Chapter 250  ◆  Mycoplasma pneumoniae  1609
of age but can occur. Children younger than 5 yr of age appear to have
Section  9
Mycoplasmal Infections
Chapter 250  B and C, P116, and HMW1-3). M. pneumoniae rarely invades beyond
Mycoplasma pneumoniae
Asuncion Mejias and Octavio Ramilo
Among the 7 Mycoplasma species isolated from the human respiratory
tract, Mycoplasma pneumoniae remains the most common species causing
respiratory infections in school-age children and young adults.
THE ORGANISM
Mycoplasmas are the smallest self-replicating prokaryotes known to
cause disease in humans. Their size of 150-250 nm is more on the order
of viruses than bacteria. Mycoplasma pneumoniae is a fastidious double-
stranded DNA bacterium that is distinguished by a small genome
(~800,000 base pairs) and a long doubling time, which makes culturing
it a slow process (5-20 days) compared to other bacteria. M. pneumoniae
isolates can be classified in 2 major genetic groups (subtype 1 and 2)
based on the P1 adhesion protein. Distinguishing these 2 subtypes is
important for epidemiologic and clinical purposes. Like other myco-
plasmas, M. pneumoniae is distinguished by the complete absence of a
cell wall that results in (1) their dependence to host cells for obtaining
essential nutrients, (2) the intrinsic resistance to β-lactam agents, and
(3) their pleomorphic shape and lack of visibility on Gram staining.
EPIDEMIOLOGY
M. pneumoniae infections occur worldwide and throughout the year.
This organism is a frequent cause of community-acquired pneumonia
(CAP) in children and adults, accounting for ~20% of all CAP in middle
and high school children and up to 50% of CAP in college students
and military recruits. The proportion of cases increases according to
age, as recently shown in a population-based study of CAP conducted
in the United States (5% in < 5 yr; 16% in 5-9 yr; and 23% in 10-17 yr).
In contrast to the acute, short-lived epidemics associated with some
respiratory viruses, M. pneumoniae infection occurs endemically
worldwide. Infections tend to occur most commonly during summer
or early fall, although mycoplasma infections have been described all
year long. Epidemic outbreaks of variable intensity occur every few
years and they are likely related to the alternative circulation of the two
M. pneumoniae subtypes. Transmission occurs through the respiratory
route by large droplet spread during close contact with a symptomatic
person. Community outbreaks have been described in closed settings
(colleges, boarding schools, military bases) and can spread largely through
school contacts. Attack rates within families are high, with transmission
rates of 40 to > 80% for household adult and children contacts, respec-
tively. In contrast to many other respiratory infections, the incubation
period is 2-3 wk; hence, the course of infection in a specific population
(family) may last several weeks.
The occurrence of mycoplasma illnesses is related, in part, to age
and preexposure immunity. Overt illness is less common before 3 yr
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milder illnesses associated with upper respiratory tract involvement,
vomiting, and diarrhea. Immunity after infection is not long lasting, as
evidenced by the frequency of reinfections over time. The 2 mycoplasma
subtypes are immunologically different, and infection with 1 subtype
does not appear to confer immunity against the other. Asymptomatic
carriage after infection can last up to 4 mo despite antibiotic therapy
and may contribute to prolonged outbreaks. Children are often the
reservoir from whom mycoplasma spreads. In the clinical setting, there
are no available tools yet to differentiate carriage vs. infection.
PATHOGENESIS
The pathogenicity of M. pneumoniae is dependent upon its extracellular
attachment and the initiation of the host cell immune response. Cells
of the ciliated respiratory epithelium are the target cells of M. pneumoniae
infection. The organism is an elongated snake-like structure with a
one-end organelle, which mediates the attachment to sialic acid receptors
in the cilia through a complex set of adhesion proteins (P1, P30, proteins
the respiratory tract basement membrane. Virulent organisms attach
to ciliated respiratory epithelial cell surfaces located in the bronchi,
bronchioles, alveoli, and possibly upper respiratory tract and burrow
down between cells, resulting in ciliostasis and eventual sloughing of
the cells. M. pneumoniae also causes cytolytic injury to the host cells
in part by the production of hydrogen peroxide and possibly through
the adenosine diphosphate–ribosylating and vacuolating toxin termed
CARDS (community-acquired respiratory distress syndrome). This
exotoxin is associated with more severe or even fatal disease. This
bacterium facilitates the formation of biofilms, with strain-specific
phenotypic differences, which hinder antibiotic penetration and recogni-
tion by the immune system.
Once M. pneumoniae reaches the lower respiratory tract, it promotes
the polyclonal activation of B lymphocytes and CD4+ T cells, and
amplifies the immune response with the production of various proinflam-
matory and antiinflammatory cytokines and chemokines, such as tumor
necrosis factor-α, interleukin (IL)-8, IL-1β, Il-6, and IL-10.
Although it is well documented that specific cell-mediated immunity
and antibody titers against M. pneumoniae increase with age (and
therefore probably follow repeated infections), the immune mechanisms
that protect against or clear the infection are not well defined. In humans,
nasal IgA antibodies correlated with protection after experimental
challenge. A distinct aspect of M. pneumoniae is its ability to induce
the production of cold agglutinins (IgM antibodies) directed against
the I antigen expressed in the surface of erythrocytes. Even though
antibody responses do not confer complete protection against reinfections,
the importance of a robust humoral response is apparent, since patients
with congenital antibody deficiencies, such as those with hypogam-
maglobulinemia, can develop severe and prolonged disease and have
a higher risk of extrapulmonary manifestations. In children with sickle
cell disease or sickle-related hemoglobinopathies, M. pneumoniae is a
common infectious trigger of acute chest syndrome. These children
and also children with Down syndrome can develop more severe forms
of Mycoplasma pneumonia. On the other hand, M. pneumoniae does
not seem to be a common opportunistic agent in patients with AIDS.
M. pneumoniae has been detected by polymerase chain reaction (PCR)
in many nonrespiratory sites, including blood, pleural fluid, cerebrospinal
fluid (CSF), and synovial fluid. The mechanisms of extrapulmonary
disease associated with M. pneumoniae are unclear and appear to be
different according to the duration of symptoms at the time of presenta-
tion: direct invasion vs. immune-mediated.
CLINICAL MANIFESTATIONS
Most of the M. pneumoniae infections are symptomatic and most of
them occur in children and adolescents.
Respiratory Tract Disease
Tracheobronchitis and atypical pneumonia are the most commonly
recognized clinical syndromes associated with M. pneumoniae. This
agent is responsible for up to 20% of all cases of CAP. Although the
1609.e2  Part XVI  ◆  Infectious Diseases

Keywords
atypical pneumonia
macrolides
encephalitis
hemolytic anemia

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1610  Part XVI  ◆  Infectious Diseases

