur in medical centers;
most occur at home or in community settings before lifesaving medical
care can be administered. This point highlights the importance of
home and community management of asthma exacerbations, early
intervention measures to keep exacerbations from becoming severe,
and steps to reduce asthma severity. A follow-up appointment within
1-2 wk of a child’s discharge from the hospital after resolution of an
asthma exacerbation should be used to monitor clinical improvement
and to reinforce key educational elements, including action plans and
controller medications.
Special Management Circumstances
Management of Infants and Young Children. Recur-
rent wheezing episodes in preschool-age children are very common,
occurring in as much as one-third of this population. Of them, most
improve and even become asymptomatic during the prepubescent
school-age years, whereas others have lifelong persistent asthma. All
require management of their recurrent wheezing problems (see Tables
144-5, 144-7, and 144-12). The updated NIH guidelines recommend
risk assessment to identify preschool-age children who are likely to
have persistent asthma. One implication of this recommendation is
that these at-risk children may be candidates for conventional asthma
management, including daily controller therapy and early intervention
with exacerbations (see Tables 144-8, 144-9, and 144-12). Nebulized
budesonide and montelukast appear to be more effective than cromo-
lyn. For young children with a history of moderate to severe exacerba-
tions, nebulized budesonide is FDA approved, and its use as a controller
medication could prevent subsequent exacerbations.
Using aerosol therapy in infants and young children with asthma
presents unique challenges. There are 2 delivery systems for inhaled
medications for this age group, the nebulizer and the MDI with spacer/
holding chamber and face mask. Multiple studies demonstrate the
effectiveness of both nebulized albuterol in acute episodes and nebu-
lized budesonide in the treatment of recurrent wheezing in infants and
young children. In such young children, inhaled medications admin-
istered via MDI with spacer and face mask may be acceptable, although
perhaps not preferred owing to limited published information and lack
of FDA approval for children <4 yr of age.
Asthma Management in Pregnancy. The goals of asthma
management during pregnancy should include prevention of exacerba-
tions and control of chronic symptoms through the use of medications
that pose minimal risk to the mother and fetus because most drugs
cross the placenta. It is considered safer for pregnant asthmatic women
to be treated with controller medications than it is to have uncontrolled
symptoms and severe exacerbations. Albuterol is the preferred SABA
for use during pregnancy. There is reassuring efficacy and safety data
from prospective cohort studies supporting ICS use in pregnant women
Chapter 144 ◆ Childhood Asthma 1115
with asthma. Budesonide is currently the preferred ICS for pregnant
women, attaining an FDA Pregnancy Category B rating because
of substantial reassuring safety data. Nonmedication approaches to
improve asthma control are encouraged. A multidisciplinary approach
with monthly evaluations (including pulmonary function tests when
not contraindicated) and ongoing consultation with the obstetrician
and asthma specialist is recommended. Frequent fetal and maternal
surveillance is especially important for adolescents with suboptimal
asthma control, those with moderate to severe asthma, and those with
a recent exacerbation.
Asthma Management During Surgery. Patients with
asthma are at risk from disease-related complications from surgery,
such as bronchoconstriction and asthma exacerbation, atelectasis,
impaired coughing, respiratory infection, and latex exposure, that may
induce asthma complications in patients with latex allergy. All patients
with asthma should be evaluated before surgery, and those who are
inadequately controlled should allow time for intensified treatment in
order to improve asthma stability before surgery if possible. A systemic
corticosteroid course may be indicated for the patient who is having
symptoms and/or FEV1 or PEF values <80% of the patient’s personal
best. In addition, patients who have received >2 wk of systemic corti-
costeroid and/or moderate- to high-dose ICS therapy may be at risk
for intraoperative adrenal insufficiency. For these patients, anesthesia
services should be alerted to provide “stress” replacement doses of
systemic corticosteroid for the surgical procedure and possibly the
postoperative period if needed.
PROGNOSIS
Recurrent coughing and wheezing occurs in 35% of preschool-age
children. Of these, approximately one-third continue to have persistent
asthma into later childhood, and approximately two-thirds improve on
their own through their teen years. Asthma severity by the ages of
7-10 yr is predictive of asthma persistence in adulthood. Children with
moderate to severe asthma and with lower lung function measures are
likely to have persistent asthma as adults. Children with milder asthma
and normal lung function are likely to improve over time, with some
becoming periodically asthmatic (disease-free for months to years);
however, complete remission for 5 yr in childhood is uncommon.
PREVENTION
Although chronic airways inflammation may result in pathologic
remodeling of lung airways, conventional anti-inflammatory
interventions—the cornerstone of asthma control—do not help chil-
dren outgrow their asthma. Although controller medications reduce
asthma morbidities, most children with moderate to severe asthma
continue to have symptoms into young adulthood. Investigations into
the environmental and lifestyle factors responsible for the lower preva-
lence of childhood asthma in rural areas and farming communities
suggest that early immunomodulatory intervention might prevent
asthma development. A hygiene hypothesis purports that naturally
occurring microbial exposures in early life might drive early immune
development away from allergic sensitization, persistent airways
inflammation, and remodeling. If these natural microbial exposures
truly have an asthma-protective effect, without significant adverse
health consequences, then these findings may foster new strategies for
asthma prevention.
Several nonpharmacotherapeutic measures with numerous positive
health attributes—avoidance of environmental tobacco smoke (begin-
ning prenatally), prolonged breastfeeding (>4 mo), an active lifestyle,
and a healthy diet—might reduce the likelihood of asthma develop-
ment. Immunizations are currently not considered to increase the like-
lihood of development of asthma; therefore, all standard childhood
immunizations are recommended for children with asthma, including
varicella and annual influenza vaccines.
Bibliography is available at Expert Consult.
 GINA Guidelines

CE
HOW TO ASSESS ASTHMA CONTROL
Asthma control means the extent to which the effects of asthma can be seen

U
in the patient, or have been reduced or removed by treatment. Asthma control

OD
has two domains: symptom control (previously called ‘current clinical control’)
and risk factors for future poor outcomes.

PR
Poor symptom control is a burden to patients and a risk factor for flare-ups.
Risk factors are factors that increase the patient’s future risk of having

RE
exacerbations (flare-ups), loss of lung function, or medication side-effects.
Box 4. Assessment of symptom control and future risk

OR
A. Level of asthma symptom control

Well Partly Uncontrolled

ER
In the past 4 weeks, has the patient had:
controlled controlled
Daytime symptoms more than twice/week? Yes No

LT
Any night waking due to asthma? Yes No None 1–2 3–4
Reliever needed* more than twice/week? Yes No of these of these of these

TA
Any activity limitation due to asthma? Yes No
B. Risk factors for poor asthma outcomes
NO
Assess risk factors at diagnosis and periodically, particularly for patients experiencing
exacerbations.
O

Measure FEV1 at start of treatment, after 3–6 months of controller treatment to record
personal best lung function, then periodically for ongoing risk assessment.
-D

Potentially modifiable independent risk factors for exacerbations include:

• Uncontrolled asthma symptoms (as above)
AL

• ICS not prescribed; poor ICS adherence; incorrect inhaler technique

• High SABA use (with increased mortality if >1x200-dose canister/month)
Having one or more
RI

• Low FEV1, especially if <60% predicted

of these risk factors
• Major psychological or socioeconomic problems
increases the risk of
TE

• Exposures: smoking; allergen exposure if sensitized

• Comorbidities: obesity; rhinosinusitis; confirmed food allergy exacerbations even
• Sputum or blood eosinophilia if symptoms are well
MA

• Pregnancy controlled.
Other major independent risk factors for flare-ups (exacerbations) include:
• Ever being intubated or in intensive care for asthma
D

• Having 1 or more severe exacerbations in the last 12 months.

TE

Risk factors for developing fixed airflow limitation include lack of ICS treatment; exposure to tobacco
smoke, noxious chemicals or occupational exposures; low FEV1; chronic mucus hypersecretion; and
GH

sputum or blood eosinophilia

Risk factors for medication side-effects include:
I

• Systemic: frequent OCS; long-term, high dose and/or potent ICS; also taking P450 inhibitors
YR

• Local: high-dose or potent ICS; poor inhaler technique

P
CO

9
 CE
What is the role of lung function in monitoring asthma?
Once asthma has been diagnosed, lung function is most useful as an

U
indicator of future risk. It should be recorded at diagnosis, 3–6 months after

OD
starting treatment, and periodically thereafter. Patients who have either few or
many symptoms relative to their lung function need more investigation.

PR
How is asthma severity assessed?

RE
Asthma severity can be assessed retrospectively from the level of treatment
(p14) required to control symptoms and exacerbations. Mild asthma is asthma
that can be controlled with Step 1 or 2 treatment. Severe asthma is asthma

OR
that requires Step 4 or 5 treatment, to maintain symptom control. It may
appear similar to asthma that is uncontrolled due to lack of treatment.

ER
HOW TO INVESTIGATE UNCONTROLLED ASTHMA
Most patients can achieve good asthma control with regular controller

LT
treatment, but some patients do not, and further investigation is needed.

TA
Box 5. How to investigate uncontrolled asthma in primary care
NO
O
-D
AL
RI
TE
MA
D
TE
I GH
YR

This flow-chart shows the most common problems first, but the steps can be
carried out in a different order, depending on resources and clinical context.
P
CO

10
 CE
MANAGEMENT OF ASTHMA
GENERAL PRINCIPLES

U
OD
The long-term goals of asthma management are symptom control and
risk reduction. The aim is to reduce the burden to the patient and their risk of

PR
exacerbations, airway damage, and medication side-effects. The patient’s
own goals regarding their asthma and its treatment should also be identified.

RE
Population-level recommendations about ‘preferred’ asthma treatments
represent the best treatment for most patients in a population.

OR
Patient-level treatment decisions should take into account any individual
characteristics or phenotype that predict the patient’s likely response to
treatment, together with the patient’s preferences and practical issues such as

ER
inhaler technique, adherence, and cost.
A partnership between the patient and their health care providers is

LT
important for effective asthma management. Training health care providers in

TA
communication skills may lead to increased patient satisfaction, better
health outcomes, and reduced use of health care resources.
NO
Health literacy – that is, the patient’s ability to obtain, process and
understand basic health information to make appropriate health decisions –
should be taken into account in asthma management and education.
O

TREATING TO CONTROL SYMPTOMS AND MINIMIZE RISK

-D

Treatment of asthma for symptom control and risk reduction includes:

• Medications. Every patient with asthma should have a reliever
AL

medication, and most adults and adolescents with asthma should have a
RI

controller medication
• Treating modifiable risk factors
TE

• Non-pharmacological therapies and strategies

Importantly, every patient should also be trained in essential skills and guided
MA

asthma self-management, including:

• Asthma information
D

• Inhaler skills (p18)

TE

• Adherence (p18)
• Written asthma action plan (p22)
GH

• Self-monitoring
• Regular medical review (p8)
I
YR
P
CO

11
 CE
CONTROL-BASED ASTHMA MANAGEMENT
Asthma treatment is adjusted in a continuous cycle to assess, adjust

U
treatment and review response. The main components of this cycle are

OD
shown in Box 6.

PR
Box 6. The control-based asthma management cycle

RE
OR
ER
LT
TA
NO
O
-D
AL
RI
TE
MA
D
TE
I GH
YR
P
CO

12
 CE
INITIAL CONTROLLER TREATMENT
For the best outcomes, regular daily controller treatment should be initiated as

U
soon as possible after the diagnosis of asthma is made, because:

OD
• Early treatment with low dose ICS leads to better lung function than if
symptoms have been present for more than 2–4 years

PR
• Patients not taking ICS who experience a severe exacerbation have
lower long-term lung function than those who have started ICS

RE
• In occupational asthma, early removal from exposure and early treatment
increase the probability of recovery
Regular low dose ICS is recommended for patients with any of the

OR
following:
• Asthma symptoms more than twice a month

ER
• Waking due to asthma more than once a month
• Any asthma symptoms plus any risk factor(s) for exacerbations

LT
(e.g. needing OCS for asthma within the last 12 months; low FEV1; ever
in intensive care unit for asthma)

TA
Consider starting at a higher step (e.g. medium/high dose ICS, or ICS/LABA)
if the patient has troublesome asthma symptoms on most days; or is waking
NO
from asthma once or more a week, especially if there are any risk factors for
exacerbations.
If the initial asthma presentation is with severely uncontrolled asthma, or with
O

an acute exacerbation, give a short course of OCS and start regular controller
-D

treatment (e.g. high dose ICS, or medium dose ICS/LABA).

