Normal Host

The relative importance of the different viruses as causes of pneumonia depends on the season and the age distribution of the population under study. During outbreaks, influenza virus accounts for more than 50% of viral pneumonia in adults. In addition, RSV, adenovirus, parainfluenza virus, and varicella virus cause pneumonia in normal adults. Unusual viruses continue to emerge in epidemics of severe acute pneumonitis, including hantavirus, coronavirus (SARS), and avian influenza A viruses.

In children, RSV, parainfluenza virus, and adenovirus, in addition to influenza viruses, are the most important causes of pneumonia. Measles virus pneumonia affects children and adults during epidemics in susceptible populations. There are reports of cases of pneumonia in adults and children attributable to rhinovirus, but the evidence that these viruses are definite causes of pneumonia is circumstantial.

The clinical and radiographic features of sporadic cases of viral pneumonia are usually not sufficiently characteristic to permit specific viral diagnosis or differentiation from bacterial pneumonias on clinical grounds alone. Exceptions include measles ( eFig. 32-4 ) and varicella pneumonia, in which the associated rash establishes the diagnosis. Therefore, attention is first directed at excluding primary or secondary bacterial pneumonia. Tests to detect viral antigens or nucleic acid are increasingly available and are rapidly being adopted as the preferred approaches for establishing the etiologic diagnosis (see Chapter 17 ).

Treatment of viral pneumonia in the normal host is supportive in nature and directed at early antimicrobial therapy of secondary bacterial infections, if present. Specific antiviral therapy may be beneficial and is discussed with the individual pathogens. Viral pneumonias with extensive involvement of lung tissue may require prolonged ventilatory assistance and pulmonary rehabilitation. Some cases of viral pneumonia have a rapid and relentless fatal course, with generalized alveolar and interstitial opacities, development of the adult respiratory distress syndrome (ARDS), and progressive respiratory failure.

Immunocompromised Host

Viral pneumonia can be an important problem for the increasing number of persons in the population who have deficiencies in immunity as the result of cytotoxic chemotherapy, organ transplantation, and the acquired immunodeficiency syndrome (AIDS). The major respiratory viruses that affect normal persons may also cause pneumonia in impaired hosts; severe and prolonged pneumonias due to adenovirus, respiratory syncytial, influenza, measles, or parainfluenza virus can develop in such patients. Immunocompromised patients can also shed respiratory viruses for prolonged periods and thus be responsible for extensive transmission of infection to others. In addition, these individuals may develop pneumonia due to viruses, such as cytomegalovirus, that rarely cause lower respiratory tract disease in normal hosts. Cytomegalovirus causes severe primary viral pneumonia (see eFig. 91-3 , eFig. 91-4 , eFig. 91-5 ), as well as predisposing patients to bacterial and fungal superinfections because of its immunosuppressive effects. Varicella-zoster and herpes simplex virus pneumonias are relatively uncommon but serious infections in immunosuppressed patients.

Epidemiology and Transmission

The adenoviruses that cause human disease do not have nonhuman reservoirs, although nonhuman adenoviruses are found in other species. Some serotypes, especially types 1 and 2, routinely infect infants and young children, who then have prolonged asymptomatic viral shedding from the respiratory and gastrointestinal (GI) tracts. Other types, including those that have been most often implicated in respiratory disease (e.g., types 3, 4, and 7), are acquired later in life, characteristically in epidemic settings. In most instances, viral transmission probably takes place by direct contact with infectious secretions. However, the explosive nature of adenoviral acute respiratory disease in military recruits probably reflects airborne spread.

Most community adenovirus respiratory disease has been recognized in the summer months in association with outbreaks or sporadic cases of febrile pharyngitis or bronchitis. Nosocomial outbreaks of adenovirus infection have arisen in hospital wards, special care units, and psychiatric facilities. New variants of adenovirus have occasionally emerged and have been associated with outbreaks worldwide. Since 1996, a specific variant of adenovirus type 7 (Ad7d2) has been responsible for several civilian outbreaks and a large military outbreak. More recently, adenovirus type 14 (Ad14), a previously rare serotype, has been responsible for outbreaks of disease both in the military and in civilian populations. Most cases have been relatively mild febrile respiratory illnesses, but some cases have been seen with severe pneumonia requiring hospitalization. Infection with adenovirus type 36 is associated with weight gain in mice, and serologic positivity for this serotype appears to be more common in adults and children with obesity.

Pathogenesis

Adenoviruses have been isolated from the upper airway, eye, urine, stool, and rarely, blood. The incubation period for naturally acquired adenovirus disease of the respiratory tract is usually 4 to 7 days but may be up to 2 weeks.

Cytopathologic changes have also been observed in bronchial epithelial cells, and crystalline arrays of virus particles have been found in alveolar lining cells of infected persons with severe illness. The extent of damage to the respiratory tract in nonfatal adenovirus respiratory disease is not well defined but may result from a combination of direct viral mechanisms and host-related inflammatory responses to infection. In cases of fatal adenovirus pneumonia, bronchial epithelial necrosis, bronchial obstruction, and interstitial pneumonia have been seen. Cells containing large basophilic, intranuclear inclusions, so-called “smudge cells,” appear to be characteristic ( Fig. 32-5 ). In lung transplant recipients, necrotizing bronchocentric pneumonia with diffuse alveolar damage has been reported.

Adenovirus causing necrotizing pneumonia.

Focal necrosis is apparent; the prominent cell in the center of the field is an adenovirus-infected “smudge cell,” with an enlarged nucleus with basophilic inclusions surrounded by a thin rim of cytoplasm (H&E, ×80 original magnification).

(Courtesy William D. Travis, MD, Memorial Sloan Kettering Cancer Center, New York, NY.)

Clinical Illness

Adenovirus Respiratory Disease.

