What every physician needs to know:
Pneumonia is the fourth leading cause of death in the world, accounting for about 5% of deaths annually. 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, the influenza A (H1N1) virus of 2009, and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) of 2012. 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 up to 50% of young children and 10-30% of adults. The highest incidence rates are found in children younger than age five, adults older than 75, and immunocompromised hosts. Recently, there has been a trend towards increased identification of viral pathogens in community-acquired lung infections, probably because of improved vaccination against bacterial pathogens (Haemophilus influenza type B and S. pneumoniae), 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 antiviral therapy promptly and implement adequate infection control measures to prevent community and nosocomial spread.
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, acute 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 in childhood pneumonia requiring hospitalization are respiratory syncytial virus (RSV, 28%), rhinovirus (27%), human metapneumovirus (HMPV, 13%), adenovirus (11%), influenza viruses (7%), parainfluenza (7%), and coronavirus (5%). In adult CAP, viruses are isolated at a lower rate of 10-29%, and the most common viruses among adults requiring hospitalization are rhinovirus (9%), influenza viruses (6%), human metapneumovirus (4%), RSV (3%), parainfluenza (2%), and coronavirus (2%). See Table I for details.
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 indistinguishable from those of bacterial lung infections and include cough, dyspnea, sputum production, and pleurisy. In children under five years of age, upper airway symptoms of rhinorrhea and congestion, low-grade fever, 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. Other key clinical features that suggest a viral etiology are a seasonal pattern with RSV in late fall and winter, rhinovirus in the fall and spring, and influenza in the 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, procalcitonin levels, and C-reactive protein levels. Finally, a recent study demonstrates that patients with viral pneumonia have higher creatinine kinase levels, lower platelet counts, and an increased frequency of alveolar-interstitial infiltrates compared to patients with bacterial pneumonia.
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 and winter, rhinovirus in the fall and spring, and influenza in the 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 endemic area is an important epidemiological clue. The severe acute respiratory syndrome (SARS) coronavirus pandemic of 2002-2003 originated in a province of China and spread rapidly, causing severe pneumonia in 8,000 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 pandemic influenza 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%. 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%. By March 2010, virtually all countries reported cases, resulting in more than 18,500 deaths from laboratory-confirmed cases worldwide. Eighty percent of the global mortality from H1N1 occurred in people under age 65.
In the fall of 2012, Middle East Respiratory Syndrome coronavirus (MERS-CoV) emerged in Saudi Arabia, producing ARDS and acute kidney injury in two patients. Since 2012, 1879 laboratory-confirmed cases have been reported, primarily in the Arabian Peninsula but with several cases reported from North Africa, Europe, Asia, and North America. MERS-CoV should be suspected in patients with either pneumonia or ARDS and contact with a confirmed MERS-CoV case or recent travel to the Middle East.
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 75. 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 for viral pneumonia include HIV infection, 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 count compared to those with bacterial pneumonia. For patients with a clinical diagnosis of pneumonia, a procalcitonin level of < 0.1 mcg/L is suggestive of a viral etiology, while a level > 0.25 mcg/L suggests bacterial infection. CRP is less sensitive for bacterial pneumonia than procalcitonin, but a CRP level >40 has a sensitivity of roughly 70% for bacterial pneumonia.
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 American Thoracic Society recommend obtaining a CXR in all patients with suspected pneumonia to document the presence of pulmonary infiltrates. 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 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, direct immunofluorescence, or PCR to viral antigens. Higher yields are obtained with the use of nasopharyngeal aspirates in children and nasopharyngeal swabs in adults. When these procedures are performed, the nasal swabs should enter the nares and advance to a depth of at least 2 cm. 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. However, H1N1 was found to have a predilection for the lower respiratory tract, so if clinical suspicion is high, a tracheal aspirate, sputum culture, or bronchoalveolar lavage may be necessary to detect the virus.
Because viral cultures typically take between 3-14 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 24-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 have an identified viral pathogen. The clinician must remember that a positive viral PCR is suggestive of viral infection; however, because respiratory viruses can be present in the nasopharynx without causing illness, positive viral PCR results may overestimate the actual incidence of viral pneumonia. During the pandemic influenza outbreaks with H1N1 and H5N1, viral RNA detection by reverse-transcriptase-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 can assist in the diagnosis of community-acquired viral lung infections. Lung biopsy specimens are rarely obtained during episodes of viral pneumonia. Post-mortem examination typically reveals interstitial pneumonitis with lymphocytic infiltration. RSV typically invades bronchial and alveolar epithelial cells with alveolar macrophages and inflammation with CD3-lymphocytes inflammation in 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), influenza A (H1N1), or MERS-CoV 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, CURB-65, IDSA-ATS criteria, and SMART-COP. In one study that compared the available prediction scores for intubation and mortality in pneumonia, the IDSA-ATS criteria had the highest sensitivity (74%) for predicting intubation or death, while CURB-65 had the best specificity (80%). Please note that these prediction scores were validated for bacterial pneumonia rather than viral etiologies.
