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104 INFLUENZA AND OTHER VIRAL RESPIRATORY DISEASES

104 INFLUENZA AND OTHER VIRAL RESPIRATORY DISEASES
Harrison’s Manual of Medicine

104

INFLUENZA AND OTHER VIRAL RESPIRATORY DISEASES

Influenza
Other Viral Respiratory Infections

Rhinovirus

Coronavirus

Respiratory Syncytial Virus

Parainfluenza Virus

Adenovirus
Bibliography

INFLUENZA
ETIOLOGY   Influenza viruses, members of the Orthomyxoviridae family, include types A, B, and C. Strains are designated according to the site of origin, isolate number, year of isolation, and (for influenza A virus) subtype, which is based on surface hemagglutinin (H) and neuraminidase (N) antigens. The genome of influenza A virus is segmented, consisting of eight single-stranded segments of RNA; this characteristic leads to a high frequency of gene reassortment.
EPIDEMIOLOGY   Outbreaks of influenza occur virtually every year, although their extent and severity vary widely. Localized outbreaks take place at variable intervals, usually every 1–3 years. Except for the past two decades, global epidemics or pandemics have occurred approximately every 10–15 years since the 1918–1919 pandemic. The most extensive and severe outbreaks are caused by influenza A virus because of the propensity of its antigens to undergo variation. Major antigenic variations, referred to as antigenic shifts, likely arise from genome segment reassortment between viral strains, which results in the expression of a different H and/or N antigen. Minor variations, referred to as antigenic drifts, probably arise from point mutations. In human infections, three major H antigens (H1, H2, and H3) and two N antigens (N1 and N2) have been recognized. Epidemics of influenza A begin abruptly, peak over 2–3 weeks, generally last 2–3 months, and often subside rapidly. These epidemics take place almost exclusively during the winter months in the temperate zones of the northern and southern hemispheres. In contrast, influenza occurs throughout the year in the tropics. Outbreaks of influenza B are generally less extensive and less severe. The H and N antigens of influenza B virus undergo less frequent and less extensive variation. Influenza B outbreaks are most common in schools and military camps. Influenza C virus appears to cause subclinical infection; the prevalence of antibody is high in the general population, but the virus is infrequently associated with human disease.
CLINICAL MANIFESTATIONS   Influenza is an acute respiratory illness characterized by the abrupt onset of headache, fevers, chills, myalgia, malaise, cough, and sore throat. In uncomplicated influenza, the acute illness generally resolves over 2–5 d, and most pts largely recover within 1 week.
The major problem posed by influenza consists of its complications, the most common of which is pneumonia—primary influenza viral pneumonia, secondary bacterial pneumonia, or mixed viral and bacterial pneumonia. Primary influenza pneumonia is the least common but most severe of the pneumonic complications. Fever persists, and pts develop progressive dyspnea, cough with scant sputum, and eventually cyanosis. CXR reveals diffuse interstitial infiltrates and/ or acute respiratory distress syndrome. Pts with cardiac disease, especially mitral stenosis, appear to have a predilection for developing influenza pneumonia.
The hallmark of secondary bacterial pneumonia is the reappearance of fever, accompanied by productive cough and physical signs of consolidation, in a pt whose condition has improved for 2–3 d following acute influenza. Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae are common pathogens. Pts at particular risk for this complication include elderly individuals or persons with chronic pulmonary or cardiac disease.
Mixed viral and bacterial pneumonia may be the most common pneumonic complication and has clinical features of both primary and secondary pneumonia. This complication occurs primarily in pts with chronic cardiovascular or pulmonary disease.
Extrapulmonary complications include Reye’s syndrome, myositis, rhabdomyolysis, and myoglobinuria. Encephalitis, transverse myelitis, and Guillain- Barré syndrome have been associated with influenza, but an etiologic role for influenza virus has not been established in these conditions. Reye’s syndrome occurs in children as a serious complication of influenza B or—less often—of influenza A or varicella-zoster virus infection. The syndrome begins with 1–2 d of nausea and vomiting followed by CNS symptoms, including changes in mental status that range from lethargy to coma and can encompass delirium and seizures. Elevated serum aminotransferase levels, elevated serum ammonia concentrations, and hepatomegaly are common; serum bilirubin levels are usually normal. An epidemiologic association of Reye’s syndrome with the ingestion of aspirin has been noted; the syndrome’s incidence in this context has declined markedly with widespread warnings about aspirin use in children with viral infections.
DIAGNOSIS   Influenza can be diagnosed during its acute phase by isolation of virus from throat swabs, nasopharyngeal washes, or sputum in tissue culture within 48–72 h after inoculation. Viral antigens may be detected somewhat earlier by immunodiagnostic techniques in tissue culture or in exfoliated nasopharyngeal cells obtained by washings; these techniques have sensitivities of 57–81% compared with tissue culture. Acute infection can be diagnosed retrospectively by fourfold or greater rises in titers of hemagglutination inhibition or CF antibody or by significant rises in ELISA antibody between the acute illness and 10–14 d after onset.