The nonpneumonic respiratory syndromes associated with adenovirus infection include acute respiratory disease of military recruits and pharyngoconjunctival fever of civilians, which have similar characteristics ( Fig. 32-6 ). Adenovirus respiratory disease typically involves the pharynx as a moderate to severe, sometimes purulent, pharyngitis. Also characteristic of this disease is marked tracheitis, bronchitis, or tracheobronchitis, as well as rhinitis and conjunctivitis. Conjunctivitis is not a feature of infection with the other major respiratory viruses and therefore, when present, is a useful diagnostic finding in adenovirus respiratory disease. With adenovirus respiratory disease, the conjunctivitis is typically mild and follicular, although some adenovirus types also cause the more severe condition, epidemic keratoconjunctivitis. Fever, chills, myalgia, and prostration are prominent features of adenovirus infection, so it is often perceived by the patient as a “flulike” illness or an unusually severe cold.

Graph showing comparison of the clinical characteristics of acute respiratory disease (ARD) of military recruits and pharyngoconjunctival fever of civilians.

(Adapted from Dascomb HE, Hilleman MR: Clinical and laboratory studies in patients with respiratory disease caused by adenoviruses. Am J Med 21:161–174, 1956, and Martone WJ, Hierholzer JC, Keenlyside RA, et al: An outbreak of adenovirus type 3 disease at a private recreation center swimming pool. Am J Epidemiol 111:229–237, 1980.)

Cases of acute respiratory disease tend to have more tracheobronchitis, perhaps reflecting acquisition of infection by the airborne route. Conversely, in pharyngoconjunctival fever, the infrequency of cough and other tracheobronchial complaints in some outbreaks may reflect infection contracted by pharyngeal and/or conjunctival inoculation with virus from contaminated water. The two syndromes are associated with the same viral serotypes and, in civilian populations, both can be seen as sporadic cases. In young children, adenovirus infection has been associated with both mild and febrile respiratory illness, with an associated otitis media in approximately 40% of these cases.

Diagnosis

Although diagnosis was traditionally achieved by virus culture, viral antigens or nucleic acid can be detected directly from appropriate specimens of respiratory secretions, conjunctival swabs, stool, or urine, depending on the clinical syndrome. Rapid detection of viral antigens in clinical specimens by ELISA or immunofluorescence and of viral DNA by nucleic acid amplification techniques is increasingly used instead of viral culture because of the fastidiousness of some serotypes and slow rate of isolation (see Chapter 17 ). Quantitative measurement of adenovirus DNA levels in plasma may be useful for diagnosis and response to therapy.

Frozen specimens (−70° C) are satisfactory for testing because of the relative stability of adenoviruses. In cell culture, cytopathic effect usually appears in 3 to 7 days but may take several weeks, thus limiting the utility of viral culture in guiding clinical management. The time required to detect virus in cell culture can be shortened to as little as 2 days by employing centrifugation culture systems. Serodiagnosis has relied primarily on testing for a group-specific complement-fixation antibody response, using acute and convalescent serum specimens; however, infection with some adenovirus types is not detected by the complement-fixation test. In biopsy specimens, the appearance of characteristic intranuclear basophilic inclusion bodies seen by light microscopy or of crystalline arrays of virus seen by electron microscopy is useful in histopathologic diagnosis.

Treatment and Prevention

Antiviral treatment of adenovirus infection does not have proven value. Ganciclovir and cidofovir are active in vitro, and an increasing number of reports indicate that intravenous ganciclovir may be useful in seriously ill patients, although at the expense of significant renal toxicity. Cidofovir has also been used for treatment and for presumptive therapy of adenovirus infection in high-risk immunocompromised patients. Although intravenous ribavirin (which is active for group C adenoviruses in vitro) or ribavirin combined with immunoglobulin has been used in individual patients, failures are common.

Because of the prominent fever and systemic complaints associated with adenovirus respiratory disease, analgesics, such as aspirin and acetaminophen, are needed more often than with a milder coryzal illness such as a rhinovirus cold. Warm saline gargles are helpful for relieving throat pain, which does not usually require narcotics. The presence of pharyngeal exudate may sometimes lead to an incorrect diagnosis of streptococcal pharyngitis, resulting in the initiation of antimicrobial therapy.

Effective and safe live oral vaccines for adenovirus types 4 and 7 were developed for military use and, when delivered in enteric-coated capsules, have controlled acute respiratory disease in recruit populations. Use of these vaccines was not associated with replacement by nonvaccine serotypes. When manufacturing of these vaccines was discontinued, adenoviruses reemerged as important causes of acute respiratory disease in this population. A new vaccine for Ad4 and Ad7 has subsequently been introduced.

Epidemiology and Transmission

Human coronaviruses OC43 and 229E have been recognized as causes of the common cold for many years and cause frequent reinfections throughout life. In adults, these viruses account for 4% to 15% of acute respiratory disease annually and up to 35% during peak periods. Annual illness rates in children reach 8%, with peak rates up to 20%. When polymerase chain reaction (PCR) techniques were applied to samples collected over 20 years from children younger than 5, coronaviruses were associated with 11.4 lower respiratory tract episodes and 67.3 upper respiratory tract illnesses per 1000 person-years. The reported frequency of infection in adults for 229E and OC43 viruses has ranged from 15 to 25 per 100 persons per year, with up to 80% of infections seen in persons with prior antibody to the infecting virus. Coronaviruses usually circulate during winter and early spring but can be detected year-round.

