AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Viral respiratory tract infections are the most common cause of symptomatic human disease among children and adults. They account for more time lost from school and work than any other infection. Approximately 1-3 respiratory tract illnesses occur in adults, compared to 2-7 respiratory tract illnesses in children, each year. These infections may cause a wide variety of diseases, from the common cold to severe pneumonia, and may result in significant morbidity and mortality.

The incidence of viral pneumonia has increased during the past decade. The increase primarily is because of improved diagnostic techniques and the growing population of patients who are immunocompromised.

In the past, the diagnosis of viral pneumonia was made essentially on clinical grounds. Over the past 10 years, new biotechnology has greatly facilitated the diagnosis of viral pneumonias. Clinicians are able to obtain a virologic diagnosis with a high degree of sensitivity and specificity, often within a few hours of the diagnostic procedure. Furthermore, improved approaches to prevention and treatment of viral pneumonias have also become available.

Although widely recognized that viruses are the most frequent cause of pneumonia in children, most clinicians do not appreciate that viral pneumonia in adults also is not uncommon. The 3 most frequent etiologies of viral pneumonia in adults are influenza virus, respiratory syncytial virus (RSV), and parainfluenza virus (PIV). Influenza virus types A and B are responsible for more than one half of community-acquired viral pneumonias, particularly during influenza outbreaks. RSV and PIV rank second among the common causes of viral pneumonia in adults.

Pathophysiology

A brief description of the viruses known to cause pneumonia in adult humans is provided below.

Influenza virus

The influenza viruses are enveloped single-stranded RNA viruses of the family Orthomyxoviridae. They are classified as types A, B, and C and are distinguished by the antigenic differences in the internal proteins. The influenza A virus can be subtyped further based on the antigenic qualities of surface glycoproteins, hemagglutinin or neuraminidase. Influenza virus is capable of undergoing minor or major changes in antigenicity, which allows the virus to evade the preexisting immunity in the population.

Influenza epidemics occur during the winter months and are associated with significant morbidity and mortality. Patients with chronic obstructive pulmonary disease (COPD), congestive heart failure, hemoglobinopathies, and immunosuppression are at increased risk for severe disease leading to death. Influenza virus is transmitted from person to person primarily by airborne exposure to respiratory secretions contaminated with the virus. The incubation period generally is from 1-5 days after exposure.

Respiratory syncytial virus

Structurally, RSV has 10 unique viral polypeptides, 4 of which are associated with virus envelope, 2 of these (F and G) are important in infectivity and pathogenicity. RSV is highly contagious and spreads via aerosolized respiratory secretions. RSV is a well-established cause of lower respiratory infection in the elderly population and in adults who are immunocompromised. Infection may occur as a seasonal occurrence during the winter months or as outbreaks in hospitals and nursing homes.

RSV is the most frequent cause of lower respiratory tract infection among infants and children. It is a medium-sized virus of the Paramyxoviridae family but consists of only 1 serotype. Most children are infected before age 5 years, but the immunity is incomplete and reinfection may occur later in life. RSV pneumonia is rare in adults who are immunocompetent.

Parainfluenza virus

PIVs are characterized by nucleocapsids, which develop in the cytoplasm of infected cells with hemagglutinin present in the virion envelope. These can be separated into 4 subtypes based on antigenic characteristics. Parainfluenza is a common virus that infects most persons during childhood. Immunity is short term, and recurrent upper or lower respiratory tract infections may occur. The infections vary from a mild illness to life-threatening croup or bronchiolitis. Infection in hosts who are immunocompromised can result in life-threatening pneumonia with lung injury and respiratory failure.

Herpes simplex virus

Herpes simplex virus (HSV) is a rare cause of lower respiratory tract infections. Immunocompromised patients are at particular risk for HSV pneumonia. These include patients receiving cancer chemotherapy, patients who are neutropenic, patients infected with HIV, burn victims, and patients with congenital immunodeficiency or malnutrition. HSV pneumonia develops either secondary to upper airway infection because of direct extension of viral infection from the upper to the lower respiratory tract or following viremia secondary to dissemination of HSV from genital or oral lesions.

Varicella-zoster virus

Varicella-zoster virus (VZV) infection is a highly contagious herpes infection. Primary infection manifests as varicella (chickenpox); the reactivation results in zoster (shingles). Pneumonia is a common complication in adults and can result in significant morbidity and mortality. Hosts who are immunocompromised (including pregnancy) are especially prone to developing pneumonia and its complications, which include secondary bacterial infections, encephalitis, hepatitis, and, with concomitant aspirin use, Reye syndrome. VZV pneumonia also tends be more severe in individuals who smoke.

Measles virus

Measles virus is a member of the Paramyxoviridae family and the genus Morbillivirus. It is a single-stranded RNA virus contained within a nucleocapsid and surrounded by an envelope. Measles is a respiratory virus that causes a febrile illness with rash in children; mild pneumonia often occurs but is of no consequence in healthy adults. Measles may result in severe lower respiratory tract infection and in morbidity in hosts who are immunocompromised and malnourished. Measles is highly contagious and is transmitted from person to person by aerosolized droplet nuclei. The incubation period is 10-14 days and peaks in late winter and early spring.

Adenoviruses

Adenoviruses are enveloped DNA viruses that cause upper and lower respiratory tract infections. Pneumonia is uncommon in adults outside of military recruit camps and similar facilities, but fulminant disease has been described in the immunocompromised population and occurs occasionally in apparently healthy hosts. Although 42 serotypes exist, pulmonary disease is predominantly caused by serotypes 1, 2, 3, 4, 5, 7, 14, and 21. Adenoviruses are spread through aerosol transmission; close living arrangements (eg, college campuses, military camps) are likely places for spread.