Low, medium and high dose categories for different ICS medications are
AL

shown in Box 8 (p14).

Before starting initial controller treatment
RI

• Record evidence for the diagnosis of asthma, if possible

TE

• Document symptom control and risk factors

• Assess lung function, when possible
MA

• Train the patient to use the inhaler correctly, and check their technique
• Schedule a follow-up visit
D

After starting initial controller treatment

TE

• Review response after 2–3 months, or according to clinical urgency

• See Box 7 for ongoing treatment and other key management issues
GH

• Consider step down when asthma has been well-controlled for 3 months
I
YR
P
CO

13
Box 7. Stepwise approach to asthma treatment

E
UC
OD
PR
RE
OR
ER
LT
TA
NO
O
-D
AL
RI
TE

*For children 6–11 years, theophylline is not recommended, and the preferred Step 3 treatment is medium dose ICS.
MA

**Low dose ICS/formoterol is the reliever medication for patients prescribed low dose budesonide/formoterol or low dose beclometasone/formoterol
## Tiotropium by soft-mist inhaler is an add-on treatment for patients with a history of exacerbations; it is not indicated in children <18 years.
D

For medication Glossary, see p26. For details about treatment recommendations, supporting evidence, and clinical advice about
TE

implementation in different populations see the full GINA 2015 report (www.ginasthma.org).
Box 8. Low, medium and high daily doses of inhaled corticosteroids (mcg)
GH

Inhaled corticosteroid Adults and adolescents Children 6–11 years

Low Medium High Low Medium High
RI

Beclometasone dipropionate (CFC)* 200–500 >500–1000 >1000 100–200 >200–400 >400

PY

Beclometasone dipropionate (HFA) 100–200 >200–400 >400 50-100 >100-200 >200

Budesonide (DPI) 200–400 >400–800 >800 100–200 >200–400 >400
CO

Budesonide (nebules) 250–500 >500–1000 >1000

Ciclesonide (HFA) 80–160 >160–320 >320 80 >80-160 >160
Fluticasone propionate( DPI) 100–250 >250–500 >500 100–200 >200–400 >400
Fluticasone propionate (HFA) 100–250 >250–500 >500 100–200 >200–500 >500
Mometasone furoate 110–220 >220–440 >440 110 ≥220–<440 ≥440
Triamcinolone acetonide 400–1000 >1000–2000 >2000 400–800 >800–1200 >1200
CFC: chlorofluorocarbon propellant; DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant.
*Included for comparison with older literature.
15
 CE
STEPWISE APPROACH FOR ADJUSTING TREATMENT

U
Once asthma treatment has been started, ongoing decisions are based on a

OD
cycle to assess, adjust treatment and review response. The preferred
treatments at each step are summarized below and in Box 7 (p14); for details,
see full GINA 2015 report. See Box 8 (p14) for ICS dose categories.

PR
STEP 1: As-needed SABA with no controller (this is indicated only if

RE
symptoms are rare, there is no night waking due to asthma, no
exacerbations in the last year, and normal FEV1).
Other options: regular low dose ICS for patients with exacerbation risks.

OR
STEP 2: Regular low dose ICS plus as-needed SABA
Other options: LTRA are less effective than ICS; ICS/LABA leads to faster

ER
improvement in symptoms and FEV1 than ICS alone but are more
expensive and the exacerbation rate is similar. For purely seasonal allergic

LT
asthma, start ICS immediately and cease 4 weeks after end of exposure.
STEP 3: Low dose ICS/LABA either as maintenance treatment plus as-

TA
needed SABA, or as ICS/formoterol maintenance and reliever therapy
For patients with ≥1 exacerbation in the last year, low dose BDP/formoterol
NO
or BUD/formoterol maintenance and reliever strategy is more effective than
maintenance ICS/LABA with as-needed SABA.
Other options: Medium dose ICS
O

Children (6–11 years): Medium dose ICS. Other options: low dose
-D

ICS/LABA
STEP 4: Low dose ICS/formoterol maintenance and reliever therapy, or
AL

medium dose ICS/LABA as maintenance plus as-needed SABA

Other options: Add-on tiotropium by soft-mist inhaler for adults (≥18 years)
RI

with a history of exacerbations; high dose ICS/LABA, but more side-effects

TE

and little extra benefit; extra controller, e.g. LTRA or slow-release

theophylline (adults)
MA

Children (6–11 years): Refer for expert assessment and advice.

STEP 5: Refer for expert investigation and add-on treatment
Add-on treatments include anti-IgE (omalizumab) for severe allergic asthma.
D

Sputum-guided treatment, if available, improves outcomes.

TE

Other options: Add-on tiotropium by soft-mist inhaler for adults (≥18 years)
with a history of exacerbations. Some patients may benefit from low dose
GH

OCS but long-term systemic side-effects occur.

I
YR
P
CO

16
 CE
REVIEWING RESPONSE AND ADJUSTING TREATMENT
How often should patients with asthma be reviewed?

U
OD
Patients should preferably be seen 1–3 months after starting treatment and
every 3–12 months after that, except in pregnancy when they should be
reviewed every 4–6 weeks. After an exacerbation, a review visit within 1 week

PR
should be scheduled. The frequency of review depends on the patient’s initial
level of control, their response to previous treatment, and their ability and

RE
willingness to engage in self-management with an action plan.
Stepping up asthma treatment

OR
Asthma is a variable condition, and periodic adjustment of controller treatment
by the clinician and/or patient may be needed.

ER
• Sustained step-up (for at least 2–3 months): if symptoms and/or
exacerbations persist despite 2–3 months of controller treatment, assess

LT
the following common issues before considering a step-up
o Incorrect inhaler technique

TA
o Poor adherence
o Modifiable risk factors, e.g. smoking
o Are symptoms due to comorbid conditions, e.g. allergic rhinitis
NO
• Short-term step-up (for 1–2 weeks) by clinician or by patient with written
asthma action plan (p22), e.g. during viral infection or allergen exposure
O

• Day-to-day adjustment by patient for patients prescribed low dose

-D

beclometasone/formoterol or budesonide/formoterol as maintenance and

reliever therapy.
AL

Stepping down treatment when asthma is well-controlled

Consider stepping down treatment once good asthma control has been
RI

achieved and maintained for 3 months, to find the lowest treatment that
TE

controls both symptoms and exacerbations, and minimizes side-effects.

• Choose an appropriate time for step-down (no respiratory infection,
MA

patient not travelling, not pregnant)

• Document baseline status (symptom control and lung function), provide a
written asthma action plan, monitor closely, and book a follow-up visit
D

• Step down through available formulations to reduce the ICS dose by

TE

25–50% at 2–3 month intervals (see full GINA report for details)
• Do not completely withdraw ICS (in adults or adolescents) unless it is
GH

needed temporarily to confirm the diagnosis of asthma

I
YR
P
CO

17
 CE
Box 10. Management of asthma exacerbations in primary care

U
OD
PR
RE
OR
ER
LT
TA
NO
O
-D
AL
RI
TE
MA
D
TE
I GH
YR

O2: oxygen; PEF: peak expiratory flow; SABA: short-acting beta2-agonist (doses are for
salbutamol)
P
CO

24

GLOSSARY OF ASTHMA MEDICATION CLASSES
For more details, see full GINA 2015 report and Appendix (www.ginasthma.org) and
Product Information from manufacturers.
Medications
CONTROLLER MEDICATIONS
Inhaled corticosteroids
(ICS) (pMDIs or DPIs) e.g.
beclometasone,
budesonide, ciclesonide,
fluticasone propionate,
fluticasone furoate,
mometasone, triamcinolone
ICS and long-acting beta2
agonist bronchodilator
combinations (ICS/LABA)
(pMDIs or DPIs) e.g.
beclometasone/ formoterol,
budesonide/formoterol,
fluticasone furoate/
vilanterol, fluticasone
propionate/formoterol,
fluticasone propionate/
salmeterol, and
mometasone/formoterol.
Leukotriene modifiers
(tablets) e.g. montelukast,
pranlukast, zafirlukast,
TE
zileuton
MA
Chromones (pMDIs or
DPIs) e.g. sodium
D
cromoglycate and
nedocromil sodium
TE
Anti-IgE (omalizumab)
GH
Long-acting An add-on option at Step 4 or 5 bny soft-
I
YR
anticholinergic, tiotropium mist inhaler for adults (≥18 years) whose
asthma is uncontrolled by ICS ± LABA
P
CO
26
Action and use
The most effective anti-inflammatory
medications for persistent asthma. ICS
reduce symptoms, increase lung function,
improve quality of life, and reduce the risk
of exacerbations and asthma-related
hospitalizations or death. ICS differ in
their potency and bioavailability, but most
of the benefit is seen at low doses (see
ER
Box 8 (p14) for low, medium and high
doses of different ICS).
LT
When a medium dose of ICS alone fails to
achieve good control of asthma, the
TA
addition of LABA to ICS improves
symptoms, lung function and reduces
NO
exacerbations in more patients, more
rapidly, than doubling the dose of ICS.
Two regimens are available: maintenance
O
ICS/LABA with SABA as reliever, and low-
dose combination beclometasone or
-D
budesonide with formoterol for
maintenance and reliever treatment.
AL
Target one part of the inflammatory
RI
pathway in asthma. Used as an option for elevated liver function tests
controller therapy, particularly in children. with zileuton and zafirlukast.
Used alone: less effective than low dose
ICS; added to ICS: less effective than
ICS/LABA.
Very limited role in long-term treatment of
asthma. Weak anti-inflammatory effect,
less effective than low-dose ICS. Require
meticulous inhaler maintenance.
A treatment option for patients with severe Reactions at the site of
persistent allergic asthma uncontrolled on injection are common but
Step 4 treatment (high dose ICS/LABA). minor. Anaphylaxis is rare.
CE
U
OD
Adverse effects
PR
Most patients using ICS do
not experience side-effects.
RE
Local side-effects include
oropharyngeal candidiasis and
dysphonia. Use of spacer with
OR
pMDI, and rinsing with water
and spitting out after
inhalation, reduce local side
effects. High doses increase
the risk of systemic side-
effects.
The LABA component may be
associated with tachycardia,
headache or cramps. Current
recommendations are that
LABA and ICS are safe for
asthma when used in
combination. Use of LABA
without ICS in asthma is
associated with increased risk
of adverse outcomes.
Few side-effects except
Side effects are uncommon
but include cough upon
inhalation and pharyngeal
discomfort.
Side-effects are uncommon
but include dry mouth.
 CE
Medications Action and use Adverse effects
Systemic corticosteroids Short-term treatment (usually 5–7 days in Short-term use: some adverse

U
(tablets,suspension or adults) is important early in the treatment effects e.g. hyperglycaemia,

OD
intramuscular (IM) or of severe acute exacerbations, with main gastro-intestinal side-effects,
intravenous (IV) injection) effects seen after 4–6 hours. Oral mood changes.
e.g. prednisone, corticosteroid (OCS) therapy is preferred Long-term use: limited by the

PR
prednisolone, and is as effective as IM or IV therapy in risk of significant systemic
methylprednisolone, preventing relapse. Tapering is required if adverse effects e.g. cataract,

RE
hydrocortisone treatment given for more than 2 weeks. glaucoma, osteoporosis,
Long-term treatment with OCS may be adrenal suppression. Patients
required for some patients with severe should be assessed for

OR
asthma. osteoporosis risk and treated
appropriately.
RELIEVER MEDICATIONS

ER
Short-acting inhaled Inhaled SABAs are medications of choice Tremor and tachycardia are
beta2-agonist for quick relief of asthma symptoms and commonly reported with initial