TREATMENT
Treatment for uncomplicated influenza is for relief of symptoms only. Salicylates should be avoided in children (<18 years old) because of the association of their use with Reye’s syndrome. Amantadine or rimantadine (either given at a dose of 200 mg/d PO for 3–7 d) reduces the duration of systemic and respiratory symptoms by 50% if given within 48 h of onset. These agents are active only against influenza A virus. Amantadine causes mild CNS side effects (jitteriness, anxiety, insomnia, difficulty concentrating) in 5–10% of pts. Rimantadine is less frequently associated with CNS side effects. Both agents are given at a reduced dose of £100 mg/d to the elderly and to persons with renal insufficiency. Zanamivir (10 mg inhaled bid for 5 d) and oseltamivir (75 mg PO bid with food for 5 d) are active against both influenza A and influenza B. These agents have been shown to reduce the duration of symptoms and signs of influenza by 1–1.5 d if treatment is started within 2 d of the onset of illness. Zanamivir may exacerbate bronchospasm, and oseltamivir has been associated with nausea and vomiting. Ribavirin has been reported to be effective against both type A and type B viruses when administered as an aerosol but is relatively ineffective when administered orally. It is not known whether these antiviral agents are effective in the treatment of complications such as influenza pneumonia. Antibacterial therapy should be reserved for bacterial complications of influenza, such as bacterial pneumonia.

PROPHYLAXIS   The most common preventive measure is yearly vaccination against influenza A and B; an inactivated vaccine derived from strains circulating the previous year is used. Vaccination is recommended for individuals >6 months of age who are at increased risk for complications of influenza. Included are pts with chronic pulmonary or cardiovascular disorders, residents of nursing homes or chronic care facilities, all persons >55 years old, health care providers, and pts with diabetes, renal disease, hemoglobinopathies, or immunosuppression. Individuals who care for high-risk pts or who come into frequent contact with them (including household members) should also be vaccinated to reduce the risk of transmission. Since the vaccine is “killed,” it may be administered to immunosuppressed pts.
Amantadine and rimantadine are 70–100% effective in the prophylaxis of influenza A. Prophylaxis with one of these drugs (200 mg/d PO) is indicated for high-risk individuals who have not been vaccinated or over the duration of outbreaks caused by a strain not well covered by the current vaccine. Simultaneous administration of amantadine and vaccine may offer additive protection. Zanamivir and oseltamivir are under review for prophylaxis.
OTHER VIRAL RESPIRATORY INFECTIONS
Acute viral respiratory illnesses are among the most common of human diseases, accounting for one-half or more of all acute illnesses. The syndromes most commonly associated with the major respiratory virus groups are summarized in Table 104-1.

