Chapter 22 Influenza and Other Viral Respiratory Tract Infections JASON W. CHIEN, MD, MS JOHN L. JOHNSON, MD Key Learning Points 1. Clinical manifestations of viral respiratory infections are nonspecific 2. Diagnostic procedures should be pursued if a viral infection is considered, particularly among immunocompromised hosts. 3. Vaccination, when available, is the most effective method of avoiding respiratory viral infections. 4. Resistance to existing antiviral therapy is on the rise and resistance patterns should be considered before an antiviral is prescribed. 5. Preemptive therapy is important for preventing opportunistic viral infections in immunocompromised hosts. Viruses are important causes of community-acquired pneumonia in children and adults (Table 22-1). Although influenza and respiratory syncytial viruses (RSVs) are the most common causes of serious viral respiratory illness; parainfluenza, adenoviruses, and other agents are also significant pathogens (1). In adults, severe viral pneumonia is more frequent in elderly patients, persons with chronic lung disease such as chronic obstructive pulmonary disease (COPD), and other chronic medical illnesses and immunosuppressive conditions. The true proportion of community-acquired pneumonia in adults caused by viruses is difficult to determine because of the limited testing for viral pathogens in many settings and the limited sensitivity of some diagnostic tests. However, viral infections have been identified in approximately 10% (range 4% to 39%) of relatively immunocompetent adults hospitalized with community-acquired pneumonia (2). In a recent well-done prospective study 417
418 Expert Guide to Infectious Diseases New Developments There has been an increased recognition of new viral respiratory infections including avian influenza, human metapneumovirus and SARS. The appearance of severe acute respiratory syndrome (SARS) was dramatic and short lived but there was rapid recognition of the epidemiology, pathogenesis and etiology through worldwide efforts by public health agencies. There is increasing resistance of seasonal influenza strains to amantadine and rimantadine globally. Table 22-1 Common Causes of Viral Pneumonia in Adults and Children Children Adults Respiratory syncytial virus Influenza A and B Parainfluenza virus, types 1-3 Herpes simplex virus type 1 Adenovirus Varicella-zoster virus Influenza A and B Adenovirus Varicella-zoster virus Cytomegalovirus Herpes simplex virus type 1 Hantavirus Human metapneumovirus from the United Kingdom, of 267 adults with community-acquired pneumonia, viruses were suspected to be the cause of pneumonia in 23% (3). The frequency of reported viral pneumonias has increased during the past decade, most likely caused by a combination of better diagnostic techniques and an increasing risk for viral pneumonias among the growing immunocompromised population. This chapter will focus on modern diagnostic techniques and the most frequent viral pathogens causing severe lower respiratory disease in adults. The clinical and public health challenges imposed by new respiratory pathogens such as avian influenza, severe acute respiratory syndrome (SARS), and human metapneumovirus will also be discussed. Diagnosis: General Principles Diagnosing viral lower respiratory tract infections can be challenging. The clinical presentation of viral pneumonia varies, is often nonspecific, and can be mimicked by other processes such as severe community-acquired or atypical pneumonias, acute lung injury from a systemic inflammatory syndrome, or noninfectious diffuse lung processes such as hypersensitivity pneumonitis. Clinical suspicion should be based on the combination of epidemiologic characteristics such as characteristic seasonal patterns, and constitutional symptoms such as fever, chills, nonproductive cough, rhinitis, myalgias, headaches, and fatigue. Although physical examination findings such as
Influenza and Other Viral Respiratory Tract Infections 419 wheezing, rales, increased fremitus, and signs of wide spread bronchial inflammation frequently accompany viral processes, they are also seen in pyogenic pneumonia. However, viral respiratory tract infections are more likely to be associated with extrapulmonary manifestations, especially conjunctivitis, gastroenteritis, lymphadenopathy, and exanthems. Unfortunately, the radiological features of viral pneumonias are also nonspecific. Findings can mimic bacterial pneumonia and range from patchy bronchopneumonia to fleeting infiltrates to more characteristic diffuse interstitial or nodular infiltrates. Cavitation and pleural effusions, although possible, are rare. Because severe leukocytosis is uncommon in viral pneumonia, a total leukocyte count of less than 15,000 cells/mm 3 in the setting of severe pneumonia should also suggest a viral cause. Laboratory Testing Viral Culture and Antigen Detection An etiologic diagnosis of viral pneumonia can be made by isolation and identification of the viral pathogen through viral culture or by isolating its DNA or antigens in lower respiratory tract secretions or lung tissue (Table 22-2) (4). Most respiratory viruses can be isolated by cell culture of specimens from the upper and lower respiratory tract, which include nasopharyngeal swabs, sputum, and bronchoalveolar lavage (BAL) and biopsy specimens. Nasopharyngeal swabs or washings are useful for RSV, influenza, parainfluenza, and adenovirus culture. For best results viral cultures should be obtained early during the course of the illness. Cell cultures can be used to detect changes in appearance called viral cytopathic effect (CPE) as evidence of viral growth, or for hemadsorption testing by adding guinea pig erythrocytes to cultured cell monolayers and noting adherence of erythrocytes to the monolayer in the presence of viral growth. Once CPE is seen or hemadsorption tests are positive, the responsible virus can be further identified using immunofluorescent enzyme-linked immunosorbent assays (ELISA) and nucleic acid probes. Because of the slow growing nature of conventional fibroblast cell cultures, shell vial culture systems are now widely used to speed the detection of cytomegalovirus (CMV), RSV, herpes simplex virus (HSV), adenovirus, influenza, parainfluenza virus, and other pathogens. Rapid antigen detection tests based on ELISA methods are available for HSV, RSV, influenza A and B, parainfluenza types 1 through 4, CMV, and other respiratory viruses (4). Although the sensitivity of antigen detection tests is lower than viral cultures, many laboratories use panels of antibodies to common respiratory viruses for screening clinical specimens because this approach is faster. A recently developed molecular diagnostic technique, the multiplex reverse transcriptionpolymerase chain reaction (RT-PCR) assay, overcomes the low sensitivity of antigen detection assays, the delay of viral cultures, and the limitation of
