Pathobiology

Influenza virus infection is transmitted from person to person by virus-containing respiratory

secretions. Large- and small-particle aerosols over short distances (1-2 meters) both appear to
contribute, but transmission by other routes, including fomites, may be possible. Infection by
avian viruses also can occur after direct contact with infected birds or their excreta, possibly,
ingestion of contaminated food, and sometimes inoculation into the conjunctiva. Virtually all
cells lining the respiratory tract can support viral replication, although receptors for avian
viruses appear to be concentrated on cells in the distal bronchioles and alveoli. Once the virus
initiates infection of the respiratory tract epithelium, successive cycles of viral replication infect
large numbers of cells and result in destruction of ciliated epithelium through direct cytopathic
effects or apoptosis. The incubation period, which averages 2 days and varies from 1 to 4 days,
may be somewhat longer in infections caused by avian viruses. The quantity of virus in
respiratory tract specimens correlates with the severity of illness and levels of host pro-
inflammatory cytokine-chemokine responses, findings that support the importance of ongoing
viral replication in producing illness. Elevated levels of pro-inflammatory cytokines such as
interferon-α, interleukin-6, and tumor necrosis factor-α occur in blood and respiratory
secretions and probably contribute to systemic symptoms and fever. The duration of viral
replication depends on age and immune status. Shedding generally lasts for 3 to 5 days in
adults, often into the second week in children, and may persist for weeks to months in
immunocompromised hosts. Prolonged viral replication and excessive cytokine-chemokine
responses have been found in H5N1 infections. Viremia or extrapulmonary dissemination is
rarely associated with typical human influenza, but both occur in some patients with avian
H5N1 infections, in whom gastrointestinal replication may also occur.
Nasal and bronchial biopsy specimens from persons with uncomplicated influenza reveal
desquamation of the ciliated columnar epithelium. Individual cells show shrinkage, pyknotic
nuclei, and loss of cilia. In addition, the lungs in fatal influenza may show necrotizing bronchitis,
alveolar edema and hemorrhage, hyaline membrane formation, diffuse alveolar damage, and
later, fibrosis and squamous metaplasia. Secondary bacterial infections develop as a result of
altered bacterial flora, damage to bronchial epithelium with depressed mucociliary clearance,
decreased polymorphonuclear and alveolar macrophage functions, accumulation of alveolar
fluid, and possibly viral NA–mediated exposure of cellular receptors for bacteria.
Neutralizing, hemagglutination-inhibiting (HAI), anti-NA, complement-fixing, enzyme-linked
immunosorbent assay, and immunofluorescent antibodies begin to develop in the sera of
persons with primary influenza virus infection during the second week after infection and reach
a peak by 4 weeks. Secretory antibodies develop in the upper respiratory tract and consist
predominantly of IgA antibodies. Cell-mediated immune responses develop by 1 week after
infection. Adaptive immunity to influenza appears to be largely subtype specific and durable for
a particular strains. Protection against illness caused by human viruses is generally associated
with serum HAI titers of 1:40 or greater, serum-neutralizing antibody titers of 1:8 or greater, or
nasal-neutralizing antibody titers of 1:4 or greater.

