Pulmonary Medicine

Community-Acquired Viral Pneumonia

What every physician needs to know:

More than four million people die each year from pneumonia, which equates to 7 percent of the total population's mortality. Over the last decade, community-acquired viral infections of the lung have captured media and public attention after pandemic outbreaks of the severe acute respiratory syndrome (SARS) coronavirus of 2002-2003, the avian influenza A (H5N1) virus of 2005, and the influenza A (H1N1) virus of 2009. These pandemics demonstrated the capacity of respiratory viruses to cause worldwide epidemics with high attack rates, morbidity, and mortality.

In clinical studies of community-acquired pneumonia (CAP) utilizing polymerase chain reaction (PCR) techniques and serological testing, respiratory viruses are detected in 43-67 percent of children and 10-23 percent of adults. The highest incidence rates are found in children younger than age five, adults age seventy-five or older, and immunocompromised hosts. Recently, there has been a trend toward increased identification of viral pathogens in community-acquired lung infections, probably because of improved vaccination against bacterial pathogens ( Haemophilus influenza type B and Pneumococcus), increased numbers of immunocompromised hosts, and improved diagnostic assays, such as rapid viral antigen and PCR techniques. All clinicians should have a high index of suspicion for viral infections of the lung in order to initiate anti-viral therapy promptly and implement adequate infection control measures to prevent community and nosocomial spread.

Classification:

Viral infections of the lung can present with acute tracheobronchitis, bronchiolitis, bronchopneumonia, and pneumonia. These infections are difficult to distinguish from bacterial etiologies. Acute respiratory failure requiring mechanical ventilation, adult respiratory distress syndrome (ARDS), and diffuse alveolar hemorrhage were reported during the pandemic SARS and influenza A (H5N1) and (H1N1) infections.

The most commonly isolated viruses of childhood pneumonia are respiratory syncytial virus (RSV, 11-18%), influenza viruses (10%), parainfluenza (8%), enteroviruses (7%) and adenovirus (3%). In adult CAP, viruses are isolated at a lower rate of 22 percent, and the most common viruses are influenza viruses (8%), RSV (3%), parainfluenza (2%), and adenovirus (2%). See Table 1 for details.

Table 1

Viruses associated with community-acquired pneumonia in children and adults
Respiratory syncytial virus
Rhinovirus
Influenza A, B, and C viruses
Human metapneumovirus
Parainfluenza viruses types 1, 2, 3, and 4
Human bocavirus (mainly children)
Coronavirus types 229E, OC43, NL63, HKU1, SARS
Adenovirus
Enteroviruses
Varicella-zoster virus
Hantavirus
Parechoviruses
Epstein-Barr virus
Human herpesvirus 6 and 7
Herpes simplex virus
Mimivirus
Cytomegalovirus
Measles

Are you sure your patient has community-acquired viral pneumonia? What should you expect to find?

The symptoms and signs of community-acquired viral pneumonia are cough, dyspnea, sputum production, and pleurisy, symptoms that are indistinguishable from those of bacterial lung infections. In children, age less than five years, low-grade fever less than 38.5 degrees C, wheezing, and prominent intercostal retractions are highly suggestive of viral lung infection. Recent studies in adults suggest that patients with viral pneumonia have less sputum production, chest pain, and rigors than bacterial pneumonia patients do. Other key clinical features that suggest a viral etiology are a seasonal pattern with RSV in late fall, rhinovirus in the fall and spring, and influenza in the late fall and early winter.

Beware: there are other diseases that can mimic community-acquired viral pneumonia:

Bacterial pneumonia is typically indistinguishable from viral community-acquired pneumonia, as both processes present with cough, dyspnea, fever, and pleurisy. This confusion may delay establishment of proper droplet and respiratory isolation for contagious viral pathogens. Viral pneumonias are more common in older patients with cardiac co-morbidities, who usually complain less of chest pain or rigors. Systemic symptoms, such as sore throat, rhinorrhea, myalgias, headaches, nausea, vomiting, and diarrhea, are more common in viral pneumonia, particularly seasonal influenza. Patients with viral pneumonia also have lower peripheral white blood cell counts and C-reactive protein levels.

How and/or why did the patient develop community-acquired viral pneumonia?

The epidemiology of community-acquired viral infections of the lung is characterized by a seasonal pattern or pandemic events associated with high attack rates and person-to-person transmission. Upper and lower respiratory tract infections from RSV occur in the late fall, rhinovirus in the fall and spring, and Influenza in the late fall and early winter. Another important epidemiological clue is the patient's home environment. For example, rhinoviruses have caused outbreaks of severe and even fatal pneumonia in elderly nursing home residents, and adenovirus pneumonia outbreaks have occurred in military recruits housed in barracks.

