Appendix E1. Epidemiology

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1 Appendix E1 Epidemiology Viruses are the most frequent cause of human infectious diseases and are responsible for a spectrum of illnesses ranging from trivial colds to fatal immunoimpairment caused by human immunodeficiency virus destruction of CD4+ T lymphocytes (2,92,93,180,181). Some of the viruses discussed in this review are shown in Table 2 in the article. Despite the fact that many respiratory viral infections begin in the upper respiratory tract, only a few pathogenic viruses have the potential for invasion of the lower respiratory tract (78,95,132,182). Immunocompromised patients may develop viral pneumonia with the same viruses that afflict the healthy host. In the past several decades, the AIDS epidemic, advances in the treatment of cancer, immunosuppressive therapy, and hematopoietic stem cell (HSC) transplantation and solid organ transplantation have resulted in large numbers of persons who are severely immunocompromised ( ). As a result, the incidence of opportunistic infections of the lungs has risen substantially and the range and diversity of viruses that cause respiratory diseases have broadened (189). This is important because, despite marked advances in antiviral therapy, respiratory viral infections (rare and emerging) continue to be associated with high morbidity, high mortality, and poor patient outcomes (189). In 2004, pneumonia, along with influenza, was the eighth leading cause of death in the United States, the sixth leading cause of death in those older than 65 years, and the number one cause of death from infectious diseases (190). Despite its frequency and mortality, specific etiologic diagnosis remains a major clinical challenge (4,191). A clear understanding of likely pathogens is essential for treating patients with respiratory tract infection (192,193). Many common viruses exhibit seasonal variations. Influenza, RSV, and parainfluenza virus 1 and 2 circulate every winter. Adenovirus, parainfluenza virus 3, CMV, and herpes simplex infections occur year-round. Enterovirus disease clusters in late summer and early autumn (21,66,67,191,194,195). RSV, influenza A and B viruses, parainfluenza viruses, and adenoviruses are common causes of community-acquired pneumonia in children. RSV is estimated to be responsible for hospital admissions per year in the United States, and approximately 1% of infants with lower respiratory tract infections require hospitalization (196). Eighty percent of these hospitalizations occur in infants younger than 1 year, with peak incidence at 2-8 months of age. In adults, viral causes of community-acquired pneumonia are less well characterized, and specific recommendations about the assessment and management of viral community-acquired pneumonia are sparse (192,193). Respiratory viruses are thought to contribute to a substantial number of lower respiratory tract infections, especially when such viruses are circulating in the community (3,192,197,198). In one investigation of 340 patients with community-acquired pneumonia, 112 had nasopharyngeal swabs processed for study of respiratory viruses through antigen detection by indirect immunofluorescence assay, isolation of viruses in cell culture, and detection of nucleic acids by means of two independent multiplex reverse transcriptase PCR Page 1 of 6

2 assays; a viral cause was found in 48 patients (influenza virus A, adenovirus, and RSV were the most commonly identified viral pathogens) (197). Important new viral pathogens have also been recognized in the past 2 decades. These include Hantaviruses, HMPV, the H5N1 strain of the influenza virus (avian influenza A viruses), SARS-associated coronavirus, and the recently described human bocavirus and swine-origin influenza A virus (H1N1 strain of influenza virus) (3,105, ). The diagnosis of viral pneumonia is often one of exclusion. Pulmonary involvement may be widespread or focal and segmental and is accompanied by signs including rales, rhonchi, and decreased breath sounds. Clinical symptoms are nonspecific and based on an absence of sputum production, a failure to culture pathogenic bacteria, and a white blood cell count that is normal or only slightly elevated. The imaging findings are also variable and overlapping. Molecular diagnostic techniques are useful for detecting and identifying pathogens for which culture and serologic tests are difficult, slow, or not available (27). Pathogenesis Although the most common mechanism of transmission in humans is the inhalation of contaminated aerosols, the routes by which the various respiratory viruses spread from person to person are still not clearly defined. Direct hand contact with contaminated skin and environmental surfaces and posterior self-inoculation of the virus onto the nasal mucosa and conjunctiva is characteristic of rhinovirus and RSV (194). Other viruses may spread in small-particle aerosols (eg, influenza, measles, and varicella-zoster virus) or by direct contact with infectious secretions (eg, RSV, rhinoviruses, and coronaviruses) (12,68). The initial sites of infection differ for the various virus groups. The pathogenesis of respiratory virus infection is related to both virus-induced damage to the respiratory tract and damage to the host responses to infection. The respiratory tract is capable of a limited number of pathophysiologic responses to respiratory viral infections (12,69,70). Although upper respiratory tract involvement is a characteristic feature of rhinoviruses, extensive damage to the lower respiratory epithelium and sometimes to the pulmonary parenchyma is a characteristic feature of influenza virus infection. Although the clinical diagnosis is predictive under certain circumstances (eg, epidemics of influenza or outbreaks of bronchiolitis due to RSV), there is a poor correlation between agent and clinical syndrome; a particular syndrome can result from infection with different viruses. In addition, severe pulmonary disease due to new viral respiratory pathogens, including Hantaviruses and HMPV, has been reported (102,103,123,206). Influenza virus type A can infect swine, horses, birds, and marine mammals; an important animal reservoir for generating diverse influenza viruses is the pig. The close contact between humans and pigs in Asia and, specifically, southern China is believed to potentiate transfer of new genetically re-assorted influenza virus into the human population. Recently, the reemergence of H5N1 strains of avian influenza and the emergence of SARS both in Asia in 2003 has also been reported (73,75,79,82). Actually, world attention is focused on H1N1 swine flu, a pulmonary disease caused by a new subtype of influenza A (H1N1) not previously detected in pigs or humans (84,85, ). Page 2 of 6