LT
bronchodilators (SABA) bronchoconstriction including in acute use of SABA, but tolerance to
(pMDIs, DPIs and, rarely, exacerbations, and for pre-treatment of these effects usually develops

solution for nebulization or
injection) e.g. salbutamol
(albuterol), terbutaline.
Short-acting
anticholinergics (pMDIs
or DPIs) e.g. ipratropium
TA
exercise-induced bronchoconstriction. rapidly. Excess use, or poor
SABAs should be used only as-needed at response indicate poor
the lowest dose and frequency required. asthma control.
NO
Long-term use: ipratropium is a less Dryness of the mouth or a
effective reliever medication than SABAs. bitter taste.
Short-term use in acute asthma: inhaled
O

bromide, ipratropium added to SABA reduces the

-D

oxitropium bromide risk of hospital admission

AL
RI

Abbreviations used in this pocket guide

TE

BDP Beclometasone dipropionate

BUD Budesonide
MA

DPI Dry powder inhaler

FEV1 Forced expiratory volume in 1 second
FVC Forced vital capacity
D

ICS Inhaled corticosteroids

TE

LABA Long-acting beta2-agonists

O2 Oxygen
GH

OCS Oral corticosteroids

PEF Peak expiratory flow
I
YR

pMDI Pressurized metered dose inhaler

SABA Short-acting beta2-agonists
P
CO

27
1- RECOGNIZE ALLERGIC RHINITIS ARIA Guidelines
ALLERGIC RHINITIS QUESTIONNAIRE1

.
CE
Instructions: To evaluate the possibility of allergic rhinitis, start by asking the questions below to patients with nasal symptoms.
This questionnaire contains the questions related to allergic rhinitis symptoms that have been identified in peer-reviewed literature

U
as having the greatest diagnostic value. It will not produce a definitive diagnosis, but may enable you to determine whether a
diagnosis of allergic rhinitis should be further investigated or is unlikely.

OD
Allergic Rhinitis Questionnaire
Question Response Choices

PR
1. Do you have any of the following symptoms?
• Symptoms on only one side of your nose Yes No

RE
• Thick, green or yellow discharge from your nose (see NOTE) Yes No
• Postnasal drip (down the back of your throat) with thick mucus and/or runny nose (see NOTE) Yes No
• Facial pain (see NOTE) Yes No

OR
• Recurrent nosebleeds Yes No
• Loss of smell (see NOTE) Yes No
2. Do you have any of the following symptoms for at least one hour on most days (or on most days
during the season if your symptoms are seasonal)?

ER
• Watery runny nose Yes No
• Sneezing, especially violent and in bouts Yes No

LT
• Nasal obstruction Yes No
• Nasal itching Yes No
• Conjunctivitis (red, itchy eyes) TA Yes No
Evaluation:
• The symptoms described in Question 1 are usually NOT found in allergic rhinitis. The presence of ANY ONE of them suggests
NO

that alternative diagnoses should be investigated. Consider alternative diagnoses and/or referral to a specialist.
• NOTE: Purulent discharge, postnasal drip, facial pain, and loss of smell are common symptoms of sinusitis. Because most
patients with sinusitis also have rhinitis (though not always allergic in origin), in this situation the clinician should also evaluate
the possibility of allergic rhinitis.
DO

• The presence of watery runny nose with ONE OR MORE of the other symptoms listed in Question 2 suggests allergic rhinitis,
and indicates that the patient should undergo further diagnostic assessment.
• The presence of watery runny nose ALONE suggests that the patient MAY have allergic rhinitis. (Additionally, some patients
with allergic rhinitis have only nasal obstruction as a cardinal symptom.)
• If the patient has sneezing, nasal itching, and/or conjunctivitis, but NOT watery runny nose, consider alternative diagnoses
L,

and/or referral to a specialist.

• In adults with late-onset rhinitis, consider and query occupational causes. Occupational rhinitis frequently precedes or
IA

accompanies the development of occupational asthma. Patients in whom an occupational association is suspected should be
referred to a specialist for further objective testing and assessment.
ER

ALLERGIC RHINITIS DIAGNOSIS GUIDE1

T

Instructions: In patients of all ages with lower nasal symptoms only, whose responses to the Allergic Rhinitis Questionnaire sug-
gest that this diagnosis should be investigated, use this guide to help you evaluate the possibility of allergic rhinitis. All of the diag-
MA

nostic investigations presented in this guide may not be available in all areas; in most cases, the combination of those diagnostic
investigations that are available and the individual health care professional’s clinical judgement will lead to a robust clinical
diagnosis. This guide is intended to supplement, not replace, a complete physical examination and thorough medical history.
D

Allergic Rhinitis Diagnosis Guide

Findings that Support Diagnosis
TE

Diagnostic Tool
Physical examination Transverse crease of nose, allergic shiners, allergic salute.
GH

In persistent rhinitis: Exclusion of other causes.

• anterior rhinoscopy using speculum and mirror gives
limited but often valuable information
• nasal endoscopy (usually performed by specialist) may
RI

be needed to exclude other causes of rhinitis, nasal

polyps, and anatomic abnormalities
PY

Trial of therapy Improvement with antihistamines or intranasal

glucocorticosteroid.
CO

Allergy skin testing or measurement of allergen-specific • Confirm presence of atopy.

IgE in serum (if symptoms are persistent and/or • Specific triggers identified.
moderate/severe, or if quality of life is affected)
Nasal challenge tests (if occupational rhinitis suspected) Confirm sensitivity to specific triggers.
1International Primary Care Airways Group (IPAG) Handbook available at www.globalfamilydoctor.com.

2
2- DIFFERENTIAL DIAGNOSIS OF ALLERGIC
RHINITIS2

.
CE
Symptoms suggestive Symptoms usually NOT associated

U
of allergic rhinitis with allergic rhinitis

OD
PR
– unilateral symptoms
2 or more of the following symptoms for – nasal obstruction without other symptoms
– mucopurulent rhinorrhea

RE
> 1 hr on most days:
– watery anterior rhinorrhea – posterior rhinorrhea (post nasal drip)
–with thick mucous
– sneezing, especially paroxysmal –and/or no anterior rhinorrhea

OR
– nasal obstruction – pain
– nasal pruritis – recurrent epistaxis
± conjunctivitis – anosmia

ER
LT
Classify and assess severity
(see section 4) TA
NO

3- MAKE THE DIAGNOSIS OF ALLERGIC RHINITIS2

DO

Symptoms suggestive of allergic rhinitis

Anterior rhinorrhea
Sneezing
L,

Nasal obstruction
(and possibly other nasal or ocular symptoms)
IA
ER

t t
Primary care Specialist
t
T

t t
MA

Phadiatop or Skin prick test

Multi-allergen test
Refer the t t
patient to Positive Negative
D

t t specialist + correlated
t
TE

Negative Positive with

symptoms If strong suggestion of
t allergy: perform serum
GH

allergen specific IgE

Rhinitis is likely to be allergic. t
If more information needed Allergic rhinitis
or immunotherapy to be
RI

t t
proposed Negative Positive
t
PY

+ correlated
t with
Rhinitis is unlikely
Non allergic symptoms
to be allergic
rhinitis
CO

t
Allergic rhinitis

2Allergic Rhinitis and its impact on Asthma (ARIA) 2007. Full text ARIA documents and resources: http://www.whiar.org.

3
4- CLASSIFY ALLERGIC RHINITIS2

.
CE
Intermittent Persistent
symptoms symptoms
• <4 days per week • >4 days/week

U
• or <4 consecutive weeks • and >4 consecutive weeks

OD
PR
Mild Moderate-Severe
all of the following one or more items

RE
• normal sleep • sleep disturbance
• no impairment of daily activities, sport, leisure • impairment of daily activities, sport, leisure
• no impairment of work and school • impairment of school or work
• symptoms present but not troublesome • troublesome symptoms

OR
5- TREAT ALLERGIC RHINITIS

ER
Treatment Goals

LT
Goals for the treatment of rhinitis assume accurate diagnosis and assessment of severity as well as any link
with asthma in an individual patient. Goals include:

· Unimpaired sleep
TA
· Ability to undertake normal daily activities, including work and school attendance, without limitation or
NO

impairment, and the ability to participate fully in sport and leisure activities
· No troublesome symptoms
· No or minimal side-effects of rhinitis treatment
DO

STRENGTH OF EVIDENCE FOR EFFICACY OF

RHINITIS TREATMENT2
L,
IA

ARIA 2007
ER

Intervention SAR PAR PER

adults children adults children
T

Oral H1 Antihistamine A A A A A
MA

Intranasal H1 Antihistamine A A A A A**

Intranasal CS A A A A A**
D

Intranasal cromone A A A A
TE

LTRAs A A (>6 yrs) A A**

Subcutaneous SIT A A A A A**
GH

Sublingual / nasal SIT A A A B A**

Allergen avoidance D D A* B*
RI

SAR - Seasonal Allergic Rhinitis *not effective in the general population

PY

PAR - Perennial Allergic Rhinitis **extrapolated from studies in SAR/PAR

PER - Persistent Allergic Rhinitis
CS - Corticosteroids
CO

LTRAs - Anti-Leukotrienes
SIT - Specific Immunotherapy
2Allergic Rhinitis and its impact on Asthma (ARIA) 2007. Full text ARIA documents and resources: www.whiar.org.

4
DIAGNOSIS AND SEVERITY ASSESSMENT OF
ALLERGIC RHINITIS2

.
CE
Diagnosis of allergic rhinitis
Check for asthma
especially in
patients with

U
moderate-severe
Intermittent Persistent

OD
and/or persistent
symptoms symptoms rhinitis

PR
mild moderate- mild moderate
severe severe

RE
Not in preferred order
oral H1-antihistamine Not in preferred order In preferred order

OR
or intranasal oral H1-antihistamine intranasal CS
H1-antihistamine or intranasal H1-antihistamine or LTRA**
and/or decongestant H1-antihistamine
or LTRA** and/or decongestant review the patient

ER
or intranasal CS* after 2-4 wks
or LTRA**
(or cromone)

LT
improved failure
in persistent rhinitis
review the patient
after 2-4 weeks TAstep-down
and continue
review diagnosis
review compliance
query infections
treatment or other causes
NO

for 1 month
if failure: step-up
if improved: continue
for 1 month
DO

increase rhinorrhea
intranasal CS add ipratropium
dose itch/sneeze blockage
add H1 antihistamine add
L,

decongestant
IA

or oral CS
(short-term)
ER

failure
*Total dose of topical CS should be considered if
T

inhaled steroids are used for concomitant asthma

surgical referral
MA

**In particular, in patients with asthma

Allergen and irritant avoidance may be appropriate

D

If conjunctivitis add:
TE

oral H1-antihistamine
or intraocular H1-antihistamine
GH

or intraocular cromone
(or saline)
RI

Consider specific immunotherapy

PY

PEDIATRIC ASPECTS
Allergic rhinitis is part of the "allergic march" during childhood but intermittent allergic rhinitis is unusual before two years
CO

of age. Allergic rhinitis is most prevalent during school age years. In preschool children, the diagnosis of AR is difficult.
In school children and adolescents, the principles of treatment are the same as for adults, but doses may be adapted,
and special care should be taken to avoid the side effects of treatments typical in this age group.

2Allergic Rhinitis and its impact on Asthma (ARIA) 2007. Full text ARIA documents and resources: www.whiar.org.

5
6- ASSESS POSSIBILITY OF ASTHMA2
The patient does not know if he

.
Patient with a diagnosis of asthma

CE
(she) is asthmatic

U
4 simple questions:
– have you had an attack or recurrent attacks of wheezing?

OD
Use Asthma Diagnosis and Asthma Control
– do you have a toublesome cough, especially at night?
Questionnaires on ARIA website (www.whiar.org)
– do you cough or wheeze after exercise?
– does your chest feel tight?