420 Expert Guide to Infectious Diseases Table 22-2 Diagnostic Techniques for Viral Infections Virus Method of Diagnosis Herpesviruses HSV Tracheal aspirate or BAL for viral cultures and antigen testing by ELISA, immunoabsorbent assays VZV Samples from lesions for Tzanck smears, viral culture, and immunofluorescent assays Serum for immunofluorescent assays, complement fixation, neutralizing antibody test, and enzyme immunoassay CMV BAL specimens for cytology, viral culture, DNA PCR Serum for DNA PCR and antigen testing Paramyxoviruses RSV Tracheal aspirate or BAL for viral culture, antigen testing by ELISA and fluorescein conjugate monoclonal or polyclonal antibody, RT- PCR Parainfluenza Nasal and bronchial secretions for viral culture and immunofluorescent assays (serotypes 1, 2, and 3), RT-PCR Serum for complement fixation and hemagglutination Measles BAL specimens for cytology Tracheal, respiratory secretions, or BAL samples for viral culture and immunofluorescent assays Influenza Respiratory secretions for viral cultures and immunofluorescent and ELISA assays, RT-PCR Adenovirus Respiratory secretions for viral culture, complement fixation, hemagglutinate inhibition, and neutralization Hantavirus Serum for hantavirus IgM antibodies or acute and convalescent IgG antibody Tissue for immunohistochemistry and RT-PCR Abbreviations: BAL, bronchoalveolar lavage; CMV, cytomegalovirus; HSV, herpes simplex virus; ELISA, enzyme-linked immunoabsorbent assay; PCR, polymerase chain reaction; RSV, respiratory syncytial virus; RT-PCR, reverse transcriptase polymerase chain reaction; VZV, varicella-zoster virus. assaying for only one virus per specimen by traditional PCR (5). An example is the Hexaplex assay (Prodesse, Inc., Milwaukee, Wis.), a multiplex RT-PCR assay for the detection of parainfluenza virus types 1, 2, and 3, respiratory syncytial virus (RSV) types A and B, and influenza virus types A and B in a single-step multiplex RT-PCR with much higher sensitivity and specificity than conventional viral culture and immunofluorescence methods (6,7). An extension of this method, real-time RT-PCR, has also been useful for detection of all four genetic lineages of human metapneumovirus (8). Test results should be interpreted with caution. Although recovery of influenza, parainfluenza, and RSV confirms the diagnosis of viral pneumonia caused by these pathogens, the significance of positive respiratory secretion and tissue cultures for herpes viruses such as CMV and HSV must be established by correlation with clinical and histologic findings. This is because herpes viruses can establish latency and are often shed intermittently in the absence of invasive disease. A positive culture of for herpes viruses alone is not diagnostic of active disease.
Influenza and Other Viral Respiratory Tract Infections 421 Cytology and Histology Respiratory secretions, BAL samples, and tissue specimens can be examined using cytologic and histologic methods (4). Although intranuclear inclusions are often seen in cells infected with DNA viruses, cytoplasmic inclusions are usually present in RNA virus infected cells. For example, CMV infection is associated with the presence of characteristic owl s eye cells, which appear as large cells with basophilic intranuclear inclusions with a surrounding clear zone. Although the presence of viral inclusions is diagnostic of a viral infection, cytologic methods have low sensitivity and the absence of inclusions does not reliably exclude infection or active disease. Treatment: General Principles A decision to empirically treat for viral pneumonias should be made only after considering common etiologies of pulmonary infection. A suggested algorithm for assessment and treatment of the immunocompetent and immunocompromised host is summarized in Figure 22-1. Empiric therapy for community-acquired pneumonia, and especially atypical pneumonia, should be instituted until their absence is confirmed. An aggressive diagnostic approach with the aid of fiberoptic bronchoscopy is useful for ruling out pyogenic as well as noninfectious etiologies of diffuse pulmonary disease. As will be discussed next, there are few options available for treatment of viral pneumonias that have proven efficacy. However, because acyclovir and ganciclovir have relatively benign side-effect profiles, these antivirals should be considered for empiric therapy whenever herpes viruses such as varicella-zoster virus (VZV), HSV, and CMV are possible culprits. If a noninfectious cause such as hypersensitivity pneumonitis is a serious consideration and corticosteroid treatment can be indicated, one should make every effort to rule out an infectious process before initiating corticosteroid therapy. Influenza Influenza viruses are enveloped, single-stranded RNA viruses of the family, Orthomyxoviridae. Influenza viruses are classified as type A, B, or C based on antigenic differences in internal matrix and nuclear proteins and subtyped based on differences in surface hemagglutinin (H) and neuraminidase (N) glycoproteins (9). Influenza A, the leading cause of influenza in adults in the United States, is responsible for up to 90% of cases of epidemic influenza. Influenza epidemics occur almost annually during the winter months and are associated with 10,000 to 40,000 excess deaths in the United States during severe outbreaks. Eighty percent of these deaths
Normal Stop Immunocompetent patient Chest radiograph Initiate medical therapy for community acquired bacterial pathogens Lobar pattern Abnormal Atypical pattern Screen for community acquired bacterial, atypical, and viral pathogens, Initiate medical treatment for bacterial and atypical pathogens Immunosuppressed patient Normal Screen for respiratory viruses, serologic studies Normal Abnormal Chest radiograph Abnormal Bronchoscopy with BAL, for bacterial, atypical, opportunistic, and viral pathogens, serologic studies Initiate empirical medical treatment for bacterial pathogens 422 Expert Guide to Infectious Diseases Symptoms resolve. Stop Symptoms persist, repeat chest radiograph, consider bronchoscopy with BAL if etiology not known Stop Initiate medical therapy Adjust medical therapy according to BAL results Figure 22-1 Algorithm for the evaluation and treatment of immunocompetent and immunocompromised patients with viral respiratory tract infections.
