Viral Pneumonia 

Updated: Jun 20, 2019
Author: Zab Mosenifar, MD, FACP, FCCP; Chief Editor: John J Oppenheimer, MD 

Overview

Practice Essentials

The reported incidence of viral pneumonia (see the image below) has increased during the past decade. In part, this apparent increase simply reflects improved diagnostic techniques, but an actual increase appears to have also occurred. Depending on the virulence of the organism, as well as the age and comorbidities of the patient, viral pneumonia can vary from a mild, self-limited illness to a life-threatening disease.

Bilateral interstitial infiltrates in a 31-year-ol Bilateral interstitial infiltrates in a 31-year-old patient with influenza pneumonia.

Signs and symptoms

The common constitutional symptoms of viral pneumonia are as follows:

  • Fever

  • Chills

  • Nonproductive cough

  • Rhinitis

  • Myalgias

  • Headaches

  • Fatigue

During physical examination, the patient may also display the following:

  • Tachypnea and/or dyspnea

  • Tachycardia or bradycardia

  • Wheezing

  • Rhonchi

  • Rales

  • Sternal or intercostal retractions

  • Dullness to percussion

  • Decreased breath sounds

  • Pleurisy

  • Pleural friction rub

  • Cyanosis

  • Rash

  • Acute respiratory distress

Influenza pneumonia

The influenza viruses are the most common viral cause of pneumonia. Primary influenza pneumonia manifests with persistent symptoms of cough, sore throat, headache, myalgia, and malaise for more than three to five days. The symptoms may worsen with time, and new respiratory signs and symptoms, such as dyspnea and cyanosis, appear.

Respiratory syncytial virus pneumonia

Respiratory syncytial virus (RSV) is the most frequent cause of lower respiratory tract infection in infants and children and the second most common viral cause of pneumonia in adults.

Patients with RSV pneumonia typically present with fever, nonproductive cough, otalgia, anorexia, and dyspnea. Wheezes, rales, and rhonchi are common physical findings.

Parainfluenza virus pneumonia

Parainfluenza virus (PIV) is second in importance only to RSV as a cause of lower respiratory tract disease in children and pneumonia and bronchiolitis in infants younger than 6 months. PIV pneumonia and bronchiolitis are caused primarily by the PIV-3 strain. The signs and symptoms include fever, cough, coryza, dyspnea with rales, and wheezing.

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

  • Cytologic evaluation: Intranuclear inclusions often exist in cells infected with a deoxyribonucleic acid (DNA) virus. Cytoplasmic inclusions usually are present in cells infected with a ribonucleic acid (RNA) virus.

  • Viral culture

  • Rapid antigen detection

  • Polymerase chain reaction (PCR) assay

  • Serologies: Particularly useful for definitively confirming the diagnosis

Radiography

Chest radiography usually demonstrates bilateral lung involvement, but none of the viral etiologies of pneumonia result in pathognomonic findings with this modality

Lung biopsy and histologic studies

Infrequently, lung biopsy is required to establish a diagnosis in very ill patients, who often are immunocompromised.

See Workup for more detail.

Management

All patients with viral pneumonia must receive supportive care with the following:

  • Oxygen

  • Rest

  • Antipyretics

  • Analgesics

  • Nutrition

  • Close observation

  • Intravenous fluids

  • Mechanical ventilation

Specific treatments for the various types of viral pneumonia include the following:

  • Influenza pneumonia: Amantadine hydrochloride and rimantadine hydrochloride are approved for the prevention and treatment of influenza A virus infection. Their efficacy in patients with influenza viral pneumonia or severe influenza is unknown.

  • RSV pneumonia: Ribavirin is the only effective antiviral agent available for the treatment of RSV pneumonia,[1] but there are conflicting data regarding its efficacy.

  • PIV pneumonia: Treatment is mainly supportive, but aerosolized and oral ribavirin have been associated with reduction in PIV shedding and clinical improvement in immunocompromised patients.

See Treatment and Medication for more detail.

Background

Viruses account for the largest proportion of childhood pneumonia. Viral pneumonia decreases in frequency in healthy young and middle-aged adults, but it then increases substantially among the elderly. Studies on community-acquired pneumonias consistently demonstrate viruses to be the second most common etiologic cause (behind Streptococcus pneumoniae), ranging from 13-50% of diagnosed cases.[2, 3, 4, 5, 6, 7]

The reported incidence of viral pneumonia has increased during the past decade. In part, this apparent increase simply reflects improved diagnostic techniques, but an actual increase has also appeared to occur. This observation is explained by the growing population of patients who are immunocompromised.[8] (See Epidemiology.)

Depending on the virulence of the organism as well as the age and comorbidities of the patient, viral pneumonia can vary from a mild and self-limited illness to a life-threatening disease. Especially in immunocompromised patients, viral pneumonia may result in respiratory failure, severe hypoxemia, and other pulmonary pathology. (See Prognosis.)

The four most frequent etiologies of viral pneumonia in children and immunocompetent adults are influenza virus, respiratory syncytial virus (RSV), adenovirus, and parainfluenza virus (PIV). Influenza virus types A and B are responsible for more than half of all community-acquired viral pneumonia cases, particularly during influenza outbreaks. (See Etiology.)

The image below depicts right-middle-lobe infiltrate in a two-month-old boy with pneumonia due to RSV

Right-middle-lobe infiltrate in a 2-month-old boy Right-middle-lobe infiltrate in a 2-month-old boy with pneumonia due to respiratory syncytial virus (RSV).

The relative importance of additional viruses (eg, parainfluenza, rhinoviruses, coronaviruses, human metapneumovirus) will likely increase as diagnostic tests such as reverse-transcription polymerase chain reaction (PCR), become more widely available.[9] (See Workup.)

Outbreaks of adenovirus of various serotypes frequently occur in military recruits. Adenovirus type 14 (Ad 14), a new variant in the United States, has been documented to cause severe and sometimes fatal acute respiratory illness in patients of all ages but especially the young, the old, patients with underlying comorbid conditions, and those who are immunocompromised.

Viral pneumonia is a subset of the pneumonitides, which were at one time called atypical pneumonias. In the past, all pneumonias were labeled atypical if a bacterial pathogen could not be identified with Gram staining and if the pneumonia did not respond to antibiotics.

Many viral pneumonias have overlapping clinical presentations with each other and with bacterial pneumonia—and may occur together with bacterial pneumonia—making diagnosis on purely clinical grounds difficult or impossible.[2] A number of rapid tests to determine viral etiologies have now been developed, and their use in the emergency department (ED) has allowed bedside diagnosis of the etiology of viral pneumonia.

An accurate and early etiologic diagnosis is important because specific therapies are used against certain viruses (see Treatment and Management). Even with currently available tests, however, in some series a causative microorganism could not be identified in 50-80% of symptomatic patients.

Agents used to treat cases of viral pneumonia include acyclovir, ganciclovir, and immunoglobulin. (See Medication.)

For more information, see Medscape’s Pneumonia Resource Center and Influenza Resource Center.

Pathophysiology

A full understanding of the pathophysiology and pathogenesis of viral diseases does not presently exist.

After contamination, most respiratory viruses tend to multiply in the epithelium of the upper airway and secondarily infect the lung by means of airway secretions or hematogenous spread. Severe pneumonias may result in extensive consolidation of the lungs with varying degrees of hemorrhage, with some patients developing bloody pleural effusions and diffuse alveolar damage.[10]

The mechanism of damage to tissues depends on the virus involved. Some viruses are mainly cytopathic, directly affecting the pneumocytes or the bronchial cells. With others, overexuberant inflammation from the immune response is the mainstay of the pathogenic process.

Immune responses can be categorized according to patterns of cytokine production. Type 1 cytokines promote cell-mediated immunity, while type 2 cytokines mediate allergic responses. Children infected with respiratory syncytial virus (RSV) who develop acute bronchiolitis, rather than mild upper respiratory infection symptoms, have impaired type 1 immunity or augmented type 2 immunity.[11]

In addition to humoral responses, cell-mediated immunity appears to be important for recovery from certain respiratory viral infections.[12] Impaired type 1 response may explain why immunocompromised patients have more severe viral pneumonias.

Respiratory viruses damage the respiratory tract and stimulate the host to release multiple humoral factors, including histamine, leukotriene C4, and virus-specific IgE in RSV infection and bradykinin, interleukin (IL)–1, IL-6, and IL-8 in rhinovirus infections. RSV infections can also alter bacterial colonization patterns, increase bacterial adherence to respiratory epithelium, reduce mucociliary clearance, and alter bacterial phagocytosis by host cells.

Influenza virus

Infection by influenza virus leads to cell death, especially in the upper airway. When direct viral infection of lung parenchyma occurs, hemorrhage is seen along with a relative lack of inflammatory cells. Mucociliary clearance is impaired, and bacterial adherence to respiratory epithelium occurs.

Infection with the influenza virus impairs T lymphocytes, neutrophils, and macrophage function, which leads to impairment of host defenses and may foster bacterial infection of normally sterile areas, including the lower respiratory tract. This impairment of host defenses may explain why as many as 53% of outpatients with bacterial pneumonia have a concurrent viral infection.

Adenoviruses

Little is known regarding mechanisms of pathogenicity of adenoviruses. Studies in children have identified increased production of cytokines, particularly tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 8 (IL-8). Age, health of the patient, and other unknown host factors are believed to play key roles.

Viral pneumonia in elderly persons

Elderly persons are at increased risk of infection and complications in viral pneumonia because of comorbidities. Waning cellular, humoral, and innate immune functioning may impair viral clearance, which allows spread of the virus to the lower respiratory tract resulting in increased inflammation. Elderly persons also have decreased respiratory muscle strength and impaired protection of the respiratory tract from mucus.[13]

Viral transmission

The mechanism of viral transmission varies with the type of virus. Routes include large-droplet spread over short distances (< 1 m), hand contact with contaminated skin and fomites and subsequent inoculation onto the nasal mucosa or conjunctiva (eg, rhinovirus, RSV), and small-particle aerosol spread (eg, influenza, adenovirus). Some viruses are extremely fastidious, whereas others have the capability of surviving on environmental surfaces for as long as 7 hours, on gloves for 2 hours, and on hands for 30 minutes.

Transmission routes for selected viral pneumonias are as follows:

  • Environmental factors (adenovirus, enterovirus, rhinovirus)

  • Direct contact with contaminated objects (VZV)

  • Transplantation of contaminated organs (cytomegalovirus [CMV]) or blood products (CMV)

  • Lower-respiratory aspiration of virus asymptomatically shed in the saliva (CMV, herpes simplex virus [HSV])

  • Reactivation of a latent infection (HSV, CMV)

  • Hematogenous spread (CMV)

  • Spread by healthcare personnel (SARS, measles, adenovirus, parainfluenza virus, RSV).

Hantavirus transmission is thought to occur primarily through inhalation of infected excreta from diseased rodents. The virus is also present in rodent saliva, so transmission can also occur from bites.

A number of viruses, including adenoviruses, influenza virus, measles virus, PIV, RSV, rhinoviruses, and VZV, are easily transmitted during hospital stays and cause nosocomial pneumonia. Adenoviruses, influenza viruses, PIV, and RSV account for 70% of nosocomial pneumonias due to viruses.

Pulmonary host defense

The pulmonary host defense is complex and includes the following components:

  • Mechanical barriers

  • Humoral immunity

  • Phagocytic cells

  • Cell-mediated immunity

Mechanical barriers are hairs from the nostrils that filter particles larger than 10 microns, mucociliary clearance, and sharp-angle branching of the central airways that helps the 5- to 10-micron particles to become impacted in the mucosa.

Humoral immunity is represented by mucosal immunoglobulin A (IgA), alveolar immunoglobulin M (IgM), and immunoglobulin G (IgG) present in transudates from the blood.

Phagocytic cells consist of polymorphonuclear (PMN) cells; alveolar, interstitial, and intravascular macrophages; and respiratory dendritic cells. Alveolar macrophages provide the first defense involved in internalizing and degrading the viral pathogens. They act as antigen-presenting and opsonin-producing cells.

Respiratory dendritic cells undergo maturation, activation, and early migration into the regional lymph nodes after the viral exposure. They act as antigen-presenting cells and are involved in the activation and differentiation of CD8+ T cells.

Cell-mediated immunity is the most important defense mechanism against the intracellular viral pathogens. This immunity is involved in antibody production, cytotoxic activity, and cytokine production. CD8+ memory or effector T cells tend to dominate the lymphocyte component of the virus-induced inflammatory component.

Experimental models demonstrated that 30-90% of CD8+ T cells recovered from bronchoalveolar lavage (BAL) are virus specific at the peak of the primary response. Studies in transgenic mice infected with influenza viruses documented that the CD8+ T cells are not recruited in the lung during the viral infection. They are resting memory cells formed after a previous encounter with the antigen, or they are acutely activated T cells after a nonrespiratory infection that undergo early migration in the lung and that are maintained there by specific ligands.

A substantial number of peripheral CD8+ memory T cells reside in the lung after a viral infection.

A secondary infection induces extensive renewal of CD8+ T cells in both lymphoid nodes and lungs. This replacement takes place in the absence of substantial inflammation or a substantial effector-cell population in the lungs. Respiratory infection allows numerous T cells to enter the airways and may permanently alter the permeability of the lung and mediastinal lymph nodes to lymphocytes.

Etiology

Both DNA and RNA viruses are involved in the etiology of viral pneumonia. Some are well-known lung pathogens that produce common clinical and radiologic manifestations. Others are rarely involved as lung pathogens.

Etiologic viruses include various families, as follows:

  • Adenoviridae (adenoviruses)

  • Coronaviridae (coronaviruses) -SARS, MERS

  • Bunyaviridae (arboviruses) -Hantavirus

  • Orthomyxoviridae (orthomyxoviruses) - Influenza virus

  • Papovaviridae (polyomavirus) – JC virus, BK virus

  • Paramyxoviridae (paramyxoviruses) -Parainfluenza virus (PIV), respiratory syncytial virus (RSV), human metapneumovirus (hMPV), measles virus

  • Picornaviridae (picornaviruses) – Enteroviruses, coxsackievirus, echovirus, enterovirus 71, rhinovirus

  • Reoviridae (rotavirus)

  • Retroviridae (retroviruses)- Human immunodeficiency virus (HIV), human lymphotropic virus type 1 (HTLV-1)

Most of the members of Herpesviridae family are documented lung pathogens in hosts with compromised cell immunity and include the following:

  • Herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2), also called human herpesvirus 1 (HHV-1) and human herpesvirus 2 (HHV-2), respectively

  • Herpesvirus 6, herpesvirus 7, and herpesvirus 8

  • Varicella-zoster virus (VZV)

  • Cytomegalovirus (CMV)

  • Epstein-Barr virus (EBV)

Influenza virus, respiratory syncytial virus, adenovirus, parainfluenza virus, coronavirus, rhinovirus, and human metapneumovirus may cause community-acquired viral pneumonia.

Influenza virus

The influenza viruses are enveloped, single-stranded, RNA viruses of the family Orthomyxoviridae and are the most common viral cause of pneumonia. Three serotypes of influenza virus exist: A, B, and C.

Influenza type A can alter surface antigens and infect livestock. This characteristic may account for its ability to create a reservoir for infection and cause epidemics in humans. The virus is spread by means of small-particle aerosol and targets the columnar epithelial cells along the entire respiratory tract.

Influenza type B causes illness that usually is seen in relatively closed populations such as boarding schools. Influenza type C is less common and occurs as sporadic cases.

Influenza type A is usually the most virulent pathogen. The influenza virus has two envelope glycoproteins, hemagglutinin (H) and neuraminidase (N), which are important for a number of reasons. The hemagglutinin initiates infectivity by binding to cellular sialic acid residues, whereas the N protein cleaves newly synthesized virus from sialic acid on cell surfaces, thus allowing spread of the virus to other cells.