3 Patients at Risk for Viral Pneumonia Although viruses are commonly identified causes of pneumonia in infants and young children, it is clear that in adults the involvement of viruses as causative agents of pneumonia has been underestimated (3,197, ). About one-third of adults hospitalized with pneumonia (at least half of those with an identifiable pathogen) have evidence of infection with one or more respiratory viruses (189,213). Whereas RSV and parainfluenza viruses are the most frequent viral pathogens in infants and children, influenza virus types A and B account for more than half of viral pneumonias in adults (4, ). In elderly patients with viral pneumonia, influenza virus A and RSV are the most commonly identified viral pathogens (180). Viruses contribute to 5% of identified pathogens in pneumonia during pregnancy, with varicella and influenza the most common viral pathogens (217). Transplant recipients living in the community are exposed to seasonal outbreaks of respiratory viruses (153, ). During the past decade, epidemiologic studies have showed that respiratory viruses are commonly associated with acute exacerbations in adults with pre-existing chronic lung disease such as asthma and chronic obstructive pulmonary disease (214, ). Virus-induced chronic obstructive pulmonary disease exacerbations. Bacteria, viruses, and environmental agents account for the vast majority of episodes of exacerbation (224). Approximately 50% of exacerbations are associated with community respiratory viruses including rhinovirus, influenza virus, parainfluenza virus, RSV, and influenza and coronavirus ( ). Twenty-five percent of patients admitted to hospital with an exacerbation of chronic obstructive pulmonary disease had co-infection with bacteria and viruses (222). The problem in defining the microbial origin of a chronic obstructive pulmonary disease exacerbation is that a great proportion of these patients have bacteria colonizing their lower airways in the stable phase of the disease (227). Viral infection of epithelial cells leads to the release of proinflammatory cytokines and chemokines. Chemokines attract inflammatory cells that release toxic products, stimulating mucus production and leading to tissue damage with possible long-term loss of lung function. Some mediators (eg, endothelin-1) have a direct effect in causing bronchoconstriction and vasoconstriction, resulting in airflow obstruction and impaired gas exchange (228). Virus-induced asthma exacerbations. Asthma, a chronic inflammatory disease of the airways, is characterized by bronchial constriction together with symptoms of cough, wheezing, and difficulty breathing. Its cause is complex, involving interactions between genetic susceptibility, exposure to allergens and external aggravating factors (eg, smoking, air pollution), and respiratory tract infections. Viruses have been detected in 80% 85% of asthma exacerbations in children and 75% 80% of asthma exacerbations in adults (214, ). Their role may have been underestimated in early epidemiologic studies because of difficulties in isolation and identification (231). Respiratory viral infections may facilitate secondary bacterial infections and increase host immunopathology through the overproduction of inflammatory cytokines (232). Both inflammatory mediators and impairment of the host defense mechanisms are involved in Page 3 of 6

