VIRAL COMMUNITY-ACQUIRED PNEUMONIA
The frequency of viruses as a cause of community-acquired pneumonia (CAP) is difﬁcult to estimate because very few patients have routine serologic testing (acute and convalescent titers), some viral pathogens do not have routinely available diagnostic tests, and viral cultures of respiratory tract secretions in the setting of pneumonia are not commonly collected or available. During the fall and early winter in North America, inﬂuenza should be considered in all patients with CAP, and it can lead to a primary viral pneumonia or to secondary bacterial pneumonia. One careful study of more than 300 non–immune-compromised CAP patients looked for viral pneumonia by paired serologies and found that 18% had a viral cause, with about half being pure viral infection and the others being mixed with bacterial pneumonia. Inﬂuenza (A more than B), parainﬂuenza, and adenovirus were the most commonly identiﬁed viral agents.
Although inﬂuenza A and B are the most common causes of viral pneumonia, they can be prevented to a large extent by vaccination. Other viruses also cause severe forms of pneumonia, as evidenced by the recent experience with severe acute respiratory syndrome (SARS), which demonstrated the potential of epidemic, person-to-person spread of a virulent respiratory viral infection. Continued concern about epidemic viral pneumonia remains with the current focus on avian inﬂuenza and bioterrorism with agents such as smallpox and Ebola.
ETIOLOGIC VIRAL PATHOGENS
This RNA virus can be of either type A, B, or C with the disease from type A being generally more severe and serving as the most important respiratory virus on a global scale with the highest overall morbidity and mortality rates (see Plates 4-73 and 4-74). Inﬂuenza B can also cause severe disease, but inﬂuenza C is a mild disease that does not have a seasonal occurrence. Inﬂuenza A has two major surface glycoprotein antigens, the hemagglutinin (H, with 15 subtypes) and neuraminidase (N, with nine subtypes), which can change yearly (antigenic drift), making previous immunity at least partially ineffective, and thus the disease appears in epidemics annually. Infrequently, major antigenic changes in inﬂuenza A occur, and this antigenic shift exposes individuals to a new virus, against which they have no immunity. This has led to worldwide pandemics, with high attack rates and high mortality. Both antigenic drift and waning immunity make this infection a particular threat to those who have underlying chronic cardiac or respiratory illnesses, elderly individuals, people with HIV infection, and pregnant women. The virus has an incubation period of 2 to 4 days and is spread via aerosol or mucosal contact with infected secretions. The yearly epidemics occur in North America in the late fall and extend into the early spring and can be caused by one of three types of inﬂuenza—inﬂuenza A/H3N2, inﬂuenza A/H1N1, and inﬂuenza B. Inﬂuenza A can coexist with other viral infections, including respiratory syncytial virus (RSV) and parainﬂuenza virus, particularly in elderly people.
This DNA virus leads to chickenpox, which is primarily a viral exanthema of children, but in adults, the virus can disseminate and lead to viral pneumonia, especially in pregnant women (see Plate 4-75). Adults with chickenpox are more prone to disseminated disease than are children. Most reports have shown that when varicella pneumonia complicates pregnancy, it is usually in the third trimester and that infection occurring at this time is more severe and complicated than if it occurs earlier. The incidence of pulmonary involvement in primary varicella infection in pregnancy ranges from 15% to 30%. When varicella occurs in pregnancy, it not only affects the mother but can also lead to a congenital varicella syndrome characterized by limb hypoplasia, skin scarring, central nervous system involvement, and other skeletal lesions. This embryopathy has been reported with infection occurring as late as 26 weeks of gestation.
By serologic data, up to 60% of adults have been infected with cytomegalovirus (CMV), but it can be a cause of pneumonia in immunosuppressed patients, particularly those with HIV infection, when it reactivates from a latent form of infection (see Plate 4-76). In those with HIV infection, retinitis is the most common form of infection, but pneumonia can also occur.
Other Viral Pathogens
SARS can be a severe type of primary viral pneumonia caused by a coronavirus that often leads to respiratory failure (see Plate 4-77). Other common, important viral pathogens include RSV (bronchiolitis, especially in children), rhinovirus, adenovirus, and parainﬂuenza viruses (common cold). Unusual causes of viral pneumonia further include Hantavirus (inhalation of rodent excreta, acute respiratory distress syndrome [ARDS], neutrophilia, thrombocytopenia, elevated hematocrit), measles, and herpes simplex (immunocompromised patients).
Viral lower respiratory infections usually involve the tracheobronchial tree or small airways, but primary pneumonia may also occur. The virus ﬁrst localizes to the respiratory epithelial cells and causes destruction of the cilia and mucosal surface. The resulting loss of mucociliary function may then predispose the patient to a secondary bacterial pneumonia. If the infection reaches the alveoli, there may be hemorrhage, edema, and hyaline membrane formation, and the physiology of ARDS may follow. For example, the main site of infection for inﬂuenza virus is the respiratory mucosa, leading to desquamation of the respiratory mucosa with cellular degeneration, edema, and airway inﬂammation with mononuclear cells. When viral lower respiratory tract involvement only involves the airway, the chest radiograph is normal, but the radiograph can be abnormal if the patient has a primary viral pneumonia, a bacterial superinfection, or a combined viral and bacterial pneumonia.