Clinical Manifestations
Influenza Syndrome
An abrupt onset of feverishness, chilliness, rigors, headache, myalgia, and malaise is
characteristic of influenza but occurs in less than two thirds of cases. Systemic symptoms
predominate initially, and prostration occurs in more severe cases. Usually, myalgia and
headaches are the most troublesome early symptoms, and their severity is related to the level
of fever. Arthralgia is common. Sometimes ocular symptoms, including photophobia, tearing,
burning, and pain on moving the eyes, are helpful diagnostically. Conjunctivitis is characteristic
in avian H7 virus infections. Respiratory symptoms, particularly dry cough and nasal discharge,
are also generally present at the onset but are overshadowed by the systemic symptoms. Nasal
obstruction, hoarseness, and sore throat are likewise common. As systemic illness diminishes,
respiratory complaints and findings become more apparent. Cough is the most frequent and
troublesome symptom and may be accompanied by substernal discomfort or burning. Cough,
lassitude, and malaise may persist for several weeks before full recovery.
Fever is the most important initial physical finding. The temperature usually rises rapidly to a
peak of 38 to 40° C within 12 hours of onset, concurrently with systemic symptoms. Fever is
usually continuous but may be intermittent, especially if antipyretics are administered.
Typically, the duration of fever in adults is 3 days, but it may last from 1 to 5 or more days.
Uncommonly, the fever takes a biphasic course. Early in the course of illness, the patient
appears toxic, the face is flushed, and the skin is hot and moist. The eyes are watery and
reddened. Clear nasal discharge is common. The mucosa of the nose and throat is hyperemic,
but exudate is not observed. Small, tender cervical lymph nodes are often present. Transient
scattered rhonchi or localized areas of rales are found in less than 20% of cases.
The pattern of illness just described occurs with any strain of influenza A or B virus. Illness is
more frequent and severe in smokers, and attack rates are higher in children than in adults.
Maximum temperatures are higher in children, cervical adenopathy may be more frequent, and
gastrointestinal symptoms of nausea, emesis, or abdominal pain are more common. Women
experience increased complications of influenza during the second and third trimesters of
pregnancy. Symptoms may be protracted for some persons infected with human
immunodeficiency virus (HIV), and they are also at higher risk for complications. Older adults,
especially the infirm elderly, develop fever, muscle aches, sore throat, and headache less often
but have higher rates of altered mental status and pulmonary complications. In sporadic illness
attributable to H5N1 virus, upper respiratory complaints are less frequent, diarrhea is more
common, and progressive viral pneumonia with high mortality is much more likely. Influenza C
virus generally causes sporadic upper respiratory tract illness or febrile bronchitis.

Diagnosis
In an individual case, influenza often cannot be distinguished from infection with a number of
other viruses (and occasionally streptococcal pharyngitis; Chapters 312 and 455 ) that produce
headache, muscle aches, fever, sore throat, or cough (or various combinations thereof). On the
other hand, when public health authorities report an epidemic of influenza A and B virus
infection in a given community and a patient is seen with typical illness, it is highly likely that
these symptoms are caused by an influenza virus infection. In such circumstances, the presence
of fever and cough has a positive predictive value of about 80% for laboratory-proven influenza
in adults. Influenza virus is readily isolated from nasal, sputum, or tracheal secretion specimens
in the first 2 or 3 days of illness. Throat samples have lower yield than nasal samples in
infections by human viruses but appear to be superior to nasal samples for detection of H5N1
infections. Usually, infectious virus is recovered in cell culture within 48 to 72 hours.
Immunofluorescence testing of respiratory cells or inoculated cell cultures (shell vials) can
reduce time to detection. Commercially available enzyme immunoassays or NA detection–
based assays can document influenza virus infection rapidly but may have limited sensitivity (50
to 70%) in adults; some do not distinguish between influenza A and B. The limited specificity of
some assays makes their predictive value low, especially outside the influenza season.
Detection of viral RNA by reverse transcription–polymerase chain reaction appears to be highly
sensitive and specific; this is the rapid test of choice for suspected H5N1 illness. Serologic
methods are less useful clinically because they require convalescent serum obtained 14 to 21
days after the onset of infection.