Cytomegalovirus

Cytomegalovirus (CMV) infection is a common, usually asymptomatic herpesvirus infection in the general population. In hosts who are immunocompetent, acute CMV infection causes a mononucleosislike syndrome that is associated with pneumonia in 6% of cases. CMV pneumonia is common and often fatal in individuals who are immunocompromised; the severity of pneumonia is related to the intensity of immunosuppression. CMV infection is a well-recognized complication of HIV infection, but retinitis and colitis are more common than pneumonia in persons who are infected with HIV. When transmitted through blood transfusion or organ transplantation, the incidence of clinically significant CMV disease is higher. Otherwise, CMV transmission occurs through close contact with body fluids.

Epstein-Barr virus

Epstein-Barr virus (EBV) is a DNA virus of the Herpesviridae family; it mainly targets B lymphocytes and the epithelium of the nasopharynx, oropharynx, and salivary glands. Primary infection with EBV usually manifests as infectious mononucleosis, characterized by fever, pharyngitis, lymphadenitis, and, rarely, splenomegaly. Pulmonary involvement may occur but is uncommon. Pneumonia has been reported to occur in less than 10% of people with infectious mononucleosis.

Hantavirus

Hantavirus pulmonary syndrome is an acute pneumonitis caused by North American Hantavirus. Rodents are the usual hosts of hantaviruses, but some of these viruses also can infect humans and cause disease. Hantaviruses originally were recognized in the 4-corners region of the southwestern United States (New Mexico, Arizona, Utah, and Colorado) in May of 1993. The disease causes rapidly progressive respiratory failure, noncardiogenic pulmonary edema, intravascular volume contraction and hemoconcentration, lactic acidosis, depressed cardiac output, and cardiac dysrhythmias. Hantaviruses are a genus of enveloped RNA viruses in the family Bunyaviridae. Most cases occur in locations where deer mice are prevalent. Each species of the Hantavirus genus normally infects a single rodent species. The rodents are infected chronically, do not develop disease, and excrete the virus in urine and feces.

Avian influenza

An influenza virus (H5N1) previously known to infect only birds was found to infect humans, causing disease and death in Hong Kong in 1997. Prior to the human outbreak, the H5N1 virus caused widespread deaths in chickens on 3 farms in Hong Kong. The epidemiologic investigations of this outbreak demonstrated that individuals in close contact with the index case or with exposure to poultry were at risk of being infected. All severe cases presented with lower respiratory infection and lymphopenia and 6 people eventually died. Asian H5N1 viruses were first detected in domestic geese in southern China in 1996; by 2000, domestic ducks were infected. This likely played a key role in the genesis of the 2003/2004 outbreaks.

The H5N1 viruses isolated from China and Hong Kong had a range of genotypes. The rising incidence and widespread reporting of disease can probably be attributed to the increasing spread of the viruses from existing reservoirs of infection in domestic waterfowl and live bird markets leading to greater environmental contamination.

Frequency

United States

The chief causes of viral pneumonia in adults are influenza viruses types A and B, adenovirus, PIVs, and RSV. The viruses cause approximately 8% of cases of community-acquired pneumonia for which patients are hospitalized. A combination infection with both a bacterial pathogen and viruses also may occur.

• Influenza virus types A and B account for more than 50% of all community-acquired viral pneumonias in adults. Approximately 15% of viral pneumonia is associated with PIVs, especially type 3. Other viruses also cause pneumonia in adults who are immunocompetent, but the incidences are not well established.
• Patients who are immunocompromised are at risk for pneumonia from infection with CMV, VZV, HSV, measles, and adenoviruses. Organ transplant recipients are particularly at risk of acquiring lower respiratory tract infection due to herpesviruses, CMV, and RSV. CMV pneumonia has been observed in 25% of patients with bone marrow and renal transplants. Simultaneous infection with other organisms frequently occurs.
• In one study (Meyers, 1982), 5% of nonbacterial pneumonias in patients with bone marrow transplants were secondary to HSV, compared to CMV pneumonia, which had an incidence of 46%. Adenovirus pneumonia has been reported to comprise up to 15% of the incidence of viral pneumonia in patients with transplants. The mortality rate from infection with adenoviruses may be as much as 60%.

Mortality/Morbidity

• Influenza epidemics occur during the winter months and are associated with 10,000-40,000 deaths in the United States during severe outbreaks. Of these, 80% occur in people older than 65 years. The highest rates of hospitalization occur in preschool-aged children and in the elderly population. During outbreaks, the hospitalization rates are 27.9 cases per 10,000 persons younger than 5 years and 55 cases per 10,000 persons older than 65 years.
• RSV infections occur as seasonal community-based upper respiratory tract infections during winter months or as outbreaks in hospitals, nursing homes, and long-term care facilities. RSV now ranks second to influenza as a major viral pathogen in the elderly population. RSV pneumonia is associated with a mortality rate ranging from 11-78%, depending on the severity of underlying immune suppression.
• Parainfluenza viral serologic surveys reveal that 90-100% of children have antibodies to PIV type 3 by age 5 years. Antibodies to PIV 1 and 2 develop in 74% of children older than 5 years.
• HSV pneumonia has been reported in 0.8-2.9% of liver transplant recipients, in 1-10% of cardiac transplant recipients, and in 1.5% of renal transplant recipients.
• Varicella pneumonia complicates approximately 2-10% of the cases of varicella in adults. At least 25% of the fatalities from varicella in adults occur in those who develop varicella pneumonia. The severity of varicella pneumonia is highest in immunosuppressed persons, pregnant women, and individuals who smoke.
• During a large measles outbreak in military recruits, the rate of pneumonia was reported to be 3.3%. However, in a different study using different diagnostic criteria, pneumonia was found in 50% of recruits with measles. In the United States, pneumonia is responsible for 60% of the measles mortality in children.
• Adenovirus infection is responsible for approximately 8% of cases of pneumonia in children, the incidence of adenovirus pneumonia in adults is estimated to be 1-3%. In patients who are immunocompromised, the mortality rate can be higher than 50%, but death is unusual in healthy adults.
• In developing countries, up to 90% of children have antibodies to EBV by age 3 years. Pneumonia has been reported to occur in less than 10% of people with infectious mononucleosis. Seropositivity to CMV is present in 50-80% of healthy adults in the United States. In hosts who are immunocompetent, acute CMV infection causes a mononucleosislike syndrome, which is associated with pneumonia in 6% of cases. Acquisition of virus from CMV-seropositive bone marrow, blood products, or donor organs leads to CMV pneumonia in approximately 36% of CMV-seronegative graft recipients. CMV pneumonia affects 10-40% of bone marrow recipients. The mortality rate for CMV pneumonia in severely immunosuppressed patients is 40-50%.
• Approximately 200 cases of Hantavirus pulmonary syndrome have been reported. Most of these cases have been reported from New Mexico, Arizona, Utah, and Colorado. The mortality rate from Hantavirus pulmonary syndrome is 52%.