PR
If YES to any of these questions

RE
your patient may be asthmatic

Need for asthma evaluation

OR
GLOSSARY OF RHINITIS MEDICATIONS1

ER
Name and Generic name Mechanism of Side effects Comments
Also known as action

LT
Oral H1 2nd generation - blockage of H1 2nd generation - First-line therapy except in
antihistamines Cetirizine - no sedation for Moderate/ Severe
receptor Persistent Allergic Rhinitis
H1-blockers Ebastine
Fexofenadine activity
TA
- some anti-allergic most drugs
- no anti-cholinergic
- 2nd generation oral H1-
blockers are preferred for
Loratadine - new generation effect their favorable efficacy/
safety ratio and pharma-
Mizolastine drugs can be used - no cardiotoxicity
NO
cokinetics; first generation
Acrivastine once daily - acrivastine has molecules are no longer
Azelastine - no development of sedative effects recommended because of
Mequitazine tachyphylaxis - oral azelastine their unfavorable safety/
efficacy ratio
New products may induce
DO

- Rapidly effective (less than 1hr)

Desloratadine sedation and a on nasal and ocular symptoms
Levocetirizine bitter taste - Moderately effective on
Rupatadine nasal congestion
* Cardiotoxic drugs
L,

(astemizole, terfenadine)
are no longer marketed in
IA

most countries

Local H1 Azelastine - blockage of H1 - Minor local side Rapidly effective

ER

antihistamines Levocabastine receptor effects (less than 30 min)

(intranasal, Olopatadine - some anti-allergic - Azelastine: bitter taste on nasal or ocular
intraocular) activity for azelastine in some patients symptoms
T

Intranasal Beclomethasone - potently reduce - Minor local side - The most effective
MA

glucocortico- dipropionate nasal inflammation effects pharmacologic

steroids treatment of allergic
Budesonide - reduce nasal - Wide margin for rhinitis; first-line
Ciclesonide hyperreactivity systemic side treatment for
Flunisolide effects
D

Moderate/ Severe
Fluticasone - Growth concerns Persistent Allergic
TE

propionate with BDP only Rhinitis

Fluticasone furoate - In young children - Effective on nasal
congestion
Mometasone furoate consider the - Effective on smell
GH

Triamcinolone combination of - Effect observed after

acetonide intranasal and 6-12 hrs but maximal
inhaled drugs effect after a few days
RI

- Patients should be
advised on the proper
method of administering
PY

intranasal glucocortico-
steroids, including the
importance of directing
the spray laterally rather
CO

than medially (toward

the septum) in the nose

1International Primary Care Airways Group (IPAG) Handbook available at www.globalfamilydoctor.com.

2Allergic Rhinitis and its impact on Asthma (ARIA) 2007. Full text ARIA documents and resources: www.whiar.org.

6
 Oral / IM Dexamethasone - Potently reduce - Systemic side When possible,
glucocortico- Hydrocortisone nasal inflammation effects common in intranasal glucocortico-
steroids Methylpredisolone particular for IM steroids should replace
Prednisolone oral or IM drugs

.
- Reduce nasal drugs

CE
Prednisone hyperreactivity - Depot injections
Triamcinolone may cause local However, a short
Betamethasone course of oral gluco-
tissue atrophy
corticosteroids may be

U
Deflazacort needed if moderate/

OD
severe symptoms
Local cromones Cromoglycate - mechanism of - Minor local side Intraocular cromones
(intranasal, Nedocromil action poorly effects are very effective

PR
intraocular) Naaga known
Intranasal cromones
are less effective

RE
and their effect is
short lasting

Overall excellent

OR
safety
Oral Ephedrine - sympathomimetic - Hypertension Use oral decongestants
decongestants Phenylephrine drug - Palpitations with caution in patients

ER
- Restlessness with heart disease
Phenyl- - relieve symptoms - Agitation
propanolamine of nasal - Tremor Oral H1-
Pseudoephedrine congestion - Insomnia antihistamine

LT
- Headache decongestant
- Dry mucous combination
Oral H1- products may be more
membranes
antihistamine-
decongestant
combination
TA - Urinary retention
- Exacerbation of
glaucoma or
effective than either
product alone but side
effects are combined
thyrotoxicosis
NO

Intranasal Oxymethazoline - sympathomimetic - Same side effects as Act more rapidly and
decongestants Others drugs oral decongestants but more effectively than
less intense oral decongestants
- relieve symptoms - Rhinitis
DO

of nasal medicamentosa Limit duration of

congestion is a rebound pheno- treatment to less than
menon occurring with 10 days to avoid
prolonged use rhinitis medicamentosa
(over 10 days)
L,

Intranasal Ipratropium - anticholinergics block - Minor local side Effective in allergic

IA

anti- almost effects and nonallergic

cholinergics exclusively - Almost no systemic patients with
rhinorrhea rhinorrhea
ER

anticholinergic activity

CysLT Montelukast - Block CysLT - Excellent tolerance Effective on rhinitis and

antagonists Pranlukast receptor asthma
T

Antileukotrienes Zafirlukast Effective on all symptoms

MA

of rhinitis and on
ocular symptoms

References: 1) International Primary Care Airways Group (IPAG) Handbook available at www.globalfamilydoctor.com.
D

2) Allergic Rhinitis and its impact on Asthma (ARIA) 2007. Full text ARIA documents and resources: www.whiar.org.
TE

GINA materials have been used with permission from the Global Initiative for Asthma (www.ginasthma.org). Material from the IPAG
Handbook has been used with permission from the International Primary Care Airways Group.
GH

The printing of this ARIA Pocket Guide has been The ARIA Initiative has been supported
supported by an educational grant from: by educational grants from:
RI