Influenza and Other Viral Respiratory Tract Infections 423 occur in persons older than 65 years of age. Individuals with emphysema, congestive heart failure, hemoglobinopathies, and immunosuppression are at increased risk for severe disease. Pathogenesis and Etiology Influenza is transmitted primarily by respiratory secretions from individuals actively shedding virus. It can also be transmitted by direct contact, and possibly by contact with infected surfaces or objects with self-inoculation of the nasal or oral mucosa or conjunctiva. The incubation period in humans is short and ranges from 1 to 5 days. The virus infects and kills ciliated respiratory epithelial cells causing diffuse inflammation throughout the tracheobronchial tree. Therefore, transient increases in airway reactivity are frequent and wheezing can be present. Influenza manifests as an acute febrile respiratory illness associated with cough, sore throat, headache, myalgias, and malaise. The illness is usually selflimited; major symptoms usually alleviate within 3 to 5 days. Influenza can be complicated by either direct involvement of the lung parenchyma, or more seriously, superimposed bacterial infections caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, or gram-negative pathogens. In the latter instances there is often a history of initial alleviation of influenza symptoms followed by clinical deterioration, recurrent fever, and pneumonia several days later. Patients with suspected secondary bacterial pneumonia require culture of blood and respiratory secretions and appropriate antibiotic coverage for bacterial pathogens. Diagnosis During community outbreaks of influenza in the winter months, the diagnosis can be confidently made based on typical clinical symptoms. At other times laboratory confirmation by detecting the virus or viral antigens in nasal washes, throat swab, sputum, or BAL fluid is required. Influenza virus can be isolated from respiratory secretions by tissue culture. Immunofluo-rescent and ELISA antigen detection methods for testing respiratory and nasopharyngeal secretions have a sensitivity of more than 80%. PCR-based laboratory tests are also available. Diagnostic yields are better on nasopharyngeal specimens than throat swabs. A fourfold increase in acute and convalescent serum hemagglutination inhibition, enzymatic immunoassay (EIA), complement fixation, or neutralization antibody titers, is diagnostic but requires several weeks for completion and is mainly of epidemiologic importance. Several office and point-of-care tests (Directogen Flu A, Directogen Flu A+B, Flu OIA, Flu OIA A/B, Xpect Flu A&B, Quickvue influenza A, Quickvue influenza A+B, and ZstatFlu) are now available for rapid diagnosis of influenza. These are immunoassays to detect viral nucleoproteins or enzyme assay to detect viral neuraminidase and require 10 to 20 minutes to do on
424 Expert Guide to Infectious Diseases nasal or throat swabs or aspirates or sputum. Their specificity for influenza is high (approximately 90%); however, sensitivity is intermediate (approximately 70%), and a negative rapid test does not rule out influenza (10). Treatment Based on worldwide epidemiologic surveillance data, each year s vaccine contains the three virus strains (usually two type A and one type B strains) felt most likely to be transmitted in the United States that year. Two influenza vaccines are currently available in the United States an inactivated split virus vaccine administered intramuscularly and an attenuated live virus vaccine given intranasally. The attenuated live virus vaccine is approved only for healthy individuals. Because of a small risk of transmission of the vaccine virus, health care workers and close contacts of immunosuppressed individuals should avoid contact with the immunosuppressed person for 7 days after receiving the live intranasal vaccine. The inactivated and attenuated live virus vaccines seem to have similar protective efficacy against influenza. The effectiveness of the vaccine depends on the age and general health status of the vaccinee and the antigenic similarity of the influenza strains in the vaccine to those being transmitted in the community. In years when the vaccine is well matched to circulating influenza strains, vaccine efficacy in healthy adults is in the range of 70% to 90% (11). Adults older than 65 years of age and immunocompromised individuals receive lower, but still substantial, benefit. Influenza vaccination is highly beneficial in preventing severe influenza and death in these high-risk groups. Annual influenza vaccination is recommended for all individuals 6 or more months old in highrisk groups and for healthy individuals wishing to decrease their risk for influenza. Health care workers and other staff members of chronic care facilities, and household contacts of high-risk individuals should also be vaccinated (10). The optimal time for influenza vaccination in the United States is late October through November as the influenza season usually occurs from late December through early March. Persons vaccinated after an outbreak of influenza in the community require at least 2 weeks for effective antibody titers to develop. Protective antibody levels typically last for 4 to 6 months after vaccination. Annual vaccination of persons at high risk before the influenza season each year is the most effective measure to decrease illness and death from influenza (Table 22-3). Humoral, and to a lesser degree, mucosal immunity, are required for protection against influenza. Antibodies against the hemagglutinin (H), and, to a lesser degree, the neuraminidase (N) antigens, are the major determinants of host immunity. The surface antigens of influenza A viruses, especially the hemagglutinin antigens, undergo periodic changes. Minor changes caused by point mutations are known as antigenic drift whereas major changes or antigenic shifts are caused by genetic reassortment between strains. Antigenic shifts result in the expression of new