Table 104-1 Illnesses Associated with Respiratory Viruses

Rhinovirus
Rhinoviruses, members of the Picornaviridae family, are small and nonenveloped and have a single-stranded RNA genome. One hundred distinct serotypes of rhinovirus have been recognized.
EPIDEMIOLOGY   Rhinoviruses have been isolated from 15–40% of adults with the common cold, with seasonal peaks in the early fall and spring. Infection rates are highest among infants and young children and decrease with age. The infection is spread by contact with infected secretions or respiratory droplets or by hand-to-hand contact, with subsequent self-inoculation of the conjunctival or nasal mucosa. Exposure to cold, fatigue, and sleep deprivation have not been associated with increased rates of rhinovirus-induced illness.
CLINICAL MANIFESTATIONS   After an incubation period of 1–2 d, pts develop rhinorrhea, sneezing, nasal congestion, and sore throat. Systemic symptoms, including fever, are unusual. The illness generally lasts 4–9 d and resolves spontaneously. Although bronchitis, bronchiolitis, and bronchopneumonia have been reported in children, rhinoviruses are not a major cause of pediatric lower respiratory tract disease. Rhinoviruses may cause exacerbations of asthma and chronic pulmonary disease in adults.
DIAGNOSIS   Because of the mild nature and short duration of the illness, a specific diagnosis is not commonly needed. If isolation of the virus is of interest, tissue culture of nasal washes or secretions is performed.

TREATMENT
Treatment is not usually required, and no specific antiviral therapy is available. Antibiotics should not be used in uncomplicated infections but rather should be reserved for any bacterial superinfections (e.g., otitis media, sinusitis) that develop.

Coronavirus
Coronaviruses are pleomorphic, single-stranded RNA viruses.
EPIDEMIOLOGY   Coronaviruses account for 10–20% of common colds. They are most active in late fall, winter, and early spring—a period when rhinovirus is relatively inactive.
CLINICAL MANIFESTATIONS   Symptoms are similar to those of rhinovirus infections, but the incubation period is longer (3 d). The illness usually lasts 6–7 d.

TREATMENT
The approach to the treatment of common colds caused by coronaviruses is similar to that for rhinovirus-induced illness.

Respiratory Syncytial Virus
Respiratory syncytial virus (RSV) is an enveloped virus of the Paramyxoviridae family with a single-stranded RNA genome. Two distinct subtypes, A and B, have been described.
EPIDEMIOLOGY   RSV is the major respiratory pathogen of young children and is the foremost cause of lower respiratory disease in infants. Rates of illness peak at 2–3 months of age, when attack rates among susceptible individuals approach 100%. RSV accounts for 20–25% of hospital admissions of infants and young children for pneumonia and for up to 75% of cases of bronchiolitis in this age group. This virus is an important nosocomial pathogen in both children and adults. It is transmitted by close contact with contaminated fingers or fomites as well as through coarse (not fine) aerosols produced by coughing or sneezing. The incubation period is 4–6 d; viral shedding by children may last ³2 weeks, with a shorter duration in adults.
CLINICAL MANIFESTATIONS   In infants, RSV disease begins with rhinorrhea, low-grade fever, and mild systemic symptoms, often accompanied by cough and wheezing; 25–40% of cases include lower respiratory tract involvement. RSV illness is especially severe in children born prematurely and in those with congenital cardiac disease, bronchopulmonary dysplasia, nephrotic syndrome, or immunosuppression. The mortality rate for RSV pneumonia among infants with congenital cardiac disease was 37% in one study. In adults, the symptoms of RSV infection are usually the same as those of the common cold. RSV can cause severe pneumonia in immunocompromised or elderly adults.
DIAGNOSIS   RSV can be isolated in tissue culture from sputum, throat swabs, or nasopharyngeal washes. Immunofluorescence microscopy of nasal washings or scrapings provides a rapid diagnosis. Serologic diagnosis requires a fourfold rise in antibody titer between acute- and convalescent-phase specimens and is therefore not useful during acute illness.