Novel coronaviruses have recently been associated with severe respiratory disease in outbreaks around the world. SARS emerged in southern China in 2003 and quickly spread globally. The causative virus was subsequently named SARS-CoV. Ultimately, at least 8098 probable cases of severe respiratory disease and 774 deaths in all ages were attributable to SARS worldwide before the outbreak terminated in 2004. The source of this outbreak is believed to have been from an animal reservoir, the civet cat. More recently, a second outbreak of coronavirus severe respiratory illness has been recognized, with cases primarily found in Middle Eastern countries. In May 2014, the first case of MERS was confirmed in a traveler from Saudi Arabia to the United States. A second case was identified in a traveler from Saudi Arabia to Florida. The two cases were not linked. The virus responsible for MERS has been named MERS-CoV. It is genetically closely related to coronaviruses found in bats, and evidence indicates that MERS-CoV also infects camels, but the role of each of these in transmission to humans remains to be defined. Information on MERS-CoV is actively evolving; current information can be found at http://www.cdc.gov/coronavirus/mers/ .

For all coronaviruses, transmission likely involves close contact and inoculation of the respiratory tract with infectious secretions via large droplets as demonstrated in human challenge experiments for OC43 and animal studies for SARS-CoV. For SARS-CoV, virus shedding peaked at day 10 of symptom onset, which was at the height of disease severity. This phenomenon accounted for the preponderance of transmission in hospitals, a feature that allowed the outbreak to be controlled with infection control procedures. The incubation period for SARS is estimated from 2 to 10 days, and for conventional human coronaviruses 3 to 4 days.

Pathogenesis

Conventional coronavirus antigen has been detected in epithelial cells shed from the nasopharynx of infected volunteers and, during experimental infection, nasal airway resistance, mucosal temperature, and the albumin content of nasal secretions increase. However, relatively little is known about the pathogenesis of the common cold induced by conventional human coronaviruses.

The hallmark of pulmonary pathology in fatal cases of SARS was diffuse alveolar damage, type II pneumocyte hyperplasia, squamous metaplasia, and multinucleated giant cells. Hemophagocytosis, or the phagocytosis of erythrocytes, leukocytes, and platelets by histiocytes, was reported, potentially as a consequence of cytokine dysregulation. Furthermore, virus was detected within pulmonary epithelial cells. From these findings, it is postulated that disease pathogenesis involves both direct damage to pulmonary epithelia by the virus in combination with an excessive or dysregulated host immune response.

Clinical Illness

Conventional human coronaviruses produce a typical coryzal illness that is indistinguishable from colds due to other viruses. Coronaviruses have also been linked with acute otitis media, exacerbations of asthma in children, and with exacerbations of chronic bronchitis and pneumonia in adults.

In contrast, SARS has a nonspecific presentation that is difficult to distinguish from other viral acute respiratory illnesses, particularly influenza. Common symptoms on presentation are fever, chills and/or rigors, myalgias, and occasionally diarrhea. Cough and dyspnea are the predominant respiratory symptoms but may not be present initially. Respiratory disease becomes more severe over 4 to 7 days, and about 20% of patients require respiratory support. MERS has had a similar presentation, although GI symptoms may be more prominent. SARS fatality rates were 9.6% for all ages but higher in older adults, and children had milder disease. Similarly, the majority of recognized cases of MERS to date have been in individuals with comorbidities. SARS laboratory abnormalities include elevations in lactate dehydrogenase, transaminases, and creatine kinase, as well as hematologic abnormalities, particularly lymphopenia (depletion of CD4 and CD8 T cells) and thrombocytopenia.

Diagnosis

Common findings on chest CT include unilateral or bilateral areas of ground-glass opacifications and interlobular septal and intralobular interstitial thickening. In most patients, peripheral involvement in the lower lung zones has been observed. In some cases, after recovery from acute illness, pulmonary fibrosis has developed. Clinical features predictive of poor outcomes included the presence of bilateral disease at presentation, markedly elevated lactate dehydrogenase, older age, and other comorbid conditions.

The main site of viral replication of SARS-CoV appears to be the lower respiratory tract. PCR detection is most reliable in the sputum, but viral RNA can also be detected in the blood and stool. Serum antibodies rise within 2 to 3 weeks of illness, although measurements at 4 weeks have become the standard to exclude SARS.

Treatment and Prevention

Immunity against coronaviruses appears to be short-lived. Epidemiologic studies of coronavirus infection have demonstrated high reinfection rates. In human volunteer experiments, infection with a 229E-like coronavirus only induced effective immunity short-term because rechallenge with homotypic virus, the 229E serotype, resulted in infection and illness. In addition, under certain circumstances, vaccines against animal coronaviruses have led to enhanced disease. This is being taken into consideration but is not deterring efforts to develop an efficacious SARS-CoV vaccine.

There are no currently available antiviral agents with demonstrated clinical activity against coronaviruses in humans. Agents with potential activity against SARS-CoV include chloroquine, protease inhibitors, ribavirin, type I interferons, niclosamide, and anti-inflammatory agents such as indomethacin. Ribavirin in combination with lopinavir/ritonavir (protease inhibitors used in HIV disease) was associated with a lower incidence of adverse outcomes compared with historical controls of ribavirin alone in one study. Nelfinavir, another protease inhibitor, has also demonstrated in vitro antiviral activity. Other targets for controlling SARS viral replication have included interferons. Although the mechanisms are unknown, chloroquine, niclosamide, and indomethacin all inhibit SARS-CoV in vitro.

Epidemiology and Transmission

Infection with CMV, whether symptomatic or not, is followed by prolonged excretion of virus in urine, saliva, stool, tears, breast milk, vaginal secretions, and semen. Thus, the major reservoir for CMV is asymptomatic infected persons. Virus shedding persists for years in children with congenital and perinatal CMV infections. The virus is believed to be transmitted by direct contact, especially under conditions of intimacy such as found in child care centers and the family setting. Thus, the rate of acquisition of infection is greater in populations with high density, leading to infection at an early age. In addition to transmission by sexual intercourse, passage through a contaminated birth canal, and ingestion of breast milk, CMV infection can be acquired from transfused blood products and from transplanted organs. No seasonal patterns of CMV infection have been observed.

