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The 4 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 communityacquired viral pneumonia cases, particularly during influenza outbreaks.

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. Some patients showed bloody effusions and diffuse alveolar damage.[5] 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.[6] In addition to humoral responses, cell-mediated immunity appears to be important for recovery from certain respiratory viral infections. 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 immunoglobulin E in RSV infection and bradykinin, interleukin 1, interleukin 6, and interleukin 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 cells and neutrophil 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 in general. Studies in children have identified increased production cytokines, particularly tumor necrosis factor-alpha (TNF-), 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 the elderly


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 protection of the respiratory tract by mucus levels.[7]

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 showed 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 showed 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. 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) 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; perhaps, this characteristic accounts 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 2 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 (2 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 yearsthe 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.[8] 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.[9, 10, 11] 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.[12] 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.[9] 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 6 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 4 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.[13]

Rhinovirus
According to some authors, 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 showed 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.[14] 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 5 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 for a long time. 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.[15] In immunocompromised hosts (eg, hematologic malignancies), severe pneumonitis requiring intensive care or resulting in death has been reported.[16, 17]

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). Four human coronaviruses (HCoVs) have now been identified: HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1.[18] 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 HCoVNL63 infections mainly occurred in early summer and autumn.[19] Viral pneumonias that manifest as a rash include varicella-zoster virus (chickenpox) and measles virus.

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 and immunocompromised hosts (including pregnant women). 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. Viral pneumonias that occur in immunodeficient patients include cytomegalovirus and herpes simplex virus.

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 40100%, 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 graftversus-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. 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 of which 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.[20, 21] Two other agents, isolated in other parts of North America, can also cause HPS. Hantaviruses originally were recognized in the 4-corners region of the southwestern United States (New Mexico, Arizona, Utah, and Colorado) in May 1993, where the deer mouse (Peromyscus maniculatus) was found 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.[22]

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 3 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 August 2010, 504 cases of H5N1 human infections have been reported from 15 countries since 2003, with 299 deaths (59% mortality).[23]

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.[24] 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.[25] 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.[26]

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