During pandemic viral infections, a history of recent travel to an Asian country is an important epidemiological clue for a viral respiratory infection. The severe acute respiratory syndrome (SARS) coronavirus pandemic of 2002-2003 originated in a province of China with rapid spread causing severe pneumonia in eight thousand patients and 774 deaths in 26 countries and five continents. This virus infects people who are engaged in the commercial trade of exotic animals.

The most recent pandemic of 2003-2004 was caused by a highly virulent H5N1 avian influenza virus that was first detected in Thailand and spread worldwide, resulting in 450 human infections and a high case mortality of approximately 60 percent. In the spring of 2009, a novel influenza A (H1N1) infection originated in Mexico with high attack rates (17%) and a low case fatality rate of less than 0.5 percent. By March 2010, virtually all countries reported cases resulting in more than 17,700 deaths worldwide. Most of the illnesses were seen in children and young adults, while those older than age sixty were generally spared.

Which individuals are at greatest risk of developing community-acquired viral pneumonia?

Patients at higher risk for viral infections of the lung include children under age five and adults older than age seventy-five. Infants younger than six months are at particularly high risk for RSV and parainfluenza infection. In elderly patients, frail condition or the presence of congestive heart failure and/or pulmonary disease pose greater risk. Pregnant women are susceptible to pneumonia from varicella and pandemic influenza A (H1N1) with higher virulence and mortality. Other risk factors include human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS), cancer, radiation, chemotherapy, malnutrition, skin breakdown, and burns.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Laboratory studies may suggest the diagnosis of viral pneumonia, but they are not diagnostic. Viral pneumonia patients have lower peripheral white blood cell and neutrophil counts than those with bacterial infection. Elevated serum C-reactive protein and procalcitonin levels are usually associated with bacterial infection. Procalcitonin levels rise six to twelve hours after the onset of a bacterial infection with serum levels greater than 0.5 mcg/L highly suggestive of bacterial infection.

What imaging studies will be helpful in making or excluding the diagnosis of community-acquired viral pneumonia?

The community-acquired pneumonia guidelines published by the Infectious Disease Society of America and the American Thoracic Society recommend obtaining a chest radiograph in all patients with suspected pneumonia to document the presence of pulmonary infiltrate(s). Bilateral interstitial infiltrates are highly suggestive of a viral pneumonia, but alveolar infiltrates are seen in about half of infected children.

Multilobar infiltrates are reported in approximately half of patients with confirmed viral infection. Chest computed tomography (CT) commonly demonstrates multifocal ground-glass opacities or consolidation and centrilobular nodules following a "tree-in-bud" pattern. These CT findings are non-specific so routine chest CT scanning is not recommended for evaluation of the etiology of pneumonia.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of community-acquired viral pneumonia?

Non-invasive pulmonary diagnostic studies, such as pulmonary function tests and cardiopulmonary exercise testing, are not helpful in diagnosing or differentiating the community-acquired viral infections of the lung.

What diagnostic procedures will be helpful in making or excluding the diagnosis of community-acquired viral pneumonia?

Diagnostic confirmation of viral infections of the lung requires the detection of viruses or viral antigens in upper or lower respiratory tract samples via culture or direct immunofluorescence to viral antigens. Higher yields are obtained with the use of nasopharyngeal aspirates in children and with nasopharyngeal swabs in adults. When these procedures are performed, the nasal swabs should enter the nares and advance to a depth of at least 2cm. Suitable samples may be obtained from throat swabs, tracheal aspirates, and sputum cultures. Bronchoalveolar lavage, which is more difficult to obtain, typically has a lower antigen or viral particle burden because of low-level viral shedding at the peripheral lung.

Since viral cultures typically take between three and fourteen days for results, many medical centers have respiratory viral panels that utilize direct fluorescent antigen detection assays to diagnose common viral pathogens more quickly. Serologic testing may confirm a diagnosis of a recent viral infection if there is a four-fold increase in titer from acute to convalescent viral-specific antibodies. Recently, PCR-based methods have revolutionized the rapid diagnosis of viral infections by simultaneously testing for a large number of common respiratory viruses with a single specimen. This technique, which can rapidly identify viral infection with less than a twenty-four-hour turnaround, is quickly becoming the test of choice. With the use of PCR, recent microbiological studies have demonstrated that almost a third of adult CAPs are due to viral pathogens.