Sex

• All of the viruses cause pneumonia in both sexes.

Age

• Most viruses generally infect children and cause a mild illness; healthy adults also develop mild disease. In contrast, elderly persons and persons who are immunosuppressed develop severe viral pneumonia, resulting in high morbidity and mortality rates.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The clinical manifestations of viral pneumonia vary because of the number of diverse etiologic agents. Their presentations are described briefly below. Various viral pneumonias typically occur during specific times of the year, among close populations, or in populations with underlying cardiopulmonary or immunocompromising disease. The common constitutional symptoms of all viral pneumonias are fever, chills, nonproductive cough, rhinitis, myalgias, headaches, and fatigue.

• Influenza
• • The typical infection with influenza virus consists of sudden onset of fever, chills, myalgia, arthralgia, cough, sore throat, and rhinorrhea. Diarrhea generally is not part of the clinical presentation in adults. These symptoms last 3-5 days. These symptoms are common to other respiratory viral infections but are highly suggestive of influenza virus infection when an outbreak is occurring in the community.
  • The illness is self-limited; however, people with underlying cardiopulmonary disease or immunosuppression may develop severe life-threatening pneumonia.
  • Influenza virus pneumonia is associated with fever, malaise, respiratory distress, and hypoxemia. These patients are predisposed to secondary bacterial pneumonia requiring hospitalization.
• Respiratory syncytial virus
• • In healthy hosts, RSV causes upper respiratory tract illness, tracheal bronchitis, bronchiolitis, and pneumonia.
  • Upper respiratory tract symptoms, such as coryza and pharyngitis, precede lower respiratory tract involvement.
  • Pneumonia and bronchiolitis often are difficult to differentiate, and both can be associated with wheezing, rales, and hypoxemia.
  • Hosts who are immunocompromised may have a range of respiratory involvement. These patients develop fever, cough, rhinorrhea, and respiratory difficulties. In these patients, the symptoms range from mild dyspnea to severe respiratory distress and respiratory failure.
• Herpes simplex virus
• • The spectrum of respiratory diseases due to HSV infection ranges from oral pharyngitis to membranous tracheobronchitis and diffuse or localized pneumonia.
  • Dyspnea, cough, fever, tachypnea, intractable wheezing, chest pain, and hemoptysis are common symptoms of HSV pneumonia.
• Measles
• • Immunocompetent individuals present with fever, rash, cough, conjunctivitis, coryza, and a dry barking cough.
  • The pulmonary findings parallel the cutaneous signs; the severity of pneumonia correlates with worsening rash.
• Adenovirus
• • The features include fever, malaise, headache, sore throat, hoarseness, and cough.
  • In adults who are immunocompromised, fever is predominant and gastrointestinal symptoms can be severe.
• Cytomegalovirus
• • Clinical symptoms of CMV pneumonia are subacute and nonspecific.
  • In adults who are immunocompetent, dry cough, tachypnea, and low-grade fever are the usual complaints.
  • CMV can cause multiorgan disease such as enterocolitis, retinitis, hepatitis, bone marrow suppression, and encephalitis.
  • In recipients of organ transplants, the development of CMV pneumonia may be a subacute process rather than an acute process. The infection may develop into severe pneumonia and may progress to respiratory failure.
• Epstein-Barr virus: Patients have nonspecific pulmonary symptoms such as nonproductive cough, tachypnea, malaise, fever, and fatigue.
• Hantavirus
• • Hantavirus pulmonary syndrome is characterized by 4 clinical phases, as follows: (1) prodrome, (2) noncardiogenic pulmonary edema/adult respiratory distress syndrome and shock, (3) diuresis, and (4) convalescence.
  • Fever and myalgia are prominent in almost all phases and precede the onset of respiratory symptoms by 1-10 days.
  • These patients often complain of severe back and hip pain, and they develop nausea, vomiting, abdominal pain, and diarrhea.
  • Dry cough and shortness of breath herald the development of pulmonary edema. The onset of the shock and pulmonary edema phase is abrupt and dramatic.

    The interval between the onset of dyspnea and respiratory failure requiring ventilatory support may be a few hours; the earliest indication is hypoxemia.

• Avian influenza: Avian influenza has a high mortality rate because of systemic viral dissemination, cytokine storm, or alveolar flooding. The virus is intrinsically resistant to amantadine and rimantadine. Prognosis may be improved by early treatment with a neuraminidase inhibitor with good systemic drug levels. Postexposure prophylaxis for health care workers is recommended.