TREATMENT
Treatment of upper respiratory tract infections due to RSV is similar to that for URIs of other etiologies. Therapy with aerosolized ribavirin has been beneficial in infants with RSV infection. No data exist on treatment in adults.

PROPHYLAXIS   Monthly administration of human immunoglobulin with high titers of antibody to RSV (RSVIG) or of a chimeric mouse-human IgG antibody to RSV (palivizumab) is approved as prophylaxis in high-risk pts <2 years old. No data exist on prophylaxis in adults.
Parainfluenza Virus
Parainfluenza viruses are single-stranded RNA viruses of the Paramyxoviridae family.
EPIDEMIOLOGY   In the U.S., parainfluenza viruses cause 4–22% of respiratory illnesses in children and <5% of respiratory illnesses in adults. Parainfluenza virus is an important cause of mild illnesses and of croup (laryngotracheobronchitis), bronchiolitis, and pneumonia. In young children, parainfluenza virus ranks second only to RSV as a cause of lower respiratory infection. In adults, parainfluenza infections are generally mild.
CLINICAL MANIFESTATIONS   In adults and older children, parainfluenza virus infection presents as a mild common cold or hoarseness with cough. In young children, it may present as an acute febrile illness with coryza, sore throat, hoarseness, and cough. The brassy or barking cough of croup may progress to frank stridor. Most children recover in 1–2 d, but progressive airway obstruction and hypoxia occasionally ensue, and bronchiolitis or pneumonia may develop. Severe or even fatal infection has been reported in both children and adults with profound immunosuppression.
DIAGNOSIS   The diagnosis is established by tissue culture of the virus from respiratory tract secretions, throat swabs, or nasopharyngeal washings or by immunofluorescence microscopy of exfoliated respiratory cells. Serologic diagnosis is available.

TREATMENT
In mild illness, treatment is symptom-based. Mild croup may be treated with moisturized air from a vaporizer. More severe cases require hospitalization and close observation for development of respiratory distress. No specific antiviral treatment is available.

Adenovirus
Adenoviruses are complex DNA viruses belonging to the genus Mastadenovirus.
EPIDEMIOLOGY   Infections with adenovirus occur most frequently in infants and children, accounting for 3–5% of respiratory infections in children and for <2% of respiratory illnesses in civilian adults. There is a seasonal distribution of fall to spring. Certain serotypes are associated with outbreaks of acute respiratory disease in military recruits. Transmission can take place via the inhalation of aerosolized virus, through the inoculation of the conjunctival sacs, and probably by the fecal-oral route.
CLINICAL MANIFESTATIONS   The spectrum of clinical symptoms in children includes rhinitis and occasional cases of bronchiolitis and pneumonia. Adenovirus types 3 and 7 cause pharyngoconjunctival fever (bilateral conjunctivitis, low-grade fever, rhinitis, sore throat, and cervical adenopathy). Adenovirus types 4 and 7 cause the most frequent syndrome in adults (classically affecting military recruits): an acute respiratory illness with prominent sore throat, fever on the second or third day, cough, coryza, and regional lymphadenopathy. Adenoviruses have also been associated with pneumonia in immunosuppressed pts (including pts with AIDS) and with diseases outside the respiratory tract, including acute diarrhea in young children, hemorrhagic cystitis, and epidemic keratoconjunctivitis.
DIAGNOSIS   The diagnosis is established by the isolation of the virus in tissue culture from the conjunctivae, oropharynx, sputum, urine, or stool. ELISA or nucleic acid hybridization techniques may also be used for detection of the virus in clinical specimens. Serologic diagnosis is available.

TREATMENT
No specific antiviral therapy is available. A live oral vaccine is used to prevent outbreaks among military recruits. Purified subunit vaccines are under investigation.

Bibliography

For a more detailed discussion, see Dolin R: Common Viral Respiratory Infections, Chap. 189, p. 1120; and Dolin R: Influenza, Chap. 190, p. 1125, in HPIM-15.

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