During the pandemic influenza outbreaks with H1N1 and H5N1, viral RNA detection by reverse-transcriptase polymerase chain reaction (RT-PCR) had the highest diagnostic yield. In fact, commercial influenza antigen assays had low sensitivity and were unable to distinguish between influenza A subtypes.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of community-acquired viral pneumonia?

There are no cytologic or genetic studies that could assist in the diagnosis of community-acquired viral lung infections. Lung biopsy specimens are rarely obtained during episodes of viral pneumonia. When they are performed, post-mortem examination typically reveals interstitial pneumonitis with lymphocytic infiltration. RSV typically invades bronchial and alveolar epithelial cells with alveolar macrophages and CD3-lymphocytes inflammation following a bronchocentric pattern.

Some viruses, such as adenovirus and human metapneumovirus, demonstrate histological evidence of a hemorrhagic pneumonia. Patients who died from SARS coronavirus, influenza A (H5N1), or influenza A (H1N1) infection demonstrated a diffuse alveolar damage pattern with pneumocyte desquamation, hyaline membranes, and interstitial edema.

If you decide the patient has community-acquired viral pneumonia, how should the patient be managed?

Patients with viral pneumonia should be triaged for admission based on CAP mortality prediction scores, such as PORT and CURB-65. When clinicians suspect a viral pneumonia, respiratory and droplet isolation is strongly recommended. It is important that visitors and hospital personnel wear disposable gloves, masks, and gowns, especially when entering the rooms of patients with respiratory syncytial virus (RSV). Most experts recommend treating with antibiotics, since bacterial co-infection or superinfection is not easily excluded. The use of anti-viral therapy for management of viral pneumonia is limited and is discussed in the section below.

The treatment of viral pneumonia is primarily supportive with oxygen therapy, adjuvant antibacterial antibiotics, and non-invasive or invasive ventilation (if required). Table 2 lists a few antiviral agents available for specific treatment of viral pneumonias:

Table 2

Antiviral Agents with Potential Benefits in Viral Pneumonia
Agent: Virus(es):
Amantidine, Rimantidine Influenza A
Zanamivir (inhalation) Influenza A and B; Pandemic influenza A (H1N1)
Oseltamivir (oral) Influenza A and B; Pandemic influenza A (H1N1) and (H5N1)
Peramivir (intravenous) Influenza A and B; Pandemic influenza A (H1N1)
Ribavirin (inhalation, intravenous)* RSV, Parainfluenza, Adenovirus, Measles, SARS-associated coronavirus, Pandemic influenza A (H5N1)
Gancyclovir, Foscarnet, Immunoglobulin Cytomegalovirus
Aciclovir (intravenous) Varicella-zoster, Herpes simplex
Cidofovir (intravenous) Adenovirus subtype 14

Seasonal influenza: When started within forty-eight hours from onset of influenza symptoms, the neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza) decrease the duration of influenza by 0.5 to 2.5 days. If patients are hospitalized, the recommendation is to utilize these agents even in patients presenting late with symptoms for more than forty-eight hours.

Coronavirus-associated SARS:This pandemic was treated with ribavirin based on its broad-spectrum antiviral action against DNA and RNA viruses, despite lack of in vitro virucidal activity. High-dose methylprednisolone was utilized for modulation of the inflammatory immune response with some anecdotal success. In vitro and animal models suggest that interferon beta and pegylated interferon alfa may be therapeutic alternatives for SARS, and clinical studies may be warranted. Other agents tested include combined lopinavir and ritonavir or intravenous immunoglobulin.

Pandemic influenza H5N1:Avian influenza A (H5N1) should be treated with oseltamivir (Tamiflu) and antibacterial antibiotics. Resistance to amantidine has been reported, and its use is not recommended. Adjuvant corticosteroids are not beneficial and may be associated with increased mortality, as demonstrated during the last pandemic.

Pandemic influenza H1N1:The most recent swine-origin influenza A (H1N1) infection was treated with the neuramidase inhibitors oral oseltamivir (Tamiflu) and inhaled zanamivir (Relenza). This influenza A was resistant to amantidine and rimantidine. For hospitalized patients, the preferred agent is intravenous zanamivir, which may be obtained via a compassionate-use request. Recently, intravenous peramivir was released for emergency use in critically ill patients in the United States. Varying doses and duration of empiric corticosteroids were used in up to 69 percent of patients during the pandemic with no clear benefit.

Respiratory syncytial virus (RSV): Inhaled ribavirin has been utilized for the treatment of children and immunocompromised hosts with modest benefits. Its use requires supervised nebulization in a closed room to prevent spread of RSV to hospital personnel. An intravenous formulation has been studied for severe disease. RSV hyperimmune globulin and monoclonal antibody preparations are used for severe infection in recipients of bone marrow and solid organ transplants. Corticosteroids are ineffective.