Physical

The physical examination findings are similar to those of pyogenic pneumonia and are nonspecific. Physical examination demonstrates wheezing, crackles, increased fremitus, and bronchial breath sounds over the involved regions of the lungs.

• In varicella zoster, pneumonia usually develops 2-5 days after the onset of fever and rash. The characteristic chickenpox rash is a clue to pulmonary involvement.
• Patients with measles develop a characteristic erythematous macular rash. In atypical measles, which occurs in patients immunized from 1963-1967 with a killed vaccine, the rash starts in the hands and feet rather than in a central distribution. Patients with measles also develop conjunctivitis and Koplik spots (small white punctate lesions of the buckle mucosa that generally appear before the cutaneous rash). The severity of pneumonia generally correlates with that of the rash.
• Herpesvirus pneumonia often is preceded by oral mucocutaneous lesions or esophagitis. Therefore, the presence of cutaneous, genital, or oral lesions may herald pulmonary or disseminated disease.
• EBV causes a classic syndrome of infectious mononucleosis, which includes the triad of fever, pharyngitis, and lymphadenopathy. Upon physical examination, hepatosplenomegaly or splenomegaly may be demonstrated.

Causes

The following are the common viruses known to cause pneumonia in healthy or immunocompromised children and adults:

• Children
• • Respiratory syncytial virus
  • Influenza viruses A and B
  • Parainfluenza virus
  • Adenovirus
  • Measles virus
• Adults
• • Adenovirus
  • Cytomegalovirus
  • Herpes simplex virus
  • Influenza viruses A and B
  • Measles virus
  • Parainfluenza virus
  • Respiratory syncytial virus
  • Varicella-zoster virus

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Over the past decade, developments in diagnostic techniques have led to a significant improvement in the ability to detect viruses in the respiratory tract. However, the detection of viral pathogens does not always indicate active disease. For example, herpesviruses may become reactivated without causing significant active disease. Similarly, RSV and CMV can be detected in the presence of other known bacterial pathogens, making it difficult to decide whether these are the causative agents of pneumonia.

  Table 1. Diagnostic Techniques Used for Viral Pneumonia

  Virus	Viral Culture	Cytologic Evaluation	Rapid Antigen Detection	Gene Amplification
  Influenza virus	HA*, SV†		IF‡, ELISA§
  Adenovirus	CE¶, SV	Intranuclear inclusions	IF, ELISA	RT-PCR#
  Paramyxoviruses
  Respiratory syncytial virus	CE, SV	Eosinophilic cytoplasmic inclusions	IF, ELISA	RT-PCR
  Parainfluenza virus	HA, SV	Eosinophilic intranuclear inclusions	IF, ELISA	RT-PCR
  Measles virus	HA
  Herpes viruses
  Herpes simples virus	CE, SV	Cytoplasmic inclusions	IF, ELISA	PCR
  Varicella-zoster virus	CE	Cytoplasmic inclusions	IF	RT-PCR
  Cytomegalovirus	CE, SV	"Owl's eye" cells	IF, ELISA	RT-PCR
  Hantavirus			Antibodies against FCV**	FVC RNA by RT-PCR