The influenza virus maintains its infectivity by undergoing antigenic drift (small number of amino acid substitutions) and shift (large number of amino acid substitutions) due to changes in the protein structure of the surface protein, hemagglutinin. Epidemics occur when a viral drift occurs, and pandemics are seen with viral shift (two influenza A viruses exchange H or N genes during infection of the same hosts) because most people have no prior immunity to the virus.

Two influenza types have emerged of particular importance: H5N1 avian influenza strain and the novel H1N1 swine influenza strain.

Respiratory syncytial virus

Respiratory syncytial virus (RSV) is the most frequent cause of lower respiratory tract infection among infants and children and the second most common viral cause of pneumonia in adults. It is a medium-sized virus of the Paramyxoviridae family that consists of only 1 serotype. Structurally, RSV has 10 unique viral polypeptides, 4 of which are associated with virus envelope, and 2 of these (F and G) are important for infectivity and pathogenicity. Classic RSV infection causes syncytia formation in cell culture, giving the virus its name.

RSV is highly contagious, spreading via droplet and fomite exposure. Most children are infected before age 5 years—the infection rate during an epidemic approaches 100% in certain settings such as daycare centers—but the resulting immunity is incomplete. Reinfection in older children and young adults is common but mild. However, the likelihood of more severe disease and pneumonia increases with advancing age.

Adenoviruses

Adenoviruses are enveloped DNA viruses that cause a wide spectrum of clinical illnesses depending on the serotype of the infecting agent. These include asymptomatic illness, conjunctivitis, febrile upper respiratory disease, pneumonia, gastrointestinal illness, hemorrhagic cystitis, rash, and neurologic disease. Pneumonia is less common in adults outside of military recruit camps and similar facilities, but fulminant disease has been described in infants and in the immunocompromised population and can occur in apparently healthy hosts.[14]

Although 52 serotypes exist, classified into 7 subgroups or species (A-G), pulmonary disease is predominantly caused by serotypes 1, 2, 3, 4, 5, 7, 14, and 21. Type 7 viruses can cause bronchiolitis and pneumonia in infants. Types 4 and 7 viruses are responsible for outbreaks of respiratory disease in military recruits.

Adenovirus serotype 14 (subgroup B) is a more virulent strain that has been reported to cause severe respiratory illness and pneumonia. Emergence of this strain was reported in 2005 among civilian and military populations, with outbreaks occurring subsequently at military training centers throughout the United States.

In 2007, adenovirus serotype 14 caused a large, sustained outbreak of febrile respiratory illness among military trainees in Texas and, more recently, in a residential care facility in Washington State.[15, 16, 17] In a community outbreak in Oregon, the median age was 52 years, and 76% required hospitalization, 47% required critical care, 24% required vasopressors, and 18% died. The majority of these patients were otherwise immunocompetent adults.[18]

Spread of adenovirus is by respiratory secretions, infectious aerosols, feces, and fomites. Neonates may acquire infection from exposure to cervical secretions at birth.

Contaminated environmental surfaces can harbor virus capable of causing infection for weeks. The virus is resistant to lipid disinfectants but is inactivated by heat, formaldehyde, and bleach.

Adenoviruses are extremely contagious. Studies of new military recruits have shown seroconversion rates of 34-97% over a 6-week period.[15] The majority of children have serologic evidence of prior adenovirus infection by the age of 10.

Parainfluenza virus

Parainfluenza virus (PIV) is a common virus that infects most persons during childhood. PIV is second in importance to only RSV in causing lower respiratory tract disease in children and pneumonia and bronchiolitis in infants younger than six months. Transmission is through direct person-to-person contact or large-droplet spread.

PIV is characterized by nucleocapsids, which develop in the cytoplasm of infected cells, with hemagglutinin present in the virion envelope.

There are four subtypes of PIV, based on antigenic characteristics. PIV type 3 is endemic year-round, while types 1 and 2 peak during the fall season. Immunity is short term, and recurrent upper or lower respiratory tract infections occur throughout life. The infections vary from a mild illness to life-threatening croup, bronchiolitis, or pneumonia. Infection in immunocompromised hosts can result in life-threatening pneumonia with lung injury and respiratory failure. In one study, 44% of hematopoietic stem cell transplant (HSCT) patients with PIV progressed to develop pneumonia, of which 37% died.[19]

Rhinovirus

Some authors report that rhinovirus accounts for up to 30% of cases of all virus-related pneumonia. Clinical studies show that rhinovirus is the second most frequently recognized agent associated with pneumonia and bronchiolitis in infants and young children. Rhinovirus infection is linked to asthma hospitalizations in both adults and children.

A study of 211 French children with rhinovirus infection revealed bronchiolitis or bronchitis in 25.6% and pneumonia in 6.2%, after cases of dual bacterial or viral infections were eliminated.

A study from the Netherlands demonstrated that rhinoviruses cause 32% of all lower respiratory tract infections with an identified pathogen in the elderly (> 60 y) symptomatic population. Rhinoviruses were identified more frequently than coronaviruses (17%) or influenza viruses (7%).

Human metapneumovirus

Human metapneumovirus (hMPV) is a relatively newly discovered respiratory pathogen, initially described in the Netherlands in 2001.[20] hMPV is in the Paramyxoviridae family (like RSV and PIV) and is a pleomorphic-shaped virus surrounded by surface protein projections. This virus is a ubiquitous organism, and most surveys indicate that by age five years, almost all children have been exposed to it. However, reinfection occurs throughout life, including in adults. This virus is spread via droplet and fomite exposure.

As a human pathogen, hMPV may have been underestimated. In children and infants, hMPV was reported to be a notable cause of lower respiratory tract infections such as bronchiolitis (59%), croup (18%), asthma (14%), and pneumonia (8%).

As with other viruses, the severity of infection increases with older age and with comorbid (cardiopulmonary disease) or immunosuppressive conditions. The most common diagnoses associated with adult hospitalizations with hMPV infection are chronic obstructive pulmonary disease (COPD) exacerbations, bronchitis, and pneumonia.[21] In immunocompromised hosts (eg, hematologic malignancies), severe pneumonitis requiring intensive care or resulting in death has been reported.[22, 23]

Coronavirus

Coronaviruses are from the family Coronaviridae and are single-stranded RNA viruses, the surface of which is covered by crownlike projections, giving the virus its name. This virus is spread via droplet and fomite exposure. Long known to cause upper respiratory infections, coronaviruses were not felt to significantly cause pneumonia until relatively recently. However, the severe acute respiratory syndrome (SARS) pandemic in 2003 brought the ability of this virus to cause life-threatening pneumonia to worldwide attention (see Zoonotic Viral Pneumonia, below).

Six human coronaviruses (HCoVs) have now been identified: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-COV (which causes severe acute respiratory syndrome), and MERS-COV (Middle East respiratory syndrome). These HCoVs appear to be established human pathogens with worldwide distribution, causing upper and lower respiratory tract infections, especially in children. Typically, HCoV infection follows a seasonal pattern similar to that of influenza, although Hong Kong researchers found that HCoV-NL63 infections mainly occurred in early summer and autumn.[24]

Varicella-zoster virus

Varicella-zoster virus (VZV) is a highly contagious herpes virus that is spread by the respiratory route or direct contact with skin lesions. Primary infection manifests as chickenpox. The reactivation results in zoster (shingles).

Pneumonia is a significant and life-threatening complication in otherwise healthy adults (including pregnant women) and immunocompromised hosts. This pneumonia is rare in otherwise healthy children but does occur in immunocompromised children.

Complications 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 tract virus that causes a febrile illness with rash in children. Mild pneumonia often occurs but is usually of no consequence in healthy adults.

Measles may result in severe lower respiratory tract infection and high morbidity in hosts who are immunocompromised and malnourished. This virus is highly contagious and is transmitted from person to person by droplets. The incubation period is 10-14 days and peaks in late winter and early spring.

Cytomegalovirus

Cytomegalovirus (CMV) is a herpesvirus that is a common cause of infections, usually asymptomatic, in the general population. In hosts who are immunocompetent, acute CMV infection causes a mononucleosis-like syndrome. Transmission is primarily through body fluid contact. The virus has been found in the cervix and in human milk, semen, and blood products. The prevalence of antibodies to CMV in adults ranges from 40-100%, with higher rates in lower socioeconomic areas.

Reactivation of latent infection is almost universal in transplant recipients and individuals infected with the human immunodeficiency virus. CMV pneumonia may occur and is often fatal in immunocompromised individuals, primarily hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. The severity of pneumonia is related to the intensity of immunosuppression. Additionally, CMV infection is itself immunosuppressive, causing further immunocompromise in these patients.

In cancer patients receiving allogeneic bone marrow transplants, CMV pneumonia has a prevalence of 15% and a mortality rate of 85%, making it the most common cause of death in this population. Acute graft-versus-host disease is the major risk factor for CMV pneumonia in these patients.

Interestingly, although CMV is a well-recognized pathogen in patients with AIDS (manifesting as retinitis, colitis, encephalitis, polyradiculitis, and/or cholangiopathy), clinically relevant pneumonia is very uncommon in this group, even if CMV is cultured from alveolar fluid and/or seen on lung histology.

Herpes simplex virus

Herpes simplex virus (HSV) is a rare cause of lower respiratory tract infections and is seen primarily in severely immunocompromised patients, primarily HSCT and SOT recipients, patients who are undergoing chemotherapy or are neutropenic, or those who have congenital immunodeficiency.[25] HSV pneumonia develops either secondary to upper airway infection (because of direct extension of the virus from the upper to the lower respiratory tract) or following viremia secondary to dissemination of HSV from genital or oral lesions.

Herpes simplex virus is spread by contact with active lesions or viral shed by asymptomatic excreters. While not a classic respiratory virus, herpes simplex virus can cause pneumonia in compromised hosts, with a mortality rate of 80%. Pneumonia may develop from primary infection or reactivation.

Zoonotic viral pneumonias

Zoonotic viral pneumonias include those caused by the hantavirus, avian influenza, severe acute respiratory syndrome (SARS), and H1N1 (swine) influenza.

Hantavirus

Hantavirus is a genus of enveloped RNA viruses in the family Bunyaviridae. The majority are transmitted by arthropod vectors. Hantaviruses, however, are harbored by rodents, with each viral species having one major rodent host species. Rodents, which are chronically infected, excrete hantaviruses from urine, saliva, and feces. Infection occurs after aerosols of infectious excreta are inhaled.

The hantavirus pulmonary syndrome (HPS) is seen in the Americas and is an acute pneumonitis caused by the North American hantavirus, most notably the Sin Nombre Virus.[26, 27] Two other agents, isolated in other parts of North America, can also cause HPS.

Hantaviruses originally were recognized in the four-corners region of the southwestern United States (New Mexico, Arizona, Utah, and Colorado) in May 1993. The deer mouse (Peromyscus maniculatus) was identified to be the reservoir.

Cases of HPS have continued to be reported in the United States. As of July 2010, 545 cases of HPS had been reported in the United States from 32 states.[28]

Avian influenza

In Hong Kong in 1997, an influenza virus (H5N1 virus) previously known to infect only birds was found to infect humans. Manifestations included pneumonia, which in some cases led to fatal acute respiratory distress syndrome (ARDS) or multisystem organ failure.

Prior to the human outbreak, the H5N1 virus caused widespread deaths in chickens on three farms in Hong Kong. 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.

Concern is growing that avian influenza, which is a subtype of influenza A, may result in a worldwide pandemic in the near future. The avian influenza virus A/H5N1 has several ominous characteristics, including increased virulence and human-to-human transmission in several cases, rather than bird-to-human transmission, as is usually necessary. The disease causes high mortality as a result of pneumonia and respiratory failure.

The 1997 outbreak in Hong Kong was thought to be controlled by depopulating 1.5 million chickens in local farms and markets. However, human infections occurred in 2001 through 2003 in other parts of Asia, and the virus has been found in poultry and birds in Europe.

The rising incidence and widespread reporting of disease from H5N1 influenza viruses can probably be attributed to the increasing spread of the virus from existing reservoirs in domestic waterfowl and live bird markets, leading to greater environmental contamination. As of January 2014, 650 cases of H5N1 human infections have been reported from 16 countries since 2003, with 386 deaths (59% mortality).[29]

Severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) was due to a novel coronavirus (CoV) that crossed the species barrier through close contact between humans and infected animals. Viral isolation and genomic sequencing have revealed that the SARS virus originated in the masked palm civet cat (Paguma larvata), raccoon dog (Nyctereutes procyonoides), and possibly the Chinese ferret-badger (Melogale moschata), with subsequent interspecies jumping, during which a partial loss of genome probably led to more efficient human-to-human transmission.

Horseshoe bats (Rhinolophus sinicus) have also been found to harbor SARS-like coronaviruses (more distantly related to SARS-CoV than that of the palm civets), raising the possibility of bats being a reservoir for future SARS infections.

SARS was a particularly challenging disease because its long incubation period allowed seemingly healthy travelers who were infected with the virus to spread it. The SARS coronavirus (SARS-CoV) quickly spread from China to the rest of the world over a period of 1 year, affecting more than 8000 patients in 29 countries and resulting in 774 deaths.

Global transmission of SARS was halted in June 2003 after the World Health Organization instituted traditional public health measures, including finding and isolating case-patients, quarantining contacts, and using enhanced infection control.[30] No cases of SARS have been reported since 2004.

H1N1 (swine) influenza

Initially reported as an outbreak in Mexico and subsequently the United States, infection from a novel swine-origin influenza A (H1N1) virus rapidly spread to become a worldwide pandemic in 2009. The World Health Organization declared an end to the pandemic in August 2010.

Virus-associated hemophagocytic syndrome may play an important role in development of multiorgan failure and ensuing death in H1N1 infection.[31]

For more information on H1N1 influenza, see H1N1 Influenza (Swine Flu). Rare causes of viral pneumonia include Epstein-Barr virus and rotavirus.

Epstein-Barr virus

Epstein-Barr virus (EBV) is transmitted through infected saliva. Pneumonia as a complication of mononucleosis is very uncommon. The virus can cause pneumonia in the absence of mononucleosis.

Lung involvement secondary to EBV infections is more often reported in immunocompromised people than in others. In 25% of pediatric patients with HIV infection, EBV can cause lesions related to lymphocytic interstitial pneumonia or pulmonary lymphoid hyperplasia.[32]

Rotavirus

Although upper respiratory tract infection secondary to rotavirus is common, rotavirus pneumonia is rare. Just a few cases have been reported.

Epidemiology

Traditionally, viruses were felt to cause approximately 8% of cases of community-acquired pneumonia for which patients are hospitalized. More recent investigations have demonstrated viruses to play a larger role, causing 13-50% of pathogen-diagnosed community-acquired pneumonia cases as sole pathogens and 8-27% of cases as mixed bacteria-virus infections.[3, 4, 5, 33]

Influenza virus types A and B account for more than 50% of all community-acquired viral pneumonias in adults. Various studies have reported differing frequencies of the other viruses causing community-acquired pneumonias, with RSV ranging from 1-4%, adenovirus 1-4%, PIV 2-3 %, hMPV 0-4%, and coronavirus 1-14% of pathogen-diagnosed pneumonia cases.[3, 4, 5, 33]

The impact of influenza is high in elderly persons and greatest for those with chronic illnesses. It has been estimated that at least 63% of the 300,000 influenza-related hospitalizations and 85% of 36,000 influenza-related deaths occur in patients aged 65 years or older, despite the fact that this group accounts for only 10% of the population.[34]

RSV is the most common etiology of viral pneumonia in infants and children.[35] In addition, RSV has become an increasingly important pathogen in the elderly population and is now the second most commonly identified cause of pneumonia in elderly persons, causing 2-9% of the annual 687,000 hospitalizations and 74,000 deaths from pneumonia in this population.[13]

Some studies have suggested that RSV-related disease is as frequent as influenza in elderly persons. Approximately 10% of nursing home patients develop RSV infection annually, while 10% of these patients will develop pneumonia.