Pathogenesis

In human fibroblast cell cultures, CMV produces a slowly progressive lytic infection. Infected cells contain large irregular basophilic intranuclear inclusions and also eosinophilic inclusions in paranuclear areas. The intranuclear inclusions are a hallmark of CMV infection and have been found in cells of a number of organs, including kidney, liver, and the GI tract, as well as the lung ( Fig. 32-7 ). In the lung, fibroblasts, epithelial cells, endothelial cells, and smooth muscle cells are all targets for CMV infection.

Cytomegalovirus infection.

A, CMV pneumonitis with mild alveolar wall thickening and hyperplastic type II pneumocytes, some of which are infected, showing cytomegaly, nucleomegaly, thickened basophilic nuclear membranes and nuclear inclusion and small basophilic cytoplasmic inclusions (hematoxylin and eosin x80 original magnification).

B, CMV pneumonitis with infected cells highlighted by immunohistochemistry with a brown color (CMV immunohistochemistry, ×40 original magnification).

(Images courtesy William D. Travis, MD, Memorial Sloan Kettering Cancer Center, New York, NY.)

In immunocompetent persons, most infections are subclinical. If symptoms arise, the most typical manifestation is that of acute pharyngitis with features similar to mononucleosis. In immunocompromised hosts, there may be a variety of clinical syndromes, the severity of which is impacted by whether infection is acquired de novo or represents reactivation of endogenous virus. The risk of severe disease is particularly high in transplant patients when a CMV-seronegative recipient receives an organ from a seropositive donor.

The pathogenesis of CMV pneumonia is partly related to viral replication but also thought to have an immunopathologic basis. The development of CMV pneumonitis reflects a complex interaction between viral infection and graft-versus-host disease, particularly in marrow transplant recipients (see Chapter 91 ). Two patterns of histopathology have been described in the lung tissue of bone marrow transplant patients with serious pneumonia. One is a miliary pattern, with multiple focal lesions showing extensive cytomegaly with localized necrosis, alveolar hemorrhage, fibrin deposition, and neutrophilic response (see Fig. 32-7 ). The other is an interstitial pattern, with alveolar cell hyperplasia, interstitial edema, lymphoid infiltration, and diffusely distributed cytomegalic cells.

Clinical Illness

Cytomegalovirus causes a variety of human diseases, including congenital and perinatal infections, infectious mononucleosis, hepatitis, posttransfusion infection, and invasive infection in patients with impaired immunity. In transplant populations, CMV infection often involves multiple organ systems in conjunction with other opportunistic infectious agents.

Because the virus rarely causes pneumonia in healthy hosts, the main impact of CMV as a respiratory pathogen is in immunocompromised patients. In recipients of allogeneic bone marrow transplants, CMV is the most common infectious cause of interstitial pneumonia and, if untreated, is responsible for the highest fatality rate. The risk of CMV pneumonia is greatest between 30 and 90 days after bone marrow transplant. However, late-onset CMV syndromes, at more than 180 days posttransplantation, have been increasingly recognized with effective control of earlier-onset disease.

Risk factors for the disease include advanced age, the presence of acute graft-versus-host disease, intensive conditioning regimens, and allografts. CMV infection and pneumonitis also develop in the majority of lung transplant recipients who are seronegative and, if infection develops in a single-lung recipient, disease is especially marked in the transplanted lung. In these patients, CMV pneumonitis may be a factor in the development of bronchiolitis obliterans. CMV can also be a primary pathogen in persons with AIDS, although it is more often encountered in conjunction with other pulmonary pathogens (see Chapter 90 ). Characteristically, patients with CMV pneumonia have sustained fever, nonproductive cough, and dyspnea. Rales and tachypnea are often present, and marked hypoxemia is an indicator of life-threatening infection. Pneumonitis may be accompanied by mild neutropenia, thrombocytopenia, and elevated liver enzymes, which may be helpful in differential diagnosis.

Recently, CMV reactivation has been demonstrated to play a role in critically ill, previously immunocompetent patients. During the critical illness, some evidence suggests a transient and vulnerable period of “immunoparalysis,” making reactivation and not exogenous infection of CMV more likely. In these patients, CMV viremia was found in 33% and was associated with prolonged hospitalization and death. It is currently unclear whether CMV prophylaxis would be beneficial in this setting.

Diagnosis

Cytomegalovirus pneumonia should be in the differential diagnosis for any immunosuppressed patient with unexplained lower respiratory complaints or pulmonary opacities. However, the clinical assessment of patients with suspected CMV pneumonia is complicated because there are often simultaneous pulmonary infections with other microbes and because the clinical features and radiographic appearance of CMV pneumonia are not sufficiently characteristic to permit an accurate etiologic diagnosis. In addition, noninfectious pulmonary conditions are also common in the population at risk for CMV pneumonitis, including pulmonary malignancy or hemorrhage and post-transplant lymphoproliferative disorder (see eFigs. 91-16 and 91-17 ).

Chest radiographic changes (see eFig. 91-5A ) are usually bilateral, with diffuse or focal haziness involving the mid and lower lung fields. Both miliary and interstitial radiographic patterns have been described. Patients with a miliary pattern may have a sudden onset of tachypnea, severe respiratory distress, and hypoxemia resulting in a rapidly fatal course, whereas patients with an interstitial pattern of disease often have an insidious onset of pneumonia with slowly progressive hypoxemia. In these patients, pulmonary opacities may be initially localized, with bilateral spread over days or weeks. Often the perihilar distribution of the opacity is suggestive of pulmonary edema. Common chest CT scan findings include small nodules (see eFig. 91-3B , eFig. 91-4 , eFig. 91-5 ), consolidation (see eFig. 91-2 ), and ground-glass attenuation (see eFigs. 91-3 and 91-5 ).