  ^*HA - Hemaglutination
  ^† SV - Shell viral culture
  ^‡IF - Immunofluorescence
  ^§ELISA - Enzyme-linked immunosorbent assay
  ^¶CE - Cytopathogenic effects
  ^#RT-PCR - Reverse transcriptase-polymerase chain reaction
  ^**FCV - Four corners' virus
• Cytologic evaluation
• • Respiratory secretions, bronchoalveolar lavage samples, and tissue specimens can be examined using cytologic and histologic techniques.
  • Intranuclear inclusions often exist in cells infected with DNA viruses; cytoplasmic inclusions usually are present in cells infected with RNA viruses.
  • CMV infection characteristically is associated with "owl's-eye" cells, which are large cells with basophilic intranuclear inclusions and a surrounding clear zone.
  • The presence of viral inclusions is diagnostic, although this method has low sensitivity. Therefore, absence of inclusions does not always exclude infection or active disease.
• Viral culture
• • Viral pneumonia can be diagnosed by isolation and identification of the pathogen through viral culture.
  • Tissue from the upper or lower respiratory tract, sputum samples, and samples obtained by nasopharyngeal washing, bronchoalveolar lavage, and biopsy may be submitted for viral culture. The use of an appropriate viral transport medium is required; this consists of enriched broth containing antibiotics and a protein substrate.
  • Viral cultures are performed on various cell lines (eg, monkey kidney cells, diploid fibroblasts). The cell cultures are incubated at 35°C and are examined microscopically on alternate days for an incubation period of 14 days.
  • The cultures are examined for cytopathogenic effects and for evidence of viral growth. The cytopathogenic effect is the formation of syncytial collections of multinucleated giant cells and rarely is virus specific. Viral growth is detected through hemadsorption testing by demonstrating adherence of red blood cells to the cultured cell monolayer of infected tissue.
  • Further identification of viruses is accomplished using immunofluorescence (direct or indirect) methods or nucleic acid probes. These techniques are used to identify the specific virus in cell cultures.
  • Modified cell culture methods called shell vial culture systems are able to detect slow-growing viruses such as CMV. CMV often requires 14-18 days to produce a cytopathogenic effect by fibroblast cell culture technique. The prepared clinical specimens are inoculated on to adherent cell monolayers grown on round coverslips in small vials. The vials are centrifuged at low speed for 1 hour, after which fresh culture medium is added. Next, the vials are incubated and examined serially to detect viral antigen or DNA expression. Shell vial culture systems are used widely for earlier detection of CMV, RSV, HSV, adenovirus, influenza viruses, PIV, and other viral pathogens.
• Rapid antigen detection
• • Rapid antigen detection tests provide faster results because the test is performed directly on specimens obtained from patients.
  • Immunofluorescence assay and enzyme-linked immunosorbent assay (ELISA) are available for the diagnosis of HSV, RSV, influenza virus A and B, PIV, CMV, and other respiratory viruses. ELISA can detect viral antigens, while an immunofluorescence assay requires the presence of prepared, intact, infected cells. The sensitivity and specificity of these methods varies depending on the virus being sought and the particular diagnostic assay being used.
  • The advantages of antigen detection tests are higher specificity for individual viruses. Furthermore, these assays remain positive for several days to weeks, long after the culture technique can detect viable virus.
  • The disadvantages of these methods are that the overall sensitivity is lower than that of viral cultures. Therefore, antigen detection methods should be used in conjunction with cell culture for optimal diagnosis of viral infections.
• Gene amplification
• • Polymerase chain reaction (PCR) is a highly sensitive and specific technique for amplifying genes to detect the presence of a virus. PCR has become especially useful for the detection of CMV in various body fluids (eg, blood, urine, respiratory secretions). PCR detection should be used in combination with viral culture and immunocytologic and rapid antigen detection.
  • A newly developed molecular diagnostic technique, multiplex reverse transcriptase-polymerase chain reaction (MRT-PCR), permits rapid detection of RSV, adenoviruses, and PIV in appropriate respiratory tract secretions. The single-step MRT-PCR technique has high sensitivity and specificity. The sensitivity for diagnosis of CMV pneumonitis by PCR has been reported to be 85-100%.
• Cultures of nonrespiratory specimens also may be helpful in diagnosing the specific virus causing pneumonia. Adenoviruses are secreted into the stool for weeks. CMV may be detected in the urine and in buffy coat preparations from heparinized blood. Serologic studies have been helpful in diagnosing pneumonia caused by measles virus and CMV. The presence of immunoglobulin M antibodies indicates a recent infection.
• The diagnosis of Hantavirus infection is based on detection of Four Corners virus–specific antibody reactivities in serum and the detection of Four Corners virus (FCV) RNA in peripheral blood mononuclear cells by reverse transcriptase-polymerase chain reaction (RT-PCR). The serodiagnosis of acute FCV infection is confirmed by detecting FCV genetic material in peripheral blood mononuclear cell preparations with RT-PCR.
• VZV infection and pneumonia can be diagnosed mostly on clinical grounds. VZV can be isolated from vesicular fluid, respiratory secretions, blood, or cerebrospinal fluid. Rapid antigen detection tests such as direct immunofluorescence can be performed on cell scrapings. A Tzanck smear obtained by unroofing a cutaneous lesion for material may show multinucleated giant cells with eosinophilic intranuclear inclusions but cannot distinguish between HSV and VZV. Serologic assays include indirect immunofluorescence, complement fixation, neutralizing antibody test, and ELISA.
• Diagnosis of measles pneumonia is clinical, but laboratory diagnosis can be helpful. Measles virus can be grown in primary culture in monkey and human kidney cells. Cytopathic effects are observed in 6-10 days; eosinophilic inclusions are found in the cytoplasm and nucleus of the infected cells.
• Adenoviruses can be isolated from respiratory secretions and can be grown in human embryonic kidney cells, human laryngeal tumor cells (HEp-2), and HeLa cells. Cytopathic effects appear in 2-20 days and include eosinophilic and diffuse basophilic intranuclear inclusions.
• The diagnosis of HSV pneumonia can be confirmed using respiratory culture, immunofluorescence antigen assays, PCR, cytologic techniques, and serology.
• The diagnosis of CMV pneumonia is based on clinical presentation and positive culture and histopathologic findings. Positive CMV cultures should be interpreted in view of other evidence of disease because asymptomatic shedding can occur in saliva, urine, and other bodily fluids. Documentation of viremia by shell vial culture technique usually signifies CMV disease.

Imaging Studies

• Chest radiographic findings usually are nonspecific, but some features are characteristic of individual viruses.
• • HSV can produce focal lesions on chest x-ray that begin as small nodules in the periphery. As the disease progresses, the nodules coalesce to form extensive infiltrates.
  • In influenza pneumonia, radiographic findings are similar to those described for other respiratory viral infections. Perihilar and peribronchial infiltrates occur commonly, while progression to diffuse interstitial infiltrates is observed with severe disease. Other findings of influenza pneumonia include hyperexpansion of the lungs, subsegmental atelectasis of multiple lobes, and lobar atelectasis, particularly of the right-upper or right-middle lobe.
  • In CMV pneumonia, chest radiographs show interstitial infiltrates predominantly in the lower lobes. Advancement to diffuse interstitial infiltrates is observed in patients with organ transplant.
  • In RSV, chest radiographs show bilateral interstitial or patchy infiltrates. Lobar consolidation and pleural effusions are present in 25% and 5% of cases, respectively.
  • In PIV, chest radiographs may reveal findings ranging from focal infection to diffuse interstitial infiltrates or diffuse mixed alveolar-interstitial infiltrates consistent with acute lung injury.
  • In varicella pneumonia, radiographic findings are diffuse, fluffy, reticular or nodular infiltrates that can be rapidly progressive. Pleural effusion and peripheral adenopathy can occur. Radiographic abnormalities are more prominent during the peak of the rash and resolve rapidly with clinical improvement. Long-term respiratory sequelae are infrequent in survivors, although small, diffusely scattered, punctate lung calcifications may persist on chest films.
  • Hantavirus infection may result in normal chest radiograph findings during early disease. This is followed by signs of interstitial edema, Kerley B lines, peribronchial cuffing, and indistinct hila. Progression to the pulmonary edema phase over the subsequent 48 hours is indicated by centrally located dense alveolar infiltrates unlike the more peripheral infiltrates of adult respiratory distress syndrome from other causes. With further progression, pleural effusions also may develop.