Prevention
The mainstay of prevention is influenza virus vaccine ( Chapter 16 ). Inactivated vaccines given
by intramuscular injection provide 70 to 90% protection in young and middle-aged adults
against influenza illness when the vaccine matches the epidemic strain. Immunogenicity and
hence protection rates are often lower in elderly persons, particularly infirm nursing home
residents, and in immunosuppressed patients, including those with advanced HIV infection,
transplant recipients, and chemotherapy patients. In institutionalized elderly people,
immunization is 50 to 60% effective in preventing hospitalization and pneumonia and reduces
influenza-related mortality by 70 to 80%. In ambulatory high-risk patients, immunization
reduces hospitalizations from pneumonia, influenza, and cardiovascular disease, as well as all-
cause mortality during the influenza season. Immunization also appears to be cost-effective in
working adults, depending on the size of the epidemic. Immunization of school-aged children
appears to reduce respiratory illness in household contacts and, in one Japanese study, excess
deaths in the elderly. Immunization of health care providers reduces the risk of transmission to
patients. An intranasal, live attenuated vaccine that is highly protective against influenza in
children and to a lesser extent in adults is currently approved in the United States for persons
aged 5 to 49 years.
The antigenic composition of vaccines is reviewed annually so that these trivalent vaccines
contain the most recently circulating strains, usually two subtypes of influenza A and an
influenza B virus. Both vaccines are grown in eggs, and episodic production problems have led
to shortages of the inactivated vaccine. With inactivated vaccine, fever and systemic symptoms
occur at rates comparable to those of adults given placebo but are more common in young
children. Among adults, 25% or more may have mild local reactions at the site of injection.
Persons with malignant disease should receive vaccine between courses of chemotherapy.
Intranasal vaccine causes coryza and sore throat in adults. Studies of investigational H5 vaccines
indicate that two doses of high–HA antigen content or coadministration with an adjuvant
appear to be necessary for adequate immunogenicity.
The priority groups for seasonal vaccine continue to expand and include those at increased risk
for influenza complications and their immediate contacts ( Table 387-4 ), although vaccine can
be safely administered to anyone trying to avoid influenza. Vaccine should be given each year in
the fall, preferably October or November, before the influenza season. The vaccine is
contraindicated in persons with chicken egg anaphylactic hypersensitivity. Inactivated vaccine
does not cause exacerbation of asthma but may rarely be associated with Guillain-Barré
syndrome in older adults.

Treatment

Oral rimantadine or amantadine therapy shortens the duration of fever and systemic and
respiratory symptoms in uncomplicated influenza A caused by susceptible strains by 1 to 2
[1] [2]
days and speeds functional recovery (see Table 387-5 ). The possible effectiveness of
these drugs in preventing or treating the pulmonary complications of influenza is unknown.
Rimantadine carries a lower risk for CNS side effects than amantadine does, but both may
cause gastrointestinal upset. These agents are ineffective for influenza B infections. Antiviral
resistance because of point mutations in the M2 gene emerges in 30% or more of treated
persons, who sometimes transmit drug-resistant virus to close contacts. Circulating H3N2 and
increasingly H1N1 viruses often show high-level resistance to this antiviral class, as do many
human isolates of avian A/H5N1 virus, so these drugs are not recommended for routine use
at present.
The NA inhibitors inhaled zanamivir and oral oseltamivir are active against both influenza A
and B viruses.[2] Therapy within 2 days of the onset of illness reduces symptoms, time to
functional recovery, and risk for lower respiratory complications, including bronchitis and
pneumonia. Early oseltamivir therapy also decreases the risk for hospitalization. Zanamivir
may be infrequently associated with bronchospasm, sometimes severe, and oseltamivir is
associated with nausea or emesis.
Other symptomatic measures include antipyretics and cough suppressants. Aspirin should not
be used, especially in children younger than 16 years, because of its association with Reye's
syndrome.
Influenza viral pneumonia, including H5N1 disease, often requires intensive respiratory
monitoring and ventilator support. Oral amantadine or rimantadine, intravenous ribavirin,
aerosolized ribavirin, nebulized zanamivir, and oral oseltamivir have been used with uncertain
benefit.[2] Intensive care unit complications, including ventilator-associated pneumonia, are
common. Secondary bacterial pneumonia should be treated with appropriate antibiotics.
When studies of sputum do not clearly indicate an infecting bacterium, antibiotics that are
effective against the probable pathogens, including S. aureus, should be used.