4 exacerbations. The interaction of respiratory virus infection and chronic asthmatic airway inflammation results in respiratory symptoms that are more severe than those suffered by nonasthmatic individuals (233). In normal airway epithelial cells, viral infection induces the production of interferon-β, which in turn induces apoptosis in virus-infected cells and limits virus replication. This is followed by an adaptive immune response characterized by Th1 cells that produce interferon-γ and interleukin-12, leading to a strong antiviral response, rapid clearance of the virus, and minimal inflammation (231,233). In asthmatic patients, both innate and adaptive antiviral immunity may be impaired, resulting in cell necrosis and the release of inflammatory mediators and virus. The increased viral load and levels of inflammatory mediators released from necrotic cells result in uncontrolled airway inflammation and exacerbation (221,229). Transplantation Community respiratory viruses are responsible for a substantial number of respiratory infections in transplant recipients (234). The frequency of lung involvement by viruses is highly dependent on allograft type. Solid organ transplantation. Solid organ transplantation has become the treatment of choice for patients with end-stage diseases of the kidney, liver, heart, and lung. Patients undergoing solid organ transplantation have increased susceptibility to infection, which varies according to the time since transplantation (32,72,184,187,219, ). The period of highest risk for viral infections is generally within the 1st year after transplantation. Intensification of immunosuppressive therapy to treat allograft rejection increases the risk of opportunistic infections. Suppression of the immune system is more severe during the 1-4-month period after organ transplantation (32). In the immediate postoperative period, opportunistic infections are usually not encountered because there is a delay between the onset of the immunosuppressive therapy and the development of immune system dysfunction. Because solid organ transplantation involves a surgical procedure, the immediate period after transplantation is associated with a risk of fungal and bacterial infections in those transplants involving organs in the abdominal cavity, especially the liver, pancreas, and intestine (32,169,240). Lung transplantation is an established treatment for end-stage pulmonary disease. Complications of lung transplantation include airway stenosis and dehiscence, reimplantation response, acute rejection, infection, posttransplantation lymphoproliferative disorder, and bronchiolitis obliterans syndrome (241,242). Host factors, including the underlying lung disease and the type of lung transplantation (single vs bilateral), appear to influence the risk and type of complication. Infection is currently the most common cause of mortality during the first 6 months after lung transplantation (243). Patients have increased susceptibility to infection because of immunosuppression, lung denervation and loss of the cough reflex, impaired mucociliary function, and lymphatic drainage (241). Pulmonary infection occurs in up to 50% of cases and is several-fold higher than that in recipients of other solid organs (244). Page 4 of 6

5 Gram-negative bacterial pneumonia, which occurs in up to 50% of cases, is the most common infectious complication during the 1st month after heart and heart-lung transplantation (245,246). Herpesviruses account for a high proportion of complications after lung transplantation (247). CMV, the most common viral pathogen, typically emerges within the first 3 months after transplantation. Primary infection is the most serious and occurs in 50%-100% of seronegative recipients who receive a graft from a seropositive donor (248,249). Lung injury may occur either by causing disease directly or by indirect involvement in rejection processes, finally leading to the development of bronchiolitis obliterans syndrome (247). The other human herpesviruses may also be involved in some cases. Bacterial pneumonias are not as often lethal as are viral and fungal infections. Gramnegative bacteria (Enterobacter and Pseudomonas species) and Staphylococcus species are also a common cause of infection in kidney and liver transplants (169,240,250,251). HSC transplantation. HSC transplantation is currently the treatment of choice for many hematologic malignancies and severe congenital or acquired disorders of the hematopoietic or immune systems. An estimated allogeneic and autologous stem cell transplantations are performed worldwide annually (32). A substantial number of studies have highlighted the increasing recognition of community respiratory viruses, particularly RSV, influenza, parainfluenza, adenovirus, and HMPV, as serious pathogens in HSC transplant recipients (103,105,189,194,252). Viral pneumonia varies according to the type of transplant (autologous or allogeneic), HLA matching (matched or mismatched), relatedness of the donor (related or unrelated), and source of stem cells (bone marrow, peripheral blood, or cord blood). Allogeneic (HSC) transplant recipients have a higher risk of viral infections than do autologous HSC transplant recipients because of the greater intensity of immunosuppression. The spectrum of pathogens to which allogeneic HSC transplant recipients are most susceptible follows a timeline corresponding to the predominant immune defects at different periods. The prevalence of viral pneumonia among HSC transplant recipients varies considerably among different studies (238,253). In a prospective study conducted by the European Group for Blood and Marrow Transplantation, 40 respiratory virus infections (2%) were diagnosed in 1863 patients (236,238,253). Whimbey and Ghosh (252) evaluated the role of respiratory viral infections in HSC transplant recipients and found an incidence of RSV pneumonia of 9.2%. The importance of viruses in the cause of respiratory infections in adult patients has varied from study to study, depending mostly on the number of tests performed. Franquet et al (40) found a high prevalence of respiratory viral infections (20%) among 130 HSC transplant recipients. Respiratory viruses were diagnosed by systematically using antigen detection with direct fluorescent antibody tests, viral cultures, and/or sensitive reverse transcriptase PCR assays on appropriate samples such as bronchoalveolar lavage specimens (40,254,255). Rapid detection methods are essential when HSC transplant recipients have fever along with signs, symptoms, or radiographic indications of pulmonary infection. Page 5 of 6

6 Although many pulmonary complications after HSC transplantation have nonspecific radiologic findings, respiratory viruses can be responsible for a large number of pneumonias previously classified as idiopathic (189). Page 6 of 6