onset of illness may be abrupt, it is usually characterized by gradual response to M. pneumonia, while its occurrence early in the course
development of headache, malaise, fever, and sore throat, followed by of the disease may be associated with direct bacterial invasion of
progression of lower respiratory symptoms, including hoarseness and the CNS. Involvement of the brainstem can result in severe dystonia
nonproductive cough. The gradual onset in children with atypical and movement disorders. The CSF may be normal or have mild
pneumonia is in contrast to the sudden onset of lobar pneumonia. mononuclear pleocytosis and/or increase CSF protein concentrations.
Coryza and gastrointestinal complaints are unusual and usually suggest Diagnosis is confirmed with positive CSF PCR, positive PCR from a
a viral etiology. Although the clinical course in untreated patients is throat swab, or demonstration of seroconversion. Findings on MRI
variable, cough, the clinical hallmark of M. pneumoniae infection, usually include focal ischemic changes, ventriculomegaly, diffuse edema,
worsens during the 1st wk of illness, and symptoms generally resolve or multifocal white matter inflammatory lesions consistent with
within 2 wk. Cough can last up to 4 wk and may be accompanied by postinfectious ADEM. Long-term sequelae have been reported in
wheezing. Patients generally recover without complications, although 23–64% of cases.
some individuals can develop prolonged wheezing. 2. Dermatologic disease: a variety of exanthems have been associated
Chest examination may be unrevealing, even in patients with severe with M. pneumoniae, most notably maculopapular rash, urticaria
cough. There may be no auscultative or percussive findings or only and the mycoplasma associated rash and mucositis syndrome previ-
minimum dry rales. Clinical findings are often less severe than suggested ously called erythema multiforme or Stevens-Johnson syndrome (SJS).
by the patient chest radiograph, explaining why the term walking Gianotti-Crosti syndrome and erythema nodosum are also associated
pneumonia is often used to describe CAP caused by M. pneumoniae. with M. pneumoniae infections. Approximately 10% of children with
Radiographic findings are variable and nonspecific, not allowing dif- M. pneumoniae CAP will exhibit a maculopapular rash. Mycoplasma-
ferentiation from viral or bacterial pathogens. Pneumonia is usually associated rash and mucositis usually develops 3-21 days after initial
described as interstitial or bronchopneumonic, and involvement is most respiratory symptoms, lasts less than 14 days, and is rarely associated
common in the lower lobes. Bilateral diffuse infiltrates, lobar pneumonia, with severe complications (Figs. 250.1 and 250.2). M. pneumoniae
or hilar lymphadenopathy can occur in up to 30% of patients. Although may also produce an isolated oral mucositis in absence of rash.
unusual, large pleural effusions associated with lobar infiltrates and 3. Hematologic abnormalities: include mild degrees of hemolysis with
necrotizing pneumonia have been described in patients with sickle cell a positive Coombs test and minor reticulocytosis 2-3 wk after the
disease, immunodeficiencies, Down syndrome, and chronic cardiopul-
monary disease. Bronchiolitis obliterans has also been described as a
complication of M. pneumoniae in otherwise healthy children. The white
blood cell and differential counts are usually normal, whereas the
erythrocyte sedimentation rate and C-reactive protein are often elevated.
Appropriate antibiotics shorten the duration of illness but do not reliably
eradicate the bacteria from the respiratory tract.
Other respiratory illnesses caused occasionally by M. pneumoniae
include undifferentiated upper respiratory tract infections, intractable,
nonproductive cough, pharyngitis (usually without marked cervical
lymphadenopathy), sinusitis, croup, and bronchiolitis. M. pneumoniae
is a common trigger of wheezing in asthmatic children and can cause
chronic colonization in the airways, resulting in lung dysfunction in
adolescents and adult asthmatic patients. Otitis media and bullous
myringitis, which also occur with other viral and bacterial infections,
have been described but are rare, and their absence should not exclude
the diagnosis of M. pneumoniae.

Extrapulmonary Disease
Despite the reportedly rare isolation of M. pneumoniae from nonrespira-
tory sites, the improved sensitivity of PCR for M. pneumoniae DNA
detection has led to increasing identification of this bacterium in Fig. 250.1  Lip changes found in Mycoplasma pneumoniae–associated
nonrespiratory sites, particularly the central nervous system (CNS). mucositis.
Patients with or without respiratory symptoms can have involvement
of the skin, CNS, blood, heart, gastrointestinal tract, and joints. Non-
respiratory manifestations of M. pneumoniae include:
1. CNS disease: occurs in 0.1% of all patients with M. pneumoniae
infection and in 7–16% of those requiring hospitalization. Manifes-
tations include encephalitis, acute disseminated encephalomyelitis
(ADEM), transverse myelitis, cerebellar ataxia, aseptic meningitis,
Guillain-Barré syndrome, Bell palsy, and peripheral neuropathy. CNS
disease manifestations occur 3-23 days (mean: 10 days) after onset of
respiratory illness but may not be preceded by any signs of respiratory
infection in up to 20% of cases. Studies in children suggest that
there are two pathogenic mechanisms for M. pneumoniae-associated
neurologic disease: the first pattern is characterized by almost absent
or no prodromal respiratory symptoms (<7 days) and non-reactive
IgM responses. On the other hand, the second pattern is characterized
by the presence of respiratory symptoms (most commonly cough)
for ≥7 days and reactive IgM in acute serum. In the first group M.
pneumoniae is usually identified in cerebrospinal fluid by PCR but
not in the respiratory tract, while in children presenting with ≥7
days of respiratory symptoms the opposite is true. These studies
suggest that encephalitis occurring more than 7 days after onset of Fig. 250.2  Classic skin lesions found in Mycoplasma pneumoniae–
prodromal symptoms is more likely to be caused by an autoimmune associated rash.