In patients with possible CMV pneumonia, the preferred approach to diagnosis is quantitative PCR in serum or bronchoalveolar lavage (BAL) fluid. Culture and pathologic examination of specimens obtained by BAL and transbronchial biopsy may also be diagnostic, although these specimens are less suitable for making management decisions in acutely ill patients. The detection of virus in respiratory secretions, urine, or blood does not establish with certainty that CMV is responsible for a particular clinical syndrome. This is particularly true in patients with AIDS, in whom detection of CMV in BAL is often not associated with pulmonary pathology. However, in transplant recipients, the presence of CMV in blood does increase the risk of subsequent development of CMV pneumonia and is used in guiding preemptive therapy. Serologic testing has no role in diagnosis of acute infection and is used only to determine the serologic status of donors and recipients before transplantation.

Treatment and Prevention

Once CMV pneumonitis is established, particularly in allogeneic bone marrow transplant patients, poor outcomes are common. Ganciclovir is highly active against CMV in vitro, but monotherapy is not effective in pneumonitis in bone marrow/stem cell transplant recipients. The combination of ganciclovir therapy and intravenous CMV immune globulin can reduce mortality from approximately 90% to 50% or lower in these patients. The effect of the immune globulin in this situation may mostly be to ameliorate graft-versus-host disease. Whether combination therapy is required in solid organ transplant recipients with CMV pneumonia is uncertain. Cidofovir and foscarnet are other antiviral drugs with activity against CMV. Both have been used successfully to treat CMV retinitis, but their effectiveness for treating CMV pneumonia has not been established. All of the available CMV antivirals have the potential for serious side effects that require close monitoring.

Guidelines for reducing the risk of CMV disease in stem cell transplant recipients have been published. Transplant candidates should be screened for evidence of CMV immunity, and CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors should receive only leukocyte-reduced or CMV-seronegative RBCs and/or leukocyte-reduced platelets. In mismatched solid organ transplant recipients (seronegative recipient/ seropositive donor), posttransplant prophylaxis with oral ganciclovir or its prodrug valganciclovir significantly reduces the risk of CMV disease, although late-onset disease still happens. Another strategy is preemptive therapy with ganciclovir or another anti-CMV agent when screening detects infection, but before clinically detectable disease develops. This strategy requires the use of rapid, sensitive, and specific laboratory tests for diagnosis.

No vaccines are available for the prevention of CMV infection or disease, although several strategies are being actively pursued, including live attenuated and inactivated subunit vaccines.

Epidemiology and Transmission

The hantavirus pulmonary syndrome (HPS) is a zoonosis in which humans experience severe, often fatal disease. Each of the individual hantavirus strains appears to be associated with a specific rodent host (e.g., Sin Nombre virus with the deer mouse, Bayou virus with the rice rat, Black Creek Canal virus (BCCV) with the cotton rat, and New York virus with the white-footed mouse). The rodent hosts experience prolonged asymptomatic infection, but the features that are associated with maintenance of these viruses in rodent populations and with rodent-to-rodent transmission are unclear. Serologic studies suggest that hantaviral infection of feral rodents is widespread throughout North America.

Transmission to humans is presumed to result from contact with infected rodent excreta. Hantaviruses are stable and can persist in the environment for 10 to 15 days without loss of viability. Risk factors for acquisition of HPS include high densities of rodents in the household, cleaning of contaminated environments, agricultural activities, and other forms of occupational exposure to rodent droppings. In the Four Corners region of the southwestern United States, El Niño–southern oscillation events have been linked to increased rainfall, high rodent population densities, and increased numbers of cases of HPS.

Person-to-person transmission was not seen in the North American outbreaks. In contrast, a recent outbreak of HPS in South America has suggested that, under certain circumstances, person-to-person transmission can take place. This feature appears to be unique to the particular hantavirus implicated in that outbreak (Andes virus) and has not been a major component of other outbreaks. Currently, approximately 11 to 48 cases of HPS per year are reported in the United States, with a case fatality rate of 35%.

Pathogenesis

Infection with Sin Nombre virus or other agents of HPS have relatively long incubation periods (median 14 to 17 days; range 1 to 51 days), and antibody and cellular responses in humans are usually detectable at the time of presentation. Neutralizing antibody is directed against the surface glycoproteins G1 and G2, and lower titers on presentation correlate with greater disease severity. Viremia is detectable at presentation and declines promptly after resolution of fever.

Pathologic findings in fatal cases include pleural effusions, alveolar edema and fibrin, and interstitial mononuclear cell infiltrate with little necrosis or neutrophil infiltration. These findings are felt to be most consistent with a capillary leak syndrome with subsequent noncardiogenic pulmonary edema. Immunopathologic responses play a major role in HPS. Infection of humans with Sin Nombre virus and other hantaviruses results in widespread expression of viral antigens in endothelial cells of pulmonary and cardiac tissues, and CD8 T cell responses peak at the time of maximal clinical symptoms, implicating these responses in the pathogenesis of disease. Myocardial depression has also been ascribed to induction of nitric oxide and locally secreted cytokines in response to infection. Another pathogenic mechanism may be antagonism of the host innate immune response by the hantavirus G1 tail.

Clinical Features

Presentation of HPS begins with a prodrome of fever, chills, and myalgias, occasionally accompanied by abdominal discomfort and GI symptoms, and generalized malaise. Upper respiratory symptoms are usually absent. After a variable period of several days, the patient presents with a mild, nonproductive cough and progressive dyspnea resulting from leakage of high-protein edema fluid into the alveoli. On physical examination patients are febrile, with tachypnea and tachycardia with mild hypotension. Examination of the chest may reveal fine crackles but is otherwise unremarkable.

