Introduction
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.
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.
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.
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 (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 (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 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 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.1 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 (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 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.
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 tract 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.
Swine influenza
On April 26th, 2009 the US Department of Health and Human Services issued a nationwide public health emergency regarding human cases of swine influenza A (H1N1) virus infection.7 In the past several weeks, an outbreak of the virus has occurred in Mexico (approximately 1600 cases) and the United States (40 cases, according to the US Centers for Disease Control and Prevention (CDC) as on 1 pm on April 27, 2009) caused by a new strain of influenza virus that contains a combination of swine, avian, and human influenza virus genes. In Mexico, 103 deaths are suspected to be caused by the recent swine influenza outbreak.
Cases of the viral infection have been confirmed in patients in California (7), Kansas (2), New York City (28), Ohio (1), and Texas (2). No deaths from the virus have been confirmed in the United States.8 Internationally, confirmed cases have also been reported in Canada, New Zealand, Spain, and the United Kingdom (Scotland), with suspected cases in Brazil, Israel, and France.9
If swine flu is suspected, clinicians should obtain a respiratory swab for swine influenza testing and place it in a refrigerator (not a freezer). Once collected, the clinician should contact their state or local health department to facilitate transport and timely diagnosis at a state public health laboratory.10
The new virus is resistant to the antiviral agents amantadine and rimantadine but sensitive to oseltamivir (Tamiflu) and zanamivir (Relenza). Initiation of antiviral agents within 48 hours of symptom onset is imperative to provide treatment efficacy against influenza virus. The usual vaccine for influenza administered at the beginning of the flu season is not effective for this viral strain.
Initial symptoms of swine influenza include high fever, myalgias, rhinorrhea, and sore throat. Nausea, diarrhea, and vomiting have also been reported. Infection control precautions (ie, handwashing, covering mouth with tissue when sneezing or coughing) are encouraged. If suspected swine flu occurs, isolation is recommended for infected individuals and household contacts. For more information, see updated information from the CDC's Guidance for Clinicians and Public Health Professionals.
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.11,12 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, 5% of nonbacterial pneumonias in patients with bone marrow transplants were secondary to HSV, compared to CMV pneumonia, which had an incidence of 46%.13 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.14
Clinical
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
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Further Reading
Guidelines
- Centers for Disease Control and Prevention - Swine Influenza
- Influenza vaccination of health-care personnel. Recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP).
- Using live, attenuated influenza vaccine for prevention and control of influenza: supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP).
- Guidelines for environmental infection control in health-care facilities. Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee.
Clinical trials
Keywords
viral pneumonia, viral respiratory tract infections, influenza virus, respiratory syncytial virus, RSV, parainfluenza virus, PIV, Orthomyxoviridae, severe acute respiratory syndrome, SARS, avian influenza, swine flu