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onset of illness. Severe hemolysis is associated with high titers of
cold hemagglutinins (≥1 : 512) and occurs rarely. Thrombocytopenia,
aplastic anemia, and coagulation defects occur occasionally.
4. Musculoskeletal: arthritis appears to be less common in children
than in adults, but monoarthritis, polyarthritis, and migratory arthritis
have been described. Rhabdomyolysis has also been documented,
often associated with other organ system manifestations.
5. Other conditions, such as mild hepatitis, pancreatitis, acute glomeru-
lonephritis, iritis or uveitis, and cardiac complications (pericarditis,
myocarditis, and rheumatic fever-like syndrome, most commonly
seen in adults) are also described. Fatal M. pneumoniae infections
are rare.
DIAGNOSIS
No specific clinical, epidemiologic, or laboratory parameters allow for
a definite diagnosis of M. pneumoniae infection. Nevertheless, pneumonia
in school-age children and young adults with a gradual onset and cough
as a prominent finding suggests M. pneumoniae infection. The best
method for diagnosis is a combination of PCR from respiratory samples
and serology (acute and convalescent).
Cultures on special media (SP4 agar media) of the throat or sputum
might demonstrate the classic M. pneumoniae “mulberry” colonies, but
growth generally requires incubation for 2-3 wk, and few laboratories
maintain the capability of culturing M. pneumoniae. The fastidious nutri-
tional requirements of Mycoplasma make cultures slow and impractical.
Serologic tests (immunofluorescence tests, enzyme-linked immune
assays [EIAs], or complement fixation) to detect serum immunoglobulin
(Ig) M and IgG antibodies against M. pneumoniae are commercially
available. IgM antibodies have a high rate of false-positive and false-
negative results. In most cases, IgM antibodies are not detected within
the 1st wk after onset of symptoms or in children with recurrent infections
and may be positive for up to 6-12 mo after infection. A 4-fold or
greater increase in IgG antibody titers against M. pneumoniae between
acute and convalescent sera obtained 2-4 wk apart is diagnostic.
Cold hemagglutinins (cold-reacting antibodies [IgM] against red
blood cells) can be detected in approximately 50% of patients with M.
pneumoniae pneumonia. These antibodies are nonspecific, especially
at titers <1 : 64, as modest increases in cold hemagglutinins can be
observed in other viral infections. Cold agglutinin antibodies should
not be used for the diagnosis of M. pneumoniae infections if other
methods are available.
PCR-based tests for M. pneumoniae have replaced other diagnostic
tests. PCR of a nasopharyngeal or throat swab (the combination of both
increases sensitivity) for M. pneumoniae genomic DNA carries a sensitiv-
ity and a specificity of 80 to >97%. In adults, sputum samples are more
likely than nasopharyngeal or throat swabs to yield positive results.
Different primers have been used to identify gene sequences of the P1
cytoadhesion protein or the ribosomal (r) 16S RNA. PCR allows a more
rapid diagnosis in acutely ill patients and can be positive earlier in the
course of infection than serologic tests. Mycoplasma PCR from respiratory
samples may be positive in asymptomatic subjects. Nonetheless, identifica-
tion of M. pneumoniae by PCR (or culture) from a patient with compatible
clinical manifestations suggests causation.
Other diagnostic methods: The matrix-assisted laser desorption
ionization-time of flight mass spectrometry (MALDI-TOF MS) could
represent an accurate tool for identification and subtyping of M.
pneumoniae. However, the need for culture to subsequently be able to
perform MALDI-TOF MS limits its applicability in the clinical setting.
Silver nanorod array-surface enhanced Raman spectroscopy (NA-SERS)
is an investigational system that does not require growth of the bacterium.
It appears a promising and sensitive tool for mycoplasma detection and
strain characterization.
The diagnosis of extrapulmonary disease associated with M. pneu-
moniae is challenging. Although M. pneumoniae has been identified
by PCR in the CSF of children with encephalitis, there are currently
no reliable tests for the diagnosis of CNS or other nonrespiratory sites
associated with M. pneumoniae. Since the extrapulmonary manifestations
of M. pneumoniae may have an immunologic base, measuring acute
and convalescent IgM and IgG antibody levels is advisable.
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Chapter 250  ◆  Mycoplasma pneumoniae  1611
TREATMENT
M. pneumoniae illness is usually mild, and most cases of pneumonia
can be managed without the need for hospitalization. Because myco-
plasmas lack a cell wall, they inherently are resistant to β-lactam agents
that act by inhibiting the cell wall synthesis. In addition, other drug
classes, such as trimethoprim, rifampin, or linezolid are inactive against
M. pneumoniae. Studies regarding the effectiveness of antimicrobial
therapy for M. pneumoniae infections in children are contradictory.
Nevertheless, empiric treatment is often initiated based on clinical
suspicion due to the difficulty of a definitive diagnosis.
Antimicrobial Therapy
M. pneumoniae is typically sensitive to macrolides (erythromycin,
clarithromycin, azithromycin), tetracyclines, and quinolones in vitro.
Treatment of mycoplasma does not assure eradication. Data from
observational studies showed that macrolide treatment of children with
M. pneumoniae CAP markedly shortened the course of illness. Treatment
may be more effective when started within 3-4 days of illness onset.
Although macrolides do not have bactericidal activity, they are preferred
in children younger than 8 yr of age. Two multicenter studies of pediatric
CAP demonstrated comparable clinical and bacteriologic success rates
between erythromycin and clarithromycin or azithromycin. However,
the newer macrolides were better tolerated. The recommended treatment
is clarithromycin (15 mg/kg/day divided into 2 doses PO for 10 days)
or azithromycin (10 mg/kg once PO on day 1 and 5 mg/kg once daily
PO on days 2-5). In addition to the antibacterial effect, macrolides may
have immunomodulatory properties, but the relevance of the antiinflam-
matory properties of macrolides for the treatment of M. pneumoniae
CAP is not known. Tetracyclines (doxycycline 100 mg twice a day for
7-14 days) are also effective and may be used for children older than
8 yr of age. Fluoroquinolones such as levofloxacin (750 mg once a day
for 7-14 days) are effective and bactericidal but have higher minimum
inhibitory concentrations (MIC) compared with macrolides and currently
are not recommended as a first-line therapy in children.
Macrolide-resistant strains, mostly associated with mutations in the
23S rRNA, have been increasingly reported in Asia (>90% in Japan and
China) and are also present in Europe with great variability from country
to country (0% in the Netherlands vs. 26% in Italy). In the United States
and Canada, the rates of resistance varied from 3.5 to 13% of cases.
Although not routinely performed at clinical laboratories, identification
of macrolide-resistant strains can be performed by sequencing and
identification of specific mutations in the 23S rRNA gene. The clinical
significance of macrolide-resistant infections has not been completely
elucidated, however, studies in children indicated that the clinical efficacy
of macrolide-susceptible M. pneumoniae infections is >4-fold higher
compared with infections caused by resistant strains (91% vs. 22%
respectively). Thus, for patients with severe infections not responding
to macrolide therapy within the first 48 hr of treatment, the possibility of
macrolide-resistant M. pneumoniae should be considered and switching
to a non-macrolide antimicrobial regimen might be prudent. Doxycycline
(2-4 mg/kg in one or two divided doses for 10 days; max 200 mg or
100 mg q12h) for children >8 yr, or levofloxacin (10 mg/kg per dose
every 12 hr in children <5 yr or once a day in older children) after
assessment of risk and benefits of using quinolones in children, are
potential alternatives for macrolide-resistant M. pneumoniae infections.
Other quinolones such as tosufloxacin or garenoxacin are used in Japan.
There are new ketolides in development that appear promising.
Adjunctive Therapy
There is no evidence that treatment of upper respiratory tract or
nonrespiratory tract disease with antimicrobial agents alters the course
of illness. However, patients with severe manifestations of extrapulmonary
disease may benefit from antimicrobial treatment, since direct involve-
ment of the bacterium cannot be excluded. Oftentimes antibiotics are
administered in combination with immunomodulatory therapy. In this
regard, corticosteroids with or without intravenous immunoglobulin
are the most commonly used agents for managing severe M. pneumoniae
extrapulmonary manifestations, particularly for patients with CNS
involvement or rash and mucositis. Although definitive data are lacking,
case studies suggest the associated clinical benefit of steroids in the
management of severe lung disease, SJS, and hemolytic anemia.

PREVENTION
Trials with inactivated and live attenuated vaccines for M. pneumoniae
have been conducted with disappointing results. In hospitalized patients
standard and droplet precautions are recommended for the duration
of symptoms. It is important to emphasize that mycoplasma infection
remains contagious as long as cough persists and despite successful
antibiotic therapy. Prophylaxis with tetracyclines or azithromycin
substantially reduces the secondary attack rates in institutional outbreaks
and family close contacts. Antimicrobial prophylaxis is not recommended
routinely; however, it can be considered in patients at high risk for
severe disease, such as children with sickle cell disease.

Bibliography is available at Expert Consult.

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2266  Part XVIII  ◆  The Respiratory System

Chapter 428 
Community-Acquired
Pneumonia
Matthew S. Kelly and Thomas J. Sandora

EPIDEMIOLOGY
Pneumonia, defined as inflammation of the lung parenchyma, is the
leading infectious cause of death globally among children younger than
5 yr, accounting for an estimated 920,000 deaths each year (Fig. 428.1).
Pneumonia mortality is closely linked to poverty. More than 99% of
pneumonia deaths are in low- and middle-income countries, with the
highest pneumonia mortality rate occurring in poorly developed countries
in Africa and South Asia (Table 428.1).
In the United States, mortality from pneumonia in children declined
by 97% between 1939 and 1996. This decline likely resulted from the
development of antibiotics and vaccines and the expansion of medical
insurance coverage for children. Effective vaccines against measles (see
Chapter 273) and pertussis (see Chapter 224) contributed to the decline
in pneumonia-related mortality during the 20th century. Haemophilus
influenzae type b (see Chapter 221) was also an important cause of
bacterial pneumonia in young children but became uncommon following
licensure of a conjugate vaccine in 1987. The introduction of pneumococ-
cal conjugate vaccines (PCVs) (see Chapter 209) has been an important
contributor to the further reductions in pneumonia-related mortality
achieved over the past 15 yr.

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 reactions,
and drug- or radiation-induced pneumonitis (see Chapter 427). The
cause of pneumonia in an individual patient is often difficult to determine
because direct sampling of lung tissue is invasive and rarely performed.
Bacterial cultures of sputum or upper respiratory tract samples from
children typically do not accurately reflect the cause of lower respiratory
tract infection. Streptococcus pneumoniae (pneumococcus) is the most
common bacterial pathogen in children 3 wk to 4 yr of age, whereas
Mycoplasma pneumoniae and Chlamydophila pneumoniae are the most
frequent bacterial pathogens in children age 5 yr and older. In addition
to pneumococcus, other bacterial causes of pneumonia in previously
healthy children in the United States include group A streptococcus
(Streptococcus pyogenes; see Chapter 210) and Staphylococcus aureus

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2266.e2  Part XVIII  ◆  The Respiratory System

Keywords
pneumonia
lower respiratory infection
infants
children
community-acquired infections

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 Chapter 428  ◆  Community-Acquired Pneumonia  2267