Laboratory studies generally reveal hemoconcentration, mild thrombocytopenia, and mildly elevated liver function tests. The triad of thrombocytopenia, left shift with circulating myeloblasts, and circulating immunoblasts is highly suggestive of HPS. Multivariate analysis has identified dizziness, nausea, and the absence of cough as clinical symptoms predictive of HPS, as well as thrombocytopenia, elevated hematocrit, and decreased serum bicarbonate as features that help distinguish HPS from other causes of acute respiratory distress such as pneumococcal pneumonia and influenza. Mild renal abnormalities may be detected but, unlike the situation with another hantaviral illness, hemorrhagic fever with renal syndrome, do not progress to renal failure. Renal dysfunction may be more common in HPS associated with the Bayou hantavirus.

Pleural effusions are present in most cases. Early in the course of HPS, these effusions are transudative, while later they develop higher fluid protein content and in severe cases have the protein characteristics of plasma. Cardiopulmonary manifestations in severe cases include a shock state with low cardiac index, low stroke volume index, and high systemic vascular resistance. Progression is associated with worsening cardiac dysfunction and development of lactic acidosis. In those patients who survive, exertional dyspnea and reduced expiratory flow are common in early convalescence and resolve in most patients. However, some patients have manifested long-term pulmonary and cognitive dysfunction.

Diagnosis

Chest radiographs are typical of pulmonary edema, without consolidation. In the absence of immunodeficiency, patients universally have detectable serum immunoglobulin M (IgM) and IgG antibody at the time of admission, and serologic techniques are the mainstay of diagnosis. In low-prevalence areas, a positive IgM is diagnostic. Virus can also be detected in blood by reverse transcriptase polymerase chain reaction (RT-PCR) during the first 10 days of illness. In contrast, hantaviruses are difficult to isolate from clinical material in cell culture and grow slowly. Isolation of virus from tissue is laborious and time consuming and must be undertaken in suitable containment facilities, so it is not useful for diagnosis.

Treatment and Prevention

Treatment is supportive and requires careful management of fluid status to maintain perfusion without exacerbating pulmonary edema. It has been suggested that high-dose steroid therapy may be useful because of the pathogenesis of the disease and potential utility of steroids in systemic capillary leak syndrome. In severe cases, extracorporeal membrane oxygenation may be beneficial. The broad-spectrum antiviral agent ribavirin is active against hantavirus in vitro and was demonstrated to be effective against hantavirus-induced hemorrhagic fever with renal syndrome in Korea. However, trials of ribavirin in HPS have not shown efficacy.

Epidemiology and Transmission

Humans are the reservoir for HSV-1 and HSV-2 viruses. With primary infection, infectious virus is produced in the skin and mucous membranes, being present in vesicle fluid and cellular debris from herpetic ulcers. After establishment of latency in nerve ganglia, virus is intermittently shed in respiratory, vaginal, and urethral secretions in the absence of clinical disease. Asymptomatic respiratory tract shedding can be detected in about 1% to 2% of seropositive children and adults.

HSV-1 spreads by means of transfer of virus-containing respiratory secretions, vesicle fluid, and cell debris under conditions of close personal contact. The portals of entry for primary infection are the mucous membranes of the oropharynx and possibly the eye. Virus deposited onto areas of burned or abraded skin, and exogenous inoculation or autoinoculation of virus, also lead to clinical lesions. Cases of HSV-1 arise sporadically throughout the year, occasionally in small clusters. HSV-1 infection is usually acquired in childhood or adolescence, with epidemiologic surveys showing a prevalence of antibody to HSV-1 in 30% to 100% in adults.

Pathogenesis

Primary HSV infection has a mean incubation period of approximately 1 week. Primary infection begins at a local site, with viral replication in parabasal and intermediate epithelial cells and resultant cell destruction and initiation of host inflammatory responses. Cells containing characteristic nuclear inclusions and sometimes multinucleation may be observed in lesions. In immunocompetent individuals, regional lymph nodes may be involved during primary infection, but the disease is usually contained at the primary site by innate antiviral responses. In neonates and others with deficient or impaired immune systems, local infection may be followed by viremic spread to multiple organs, including skin, liver, brain, adrenals, and lungs. Disease may also disseminate in such individuals following reactivation of latent infection. Visceral infection is characterized by a highly destructive coagulation necrosis of involved sites. In a series of fatal cases of HSV pneumonia, inflammatory infiltrates, parenchymal necrosis, and hemorrhage were found at autopsy. Patients with associated herpetic laryngotracheitis have necrotizing lesions in these areas.

Latent infection is established in sensory nerve ganglia and is followed by life-long recurrences of virus shedding and often lesions on skin and mucous membranes of the involved dermatomes. Cellular immunity is of primary importance in controlling HSV infection; studies in patients with AIDS and severe mucocutaneous HSV indicate that both CD4 and CD8 T cells contribute to control of viral replication and spread.

Clinical Illness

Diagnosis

The clinical features of herpetic gingivostomatitis are sufficiently characteristic to permit accurate diagnosis in most cases. Other conditions with similar oral lesions are limited and include herpangina, aphthous stomatitis, Steven-Johnson syndrome, and other enanthems resulting from infection and drug sensitivities. In herpangina, the lesions are smaller (1 to 3 mm), more often vesicular, and usually localized to the soft palate. The ulcers in aphthous stomatitis are few, relatively deep, and circumscribed. Aphthosis is characterized by periodic recurrence, whereas acute herpetic gingivostomatitis and pharyngitis are limited to a single occurrence. Herpetic pharyngitis, when exudative, must be distinguished from pharyngitis due to Streptococcus pyogenes, adenovirus, Epstein-Barr virus, and diphtheria. The diagnosis of acute herpetic disease of the oropharynx can be confirmed by examination of Giemsa- or Wright-stained smears of scrapings from the base of a fresh lesion (Tzanck test) and by culture of scrapings or swab specimens. Techniques for the rapid detection of viral antigens or DNA are widely available.