Influenza and Other Viral Respiratory Tract Infections 425 Table 22-3 High Risk Groups for Complicated Influenza Person older than 65 years of age Nursing home residents Adults and children with chronic cardiopulmonary disease Immunocompromised adults with diabetes mellitus, renal failure, HIV infection, and other immunosuppressive diseases Patients receiving chronic corticosteroids or other immunosuppressive medications Pregnant women who will be in the second and third trimester of pregnancy during influenza season hemagglutinin and neuraminidase proteins to which most or all of the population have no resistance and thus, are associated with pandemic disease with severe illness and death. Because of the rapid loss of mucosal immunity and these antigenic drifts and shifts, annual vaccination is necessary. The treatment of uncomplicated influenza is supportive with rest, antipyretics, and analgesics. Prophylaxis with antiviral drugs can be useful for unvaccinated individuals, if an outbreak occurs during the 2-week period after vaccination required to develop protective antibodies, and or if the vaccine strains are different from those in the vaccine. Antiviral drugs also are useful in treating vaccinated and unvaccinated persons who develop influenza. Amantadine and rimantadine are oral tricyclic amines (adamantanamine) that target the influenza A M2 protein, a membrane protein essential for viral replication. These drugs prevent viral uncoating after cell entry and are highly active against influenza A. Amantadine and rimantadine are approved in the United States for the prevention and treatment of influenza A infection. Treatment with amantadine or rimantadine within 48 hours after the onset of symptoms decreases the duration of fever and symptoms by several days in adults with uncomplicated disease (11). The efficacy of these drugs in patients with influenza pneumonia or severe influenza is unknown. Amantadine and rimantadine are only active against the influenza A virus. In addition, resistance of influenza A viruses to adamantine can occur spontaneously or emerge rapidly during treatment. A single point mutation in the codons for amino acids at positions 26, 27, 30, 31, or 34 of the M2 protein can confer cross-resistance to both amantadine and rimantadine (Table 22-4). In the United States, the frequency of adamantine resistance increased from 1.9% during the 2003-2004 influenza season to 91% during the 2005-2006 season (12). Based on these data, the Centers for Disease Control recommended that neither amantadine nor rimantadine was to be used for the treatment or chemoprophylaxis of influenza A infections in the United States for the remainder of the 2006-2007 influenza season. Future use of these medications should be only considered if resistance data indicates influenza A is susceptible. The usual adult dosage for amantadine and rimantadine is 100 mg twice a day. Because amantadine and rimantadine are excreted unchanged in the
426 Expert Guide to Infectious Diseases Table 22-4 Key Elements of the Revised Centers for Disease Control Case Definition for Severe Acute Respiratory Syndrome Clinical and Epidemiologic Fever >38ºC (100.4ºF) One or more symptoms of respiratory illness (cough, shortness of breath, or radiographic findings of pneumonia or adult respiratory distress syndrome) Recent travel to an area with documented or suspected recent transmission of SARS Close contact (having care for, lived with or having had direct contact with respiratory secretions and/or body fluids) of a person suspected of having SARS and travel within 10 days of onset of symptoms to an area with documented or suspected transmission of SARS Laboratory Detection of antibody to SARS-CoV by a reliable test and laboratory Isolation of SARS-CoV in cell culture from a clinical specimen Detection of SARS-CoV RNA by RT-PCR by a reliable test and laboratory Abbreviations: RT-PCR, reverse transcription polymerase chain reaction; SARS, severe acute respiratory syndrome; SARS-CoV, SARS-associated coronavirus. urine and are approximately 75% hepatically metabolized, individuals with severe hepatic and renal dysfunction should receive no more than 100 mg daily. Amantadine and rimantadine are also teratogenic in animals and should not be used in pregnant women. Side effects of amantadine include edema, anorexia, nausea, nervousness, insomnia, and lightheadedness. Rimantadine is less likely to cause central nervous system (CNS) side effects than amantadine. Confusion, hallucinations, and seizures also have been reported and are more frequent in the elderly. Influenza virus neuraminidase, which is critical for viral attachment to surface epithelial cells, agglutination of the virus to erythrocytes, and release of mature virions, is the target for the neuraminidase inhibitors, which are active against both influenza A and B (13). Neuraminidase inhibitors block release of virions from infected cells and decrease viral spread in the respiratory tract (14). Zanamivir, the first agent of this class, is poorly bioavailable by mouth and is administered by intranasal inhalation as a dry powder. It has been shown to be effective for the prevention and early treatment of influenza infection when given at 10 mg twice daily for 5 days if started within the first 48 hours of symptoms (15,16). As of the 2005-2006 influenza season, all U.S. influenza viruses screened for antiviral resistance at the Centers for Disease Control had demonstrated susceptibility to neuraminidase inhibitors (12). Zanamivir is administered as a dry powder by inhaler and can cause bronchospasm in patients with asthma and chronic obstructive lung disease. Oseltamivir is an orally bioavailable neuraminidase inhibitor that can be used for prevention of influenza when given at a dose of 75 mg once daily for 6 weeks during periods of local disease activity and for treatment of influenza at 75 mg twice daily for 5 days if started within 36 to 48 hours of symptom onset (17-
