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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	HA^a, SV^b		IF^c, ELISA^d	RT-PCR^e
Adenovirus	CE^f, 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 FCV^g	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),^[65]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.^[66]

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.^{[67, 68]}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.^{[69, 70]}

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.^[71]

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.^[72]

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.^[73]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^{[74, 75]}:

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).^[52]

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.^{[20, 53]}

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.^[16]

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%.^[50]In HSCT recipients, CT scans have shown bilateral nodular and extensive infiltrates and pleural effusion.^[49]

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.^[55]

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 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.

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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%).^[39]

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.^[39]

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.^[76]

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.^[77]

Treatment & Management

Wald TG, Miller BA, Shult P, Drinka P, Langer L, Gravenstein S. Can respiratory syncytial virus and influenza A be distinguished clinically in institutionalized older persons?. J Am Geriatr Soc. 1995 Feb. 43(2):170-4. [QxMD MEDLINE Link].
Korppi M, Don M, Valent F, Canciani M. The value of clinical features in differentiating between viral, pneumococcal and atypical bacterial pneumonia in children. Acta Paediatr. 2008 Jul. 97(7):943-7. [QxMD MEDLINE Link].
Jennings LC, Anderson TP, Beynon KA, Chua A, Laing RT, Werno AM, et al. Incidence and characteristics of viral community-acquired pneumonia in adults. Thorax. 2008 Jan. 63(1):42-8. [QxMD MEDLINE Link].
Marcos MA, Camps M, Pumarola T, et al. The role of viruses in the aetiology of community-acquired pneumonia in adults. Antivir Ther. 2006. Vol. 11:351-359.
Templeton KE, Scheltinga SA, van den Eeden WC, Graffelman AW, van den Broek PJ, Claas EC. Improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction. Clin Infect Dis. 2005 Aug 1. 41(3):345-51. [QxMD MEDLINE Link].
Kim MA, Park JS, Lee CW, Choi WI. Pneumonia severity index in viral community acquired pneumonia in adults. PLoS One. 2019. 14 (3):e0210102. [QxMD MEDLINE Link]. [Full Text].
McLaren SH, Mistry RD, Neuman MI, Florin TA, Dayan PS. Guideline Adherence in Diagnostic Testing and Treatment of Community-Acquired Pneumonia in Children. Pediatr Emerg Care. 2019 Feb 14. [QxMD MEDLINE Link].
Dugan VG, Blanton L, Elal AIA, et al. Update: Influenza Activity - United States, October 1-November 25, 2017. MMWR Morb Mortal Wkly Rep. 2017 Dec 8. 66 (48):1318-1326. [QxMD MEDLINE Link].
Almansa R, Martínez-Orellana P, Rico L, Iglesias V, Ortega A, Vidaña B, et al. Pulmonary transcriptomic responses indicate a dual role of inflammation in pneumonia development and viral clearance during 2009 pandemic influenza infection. PeerJ. 2017. 5:e3915. [QxMD MEDLINE Link].