Pneumonia 33% (RSV; see Chapter 287) and rhinoviruses (see Chapter 290) are the most
commonly identified pathogens, especially in children younger than
2 yr of age. However, the role of rhinoviruses in severe lower respiratory
Diarrhea 19%
tract infection remains unclear as these viruses are frequently detected
with co-infecting pathogens and among asymptomatic children. Other
common viruses causing pneumonia include influenza viruses (see
Chapter 285), human metapneumovirus (see Chapter 288), parainfluenza
Other infections 12% viruses (see Chapter 286), adenoviruses (see Chapter 289), and entero-
Neonatal sepsis 15% viruses (see Chapter 277). Infection with more than one respiratory
HIV/AIDS 3%
virus occurs in up to 20% of cases. The age of the patient can suggest
Meningitis 3% the likely pathogens (see Table 428.3).
Malaria 11% Measles 4% Lower respiratory tract viral infections are much more common in
Fig. 428.1  Pneumonia is the leading infectious killer of children the fall and winter in both the northern and southern hemispheres in
worldwide, as shown by this illustration of global distribution of cause- relation to the seasonal epidemics of respiratory viruses that occur each
specific infectious mortality among children younger than age 5 yr in year. The typical pattern of these epidemics usually begins in the fall,
2015. Pneumonia causes one-third of all under-5 deaths from infection. when parainfluenza virus infections appear and most often manifest as
(From World Health Organization and Maternal and Child Epidemiology croup. Later in winter, RSV, human metapneumovirus, and influenza
Estimation Group estimates, 2015.) viruses cause widespread infection, including upper respiratory tract
infections, bronchiolitis, and pneumonia. RSV is particularly severe
among infants and young children, whereas influenza viruses cause
disease and excess hospitalization for acute respiratory illness in all age
Table 428.1  Pneumonia Cases and Mortality Rate in groups. Knowledge of the prevailing viruses circulating in the community
Children Younger Than Age 5 Yr by may lead to a presumptive initial diagnosis.
UNICEF Region, 2015 Immunization status is relevant because children fully immunized
against H. influenzae type b and S. pneumoniae are less likely to have
PNEUMONIA PNEUMONIA pneumonia caused by these pathogens. Children who are immuno-
CASES IN MORTALITY RATE compromised or who have certain medical comorbidities may be at
CHILDREN (UNDER-5 DEATHS
risk for specific pathogens, such as Pseudomonas spp. in patients with
YOUNGER THAN PER 1,000 LIVE
UNICEF REGIONS 5 YR OF AGE BIRTHS) cystic fibrosis (see Chapter 432).
West and Central Africa 298,000 16.2 PATHOGENESIS
Sub-Saharan Africa 490,000 13.7 The lower respiratory tract possesses a number of defense mechanisms
against infection, including mucociliary clearance, macrophages and
Eastern and Southern 177,000 10.9
Africa secretory immunoglobulin A, and clearing of the airways by coughing.
Previously, it was believed that the lower respiratory tract was—in the
South Asia 282,000 7.9 absence of infection—kept sterile by these mechanisms, supported
Middle East and North 46,000 4.1 primarily by culture-based studies. However, recent use of culture-
Africa independent techniques, including high-throughput sequencing methods,
suggests that the lower respiratory tract contains diverse microbial
East Asia and the 81,000 2.7
Pacific communities. These data have challenged the traditional model of
pneumonia pathogenesis that maintained that pneumonia was the result
Latin America and the 23,000 2.1 of invasion of the sterile lower respiratory tract by a single pathogen.
Caribbean More recent conceptual models postulate that pneumonia results from
Least Developed 363,000 12.0 disruption of a complex lower respiratory ecosystem that is the site of
Countries dynamic interactions between potential pneumonia pathogens, resident
World 920,000 6.6 microbial communities, and host immune defenses.
Viral pneumonia usually results from spread of infection along the
From United Nations Children’s Fund: One is too many—ending child deaths airways, accompanied by direct injury of the respiratory epithelium,
from pneumonia and diarrhoea. https://data.unicef.org/resources/one-many- which results in airway obstruction from swelling, abnormal secretions,
ending-child-deaths-pneumonia-diarrhoea/. Accessed January 21, 2017.
and cellular debris. The small caliber of airways in young infants makes
such patients particularly susceptible to severe infection. Atelectasis,
interstitial edema, and hypoxemia from ventilation–perfusion mismatch
(see Chapter 208.1) (Tables 428.2, 428.3, and 428.4). S. aureus pneumonia often accompany airway obstruction. Viral infection of the respiratory
often complicates an illness caused by influenza viruses. tract can also predispose to secondary bacterial infection by disturbing
S. pneumoniae, H. influenzae, and S. aureus are the major causes of normal host defense mechanisms, altering secretions, and through
hospitalization and death from bacterial pneumonia among children disruptions in the respiratory microbiota.
in developing countries, although in children with HIV infection, Bacterial pneumonia most often occurs when respiratory tract
Mycobacterium tuberculosis (see Chapter 242), non-tuberculous myco- organisms colonize the trachea and subsequently gain access to the
bacteria (see Chapter 244), Salmonella (see Chapter 225), Escherichia lungs, but pneumonia may also result from direct seeding of lung tissue
coli (see Chapter 227), Pneumocystis jiroveci (see Chapter 271), and after bacteremia. When bacterial infection is established in the lung
cytomegalovirus (see Chapter 282) must be considered. The incidence parenchyma, the pathologic process varies according to the invading
of pneumonia caused by H. influenzae or S. pneumoniae has been organism. M. pneumoniae (see Chapter 250) attaches to the respiratory
significantly reduced in areas where routine immunization has been epithelium, inhibits ciliary action, and leads to cellular destruction and
implemented. an inflammatory response in the submucosa. As the infection progresses,
Viral pathogens are the most common causes of lower respiratory sloughed cellular debris, inflammatory cells, and mucus cause airway
tract infections in infants and children older than 1 mo but younger obstruction, with spread of infection occurring along the bronchial
than 5 yr of age. Viruses can be detected in 40–80% of children with tree, as is seen in viral pneumonia. S. pneumoniae produces local edema
pneumonia using molecular diagnostic methods (e.g., polymerase chain that aids in the proliferation of organisms and their spread into adjacent
reaction [PCR]). Of the respiratory viruses, respiratory syncytial virus portions of lung, often resulting in the characteristic focal lobar

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2268  Part XVIII  ◆  The Respiratory System

Table 428.2  Causes of Infectious Pneumonia

BACTERIAL
COMMON
Streptococcus pneumoniae
Group B streptococci
Group A streptococci
Staphylococcus aureus
Mycoplasma pneumoniae*
Chlamydophila pneumoniae*
Chlamydia trachomatis
Mixed anaerobes
Gram-negative enterics
UNCOMMON
Haemophilus influenzae type b
Moraxella catarrhalis
Neisseria meningitidis
Francisella tularensis
Nocardia species
Chlamydophila psittaci*
Yersinia pestis (plague)
Legionella species*
Coxiella burnetii* (Q fever)
VIRAL
COMMON
Respiratory syncytial virus
Parainfluenza types 1-4
Influenza A, B
Adenovirus
Human metapneumovirus
UNCOMMON
Rhinovirus
Enterovirus
Herpes simplex
Cytomegalovirus
*Atypical pneumonia syndrome; may have extrapulmonary manifestations, low-grade fever, patchy diffuse infiltrates, and poor response to β-lactam antibiotics.
Adapted from Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis & therapy, ed 2, Philadelphia, 2004, Elsevier, p. 29.
BACTERIAL
VIRAL
Measles Rash, coryza, conjunctivitis
Consolidation, empyema Varicella Unimmunized; immunocompromised
Neonates persons
Empyema Hantavirus Southwestern United States, rodents
Pneumatoceles, empyema; infants; Coronaviruses [severe acute Asia, Arabian Peninsula
nosocomial pneumonia respiratory syndrome (SARS),
Adolescents; summer–fall epidemics Middle East respiratory
Adolescents syndrome (MERS)]
Infants FUNGAL
Aspiration pneumonia
Nosocomial pneumonia Histoplasma capsulatum Ohio/Mississippi River valley; bird,
bat contact
Blastomyces dermatitidis Ohio/Mississippi River valley
Unimmunized Coccidioides immitis Southwestern United States, Great
Lakes states
Cryptococcus neoformans and Bird contact; immunocompromised;
Animal, tick, fly contact; bioterrorism C. gattii Northwestern United States
Immunocompromised patients (C. gattii)
Bird contact (especially parakeets) Aspergillus species Immunocompromised persons;
Rat contact; bioterrorism nodular lung infection
Exposure to contaminated water; Mucormycosis Immunocompromised persons
nosocomial Pneumocystis jiroveci Immunocompromised persons
Animal (goat, sheep, cattle) exposure (particularly HIV-infected infants);
steroids
RICKETTSIAL
Bronchiolitis Rickettsia rickettsiae Tick bite
Croup
High fever; winter months MYCOBACTERIAL
Can be severe; often occurs between Mycobacterium tuberculosis Travel to endemic region; exposure
January and April to high-risk persons
Similar to respiratory syncytial virus Mycobacterium avium Immunocompromised (particularly
complex HIV-infected) persons
Other non-tuberculous Immunocompromised persons; cystic
Rhinorrhea mycobacteria fibrosis
Neonates
Neonates, immunocompromised PARASITIC
persons Various parasites (e.g., Ascaris, Eosinophilic pneumonia
Infants; immunocompromised Strongyloides species)
persons (particularly HIV-infected
infants)