Chronic ulcerative pharyngitis due to HSV has a characteristic clinical appearance that is highly suggestive of the diagnosis. The white color of the lesions may lead to confusion with candidiasis, but the lesion of thrush is an easily removable plaque, not an ulcer. Thrush and chronic herpetic pharyngitis may coexist in the same patient. The lesions of aphthous stomatitis are not characteristically found in the back of the oropharynx and are relatively small (2 to 5 mm) with a fixed diameter.

The diagnosis of herpetic laryngotracheitis may be difficult because of the inaccessibility of the lesions. The disease should be suspected in any immunocompromised patient with herpetic lesions of the mouth, upper airway, or skin of the face, especially if endotracheal intubation has been performed. In such patients, bronchoscopic examination is indicated for sampling of suspected areas for cytology and viral culture.

The diagnosis of HSV pneumonia should be suspected in any immunocompromised patient with unexplained pulmonary opacities, especially in the presence of herpetic laryngotracheitis or herpetic lesions of other mucocutaneous sites, including the genital area. Definitive diagnosis of HSV pneumonia depends on obtaining a sample of involved lung for viral culture and testing for HSV antigen or nucleic acid. Limited experience with lung biopsy in patients with HSV pneumonia suggests that obtaining adequate samples for culture and histologic examination may be a problem and that, when possible, generous biopsy specimens should be obtained.

Treatment and Prevention

No vaccines of proven value are currently available. Primary HSV gingivostomatitis in immunocompetent persons responds to oral acyclovir treatment. Specific therapy of herpes simplex pneumonia has not been evaluated in controlled trials, but most clinicians would use intravenous acyclovir. In immunosuppressed patients with chronic mucocutaneous HSV infection, including pharyngitis and laryngotracheitis, prompt treatment with acyclovir is recommended to control the local infection and prevent possible dissemination to the lung. Valacyclovir, the valine ester prodrug of acyclovir, and famciclovir, the prodrug of penciclovir, are orally administered drugs that are also effective for mucocutaneous HSV.

Antiviral susceptibility testing should be considered in patients with serious HSV infection who do not respond to initial treatment with oral valacyclovir or intravenous acyclovir. Foscarnet is probably the best available alternative therapy. Prophylactic intravenous and oral acyclovir regimens have been shown to be effective in preventing recurrences of mucocutaneous HSV infection in seropositive patients undergoing intense periods of immunosuppression, such as bone marrow transplant recipients or patients receiving combination chemotherapy for leukemia.

Epidemiology and Transmission

Influenza virus infection is acquired by transfer of virus-containing respiratory secretions. Both small particle aerosols and droplets probably play a role in this transmission, but for infection control purposes influenza is generally considered to be transmitted by droplets. In temperate climates in either hemisphere, epidemics are seen almost exclusively in the winter months (generally October to April in the Northern hemisphere and May to September in the Southern hemisphere), whereas in the tropics, influenza may be seen throughout the year.

Influenza epidemics are regularly associated with morbidity and mortality, usually expressed in the form of excess rates of pneumonia and influenza-associated hospitalizations and deaths, with as many as 51,000 deaths annually in the United States. Attack rates are generally highest in the young, whereas mortality is generally highest in the elderly. Excess morbidity and mortality are particularly high in those with medical conditions including pulmonary conditions such as asthma or COPD. Rates of influenza-related hospitalizations are particularly high in healthy children younger than 2, where rates approach those of older children with high-risk conditions.

A high frequency of antigenic variation is a unique feature of influenza virus that helps explain why this virus continues to cause epidemic disease. Antigenic variation principally involves the two external glycoproteins of the virus, the HA and NA, and is referred to as antigenic drift or antigenic shift, depending on whether the variation is small or great. Antigenic drift refers to relatively minor antigenic changes that result from amino acid changes in one or more of the five identified major antigenic sites on the HA molecule. Antigenic shift refers to the complete replacement of the HA or NA with a novel HA or NA. These viruses are “new” viruses to which the population has no specific immunity. When such a new virus is introduced into a population, a severe, worldwide epidemic, or pandemic, of influenza can result. Influenza pandemics in the 20th century include the H1N1 pandemic of 1918, the H2N2 pandemic of 1957, and the H3N2 pandemic of 1968. Extensive surveillance and sequence information suggests that these new HA and NA genes are introduced into viruses circulating in humans from resident populations of influenza A viruses in birds.

Since 1997, sporadic outbreaks of influenza in humans caused by direct transmission of avian viruses from bird to human have been reported. Although sustained human-to-human transmission has not been seen, avian subtypes such as H5N1 and H7N9 continue to pose a potential pandemic threat. In the spring of 2009, a novel H1N1 virus containing genes from viruses of swine, avian, and human origin emerged. Importantly, the HA gene of this virus was derived from swine influenza virus. Although still an H1N1 virus, the novel, or pandemic H1N1 (pH1N1) was antigenically distinct from the human H1N1 viruses in circulation since 1977. Instead, the HA was closely related to human H1 viruses from the early 20th century that had been introduced into pigs in approximately 1918 and had not undergone significant antigenic evolution in these animals since that time. Perhaps for this reason, older adults were relatively spared, and the pandemic disease affected mainly children, adolescents, and adults younger than 50.

Although the circulation of multiple antigenic subtypes is confined to influenza A viruses, influenza B viruses undergo significant antigenic variation as well. Currently, two antigenically distinct lineages of influenza B have co-circulated, designated the “Yamagata” and the “Victoria” lineages. Because antibodies to viruses in one lineage do not provide substantial protection against the other, recent influenza vaccines have included examples of both (see later).