Varicella pneumonia: Prevention with prophylactic doses of oral acyclovir or varicella zoster immunoglobulin should be considered for patients at high risk for progression to pneumonia, such as pregnant women, AIDS patients, organ transplant patients, and other immunocompromised hosts. Confirmed or suspected cases of varicella pneumonia should be treated with intravenous acyclovir at 10mg/kg three times a day for seven to ten days.

Cytomegalovirus (CMV) pneumonia: CMV, a herpes virus, may cause severe infection in recipients of organ and bone marrow transplants and in patients with AIDS. CMV usually occurs six to twelve weeks after organ or bone marrow transplantation, and it occurs commonly in patients with advanced AIDS who have low CD4 counts. This infection carries a high mortality rate, and prophylaxis with ganciclovir or valganciclovir in combination with CMV hyperimmune globulin (CMV-IVIG) is commonly utilized.

Treatment of active CMV pneumonitis usually consists of ganciclovir and immune globulin.

Each antiviral agent has its own side effect profile. Ribavirin nebulization, which may precipitate bronchospasm and respiratory compromise, is considered a teratogenic drug. Intravenous ribavirin has been associated with mild hemolytic anemia. The neuramidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) are associated with a less than 5 percent rate of reported side effects: diarrhea, nausea, sinusitis, nasal symptoms, headache, and dizziness.

Inhaled zanamivir, a neuramidase inhibitor used in seasonal influenza, may precipitate bronchospasm and should be used with caution in patients with reactive or chronic airway disease. Intravenous acyclovir may cause seizures, leukopenia, thrombocytopenia, and renal impairment. Ganciclovir and valganciclovir are associated with bone marrow suppression, nephrotoxicity, pancreatitis, and gastrointestinal symptoms.

What is the prognosis for patients managed in the recommended ways?

Although the prognosis for viral pneumonia is good, influenza A and B may cause significant morbidity and mortality in patients older than age sixty-five. A recent review of 160 patients with seasonal influenza pneumonia revealed a similar mortality as other respiratory viruses (approximately 4%). The recent pandemics with SARS-associated coronavirus and influenza A (H1N1) and (H5N1) highlighted the virulence of newly identified viral strains that originate from animal viruses. SARS-associated coronavirus was associated with 774 deaths and a case fatality rate of 9.6 percent. The case mortality rate for avian influenza A (H1N5) was very high, at 14-33 percent. Initial mortality reports for influenza A swine origin (H1N1) were as high as 14-41 percent for critically ill patients, but the final overall case fatality worldwide was less than 0.1 percent.

What other considerations exist for patients with community-acquired viral pneumonia?

A patient suffering from a community-acquired viral infection must be placed in respiratory and droplet isolation to avoid spread to close contacts and hospital personnel. Hand washing is essential to prevent person-to-person transmission. Annual influenza vaccination is essential for the prevention of seasonal influenza and the pandemic 2009 influenza A (H1N1) infection.

What’s the evidence?

Ruuskanen, O, Lahti, E, Jennings, LC. "Viral pneumonia". Lancet. vol. 377. 2011. pp. 1264-1275.

Excellent updated review of viral pneumonia with emphasis on clinical presentation and diagnostic techniques.

Mandell, LA, Wunderink, RG, Anzueto, A. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults". Clin Infect Dis. vol. 44. 2007. pp. S27-72.

The definitive guideline for community-acquired pneumonia (CAP). This guideline has been utilized extensively in the development of hospital protocols for diagnosis of and empiric antibiotic therapy for CAP.

Marcos, MA, Esperatti, M, Torres, A. "Viral pneumonia". Current Opinion in Infectious Diseases. vol. 22. 2009. pp. 143-147.

Up-to-date review with particular interest in the diagnostic studies of viruses in community-acquired pneumonia.

Lapinsky, SE. "Epidemic viral pneumonia". Current Opinion in Infectious Diseases. vol. 23. 2010. pp. 134-144.

Excellent review of epidemic and pandemic infections with a concise review of SARS-associated coronavirus and pandemic influenza A (H5N1) and (H1N1).

"Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection". New England Journal of Medicine. vol. 362. 2010. pp. 1708-19.

Goins, WP, Talbot, HK, Talbot, TR. "Health care–acquired viral respiratory diseases". Infect Dis Clin N Am. vol. 25. 2011. pp. 227-244.

Good review with special interest in hospital-acquired viral pneumonias.
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