Levy MM, Baylor MS, Bernard GR, Fowler R, Franks TJ, Hayden FG, et al. Clinical issues and research in respiratory failure from severe acute respiratory syndrome. Am J Respir Crit Care Med. 2005 Mar 1. 171(5):518-26. [QxMD MEDLINE Link].
Legg JP, Hussain IR, Warner JA, Johnston SL, Warner JO. Type 1 and type 2 cytokine imbalance in acute respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med. 2003 Sep 15. 168(6):633-9. [QxMD MEDLINE Link].
Katsurada N, Suzuki M, Aoshima M, Yaegashi M, Ishifuji T, Asoh N, et al. The impact of virus infections on pneumonia mortality is complex in adults: a prospective multicentre observational study. BMC Infect Dis. 2017 Dec 6. 17 (1):755. [QxMD MEDLINE Link].
Hansen CL, Chaves SS, Demont C, Viboud C. Mortality Associated With Influenza and Respiratory Syncytial Virus in the US, 1999-2018. JAMA Netw Open. 2022 Feb 1. 5 (2):e220527. [QxMD MEDLINE Link]. [Full Text].
Centers for Disease Control and Prevention. Novel Coronavirus 2019. CDC. Available at https://www.cdc.gov/coronavirus/novel-coronavirus-2019.html. January 16, 2020; Accessed: January 17, 2020.
Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD. Adenovirus infections in patients undergoing bone-marrow transplantation. N Engl J Med. 1985 Feb 28. 312(9):529-33. [QxMD MEDLINE Link].
Metzgar D, Osuna M, Kajon AE, Hawksworth AW, Irvine M, Russell KL. Abrupt emergence of diverse species B adenoviruses at US military recruit training centers. J Infect Dis. 2007 Nov 15. 196(10):1465-73. [QxMD MEDLINE Link].
Louie JK, Kajon AE, Holodniy M, Guardia-LaBar L, Lee B, Petru AM, et al. Severe pneumonia due to adenovirus serotype 14: a new respiratory threat?. Clin Infect Dis. 2008 Feb 1. 46(3):421-5. [QxMD MEDLINE Link].
Tate JE, Bunning ML, Lott L, Lu X, Su J, Metzgar D, et al. Outbreak of severe respiratory disease associated with emergent human adenovirus serotype 14 at a US air force training facility in 2007. J Infect Dis. 2009 May 15. 199(10):1419-26. [QxMD MEDLINE Link].
Lewis PF, Schmidt MA, Lu X, Erdman DD, Campbell M, Thomas A, et al. A community-based outbreak of severe respiratory illness caused by human adenovirus serotype 14. J Infect Dis. 2009 May 15. 199(10):1427-34. [QxMD MEDLINE Link].
Lewis VA, Champlin R, Englund J, Couch R, Goodrich JM, Rolston K, et al. Respiratory disease due to parainfluenza virus in adult bone marrow transplant recipients. Clin Infect Dis. 1996 Nov. 23(5):1033-7. [QxMD MEDLINE Link].
van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001 Jun. 7(6):719-24. [QxMD MEDLINE Link].
Falsey AR, Erdman D, Anderson LJ, Walsh EE. Human metapneumovirus infections in young and elderly adults. J Infect Dis. 2003 Mar 1. 187(5):785-90. [QxMD MEDLINE Link].
Boivin G, Abed Y, Pelletier G, Ruel L, Moisan D, Cote S, et al. Virological features and clinical manifestations associated with human metapneumovirus: a new paramyxovirus responsible for acute respiratory-tract infections in all age groups. J Infect Dis. 2002 Nov 1. 186(9):1330-4. [QxMD MEDLINE Link].
Cane PA, van den Hoogen BG, Chakrabarti S, Fegan CD, Osterhaus AD. Human metapneumovirus in a haematopoietic stem cell transplant recipient with fatal lower respiratory tract disease. Bone Marrow Transplant. 2003 Feb. 31(4):309-10. [QxMD MEDLINE Link].
Lau SK, Woo PC, Yip CC, Tse H, Tsoi HW, Cheng VC, et al. Coronavirus HKU1 and other coronavirus infections in Hong Kong. J Clin Microbiol. 2006 Jun. 44(6):2063-71. [QxMD MEDLINE Link]. [Full Text].
Luzzati R, D'Agaro P, Busca A, Maurel C, Martellani F, Rosin C, et al. Herpes simplex virus (HSV) pneumonia in the non-ventilated immunocompromised host: Burden and predictors. J Infect. 2019 Feb. 78 (2):127-133. [QxMD MEDLINE Link].