ALK Abelló Nycomed

GlaxoSmithKline Phadia
PY

Grupo Uriach Sanofi Aventis

Meda Pharma Schering-Plough
CO

MSD Stallergenes
Novartis

ARIA source documents are at www.whiar.org

© MCR Inc.
Copies of this document are available at www.us-health-network.com
 1194 ! CHAPTER 38
effective dose after the disease is brought under control
with appropriate monitoring, under the care of a specialist
familiar with the drug. Mycophenolate mofetil has also been
shown to be safe and effective in children with severe atopic
dermatitis although this was a retrospective case series.
Ultraviolet light therapy can be useful for chronic recal-
citrant atopic dermatitis in a subset of patients under the
supervision of a dermatologist. Photochemotherapy with
oral methoxypsoralen therapy followed by UVA (ultraviolet
A) has been used in a limited number of children with severe
atopic dermatitis unresponsive to other therapy, and signifi-
cant improvement has been noted. However, the increased
long-term risk of cutaneous malignancies from this therapy
prevents its widespread use.
K. Experimental and Unproved Therapies
Subcutaneous desensitization to dust mite allergen has
been shown to improve atopic dermatitis in adult patients
and one blinded, placebo-controlled study of sublingual
desensitization in dust mite allergic children showed ben-
efit in mild-moderate atopic dermatitis (currently not FDA
approved); however, further controlled trials are needed
before this form of therapy can be recommended for atopic
dermatitis in children. Treatment of atopic dermatitis with
high-dose intravenous immunoglobulin and omalizumab
is currently investigational. Although disturbances in the
metabolism of essential fatty acids have been reported in
patients with atopic dermatitis, controlled trials with fish oil
and evening primrose have shown no clinical benefit.
" Prognosis
While many children, especially those with mild disease
will outgrow their atopic dermatitis, patients with filaggrin
gene mutations are more likely to have more persistent
and severe disease. In addition, these patients appear to be
the ones at greater risk for developing asthma and allergic
sensitizations.
Boguniewicz M et al: A multidisciplinary approach to evaluation
and treatment of atopic dermatitis. Semin Cutan Med Surg
2008;27:115 [PMID: 18620133].
Boguniewicz M et al: Atopic dermatitis: a disease of altered skin
barrier and immune dysregulation. Immunol Rev 2011;242:233
[PMID: 21682749].
Schneider L et al: Atopic dermatitis: a practice parameter update
2012. J Allergy Clin Immunol 2013;131:295 [PMID: 23374261].
URTICARIA & ANGIOEDEMA
" General Considerations
Urticaria and angioedema are common dermatologic condi-
tions, occurring at some time in up to 25% of the population.
About half of patients will have concomitant urticaria and
angioedema, whereas 40% will have only urticaria and 10%
only angioedema. Urticarial lesions are arbitrarily desig-
nated as acute, lasting less than 6 weeks, or chronic, lasting
more than 6 weeks. Acute versus chronic urticaria can also
be distinguished by differences in histologic features. A
history of atopy is common with acute urticaria or angio-
edema. In contrast, atopy does not appear to be a factor in
chronic urticaria. Note that bradykinin-mediated hereditary
angioedema is discussed in the immunodeficiency chapter
(Chapter 33).
Mast cell degranulation, dilated venules, and dermal
edema are present in most forms of urticaria or angioedema.
The dermal inflammatory cells may be sparse or dense
depending on the chronicity of the lesions. Mast cells are
thought to play a critical role in the pathogenesis of urticaria
or angioedema through release of a variety of vasoactive
mediators. Mast cell activation and degranulation can be
triggered by different stimuli, including cross-linking of Fc
receptor–bound IgE by allergens or anti-FcεRI antibodies.
Non–IgE-mediated mechanisms have also been identi-
fied, including complement anaphylatoxins (C3a, C5a),
radiocontrast dyes, and physical stimuli. Chronic urticarial
lesions have greater numbers of perivascular mononuclear
cells, consisting primarily of T cells. There is also a marked
increase in cutaneous mast cells.
The cause of acute disease can be identified in about
half of patients and includes allergens such as foods, aeroal-
lergens, latex, drugs, and insect venoms. Infectious agents,
including streptococci, mycoplasmas, hepatitis B virus, and
Epstein-Barr virus, can cause acute urticaria. Urticaria or
angioedema can occur after the administration of blood
products or immunoglobulin. This results from immune
complex formation with complement activation, vascular
alterations, and triggering of mast cells by anaphylatoxins.
Opiate analgesics, polymyxin B, tubocurarine, and radio-
contrast media can induce acute urticaria by direct mast cell
activation. These disorders can also occur following inges-
tion of aspirin or nonsteroidal anti-inflammatory agents (see
later section on Adverse Reactions to Drugs & Biologicals).
Physical urticarias represent a heterogeneous group of
disorders in which urticaria or angioedema is triggered
by physical stimuli, including pressure, cold, heat, water,
or vibrations. Dermographism is the most common form
of physical urticaria, affecting up to 4% of the population
and occurring at skin sites subjected to mechanical stimuli.
Many physical urticarias are considered to be acute because
the lesions are usually rapid in onset, with resolution within
hours. However, symptoms can recur for months to years.
The cause of chronic urticaria is usually not due to aller-
gies and typically cannot be determined. It can be associated
with autoimmunity, such as autoimmune thyroid disease,
or the presence of basophil-activating IgG autoantibodies
directed at the high-affinity receptor for IgE or at IgE.
 ALLERGIC DISORDERS
" Clinical Findings
A. Symptoms and Signs
Cold-induced urticaria or angioedema can occur within
minutes of exposure to a decreased ambient temperature or
as the skin is warmed following direct cold contact. Systemic
features include headache, wheezing, and syncope. If the
entire body is cooled, as may occur during swimming, hypo-
tension and collapse can occur. Two forms of dominantly
inherited cold urticaria have been described. The immediate
form is known as familial cold urticaria, in which erythema-
tous macules appear rather than wheals, along with fever,
arthralgias, and leukocytosis. The delayed form consists of
erythematous, deep swellings that develop 9–18 hours after
local cold challenge without immediate lesions.
In solar urticaria, which occurs within minutes after
exposure to light of appropriate wavelength, pruritus is fol-
lowed by morbilliform erythema and urticaria.
Cholinergic urticaria occurs after increases in core body
and skin temperatures and typically develops after a warm
bath or shower, exercise, or episodes of fever. Occasional epi-
sodes are triggered by stress or the ingestion of certain foods.
The eruption appears as small punctate wheals surrounded
by extensive areas of erythema. Rarely, the urticarial lesions
become confluent and angioedema develops. Associated
features can include one or more of the following: headache,
syncope, bronchospasm, abdominal pain, vomiting, and
diarrhea. In severe cases, systemic anaphylaxis may develop.
In pressure urticaria or angioedema, red, deep, painful
swelling occurs immediately or 4–6 hours after the skin
has been exposed to pressure. The immediate form is often
associated with dermographism. The delayed form, which
may be associated with fever, chills, and arthralgias, may
be accompanied by elevated erythrocyte sedimentation rate
and leukocytosis. Lesions are frequently diffuse, tender, and
painful rather than pruritic. They typically resolve within
48 hours.
B. Laboratory Findings
Laboratory tests are selected on the basis of the history and
physical findings. Testing for specific IgE antibody to food
or inhalant allergens may be helpful in implicating a poten-
tial cause. Specific tests for physical urticarias, such as an ice
cube test or a pressure test, may be indicated. Intradermal
injection of methacholine reproduces clinical symptoms
locally in about one-third of patients with cholinergic urti-
caria. A throat culture for streptococcal infection may be
warranted with acute urticaria. In chronic urticaria, selected
screening studies to look for an underlying disease may
be indicated, including a complete blood count, erythro-
cyte sedimentation rate, biochemistry panel, and urinalysis.
Antithyroid antibodies may be considered. Intradermal test-
ing with the patient’s serum has been suggested as a method
! 1195
of detecting histamine-releasing activity, including autoan-
tibodies (autologous serum skin test). In patients with well-
characterized autoimmune urticaria, donor basophil and
mast cell activation markers including CD63 and CD203c
have been shown to be upregulated in patient serum. Other
tests should be done based on suspicion of a specific under-
lying disease. If the history or appearance of the urticarial
lesions suggests vasculitis, a skin biopsy for immunofluores-
cence is indicated. Patient diaries occasionally may be help-
ful to determine the cause of recurrent hives. A trial of food
or drug elimination may be considered.
" Differential Diagnosis
Urticarial lesions are usually easily recognized—the major
dilemma is the etiologic diagnosis. Lesions of urticarial vascu-
litis typically last for more than 24 hours. “Papular urticaria” is
a term used to characterize multiple papules from insect bites,
found especially on the extremities, and is not true urticaria.
Angioedema can be distinguished from other forms of edema
because it is transient, asymmetrical, and nonpitting and does
not occur predominantly in dependent areas. Hereditary
angioedema is a rare autosomal dominant disorder caused by
a quantitative or functional deficiency of C1-esterase inhibi-
tor and characterized by episodic, frequently severe, nonpru-
ritic angioedema of the skin, gastrointestinal tract, or upper
respiratory tract (discussed in Chapter 33). Life-threatening
laryngeal angioedema may occur. Rare autoinflammatory
disorders with urticaria or urticaria-vasculitic-like lesions
include cold-induced autoinflammatory syndrome, Muckle-
Wells syndrome, and Schnitzler syndrome.
" Complications
In severe cases of cholinergic urticaria, systemic anaphylaxis
may develop. In cold-induced disease, sudden cooling of the
entire body as can occur with swimming can result in hypo-
tension and collapse.
" Treatment
A. General Measures
The most effective treatment is identification and avoid-
ance of the triggering agent. Underlying infection should
be treated appropriately. Patients with physical urticarias
should avoid the relevant physical stimulus. Patients with
cold urticaria should be counseled not to swim alone and
prescribed autoinjectable epinephrine in case of generalized
mast cell degranulation with immersion in cold water or
other widespread cold exposures.
B. Antihistamines
For the majority of patients, H1 antihistamines given orally
or systemically are the mainstay of therapy. Antihistamines
 1196 ! CHAPTER 38
are more effective when given on an ongoing basis rather
than after lesions appear. Second-generation antihistamines
(discussed previously under Allergic Rhinoconjunctivitis)
are long acting, show good tissue levels, are non- or mini-
mally sedating at usual dosing levels, and lack anticholin-
ergic effects. They are the preferred treatment for treating
urticaria. The addition of H2 antihistamines may benefit
some patients who fail to respond to H1-receptor antagonists
alone. In school-aged children, but especially adolescents
who are of driving age or who operate machinery, nonse-
dating antihistamines should be used during the day and
sedating antihistamines can be added at bedtime, if needed.
Patients with urticaria may require treatment with higher
than usual doses of antihistamines if they have breakthrough
symptoms.
C. Corticosteroids
Although corticosteroids are usually not indicated in the
treatment of acute or chronic urticaria, severe recalcitrant
cases may require alternate-day or low dose therapy in an
attempt to diminish disease activity or short-term use to
facilitate control with antihistamines. However, high-dose
chronic steroid use should be avoided. Systemic corticoste-
roids may also be needed in the treatment of urticaria or
angioedema secondary to necrotizing vasculitis, an uncom-
mon occurrence in patients with serum sickness or collagen-
vascular disease.
D. Other Pharmacologic Agents
Limited studies suggest that some patients may benefit
from treatment with a leukotriene-receptor antagonist. The
tricyclic antidepressant doxepin blocks both H1 and H2 his-
tamine receptors and may be particularly useful in chronic
urticaria, although its use may be limited by the sedating
side effect. Cyclosporine has been shown to be effective in
multiple trials of severe chronic urticaria, but it does require
blood pressure and renal function monitoring. Omalizumab
trials for refractory chronic urticaria have shown promising
results, but it is not currently FDA-approved for this condi-
tion. A limited number of patients—including euthyroid
patients—with chronic urticaria and antithyroid antibod-
ies have improved when given thyroid hormone, although
this treatment remains controversial. Treatment of chronic
urticaria with hydroxychloroquine, sulfasalazine, dapsone,
colchicine, and intravenous immune globulin should be
considered investigational.
" Prognosis
Spontaneous remission of urticaria and angioedema is
frequent, but some patients have a prolonged course,
especially those with physical urticaria. In one natural his-
tory study, approximately 58% of children with chronic
urticaria became symptom free after 6 months. Reassurance
is important, because this disorder can cause significant
frustration. Periodic follow-up is indicated, particularly
for patients with laryngeal edema, to monitor for possible
underlying cause.
Maurer M et al: Omalizumab for the treatment of chronic idio-
pathic or spontaneous urticaria. New Engl J Med 2013:368:924
[PMID: 23432142].
Zuberbier T et al: EAACI/GA2LEN/EDF/WAO guideline:
definition, classification and diagnosis of urticaria. Allergy
2009:64:1417 [PMID: 19772512].
Zuberbier T et al: EAACI/GA2LEN/EDF/WAO guideline: man-
agement of urticaria. Allergy 2009;64:1427 [PMID: 19772513].
ANAPHYLAXIS
" General Considerations
Anaphylaxis is an acute life-threatening clinical syndrome
that occurs when large quantities of inflammatory media-
tors are rapidly released from mast cells and basophils after
exposure to an allergen in a previously sensitized patient.
Anaphylactoid reactions mimic anaphylaxis but are not
mediated by IgE antibodies. They may be mediated by
anaphylatoxins such as C3a or C5a or through nonimmune
mast cell degranulating agents. Some of the common causes
of anaphylaxis or anaphylactoid reactions are listed in
Table 38–6. Idiopathic anaphylaxis by definition has no
recognized external cause. The clinical history is the most
important tool in making the diagnosis of anaphylaxis.
Table 38–6. Common causes of systemic allergic and
pseudoallergic reactions.
Causes of anaphylaxis
Drugs
Antibiotics
Anesthetic agents
Foods
Peanuts, tree nuts, shellfish, and others
Biologicals
Latex
Insulin
Allergen extracts
Antisera
Blood products
Enzymes
Monoclonal antibodies (eg, omalizumab)
Insect venoms
Radiocontrast media
Aspirin and other nonsteroidal anti-inflammatory drugs
Anesthetic agents
Idiopathic
Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline

Wheals Angioedema

Recurrent unexplained fever? 1

ACE inhibitor treatment?
Joint/bone pain? Malaise?

History
+ – – +

Autoinflammatory Average wheal Remission

HAE2,5 or AAE2,5?
disease?2,3 dura on > 24h?4 a er stop?6

+ – + – – + – +

Diagnos c tests
Signs of vasculi s Are symptoms
in biopsy?7 inducible?8

+ – – +

Provoca on
test9

– +

Acquired/ Chronic Chronic ACE-Inh

Ur carial HAE I-III
hereditary spontaneous inducible induced
10 vasculi s AAE
AID ur caria11 ur caria AE