Influenza and Other Viral Respiratory Tract Infections 427 19). Oseltamivir is mainly excreted by means of the kidney, and the dose should be decreased to 75 mg once daily for adults with a creatinine clearance of less than 30 ml/min. Early treatment with zanamivir and oseltamivir reduces the severity and duration of symptoms such as cough and fever by 1 to 2 days and decreases severe influenza-related complications. The main side effects of oseltamivir are minor self-limited nausea, vomiting, and headache during the first 1 to 2 days of administration. The drug is better tolerated when taken with food. Admin-istration of zanamivir and oseltamivir can interfere with the effectiveness of the attenuated-live virus intranasal flu vaccine. Concerns about Avian Influenza Three major influenza pandemics occurred during the past century all caused by new type A avian strains of influenza. During 2004 outbreaks of severe avian influenza occurred in eight Asian nations. These strains were responsible for severe disease in poultry and for at least 44 human cases including 32 deaths. Avian influenza strains can be transmitted from birds to human but are usually not readily transmissible from person to person. Cases in humans have been associated with heavy exposure to poultry; however, a likely case of human-to-human transmission was reported from Thailand resulting in the death of a mother who cared for her severely ill daughter (20). The potential for H5N1 and other avian influenza strains to mutate into strains that are readily transmissible from humans to humans is a major global public health concern (21). Current influenza vaccines are not protective against recently encountered avian influenza strains. If human outbreaks occur, at least several months would be required for strain-specific vaccines to be developed and made available. Isolation and quarantine may not be effective in limiting the spread of a new influenza strain, and strategies for stockpiling oseltamivir for patient treatment and prophylaxis of patient contacts and health care workers are being explored. Recent H5N1 influenza strains have been highly resistant to amantadine and rimantadine, and neuraminidase inhibitors such as oseltamivir should be used for prophylaxis and treatment if outbreaks with H5N1 strains occur. Severe Acute Respiratory Syndrome In November 2002, the first cases of a highly contagious new viral pneumonia named severe acute respiratory syndrome (SARS) were reported in southern China. SARS quickly spread to Singapore, Hong Kong, Vietnam, and Thailand. A North American outbreak occurred in Toronto, Canada. Eight laboratory-confirmed cases occurred in the United States, all in travelers from affected areas. Ultimately 8098 cases with 774 fatalities were
428 Expert Guide to Infectious Diseases reported worldwide during the 2002-2003 outbreak, which was successfully contained by international cooperation and strict application of traditional public health measures including rapid case detection, contact investigation, infection control in healthcare facilities, patient isolation, and community quarantine (22). No new cases of SARS have been reported since 2003. Pathogenesis and Etiology SARS is caused by a previously unknown coronavirus called SARS-associated coronavirus (SARS-CoV) (23). SARS-CoV is genetically distinct from all earlier known coronaviruses. Coronaviruses are a common cause of mild to moderate upper respiratory tract infections in humans. SARS-CoV is highly contagious; the major methods of transmission are direct or indirect contact of oral, nasal, or ocular mucous membranes by infectious droplets from coughing patients and by contact with respiratory secretions or environmental surfaces, aerosolization, and fomites contaminated by the virus. Transmission efficiency of the virus is greatest from severely ill patients in health care settings during the second week of the illness. Most secondary cases occur in individuals with repeated close contact with severely ill SARS patients in hospital and household settings. Aerosol-generating procedures such as endotracheal intubation, airway suctioning, and nebulized aerosol treatments are high-risk procedures for spread of the virus in health care settings. Infectious virus is also present in stool and urine. Occupational exposure during the procurement, care, and slaughter of several wild animal species in live (wet) markets was associated with SARS in patients in southern China during the epidemic. SARS-CoV like viruses have been isolated from Himalayan palm civets, Chinese ferret badgers, and raccoon dogs, and available evidence suggests that the human SARS-CoV virus originated from SARS-like viruses in animals in Southern China. Diagnosis The usual incubation period is 4 to 7 days; most secondary cases occur within 10 days of close contact with an infectious case. Most patients present with the relatively insidious onset of fever over 38ºC (100.4ºF), chills, malaise, myalgias, and headache (24). Diarrhea occurs in 10% to 20% of patients. Systemic symptoms of SARS are followed within 2 to 7 days by dry cough and dyspnea, frequently without rhinorrhea or upper respiratory tract symptoms. Ten to twenty percent of patients develop severe diffuse pneumonia and acute respiratory failure requiring mechanical ventilatory support. Physical examination of the chest reveals rales and dullness to percussion in advanced SARS. Lymphopenia, mild thrombocytopenia, and mild elevations of hepatic aminotransferases are frequent. Chest radiograph findings are variable; most have peripheral patchy infiltrates that can progress quickly. Pleural effusion and mediastinal adenopathy are unusual. Case def-
Influenza and Other Viral Respiratory Tract Infections 429 Table 22-5 Treatment of Severe Respiratory Tract Infections Virus Herpesviruses HSV VZV CMV Paramyxoviruses RSV Parainfluenza Measles Influenza Adenovirus Hantavirus Therapy Acyclovir Acyclovir Ganciclovir, foscarnet, IVIG Ribavirin*, RSVIG Supportive care, ribavirin* Supportive care, ribavirin* Amantidine, rimantidine, neuraminidase inhibitors (zanamivir, oseltamivir) Ribavirin*, cidofovir* Supportive care, ribavirin* * Presently not considered standard care or still under investigation Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; IVIG, intravenous immune globulin; RSV, respiratory syncytial virus; RSVIG, respiratory syncytial virus immune globulin; VZV, varicella-zoster virus. initions for SARS based on clinical, epidemiologic, and laboratory criteria were quickly established at the time of the 2002-2003 outbreak and revised as diagnostic laboratory tests were developed (Table 22-5). Clinicians must be alert to detect the occurrence of new cases of SARS if future outbreaks occur. SARS should be considered in patients requiring hospitalization for pneumonia or adult respiratory distress syndrome of unknown cause and who have one of the following