Parainfluenza infection is the second most common viral illness, after RSV, in infants.

Adenovirus accounts for 10% of pneumonias in children. Disease from adenovirus can occur at any time of the year. Various adenovirus serotypes are responsible for essentially continuous epidemics of acute respiratory disease at military recruit training facilities in the United States and worldwide. During the prevaccination era, up to 20% of recruits had to be removed from duty due to illness.[36] Unfortunately, the vaccine against adenovirus is no longer available for administration to military personnel.

Viral pneumonia in immunocompromised hosts

Although immunocompromised patients are at higher risk for viral pneumonia from CMV, VZV, HSV, measles, and adenoviruses, seasonal viruses (influenza, RSV, PIV) remain a major cause of pneumonia. HSCT and SOT recipients are particularly at risk for acquiring lower respiratory tract infection due to CMV and RSV.[37, 38]

CMV pneumonia has been observed in 10-30% of patients with HSCT and 15-55% of heart-lung transplant recipients, making this virus the most common cause of viral pneumonia in the former patient group.[39] After CMV, the frequency of viruses isolated from HSCT patients vary, with influenza virus ranging from 14-52%, RSV 14-48%, adenovirus 2-21%, and PIV 11-49% of viral isolates.[40]

Although HSV has been shown to cause pneumonia in this patient population, it is relatively rare when compared with the other viral pathogens, with one study showing HSV to cause 5% of nonbacterial pneumonias in HSCT recipients, compared with 46% for CMV.[41]

Viral pneumonia in pregnancy

Acute viral pneumonia is common and often underdiagnosed in pregnancy. Although the severity of bacterial pneumonia does not seem to be increased in pregnancy, viral pneumonia can have a serious clinical evolution.

Among the viral pathogens, influenza virus, VZV, and measles virus are reported as etiologic agents in severe lower respiratory tract infection. The infection may result in acute respiratory decompensation, respiratory failure, and/or ARDS, which can lead to maternofetal hypoxia, preterm labor, multisystem organ failure, and even death.

Pregnant women seem to be at increased risk for influenza pneumonia. VZV pneumonia is rare but potentially lethal, with mortality rates of 35-40% in pregnant women, compared with 10% in the general population.

Measles virus can be a considerable cause of pneumonia in pregnant women. Further bacterial superinfection can complicate the clinical and radiologic picture.

Despite reports of a high mortality rate during outbreaks of hantavirus pulmonary syndrome, no cases of maternal fatalities secondary to this disorder have been reported to date.

Sex differences in viral pneumonia

Men who are infected develop viral pneumonia at a slightly higher rate than women. Pregnant women with viral pneumonia have a higher risk for severe disease than other females. Pregnant patients have a disproportionate risk of severe disease with 2009 H1N1 infection. Treatment should be initiated as soon as the diagnosis is suspected.[42]

Age-related differences in viral pneumonia

Most viruses that can cause pneumonia 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.[13]

The main exception to this was seen in the 2009-2010 H1N1 influenza pandemic, in which severe infection was more common in the population aged 5-59 years than in the elderly. This was thought to be from lack of exposure, and thus immunity, to the 1957 (and earlier) H1N1 influenza strain(s).[43]

Mortality and Morbidity

The US census for 2000-2001 listed pneumonia/influenza as the seventh leading cause of death (down from sixth) despite a 7.2% decrease in the mortality rate for these diseases during this period. Severe influenza seasons can result in more than 40,000 excess deaths and more than 200,000 hospitalizations.

Patients aged 65 years or older are at particular risk for death from viral pneumonia as well as from influenza not complicated by pneumonia. Deaths in these patients account for 89% of all pneumonia and/or influenza deaths.

Morbidity, especially in elderly persons, is also high. Up to 10-12% of patients older than 65 years required a higher level of assistance for activities of daily living after hospitalization for acute respiratory illnesses. In one nursing home outbreak, residents with acute influenza illness showed significant functional decline.[44]

Pneumonia from adenovirus serotypes other than Ad 14 has a low fatality rate, and most serotypes have a low morbidity rate.

Influenza virus

Influenza virus represents a common cause of pneumonia in the adult population, affecting 4-8% of healthy adults. Rates have been 10-20% during outbreaks and as high as 50% during epidemics. Morbidity and mortality rates related to influenza pneumonia in both the general population and in selected groups (eg, patients with chronic diseases, the elderly) are substantial.

The highest rates of hospitalization for influenza 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. Between 1972 and 1992, 426,000 deaths related to influenza pneumonia were reported in United States. Individuals 85 years or older were 16 times more likely than those aged 65-69 years to die from influenza.

Also in contrast with seasonal influenza, mortality was higher in younger patients with H1N1 influenza, with 87% of deaths and 71% of severe pneumonia in the age group of 5-51 years.[43] The higher mortality in patients younger than 60 years may reflect this cohort’s lack of exposure to the 1957 (and earlier) H1N1 influenza strains. Exposure to those early strains may have conferred some immunity in the older population. Also of interest is a report that identified obesity as a possible risk factor for more severe disease/mortality.[45]

As of February 2010, the CDC had estimated that 8,330 to 17,160 H1N1-related deaths occurred between April 2009 and January 16, 2010 in the United States,[46] and the World Health Organization (WHO) has estimated that, worldwide, at least 16,226 deaths have been directly attributable to H1N1.[47]

The H5N1 avian influenza seems to be more virulent than seasonal influenza, with a 59% mortality rate in cases reported thus far.[29] The median time from disease onset to death is nine days. The majority of these patients had no underlying medical problems.

Respiratory syncytial virus

RSV pneumonia is responsible for an average of 80,000 pediatric hospitalizations and 500 deaths every year. The mortality rate depends on the patient's immunologic status. In healthy children, the reported mortality rate is 0.5-1.7% but is higher in immunosuppressed patients (< 80-100% in untreated HSCT recipients vs 22% in treated control subjects).

In adults, RSV pneumonia is associated with a mortality rate ranging from 11-78%, depending on the severity of underlying immune suppression. In long-term care facilities, 5-27% of respiratory tract infections have been estimated to be caused by RSV, 10% of which will develop into pneumonia and 1-5% of which will be fatal.[48] In immunocompromised patients, particularly HSCT recipients, the mortality rate for RSV pneumonia is high, at 41%.[40]

Adenovirus

Adenovirus infection has been associated with low mortality in healthy adults, but death from a 2009 community outbreak of serotype 14 pneumonia was 18%.[18] In immunocompromised patients, adenovirus can be acquired not only by person-to-person transmission but also from reactivation, to produce a wide variety of syndromes, including gastroenteritis, hepatitis, and hemorrhagic cystitis (in addition to pneumonia), with mortality rates ranging from 38-100% and with a cumulative mortality rate of 56% in HSCT patients.[40]

Parainfluenza virus

PIV pneumonia causes 250,000 emergency visits annually, resulting in 70,000 admissions. Fully 18% of hospitalized children with respiratory tract infections in the United States have this disease.

Rates of PIV pneumonia are increased in immunocompromised pediatric groups, such as recipients of BMT, HSCT, lung transplantation, and solid-organ transplantation. PIV has been associated with 10% of acute respiratory illnesses in healthy adults and 10-50% in transplant recipients. In the latter group, the mortality rates range from 15-73%.[40] One study documented that 56% of PIV isolates were associated with upper respiratory symptoms in HSCT recipients but that 44% developed pneumonia, of whom 37% died.[19]

Human metapneumovirus

HMPV accounts for up to 10% of unexplained respiratory infections in children. Some authors report that HMPV can account for 30% of unidentified, suspected cases of viral pneumonia in transplant patients.

The relatively recent recognition of hMPV in causing pneumonia and the difficulty in its diagnosis has precluded accurate estimates of mortality rates, but case reports of deaths exist, primarily in patients with hematologic malignancies undergoing chemotherapy or HSCT.[23, 49] Mortality rates in transplant recipients have ranged from 50% in lung transplant patients to 80% in HSCT recipients.[50] A 2009 hMPV outbreak at a psychiatric ward in Taiwan, all in immunocompetent patients, resulted in 1 (of 13 diagnosed patients) death from respiratory failure.[51]

Varicella-zoster virus

In the United States, varicella pneumonia occurs with a frequency of 0.32-1.36 cases per 100,000 persons per year. Among Americans hospitalized because of varicella, 1.0-2.3 in 400 develop pneumonia.

Varicella pneumonia complicates approximately 2-10% of the cases of VZV infection in adults. At least 25% of the fatalities from varicella in adults occur in persons who develop varicella pneumonia. The severity of varicella pneumonia is highest in immunosuppressed persons, with mortality rates of 15-18%, and in pregnant women in the second/third trimesters, with a mortality rate of 41%.

The overall mortality in the general population has decreased from 19% (range, 10-30%) in 1960-1970 to 6%. In renal transplant patients, the mortality decreased from 53% in 1981-1990 to 22% in 1991-2000. The mortality rate is around 50% in intubated patients with acute respiratory failure. In HIV-infected patients, a mortality rate of 43% is reported, and in pregnant women, the mortality rate is about 41%.

Measles virus

In the United States, pneumonia is responsible for 60% of the measles mortality in infants. Although deaths from measles in the United States decreased steadily throughout the 20th century—from approximately 12 per 100,000 population in 1912 to approximately 0.2 per 100,000 population in 1960—mortality rates declined markedly after a measles vaccine was licensed in 1963.[52]

Measles is almost eradicated in the Western Hemisphere. Although only 71 cases were confirmed in the United States in 2009, a sharp increase occurred in 2014. Through August 1, 2014, 593 confirmed measles cases were reported to CDC's National Center for Immunization and Respiratory Diseases (NCIRD).[53] This is the highest number of cases since measles elimination was documented in the US in 2000. Measles-virus pneumonia is still a notable cause of mortality and morbidity in nonvaccinated children and immunocompromised adults.

In 1990, 6.5% of Americans with measles developed pneumonia. A study of 3220 US military recruits demonstrated that 3.3% had measles-related pneumonia. Most cases of pneumonia were secondary to bacterial superinfection. No deaths were reported among these otherwise healthy adults. However, in another study using different diagnostic criteria, pneumonia was found in 50% of recruits with measles. A follow-up study of Afghani children hospitalized for measles revealed an 85.4% rate of bronchopneumonia.

The CDC reported four cases of measles pneumonia, with two fatalities, among HIV-infected children in 1986-1987.[54] In children, mortality rates due to measles bronchopneumonia are high (28%). The mortality rate due to measles pneumonia is even higher in immunocompromised groups: 70% in those with cancer and 40% in those with AIDS. Investigators reported 10 fatalities secondary to measles pneumonia in 12 children with leukemia.

Cytomegalovirus

CMV pneumonia is considered the most common life-threatening complication of bone marrow transplantation (BMT) and solid-organ transplantation.

The rate of CMV pneumonia in BMT recipients is 10-50%, as reported in different studies. In patients receiving solid-organ transplants, CMV reactivation is reported in as many 70% of patients, but only 20% develop clinically significant infections. Studies of CMV pneumonia in BMT recipients demonstrate a 31% mortality rate in treated patients and a decrease from previously reported rates of 56-100% in untreated patients. The mortality rate is reportedly 75% in untreated immunosuppressed persons.[55]

Herpes simplex virus

HSV pneumonia develops mainly in immunocompromised patients. The rate of HSV pneumonia can be as high as 70-80% in hematopoietic stem-cell transplantation (HSCT) recipients not receiving prophylaxis, and it can be decreased to 5% with acyclovir prophylaxis. As with CMV, the mortality rate is high if disease remains untreated in immunosuppressed patients (>80% mortality).[56]

Hantavirus

As of July 2010, 545 cases of HPS had been reported in the United States from 32 states, mostly New Mexico, Colorado, Arizona, California, Washington, Texas, and Utah (in decreasing order of prevalence).[28] HPS is also reported in South America and in Canada. The mortality rate for HPS is 35%. Of individuals with HPS, 61% are men and 39% are women, with a mean age of 37 years. Caucasian patients account for 77%, people of Native American descent account for about 20%, and those of Hispanic descent account for 13%.

Prognosis

The prognosis is good in the vast majority of patients with viral pneumonia. It is guarded in elderly or immunocompromised patients. Some adenovirus serotypes, especially 2, 3, 7, and 21 have been the cause of serious chronic morbidity after acute respiratory illness, including irreversible atelectasis, bronchiectasis, bronchiolitis obliterans, and unilateral hyperlucent lung.[16] An estimated 14-60% of these children will suffer some degree of permanent lung damage. Many of these patients presented with pharyngitis, tonsillitis, and bronchitis. Adenovirus 14 has a high fatality and morbidity rate in healthy patients. Serious sequelae occurred in those who survived.

Viral pneumonia may leave patients with residual disability from interstitial fibrosis. Infants hospitalized with lower lung infection due to RSV are much more likely to later develop asthma.

Patient Education

For patient education resources, see the Lung Disease & Respiratory Health Center and the Cold and Flu Center. In addition, see the patient education articles Viral Pneumonia and Flu in Adults.

 

Presentation

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 viral pneumonias are fever, chills, nonproductive cough, rhinitis, myalgias, headaches, and fatigue. Symptoms of viral pneumonia are similar to that of bacterial pneumonia, although studies have shown a lower probability of having chest pain and rigors in viral pneumonias.[3] Most patients have cough, but in elderly persons, this may be only scant.

Ascertaining immunization status, travel history, and possible exposure is important. During outbreaks with the usual respiratory viruses, the signs and symptoms can suggest the correct diagnosis in most cases. In very elderly persons, the only complaint may be fever and change in mental status.

In immunocompromised patients, recognition of the clinical picture of viral pneumonia, risk factors, and new changes in clinical parameters is important. All of these findings can indicate the need for further imaging or other diagnostic procedures to make an etiologic diagnosis and to start early treatment.

The typical infection with influenza virus presents with sudden onset of fever, chills, myalgia, arthralgia, cough, sore throat, and rhinorrhea. The incubation period is 1-2 days, and symptoms normally 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. Influenza is usually seen in epidemics and pandemics in late winter and early spring.

Peak attack rates for respiratory syncytial virus (RSV) occur in the winter in infants younger than six months. Parainfluenza (PIV) infection most often occurs in the late fall or winter, although PIV-3 pneumonia is especially common in the spring.

Physical Examination

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

Some patients have few, if any, physical findings other than mild fever, whereas other patients may have respiratory and/or multiorgan failure. Other findings include the following:

  • Fever and/or chills

  • Cough (with or without sputum production)

  • Tachypnea and/or dyspnea

  • Tachycardia or bradycardia

  • Wheezing

  • Rhonchi

  • Rales

  • Sternal or intercostal retractions

  • Dullness to percussion

  • Decreased breath sounds

  • Pleurisy

  • Pleuarl friction rub

  • Cyanosis

  • Rash

  • Acute respiratory distress

Influenza virus

Influenza pneumonia especially affects the following groups of patients:

  • Children with cystic fibrosis or organ transplants

  • Adults with chronic cardiovascular or respiratory disease, diabetes mellitus, renal diseases, hemoglobinopathies, or immunosuppression

  • Residents of nursing homes or chronic care facilities

  • Healthy adults older than 65 years.

The three clinical forms of influenza pneumonia are primary influenza pneumonia, secondary bacterial pneumonia, and mixed viral and bacterial pneumonia.

Primary influenza pneumonia manifests with persistent symptoms of cough, sore throat, headache, myalgia, and malaise for more than 3-5 days. The symptoms may worsen with time, and new respiratory symptoms, such as dyspnea and cyanosis, may appear. This form is the least common but the most severe in terms of pulmonary complications.