The status of a patient’s immune defenses can dictate the likely infecting viral pathogens. Immunocompromised patients with AIDS, malignancy, and major organ transplantation are often infected by CMV, varicella zoster, and herpes simplex virus. As mentioned with CMV, these patients are usually ill as a result of reactivation of latent infection that was obtained years earlier. Previously healthy adults can be infected with inﬂuenza A and B, parainﬂuenza, adenovirus, the SARS virus, and RSV. Inﬂuenza can also develop with a higher frequency and more severe consequences in debilitated and elderly adults. Immune naïve children are most affected by RSV and parainﬂuenza virus, which can cause both airway and parenchymal lung infections. Children and military recruits develop pneumonia with adenovirus and inﬂuenza.
Primary viral pneumonia caused by inﬂuenza may be a severe illness with diffuse inﬁltrates and extensive parenchymal injury along with severe hypoxemia. This pattern is often seen in those with underlying cardiopulmonary disease, immunosuppression, or pregnancy. However, many patients with primary viral pneumonia get only a mild “atypical” pneumonia with dry cough, fever, and a radiograph that is more severely affected than the patient.
Although up to half of inﬂuenza infections are sub- clinical, when the typical illness occurs, it lasts 3 days and is characterized by sudden onset of fever, chills, severe myalgia, malaise, and headache. As the major symptoms recede, respiratory symptoms dominate, with dry cough and substernal burning, which may persist for several weeks. When viral pneumonia develops, the disease follows the classic 3-day illness without a hiatus and is characterized by cough (dry or productive) and severe dyspnea. The chest radiograph reveals bilateral inﬁltrates, and mortality is high. Bacterial pneumonic superinfection follows the primary inﬂuenza illness with a hiatus of patient improvement for 3 to 4 days before the pneumonia begins. In this setting, pneumonia is usually lobar, and the most common pathogens are pneumococcus, Haemophilus inﬂuenzae, enteric gram-negative organisms, and Staphylococcus aureus. Other respiratory complications include obliterative bronchiolitis, croup, airway hyperreactivity, and exacerbation of chronic bronchitis. Nonrespiratory complications include myocarditis and pericarditis, Guillain–Barré syndrome, seizures, encephalitis, coma, transverse myelitis, toxic shock, and renal failure.
Clinically, SARS patients present after a 2- to 11-day incubation period with fever, rigors, chills, dry cough, dyspnea, malaise, headache, and frequently pneumonia and ARDS. Laboratory data show not only hypoxemia but also elevated liver function test results. During the initial epidemic, up to 20% of cases occurred in health care workers, particularly those exposed to aerosols generated by infected patients, as can occur during non- invasive ventilation and during the process of endotracheal intubation. Up to 15% to 20% of infected patients developed respiratory failure, with lung involvement typically starting on day 3 of the hospital stay, but respiratory failure often did not start until day 8. The mortality rate for intensive care unit–admitted SARS patients has been greater than 30%, and when patients died, it was generally from multiple system organ failure and sepsis. There is no speciﬁc therapy, but anecdotal reports have suggested a beneﬁt to the use of pulse doses of steroids and ribavirin.
Varicella can lead to pneumonia and has an incubation period between 14 and 18 days. Clinically, varicella pneumonia presents 2 to 5 days after the onset of fever, vesicular rash (chickenpox), and malaise and is heralded by the onset of pulmonary symptoms, including cough, dyspnea, pleuritic chest pain, and even hemoptysis. In one series, all patients with varicella pneumonia had oral mucosal ulcerations. The severity of illness may range from asymptomatic radiographic inﬁltrates to fulminant respiratory failure and acute lung injury (ALI). Typically, chest radiographs reveal interstitial, diffuse miliary or nodular inﬁltrates that resolve by 14 days unless complicated by ALI and respiratory failure. The severity of inﬁltrates has been described to peak with the height of the skin eruption. One late sequela of varicella pneumonia is diffuse pulmonary calciﬁcation.
The major clinical distinctions between the many viral agents that can cause pneumonia are in the type of host who becomes infected (discussed above) and in the type of extrapulmonary manifestations that accompany the pneumonia. Extrapulmonary signs may suggest a speciﬁc viral agent. Rash may be seen with varicella zoster, CMV, measles, and enterovirus infections. Pharyngitis may accompany infection by adenovirus, inﬂuenza, and enterovirus. Hepatitis may be seen with CMV and infectious mononucleosis (Epstein-Barr virus). Retinitis is common with CMV, but the pneumonia is not distinctive, with patients having dyspnea, dry cough, and diffuse bilateral lung inﬁltrates with hypoxemia.