Duchin JS, Koster FT, Peters CJ, Simpson GL, Tempest B, Zaki SR, et al. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group. N Engl J Med. 1994 Apr 7. 330(14):949-55. [QxMD MEDLINE Link].
Levy H, Simpson SQ. Hantavirus pulmonary syndrome. Am J Respir Crit Care Med. 1994 Jun. 149(6):1710-3. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. Hantavirus Pulmonary Syndrome (HPS) Cases, by State. Available at http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/epislides/episls.htm. Accessed: August 24, 2010.
World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. Available at http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/. Accessed: August 8, 2014.
Poon LL, Guan Y, Nicholls JM, Yuen KY, Peiris JS. The aetiology, origins, and diagnosis of severe acute respiratory syndrome. Lancet Infect Dis. 2004 Nov. 4(11):663-71. [QxMD MEDLINE Link].
Beutel G, Wiesner O, Eder M, et al. Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection. Crit Care. 2011 Mar 2. 15(2):R80. [QxMD MEDLINE Link].
Abughali N, Khiyami A, Birnkrant DJ, Kumar ML. Severe respiratory syncytial virus pneumonia associated with primary Epstein-Barr virus infection. Pediatr Pulmonol. 2002 May. 33(5):395-8. [QxMD MEDLINE Link].
Johnstone J, Majumdar SR, Fox JD, Marrie TJ. Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation. Chest. 2008 Dec. 134(6):1141-8. [QxMD MEDLINE Link].
Whitney CG, Harper SA. Lower respiratory tract infections: prevention using vaccines. Infect Dis Clin North Am. 2004 Dec. 18(4):899-917. [QxMD MEDLINE Link].
Singh AM, Moore PE, Gern JE, Lemanske RF Jr, Hartert TV. Bronchiolitis to asthma: a review and call for studies of gene-virus interactions in asthma causation. Am J Respir Crit Care Med. 2007 Jan 15. 175(2):108-19. [QxMD MEDLINE Link].
Kujawski SA, Whitaker M, Ritchey MD, Reingold AL, Chai SJ, Anderson EJ, et al. Rates of respiratory syncytial virus (RSV)-associated hospitalization among adults with congestive heart failure-United States, 2015-2017. PLoS One. 2022. 17 (3):e0264890. [QxMD MEDLINE Link]. [Full Text].
Hilleman MR. Epidemiology of adenovirus respiratory infections in military recruit populations. Ann N Y Acad Sci. 1957 Apr 19. 67(8):262-72. [QxMD MEDLINE Link].
Anderson DJ, Jordan MC. Viral pneumonia in recipients of solid organ transplants. Semin Respir Infect. 1990 Mar. 5(1):38-49. [QxMD MEDLINE Link].
Harrington RD, Hooton TM, Hackman RC, Storch GA, Osborne B, Gleaves CA, et al. An outbreak of respiratory syncytial virus in a bone marrow transplant center. J Infect Dis. 1992 Jun. 165(6):987-93. [QxMD MEDLINE Link].
Kotloff RM, Ahya VN, Crawford SW. Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2004 Jul 1. 170(1):22-48. [QxMD MEDLINE Link].
Barton TD, Blumberg EA. Viral pneumonias other than cytomegalovirus in transplant recipients. Clin Chest Med. 2005 Dec. 26(4):707-20, viii. [QxMD MEDLINE Link].
Meyers JD, Flournoy N, Thomas ED. Nonbacterial pneumonia after allogeneic marrow transplantation: a review of ten years' experience. Rev Infect Dis. 1982 Nov-Dec. 4(6):1119-32. [QxMD MEDLINE Link].
Maravi-Poma E, Martin-Loeches I, Regidor E, et al. Severe 2009 A/H1N1v influenza in pregnant women in Spain. Crit Care Med. 2011 May. 39(5):945-951. [QxMD MEDLINE Link].
Chowell G, Bertozzi SM, Colchero MA, Lopez-Gatell H, Alpuche-Aranda C, Hernandez M, et al. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N Engl J Med. 2009 Aug 13. 361(7):674-9. [QxMD MEDLINE Link].
Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004 Sep 15. 292(11):1333-40. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR Morb Mortal Wkly Rep. 2009 Jul 17. 58(27):749-52. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. Updated CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April 2009 - April 10, 2010. Available at http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm. Accessed: August 8, 2014.
World Health Organization. Pandemic (H1N1) 2009 - update 89. Available at http://www.who.int/csr/don/2010_02_26/en/index.html. Accessed: August 8, 2014.
Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clin Microbiol Rev. 2000 Jul. 13(3):371-84. [QxMD MEDLINE Link]. [Full Text].
Pelletier G, Dery P, Abed Y, Boivin G. Respiratory tract reinfections by the new human Metapneumovirus in an immunocompromised child. Emerg Infect Dis. 2002 Sep. 8(9):976-8. [QxMD MEDLINE Link]. [Full Text].
Englund JA, Boeckh M, Kuypers J, Nichols WG, Hackman RC, Morrow RA, et al. Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients. Ann Intern Med. 2006 Mar 7. 144(5):344-9. [QxMD MEDLINE Link].
Tu CC, Chen LK, Lee YS, Ko CF, Chen CM, Yang HH, et al. An outbreak of human metapneumovirus infection in hospitalized psychiatric adult patients in Taiwan. Scand J Infect Dis. 2009. 41(5):363-7. [QxMD MEDLINE Link].
Engelhardt SJ, Halsey NA, Eddins DL, Hinman AR. Measles mortality in the United States 1971-1975. Am J Public Health. 1980 Nov. 70(11):1166-9. [QxMD MEDLINE Link]. [Full Text].
Centers for Disease Control and Prevention. Measles Cases and Outbreaks. Available at http://www.cdc.gov/measles/cases-outbreaks.html. Accessed: August 9, 2014.
US Centers for Disease Control and Prevention. Epidemiologic notes and reports: measles in HIV-infected children, United States. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/00000002.htm. Accessed: October 19, 2010.
Ison MG, Fishman JA. Cytomegalovirus pneumonia in transplant recipients. Clin Chest Med. 2005 Dec. 26(4):691-705, viii. [QxMD MEDLINE Link].
Ramsey PG, Fife KH, Hackman RC, Meyers JD, Corey L. Herpes simplex virus pneumonia: clinical, virologic, and pathologic features in 20 patients. Ann Intern Med. 1982 Dec. 97(6):813-20. [QxMD MEDLINE Link].
Kallen AJ, Brunkard J, Moore Z, Budge P, Arnold KE, Fosheim G, et al. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Ann Emerg Med. 2009 Mar. 53(3):358-65. [QxMD MEDLINE Link].
Govaert TM, Dinant GJ, Aretz K, Knottnerus JA. The predictive value of influenza symptomatology in elderly people. Fam Pract. 1998 Feb. 15(1):16-22. [QxMD MEDLINE Link].
Uyeki TM. Human infection with highly pathogenic avian influenza A (H5N1) virus: review of clinical issues. Clin Infect Dis. 2009 Jul 15. 49(2):279-90. [QxMD MEDLINE Link].
Dowell SF, Anderson LJ, Gary HE Jr, Erdman DD, Plouffe JF, File TM Jr, et al. Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis. 1996 Sep. 174(3):456-62. [QxMD MEDLINE Link].
Weber DM, Pellecchia JM. Varicella Pneumonia: Study of Prevalence in Adult Men. JAMA. 1965 May 10. 192:572-3. [QxMD MEDLINE Link].
Ko FW, Ip M, Chan PK, Ng SS, Chau SS, Hui DS. A one-year prospective study of infectious etiology in patients hospitalized with acute exacerbations of COPD and concomitant pneumonia. Respir Med. 2008 Aug. 102(8):1109-16. [QxMD MEDLINE Link].
Bonzel L, Tenenbaum T, Schroten H, Schildgen O, Schweitzer-Krantz S, Adams O. Frequent detection of viral coinfection in children hospitalized with acute respiratory tract infection using a real-time polymerase chain reaction. Pediatr Infect Dis J. 2008 Jul. 27(7):589-94. [QxMD MEDLINE Link].