Pathogenesis

Infection with influenza virus in humans is generally limited to the respiratory tract. After inoculation, the incubation period is thought to be from 18 to 72 hours depending in part on the inoculum dose. Virus shedding is maximal at the onset of illness and may continue for 5 to 7 days or longer in children. In immunocompromised patients, especially recipients of solid organ or hematopoietic stem cell transplants, viral shedding can be prolonged for weeks to months.

Bronchoscopy of individuals with influenza typically reveals diffuse inflammation of the larynx, trachea, and bronchi, as well as a range of histologic findings, from vacuolization of columnar cells with cell loss, to extensive desquamation of the ciliated columnar epithelium down to the basal layer of cells. Generally, the tissue response becomes more prominent as one moves distally in the airway. Recovery is associated with rapid regeneration of the epithelial cell layer and pseudometaplasia. Fatal influenza pneumonia exhibits diffuse alveolar damage with hyaline membranes lining the alveoli, and the alveolar air spaces contain edema fluid, strands of fibrin, desquamated epithelial cells, and inflammatory cells ( Fig. 32-8A-D ).

Pulmonary involvement in 2009 H1N1 influenza A.

A, Acute necrotizing tracheitis and inflammation of the submucosal tracheal mucous glands (H&E, ×400 original magnification). Inset: Immunohistochemical stain for influenza. Viral antigen is stained red-brown on a hematoxylin-stained background, with prominent staining of the respiratory epithelium and underlying mucous glands. B, Postmortem lung section showing diffuse alveolar damage with hyaline membranes ( arrow ) lining an alveolar duct and adjacent alveoli. The alveolar air spaces contain edema fluid, strands of fibrin, desquamated epithelial cells, and inflammatory cells (H&E, ×100 original magnification). C, Massive infiltration of neutrophils in the airspaces of alveoli associated with secondary bacterial bronchopneumonia (H&E, ×100 original magnification). Inset: Brown and Hopps modified tissue Gram stain showing chains of bacteria morphologically compatible with streptococci or pneumococci ( arrow ) (×1000 original magnification). D1, Immunohistochemical staining for influenza in bronchus. Viral antigen is stained red-brown on a hematoxylin and eosin–stained background. Arrow shows influenza antigen–positive cells in the bronchial epithelium. D2, The section shows an acute necrotizing bronchitis with transmural infiltration of inflammatory cells (×100 original magnification). D3 and 4, Immunohistochemical staining for influenza in a bronchiole. Influenza antigen–positive cells are seen in the bronchiolar epithelium, including ciliated cells, and in the nuclei of some basilar cells (×400 original magnification). Immunohistochemical staining for influenza in alveolar cells, both type I ( D3 ) and type II ( D4 ) (×1000 original magnification).

(Adapted from Gill JR, Sheng ZM, Ely SF, et al: Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Arch Pathol Lab Med 134(2):235–243, 2010. Fig 1).

Abnormalities of pulmonary function are frequently demonstrated in otherwise healthy, nonasthmatic young adults with uncomplicated (non-pneumonic) acute influenza. Demonstrated defects include diminished forced expiratory flow rates, increased total pulmonary resistance, and decreased density-dependent forced expiratory flow rates consistent with generalized increased resistance in airways less than 2 mm in diameter, as well as increased responses to bronchoprovocation. In addition, abnormalities have been seen in the carbon monoxide diffusing capacity and the alveolar-arterial oxygen difference. Pulmonary function defects can persist for weeks after clinical recovery. Influenza in asthmatics or patients with chronic obstructive disease with influenza may result in acute declines in forced vital capacity or FEV ₁ . Individuals with acute influenza may be more susceptible to bronchoconstriction from air pollutants such as nitrates.

Clinical Illness

Typical uncomplicated influenza often begins with an abrupt onset of symptoms after an incubation period of 1 to 2 days. Systemic symptoms include feverishness, chilliness, or frank shaking chills, headaches, myalgia, malaise, and anorexia. Typical respiratory symptoms include dry cough, severe pharyngeal pain, and nasal obstruction and discharge. Elderly individuals may simply present with fever, lassitude, and confusion without any of the characteristic respiratory complaints. There may be a wide range of symptoms, but the presence of fever plus either sore throat or cough is predictive of positive culture results for influenza in adults.

The syndrome of primary influenza viral pneumonia was first well documented in the 1957-1958 outbreak. The illness begins with a typical onset of influenza, followed by a rapid progression of fever, cough, dyspnea, and cyanosis. Physical examination and thoracic imaging studies reveal bilateral abnormalities ( Fig. 32-9 , eFigs. 32-6 and 32-7 ), sometimes suggestive of an acute lung injury pattern or ARDS ( eFig. 32-8 ). H1N1 (“swine-origin”) influenza infection has a relatively nonspecific appearance, ranging from normal or nearly normal chest radiography at presentation to multifocal bilateral opacities resembling multifocal pneumonia ( eFig. 32-9 ) or a noninfectious acute lung injury pattern. Chest CT often shows multifocal areas of ground-glass opacity and consolidation, which may show a peripheral distribution, resembling organizing pneumonia ( eFig. 32-9B-E ), although other patterns, including small nodules ( eFigs. 32-10A and B ), ground-glass opacity associated with linear and reticular abnormalities without a clear zonal distribution ( eFig. 32-10C ), and lobar consolidation ( eFig. 32-10D ), may be observed. Gram stain of the sputum fails to reveal significant bacteria, and bacterial culture yields sparse growth of normal flora, whereas viral cultures yield high titers of influenza A virus. Such patients do not respond to antibacterial drugs and the mortality is high.

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