Secondary bacterial pneumonia is characterized by the relapse of high fever, cough with purulent sputum after initial improvement, and radiographic evidence of new pulmonary infiltrates. The most common pathogen is Streptococcus pneumoniae (48%), followed by Staphylococcus aureus,[57] Haemophilus influenzae, and Gram-negative pathogens.

Elderly persons may have a lower frequency of upper respiratory complaints. One study demonstrated that the triad of cough, fever, and acute onset had only a 30% positive predictive value, in contrast to 78% in young adults. Fever and altered mental status may be the only signs of influenza pneumonia in an older patient with chronic cognitive impairment. Gastrointestinal complaints and myalgia are more common in influenza than in RSV infection.[48, 58]

Avian influenza (H5N1) has an incubation period of 2-5 days, but symptoms may begin up to seven days after exposure. The primary initial symptom is fever, and symptoms of cough, malaise, myalgia, headache, sore throat, abdominal pain, vomiting, and diarrhea are also common. The gastrointestinal complaints may initially suggest gastroenteritis. When pneumonia develops, cough, followed by dyspnea, tachypnea, and chest pain, are reported. In severe cases, encephalitis/encephalopathy, cardiac failure, renal failure, multiorgan failure, and disseminated intravascular coagulation can occur.[59]

H1N1 influenza presents similarly to seasonal influenza. Fever and cough are almost universal symptoms. Shortness of breath (54%), fatigue/weakness (40%), chills (37%), myalgias (36%), rhinorrhea (36%), sore throat (31%), headache (31%), vomiting (29%), wheezing (24%), and diarrhea (24%) are the most common other symptoms.

Mixed viral and bacterial pneumonia is common and can manifest as a gradual progression of disease or as a transiently improving condition followed by a worsening one. Both bacterial pathogens and an influenza virus are isolated.

Respiratory syncytial virus

Risk factors for RSV infection include age younger than six months, underlying lung disease (bronchopulmonary dysplasia or cystic fibrosis), and congenital heart disease in children with asthma. Institutionalized elderly and immunosuppressed patients (eg, those with severe combined immunodeficiency, leukemia, and/or transplant) are also at risk.

RSV infections in adults are poorly characterized and rarely diagnosed. They are accompanied by long-lasting upper respiratory tract infections and are more commonly associated with a prolonged productive or bronchitic cough and wheezing than with other features. The findings tend to mimic the decompensated underlying cardiopulmonary disease rather than the acute viral disease.

Various studies reported RSV pneumonia in recipients of solid organ transplants or HSCTs. The clinical manifestations are usually severe, and supplemental oxygen and mechanical ventilation are required.

Severe cases of RSV giant-cell pneumonia have been reported in 4-10% of cases and also during concurrent viral infections with EBV, CMV, or adenovirus.

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.

Patients with RSV pneumonia typically present with fever, nonproductive cough, otalgia, anorexia, and dyspnea. Wheezes, rales, and rhonchi are common physical findings.

Pneumonia and bronchiolitis often are difficult to differentiate, and both can be associated with wheezing, rales, and hypoxemia. Dyspnea and cough are seen in 60-80% of cases. Compared with influenza, RSV is more often associated with rhinorrhea, sputum production, and wheezing and less often associated with gastrointestinal complaints and fever.[1, 60]

Immunocompromised hosts may have a range of respiratory involvement. These patients develop fever, cough, rhinorrhea, sinus congestion, and respiratory difficulties; nearly half report wheezing. In these patients, the symptoms range from mild dyspnea to severe respiratory distress and respiratory failure.

While most patients with RSV infection, including infants, have only upper respiratory symptoms, as many as 25-40% develop bronchiolitis and/or pneumonia. Statistics demonstrate that as many as 20-25% of infants with pneumonia who require hospitalization are infected with RSV.

Lower respiratory disease in infants is preceded by a prodrome of rhinorrhea and, perhaps, poor appetite. Low-grade fever, cough, and wheezing usually occur. The chest examination reveals tachypnea, rales, and fine wheezes. Disease from RSV in young, healthy adults is usually mild, although one study of community-acquired pneumonia showed RSV to be the third most common pathogen,[60] after S pneumoniae and influenza viruses A and B.

During their first RSV infection, 25-40% of infants and young children have signs or symptoms of bronchiolitis of pneumonia, and 0.5-2% require hospitalization. Most pediatric patients hospitalized for RSV infection are younger than six months.

Parainfluenza virus

Clinical manifestations of PIV infection can range from mild upper respiratory tract infections (mainly in immunocompetent patients) to severe croup, bronchiolitis, or life-threatening pneumonia in the setting of immunosuppression. Incubation is 1-3 days. The classic croup symptoms of barking cough, hoarseness, and stridor commonly seen in children is less commonly seen in adults. In adults who are immunocompromised, cough is the hallmark.

PIV-1 and PIV-2 produce croup in children that initially manifests as an upper respiratory tract infection followed by a barking cough, dyspnea, stridor, and chest-wall retractions. PIV-2 infections tend to be milder than PIV-1 infections. PIV-4 causes mild upper respiratory tract infection in both adults and children.

PIV-3 is the main strain that causes pneumonia and bronchiolitis. The signs and symptoms are nonspecific, more prominent in children, and similar to, but milder than, those of RSV pneumonia. They include fever, cough, coryza, dyspnea with rales, and wheezing.

Immunosuppression promotes the development of PIV pneumonia. Situations leading to immunosuppression include the following: BMT, solid-organ transplantation (with mild forms), severe combined immunodeficiency in children, or therapy with etanercept.

PIV infection may appear as giant-cell pneumonia. This form is most frequent in immunocompromised patients (after BMT or umbilical-cord transfusion) and rarely associated with alveolar proteinosis. The mortality rate approaches 100% in children, with a better prognosis than this in adults.

PIV pneumonia may mimic other lung infections most commonly encountered in an immunocompromised host. Several clinical findings tend to distinguish PIV or RSV lung infection from CMV or other opportunistic forms of pneumonia: upper respiratory infection before lung infection, clinical and imaging evidence of sinusitis, and wheezing.

As many as one third of children with PIV infection can have bacterial superinfection. Even if long-term sequelae are uncommon, cryptogenic organizing pneumonia is described after PIV infection.

Human metapneumovirus

Symptoms of human metapneumovirus (hMPV) infection are similar to those caused by other viruses: nasal congestion and cough are present in 82-100% of cases. Other symptoms include rhinorrhea (69-82%), dyspnea (69%), wheezing (62%), sputum production (55%), hoarseness (46-91%), and sore throat (23-45%). The incubation period is 5-6 days.

In one study, hoarseness was more common in hMPV than in RSV infection. Hoarseness, dyspnea, and wheezing were significantly more common among the elderly older than 65 years than among adults younger than 40 years.[21]

In different studies, cough was reported in 90% of patients; dyspnea, in 83%; coryza, in 88%; and fever, in 52-92%. Among the physical signs, rales, wheezing, or stridor were found in one half of infected children. In children, hMPV is an important cause of wheezing (9% in a 132 case series). Fever, cough, dyspnea, and sore throat are commonly described in adults. In HSCT recipients, hMPV pneumonia is reported and tends to cause respiratory failure.

Coronavirus

The incubation period is 2-5 days, with a mean of 3 days. Symptoms are similar to those from other respiratory viruses, including cough, rhinorrhea, sore throat, headache, and malaise, although fever was only seen in 21-23% of cases.

Varicella-zoster virus

The initial presenting symptoms of VZV infection are low-grade fever, malaise, and a rash that is typically vesicular, starts on the trunk and face, spreads centrifugally to other parts of the body, and usually is in various stages of evolution (from vesicles to crusted scabs) by the time of presentation. VZV pneumonia develops in 1 in 400 cases.

VZV pneumonia starts gradually within 1-6 days after the rash appears and manifests with fever, chest tightness, tachypnea, dyspnea, dry cough, cyanosis, and (in rare cases) pleuritic chest pain and hemoptysis. Physical examination reveals minimal findings, with rare rhonchi or wheezes. New chest symptoms are strongly associated with radiologic findings. VZV pneumonia can develop as a mild disease, or it can be severe and rapidly fatal, especially in immunocompromised individuals.

Some patients may be asymptomatic. One study in military personnel noted that only 25% of those with VZV pneumonitis experienced cough and 10% had tachypnea.[61]

Risk factors related to VZV pneumonia are smoking, pregnancy (third trimester), immunosuppression, and male gender. The presence of more than 100 spots during the skin eruption, prolonged fever, a history of contact with an index case, and chest symptoms at presentation are also reported risk factors.

Measles virus

The incubation period of measles is 10-14 days after exposure, after which a prodrome of fever, malaise, anorexia, conjunctivitis, cough, and coryza ensue. Toward the end of the prodrome, Koplik spots (small white punctate lesions) may appear on the buccal mucosa.

The rash is an erythematous, maculopapular eruption that may become confluent, beginning on the face, then progressing down the body to involve the extremities last, including palms and soles.

Atypical measles occurs in patients who were immunized from 1963-1967 with a killed vaccine and are exposed to measles virus or live measles virus vaccine. In these cases, the rash starts in the hands and feet rather than in a central distribution.

Duration of the rash is approximately 5 days, after which it may desquamate. Duration of symptoms is usually 10 days, and the cough may be the last symptom to disappear.

In adults, 3% of measles cases are complicated by significant pneumonia requiring hospitalization, with 17% of patients experiencing bronchospasm and 30%, bacterial superinfection. Bacterial superinfection most often occurs 5-10 days after the onset of the rash. The pulmonary findings parallel the cutaneous signs, and the severity of pneumonia correlates with worsening rash.

Persons at risk for measles-virus pneumonia are those with T-cell immunosuppression (eg, those taking steroids), BMT recipients, and those with HIV infection, lymphoma, leukemia, or Epstein-Barr virus infection. Others at risk are children and the elderly, pregnant women, those with vitamin A deficiency, and persons not vaccinated or those in whom primary vaccination failed.

Four types of measles-associated pneumonia are encountered. The first, measles-virus pneumonitis, usually appears within a few days after the onset of rash. High levels of KL6 (a glycoprotein secreted by pneumocyte-2) are markers for interstitial pneumonia and are associated with a poor prognosis.

The second form, bacterial superinfection, usually develops several days after rash appears. This type manifests with cough, fever, purulent expectoration, tachycardia, and pleural pain.

Third, giant cell pneumonia typically develops before or with the peak of viral exanthema. In rare cases, it develops after five months or longer. Rash may be absent. Cough may persist for 1-2 weeks during recovery. Lung biopsy may be needed for final diagnosis.

Fourth, pneumonia of atypical measles is described in adults. These patients developed a potentially fatal illness, with increased fever (7-14 d after exposure), minimal or absent rashes, headache, arthralgias, hepatitis, interstitial or nodular infiltrates, hilar lymphadenopathy, and occasional pleural effusions.

Cytomegalovirus

CMV pneumonia is usually mild in otherwise healthy individuals. It starts as a mononucleosis-like syndrome (eg, malaise, fever, myalgias) with mild hepatitis and no lymphadenopathy or splenomegaly.

In immunocompromised people, the clinical picture may vary. Most commonly, asymptomatic shedding affects pulmonary secretions, blood, and urine, with no clinical significance and low mortality rates.

CMV syndrome manifests with self-limited fever and constitutional symptoms (fever, malaise, anorexia, myalgias, arthralgias, fatigue). CMV syndrome precedes CMV pneumonitis by 1-2 weeks and usually has a sudden onset, with respiratory complaints (cough, dyspnea, tachypnea), fever, an increased A-a gradient, and radiologic infiltrates. The duration is less than two weeks. See the A-a Gradient calculator.

In allogeneic HSCT recipients, CMV disease presents post engraftment (30-99 d after transplantation) and late (≥ 100 d) in those with graft versus host disease and/or on higher-dose immunosuppressive therapy. CMV pneumonia is seen in 10-30% of such patients, and the median time to occurrence is 44 days after transplantation.

Autologous HSCT recipients are at much lower risk for CMV pneumonia, seen in only 1-9% of cases, oftentimes with milder symptoms.

Among solid organ transplant recipients, CMV pneumonia is most common in lung transplantations, ranging from 15-55% of cases. Typically, this pneumonia develops between day 15-60 post transplantation and is characterized by fever, cough, and hypoxia. In CMV donor-positive/recipient-negative cases, the onset and progression can be rapid.

Other solid organ transplantations are associated with low rates of CMV pneumonia: liver, 9.2%; heart, 0.8-6.6%; and kidney less than 1%.

For BMT recipients, risk factors include pretreatment seropositivity, total-body irradiation, certain immunosuppressive treatment, severe acute or chronic graft-versus-host disease, underlying disease (acute lymphoblastic leukemia [ALL] or chronic lymphocytic leukemia [CLL]). Patients with primary CMV infection and allogeneic HSCT are at increased risk for severe disease.

In HIV patients, the pathogenic significance of CMV is considered low, even in the condition of common identification of viruses in bronchoalveolar lavage (BAL) and biopsy specimens. CMV pneumonia is found in HIV patients with a CD4 count of less than 200 cells/µL. CMV is thought to be a co-pathogen to Pneumocystis jiroveci and a cause of alveolar hemorrhage in HIV patients (due to thrombotic microangiopathy).

Clinical outcomes range from mild, self-limited illness to rapidly fatal infection with multiorgan involvement (retinitis, colitis, hepatitis). The mortality rate can be high.

CMV complicated by obstructive bronchiolitis in heart-lung and double-lung recipients affected 47% of 36 patients in a study in France. Risk factors were CMV seropositivity among donors and CMV pneumonia or CMV recurrence.

Herpes simplex virus

Herpes simplex virus causes pneumonia in only the most severely immunocompromised patients. HSV is not usually isolated from immunocompetent patients, or even from BAL fluid from HIV-infected patients. The rate of HSV pneumonia can be as high as 70-80% in HSCT recipients not receiving prophylaxis, and it can be decreased to 5% with acyclovir prophylaxis.

HSV pneumonia often is preceded by oral mucocutaneous lesions or esophagitis. The presence of mucocutaneous disease, esophagitis, or tracheitis, especially with endotracheal intubation, increases the likelihood of this pneumonia. The spectrum of respiratory diseases due to HSV infection ranges from oral pharyngitis to membranous tracheobronchitis and diffuse or localized pneumonia, which can proceed to ARDS.

In BMT recipients, the usual presentation of HSV pneumonitis consists of dyspnea, fever, cough, and hemoptysis with associated dysphagia, liver, and CNS involvement. HSV pneumonia in organ-transplant recipients is reported.

In ICU patients, HSV pneumonia manifests as an unexplained dyspnea or as a failure of weaning the patient from a ventilator. One study showed that most ICU patients had been intubated (95%) or had undergone thoracic surgery (73%) at the time of diagnosis. Blood transfusions, use of corticosteroids and other immunosuppressants, local trauma, smoking, and burns are risk factors.

Dyspnea, cough, fever, tachypnea, intractable wheezing, chest pain, and hemoptysis are common symptoms of HSV pneumonia.

Hantavirus

Hantavirus pulmonary syndrome (HPS) has an incubation period of 9-35 days.

HPS is characterized by four clinical phases, as follows:

  • Prodrome

  • Noncardiogenic pulmonary edema/adult respiratory distress syndrome and shock

  • Diuresis

  • Convalescence

Fever and myalgia are prominent in almost all phases and precede the onset of respiratory symptoms by 1-10 days. Cough and upper respiratory symptoms are uncommon, in contrast to many of the other viral prodromes to pneumonia. 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.