Procedures

• Infrequently, lung biopsy, ie, transbronchial via a bronchoscope, transthoracic via a thoracoscope, or open lung, is required to make a diagnosis in very ill patients, who often are immunocompromised.
• Bronchiolar lavage also may be useful to obtain material for cytopathologic analysis and microbiologic studies.

Histologic Findings

Histopathologic examination of lung tissue infected with influenza pneumonia reveals edema, focal hemorrhages, and cellular infiltration. Alveoli may be denuded of epithelium, and intraalveolar hemorrhage is common. The presence of an acellular hyaline membrane lining the alveoli is typical of influenza pneumonia.

Histopathology of varicella-zoster pneumonia shows focal necrosis, consolidation, a mononuclear infiltrate, and intranuclear inclusion bodies.

Measles pneumonia has been called Hecht giant cell pneumonia because a predominantly interstitial infiltrate with mononuclear cells and multinucleated giant cells is present on histology.

Histologically, HSV pneumonia shows parenchymal necrosis, hemorrhage, and mononuclear infiltrates. Upon bronchoscopy, one may observe trachitis, bronchitis, and typical punctate mucosal lesions. Pathology findings in HSV infection show multinucleated giant cells and intranuclear inclusions.

Cytopathologic findings in CMV demonstrate typical cytomegalic cells with intranuclear and cytoplasmic inclusions. Histopathologic examination of lung tissue shows mononuclear interstitial infiltrates, thickened alveolar walls, fibrinous exudates, and hemorrhage. The cells containing inclusion bodies can be difficult to detect in mild cases.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Table 2. Treatment and Prevention of Common Causes of Viral Pneumonia*

^*All viral pneumonia patients must receive supportive care with oxygen, rest, antipyretics, analgesics, nutrition, and close observation.

• Influenza
  • Antiviral therapy is available for treatment of influenza virus infection. The treatment of uncomplicated influenza is supportive in nature, consisting of rest and administration of antipyretics and analgesics.

    Table 3. Characteristics of Anti-Influenza Drugs

    	Amantadine (Symmetrel)	Rimantadine (Flumadine)	Zanamivir (Relenza)	Oseltamivir (Tamiflu)
    Mechanism of action	M2 ion channel blockade inhibits HA* cleavage Þ block RNA encoding, which reduces early viral replication.		Viral NA† inhibition prevents sialic acid cleavage from HA Þ virus gets trapped inside cells, and epithelial spread is blocked.
    Spectrum	Influenza A only	Influenza A only	Influenza A and B	Influenza A and B
    Oral bioavailability	Good	Good	Poor	Good
    Protein binding, %	67	40	None	Minimal
    Half-life, h	12-18	24-36	2.5-5	1-3
    Excretion	Renal (not removed by hemodialysis)		Renal and gastrointestinal	Renal
    Drug interaction	Synergistic CNS toxicity with antihistamines, anticholinergics, CNS stimulants	ßPlasma level: ASA§, acetaminophen	None	None
    Renal clearance	TMP-SMZ¶, triamterene, hydrochlorothiazide, quinine sulfate, quinidine	Cimetidine	None	None

    ^*HA - Hemagglutinin
    ^† NA - Neuraminidase
    ^§ASA - Acetylsalicylic acid
    ^¶TMP-SMZ - Trimethoprim and sulfamethoxazole
  • Amantadine hydrochloride and rimantadine hydrochloride are approved for the prevention and treatment of Influenza A virus infection; they are not active against Influenza B virus infection. Both drugs are absorbed well orally, block the viral M2 protein ion channel, and inhibit the uncoating of the virus. Rimantadine is a synthetic analog of amantadine and has comparable therapeutic efficacy. Treatment with amantadine or rimantadine, given within 48 hours of the onset of symptoms, decreases the duration of fever and other symptoms by approximately 1 day in adults with uncomplicated disease. Their efficacy in patients with influenza viral pneumonia or severe influenza is unknown, but most clinicians are comfortable trying these agents in that setting.
    
