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.
INFLUENZA VIRUS AND ITS EPIDEMIOLOGY
ETIOLOGIC VIRAL PATHOGENS
Influenza
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.
Varicella Zoster
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.
Cytomegalovirus
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.
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| INFLUENZA PNEUMONIA |
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).
Pathogenesis
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.
VARICELLA PNEUMONIA
CLINICAL MANIFESTATIONS
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.
SARS
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
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.
Other
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.
CYTOMEGALOVIRUS PNEUMONIA
DIAGNOSIS
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.
THERAPY
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.
SEVERE ACUTE RESPIRATORY SYNDROME (SARS)
PREVENTION
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.