Histamine and other
Interleukin-1
mast cell mediators
Figure 1 Recommended diagnosis algorithm for urticaria. Diagnos-
tic algorithm for patients presenting with wheals, angioedema, or
both. AAE, Acquired angioedema due to C1-inhibitor deficiency;
ACE-Inh, angiotensin-converting enzyme inhibitor; AE, angioedema;
AH, Antihistamine; AID, Auto-inflammatory disease; HAE, Heredi-
tary angioedema; IL-1, Interleukin-1. 1Other (new) drugs may also
induce bradykinin-mediated angioedema. 2Patients should be asked
for a detailed family history and age of disease onset. 3Test for ele-
vated inflammation markers (C-reactive protein, erythrocyte sedi-
mentation rate), test for paraproteinemia in adults, look for signs of
neutrophil-rich infiltrates in skin biopsy; perform gene mutation
analysis of hereditary periodic fever syndromes (e.g., cryopyrin-
associated periodic syndrome), if strongly suspected. 4Patients
should be asked: ‘How long do your wheals last?’ 5Test for Com-
plement C4, C1-INH levels and function; in addition, test for C1q
and C1-INH antibodies, if AAE is suspected; do gene mutation
analysis, if former tests are unremarkable but patient’s history sug-
gests hereditary angioedema. 6Wait for up to 6 months for remis-
sion; additional diagnostics to test for C1-inhibitor deficiency should
only be performed, if the family history suggests hereditary angioe-
Treatment
Bradykinin
dema. 7Does the biopsy of lesional skin show damage of the small
vessels in the papillary and reticular dermis and/or fibrinoid deposits
in perivascular and interstitial locations suggestive of UV (urticarial
vasculitis)? 8Patients should be asked: ‘Can you make your wheals
come?’ 9In patients with a history suggestive of inducible urticaria,
standardized provocation testing according to international consen-
sus recommendations (45) should be performed. 10Acquired autoin-
flammatory syndromes (AIDs) include Schnitzler’s syndrome as
well as systemic-onset juvenile idiopathic arthritis (sJIA) and adult-
onset Still’s disease (AOSD); hereditary AIDs include cryopyrin-
associated periodic syndromes (CAPS) such as familial cold auto-
inflammatory syndromes (FCAS), Muckle–Wells syndrome (MWS)
and neonatal onset multisystem inflammatory disease (NOMID),
more rarely hyper-IgD syndrome (HIDS) and tumor necrosis factor
receptor alpha-associated periodic syndrome (TRAPS). 11In some
rare cases, recurrent angioedema is neither mast cell mediator-
mediated nor bradykinin-mediated, and the underlying pathomecha-
nisms remain unknown. These rare cases are referred to as ‘idio-
pathic angioedema’ by some authors.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 1196 ! CHAPTER 38
are more effective when given on an ongoing basis rather
than after lesions appear. Second-generation antihistamines
(discussed previously under Allergic Rhinoconjunctivitis)
are long acting, show good tissue levels, are non- or mini-
mally sedating at usual dosing levels, and lack anticholin-
ergic effects. They are the preferred treatment for treating
urticaria. The addition of H2 antihistamines may benefit
some patients who fail to respond to H1-receptor antagonists
alone. In school-aged children, but especially adolescents
who are of driving age or who operate machinery, nonse-
dating antihistamines should be used during the day and
sedating antihistamines can be added at bedtime, if needed.
Patients with urticaria may require treatment with higher
than usual doses of antihistamines if they have breakthrough
symptoms.
C. Corticosteroids
Although corticosteroids are usually not indicated in the
treatment of acute or chronic urticaria, severe recalcitrant
cases may require alternate-day or low dose therapy in an
attempt to diminish disease activity or short-term use to
facilitate control with antihistamines. However, high-dose
chronic steroid use should be avoided. Systemic corticoste-
roids may also be needed in the treatment of urticaria or
angioedema secondary to necrotizing vasculitis, an uncom-
mon occurrence in patients with serum sickness or collagen-
vascular disease.
D. Other Pharmacologic Agents
Limited studies suggest that some patients may benefit
from treatment with a leukotriene-receptor antagonist. The
tricyclic antidepressant doxepin blocks both H1 and H2 his-
tamine receptors and may be particularly useful in chronic
urticaria, although its use may be limited by the sedating
side effect. Cyclosporine has been shown to be effective in
multiple trials of severe chronic urticaria, but it does require
blood pressure and renal function monitoring. Omalizumab
trials for refractory chronic urticaria have shown promising
results, but it is not currently FDA-approved for this condi-
tion. A limited number of patients—including euthyroid
patients—with chronic urticaria and antithyroid antibod-
ies have improved when given thyroid hormone, although
this treatment remains controversial. Treatment of chronic
urticaria with hydroxychloroquine, sulfasalazine, dapsone,
colchicine, and intravenous immune globulin should be
considered investigational.
" Prognosis
Spontaneous remission of urticaria and angioedema is
frequent, but some patients have a prolonged course,
especially those with physical urticaria. In one natural his-
tory study, approximately 58% of children with chronic
urticaria became symptom free after 6 months. Reassurance
is important, because this disorder can cause significant
frustration. Periodic follow-up is indicated, particularly
for patients with laryngeal edema, to monitor for possible
underlying cause.
Maurer M et al: Omalizumab for the treatment of chronic idio-
pathic or spontaneous urticaria. New Engl J Med 2013:368:924
[PMID: 23432142].
Zuberbier T et al: EAACI/GA2LEN/EDF/WAO guideline:
definition, classification and diagnosis of urticaria. Allergy
2009:64:1417 [PMID: 19772512].
Zuberbier T et al: EAACI/GA2LEN/EDF/WAO guideline: man-
agement of urticaria. Allergy 2009;64:1427 [PMID: 19772513].
ANAPHYLAXIS
" General Considerations
Anaphylaxis is an acute life-threatening clinical syndrome
that occurs when large quantities of inflammatory media-
tors are rapidly released from mast cells and basophils after
exposure to an allergen in a previously sensitized patient.
Anaphylactoid reactions mimic anaphylaxis but are not
mediated by IgE antibodies. They may be mediated by
anaphylatoxins such as C3a or C5a or through nonimmune
mast cell degranulating agents. Some of the common causes
of anaphylaxis or anaphylactoid reactions are listed in
Table 38–6. Idiopathic anaphylaxis by definition has no
recognized external cause. The clinical history is the most
important tool in making the diagnosis of anaphylaxis.
Table 38–6. Common causes of systemic allergic and
pseudoallergic reactions.
Causes of anaphylaxis
Drugs
Antibiotics
Anesthetic agents
Foods
Peanuts, tree nuts, shellfish, and others
Biologicals
Latex
Insulin
Allergen extracts
Antisera
Blood products
Enzymes
Monoclonal antibodies (eg, omalizumab)
Insect venoms
Radiocontrast media
Aspirin and other nonsteroidal anti-inflammatory drugs
Anesthetic agents
Idiopathic
 ALLERGIC DISORDERS
" Clinical Findings
A. Symptoms and Signs
The history is the most important tool to determine whether
a patient has had anaphylaxis. The symptoms and signs of
anaphylaxis depend on the organs affected. Onset typically
occurs within minutes after exposure to the offending agent
and can be short-lived, protracted, or biphasic, with recur-
rence after several hours despite treatment.
Anaphylaxis is highly likely when any one of the follow-
ing three criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours)
with involvement of the skin, mucosal tissue, or both
(eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) and at least one of the following:
a. Respiratory compromise (eg, dyspnea, wheeze,
bronchospasm, stridor, reduced peak expiratory
flow, hypoxemia)
b. Reduced blood pressure or associated symptoms of
end-organ dysfunction (eg, hypotonia [collapse],
syncope, incontinence)
2. Two or more of the following that occur rapidly after
exposure to a likely allergen for that patient (minutes
to several hours):
a. Involvement of the skin-mucosal tissue (eg, general-
ized urticaria, itch-flush, swollen lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze,
bronchospasm, stridor, reduced PEFR, hypoxemia)
c. Reduced blood pressure or associated symptoms (eg,
hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy
abdominal pain, vomiting)
3. Reduced blood pressure after exposure to a known
allergen for that patient (minutes to several hours)
a. Infants and children: low systolic blood pressure
(age specific) or greater than 30% decrease in systolic
pressure
b. Low systolic blood pressure in children, defined as less
than 70 mm Hg in those aged from 1 month to 1 year,
less than (70 mm Hg + [2 × age]) in those 1–10 years
of age, and less than 90 mm Hg in those 11–17 years
B. Laboratory Findings
An absence of laboratory findings does not rule out anaphy-
laxis. Tryptase released by mast cells can be measured in the
serum and may be helpful when the diagnosis of anaphylaxis
is in question. The blood sample should be obtained within
3 hours of onset of the reaction, although tryptase levels are
often normal, particularly in individuals with food-induced
anaphylaxis. The complete blood count may show an ele-
vated hematocrit due to hemoconcentration. Elevation of
serum creatine kinase, aspartate aminotransferase, and lactic
! 1197
dehydrogenase may be seen with myocardial involvement.
Electrocardiographic abnormalities may include ST-wave
depression, bundle branch block, and various arrhythmias.
Arterial blood gases may show hypoxemia, hypercapnia,
and acidosis. The chest radiograph may show hyperinflation.
" Differential Diagnosis
Although shock may be the only sign of anaphylaxis, other
diagnoses should be considered, especially in the setting
of sudden collapse without typical allergic findings. Other
causes of shock along with cardiac arrhythmias must be
ruled out (see Chapters 12 and 14). Respiratory failure
associated with asthma may be confused with anaphylaxis.
Mastocytosis, hereditary angioedema, scombroid poisoning,
vasovagal reactions, vocal cord dysfunction, and anxiety
attacks may cause symptoms mistaken for anaphylaxis.
" Complications
Depending on the organs involved and the severity of the
reaction, complications may vary from none to aspiration
pneumonitis, acute tubular necrosis, bleeding diathesis, or
sloughing of the intestinal mucosa. With irreversible shock,
heart and brain damage can be terminal. Risk factors for
fatal or near-fatal anaphylaxis include age (adolescents and
young adults), reactions to peanut or tree nuts, associated
asthma, strenuous exercise, and ingestion of medications
such as β-blockers.
" Prevention
Strict avoidance of the causative agent is extremely important.
An effort to determine its cause should be made, beginning
with a thorough history. Typically, there is a strong tempo-
ral relationship between exposure and onset of symptoms.
Testing for specific IgE to allergens with either in vitro or skin
testing may be indicated. With exercise-induced anaphylaxis,
patients should be instructed to exercise with another per-
son and to stop exercising at the first sign of symptoms. If
prior ingestion of food has been implicated, eating within
4 hours—perhaps up to 12 hours—before exercise should be
avoided. Patients with a history of anaphylaxis should carry
epinephrine for self-administration, preferably in the form of
an autoinjector (eg, Auvi-Q or EpiPen in 0.15- and 0.3-mg
doses), and they and all caregivers should be instructed on its
use. When epinephrine autoinjectors are unavailable or unaf-
fordable, patients in some communities have been provided
with unsealed syringes containing premeasured epinephrine
doses, but this is not the recommended form since it needs to
be replaced every few months on a regular basis due to lack
of stability and the use of a syringe is more unwieldy in an
emergent situation. They should also carry an oral antihista-
mine such as diphenhydramine, preferably in liquid or fast-
melt preparation to hasten absorption, and consider wearing
 1198 ! CHAPTER 38
a medical alert bracelet. Patients with idiopathic anaphylaxis
may require prolonged treatment with oral corticosteroids.
Specific measures for dealing with food, drug, latex, and
insect venom allergies as well as radiocontrast media reac-
tions are discussed in the next sections.
" Treatment
A. General Measures
Anaphylaxis is a medical emergency that requires rapid
assessment and treatment. Exposure to the triggering
agent should be discontinued. Airway patency should
be maintained and blood pressure and pulse monitored.
Simultaneously and promptly, emergency medical services
or a call for help to a resuscitation team should be made.
The patient should be placed in a supine position with
the legs elevated unless precluded by shortness of breath
or emesis. Oxygen should be delivered by mask or nasal
cannula with pulse oximetry monitoring. If the reaction is
secondary to a sting or injection into an extremity, a tour-
niquet may be applied proximal to the site, briefly releasing
it every 10–15 minutes.
B. Epinephrine
Epinephrine is the treatment of choice for anaphylaxis.
Epinephrine 1:1000, 0.01 mg/kg to a maximum of 0.5 mg
in adults and 0.3 mg in children, should be injected intra-
muscularly in the midanterolateral thigh, without delay.
This dose may be repeated at intervals of 5–15 minutes as
necessary for controlling symptoms and maintaining blood
pressure. If the precipitating allergen has been injected intra-
dermally or subcutaneously, absorption may be delayed by
giving 0.1 mL of epinephrine subcutaneously at the injection
site unless the site is a digit. There is no precisely established
dosing regimen for intravenous epinephrine in anaphylaxis,
but a 5–10 mcg intravenous bolus for hypotension and
0.1–0.5 mg intravenously for cardiovascular collapse has
been suggested.
C. Antihistamines
Diphenhydramine, an H1-blocker, 1–2 mg/kg up to 50 mg,
can be given orally, intramuscularly or intravenously.
Intravenous antihistamines should be infused over a
period of 5–10 minutes to avoid inducing hypotension.
Alternatively in young patients, cetirizine 0.25 mg/kg to a
maximum dose of 10 mg could be given orally, as it was
shown to have a longer duration of action and reduced
sedation profile. Addition of ranitidine, an H2-blocker,
1 mg/kg up to 50 mg intravenously, may be more effec-
tive than an H1-blocker alone, especially for hypotension,
but histamine blockers should be considered second-line
treatment for anaphylaxis.
D. Fluids
Treatment of persistent hypotension despite epinephrine
requires restoration of intravascular volume by fluid replace-
ment, initially with a crystalloid solution, 20–30 mL/kg in
the first hour.
E. Bronchodilators
Nebulized β2-agonists such as albuterol 0.5% solution,
2.5 mg (0.5 mL) diluted in 2–3 mL saline, or levalbuterol,
0.63 mg or 1.25 mg, may be useful for reversing broncho-
spasm. Intravenous methylxanthines are generally not rec-
ommended because they provide little benefit over inhaled
β2-agonists and may contribute to toxicity.
F. Corticosteroids
Although corticosteroids do not provide immediate benefit,
when given early they may prevent protracted or biphasic
anaphylaxis. Intravenous methylprednisolone, 50–100 mg
(adult) or 1 mg/kg, maximum 50 mg (child), can be given
every 4–6 hours. Oral prednisone, 1 mg/kg up to 50 mg,
might be sufficient for less severe episodes.
G. Vasopressors
Hypotension refractory to epinephrine and fluids should be
treated with intravenous vasopressors such as noradrenaline,
vasopressin, or dopamine (see Chapter 14).
H. Observation
The patient should be monitored after the initial symptoms
have subsided, because biphasic or protracted anaphylaxis
can occur despite ongoing therapy. Biphasic reactions occur
in 1%–20% of anaphylactic reactions, but no reliable clinical
predictors have been identified. Observation periods should
be individualized based on the severity of the initial reaction,
but a reasonable time for observation is 4–6 hours in most
patients, with prolonged observation or admission for severe
or refractory symptoms.
" Prognosis
Anaphylaxis can be fatal. In two reports describing chil-
dren, adolescents, and adults who died from food-induced
anaphylaxis (eg, from peanuts, tree nuts, fish, shellfish, and
milk) over the past 12 years, treatment with epinephrine
was delayed for more than 1 hour after onset as it was not
readily accessible in the majority of subjects. The prognosis,
however, is good when signs and symptoms are recognized
promptly and treated aggressively, and the offending agent
is subsequently avoided. Exercise-induced and idiopathic
anaphylaxis may be recurrent. Because accidental exposure
to the causative agent may occur, patients, parents, and
 746 ! CHAPTER 23