risk factors during the 10 days before becoming ill: (a) travel to affected areas or close contact with sick persons who have recently traveled or resided in affected areas; (b) employment in an occupation associated with risk for SARS-CoV exposure (health care workers with direct patient contact, laboratory workers); or (c) being part of a cluster of cases of atypical pneumonia without an alternative diagnosis. Patients with suspected SARS should be placed on strict droplet (negative pressure rooms, N-95 personal respirator masks for health care workers) and contact isolation precautions. Available laboratory tests for SARS include antibody testing by enzyme immunoassay and RT-PCR methods on respiratory, blood, and stool specimens. Testing is available at state and national laboratories and should be done after consultation with local and regional health authorities. Treatment Treatment of SARS is supportive. Supplemental oxygen, mechanical ventilation, and hemodynamic support are required in severe cases where management is similar to patients with the adult respiratory distress syndrome. The overall case fatality rate for SARS was approximately 15%; however, death was higher in older patients, up to 50% in patients older than 60 years of age.
430 Expert Guide to Infectious Diseases Because of its nonspecific presentation, many patients with SARS were initially treated with broad-spectrum antibiotics for suspected severe bacterial pneumonia. Antibiotics can be stopped after the diagnosis is established, as there is no evidence that they are beneficial. Early anecdotal reports of benefit from treatment with ribavirin (usually in combination with other agents such as corticosteroids) have not been confirmed, and later in vitro studies have shown that ribavirin has little activity against SARS-CoV. Although widely used, there also is no clear evidence that corticosteroids are beneficial in treating patients with SARS, and acute respiratory failure and cases of secondary sepsis and fungal infections have been reported. Interferons alpha and beta and the HIV-protease inhibitors nelfinavir and lopinavir/ritonavir have activity against SARS-CoV in vitro. Reports of uncontrolled studies using treatment with interferon and corticosteroids (25) and combination therapy with ribavirin and lopinavir/ritonavir (26) have suggested some benefit from these approaches. SARS-CoV receptor binding and fusion inhibitors are also being developed. Controlled trials with these agents are needed. Strict airborne aerosol (negative pressure room isolation, use of fittested N95 personal respirator masks by health care workers) and contact (handwashing and glove, gown and goggle use) precautions must be followed to prevent secondary cases in health care settings. Updated epidemiologic and infection control guidelines for suspected cases of SARS are available at the CDC Web site (www.cdc.gov). Although no vaccine is currently available, the prospects for developing one seem to be good. SARS-CoV was fully genetically sequenced within weeks of the initial 2003 outbreak. Follow-up studies of patients with SARS- CoV infection have shown that natural infection results in a broad, longlasting neutralizing antibody response to the virus. Recent studies have shown that the virus s spike protein on its outer surface is the dominant protective antigen and that spike protein vaccines elicit neutralizing antibody responses. Additional studies with adenovirus, modified vaccinia Ankara virus, and parainfluenza virus-vectored and DNA vaccines against SARS-CoV spike proteins are being conducted and early human trials have begun (27). Paramyxoviruses The paramyxovirus family consists of enveloped, single-stranded RNA viruses that were first recognized to be causes of respiratory tract infections among children. RSV, parainfluenza virus, and measles virus cause significant respiratory tract infections in children and adults. Respiratory Syncytial Virus RSV is the most common cause of lower respiratory tract infections among infants and children. RSV is the responsible pathogen for 40% to 50% of children hospitalized with bronchiolitis and 25% of children hospitalized
Influenza and Other Viral Respiratory Tract Infections 431 with pneumonia (28). At highest risk for severe disease are premature infants and children with bronchopulmonary dysplasia, congenital heart disease, or immunodeficiency. Manifestations of RSV infection range from mild upper respiratory tract infection (URI) to bronchiolitis, pneumonia, or rarely, croup. Unfortunately, immunity is incomplete and reinfection can occur later in life presenting as mild URI or tracheobronchitis. Since 1986, RSV has been recognized as a cause of lower respiratory tract infection in the elderly and immunocompromised adults (28-30). It ranks second to influenza as a major viral pathogen in the elderly, and, in fact, can account for a significant portion of adult wintertime deaths previously attributed to influenza (31). Pathogenesis and Etiology RSV is spread by self-inoculation of the ocular, nasal, or oral mucosa after contact with infected patient secretions or fomites. RSV can survive for several hours on hands or environmental surfaces. Hand washing and contact isolation are important infection control practices to prevent transmission in health care settings. RSV infections can originate in both the community and health care facilities (32,33). Infection can present as a seasonal URI during the winter months in the United States or an outbreak in hospitals, nursing homes, and long-term care facilities. When pneumonia is present it has a death rate ranging from 11% to 78%, depending on the degree of underlying immunocompromise (33). Clinical Manifestations Unlike herpesviruses, asymptomatic RSV infections are rare, even during reinfections. In children RSV causes nasal congestion, sinusitis, otitis media, coryza, and pharyngitis. Lower respiratory tract infection can manifest as tracheobronchitis, bronchiolitis, or pneumonia. In general, RSV manifests similarly in immunocompromised and elderly patients, except that the lower respiratory tract is involved in up to 80% of cases. RSV infection typically presents with fever, nonproductive cough, anorexia, and dyspnea. On physical examination, wheezing and rales are common. Bronchial wall thickening and hyperinflation are distinctive radiographic features of lower respiratory tract RSV infection in hospitalized children (30). Among adults, chest radiographs generally demonstrate bilateral interstitial or patchy infiltrates, with lobar consolidation and pleural effusions present in 25% and 5% of cases, respectively (33), but can also have a bronchiolar reticulonodular distribution. Diagnosis The diagnosis of RSV infection can be made by examination of respiratory tract secretions. Although the nasopharynx is easily accessible for sampling, BAL is twice as sensitive but more invasive. Viral culture is the gold standard but requires several days. The more rapid and recommended test is identification of RSV antigen using a fluorescein-conjugated monoclonal or