Onset and rapid progression of cough, shortness of breath, fever, and hypotension herald the cardiopulmonary phase of the disease. Progressive pulmonary edema and respiratory failure can occur in 80-90% of patients within two days of hospitalization. The interval between the onset of dyspnea and respiratory failure requiring ventilatory support may be a few hours. The earliest indication is hypoxemia.

In addition to the rapidly progressive, fulminant, and often fatal form of HPS, there is also a limited, less severe form associated with mild interstitial edema and minimal airspace disease.

Adenovirus

Symptoms of adenovirus infection include fever, malaise, headache, sore throat, hoarseness, and cough. The incubation period is 4-5 days. Keratoconjunctivitis and diarrhea may or may not be seen, depending on the serotype (8, 19, 37 causing the former, and 2, 3, 5, 40, 41 causing the latter).

Serotype 14 pneumonia is associated most commonly with fever (89%) and cough (82%). Other common symptoms include shortness of breath (58%), vomiting (42%), diarrhea (34%), headache (29%), myalgias (29%), coryza (26%), chills (26%), sore throat (21%), and chest pain (16%).[17]

In adults who are immunocompromised, fever is predominant and gastrointestinal symptoms can be severe. Although adenovirus is almost always isolated from the respiratory tract, pulmonary symptoms may not be prominent and dissemination can occur without significant evidence of pneumonia (by symptoms or radiographs). Dissemination can lead to gastroenteritis, hepatitis, and hemorrhagic cystitis.[40]

Avian influenza

Avian influenza has a fulminant course and a high mortality rate. The clinical symptoms of avian influenza depend on the etiologic agent. Those infected with A/H7N7 have conjunctivitis and/or an influenzalike illness. In the 1997 outbreak of A/H5N5, 11 of 18 patients were younger than 14 years. Gastrointestinal symptoms of abdominal pain, diarrhea, and vomiting were prominent. Seven recovered, but 11 progressed to pneumonia and six died of ARDS or multiorgan failure.

In the 2004 outbreak, the young were affected more frequently, diarrhea was again prominent, fever was universally present, and the main presenting syndrome was community-acquired pneumonia. Lymphopenia and thrombocytopenia were common findings in all series of outbreaks and were prognostic indicators of ARDS and death. The case-fatality rate ranged from 64-80%. The incidence of asymptomatic or mild infection is unknown.

Epstein-Barr virus

Lung involvement secondary to EBV infection is rare and can occur as a complication of infectious mononucleosis. In healthy individuals, pulmonary manifestations, such as dyspnea and cough, are rare. Chronic interstitial lung disease is reported in immunocompetent patients.

In children with cystic fibrosis, EBV can cause deterioration in pulmonary function that lasts longer than six months after the infection is diagnosed.

In HIV patients, relatively few studies have been conducted to investigate EBV-related pulmonary disease. EBV seems to be related to the development of AIDS-associated non-Hodgkin lymphoma. BAL fluid samples from 72 European patients with AIDS were positive for EBV in five. The patients had fever and low PaO2, with no radiographic infiltrates, and recovery was the rule.

In BMT recipients, EBV-related lung manifestations are among widespread extrarenal manifestations of posttransplant lymphatic disease. A fulminant presentation soon after transplantation is associated with a dire prognosis. Young age and primary infection are risk factors. Patients with EBV infection are at subsequent risk for other viral lung superinfection (eg, severe RSV or Mycoplasma pneumoniae infection).

Human herpesvirus

HHV 6 (A and B) and HHV 7 have a limited clinical significance and prevalence as lung pathogens. HHV 6 appears in healthy individuals or HIV-infected patients with a high CD4+ count, in whom it may result in further immunosuppression. HHV 8 is an important pathogen in HIV patients with a 200 CD4+ count of less than 200 cells/µL and has been associated with Kaposi sarcoma in the lungs, sometimes with alveolar hemorrhage.

Human immunodeficiency virus

HIV pneumonitis usually manifests as several months of mild cough and dyspnea and bilateral infiltrates on chest radiograph. Transbronchial biopsy is usually required for diagnosis. The differential diagnosis includes Pneumocystis pneumonia.

Human lymphotropic virus

HTLV-1–related lung inflammatory disorders (eg, bronchopneumopathy associated with HTLV-1) encountered in HTLV-1 carriers include lymphocytic interstitial pneumonia, diffuse panbronchiolitis, bronchiectasis, and bullous lung disease.

Rhinovirus

Rhinoviruses are a common cause of upper respiratory tract infection, but in rare cases they can trigger lower respiratory tract infections, too. Rhinoviruses commonly cause exacerbations of preexisting airway disease in those with asthma, chronic obstructive pulmonary disease (COPD),[62] or cystic fibrosis.

Rhinovirus-induced lower respiratory infections in children include bronchiolitis or bronchitis (25.6%), pneumonia (6.2%), and acute episodes of asthma (5.7%). Among 211 French children hospitalized with rhinovirus infection, 29% had ARDS. In addition, 9% of children had an associated bacterial infection, and 9% had a dual viral involvement.

Rhinoviral infection can be complicated by S pneumoniae superinfection. This might be explained by increased adherence of this virus to epithelial tracheal cells after rhinoviral infection.

Rotavirus

Rotavirus pneumonia is rare. In one study, rotaviruses were isolated in 27% of all tracheal aspirates from children with pneumonia. One case of fatal rotaviral pneumonitis with myocarditis was reported in a two-year-old boy.

Two cases of fatal rotaviral pneumonitis were reported in adults. One patient was receiving long-term steroid therapy and developed rapidly progressive respiratory distress that evolved into severe respiratory failure not responsive to supportive measures. The other patient presented with massive pulmonary edema and pleural effusions.

Transplantation-related pneumonia

In recipients of thoracic organ transplants, chest complications, though rare, may manifest as tracheobronchitis, localized viral pneumonia, or diffuse and bilateral pneumonic infiltrates involving mainly the lower lobes. These findings may develop secondary to bacterial pneumonia, bronchiolitis obliterans syndrome, or acute allograft rejection. Mild clinical manifestations occur in 64% of lung transplant recipients with lung infection due to influenza virus or PIV.

Complications

Most viral pneumonias in immunocompetent hosts resolve with few sequelae. However, respiratory failure may develop secondary to superimposed bacterial infection.

Secondary bacterial infections are common. Common organisms are Streptococcus pneumoniae, Staphylococcus aureus,Streptococcus pyogenes (group A Streptococcus), and Haemophilus influenzae.

Late sequelae of viral pneumonias include bronchitis and bronchiolitis, especially following infection with RSV and influenza viruses.

Adenovirus serotypes 2, 3, 7, and 21 have been the cause of serious chronic morbidity after acute respiratory illness, including irreversible atelectasis, bronchiectasis, bronchiolitis obliterans, and unilateral hyperlucent lung. An estimated 14-60% of these children will suffer some degree of permanent lung damage. Serious sequelae occurred in patients who survive severe infection with adenovirus 14.

A retrospective cohort study of 100 children with RSV revealed a 79% complication rate. Nearly 24% were considered serious, and 16% of children required mechanical ventilation. The authors concluded that RSV infections in children considerably lengthen their hospital stay and medical costs. In fact, hospital costs approach $1 billion annually in the United States. In addition, 20% of all patients are rehospitalized, and more than 40% develop asthma.

Complications of RSV pneumonia in children are a considerable burden on hospital costs. About 60% of the complications are respiratory and consist of respiratory failure, apnea, stridor, hemoptysis, infiltrates and/or atelectasis, hyperinflation, pneumothorax, or pleural effusions. About 15% of radiographs are described as normal in children with complications. Prematurity and congenital diseases are risk factors for complications.

Viral (mainly PIV) or bacterial (especially S pneumoniae) superinfections, tuberculosis reactivation, and subsequent bronchiectasis are complications of measles pneumonia.

Temporary decreases in the forced expiratory volume in 1 second (FEV1) and/or forced vital capacity (FVC) or a permanent decrease in the lung transfer factor for carbon monoxide (TLCO) are reported in patients with VZV pneumonia. One case of VZV pneumonia complicated by a bacterial lung abscess in a child is reported.

 

DDx

Diagnostic Considerations

Studies document that patients are frequently infected with both bacterial and viral pathogens, making it impossible to rule out bacterial disease even when rapid viral test results are positive. Additionally, no unique identifying clinical characteristics are present that allow the physician to differentiate viral disease from bacterial disease in the emergency department (ED).

Although the most common cause of community-acquired pneumonia remains Streptococcus pneumoniae (a fact that may change with the increasing use of pneumococcal vaccines), in as many as 40-60% of patients with community-acquired pneumonia, the etiologic agent is not identified. Furthermore, convincing associations between the patient's symptoms, physical findings, laboratory test results, and specific etiologies are lacking.

Therefore, no way of accurately determining the etiology of pneumonia during the initial visit to the ED exists. Obtaining a chest radiograph in patients with suspected pneumonia is recommended, both to find complications, such as pleural effusions, and to discourage the use of antibiotics in healthy patients with bronchitis rather than pneumonia.

Influenza viruses are the most common cause of viral pneumonia in civilian adults. Influenza usually is seen in epidemics and pandemics. Influenza A is the serotype most frequently responsible for major epidemics and pandemics; it is the most frequent cause of viral pneumonia in adults.

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

Patients with high-grade fever, myalgias, and cough during the winter months should be suspected to have influenza. If test results are negative for influenza, RSV pneumonia should also be suspected during the winter in patients with coryza, wheezing, low-grade fever, and patchy infiltrates on chest radiographs. 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.

Viral pathogens and host factors

Patient age and immune status can offer a clue to the possible etiology of viral pneumonia. The following viruses commonly cause pneumonia in children:

  • Respiratory syncytial virus

  • Influenza viruses A and B

  • Parainfluenza virus

  • Adenovirus

  • Human metapneumovirus

  • Coronavirus

  • Measles virus (in unvaccinated children)

The following viruses commonly cause pneumonia in immunocompetent adults:

  • Influenza viruses A and B

  • Adenovirus

  • Respiratory syncytial virus

  • Parainfluenza virus

  • Coronavirus

  • Varicella-zoster virus

The following viruses commonly cause pneumonia in immunocompromised hosts:

  • Cytomegalovirus

  • Herpes simplex virus

  • Influenza

  • Respiratory syncytial virus

  • Parainfluenza virus

  • Adenovirus

  • Varicella-zoster virus

Differential Diagnoses

 

Workup

Approach Considerations

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, respiratory syncytial virus (RSV) and cytomegalovirus (CMV) can be detected in the presence of other known bacterial pathogens.

In most circumstances, virologic tests are the mainstay of precise etiologic diagnosis. Rapid antigen detection kits can provide results within hours, making them useful in the emergency department. The sensitivity and specificity of these kits varies between 80% and 95%. See Table 1.

Table 1. Diagnostic Techniques Used for Viral Pneumonia (Open Table in a new window)

Virus

Viral Culture

Cytologic Evaluation

Rapid Antigen Detection

Gene Amplification

Influenza virus

HAa, SVb

 

IFc, ELISAd

RT-PCRe

Adenovirus

CEf, 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 simplex 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 FCVg

FVC RNA by RT-PCR

a HA - Hemaglutination

b SV - Shell viral culture

c IF - Immunofluorescence

d ELISA - Enzyme-linked immunosorbent assay

eRT-PCR - Reverse transcriptase polymerase chain reaction

fCE - Cytopathogenic effects

gFCV - Four corners virus

Viral cultures are still the criterion standard for most viral pathogens, but they take a long time to complete. Therefore, methods faster than this have been introduced. Viral-antigen detection is one of the new tests, but the results are generally less sensitive and less specific than those of conventional cell cultures.

Viral nucleic material amplification, such as hybridizations, various polymerase chain reactions (PCRs),[63] and serologic tests, can be used to follow the increase in specific serum antibodies and for diagnostic purposes.

Recent interest has focused on developing PCR-based tests with single, multiplex, and real-time readings. These tests have sensitivity better than that of cultures.

Nested PCR and reverse-transcriptase (RT) PCR are the most sensitive methods. They increase the detection rate of respiratory viruses in adults with hematologic cancers and pneumonia from 19% to 35%.

PCR is limited by the fact that the results cannot completely rule out contamination of the specimens. In some immunocompromised patients, who shed the virus for long periods, the diagnosis can be of little clinical significance. This limitation is overcome by using quantitative PCR, which shows the level of viral load. The findings can also help in differentiating active infection from contamination.

Because of the difficulty in distinguishing between the various etiologic agents, both viral and bacterial, causing pneumonia, the workup for symptomatic patients with an infiltrate on chest radiograph should include laboratory studies.

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.

Viral cultures are of lower yield in RSV infection (viral lability, lower titers in samples), human metapneumovirus (hMPV) infection, and coronavirus infection (special growth requirements).

Modified cell culture methods called shell vial culture systems are able to detect certain slow-growing viruses. Shell vial culture systems are used widely for earlier detection of CMV, RSV, herpes simplex virus (HSV), adenovirus, influenza viruses, parainfluenza virus (PIV), and other viral pathogens.

In this 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 one hour, after which fresh culture medium is added. Next, the vials are incubated and examined serially to detect viral antigen or DNA expression. Results typically become available in 2-3 weeks.

Sputum Gram stains

Sputum Gram stains are often contaminated with oral pathogens and are difficult to obtain. They are not recommended by the American Thoracic Society or the American College of Emergency Physicians, although the Infectious Diseases Society of America recommends obtaining a sputum sample, particularly in hospitalized patients.

Blood cultures

The utility of blood cultures in patients with pneumonia remains controversial. Local hospital protocols should be consulted to determine which patients with pneumonia are candidates for hospitalization and who should have blood cultures drawn prior to administration of medications.

Rapid Antigen Detection

Rapid antigen detection tests provide faster results because the test is performed directly on specimens obtained from patients. Nasal swabs or washings are easy to obtain

Immunofluorescence assay and enzyme-linked immunosorbent assay (ELISA) are available for the diagnosis of HSV, RSV, influenza viruses 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.[64]

RSV rapid antigen detection is useful in young children, who shed high titers of virus, but sensitivity is low in adults (0-20%) when compared with RT-PCR.

Sensitivity for seasonal influenza in adults ranges between 50% and 60%, and specificity is greater than 90%. Novel swine-origin influenza A H1N1 virus should be detectable by rapid influenza testing. However, sensitivity with rapid tests is significantly lower (51-63%) when compared with RT-PCR. Rapid influenza tests unfortunately have very poor sensitivity and specificity for the avian H5N1 influenza virus and are therefore not recommended.

With ED patients, a call to the hospital laboratory is suggested to determine the optimal test to be ordered and whether a specific viral identification should be requested or whether a general request for viral detection will result in testing for a panel of pathogens. If rapid test results are negative but clinical suspicion is high, cultures can be obtained and the patient treated until results are known. Positive viral identification cannot rule out bacterial co-infection.

Gene Amplification

PCR is a highly sensitive and specific technique for amplifying genes to detect the presence of a virus. For many viruses, this is the diagnostic test of choice, and if possible, it should be used in combination with viral culture and immunocytologic and rapid antigen detection. PCR technology allowed the discovery of such viruses as RSV, hMPV, and coronaviruses in causing pneumonias.

For influenza H1N1 and avian influenza, RT-PCR of either nasopharyngeal swabs or bronchial aspirates/sputa is the diagnostic modality of choice.

PCR has become especially useful for the detection of CMV in various body fluids (eg, blood, urine) in severely immunocompromised patients, particularly hematopoietic stem cell transplant (HSCT) recipients.

A newly developed molecular diagnostic technique, multiplex reverse transcriptase polymerase chain reaction (MRT-PCR), permits rapid detection of influenza virus types A and B, RSV (types A and B), adenoviruses, PIV (types 1, 2, and 3), hMPV, and rhinovirus in appropriate respiratory tract secretions.[65, 66] The single-step MRT-PCR technique has high sensitivity and specificity. Influenza H1N1 is reported as "non-typeable influenza" by the MRT-PCR.