Table 428.3  Pneumonia Etiologies Grouped by Age of the Patient

AGE GROUP FREQUENT PATHOGENS (IN ORDER OF FREQUENCY)
Neonates (<3 wk) Group B streptococcus, Escherichia coli, other 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, human
metapneumovirus, 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, human
metapneumovirus, 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 immunization.
Adapted from Kliegman RM, Marcdante KJ, Jenson HJ, et al: Nelson essentials of pediatrics, ed 5, Philadelphia, 2006, Elsevier, p. 507.

involvement. Group A streptococcus lower respiratory tract infection
typically results in more diffuse lung involvement with interstitial
pneumonia. The pathology includes necrosis of tracheobronchial mucosa;
formation of large amounts of exudate, edema, and local hemorrhage,
with extension into the interalveolar septa; and involvement of lymphatic
vessels with frequent pleural involvement. S. aureus pneumonia manifests
as confluent bronchopneumonia, which is often unilateral and character-
ized by the presence of extensive areas of hemorrhagic necrosis and
irregular areas of cavitation of the lung parenchyma, resulting in
pneumatoceles, empyema, and, at times, bronchopulmonary fistulas.
Recurrent pneumonia is defined as 2 or more episodes in a single
year or 3 or more episodes ever, with radiographic clearing between

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 Chapter 428  ◆  Community-Acquired Pneumonia  2269

Table 428.4  Pneumonia: Etiology Suggested by Table 428.5  Differential Diagnosis of Recurrent
Exposure History Pneumonia
EXPOSURE HISTORY INFECTIOUS AGENT HEREDITARY DISORDERS
Exposure to concurrent illness in Neisseria meningitidis, Cystic fibrosis
school dormitory or household Mycoplasma Sickle cell disease
setting pneumoniae DISORDERS OF IMMUNITY
ENVIRONMENTAL EXPOSURES HIV/AIDS
Exposure to contaminated aerosols Legionnaires’ disease Bruton agammaglobulinemia
(e.g., air coolers, hospital water Selective immunoglobulin G subclass deficiencies
supply) Common variable immunodeficiency syndrome
Exposure to goat hair, raw wool, Anthrax Severe combined immunodeficiency syndrome
animal hides Chronic granulomatous disease
Ingestion of unpasteurized milk Brucellosis Hyperimmunoglobulin E syndromes
Exposure to bat droppings (caving) or Histoplasmosis Leukocyte adhesion defect
dust from soil enriched with bird DISORDERS OF CILIA
droppings Primary ciliary dyskinesia
Exposure to water contaminated with Leptospirosis Kartagener syndrome
animal urine
Exposure to rodent droppings, urine, Hantavirus ANATOMIC DISORDERS
saliva Pulmonary sequestration
Potential bioterrorism exposure Anthrax, plague, tularemia Lobar emphysema
Congenital cystic adenomatoid malformation
ZOONOTIC EXPOSURES
Gastroesophageal reflux
Employment as abattoir work or Brucellosis Foreign body
veterinarian Tracheoesophageal fistula (H type)
Exposure to cattle, goats, pigs Anthrax, brucellosis Bronchiectasis
Exposure to ground squirrels, Plague Aspiration (oropharyngeal incoordination)
chipmunks, rabbits, prairie dogs, rats Aberrant bronchus
in Africa or southwestern United
States Adapted from Kliegman RM, Marcdante KJ, Jenson HJ, et al: Nelson essentials
Hunting or exposure to rabbits, foxes, Tularemia of pediatrics, ed 5, Philadelphia, 2006, Elsevier, p. 507.
squirrels
Bites from flies or ticks Tularemia
Exposure to birds (parrots, Psittacosis than in bacterial pneumonia. Tachypnea is the most consistent clinical
budgerigars, cockatoos, pigeons, manifestation of pneumonia. Increased work of breathing accompanied
turkeys) by intercostal, subcostal, and suprasternal retractions, nasal flaring, and
Exposure to infected dogs and cats Pasteurella multocida, Q
use of accessory muscles is common. Severe infection may be accom-
fever (Coxiella burnetii)
Exposure to infected goats, cattle, Q fever (C. burnetii) panied by cyanosis and lethargy, especially in infants. Auscultation of
sheep, domestic animals, and their the chest may reveal crackles and wheezing, but it is often difficult to
secretions (milk, amniotic fluid, localize the source of these adventitious sounds in very young children
placenta, feces) with hyperresonant chests. It is often not possible to distinguish viral
pneumonia (especially adenovirus) clinically from disease caused by
TRAVEL EXPOSURES
Mycoplasma and other bacterial pathogens.
Residence in or travel to San Joaquin Coccidioidomycosis
Valley, southern California, Bacterial pneumonia in adults and older children typically begins
southwestern Texas, southern suddenly with high fever, cough, and chest pain. Other symptoms that
Arizona, New Mexico may be seen include drowsiness with intermittent periods of restlessness;
Residence in or travel to Mississippi or Histoplasmosis, rapid respirations; anxiety; and, occasionally, delirium. In many children,
Ohio river valleys, Great Lakes States, blastomycosis splinting on the affected side to minimize pleuritic pain and improve
Caribbean, Central America, or Africa ventilation is noted; such children may lie on one side with the knees
Residence in or travel to southern SARS, avian influenza drawn up to the chest.
China Physical findings depend on the stage of pneumonia. Early in the
Residence in or travel to Arabian MERS-CoV
course of illness, diminished breath sounds, scattered crackles, and
peninsula
Residence in or travel to Southeast Paragonimiasis, rhonchi are commonly heard over the affected lung field. With the
Asia melioidosis development of increasing consolidation or complications of pneumonia
Residence in or travel to West Indies, Melioidosis such as pleural effusion or empyema, dullness on percussion is noted
Australia, or Guam and breath sounds may be diminished. A lag in respiratory excursion
often occurs on the affected side. Abdominal distention may be prominent
MERS-CoV, Middle East respiratory syndrome coronavirus; SARS, severe acute
respiratory syndrome.
because of gastric dilation from swallowed air or ileus. Abdominal pain
From Ellison RT III, Donowitz GR: Acute pneumonia, In Bennett JE, Dolin R, is common in lower-lobe pneumonia. The liver may seem enlarged
Blaser MJ, editors: Mandell, Douglas, and Bennett’s principles and practice of because of downward displacement of the diaphragm secondary to
infectious diseases, ed 8, vol 1, Philadelphia, 2015, Elsevier, Table 69.3, p. 828. hyperinflation of the lungs or superimposed congestive heart failure.
Symptoms described in adults with pneumococcal pneumonia may
be noted in older children but are rarely observed in infants and young
occurrences. An underlying disorder should be considered if a child children, in whom the clinical pattern is considerably more variable.
experiences recurrent pneumonia (Table 428.5). In infants, there may be a prodrome of upper respiratory tract infection
and poor feeding, leading to the abrupt onset of fever, restlessness,
CLINICAL MANIFESTATIONS apprehension, and respiratory distress. These infants typically appear
Pneumonia is frequently preceded by several days of symptoms of an ill, with respiratory distress manifested as grunting; nasal flaring; retrac-
upper respiratory tract infection, typically rhinitis and cough. In viral tions of the supraclavicular, intercostal, and subcostal areas; tachypnea;
pneumonia, fever is usually present but temperatures are generally lower tachycardia; air hunger; and often cyanosis. Auscultation may be