432 Expert Guide to Infectious Diseases polyclonal antibody or ELISA, both of which have a sensitivity and specificity between 80 and 95% (28). PCR-based assays for diagnosis of RSV infection have been developed but are not yet licensed. A fourfold or greater increase in serum RSV-specific IgG is diagnostic of RSV infection (34). However, convalescent antibody titers are useful only for retrospective diagnosis and epidemiologic studies. Treatment Ribavirin, a nucleoside analog of guanosine, is the only effective antiviral currently available for the treatment of RSV pneumonia. Because of its high toxicity profile when administered intravenously, ribavirin is delivered as a small-particle aerosol. Although early pediatric investigations demonstrated positive results, several recent studies have found the contrary (35). In adult bone marrow transplant patients with adenovirus pneumonia, treatment with ribavirin was shown to decrease illness and improve survival in one study (36). Combination therapy with ribavirin and intravenous immune globulin (IVIG) increased survival in bone marrow (37) and lung transplant patients with severe RSV pneumonia and, despite data from controlled trials, is now widely used in this setting. Prevention Prophylactic use of ribavirin among high-risk patients has not been demonstrated to decrease the occurrence of severe RSV infections. Palivizumab, a humanized monoclonal antibody against the RSV F glycoprotein, is licensed for use in infants and children with prematurity, chronic lung disease, and congenital heart disease for the prevention of severe RSV disease. Vaccine development has been unsuccessful. An earlier formalininactivated vaccine was not protective and, in fact, was associated with more severe disease among vaccines. Subsequent efforts have focused on the development of live attenuated or subunit vaccines, which although capable of eliciting antibody responses, have not been shown to be protective (38). Human Metapneumovirus A new paramyxovirus causing upper and lower respiratory tract infection in humans was described by researchers from the Netherlands in 2001 (39). Human metapneumoviruses (hmpv) are found worldwide, are closely related to RSV, and cause a similar spectrum of disease. Transmission is most likely caused by close contact with infected respiratory secretions and fomites. Human metapneumoviruses cause mild, self-limited upper respiratory tract infections in children and adults; however, they also can result in bronchiolitis, asthma exacerbations, and pneumonia in older adults. Most children are infected with human metapneumovirus during infancy. Adult
Influenza and Other Viral Respiratory Tract Infections 433 disease is usually caused by re-infection, which is frequent. Among hematopoietic cell transplant and lung transplant patients, hmpv is now recognized as a potential cause for serious respiratory tract infections (40-42). The most common symptoms of hmpv infection in adults are cough, nasal congestion, rhinorrhea, dyspnea, hoarseness, and wheezing (43). Fever is infrequent. Human metapneumovirus grows poorly and slowly in tissue culture and is difficult to isolate. Reverse transcriptase PCR-based methods are the most sensitive diagnostic tests but are available only in research laboratories. Serum neutralizing antibody tests are also used in research laboratories but are not well standardized. Treatment is supportive. Ribavirin is active against hmpv in vitro. No vaccine is available. Parainfluenza Virus There are four serotypes of parainfluenza virus, all of which can produce respiratory diseases in humans. Parainfluenza virus is a common virus that infects most persons during childhood; 90% to 100% of children have antibodies to parainfluenza type 3 by the age of 5 years (33). Unfortunately, immunity is transient and reinfection manifesting as mild upper respiratory tract infections can occur in older children and adults. Depending on the serotype, infection in children can cause croup, bronchitis, pharyngitis, or pneumonia. Because previous episodes of infection result in partial immunity, upper respiratory infections in adults are usually mild, self-limited, and rarely cause pneumonia. Since 1979, parainfluenza virus has been noted to cause severe pneumonia in immunocompromised hosts during the winter months and outbreaks have been reported in extended care facilities in the United States. The viral serotypes differ in epidemic patterns. Infection with serotypes 1 and 2 typically occurs during fall and usually cause croup or laryngotracheobronchitis in late childhood. Upper respiratory tract infection is associated with serotype 4. Serotype 3 is a common cause of bronchiolitis and pneumonia in infants, and croup and tracheobronchitis in older children. It has also been associated with pneumonia in bone marrow and renal transplant patients (30). Clinical Manifestations Depending on whether infection is primary or secondary, symptoms can range from a very mild illness to life-threatening croup or bronchiolitis. Immunocompetent adults typically develop mild upper respiratory tract symptoms, however, parainfluenza virus infection can result in life-threatening pneumonia in immunosuppressed individuals. Signs and symptoms of parainfluenza pneumonia include fever, cough, coryza, dyspnea, and rales or wheezes. Radiographic findings range from normal to focal to diffuse interstitial infiltrates or diffuse alveolar-interstitial infiltrates consistent with acute lung injury.