Serologies

Almost all viral infections can be diagnosed via paired acute/convalescent serologies (usually measured by complement fixation or enzyme immunoassay [EIA]). Because many of these viruses are ubiquitous, this method ideally requires a four-fold rise in titers.

Because, by definition, this technique requires blood to be drawn in the convalescent phase, it is not as useful in the acute management of the patient, unless enough time has elapsed such that the acute draw might represent the convalescent titer. In this situation, one high titer may give the diagnosis.

Serologies are particularly useful for definitively confirming the diagnosis, especially the positive results of other diagnostic tests.

Arterial blood gases

ABGs may be of great value in identifying hypoxemia in severe disease but are unnecessary in mild or moderate disease. Pulse oximetry should be obtained in all patients.

Virus-Specific Laboratory Studies

Virus-specific laboratory studies exist for viruses such as influenza virus, respiratory syncytial virus, adenoviruses, parainfluenza virus, human metapneumovirus, varicella-zoster virus, measles virus, cytomegalovirus, herpes simplex virus, and hantavirus. Renal function should be checked and followed in patients with serious 2009 H1N1 disease because acute renal injury is common in such patients.[67, 68]

Influenza virus

Influenza can be isolated from nasal/throat swabs, nasal washes, and sputa on viral culture (in a variety of kidney cell lines). Throat swabs have the lowest yield. Ninety percent of positive cultures can be detected within three days of inoculation, and the remainder can be detected by day seven.

Many rapid tests exist for influenza virus types A and B, but sensitivities are 40-80% when compared with viral culture. However, the specificity is high (85-100%). Per above, novel S-OIV can be detected by rapid tests, but the sensitivity is low (51-63%), and for avian influenza, this test is not useful. RT-PCR of sputa is the most useful diagnostic test for the latter 2 influenza strains.

Respiratory syncytial virus

RSV can be isolated via culture (HEp-2, HeLa, A549 cell lines), whereby nasopharyngeal washes or tracheal secretions are of higher yield than nasal swabs. For immunocompromised hosts, 15% of nasopharyngeal wash specimens are positive, compared with 71% of endotracheal secretions and 89% of bronchioalveolar washes.

Rapid detection by EIA has a sensitivity of 50-90% (higher in children but lower in adults), but specificity is high (90-95%). RT-PCR is also available, especially in combination with primers of other viruses (such as MRT-PCR).

Adenoviruses

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.

Serotype 14 can be diagnosed by viral culture, direct fluorescent antibody rapid antigen detection, and PCR. In the HSCT population, adenovirus PCR from plasma has been shown to be a good predictor of disease, especially at a threshold of 1000 copies/mL.[69]

If adenovirus 14 is suspected, because of severity of illness and negative bacterial and viral cultures, clinicians should contact their state public health department for aid in testing.[70]

Parainfluenza virus

Parainfluenza can be isolated in cell culture (various kidney cell lines), preferably from nasal secretions. Isolation of this virus is strong evidence of its infection. PCR is more sensitive and rapid for detection and is also available in the single multiplex assay.

Human metapneumovirus

It is difficult to isolate hMPV in standard cell cultures, and it replicates (grows) very slowly. The optimal cell line is tertiary cynomolgus monkey kidney or rhesus monkey kidney cell culture with trypsin added; cultures need to be observed for 21 days for cytopathic effect. Because of culture difficulties, RT-PCR is the preferred method for diagnosis.

Varicella-zoster virus

Varicella-zoster virus (VZV) infection and pneumonia can be diagnosed mostly on clinical grounds. VZV can be isolated from vesicular fluid, respiratory secretions, or cerebrospinal fluid (CSF) by culture. Rapid antigen detection tests such as direct immunofluorescence can be performed on cell scrapings of skin lesions.

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 and has a sensitivity of 60%. VZV PCR can also be performed using many different body fluids (particularly CSF).

Measles virus

Measles pneumonia is usually diagnosed clinically, but laboratory diagnosis can be helpful. Measles virus can be grown in monkey and human kidney cell lines. Cytopathic effects are observed in 6-10 days. Eosinophilic inclusions are found in the cytoplasm and nucleus of the infected cells. Immunofluorescent examination of cells from nasal exudates can also be used. Paired acute/convalescent serologies are also used for diagnosis.

Cytomegalovirus

CMV pneumonia is diagnosed on the basis of clinical presentation in the appropriate host (severely immunocompromised patient) and histopathologic findings (owl's eyes basophilic intranuclear inclusions) on lung biopsy tissue. Blood CMV PCR and/or CMV blood culture positivity lends further support for the diagnosis. However, positive CMV cultures and/or PCR should be interpreted in view of other evidence of disease, because asymptomatic shedding can occur in saliva, sputa, blood, urine, and other body fluids.

Documentation of viremia by shell vial culture technique correlates with positive CMV blood cultures and usually signifies CMV disease, with the above caveats. Presence of pp65 antigenemia also correlates with the development of CMV disease in the HSCT population.

Herpes simplex virus

HSV pneumonia can be confirmed in the appropriate host (ie, a severely immunocompromised patient) using lower respiratory tract viral culture (preferably bronchoscopy specimen) and histology of pulmonary tissue showing multinucleated giant cells. Antigen detection and PCR of sputa are overly sensitive (false positives), and serologies are not useful for this type of pneumonia.

Hantavirus

Hantavirus infection is based on serum detection of hantavirus–specific antibody and, for the majority of the United States, on the development of Sin Nombre Virus (SNV) specific antibodies. Less commonly, in a more research-oriented setting, reverse transcriptase polymerase chain reaction (RT-PCR) can be used to detect hantavirus RNA in peripheral blood mononuclear cells, lung tissue, and/or red blood cells. The serodiagnosis of acute hantavirus infection is confirmed by detecting the genetic material in peripheral blood mononuclear cell preparations with RT-PCR.

Middle East respiratory syndrome coronavirus

The first US case of MERS-CoV was confirmed on May 2, 2014.[71] The Centers for Disease Control and Prevention (CDC) has issued the following recommendations for the evaluation and control of Middle East respiratory syndrome coronavirus (MERS-CoV) in the United States[72, 73] :

  • Testing for MERS-CoV can be performed simultaneously with testing for other respiratory pathogens

  • Confirming the presence of another respiratory pathogen does not rule out the need to test for MERS-CoV in patients who develop fever and pneumonia or acute respiratory distress syndrome (ARDS) within 14 days after leaving the Arabian Peninsula or nearby regions or following close contact with someone with fever and ARDS who recently had been to this area

  • If ARDS occurs in a cluster of patients, tests for common respiratory pathogens should be performed and the cases reported to local and state public health departments. If health-care providers are in the cluster and the cause of ARDS remains unexplained, patients should be considered for MERS-CoV testing even if travel-related disease exposure has been ruled out

  • Laboratory confirmation of MERS-CoV requires a positive PCR assay of 2 or more specific genomic targets or 1 positive target with sequencing of a second; even if an etiology other than that for MERS-CoV is found, a patient whose disorder meets these requirements can still be classified as a probable MERS-CoV case

  • Travelers to Saudi Arabia should avoid contact with ill persons, wash their hands often, and seek medical care if they develop fever with cough or shortness of breath during their trip or within 14 days after returning home

  • Standard, contact, and airborne precautions are recommended for hospitalized patients with confirmed or suspected MERS-CoV infection

  • Federal isolation and quarantine are authorized for patients with confirmed or probable MERS-CoV infection until they are no longer contagious

  • See Middle East Respiratory Syndrome (MERS) for more information.

Chest Radiology

Chest radiography usually demonstrates bilateral lung involvement (as opposed to the lobar involvement commonly seen with bacteria), but some features are characteristic of individual viruses.

For more information, see Imaging in Viral Pneumonia.

Influenza pneumonia

Radiographic findings in influenza pneumonia 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.

Avian influenza pneumonia

Avian influenza (H5N1) radiographic findings have included patchy, interstitial, and/or diffuse infiltrates, consolidation, pleural effusion, and pneumothorax. Some have progressed to acute respiratory distress syndrome (ARDS).[50]

S-OIV pneumonia

Novel S-OIV cases have primarily presented with bilateral patchy alveolar opacities, with a preference for basal sections, and interstitial opacities.[3]

RSV pneumonia

RSV pneumonia typically presents with patchy bilateral alveolar infiltrates and interstitial changes (similar to influenza). Reports of culture-proven cases of RSV pneumonia presenting with small, ill-defined infiltrates have been described.[19, 51]

Adenovirus pneumonia

Adenovirus pneumonia usually presents with diffuse, bilateral and patchy, ground-glass infiltrates with a preference for lower lobes, although it can present with lobar consolidation, which is rarer among viral pneumonias.[4] Radiographic presentation for the serotype 14 outbreak in Oregon included single-lobe infiltrates (54%), multilobe infiltrates (38%), interstitial infiltrates (12%), and pleural effusion (15%). Among those with single-lobe infiltrates, 71% progressed to multilobe involvement.[15]

PIV pneumonia

In PIV, the "steeple sign" (progressive subglottic narrowing), classic for croup in children, is rarely seen in adults. Instead, chest radiographs may reveal findings ranging from focal infection to diffuse interstitial infiltrates or diffuse mixed alveolar-interstitial infiltrates consistent with acute lung injury. CT scan findings of six HSCT recipients with PIV (type 3) diagnosed as the sole etiologic pathogen revealed multiple small nodules (diameter, < 5 mm) without cavitation in a peribronchial distribution.[5]

hMPV pneumonia

In an outbreak of hMPV pneumonia, radiographic findings were bilateral, interstitial, and alveolar infiltration in 43% and unilateral infiltration in 57%.[48] In HSCT recipients, CT scans have shown bilateral nodular and extensive infiltrates and pleural effusion.[47]

Coronavirus pneumonia

Coronavirus pneumonia, including SARS, typically shows ground-glass opacities and focal consolidations, especially in the periphery and subpleural regions of the lower zones. Progressive involvement of both lungs is common. In SARS, shifting of radiographic shadows and spontaneous pneumomediastinum have been seen.[53]

VZV pneumonia

In VZV 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

CMV pneumonia

The two patterns of CMV involvement include (1) a multifocal or miliary pattern characterized by discrete spherical lesions as large as 4 mm in diameter, with alveolar hemorrhage, fibrin deposition, and a moderate neutrophilic response; and (2) a diffuse interstitial pneumonitis with interstitial edema, varying degrees of fibrosis, lymphoid cell infiltration, and alveolar-cell hyperplasia. (See the images below.)

Pneumonia, viral: A 52-year-old woman developed fe 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.
Pneumonia, viral: A 52-year-old woman developed fe 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.

In CMV pneumonia, chest radiographs show interstitial infiltrates predominantly in the lower lobes. Advancement to diffuse, interstitial infiltrates is observed in patients with organ transplantation. The most common CT scan findings are a combination of multiple, small centrilobular nodules (55-99%), patchy ground-glass opacities (44-100%), and small bilateral/asymmetric foci of consolidation (44-70%).[37]

HSV pneumonia

HSV can produce focal lesions on chest radiographs that begin as small centrilobular nodules and patchy ground-glass opacities and consolidation. As the disease progresses, the nodules coalesce to form extensive infiltrates.[37]

Hantavirus pneumonia

Hantavirus infection may show a normal chest radiograph 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 ARDS from other causes. With further progression, pleural effusions also may develop.

Guidelines

No firm guidelines exist for when to obtain a chest radiograph in patients to aid in diagnosing lower respiratory tract infection. Chest pain, dyspnea, and productive cough are some of the indications used by clinicians.

The Infectious Diseases Society of America recommends chest radiography to confirm infiltrates when pneumonia is suspected for the following reasons: the severity of disease may be revealed, detection of pneumonia may not be possible on purely clinical grounds, and antibiotics are not useful for treatment of bronchitis. It is recommended that a chest radiograph be obtained in patients with suspected pneumonia, both to find complications, such as pleural effusions, and to discourage the use of antibiotics in healthy patients with bronchitis rather than pneumonia.

Antibiotics are recommended for pneumonia, and a chest radiograph is necessary to make this diagnosis. Antibiotics have not been shown to be efficacious in bronchitis. The widespread use of antibiotics in inappropriate situations is leading to drug resistance and may explain the increases in death rates since 1979. Antibiotics can cause adverse drug reactions. Thus, antibiotics should be avoided when they are not needed. However, if an infiltrate is seen on a chest radiograph, it may be due to viral or bacterial disease or both. In the ED, differentiating the etiology may be impossible.

None of the viral etiologies of pneumonia result in pathognomonic findings on chest radiographs, and bacterial pneumonia cannot be differentiated from viral pneumonia based on radiographic findings. Of concern was the fact that some patients with SARS had negative findings on chest radiographs but infiltrates were seen on chest CT. Chest radiography may reveal the following findings:

  • Patchy interstitial or alveolar infiltrate, which may be bilateral or involve 2 or more lobes

  • Peribronchial thickening

  • Consolidation

  • Pleural effusion

For more information, see Imaging in Viral Pneumonia.

Lung Biopsy

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

Bronchiolar lavage may be useful to obtain material for cytopathologic analysis and microbiologic studies.

Histologic Findings

In general, when viruses cause pneumonia, it initially affects the parenchyma adjacent to terminal and respiratory bronchioles and subsequently progresses to involve the entire lobule. With rapidly progressive pneumonia, diffuse alveolar damage is seen, consisting of intra-alveolar hemorrhage, interstitial lymphocyte infiltration, edema, fibrin deposition, type 2 pneumocyte hyperplasia, and formation of hyaline membranes.[74]

Influenza and avian influenza pneumonias

Influenza histopathology of lung tissue reveals edema, focal hemorrhages, and cellular infiltration. Alveoli may be denuded of epithelium, and intra-alveolar hemorrhage is common. The presence of an acellular hyaline membrane lining the alveoli is typical of influenza pneumonia.

Avian influenza (H5N1) typically shows fulminant, necrotizing, diffuse alveolar damage with patchy, interstitial, paucicellular fibrosis. (H1N1 pneumonia has shown diffuse alveolar damage, thick hyaline membranes, and prominent fibroblast proliferation.)

Varicella-zoster, measles, and CMV pneumonias

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.

CMV pneumonia histopathology demonstrates 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.

HSV and hantavirus pneumonias

HSV pneumonia causes 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.

Hantavirus pneumonia histopathology reveals interstitial infiltrates of T lymphocytes and alveolar pulmonary edema without marked necrosis or polymorphonuclear leukocyte involvement. This finding is consistent with the pathogenesis being mainly caused by vascular permeability increase, via an immunopathologic mechanism.[75]

 

Treatment

Approach Considerations

All viral pneumonia patients must receive supportive care with oxygen, rest, antipyretics, analgesics, nutrition, and close observation. See Table 2 below.

Table 2. Treatment and Prevention of Common Causes of Viral Pneumonia (Open Table in a new window)

Virus

Treatment

Prevention

Influenza virus

Oseltamivir

Peramivir

Zanamivir

Influenza vaccine[76]

Chemoprophylaxis with:

Zanamivir

Oseltamivir

Respiratory syncytial virus

Ribavirin

RSV immunoglobulin

Palivizumab

Parainfluenza virus

Ribavirin

 

Herpes simplex virus

Acyclovir

 

Varicella-zoster virus

Acyclovir

Varicella-zoster immunoglobulin

Adenovirus

Ribavirin

 

Measles virus

Ribavirin

Intravenous immunoglobulin

Cytomegalovirus

Ganciclovir

Foscarnet

Intravenous immunoglobulin

Supportive Care

Oxygen should be administered to patients with hypoxemia or shortness of breath. Emergency medical personnel should administer oxygen if the patient is dyspneic. Some prehospital providers can deliver aerosol treatments with beta-agonists, which may improve the patient's breathing. Patients with respiratory failure require endotracheal intubation and ventilator support.