that if the administered fluid volume is decreased in this
setting, as the child is weaned from supplemental IV fluids
to enteral intake, the sodium and other electrolytes will need
to be reduced accordingly to avoid progressively increasing
IV fluid tonicity that can result in hypernatremia or other
electrolyte derangements.
It is helpful to monitor the patient’s daily weight, urinary
output, fluid input, and urine specific gravity. However,
if stress-induced nonosmotic release of ADH is operative
in a given patient, serial monitoring of the urine specific
gravity may give the false impression that the child is still
dehydrated when they are fluid replete, but still generating
a concentrated urine. If fluid or electrolyte balance is abnor-
mal, serial determination of serum electrolyte concentra-
tions, blood urea nitrogen, and creatinine are necessary. In
patients with significant burns, anuria, oliguria, or persistent
abnormal stool or urine losses (eg, from a stoma, or polyuria
secondary to a renal concentrating defect), it is important to
measure output, and if needed its electrolyte components, so
appropriate replacement can be provided.
DEHYDRATION
Depletion of body fluids is one of the most commonly
encountered problems in clinical pediatrics. Children have a
high incidence of gastrointestinal diseases, including gastro-
enteritis, and may demonstrate gastrointestinal symptoms in
nongastrointestinal conditions, such as pneumonia or men-
ingitis. Infants and young children often decrease their oral
intake when ill, and their high ratio of surface area to weight
promotes significant evaporative losses. Renal concentrating
mechanisms do not maximally conserve water in early life,
and fever may significantly increase fluid needs. Dehydration
decreases ECF volume, leading to decreased tissue perfusion,
progressive uremia and abnormal renal function studies,
compensatory tachycardia, and lactic acidosis. The clinical
effects of dehydration relate to the degree of dehydration and
to the relative amounts of salt and water lost. Caregivers must
be particularly aware of dehydration occurring in breast-fed
newborn infants who go home soon after birth and whose
mothers fail to produce enough milk. This problem is more
common in the hot summer months and has been associated
with severe dehydration, brain damage, and death.
The clinical evaluation of a child with dehydration
should focus on the composition and volume of fluid intake;
the frequency and amount of vomiting, diarrhea, and urine
output; the degree and duration of fever; the nature of any
administered medications; and the existence of underlying
medical conditions. A recently recorded weight, if known,
can be very helpful in calculating the magnitude of dehydra-
tion. Important clinical features in estimating the degree of
dehydration include the capillary refill time, postural blood
pressure, and heart rate changes; dryness of the lips and
mucous membranes; lack of tears; lack of external jugular
venous filling when supine; a sunken fontanelle in an infant;
oliguria; and altered mental status (Table 23–3). Children
generally respond to a decrease in circulating volume with
a compensatory increase in pulse rate and may maintain

Table 23–3. Clinical manifestations of dehydration.

Degree of Dehydration

Clinical Signs Mild Moderate Severe

Decrease in body weight 3%–5% 6%–10% 11%–15%

Skin
Turgor Normal ± Decreased Markedly decreased
Color Normal Pale Markedly decreased
Mucous membranes Dry Mottled or gray; parched

Hemodynamic Signs
Pulse Normal Slight increase Tachycardia
Capillary refill 2–3 s 3–4 s >4s
Blood pressure Normal Low
Perfusion Normal Circulatory collapse