Falsey AR, McCann RM, Hall WJ, Criddle MM. Evaluation of four methods for the diagnosis of respiratory syncytial virus infection in older adults. J Am Geriatr Soc. 1996 Jan. 44(1):71-3. [QxMD MEDLINE Link].
Osiowy C. Direct detection of respiratory syncytial virus, parainfluenza virus, and adenovirus in clinical respiratory specimens by a multiplex reverse transcription-PCR assay. J Clin Microbiol. 1998 Nov. 36(11):3149-54. [QxMD MEDLINE Link]. [Full Text].
Luminex Corporation. Luminex Respiratory Viral Panel. Available at http://www.luminexcorp.com/rvp/overview.html.. Accessed: August 28, 2009.
Pettila V, Webb SA, Bailey M, et al. Acute kidney injury in patients with influenza A (H1N1) 2009. Intensive Care Med. 2011 May. 37(5):763-7. [QxMD MEDLINE Link].
Nin N, Lorente JA, Soto L, et al. Acute kidney injury in critically ill patients with 2009 influenza A (H1N1) viral pneumonia: an observational study. Intensive Care Med. 2011 May. 37(5):768-74. [QxMD MEDLINE Link].
Erard V, Huang ML, Ferrenberg J, Nguy L, Stevens-Ayers TL, Hackman RC, et al. Quantitative real-time polymerase chain reaction for detection of adenovirus after T cell-replete hematopoietic cell transplantation: viral load as a marker for invasive disease. Clin Infect Dis. 2007 Oct 15. 45(8):958-65. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. Acute respiratory disease associated with adenovirus serotype 14--four states, 2006-2007. MMWR Morb Mortal Wkly Rep. 2007 Nov 16. 56(45):1181-4. [QxMD MEDLINE Link].
Kapoor M, Pringle K, Kumar A, Dearth S, Liu L, Lovchik J, et al. Clinical and laboratory findings of the first imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) into the United States. Clin Infect Dis. 2014 Aug 6. [QxMD MEDLINE Link].
Barclay L. MERS-CoV: CDC Guidance for Clinical Surveillance, Management. Medscape Medical News. Sep 27 2013. Available at http://www.medscape.com/viewarticle/811800. Accessed: October 9, 2013.
Updated Information on the Epidemiology of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection and Guidance for the Public, Clinicians, and Public Health Authorities, 2012-2013. MMWR Morb Mortal Wkly Rep. 2013 Sep 27. 62(38):793-6. [QxMD MEDLINE Link].
Kanne JP, Godwin JD, Franquet T, Escuissato DL, Muller NL. Viral pneumonia after hematopoietic stem cell transplantation: high-resolution CT findings. J Thorac Imaging. 2007 Aug. 22(3):292-9. [QxMD MEDLINE Link].
Peters CJ, Khan AS. Hantavirus pulmonary syndrome: the new American hemorrhagic fever. Clin Infect Dis. 2002 May 1. 34(9):1224-31. [QxMD MEDLINE Link].
Fathima P, Blyth CC, Lehmann D, Lim FJ, Abdalla T, de Klerk N, et al. The impact of pneumococcal vaccination on bacterial and viral pneumonia in Western Australian children: record linkage cohort study of 469,589 births (1996-2012). Clin Infect Dis. 2017 Oct 23. [QxMD MEDLINE Link].
Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM, Aoki FY, Nicholson KG, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. N Engl J Med. 1997 Sep 25. 337(13):874-80. [QxMD MEDLINE Link].
Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. 1999 Oct 6. 282(13):1240-6. [QxMD MEDLINE Link].
Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. 1999 Oct 28. 341(18):1336-43. [QxMD MEDLINE Link].
Hirji Z, O'Grady S, Bonham J, Mak M, Takata-Shewchuk J, Hawkins K, et al. Utility of zanamivir for chemoprophylaxis of concomitant influenza A and B in a complex continuing-care population. Can Commun Dis Rep. 2001 Feb 1. 27(3):21-4. [QxMD MEDLINE Link].
Monto AS, Fleming DM, Henry D, de Groot R, Makela M, Klein T, et al. Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections. J Infect Dis. 1999 Aug. 180(2):254-61. [QxMD MEDLINE Link].
Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000 Feb 23. 283(8):1016-24. [QxMD MEDLINE Link].
Kohno S, Kida H, Mizuguchi M, Shimada J. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother. 2010 Nov. 54(11):4568-74. [QxMD MEDLINE Link]. [Full Text].
Watanabe A, Chang SC, Kim MJ, Chu DW, Ohashi Y. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial. Clin Infect Dis. 2010 Nov 15. 51(10):1167-75. [QxMD MEDLINE Link].
Martin-Loeches I, Lisboa T, Rhodes A, Moreno RP, Silva E, Sprung C, et al. Use of early corticosteroid therapy on ICU admission in patients affected by severe pandemic (H1N1)v influenza A infection. Intensive Care Med. 2011 Feb. 37(2):272-83. [QxMD MEDLINE Link].
Moscona A. Management of respiratory syncytial virus infections in the immunocompromised child. Pediatr Infect Dis J. 2000 Mar. 19(3):253-4. [QxMD MEDLINE Link].
Swedish Consensus Group. Management of infections caused by respiratory syncytial virus. Scand J Infect Dis. 2001. 33(5):323-8. [QxMD MEDLINE Link].
Bordigoni P, Carret AS, Venard V, Witz F, Le Faou A. Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2001 May 1. 32(9):1290-7. [QxMD MEDLINE Link].
Morfin F, Dupuis-Girod S, Frobert E, Mundweiler S, Carrington D, Sedlacek P, et al. Differential susceptibility of adenovirus clinical isolates to cidofovir and ribavirin is not related to species alone. Antivir Ther. 2009. 14(1):55-61. [QxMD MEDLINE Link].
Kapelushnik J, Or R, Delukina M, Nagler A, Livni N, Engelhard D. Intravenous ribavirin therapy for adenovirus gastroenteritis after bone marrow transplantation. J Pediatr Gastroenterol Nutr. 1995 Jul. 21(1):110-2. [QxMD MEDLINE Link].
McCarthy AJ, Bergin M, De Silva LM, Stevens M. Intravenous ribavirin therapy for disseminated adenovirus infection. Pediatr Infect Dis J. 1995 Nov. 14(11):1003-4. [QxMD MEDLINE Link].
Adenovirus. Am J Transplant. 2004 Nov. 4 Suppl 10:101-4. [QxMD MEDLINE Link].
Chakrabarti S, Collingham KE, Holder K, Fegan CD, Osman H, Milligan DW. Pre-emptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study. Bone Marrow Transplant. 2001 Oct. 28(8):759-63. [QxMD MEDLINE Link].
Safdar A. Immune modulatory activity of ribavirin for serious human metapneumovirus disease: early i.v. therapy may improve outcomes in immunosuppressed SCT recipients. Bone Marrow Transplant. 2008 Apr. 41(8):707-8. [QxMD MEDLINE Link].
Raza K, Ismailjee SB, Crespo M, Studer SM, Sanghavi S, Paterson DL, et al. Successful outcome of human metapneumovirus (hMPV) pneumonia in a lung transplant recipient treated with intravenous ribavirin. J Heart Lung Transplant. 2007 Aug. 26(8):862-4. [QxMD MEDLINE Link].
Bonney D, Razali H, Turner A, Will A. Successful treatment of human metapneumovirus pneumonia using combination therapy with intravenous ribavirin and immune globulin. Br J Haematol. 2009 Jun. 145(5):667-9. [QxMD MEDLINE Link].
Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004 Mar. 59(3):252-6. [QxMD MEDLINE Link]. [Full Text].
Chen F, Chan KH, Jiang Y, Kao RY, Lu HT, Fan KW, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol. 2004 Sep. 31(1):69-75. [QxMD MEDLINE Link].
Forni AL, Schluger NW, Roberts RB. Severe measles pneumonitis in adults: evaluation of clinical characteristics and therapy with intravenous ribavirin. Clin Infect Dis. 1994 Sep. 19(3):454-62. [QxMD MEDLINE Link].
Petarra-Del Río S, Rodriguez-Hernandez A, Anguiano-Landa L, Aguilar-Portillo G, Zavala-Trujillo I, Nava-Zavala AH, et al. Immune Reconstitution Inflammatory Syndrome and Cytomegalovirus Pneumonia Case Report: Highlights and Missing Links in Classification Criteria and Standardized Treatment. Case Rep Infect Dis. 2017. 2017:9314580. [QxMD MEDLINE Link].