Isotonic sodium chloride solution should be administered to patients who are in shock and have no component of heart failure.

Acute care may involve use of the following:

  • Oxygen, if the patient is dyspneic

  • Beta-agonists, if bronchospasm is present

  • Fluids, if dehydration is present

  • Acyclovir, if varicella or herpes pneumonia is suspected

  • Respiratory isolation

  • Antibiotics, if infiltrate is seen on the chest radiograph

  • Mechanical ventilation if respiratory failure is present or impending

Influenza Pneumonia

Antiviral therapy is available for the treatment of influenza virus infection. The treatment of uncomplicated influenza is supportive in nature, consisting of rest and administration of antipyretics and analgesics. See Table 3 below.

Table 3. Characteristics of Anti-Influenza Drugs (Open Table in a new window)

 

Amantadine

(Symmetrel)

Rimantadine

(Flumadine)

Zanamivir

(Relenza)

Oseltamivir

(Tamiflu)

Mechanism of action

M2 ion channel blockade inhibits HAa cleavage beta block RNA encoding, which reduces early viral replication.

Viral NAb inhibition prevents sialic acid cleavage from HA beta 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

Beta Plasma level: ASAc, acetaminophen

None

None

Renal clearance

TMP-SMZd, triamterene, hydrochlorothiazide, quinine sulfate, quinidine

Cimetidine

None

None

a HA - Hemagglutinin

b NA - Neuraminidase

c ASA - Acetylsalicylic acid

d 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 these compounds has been associated with the emergence of viral resistance. The clinical significance of this is not known. Many of the current strains are not susceptible to amantadine/rimantadine (including H1N1 influenza virus), so empiric use of these agents as the only drug is not recommended.

Oseltamivir, zanamivir, and peramivir block the neuraminidase surface protein on both influenza A and influenza B viruses.[77, 78, 79, 80, 81, 82]

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.

Peramivir (Rapivab) was approved by the FDA in December 2014 for use in adults as a single 600 mg IV dose. In clinical trials, a single intravenous dose of peramivir, a sialic acid analogue and a selective inhibitor of neuraminidases produced by influenza A and B viruses, is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection. At both 300 mg and 600 mg, peramivir significantly reduced the time to alleviation of symptoms in comparison with placebo.[83] Additional data from over 2,700 subjects treated with peramivir in 27 clinical trials also supported its approval. It was available in the United States by emergency protocol during the 2009 H1N1 influenza pandemic.

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 one day. Oseltamivir resistance emerged in the United States during the 2008-2009 influenza season.

For severe influenza pneumonia, antiviral medication should be given, even after the 48-hour window.

In a double-blind, randomized controlled trial, one inhalation of laninamivir octanoate was shown as effective for the treatment of seasonal influenza in adults. Effectiveness was also shown for the oseltamivir-resistant virus.[84]

H1N1 influenza

In the 2009-2010 H1N1 influenza epidemic, the US Centers for Disease Control and Prevention (CDC) recommended oseltamivir or zanamivir for treatment of all hospitalized patients with suspected or confirmed cases and for outpatients at increased risk for complications of H1N1 infection.

As of September 2009, only 28 of 10,000 H1N1 isolates tested were resistant to oseltamivir (11 from the United States), and all were susceptible to zanamivir.

Although intravenous peramivir had not been formally FDA approved for the treatment of influenza during the 2009-2010 H1N1 pandemic, the FDA issued an emergency use authorization (EUA) for its use in hospitalized patients who had potentially life-threatening suspected or laboratory confirmed infection with H1N1. Under the EUA, treatment with IV peramivir was approved for patients who had not responded to either oral or inhaled antiviral therapy and/or drug delivery by a route other than IV that was not expected to be dependable or feasible.

Early administration of corticosteroids in patients with H1N1 who are admitted to the ICU has no apparent benefit.[85]

Avian influenza

Avian H5N1 influenza should be treated with oseltamivir, even after the 48-hour window, because a reduction in mortality of hospitalized persons with seasonal influenza or avian influenza A (H5N1) virus infection was reported even when oseltamivir treatment was initiated later. The optimal duration and dose is not clear, but the WHO recommends consideration of higher dosage (eg, 150 mg PO bid) and longer duration in severe infections.

Avian H5N1 influenza has exhibited resistance to oseltamivir (clade 1 and subclade 2.1 with H274Y and N294S mutations). These resistant strains maintained susceptibility to zanamivir. Some viruses circulating in birds (subclade 2.3.4) demonstrated reduced susceptibility to zanamivir but sensitivity to the adamantanes (amantadine/rimantadine). Thus, for resistant strains (especially subclades 2.2 and 2.3.4), consideration for combination therapy with neuraminidase inhibitor-adamantane or oseltamivir-ribavirin, or even triple therapy with neuraminidase inhibitor-adamantane-ribavirin, should be given.[59]

Respiratory Syncytial Virus Pneumonia

As with influenza, treatment of uncomplicated respiratory syncytial virus (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.[1] Ribavirin acts by interfering with viral transcription. This drug is delivered as a small-particle aerosol. Data conflict regarding the efficacy of ribavirin therapy in RSV pneumonia. Overall, the preponderance of data suggests a benefit of ribavirin therapy in high-risk patients, such as hematopoietic stem cell transplant (HSCT) recipients.

Current recommendations are that ribavirin therapy should be considered only for severe illness and in high-risk patients for whom RSV infection is associated with high mortality, such as HSCT recipients.[60] In these hosts, high-dose, short-duration aerosolized ribavirin (60 mg/mL for 2 h given by mask tid) has been used.

RSV-specific intravenous immunoglobulin, such as palivizumab (Synagis), which is a monoclonal antibody directed against the RSV fusion (F) glycoprotein, has also been used with aerosolized and oral ribavirin in high-risk patients, such as HSCT recipients, because this combination has been shown to increase survival in this group.[55] Its use is endorsed in some guidelines, although not universally accepted or recommended.[86, 87]

Adenovirus Pneumonia

Cidofovir has demonstrated good in vitro activity against adenoviruses, including serotype 14. Cidofovir has shown some efficacy in treating adenovirus infection in immunocompromised patients, especially HSCT recipients.[88] The dose is 5 mg/kg/wk for two weeks, then every two weeks plus probenecid 1.25 g/m2 given three hours before cidofovir and three and nine hours after each infusion. Alternate dosing is 1 mg/kg IV three times a week.

The in vitro activity of ribavirin against adenovirus, however, has been variable. For example, in one study, species C was susceptible to ribavirin, while other species were more variable.[89] Some anecdotal reports exist regarding improvement in some patients with HSCT and leukemia, although other studies have not shown any efficacy. Thus, routine use of ribavirin is not recommended.[90, 91, 92]

Parainfluenza Virus Pneumonia

Treatment is mainly supportive in nature. Ribavirin has documented in vitro activity against parainfluenza virus (PIV), and aerosolized and oral ribavirin were associated with reduction in PIV shedding and clinical improvement in immunocompromised patients. Thus, in this latter, high-risk group, the use of ribavirin may be reasonable.[93]

Human Metapneumovirus Pneumonia

Although ribavirin has activity against human metapneumovirus (hMPV) similar to that which it has against RSV and although animal data have shown some promise, treatment data in humans are lacking, being confined to occasional case reports predominantly in the transplantation population.[94, 95]

Immunoglobulin preparations (intravenous immunoglobulin [IVIG]) also seem to contain sufficient neutralizing titers, but this has not been extensively studied for use in hMPV pneumonia either—again with only isolated case reports in patients with transplantation, usually in combination with ribavirin.[96]

Coronavirus Pneumonia

Protease inhibitors (eg, lopinavir/ritonavir) demonstrated antiviral activity against severe acute respiratory syndrome coronavirus (SARS-CoV) infection.[97] Interferon alfa and interferon beta have activity against SARS-CoV in vitro and in animal models. Limited human data seemed to demonstrate some beneficial effect.[98]

Ribavirin is not active against SARS-CoV in vitro, and studies have not shown clinical efficacy. Therefore, this medication is not recommended for this infection.[98]

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 for 7 d) has been shown to be effective.

For pregnant women in the third trimester, acyclovir at 10 mg/kg IV every eight hours for five days should be given, and consideration should be given for varicella-zoster immune globulin (VZIG) therapy.

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 (20-35 mg/kg/d for 7 d) and aerosolized ribavirin, similar to the therapy for severe infections with RSV.[99]

Cytomegalovirus Pneumonia

The primary treatment for acute cytomegalovirus (CMV) pneumonia in the immunocompromised patient (both HSCT and solid organ transplant [SOT] recipients) is ganciclovir (5 mg/kg IV 12h for 14-21 d, followed by valganciclovir 900 mg PO qd for suppression). Ganciclovir prevents viral DNA replication by inhibiting the enzyme DNA polymerase.[100]

High-dose intravenous immunoglobulin (CMV immunoglobulin or IVIG) has been used successfully in conjunction with ganciclovir for the treatment of CMV pneumonia, decreasing the mortality rate to 0-47%. Combination therapy is based on the premise that lung injury is not solely due to direct damage by the virus but is a result of virally induced immunological reaction. In lung transplant recipients, ganciclovir with CMV immunoglobulin or IVIG has been associated with increased survival.[101]

Foscarnet sodium, an inhibitor of viral DNA polymerase and reverse transcriptase, is an alternative drug for use in ganciclovir-resistant CMV pneumonia. The combination of foscarnet with ganciclovir may provide antiviral synergy, but it requires careful monitoring.[102]

Cidofovir represents a third option, but scant data exist regarding its use in CMV pneumonia.

Herpes Simplex Virus Pneumonia

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 herpes simplex virus (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.

Hantavirus Pneumonia

The treatment of hantavirus pulmonary syndrome (HPS) is supportive in nature and includes correction hypoxemia, lactic acidosis, and hypotension. Mechanical ventilation and optimal fluid management guided by hemodynamic monitoring are recommended, with avoidance of excessive administration of fluids and with use of cardiotonic drugs to counter the hemodynamic profile of decreased cardiac output and increased systemic vascular resistance. See the Cardiac Output calculator.

Although intravenous ribavirin has been associated with some success in the treatment of some Bunyaviridae viruses, such as Hantaan virus (hemorrhagic fever with renal syndrome), Rift Valley fever virus, and Crimean-Congo hemorrhagic fever virus, it has failed to show any efficacy in HPS, perhaps because death typically occurred within 24-48 hours of hospitalization.[74]

Prevention

Influenza

Annual fall vaccination of high-risk populations and healthcare workers is the most effective measure for decreasing morbidity and mortality from influenza.[87] Each year's influenza vaccine contains the three virus strains (usually two type A strains and 1 type B strain) considered most likely to cause outbreaks based on epidemiologic surveillance.

In the United States, specific recommendations for vaccination against influenza are issued each year by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC).[103]

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%.

The effectiveness of widespread vaccination in elderly persons has been called into question. A recent meta-analysis of the efficacy, effectiveness, and safety of the influenza vaccine in patients older than 65 years found that vaccination is of benefit to residents of long-term care facilities but is of modest value in the community.[104] However, the Centers for Disease Control and Prevention (CDC) still recommend immunization of all elderly patients.[103, 105]

The CDC has recommended chemoprophylaxis in the following situations:

  • Close contacts of patients who are at high risk for complications of influenza.

  • Healthcare personnel, public health workers, and first responders who have had recognized and unprotected close contact exposure to a person with influenza during the person's infectious period (up to 7 d after onset of illness).

Chemoprophylaxis should be considered when outbreaks occur in nursing homes. Everyone in the institution, including the unvaccinated staff and other coworkers, should receive prophylactic therapy for at least two weeks during the outbreak.

The CDC issues updated interim guidance on antiviral treatment and prophylaxis of seasonal influenza, based on resistance patterns of the circulating viral strains.

Local influenza surveillance data and laboratory testing can also assist the physician regarding the antiviral agent choice.

Vaccines for avian H5N1 influenza are currently being developed and studied, and vaccinations have been performed in avian livestock (via whole-virus inactivated vaccine, recombinant fowlpox vaccine, and recombinant Newcastle disease vaccine.)

Respiratory syncytial virus

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.

Vaccines are under development, including subunit vaccines directed against two major surface glycoproteins (F, G proteins), a polypeptide vaccine (BBG2Na), and live-attenuated vaccines, the latter of which have been promising in adults.

Adenovirus

An oral live vaccine was available against serotypes 4 and 7, taking advantage of the fact that exposure of these strains to the gastrointestinal tract does not result in illness. This vaccine was used primarily in military recruit populations, with excellent results, but it has not been available since 1999. Recrudescence of adenovirus type 3, 4, and 7 has occurred in the military.

Other live and inactivated virus vaccines have been hampered by their oncogenicity in animal models. Vaccines against the capsid (and free of DNA) are currently being studied.

Parainfluenza virus

No vaccine is available, but live, attenuated, intranasally administered parainfluenza type 3 vaccines were under development.

Human metapneumovirus

No vaccine is available, although a live-attenuated bovine parainfluenza virus type 3 vaccine with human metapneumovirus F gene was being studied.[106]

Varicella-zoster virus

A live attenuated varicella vaccine is recommended for patients who did not have varicella infection by age 13 years and for anyone who is susceptible to varicella-zoster virus (VZV) (VZV antibody negative). The vaccine should not be given to pregnant women. Children are now routinely immunized before age 12-18 months.

Intramuscular administration of varicella-zoster immunoglobulin (125 U/10 kg to 625 units maximum) is indicated as passive immunization of VZV-seronegative personnel at risk for complications within 96 hours of being exposed to VZV (eg, immunosuppressed hosts, such as those with HIV or with malignancies; those on long-term steroid therapy; pregnant patients, and neonates whose mothers acquire VZV within five days before, to 48 hours after, delivery).

Measles

The measles vaccine is a live attenuated virus vaccine (part of measles-mumps-rubella [MMR] vaccine) and should be given to everyone except pregnant women or persons who are severely immunocompromised. HIV-infected persons who are asymptomatic or only mildly symptomatic should be vaccinated.

Postexposure prophylaxis of patients who are immunocompromised with intravenous immune globulin is effective if administered within 6 days of exposure to infectious cases of measles.

Cytomegalovirus

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.

Hematopoietic stem cell transplant (HSCT) recipients who are CMV-negative are given prophylactic ganciclovir before and after transplantation. Solid organ transplant (SOT) recipients who are CMV-negative and receiving their organ from CMV-positive donors typically receive ganciclovir for three months post transplantation.

Preemptive therapy (with ganciclovir) based on detection of CMV in bronchoalveolar lavage specimens, CMV pp65 antigenemia, and/or polymerase chain reaction (PCR) in blood after transplantation has been shown to significantly reduce the incidence of post-transplant CMV pneumonia.

Herpes simplex virus

Chemoprophylaxis of high-risk seropositive patients during induction of immunosuppression for transplantation is recommended.

Acyclovir is routinely prescribed at maintenance doses for the first month after transplantation.

Hantavirus

No vaccine is available or in development. The only means of deterrence is by avoiding rodent contact and/or inhalation/aerosolization of areas of possible rodent excreta. If contact is unavoidable (ie, need to sweep dirty areas where rodents live), use of a respiratory mask is prudent.

Hematopoietic cell transplantation recipients

An international committee has produced guidelines for preventing infectious complications among HCT recipients. These guidelines include recommendations on use of antivirals for prevention or preemptive treatment of specific infections, as well as recommendations on vaccines.[107]

Consultations

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

 

Medication

Medication Summary

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

Few specific antiviral agents exist. Acyclovir (for varicella and herpes simplex pneumonia) is efficacious. Ganciclovir and immunoglobulin are used in immunocompromised patients with CMV pneumonia.