434 Expert Guide to Infectious Diseases Diagnosis Diagnosis of parainfluenza virus infection depends on clinical characteristics and demonstration of the virus from the respiratory tract. Radiographic findings can vary and can range from a diffuse reticulonodular pattern, to alveolar consolidation, to nodular opacities. The virus can be cultured from the nasopharynx, but this requires 5 to 14 days for identification. Therefore, rapid immunofluorescent and enzyme immunoassay antigen detection tests on nasal and bronchial secretions are preferred. Neutralization, hemagglutination, and complement fixation serologic assays also are available. Highly sensitive (95% to 100%) and specific multiplex PCR assays such as the Hexaplex assay are now available for the detection of influenza A and B, parainfluenza 1 to 3 and RSV viruses in respiratory secretions (44). Interpretation of test results should be made with the realization that parainfluenza virus has a predilection for the upper respiratory tract, and a positive result can be found in the presence of minimal to no respiratory tract symptoms. Treatment Treatment is supportive. Ribavirin has been used to treat lower respiratory tract infections with some benefit in uncontrolled studies, but no effect has been demonstrated in transplant patients. There are currently no available effective vaccines. Measles Measles typically causes a febrile illness with a typical erythematous, blanching maculopapular rash in children, and mild pneumonia in healthy adults. Severe respiratory involvement is more frequent in children than adults and pneumonia is the leading cause of death caused by measles in children. Although measles is rarely a cause of severe lower respiratory tract infection in immunocompetent adults, it can result in more severe pneumonia in immunocompromised and malnourished hosts (45). Measles is highly contagious and is transmitted from person to person by aerosolized droplet nuclei from patients with cough. The peak incidence of cases in the United States is in the late winter and early spring. Clinical Manifestations The incubation period is 10 to 14 days. A 2 to 3 day prodrome with fever, cough, headache, conjunctivitis, and coryza usually precedes the onset of the rash. Respiratory complications of measles include primary viral pneumonia, secondary bacterial pneumonia, and atypical measles pneumonia. Primary measles pneumonia typically occurs in immunosuppressed adults, such as patients with hematologic malignancies, primary and secondary immunodeficiency. Primary pneumonia is characterized histologically by diffuse bronchiolar and alveolar inflammation with characteristic multinucleated giant cells containing eosinophilic nuclear and cytoplasmic inclusions. Atypical
Influenza and Other Viral Respiratory Tract Infections 435 pneumonia tends to occur in the immunocompromised host and healthy individuals that received killed measles vaccine from 1964 to 1967. In these cases, the patient does not present with classic clinical findings. For example, the rash can be atypical (beginning on the hands and feet and then spreading to the trunk) or absent. A severe and often fatal pneumonia called Hecht giant cell pneumonia is more frequent in patients with atypical measles (30). Diagnosis The diagnosis of measles pneumonia can often be made on clinical grounds in the presence of the characteristic erythematous maculopapular rash that usually begins on the face and then spreads to the trunk and finally to the extremities. Laboratory studies can be helpful if the rash is atypical or absent. The oropharynx should be inspected for the pathognomonic Koplik spots, small raised white spots most prominent on the buccal mucosa opposite the molar teeth present during the early stages of measles. In primary measles pneumonia the chest radiograph usually shows diffuse fine reticular infiltrates and alveolar infiltrates. Like varicella, the course of primary measles pneumonia parallels that of the rash. The presence of patchy alveolar infiltrates and atelectasis should suggest secondary bacterial pneumonia. The virus can be cultured from throat washings and respiratory secretions with visible cytopathic effect in culture after 6 to 10 days incubation. Newer rapid immunofluorescent assays also can be used to detect viral antigens in respiratory secretions. Treatment Treatment is primarily supportive. Post-exposure prophylaxis of immunocompromised individuals with IVIG is effective if given within 72 hours of exposure to infectious cases of measles. Vaccination of healthy susceptible persons is accomplished by a two-dose schedule. The measles vaccine is a live attenuated virus vaccine and should not be administered to pregnant women and severely immunocompromised individuals (46,47). HIVinfected children and immunosuppressed adults with measles pneumonia have been successfully treated with intravenous and aerosolized ribavirin in doses similar to those used in severe RSV infection (48). Herpesviruses The family Herpesviridae consists of large, double-stranded DNA-containing, enveloped viruses which vary widely in their ability to infect different types of cells and share the common ability to induce lifelong latent infection. These viruses rarely cause significant lower respiratory infections in immunocompetent hosts and are more likely to cause disease among immunocompromised patients such as organ and stem cell transplant recipients, and human immunodeficiency virus (HIV) infected persons. Although the use of prophylactic therapy with antiviral drugs has significantly reduced the incidence of serious