Fluid Loss
Urinary output Mild oliguria Oliguria Anuria
Tears Decreased Absent
Urinary Indices
Specific gravity > 1.020 Anuria
Urine [Na+] < 20 mEq/L Anuria
 FLUID, ELECTROLYTE,& ACID-BASE DISORDERS& THERAPY
their blood pressure in the face of severe dehydration. A low
or falling blood pressure is, therefore, a late sign of shock in
children, and when present should prompt emergent treat-
ment. Salient laboratory parameters include a high urine
specific gravity (in the absence of an underlying renal concen-
trating defect as seen in diabetes insipidus or chronic obstruc-
tive or reflux nephropathy), a relatively greater elevation in
blood urea nitrogen than in serum creatinine, a low urinary
[Na+] excretion (< 20 mEq/L), and an elevated hematocrit or
serum albumin level secondary to hemoconcentration.
Emergent intravenous therapy is indicated when there
is evidence of compromised perfusion (inadequate capillary
refill, tachycardia, poor color, oliguria, or hypotension). The
initial goal is to rapidly expand the plasma volume and to
prevent circulatory collapse. A 20-mL/kg bolus of isotonic
fluid should be given intravenously as rapidly as possible.
Either colloid (5% albumin) or crystalloid (normal saline or
Ringer lactate) may be used. Colloid is particularly useful in
hypernatremic patients in shock, in malnourished infants,
and in neonates. If no intravenous site is available, fluid may
be administered intraosseously through the marrow space
of the tibia. If there is no response to the first fluid bolus, a
second bolus may be given. When adequate tissue perfusion
is demonstrated by improved capillary refill, decreased pulse
rate and urine output, and improved mental status, deficit
replacement may be instituted. If adequate perfusion is not
restored after 40 mL/kg of isotonic fluids, other pathologic
processes must be considered such as sepsis, occult hemor-
rhage, or cardiogenic shock. Isotonic dehydration may be
treated by providing half of the remaining fluid deficit over
8 hours and the second half over the ensuing 16 hours
in the form of 5% dextrose with 0.45% saline containing
20 mEq/L of KCl. In the presence of metabolic acidosis,
potassium acetate may be considered. Maintenance fluids
and replacement of ongoing losses should also be provided.
Typical electrolyte compositions of various body fluids are
depicted in Table 23–4, although it may be necessary to
measure the specific constituents of a patient’s fluid losses to
Table 23–4. Typical electrolyte compositions of various
body fluids.
Na+ (mEq/L) K+ (mEq/L) (mEq/L)
Diarrhea 10–90 10–80 40
Gastric 20–80 5–20 0 Isotonic
Small intestine 100–140 5–15 40
Ileostomy 45–135 3–15 40
Data from Winters RW: Principles of Pediatric Fluid Therapy. Little,
Brown; 1973.
! 747
guide therapy. If the patient is unable to eat for a prolonged
period, nutritional needs must be met through hyperalimen-
tation or enteral tube feedings.
Oral rehydration may be provided to children with mild
to moderate dehydration. Clear liquid beverages found in
the home, such as broth, soda, juice, and tea are inappropri-
ate for the treatment of dehydration. Commercially available
solutions provide 45–75 mEq/L of Na+, 20–25 mEq/L of K+,
30–34 mEq/L of citrate or bicarbonate, and 2%–2.5% of
glucose. Frequent small aliquots (5–15 mL) should be given
to provide approximately 50 mL/kg over 4 hours for mild
dehydration and up to 100 mL/kg over 6 hours for moderate
dehydration. Oral rehydration is contraindicated in children
with altered levels of consciousness or respiratory distress
who cannot drink freely; in children suspected of having an
acute surgical abdomen; in infants with greater than 10%
volume depletion; in children with hemodynamic instabil-
ity; and in the setting of severe hyponatremia ([Na+] < 120
mEq/L) or hypernatremia ([Na+] > 160 mEq/L). Failure
of oral rehydration due to persistent vomiting or inabil-
ity to keep up with losses mandates intravenous therapy.
Successful oral rehydration requires explicit instructions to
caregivers and close clinical follow-up of the child.
The type of dehydration is characterized by the serum
[Na+]. If relatively more solute is lost than water, the [Na+]
falls, and hyponatremic dehydration ([Na+] < 130 mEq/L)
ensues. This is important clinically because hypotonicity of
the plasma contributes to further volume loss from the ECF
into the intracellular space. Thus, tissue perfusion is more
significantly impaired for a given degree of hyponatremic
dehydration than for a comparable degree of isotonic or
hypertonic dehydration. It is important to note, however,
that significant solute losses also occur in hypernatremic
dehydration. Furthermore, because plasma volume is some-
what protected in hypernatremic dehydration, it poses the
risk of the clinician underestimating the severity of dehydra-
tion. Typical fluid and electrolyte losses associated with each
form of dehydration are shown in Table 23–5.
Table 23–5. Estimated water and electrolyte deficits in
dehydration (moderate to severe).
Type of H2O Na+ K+ Cl− and
Dehydration (mL/kg) (mEq/kg) (mEq/kg) (mEq/kg)
100–150 8–10 8–10 16–20
Hypotonic 50–100 10–14 10–14 20–28
Hypertonic 120–180 2–5 2–5 4–10
Adapted, with permission, from Winters RW: Principles of Pediatric
Fluid Therapy. Little, Brown; 1982.
 748 ! CHAPTER 23
HYPONATREMIA
Hyponatremia may be factitious in the presence of high
plasma lipids or proteins, which decrease the percentage of
plasma volume that is water. Hyponatremia in the absence of
hypotonicity also occurs when an osmotically active solute,
such as glucose or mannitol, is added to the ECF. Water
drawn from the ICF dilutes the serum [Na+] despite isoto-
nicity or hypertonicity.
Patients with hyponatremic dehydration generally dem-
onstrate typical signs and symptoms of dehydration (see
Table 23–3), because the vascular space is compromised as
water leaves the ECF to maintain osmotic neutrality. The
treatment of hyponatremic dehydration is fairly straightfor-
ward. The magnitude of the sodium deficit may be calcu-
lated by the following formula:
Na+ deficit = (Na+ desired − Na+ observed)
× Bodyweight (kg) × 0.6
Half of the deficit is replenished in the first 8 hours of
therapy, and the remainder is given over the following 16
hours. Maintenance and replacement fluids should also be
provided. The deficit plus maintenance calculations often
approximate 5% dextrose with 0.45% or higher saline. The
rise in serum [Na+] should not exceed 0.5–1.0 mEq/L/h or 20
mEq/L/24 h unless the patient demonstrates central nervous
system (CNS) symptoms that warrant more rapid initial
correction. The dangers of too rapid correction of hypona-
tremia include cerebral dehydration and injury due to fluid
shifts from the ICF compartment.
Hypovolemic hyponatremia also occurs in cerebral salt-
wasting associated with CNS insults, a condition character-
ized by high urine output and elevated urinary [Na+] (> 80
mEq/L) due to an increase in ANF, and is a diagnosis of
exclusion requiring a natriuresis in a patient with a con-
tracted effective circulatory blood volume in the absence of
other causes for Na+ excretion. This must be distinguished
from the syndrome of inappropriate secretion of ADH
(SIADH), which may also manifest in CNS conditions and
pulmonary disorders. In contrast to cerebral salt-wasting,
SIADH is characterized by euvolemia or mild volume
expansion and relatively low urine output due to ADH-
induced water retention. Urinary [Na+] is high in both
conditions, though generally not as high as in SIADH. It
is important to distinguish between these two conditions,
because the treatment of the former involves replacement
of urinary salt and water losses, whereas the treatment of
SIADH involves water restriction. It is also important to
remember that in SIADH patients are not necessarily oli-
guric, and that their urine does not need to be maximally
concentrated but merely inappropriately concentrated for
their degree of serum tonicity.
In cases of severe hyponatremia (serum [Na+] < 120
mEq/L) with CNS symptoms, intravenous 3% NaCl may be
given over 1 hour to raise the [Na+] to 120 mEq/L to allevi-
ate CNS manifestations and sequelae. In general, 6 mL/kg
of 3% NaCl will raise the serum [Na+] by about 5 mEq/L. If
3% NaCl is administered, estimated Na+ and fluid deficits
should be adjusted accordingly. Further correction should
proceed slowly, as outlined earlier.
Hypervolemic hyponatremia may occur in edematous
disorders such as nephrotic syndrome, congestive heart
failure, and cirrhosis, wherein water is retained in excess
of salt. Treatment involves restriction of Na+ and water
and correction of the underlying disorder. Hypervolemic
hyponatremia due to water intoxication is characterized by a
maximally dilute urine (specific gravity < 1.003) and is also
treated with water restriction.
HYPERNATREMIA
Although diarrhea is commonly associated with hypona-
tremic or isonatremic dehydration, hypernatremia may
develop in the presence of persistent fever or decreased fluid
intake or in response to improperly mixed rehydration solu-
tions. Extreme care is required to treat hypernatremic dehy-
dration appropriately. If the serum [Na+] falls precipitously,
the osmolality of the ECF drops more rapidly than that of the
CNS. Water shifts from the ECF compartment into the CNS
to maintain osmotic neutrality. If hypertonicity is corrected
too rapidly (a drop in [Na+] of > 0.5–1 mEq/L/h), cerebral
edema, seizures, and CNS injury may occur. Thus, follow-
ing the initial restoration of adequate tissue perfusion using
isotonic fluids, a gradual decrease in serum [Na+] is desired
(10–15 mEq/L/d). This is commonly achieved using 5% dex-
trose with 0.2% saline to replace the calculated fluid deficit
over 48 hours. Maintenance and replacement fluids should
also be provided. If the serum [Na+] is not correcting appro-
priately, the free water deficit may be estimated as 4 mL/kg
of free water for each milliequivalent of serum [Na+] above
145 mEq/L and provided as 5% dextrose over 48 hours. If
metabolic acidosis is also present, it must be corrected slowly
to avoid CNS irritability. Potassium is provided as indi-
cated—as the acetate salt if necessary. Electrolyte concentra-
tions should be assessed every 2 hours in order to control
the decline in serum [Na+]. Elevations of blood glucose and
blood urea nitrogen may worsen the hyperosmolar state in
hypernatremic dehydration and should also be monitored
closely. Hyperglycemia is often associated with hyperna-
tremic dehydration and may necessitate lower intravenous
glucose concentrations (eg, 2.5%).
Patients with diabetes insipidus, whether nephrogenic or
central in origin, are prone to develop profound hyperna-
tremic dehydration as a result of unremitting urinary-free
water losses (urine specific gravity < 1.010), particularly during
superimposed gastrointestinal illnesses associated with vomit-
ing or diarrhea. Treatment involves restoration of fluid and
electrolyte deficits as described earlier as well as replacement
 FLUID, ELECTROLYTE,& ACID-BASE DISORDERS& THERAPY
of excessive water losses. Formal water deprivation testing
to distinguish responsiveness to ADH should only be done
during daylight hours after restoration of normal fluid vol-
ume status.
However, if a child presents with marked dehydration
and a serum Na+ greater than 150 mEq/L, it may prove
helpful and timely to obtain a plasma vasopressin level at
the time of their initial presentation. The evaluation and
treatment of nephrogenic and central diabetes insipidus are
discussed in detail in Chapters 24 and 34, respectively.
Hypervolemic hypernatremia (salt poisoning), associated
with excess total body salt and water, may occur as a conse-
quence of providing improperly mixed formula, excessive
NaCl or NaHCO3 administration, or as a feature of primary
hyperaldosteronism. Treatment includes the use of diuret-
ics, and potentially, concomitant water replacement or even
dialysis.
POTASSIUM DISORDERS
The predominantly intracellular distribution of potassium
is maintained by the actions of Na+-K+-ATPase in the cell
membranes. Potassium is shifted into the ECF and plasma
by acidemia and into the ICF in the setting of alkalosis,
hypochloremia, or in conjunction with insulin-induced
cellular glucose uptake. The ratio of intracellular to extra-
cellular K+ is the major determinant of the cellular resting
membrane potential and contributes to the action potential
in neural and muscular tissue. Abnormalities of K+ balance
are potentially life-threatening. In the kidney, K+ is filtered
at the glomerulus, reabsorbed in the proximal tubule, and
excreted in the distal tubule. Distal tubular K+ excretion is
regulated primarily by the mineralocorticoid aldosterone.
Renal K+ excretion is primarily dependent on the urinary
flow rate, and continues for significant periods even after
the intake of K+ is decreased. Thus, by the time urinary [K+]
decreases, the systemic K+ pool has been depleted signifi-
cantly. In general, the greater the urine flow the greater the
urinary K+ excretion.
The causes of net K+ loss are primarily renal in ori-
gin. Gastrointestinal losses through nasogastric suction or
vomiting reduce total body K+ to some degree. However,
the resultant volume depletion results in an increase in
plasma aldosterone, promoting renal excretion of K+ in
exchange for Na+ reclamation to preserve circulatory vol-
ume. Diuretics (especially thiazides), mineralocorticoids,
and intrinsic renal tubular diseases (eg, Bartter syndrome)
enhance the renal excretion of K+. Systemic K+ depletion
in hypokalemic metabolic acidosis may lead to “paradoxic
aciduria” and low urine pH wherein H+ is preferentially
exchanged for Na+ in response to aldosterone. Clinically,
hypokalemia is associated with neuromuscular excitability,
decreased peristalsis or ileus, hyporeflexia, paralysis, rhab-
domyolysis, and arrhythmias. Electrocardiographic changes
! 749
include flattened T waves, a shortened PR interval, and the
appearance of U waves. Arrhythmias associated with hypo-
kalemia include premature ventricular contractions; atrial,
nodal, or ventricular tachycardia; and ventricular fibril-
lation. Hypokalemia increases responsiveness to digitalis
and may precipitate overt digitalis toxicity. In the presence
of arrhythmias, extreme muscle weakness, or respiratory
compromise, intravenous K+ should be given. If the patient
is hypophosphatemic ([PO43−]< 2 mg/dL), a phosphate salt
may be used. The first priority in the treatment of hypokale-
mia is the restoration of an adequate serum [K+]. Providing
maintenance amounts of K+ is usually sufficient; however,
when the serum [K+] is dangerously low and K+ must be
administered intravenously, it is imperative that the patient
have a cardiac monitor. Intravenous K+ should generally
not be given faster than at a rate of 0.3 mEq/kg/h. Oral K+
supplements may be needed for weeks to replenish depleted
body stores.
Hyperkalemia—due to decreased renal K+ excretion,
mineralocorticoid deficiency or unresponsiveness, or K+
release from the ICF compartment—is characterized by
muscle weakness, paresthesias, and tetany; ascending paraly-
sis; and arrhythmias. Electrocardiographic changes associ-
ated with hyperkalemia include peaked T waves, widening of
the QRS complex, and arrhythmias such as sinus bradycar-
dia or sinus arrest, atrioventricular block, nodal or idioven-
tricular rhythms, and ventricular tachycardia or fibrillation.
The severity of hyperkalemia depends on the electrocardio-
graphic changes, the status of the other electrolytes, and the
stability of the underlying disorder. A rhythm strip should
be obtained when significant hyperkalemia is suspected.
If the serum [K+] is less than 6.5 mEq/L, discontinuing K+
supplementation may be sufficient if there is no ongoing
K+ source, such as cell lysis, and if urine output continues.
If the serum [K+] is greater than 7 mEq/L or if potentiating
factors such as hyponatremia, digitalis toxicity, and renal
failure are present, more aggressive therapy is needed. If
electrocardiographic changes or arrhythmias are present,
treatment must be initiated promptly. Intravenous 10%
calcium gluconate (0.2–0.5 mL/kg over 2–10 minutes) will
rapidly ameliorate depolarization and may be repeated after
5 minutes if electrocardiographic changes persist. Calcium
should be given only with a cardiac monitor in place and
should be discontinued if bradycardia develops. The intra-
venous administration of a diuretic that acts in the loop of
Henle, such as furosemide (1–2 mg/kg), will augment renal
K+ excretion and can be very helpful in lowering serum and
total body [K+]. Administering Na+ and increasing systemic
pH with bicarbonate therapy (1–2 mEq/kg) will shift K+
from the ECF to the ICF compartment, as will therapy with a
β-agonist such as albuterol. In nondiabetic patients, 0.5 g/kg
of glucose over 1–2 hours will enhance endogenous insulin
secretion, lowering serum [K+] 1–2 mEq/L. Administration
of intravenous glucose and insulin may be needed as a
 750 ! CHAPTER 23
simultaneous drip (0.5–1 g/kg glucose and 0.3 units of
regular insulin per gram of glucose) given over 2 hours with
monitoring of the serum glucose level every 15 minutes.
The therapies outlined above provide transient benefits.
Ultimately, K+ must be reduced to normal levels by reestab-
lishing adequate renal excretion using diuretics or optimiz-
ing urinary flow, using ion exchange resins such as sodium
polystyrene sulfonate orally or as a retention enema (0.2–0.5
g/kg orally or 1 g/kg as an enema), or by dialysis.
Choong K et al: Hypotonic versus isotonic maintenance fluids
after surgery for children: a randomized controlled trial.
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12441772].
" ACID-BASE DISTURBANCES
When evaluating a disturbance in acid-base balance, the
systemic pH, partial carbon dioxide pressure (Pco2), serum
HCO3−, and anion gap must be considered. The anion gap,
Na+ − (Cl− + HCO3−), is an expression of the unmeasured
anions in the plasma and is normally 12 ± 4 mEq/L. An
increase above normal suggests the presence of an unmea-
sured anion, such as occurs in diabetic ketoacidosis, lactic
acidosis, salicylate intoxication, and so on. Although the
base excess (or deficit) is also used clinically, it is important
to recall that this expression of acid-base balance is influ-
enced by the renal response to respiratory disorders and
cannot be interpreted independently (as in a compensated
respiratory acidosis, wherein the base excess may be quite
large). Recently, there has been greater interest in the Stewart
approach to acid-base disturbances and the calculation of
the “strong ion difference,” which is beyond the scope of the
present discussion. The interested reader is referred to the
review by Gunnerson and Kellum listed in the references at
the end of this chapter.
METABOLIC ACIDOSIS
Metabolic acidosis is characterized by a primary decrease
in serum [HCO3−] and systemic pH due to the loss of HCO3−
from the kidneys or gastrointestinal tract, the addition of
an acid (from external sources or via altered metabolic
processes), or the rapid dilution of the ECF with nonbi-
carbonate–containing solution (usually normal saline).
When HCO3− is lost through the kidneys or gastrointestinal
tract, Cl− must be reabsorbed with Na+ disproportionately,
resulting in a hyperchloremic acidosis with a normal anion
gap. Thus, a normal anion gap acidosis in the absence of
diarrhea or other bicarbonate-rich gastrointestinal losses
suggests the possibility of renal tubular acidosis and should
be evaluated appropriately. (See Chapter 24.) In contrast,
acidosis that results from addition of an unmeasured acid
is associated with a widened anion gap. Examples are dia-
betic ketoacidosis, lactic acidosis, starvation, uremia, toxin
ingestion (salicylates, ethylene glycol, or methanol), and
certain inborn errors of organic or amino acid metabolism.
Dehydration may also result in a widened anion gap acido-
sis as a result of inadequate tissue perfusion, decreased O2
delivery, and subsequent lactic and keto acid production.
Respiratory compensation is accomplished through an
increase in minute ventilation and a decrease in Pco2. The
patient’s history, physical findings, and laboratory features
should lead to the appropriate diagnosis.
The ingestion of unknown toxins or the possibility
of an inborn error of metabolism (see Chapter 36) must
be considered in children without an obvious cause for a
widened anion gap acidosis. Unfortunately, some hospital
laboratories fail to include ethylene glycol or methanol in
their standard toxicology screens, so assay of these toxins
must be requested specifically. This is of critical importance
when therapy with fomepizole (4-methylpyrazole) must be
considered for either ingestion—and instituted promptly
to obviate profound toxicity. Ethylene glycol (eg, anti-
freeze) is particularly worrisome because of its sweet taste
and accounts for a significant number of toxin ingestions.
Screening by fluorescence of urine under a Wood lamp is
relatively simple but does not replace specific laboratory
assessment. Salicylate intoxication has a stimulatory effect
on the respiratory center of the CNS; thus, patients may ini-
tially present with respiratory alkalosis or mixed respiratory
alkalosis and widened anion gap acidosis.
Most types of metabolic acidosis will resolve with correc-
tion of the underlying disorder, improved renal perfusion,
and acid excretion. Intravenous NaHCO3 administration
may be considered in the setting of metabolic acidosis when
the pH is less than 7.0 or the [HCO3−] is less than 5 mEq/L,