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2270  Part XVIII  ◆  The Respiratory System

misleading, particularly in young infants, with meager findings dispro- breath sounds) who are well enough to be managed as outpatients because
portionate to the degree of tachypnea. Some infants with bacterial imaging in this context only rarely changes management.
pneumonia may have associated gastrointestinal disturbances character- Point-of-care use of portable or handheld ultrasonography is highly
ized by vomiting, anorexia, diarrhea, and abdominal distention secondary sensitive and specific in diagnosing pneumonia in children by determin-
to a paralytic ileus. Rapid progression of symptoms is characteristic in ing lung consolidations and air bronchograms or effusions (Fig. 428.4).
the most severe cases of bacterial pneumonia. However, the reliability of this imaging modality for pneumonia diagnosis
is highly user-dependent, which has limited its widespread use.
DIAGNOSIS
In 2011, the Pediatric Infectious Diseases Society (PIDS) and the Infec-
tious Diseases Society of America (IDSA) published clinical practice
guidelines for community-acquired pneumonia in children older than
3 mo of age. These evidence-based guidelines provide recommendations
for diagnostic testing and treatment of previously healthy children with
pneumonia in both outpatient and inpatient settings.
An infiltrate on chest radiograph (posteroanterior and lateral views)
supports the diagnosis of pneumonia; images may also identify a compli-
cation such as a pleural effusion or empyema. Viral pneumonia is usually
characterized by hyperinflation with bilateral interstitial infiltrates and
peribronchial cuffing (Fig. 428.2). Confluent lobar consolidation is typi-
cally seen with pneumococcal pneumonia (Fig. 428.3). The radiographic
appearance alone does not accurately identify pneumonia etiology,
and other clinical features of the illness must be considered. Repeat
A B
chest radiographs are not required for proof of cure for patients with Fig. 428.3  Radiographic findings characteristic of pneumococcal
uncomplicated pneumonia. Moreover, current PIDS–IDSA guidelines pneumonia in a 14 yr old boy with cough and fever. Posteroanterior
do not recommend that a chest radiograph be performed for children (A) and lateral (B) chest radiographs reveal consolidation in the right
with suspected pneumonia (cough, fever, localized crackles, or decreased lower lobe, strongly suggesting bacterial pneumonia.

A B

C D

B Fig. 428.4  Lung ultrasound patterns. A, Negative lung ultrasound
Fig. 428.2  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 hyperexpansion 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.
E F
pattern with A-line (arrow) and no other findings. Positive lung ultrasound
patterns with (B) B-lines (arrows); (C) large consolidation (>1 cm) with
tissue-like echo-texture (circle) and ultrasonographic bronchograms
(arrow); (D) small consolidation (<1 cm; circle); (E) pleural line abnormality
with thickening and irregularity (arrows); and (F) pleural effusion (arrow).
(From Varshney T, Mok E, Shapiro AJ, et al: Point-of-care lung ultrasound
in young children with respiratory tract infections and wheeze, Emerg
Med J 33(9):603–610, 2016, Fig. 1, p. 604.)

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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 polymorphonuclear leu-
kocytes. 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; although pneumococcal pneumonia
is associated with a higher WBC count, erythrocyte sedimentation rate,
procalcitonin, and C-reactive protein level, there is considerable overlap.
The definitive diagnosis of a viral infection rests on the detection of
the viral genome or antigen in respiratory tract secretions. Reliable
PCR assays are widely available for the rapid detection of many respiratory
viruses, including RSV, parainfluenza, influenza, human metapneumo-
virus, adenovirus, enterovirus, and rhinovirus. 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 virus. This diagnostic technique is
laborious, slow, and not generally clinically useful because the infection
usually has resolved 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.
The definitive diagnosis of a typical 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 is positive in only 10% of children with pneumococcal
pneumonia and is not recommended for nontoxic-appearing children
treated as outpatients. Blood cultures are recommended for children
who fail to improve or have clinical deterioration, have complicated
pneumonia (Table 428.6), or require hospitalization. Urinary antigen
tests should not be used to diagnose pneumonia caused by S. pneumoniae
in children because of a high rate of false positives resulting from
nasopharyngeal carriage. Pertussis infection can be diagnosed by PCR
or culture of a nasopharyngeal specimen; although culture is considered
the gold standard for pertussis diagnosis, it is less sensitive than the
available PCR assays. Acute infection caused by M. pneumoniae can be
diagnosed on the basis of a PCR test result from a respiratory specimen
or seroconversion in an immunoglobulin G assay. Cold agglutinins at
titers > 1 : 64 are also found in the blood of roughly half of patients
with M. pneumoniae infections; however, cold agglutinins are nonspecific
because other pathogens such as influenza viruses may also cause
Table 428.6  Factors Suggesting Need for Hospitalization
of Children With Pneumonia
Age <6 mo
Immunocompromised state
Toxic appearance
Moderate to severe respiratory distress
Hypoxemia (oxygen saturation <90% breathing room air, sea level)
Complicated pneumonia*
Sickle cell anemia with acute chest syndrome
Vomiting or inability to tolerate oral fluids or medications
Severe dehydration
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, or sepsis.
Adapted from Baltimore RS: Pneumonia. In Jenson HB, Baltimore RS, editors:
Pediatric infectious diseases: principles and practice, Philadelphia, 2002, WB
Saunders, p. 801.
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Chapter 428  ◆  Community-Acquired Pneumonia  2271
increases. Serologic evidence, such as antistreptolysin O and anti-DNase
B titers, may also be useful in the diagnosis of group A streptococcal
pneumonia.
There is a great deal of interest in developing a non-invasive diagnostic
test that can accurately differentiate children with bacterial versus viral
causes of pneumonia. Various biomarkers, including C-reactive protein,
procalcitonin, lipocalin-2, and tumor necrosis factor-related apoptosis-
inducing ligand, have been evaluated for their ability to differentiate
these pneumonia etiologies. For many of these biomarkers, values differ
in children with bacterial compared with viral causes of pneumonia,
but the reliability of these tests is not sufficiently high to justify routine
use. Studies of these biomarkers have also been hampered by the lack
of a gold standard for determining pneumonia etiology and the relatively
frequent occurrence of viral–bacterial co-infections. Patient peripheral
cell gene expression patterns determined by microarray reverse transcrip-
tion PCR is an emerging technology that may help differentiate bacterial
from viral causes of pneumonia, although further study is needed.
TREATMENT
Treatment of suspected bacterial pneumonia is based on the presumptive
cause and the age and clinical appearance of the child. For mildly ill
children who do not require hospitalization, amoxicillin is recommended.
With the emergence of penicillin-resistant pneumococci, high doses of
amoxicillin (90 mg/kg/day orally divided twice daily) should be prescribed
unless local data indicate a low prevalence of resistance (Table 428.7).
Therapeutic alternatives include cefuroxime and amoxicillin/clavulanate.
For school-aged children and adolescents or when infection with M.
pneumoniae or C. pneumoniae is suspected, a macrolide antibiotic is
an appropriate choice for outpatient management. Azithromycin is
generally preferred, while clarithromycin or doxycycline (for children
8 yr or older) are alternatives. For adolescents, a respiratory fluoroqui-
nolone (levofloxacin, moxifloxacin) may also be considered as an
alternative if there are contraindications to other agents.
The empiric treatment of suspected bacterial pneumonia in a hospital-
ized child requires an approach based on local epidemiology, the
immunization status of the child, and the clinical manifestations 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 may be used. If clinical features
suggest staphylococcal pneumonia (pneumatoceles, empyema), initial
antimicrobial therapy should also include vancomycin or clindamycin.
Moreover, if infection with M. pneumoniae or C. pneumoniae is suspected,
a macrolide antibiotic should be included in the treatment regimen.
If viral pneumonia is suspected, it is reasonable to withhold antibiotic
therapy, especially for preschool-aged patients who are mildly ill, have
clinical 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
basis of presumptive diagnosis of a viral infection, deterioration in
clinical status should signal the possibility of superimposed bacterial
infection, and antibiotic therapy should be initiated.
Table 428.7 notes the indications for admission to a hospital. Hospital-
ized children should receive supportive care and may require intravenous
fluids; respiratory support, including supplemental oxygen, continuous
positive airway pressure (CPAP), or mechanical ventilation; or vasoactive
medications for hypotension or sepsis physiology.
The optimal duration of antibiotic treatment for pneumonia has not
been well-established in controlled studies. However, antibiotics should
generally 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
is needed. Available data do not support prolonged courses of treatment
for uncomplicated pneumonia. Preliminary studies suggest that a
reduction of previously elevated serum procalcitonin levels to an absolute
level (0.1-0.25 µg/L) may help determine when to stop treatment.
2272  Part XVIII  ◆  The Respiratory System