For further information on albuterol and inhaled corticosteroid use, see Asthma.

Antiviral agents

Class Summary

Acute lower respiratory tract infection from viral etiologies can be treated with antiviral agents. These agents inhibit DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase.

Agents used include 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.

Zanamivir (Relenza)

Zanamivir inhibits neuraminidase, which is a glycoprotein on the surface of the influenza virus that destroys the infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, the release of viruses from infected cells and viral spread are decreased. Zanamivir is effective against influenza types A and B. The drug is inhaled through the Diskhaler oral inhalation device. Circular foil discs containing 5-mg blisters of the drug are inserted into the supplied inhalation device.

Oseltamivir (Tamiflu)

Oseltamivir inhibits neuraminidase, which is a glycoprotein on the surface of influenza virus that destroys an infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, it decreases the release of viruses from infected cells and thus viral spread. Oseltamivir is effective for treatment of influenza A or B infection, although resistant strains of seasonal influenza and H1N1 have been reported. Start within 40 hours of symptom onset.

Peramivir (Rapivab)

Peramivir elicits antiviral activity by inhibiting influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells. It is indicated for the treatment of acute uncomplicated influenza in adults who have been symptomatic for no more than 2 days. It is administered as a single 600 mg IV dose infused over 15-30 minutes.

Ribavirin (Virazole)

Ribavirin inhibits viral replication by inhibiting DNA and RNA synthesis. It has shown in vitro antiviral properties against RSV, parainfluenza, hantavirus, measles, and many other.

Acyclovir (Zovirax)

Acyclovir inhibits activity of both HSV-1 and HSV-2. It has affinity for viral thymidine kinase and, once phosphorylated, causes DNA chain termination when acted on by DNA polymerase. Patients experience less pain and faster resolution of HSV or VZV lesions when used within 24-48 hours of rash onset. Early initiation of therapy is imperative.

Ganciclovir (Cytovene, Vitrasert)

Ganciclovir is a synthetic guanine derivative that is active against CMV, HSV, HHV-6, and HHV-8. It is an acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpesviruses both in vitro and in vivo. levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells. An oral prodrug, valganciclovir, is now available.

Foscarnet (Foscavir)

Foscarnet is an organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at pyrophosphate-binding sites on virus-specific DNA polymerases. Poor clinical response or persistent viral excretion during therapy may result from viral resistance. Patients who can tolerate foscarnet well may benefit from initiation of maintenance treatment at 120 mg/kg/d early in treatment. Individualize dosing based on renal function status.

Cidofovir (Vistide)

Cidofovir has demonstrated good in vitro activity against adenoviruses, including serotype 14. Cidofovir has shown some efficacy in treating adenovirus infection in immunocompromised patients, especially HSCT recipients.

Monoclonal Antibodies

Class Summary

Humanized monoclonal antibodies such as palivizumab are useful in the prevention of lower respiratory tract disease caused by RSV in pediatric patients.

Palivizumab (Synagis)

Palivizumab is a humanized monoclonal antibody directed against the F (fusion) protein of RSV. Given monthly through the RSV season, it has been demonstrated to decrease the chances of RSV hospitalization in premature babies who are at increased risk for severe RSV-related illness.

Immune Globulins

Class Summary

High-dose intravenous immunoglobulin has been used successfully in conjunction with ganciclovir for the treatment of CMV pneumonia.

Immune globulin IV (Gamimune, Gammagard, Sandoglobulin, Gammar-P)

Immune globulin IV neutralizes circulating myelin antibodies through anti-idiotypic antibodies. It down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T cells and B cells; and augments suppressor T cells. The drug also blocks the complement cascade, promotes remyelination, and may increase CSF IgG levels (10%).

Beta-Agonists

Class Summary

Many patients with viral pneumonia have bronchospasm, which is relieved or improved with the use of beta-agonist drugs.

Albuterol (Proventil)

Albuterol is a beta-agonist used to treat bronchospasm. It relaxes bronchial smooth muscle with its action on beta2-receptors. It has little effect on cardiac muscle contractility.

 

Questions & Answers

Overview

Why has the reported incidence of viral pneumonia been increasing?

What are the signs and symptoms of viral pneumonia?

Which physical findings are characteristic of viral pneumonia?

What are the symptoms of influenza pneumonia?

What are the symptoms of respiratory syncytial virus (RSV) pneumonia?

What are the symptoms of parainfluenza virus (PIV) pneumonia?

Which lab studies are performed in the workup of viral pneumonia?

What is the role of radiography in the diagnosis of viral pneumonia?

What is the role of lung biopsy and histologic studies in the diagnosis of viral pneumonia?

What is included in supportive care for viral pneumonia?

What are specific treatments for the various types of viral pneumonia?

How common is viral pneumonia?

Which viruses causes viral pneumonia?

What is viral pneumonia?

What is the pathophysiology of viral pneumonia?

What is the role of influenza virus in the pathophysiology of viral pneumonia?

What is the role of adenoviruses in the pathophysiology of viral pneumonia?

Why are the elderly at increased risk for complications from viral pneumonia?

What are the ways viral pneumonia is transmitted?

What pathophysiology of pulmonary host defense against viral pneumonia?

What is the role of measles virus in the etiology of viral pneumonia?

What is the role of cytomegalovirus (CMV) in the etiology of viral pneumonia?

Which virus families cause viral pneumonia?

Which lung pathogens cause viral pneumonia?

What is the role of influenza virus in the etiology of viral pneumonia?

What is the role of respiratory syncytial virus (RSV) in the etiology of viral pneumonia?

What is the role of adenoviruses in the etiology of viral pneumonia?

What is the role of parainfluenza virus (PIV) in the etiology of viral pneumonia?

What is the role of rhinovirus in the etiology of viral pneumonia?

What is the role of human metapneumovirus (hMPV) in the etiology of viral pneumonia?

What is the role of coronavirus in the etiology of viral pneumonia?

What is the role of varicella-zoster virus (VZV) in the etiology of viral pneumonia?

What is the role of herpes simplex virus (HSV) in the etiology of viral pneumonia?

What causes zoonotic viral pneumonia?

What is the role of Hantavirus in the etiology of viral pneumonia?

What is the role of avian H5N1 influenza virus in the etiology of viral pneumonia?

What is the role of severe acute respiratory syndrome (SARS) in the etiology of viral pneumonia?

What is the role of H1N1 (swine) influenza in the etiology of viral pneumonia?

What is the role of Epstein-Barr virus (EBV) in the etiology of viral pneumonia?

What is the role of rotavirus in the etiology of viral pneumonia?

What is the prevalence of viral pneumonia?

What is the prevalence of viral pneumonia in immunocompromised hosts?

What is the prevalence of viral pneumonia in pregnancy?

How does the prevalence of viral pneumonia vary by sex?

How does the prevalence of viral pneumonia vary by age?

What is the mortality and morbidity of viral pneumonia?

What is the mortality and morbidity of influenza pneumonia?

What is the mortality and morbidity of respiratory syncytial virus (RSV) pneumonia?

What is the mortality and morbidity of adenovirus pneumonia?

What is the mortality and morbidity of parainfluenza virus (PIV) pneumonia?

What is the mortality and morbidity of human metapneumovirus (HMPV) pneumonia?

What is the mortality and morbidity of varicella-zoster virus (VZV) pneumonia?

What is the mortality and morbidity of measles virus pneumonia?

What is the mortality and morbidity of cytomegalovirus (CMV) pneumonia?

What is the mortality and morbidity of herpes simplex virus (HSV) pneumonia?

What is the mortality and morbidity of Hantavirus pulmonary syndrome (HPS)?

What is the prognosis of viral pneumonia?

Where are resources for patient education about viral pneumonia found?

Presentation

Which clinical history findings suggest viral pneumonia?

What are the clinical manifestations of human lymphotropic virus (HTLV) pneumonia?

Which physical findings are characteristic of viral pneumonia?

Which patient groups are at highest risk for Influenza pneumonia?

What are the clinical forms of influenza pneumonia?

What are the risk factors for respiratory syncytial virus (RSV) pneumonia?

Which physical findings are characteristic of RSV pneumonia?

What are the clinical manifestations of parainfluenza virus (PIV) pneumonia?

What are the clinical manifestations of human metapneumovirus (HMPV) pneumonia?

What are the clinical manifestations of coronavirus pneumonia?

What are the clinical manifestations of varicella-zoster virus (VZV) pneumonia?

Which factors increase the risk for varicella-zoster virus (VZV) pneumonia?

What are the clinical manifestations of Measles virus pneumonia?

Which factors increase the risk for Measles virus pneumonia?

Which physical findings are characteristic of specific types of measles-associated pneumonia?

What are the clinical manifestations of cytomegalovirus (CMV) pneumonia?

What are the possible outcomes and complications of cytomegalovirus (CMV) pneumonia?

What are the clinical manifestations of herpes simplex virus (HSV) pneumonia?

What are the clinical manifestations of Hantavirus pulmonary syndrome (HPS)?

What are the clinical manifestations of adenovirus pneumonia?

What are the clinical manifestations of avian influenza (A/H7N7) pneumonia?

What are the clinical manifestations of Epstein-Barr virus (EBV) pneumonia?

What are the clinical manifestations of human herpesvirus (HHV) pneumonia?

What are the clinical manifestations of HIV pneumonitis?

What are the clinical manifestations of rhinovirus pneumonia?

What are the clinical manifestations of rotavirus pneumonia?

What are the clinical manifestations of transplantation-related pneumonia?

What are the complications of viral pneumonia?

DDX

How is viral pneumonia differentiated from bacterial pneumonia?

Which etiologies of viral pneumonia are most common in the winter months?

What are common causes of viral pneumonia in children?

What are common causes of viral pneumonia in immunocompetent adults?

What are the common causes of viral pneumonia in immunocompromised hosts?

What are the differential diagnoses for Viral Pneumonia?

Workup

Which diagnostic techniques are used in the diagnosis of viral pneumonia?

Which tests are used to identify the etiology of viral pneumonia?

What is the role of cytologic evaluation in the evaluation of viral pneumonia?

What is the role of viral culture in the workup of viral pneumonia?

What is the role of Sputum Gram stains in the workup of viral pneumonia?

What is the role of blood cultures in the workup of viral pneumonia?

What is the role of rapid antigen detection in the workup of viral pneumonia?

What is the role of gene amplification in the workup of viral pneumonia?

What is the role of serologies in the workup of viral pneumonia?

What is the role of arterial blood gases in the workup of viral pneumonia?

What are virus-specific lab studies for the diagnosis of viral pneumonia?

Which virus-specific lab studies are used for the diagnosis of influenza pneumonia?

Which virus-specific lab studies are used for the diagnosis of respiratory syncytial virus (RSV) pneumonia?

Which virus-specific lab studies are used for the diagnosis of adenoviruses pneumonia?

Which virus-specific lab studies are used for the diagnosis of parainfluenza virus (PIV) pneumonia?

Which virus-specific lab studies are used for the diagnosis of human metapneumovirus (HMPV) pneumonia?

Which virus-specific lab studies are used for the diagnosis of varicella-zoster virus (VZV) pneumonia?

Which virus-specific lab studies are used for the diagnosis of measles virus pneumonia?

Which virus-specific lab studies are used for the diagnosis of cytomegalovirus (CMV) pneumonia?

Which virus-specific lab studies are used for the diagnosis of herpes simplex virus (HSV) pneumonia?

Which virus-specific lab studies are used for the diagnosis of hantavirus-caused pneumonia?

Which virus-specific lab studies are used for the diagnosis of Middle East respiratory syndrome coronavirus (MERS-CoV) pneumonia?

Which findings on chest radiography are characteristic of viral pneumonia?

Which findings on chest radiography are characteristic of influenza pneumonia?

Which findings on chest radiography are characteristic of avian (H5N1) influenza pneumonia?

Which findings on chest radiography are characteristic of S-OIV pneumonia?

Which findings on chest radiography are characteristic of respiratory syncytial virus (RSV) pneumonia?

Which findings on chest radiography are characteristic of adenovirus pneumonia?

Which findings on chest radiography are characteristic of parainfluenza virus (PIV) pneumonia?

Which findings on chest radiography are characteristic of human metapneumovirus (hMPV) pneumonia?

Which findings on chest radiography are characteristic of coronavirus pneumonia?

Which findings on chest radiography are characteristic of varicella-zoster virus (VZV) pneumonia?

Which findings on chest radiography are characteristic of cytomegalovirus (CMV) pneumonia?

Which findings on chest radiography are characteristic of herpes simplex virus (HSV) pneumonia?

Which findings on chest radiography are characteristic of Hantavirus pulmonary syndrome (HPS)?

What are the Infectious Diseases Society of America (IDSA) guidelines for chest radiology in the diagnosis of viral pneumonia?

What are the pathognomonic findings on chest radiographs of viral pneumonia?

What is the role of lung biopsy in patients with viral pneumonia?

What is the role of bronchiolar lavage (BAL) in the workup of viral pneumonia?

Which histologic findings are characteristic of viral pneumonia?

Which histologic findings are characteristic of influenza (H1N1) and avian (H5N1) influenza pneumonias?

Which histologic findings are characteristic of varicella-zoster, measles, and cytomegalovirus (CMV) pneumonias?

Which histologic findings are characteristic of herpes simplex virus (HSV) pneumonias?

Which histologic findings are characteristic of Hantavirus pulmonary syndrome (HPS) and pneumonia?

Treatment

What is included in supportive care for viral pneumonia?

When is oxygen administered in the supportive care of viral pneumonia?

When is isotonic sodium chloride administered in the supportive care of viral pneumonia?

What are the options for acute management of viral pneumonia?

What is the role of antiviral therapy in the treatment of influenza pneumonia?

Which medications are used for treatment of influenza A and B pneumonia?

Which medications are used for the treatment of H1N1 influenza pneumonia?

Which medications are used for the treatment of for avian (H5N1) influenza pneumonia?

Which medications are used for the treatment of respiratory syncytial virus (RSV) pneumonia?

Which medications are used for the treatment of adenovirus pneumonia?

Which medications are used for the treatment of parainfluenza virus (PIV) pneumonia?

Which medications are used for the treatment of human metapneumovirus (HMPV) pneumonia?

Which medications are used for the treatment of coronavirus pneumonia?

What are the treatment options for varicella-zoster virus (VZV) pneumonia?

Which medications are used in the treatment of measles pneumonia?

Which medications are used for the treatment of cytomegalovirus (CMV) pneumonia?

Which medications are used for the treatment of herpes simplex virus (HSV) pneumonia?

What are the treatment options for Hantavirus pulmonary syndrome (HPS)?

How is influenza pneumonia prevented?

What are the CDC guidelines for prevention of influenza pneumonia?

How is respiratory syncytial virus (RSV) pneumonia prevented?

How is adenovirus pneumonia prevented?

How is parainfluenza virus (PIV) pneumonia prevented?

How is human metapneumovirus (HMPV) pneumonia prevented?

How is varicella-zoster virus (VZV) pneumonia prevented?

How is measles pneumonia prevented?

How is cytomegalovirus (CMV) pneumonia prevented?

How is herpes simplex virus (HSV) pneumonia prevented?

How is Hantavirus pulmonary syndrome (HPS) prevented?

How is viral pneumonia prevented in hematopoietic cell transplantation recipients?

Which medical personnel provide consultation to patients with viral pneumonia?

Medications

What are the goals of drug treatment for viral pneumonia?

Which medications in the drug class Beta-Agonists are used in the treatment of Viral Pneumonia?

Which medications in the drug class Immune Globulins are used in the treatment of Viral Pneumonia?

Which medications in the drug class Monoclonal Antibodies are used in the treatment of Viral Pneumonia?

Which medications in the drug class Antiviral agents are used in the treatment of Viral Pneumonia?