    Treatment with these compounds has been associated with emergence of viral resistance; the clinical significance of this is not known. Amantadine and rimantadine are not recommended by the CDC for the 2005-2006 influenza season duetoresistance.Laboratory testing by CDC on the predominant strain of influenza (H3N2) currently circulating in the United States shows that it is resistant to these drugs.
  • Oseltamivir and zanamivir block the neuraminidase surface protein on both influenza A and influenza B viruses. These drugs trap the virus inside the infected respiratory epithelial cells and prevent spread to other cells. They are active against both influenza A and influenza B viruses. These newer drugs have a different safety profile and lower potential for inducing resistance, but they are much more expensive. The results of zanamivir studies have confirmed its efficacy only if therapy is started within 24-48 hours of symptom onset in febrile patients. Most studies have reported a similar window of opportunity for oseltamivir. Like the older agents, they reduce the course of influenza by approximately 1 day. Their role in influenza pneumonia is unclear, but most clinicians would use some influenza therapy in all patients with life-threatening influenza.
  • Whether the newer agents are superior to amantidine/rimantidine is not clear for Influenza A virus infection, but they are effective for Influenza B virus infection while the older agents are not.
• Respiratory syncytial virus
  • As with influenza, treatment of uncomplicated RSV infection is supportive in nature.
  • Ribavirin, a nucleoside analog of guanosine, is the only effective antiviral agent currently available for the treatment of RSV pneumonia. Ribavirin acts by interfering with viral transcription; this drug is delivered as a small-particle aerosol. Conflicting data exist regarding the efficacy of ribavirin therapy in RSV pneumonia. Recent studies have not demonstrated a beneficial effect of this drug. Current recommendations are that ribavirin therapy should be considered only for severe illness.
• Parainfluenza virus: Treatment is supportive in nature. Ribavirin has been used (without good evidence) to treat lower respiratory tract infections.
• Herpes simplex virus
  • Acyclovir inhibits viral DNA synthesis by competitively binding to viral DNA polymerase. Intravenous acyclovir (250 mg/m² q8h) currently is the treatment of choice for HSV pneumonia.
  • Because a significant proportion of patients may have concomitant bacterial pneumonia, empirical broad-spectrum antibiotic therapy that includes an antistaphylococcal drug should be instituted in patients with progressive HSV pneumonia who are unresponsive to antiviral therapy.
• Varicella-zoster virus pneumonia
  • Treatment of varicella pneumonia includes respiratory isolation until skin lesions heal, supportive care, administration of antiviral agents, and active and passive immunization.
  • For treatment of documented varicella pneumonia in patients who are immunocompromised, acyclovir (10 mg/kg IV q8h) has been shown to be effective.
• Measles pneumonia
  • Treatment of measles pneumonia generally is supportive in nature.
  • Children infected with HIV and adults who are immunosuppressed with measles pneumonia have been treated successfully with intravenous and aerosolized ribavirin, similar to the therapy for severe infections with RSV.
• Adenovirus
  • Treatment of adenovirus pneumonia primarily is supportive care.
  • Ribavirin has in vitro activity against adenoviruses and has been used in severe adenovirus pneumonia in adults. However, the efficacy has not been evaluated in controlled clinical trials.
• Cytomegalovirus
  • CMV infection and pneumonia are self-limited conditions in hosts who are immunocompetent. Treatment of CMV infection in patients who are immunocompromised has focused on prevention, acute therapy, and passive immunization.
  • The recommended treatment for acute CMV pneumonia is ganciclovir (2.5 mg/kg IV q8h for 20 d, followed by 2 wk of PO therapy at 5 mg/kg 3-5 times/wk for 20 doses). Ganciclovir prevents viral DNA replication by inhibiting the enzyme DNA polymerase.
  • High-dose intravenous immunoglobulin has been used successfully in conjunction with ganciclovir for the treatment of CMV pneumonia. Combination therapy is based on the premise that lung injury is not due solely to direct damage by the virus but is a result of the effects of a virally induced immunological reaction.
  • Foscarnet sodium, an inhibitor of viral DNA polymerase and reverse transcriptase, is an alternative drug for use in cases of ganciclovir-resistant CMV infection. Resistance to the drug frequently is encountered in patients infected with HIV who receive long-term suppressive ganciclovir therapy.
  • Cidofovir represents a third option, but few data exist regarding its use in CMV pneumonia.
• Epstein-Barr virus: No specific treatment is available for EBV infections.
• Hantavirus
  • Patients with Hantavirus pulmonary syndrome may have secondary infections from gram-positive or gram-negative organisms. Therefore, the recommendation is that these patients receive broad-spectrum antibiotic therapy.
  • The treatment of Hantavirus infection primarily is supportive in nature, aiming to correct hypoxemia, lactic acidosis, and hypotension.
  • Mechanical ventilation and optimal fluid management guided by hemodynamic monitoring are recommended.
  • Intravenous ribavirin has been used, but its efficacy has not been clearly demonstrated.
• Because most adult pneumonias are bacterial rather than viral, covering for bacterial pneumonia while awaiting a final etiologic diagnosis always is prudent.

Consultations

Patients suspected of having viral pneumonia may benefit from consultation with pulmonary and infectious diseases specialists.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antiviral agents

Acute lower respiratory tract infection from viral etiologies can be treated with antiviral agents. Amantadine, rimantadine, zanamivir, oseltamivir, ribavirin, acyclovir, ganciclovir, and foscarnet are used. The influenza drugs may be used as either prophylactic or therapeutic agents. Hyperimmune globulin is used primarily for passive immunization in some viral illnesses.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention

Influenza

• Annual fall vaccination of high-risk populations and healthcare workers is the most effective measure for decreasing morbidity and mortality from influenza. Antibodies against the hemagglutinin and, to a lesser degree, neuraminidase antigens are the major determinants of host immunity. Each year's influenza vaccine contains the 3 virus strains (usually 2 type A strains and 1 type B strain) considered most likely to cause outbreaks based on epidemiologic surveillance.
• The effectiveness of the vaccine depends on the age and general health status of the recipient and the antigenic similarity to the virus causing outbreaks that year. When the vaccine matches the prevalent influenza virus strain, the efficacy of the vaccine in healthy adults is reported to be in the range of 70-90%. Contrary to popular belief, the flu vaccine cannot cause the flu. Also, the potential association between flu vaccine and Guillain-Barré syndrome is highly overemphasized. Finally, patients with severe allergy to eggs should not be offered the vaccine.
• Chemoprophylaxis with amantadine or rimantadine should be considered when outbreaks occur in nursing homes. Everyone in the institution, including the unvaccinated staff and other coworkers, should be treated for at least 2 weeks during the outbreak.
• Zanamivir and oseltamivir also have been shown to be effective in the prevention of influenza if taken within 42 hours of the onset of symptoms.
• In view of the high fatality of avian influenza, a combination of contact, droplet, and airborne precautions are recommended as long as resources allow, despite the fact that the relative importance of these 3 modes in nosocomial transmission of avian influenza is still unknown.