The diagnosis of viral illness can be clinical or can be conﬁrmed by speciﬁc laboratory methods. Viruses can be isolated with special culture techniques if specimens are properly collected and prepared. Upper airway swabs, sputum, bronchial washes, rectal swabs, and tissue samples should be placed in viral transport media as early in the patient’s illness as possible while viral shedding is still prominent. Bronchoscopy serves as the most important method to obtain respiratory tract samples from immune-compromised patients. These respiratory samples can be cultured on certain laboratory cell lines, and viral growth may be detected in 5 to 7 days. More recently, the shell vial culture method has allowed for identiﬁcation of viruses within 1 to 2 days. In this method, a clinical specimen is centrifuged onto a tissue culture monolayer and then stained with virus-speciﬁc antibodies. Viral illness can also be rapidly diagnosed by using immunoﬂuorescence or enzyme-linked immunosorbent assay (ELISA) to test patient samples for viral antigens. Immunoﬂuorescent tests are available for inﬂuenza, parainﬂuenza, RSV, adenovirus, measles, rubella, coronavirus, and herpesvirus. ELISA assays are also available for most of these agents. Serology can be used retrospectively to diagnose a suspected viral infection, but this technique may be difﬁcult if speciﬁc viruses are not suspected and sought directly. A new technique that may be valuable is the use of genetic probes to detect speciﬁc viral DNA or RNA. Such methodology is now available for CMV, varicella zoster virus, herpes simplex, and adenovirus.
With the current interest and understanding of viral infections, some speciﬁc therapy with antiviral agents has become available. Patients with pneumonia from herpes simplex and varicella zoster viruses can be treated with acyclovir. Inﬂuenza A can be treated or prevented by the use of amantadine 200 mg/d orally or rimantadine, which acts against the M2 protein of inﬂuenza A, or the newer neuraminidase inhibitors oseltamivir and zanamivir (which are also active against inﬂuenza B). Amantadine dosing must be reduced with renal insufﬁciency, and confusion may occur in 3% to 7% of treated individuals. Rimantadine, a derivative of amantadine, is also effective for the therapy of patients with inﬂuenza A infection; it can be given once daily because of its long half-life, and it has fewer central nervous system and other side effects than amantadine. The neuraminidase inhibitors can be used during acute infection and reduce the duration of symptoms if given within 36 to 48 hours. Ribavirin aerosol has been used to treat patients with RSV, SARS, and inﬂuenza B. Patients with CMV infection have been successfully treated by the acyclovir analog DHPG (ganciclovir), valganciclovir, or foscarnet.
All patients with varicella pneumonia require aggressive therapy with antiviral agents (acyclovir), and multiple investigators have used acyclovir, a DNA polymerase inhibitor, even in pregnant patients, demonstrating its safety in pregnancy and its lack of teratogenicity. Treatment is recommended for 7 days. Some small series have suggested a beneﬁt from adjunctive corticosteroid therapy at modest doses. During pregnancy, women who are exposed to varicella can receive prophylactic varicella immune globulin, which may attenuate the fetal embryopathy if administered within 96 hours of exposure.
A vaccine is available for inﬂuenza, and immunization should be given to all high-risk patients yearly, with a vaccine prepared against the strains that are anticipated most likely to be epidemic. The vaccine that is generally used is a chemically inactivated vaccine, originally grown on embryonated chicken eggs (and thus cannot be used in egg-allergic patients), and the yearly vaccine is trivalent, with two strains of inﬂuenza A (one an H3N2 and the other an H1N1) and one inﬂuenza B strain. A live-attenuated vaccine is also available for individuals ages 5 to 49 years. The vaccine includes antigens from inﬂuenza A and B, and it has generally been effective, but there is concern for using it in patients with HIV or severe immune suppression because of the live nature of the vaccine.
Parenteral inﬂuenza vaccination should be given yearly in the late fall and early winter to high-risk individuals. These include individuals at high risk for complications (people who are older than age 65 years; residents of nursing homes or chronic care facilities; people with chronic heart or lung disease; those with diabetes, renal failure, or immune suppression; women who will be in the second or third trimester during inﬂuenza season; and children 6 to 23 months of age) and those who can transmit inﬂuenza to high-risk individuals (health care workers, those who work in nursing homes and contact residents, those who give home health care to patients at high risk, and household contacts of high-risk individuals).
If an epidemic of inﬂuenza develops in a closed environment (e.g., a nursing home) among nonimmunized patients, antiviral therapy should be given along with vaccination, and antiviral therapy should be continued for 2 weeks until the vaccine takes effect. Either amantadine or the neuraminidase inhibitors can be used in this setting, remembering that amantadine is active only against inﬂuenza A but the neuraminidase inhibitors act against both inﬂuenza A and B.