Despite substantial gains over the past 15 yr, in developing countries
less than two-thirds of children with symptoms of pneumonia are taken
to an appropriate caregiver, and fewer than half receive antibiotics. The
World Health Organization and other international groups have
developed systems to train mothers and local healthcare providers in
the recognition and appropriate antibiotic treatment of pneumonia. In
addition to antibiotics, oral zinc (10 mg/day for < 12 mo, 20 mg/day
for ≥ 12 mo given for 7 days) may reduce mortality among children in
developing countries with clinically defined severe pneumonia. Bubble
CPAP improves mortality from pneumonia with hypoxemia compared

Table 428.7  Selection of Antimicrobial Therapy for Specific Pathogens

PATHOGEN PARENTERAL THERAPY
Streptococcus Preferred: ampicillin (150-200 mg/kg/day every 6 hr) or
pneumoniae with penicillin (200,000-250,000 U/kg/day every 4-6 hr);
MICs for penicillin Alternatives: ceftriaxone (50-100 mg/kg/day every 12-24 hr)
≤ 2.0 µg/mL (preferred for parenteral outpatient therapy); may also
be effective: clindamycin (40 mg/kg/day every 6-8 hr) or
vancomycin (40-60 mg/kg/day every 6-8 hr)
S. pneumoniae resistant Preferred: ceftriaxone (100 mg/kg/day every 12-24 hr);
to penicillin, with Alternatives: ampicillin (300-400 mg/kg/day every 6 hr),
MICs ≥ 4.0 µg/mL levofloxacin (16-20 mg/kg/day every 12 hr for children
6 mo to 5 yr old and 8-10 mg/kg/day once daily for
children 5-16 yr old; maximum daily dose, 750 mg), or
linezolid (30 mg/kg/day every 8 hr for children <12 yr old
and 20 mg/kg/day every 12 hr for children ≥12 yr old);
may also be effective: clindamycin (40 mg/kg/day every
6-8 hr) or vancomycin (40-60 mg/kg/day every 6-8 hr)
Group A streptococcus Preferred: intravenous penicillin (100,000–250,000 U/kg/day Preferred: amoxicillin (50-75 mg/kg/day in 2 doses), or
every 4-6 hr) or ampicillin (200 mg/kg/day every 6 hr);
Alternatives: ceftriaxone (50-100 mg/kg/day every Alternative: oral clindamycin (40 mg/kg/day in 3 doses)
12-24 hr); may also be effective: clindamycin, if
susceptible (40 mg/kg/day every 6-8 hr) or vancomycin
(40-60 mg/kg/day every 6-8 hr)
Staphylococcus aureus, Preferred: cefazolin (150 mg/kg/day every 8 hr) or
methicillin susceptible semisynthetic penicillin, e.g., oxacillin (150-200 mg/kg/
(combination therapy day every 6-8 hr);
not well studied) Alternatives: clindamycin (40 mg/kg/day every 6-8 hr) or
vancomycin (40-60 mg/kg/day every 6-8 hr)
S. aureus, methicillin Preferred: vancomycin (40-60 mg/kg/day every 6-8 hr or
resistant, susceptible dosing to achieve an AUC/MIC ratio of >400) or
to clindamycin clindamycin (40 mg/kg/day every 6-8 hr);
(combination therapy Alternatives: linezolid (30 mg/kg/day every 8 hr for
not well-studied) children <12 yr old and 20 mg/kg/day every 12 hr for
children ≥ 12 yr old)
S. aureus, methicillin Preferred: vancomycin (40-60 mg/kg/day every 6-8 hr or
resistant, resistant dosing to achieve an AUC/MIC ratio of >400);
to clindamycin Alternatives: linezolid (30 mg/kg/day every 8 hr for
(combination therapy children <12 yr old and 20 mg/kg/day every 12 hr for
not well studied) children ≥12 yr old)
Haemophilus influenza, Preferred: intravenous ampicillin (150-200 mg/kg/day every
typeable (A-F) or 6 hr) if β-lactamase negative, ceftriaxone (50-100 mg/kg/
nontypeable day every 12-24 hr) if β-lactamase producing
Alternatives: intravenous ciprofloxacin (30 mg/kg/day every
12 hr) or intravenous levofloxacin (16-20 mg/kg/day every
12 hr for children 6 mo to 5 yr old and 8-10 mg/kg/day
once daily for children 5-16 yr old; maximum daily dose,
750 mg)
Mycoplasma Preferred: intravenous azithromycin (10 mg/kg on days 1
pneumoniae and 2 of therapy; transition to oral therapy if possible);
Alternatives: intravenous erythromycin lactobionate
(20 mg/kg/day every 6 hr) or levofloxacin (16-20 mg/kg/
day every 12 hr; maximum daily dose, 750 mg)
ORAL THERAPY (STEP-DOWN THERAPY
OR MILD INFECTION)
Preferred: amoxicillin (90 mg/kg/day in 2 doses or
45 mg/kg/day in 3 doses);
Alternatives: second- or third-generation cephalosporin
(cefpodoxime, cefixime, cefprozil); oral levofloxacin, if
susceptible (16-20 mg/kg/day in 2 doses for children
6 mo to 5 yr old and 8-10 mg/kg/day once daily for
children 5-16 yr old; maximum daily dose, 750 mg) or
oral linezolid (30 mg/kg/day in 3 doses for children
<12 yr old and 20 mg/kg/day in 2 doses for children
≥12 yr old)
Preferred: oral levofloxacin (16-20 mg/kg/day in 2 doses
for children 6 mo to 5 yr and 8-10 mg/kg/day once
daily for children 5-16 yr, maximum daily dose,
750 mg), if susceptible, or oral linezolid (30 mg/kg/day
in 3 doses for children <12 yr and 20 mg/kg/day in 2
doses for children ≥12 yr);
Alternative: oral clindamycin (30-40 mg/kg/day in 3
doses)
penicillin V (50-75 mg/kg/day in 3 or 4 doses);
Preferred: oral cephalexin (75-100 mg/kg/day in 3 or 4
doses);
Alternative: oral clindamycin (30-40 mg/kg/day in 3 or 4
doses)
Preferred: oral clindamycin (30-40 mg/kg/day in 3 or 4
doses);
Alternatives: oral linezolid (30 mg/kg/day in 3 doses for
children <12 yr and 20 mg/kg/day in 2 doses for
children ≥12 yr)
Preferred: oral linezolid (30 mg/kg/day in 3 doses for
children <12 yr and 20 mg/kg/day in 2 doses for
children ≥12 yr old);
Alternatives: none; entire treatment course with
parenteral therapy may be required
Preferred: amoxicillin (75-100 mg/kg/day in 3 doses) if
β-lactamase negative, or amoxicillin clavulanate
(amoxicillin component, 45 mg/kg/day in 3 doses or
90 mg/kg/day in 2 doses) if β-lactamase producing;
Alternatives: cefdinir, cefixime, cefpodoxime, or
ceftibuten
Preferred: azithromycin (10 mg/kg on day 1, followed
by 5 mg/kg/day once daily on days 2-5);
Alternatives: clarithromycin (15 mg/kg/day in 2 doses)
or oral erythromycin (40 mg/kg/day in 4 doses); for
children >7 yr old, doxycycline (2-4 mg/kg/day in 2
doses; for adolescents with skeletal maturity,
levofloxacin (500 mg once daily) or moxifloxacin
(400 mg once daily)
Continued

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 Chapter 428  ◆  Community-Acquired Pneumonia  2273