Respiratory syncytial virus

• RSV immunoglobulin is a pooled product containing immunoglobulin G antibodies against RSV. When administered intravenously to patients at high risk, fewer episodes of severe pneumonia requiring hospitalization have occurred.
• An alternative to RSV immunoglobulin is palivizumab (Synagis), which is an intramuscularly administered humanized monoclonal antibody preparation. Prophylaxis with this agent results in a 55% reduction in hospitalization secondary to RSV infection in high-risk pediatric patients.

Herpes simplex virus: Chemoprophylaxis of high-risk seropositive patients during induction of immunosuppression for transplantation is recommended. Acyclovir is prescribed at maintenance doses for the first month after transplantation.

Varicella-zoster virus

• A live attenuated varicella vaccine is recommended for patients who did not have varicella infection by age 13 years if their work involves the possibility of exposure to varicella. The vaccine should not be given to pregnant women. Children are now routinely immunized.
• Intramuscular administration of varicella-zoster immunoglobulin (125 U/10 kg) is indicated for passive immunization VZV-seronegative immunosuppressed hosts (including pregnant women and certain neonates) who have been exposed to VZV.

Measles

• The measles vaccine is a live attenuated virus vaccine and should not be administered to pregnant women or persons who are severely immunocompromised.
• Postexposure prophylaxis of patients who are immunocompromised with intravenous immunoglobulin is effective if administered within 72 hours of exposure to infectious cases of measles.

Adenovirus: An oral vaccine is available against serotypes 5 and 7. This vaccine has been used primarily in military recruit populations and is not currently available.

Cytomegalovirus: CMV infection is prevented in transplant patients by attempts to match the CMV seropositivity between the donor and the recipient and by careful administration of CMV-negative transfusions of blood and blood products. Graft recipients who are CMV negative are given prophylactic acyclovir or ganciclovir before and after transplantation. Preemptive therapy based on detection of CMV in bronchoalveolar lavage specimens and CMV antigenemia after transplant has been shown to significantly reduce the incidence of posttransplant CMV pneumonia.

Complications

• Most viral pneumonias in hosts who are immunocompetent resolve with few sequelae. However, respiratory failure may develop secondary to superimposed bacterial infection.
• Secondary bacterial infections occur commonly. Common organisms are Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae.
• A risk of acquiring other hospital-acquired bacterial infections is present.
• Late sequelae of viral pneumonias include bronchitis and bronchiolitis, especially following infection with RSV and influenza viruses.

Patient Education

For excellent patient education resources, visit eMedicine's Pneumonia Center and Cold and Flu Center. Also, see eMedicine's patient education articles Viral Pneumonia and Flu in Adults.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Patients with viral pneumonias, especially persons who are immunocompromised, should be evaluated carefully to exclude bacterial infections. Empiric therapy for bacterial pneumonia usually is warranted while the etiologic evaluation proceeds.
• Patients who meet criteria for either chemoprophylaxis or immunoprophylaxis should be offered such interventions when appropriate.
• In influenza, the antiviral drugs should usually be started within 24-48 hours of symptom onset. A later initiation may be warranted for life-threatening pneumonia, but no good data are available to address this issue.
• Zanamivir may lead to worsening of airway function in patients with asthma or COPD.
• Inadequate data are available on the use of antiinfluenza drugs in patients who are immunosuppressed and at high risk for influenza-related complications. Use if life-threatening disease is present.
• Clinical and radiographic features of viral pneumonias often are nonspecific. Newer and faster methods of viral culture and viral antigen detection have improved the capability of definitive diagnosis, but further refinements in diagnostic techniques are needed.
• Preventative measures should be practiced when applicable. These measures should focus on limiting exposure to active infection, broad use of available vaccines in children and susceptible adults, and use of hyperimmune globulins and chemoprophylaxis in patients at high risk.

Special Concerns

Viral pneumonia in the elderly: Viruses account for a substantial portion of respiratory illnesses, including pneumonia, in the elderly population. Presently, influenza virus A H3N2 and respiratory syncytial virus are the most commonly identified viral pathogens in older adults with viral pneumonia. The relative importance of additional viruses (such as parainfluenza, rhinoviruses, coronaviruses, and human metapneumovirus) will likely increase as diagnostic tests such as reverse-transcription polymerase chain reaction become more widely available.

Patients with high-grade fever, myalgias, and cough during the winter months should be suspected to have influenza. If tests are negative for influenza, respiratory syncytial virus pneumonia should also be suspected during the winter in patients with coryza, wheezing, low-grade fever, and patchy infiltrates on chest x-ray. Because clinical features and periods of activity for many viruses overlap, laboratory confirmation of influenza is recommended for cases involving patients who are seriously ill or institutionalized.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Pneumonia, viral: A 52-year-old woman developed fever, cough, and dyspnea. She also developed a rash that was prominent over the face and the trunk. The chest radiograph showed interstitial infiltrates, with suggestion of a micronodular process. The Tzanck smear results from the skin vesicle suggest varicella-zoster virus.
	View Full Size Image
Media type:  X-RAY

Media file 2:  Pneumonia, viral: A 52-year-old woman developed fever, cough, and dyspnea. She also developed a rash that was prominent over the face and the trunk. The chest radiograph showed interstitial infiltrates, with suggestion of a micronodular process. The Tzanck smear results from the skin vesicle suggest varicella-zoster virus. She was treated with acyclovir; resolution of varicella-zoster virus infection occurred after 7 days of therapy.
	View Full Size Image
Media type:  X-RAY

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References