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 RSV. Most experts recommend treating with antibiotics, since bacterial co-infection or superinfection is not easily excluded.
The treatment of viral pneumonia is primarily supportive with oxygen therapy, adjuvant antibacterial antibiotics, and non-invasive or invasive ventilation (if required). Patients with viral pneumonia who develop ARDS should be managed with lung protective ventilation strategies and conservative fluid management similar to patients with ARDS from other causes. The use of antiviral therapy for viral pneumonia is limited and discussed in the section below. Table II lists a few antiviral agents available for specific treatment of viral pneumonias:
Seasonal influenza: When started within 48 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 48 hours. The use of high-dose corticosteroids is not recommended and has been associated with increased mortality and longer viral shedding in patients suffering with H7N9 influenza pneumonia.
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 and because of its teratogenicity. An IV formulation has been studied for severe disease and oral formulations have been used as well. 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 IV acyclovir 10 mg/kg three times a day for seven to ten days.
Cytomegalovirus (CMV) pneumonia: CMV, a herpes virus, may cause severe infection in recipients of solid organ and stem cell transplants and in patients with AIDS. CMV usually occurs 6-12 weeks after solid organ or stem cell 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.
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, pegylated interferon alfa, and chloroquine may be therapeutic alternatives for SARS, and clinical studies are warranted. Other agents tested include IV immunoglobulin and combined lopinavir and ritonavir.
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 neuraminidase inhibitors, oral oseltamivir (Tamiflu) and inhaled zanamivir (Relenza). This influenza A was resistant to amantidine and rimantidine. For hospitalized patients, the preferred agent is IV zanamivir, which may be obtained via a compassionate-use request. Recently, IV peramivir was approved by the FDA for the treatment of acute influenza in patients 18 years or older and was utilized for treatment of critically-ill influenza A H1N1 patients in the U.S. Varying doses and duration of empiric corticosteroids were used in up to 69% of patients during the pandemic with no clear benefit.
Middle East respiratory syndrome coronavirus (MERS-CoV): Antiviral agents are not routinely recommended for the treatment of MERS-CoV. Retrospective observational reports of combination treatment with ribavirin and pegylated interferon alpha have shown inconsistent results. Adjunct corticosteroids are not recommended and may increase mortality. Mycophenolate demonstrates in vitro activity but was not effective in animal models. The utility of convalescent plasma and monoclonal antibodies is under investigation.
Side effects of antiviral therapy: Each antiviral agent has its own side effect profile. Ribavirin nebulization, which may precipitate bronchospasm and respiratory compromise, is also a teratogenic drug. IV ribavirin has been associated with mild hemolytic anemia. The neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza) are associated with a less than 5% 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 airway disease. IV 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 including seasonal influenza is generally good, viral infections may cause significant morbidity and mortality in immunocompromised patients and in patients older than 65. Recent pandemics with SARS-associated coronavirus, MERS, and avian and swine origin influenza A highlighted the virulence of newly identified viral strains that originate from animal viruses. The case fatality rate for MERS-CoV is approximately 36%, while SARS-associated coronavirus led to 774 deaths and a case fatality rate of about 10%. The case fatality rate for avian origin influenza virus is very high, ranging from 27% for H7N9 to 50% for H5N1. In contrast, case fatality rates for swine origin influenza A (H1N1) and seasonal influenza are much lower at 0.5% and 0.1%, respectively.
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 associated pandemics.
For suspected pandemic influenza or MERS-CoV, it is essential that the patient is rapidly triaged and isolated with standard, contact, and airborne precautions. Expert infectious disease consultation is recommended.
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- What every physician needs to know:
- Are you sure your patient has community-acquired viral pneumonia? What should you expect to find?
- Beware: there are other diseases that can mimic community-acquired viral pneumonia:
- How and/or why did the patient develop community-acquired viral pneumonia?
- Which individuals are at greatest risk of developing community-acquired viral pneumonia?
- What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
- What imaging studies will be helpful in making or excluding the diagnosis of community-acquired viral pneumonia?
- What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of community-acquired viral pneumonia?
- What diagnostic procedures will be helpful in making or excluding the diagnosis of community-acquired viral pneumonia?
- What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of community-acquired viral pneumonia?
- If you decide the patient has community-acquired viral pneumonia, how should the patient be managed?
- What is the prognosis for patients managed in the recommended ways?
- What other considerations exist for patients with community-acquired viral pneumonia?