Table 428.7  Selection of Antimicrobial Therapy for Specific Pathogens—cont’d

ORAL THERAPY (STEP-DOWN THERAPY
PATHOGEN PARENTERAL THERAPY OR MILD INFECTION)
Chlamydia trachomatis Preferred: intravenous azithromycin (10 mg/kg on days 1 Preferred: azithromycin (10 mg/kg on day 1, followed
or Chlamydophila and 2 of therapy; transition to oral therapy if possible); by 5 mg/kg/day once daily days 2-5);
pneumoniae Alternatives: intravenous erythromycin lactobionate Alternatives: clarithromycin (15 mg/kg/day in 2 doses)
(20 mg/kg/day every 6 hr) or levofloxacin (16-20 mg/kg/ or oral erythromycin (40 mg/kg/day in 4 doses); for
day in 2 doses for children 6 mo to 5 yr old and children >7 yr old, doxycycline (2-4 mg/kg/day in 2
8-10 mg/kg/day once daily for children 5-16 yr old; doses); for adolescents with skeletal maturity,
maximum daily dose, 750 mg) levofloxacin (500 mg once daily) or moxifloxacin
(400 mg once daily)
Doses for oral therapy should not exceed adult doses.
a
Clindamycin resistance appears to be increasing in certain geographic areas among S. pneumoniae and S. aureus infections.
b
For β-lactam–allergic children.
AUC, area under the time vs. serum concentration curve; MIC, minimum inhibitory concentration.
From Bradley JS, Byington CL, Shah SS, et al: The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice
guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America, Clin Infect Dis 53(7):617–630, 2011, Table 5, pp. 623–624.

with standard oxygen therapy in settings without access to ventilator-

derived CPAP or mechanical ventilation.

PROGNOSIS
Typically, patients with uncomplicated community-acquired bacterial
pneumonia show response to therapy, with improvement in clinical
symptoms (fever, cough, tachypnea, chest pain), within 48-72 hr of
initiation of antibiotics. Radiographic evidence of improvement lags
substantially behind clinical improvement. A number of possibilities
must be considered when a patient does not improve with appropriate
antibiotic therapy: (1) complications, such as pleural effusion or empyema
(see Table 428.6); (2) bacterial resistance; (3) nonbacterial etiologies
such as viruses or fungi and aspiration of foreign bodies or food; (4)
bronchial obstruction from endobronchial lesions, foreign body, or
mucous plugs; (5) preexisting diseases such as immunodeficiencies,
ciliary dyskinesia, cystic fibrosis, pulmonary sequestration, or congenital
pulmonary airway malformation; and (6) other noninfectious causes
(including bronchiolitis obliterans, hypersensitivity pneumonitis,
eosinophilic pneumonia, and granulomatosis with polyangiitis, formerly
called Wegener granulomatosis). A chest radiograph is the first step
in determining the reason for a lack of response to initial treatment.
Bronchoalveolar lavage may be indicated in children with respiratory
failure; high-resolution CT scans may better identify complications or
an anatomic reason for a poor response to therapy.
Mortality from community-acquired pneumonia in developed Fig. 428.5  Pneumococcal empyema on the chest radiography of a
countries is rare, and most children with pneumonia do not experience 3 yr old child who has had upper respiratory symptoms and fever for
long-term pulmonary sequelae. Some data suggest that up to 45% 3 days. A pleural fluid collection can be seen on the right side. The
of children have symptoms of asthma 5 yr after hospitalization for patient had a positive pleural tap and blood culture result for pneumo-
pneumonia; this finding may reflect either undiagnosed asthma at the cocci. The child recovered completely within 3 wk. (From Kuhn JP, Slovis
time of presentation or a propensity for development of asthma after TL, Haller JO, editors: Caffrey’s pediatric diagnostic imaging, ed 10,
pneumonia. Philadelphia, 2004, Mosby, p. 1002.)

COMPLICATIONS
Complications of pneumonia (see Table 428.6) are usually the result of
direct spread of bacterial infection within the thoracic cavity (pleural
effusion, empyema, and pericarditis) or bacteremia and hematologic
spread (Fig. 428.5). Meningitis, endocarditis, suppurative arthritis, and
osteomyelitis are rare complications of hematologic spread of pneumococ-
cal or H. influenzae type b infection.
S. aureus, S. pneumoniae, and S. pyogenes are the most common
causes of parapneumonic effusions and empyema. Nonetheless many
effusions that complicate bacterial pneumonia are sterile. Analysis of
pleural fluid parameters, including pH, glucose, protein, and lactate
dehydrogenase, can differentiate transudative from exudative effusions
(Table 428.8). However, current PIDS–IDSA guidelines do not recom-
mend that these tests be performed because this distinction rarely changes
management. Pleural fluid should be sent for Gram stain, and bacterial
culture as this may identify the bacterial cause of pneumonia. Molecular
methods, including bacterial species-specific PCR assays or sequencing
of the bacterial 16S ribosomal RNA gene, detect bacterial DNA and
can often determine the bacterial etiology of the effusion if the culture
is negative, particularly if the pleural fluid sample was obtained after
initiation of antibiotics. A pleural fluid WBC count with differential
may be helpful if there is suspicion for pulmonary tuberculosis or a
noninfectious etiology for the pleural effusion, such as malignancy.
Small (<1 cm on lateral decubitus radiograph), free-flowing parap-
neumonic effusions often do not require drainage but respond to
appropriate antibiotic therapy. Larger effusions should typically be
drained, particularly if the effusion is purulent (empyema) or associated
with respiratory distress. Chest ultrasound, or alternatively CT, may be
helpful in determining whether loculations are present. The mainstays
of therapy include antibiotic therapy and drainage by tube thoracostomy
with the instillation of fibrinolytic agents (urokinase, streptokinase,
tissue plasminogen activator). Video-assisted thoracoscopy is a less often
employed alternative that enables debridement or lysis of adhesions
and drainage of loculated areas of pus. Early diagnosis and intervention,

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 Table 428.8  Features Differentiating Exudative From
Transudative Pleural Effusion
FEATURE TRANSUDATE EXUDATE
Appearance Serous Cloudy
Leukocyte count <10,000/mm3 >50,000/mm3
pH >7.2 <7.2
Protein <3.0 g/dL >3.0 g/dL
Ratio of pleural fluid protein to <0.5 >0.5
serum
LDH <200 IU/L >200 IU/L
Ratio of pleural fluid LDH to serum <0.6 >0.6
Glucose ≥60 mg/dL <60 mg/dL
LDH, lactate dehydrogenase.
From Septimus EJ: Pleural effusion and empyema, In Bennett JE, Dolin R,
Blaser MJ, editors: Mandell, Douglas, and Bennett’s principles and practice of
infectious diseases, ed 8, vol 1, Philadelphia, 2015, Elsevier, Table 70-1, p. 851.

particularly with fibrinolysis or less often video-assisted thoracoscopy,

may obviate the need for thoracotomy and open debridement.

PREVENTION
The introduction of PCVs resulted in a substantial reduction in the
incidence of pneumonia hospitalizations among children. The annual
rate of all-cause pneumonia hospitalization among children younger
than 2 yr of age in the United States was 12.5 per 1,000 children during
the period from 1997 to 1999. In 2000, 7-valent pneumococcal conjugate
vaccine (PCV7) was licensed and recommended. In 2006, the pneumonia
hospitalization rate in this age group was 8.1 per 1,000 children, a 35%
decrease from the pre-vaccine rate. In 2010, 13-valent pneumococcal
conjugate vaccine (PCV13) was licensed in the United States. Early data
indicate that introduction of this vaccine resulted in a 16–27% further
reduction in pneumonia hospitalizations among children relative to
the post-PCV7 era.
Influenza vaccine may also prevent pneumonia hospitalizations among
children and should be administered to all children >6 mo of age. For
infants <6 mo of age, household contacts and other primary caregivers
should be immunized. Maintaining high rates of vaccination for H.
influenzae type b, pertussis, and measles remains important for the
prevention of pneumonia from these causes. Several RSV vaccines are
currently under development; introduction of an effective vaccine against
RSV would be anticipated to substantially reduce pneumonia incidence
among children, particularly young infants.

Bibliography is available at Expert Consult.

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