Zamora MR. Cytomegalovirus and lung transplantation. Am J Transplant. 2004 Aug. 4(8):1219-26. [QxMD MEDLINE Link].
Bacigalupo A, Bregante S, Tedone E, Isaza A, Van Lint MT, Moro F, et al. Combined foscarnet -ganciclovir treatment for cytomegalovirus infections after allogeneic hemopoietic stem cell transplantation (Hsct). Bone Marrow Transplant. 1996 Nov. 18 Suppl 2:110-4. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. Seasonal Influenza (Flu). Recommendations of the Advisory Committee on Immunization Practices (ACIP). Available at http://www.cdc.gov/flu/professionals/acip/. Accessed: August 8, 2014.
van der Hoek L. Human coronaviruses: what do they cause?. Antivir Ther. 2007. 12(4 Pt B):651-8. [QxMD MEDLINE Link].
Huijts SM, Coenjaerts FEJ, Bolkenbaas M, van Werkhoven CH, Grobbee DE, Bonten MJM, et al. The impact of 13-valent pneumococcal conjugate vaccination on virus-associated community-acquired pneumonia in elderly: Exploratory analysis of the CAPiTA trial. Clin Microbiol Infect. 2017 Oct 16. [QxMD MEDLINE Link].
Papi A, Ison MG, Langley JM, and the, AReSVi-006 Study Group. Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. N Engl J Med. 2023 Feb 16. 388 (7):595-608. [QxMD MEDLINE Link]. [Full Text].
Walsh EE, Pérez Marc G, Zareba AM, and the, RENOIR Clinical Trial Group. Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults. N Engl J Med. 2023 Apr 20. 388 (16):1465-1477. [QxMD MEDLINE Link].
Kampmann B, Madhi SA, Munjal I, and the, MATISSE Study Group. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023 Apr 20. 388 (16):1451-1464. [QxMD MEDLINE Link]. [Full Text].
Muller WJ, Madhi SA, Seoane Nuñez B, and the, MELODY Study Group. Nirsevimab for Prevention of RSV in Term and Late-Preterm Infants. N Engl J Med. 2023 Apr 20. 388 (16):1533-1534. [QxMD MEDLINE Link].
[Guideline] Caserta MT, O'Leary ST, Munoz FM, Ralston SL, COMMITTEE ON INFECTIOUS DISEASES. Palivizumab Prophylaxis in Infants and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Infection. Pediatrics. 2023 Jul 1. 152 (1):[QxMD MEDLINE Link]. [Full Text].
Tang RS, Schickli JH, MacPhail M, et al. Effects of human metapneumovirus and respiratory syncytial virus antigen insertion in two 3' proximal genome positions of bovine/human parainfluenza virus type 3 on virus replication and immunogenicity. J Virol. 2003 Oct. 77(20):10819-28. [QxMD MEDLINE Link]. [Full Text].
Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009 Oct. 15(10):1143-238. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

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 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.
Bilateral interstitial infiltrates in a 31-year-old patient with influenza pneumonia.
Right-middle-lobe infiltrate in a 2-month-old boy with pneumonia due to respiratory syncytial virus (RSV).
High-power Papanicolaou (Pap) stain showing a virus on a bronchial wash. Viruses in general show "smudgy" nuclei, may or may not show nuclear or cytoplasmic inclusions, and may demonstrate other features such as multinucleation or margination of chromatin to the periphery of the cell nucleus. Certain features are more indicative of one virus over another. This is an example of herpes virus (cells infected are located in the center right).
High-power Papanicolaou (Pap) stain of cytomegalovirus (center). This cell has a very large, dark intranuclear inclusion.
High-power hematoxin-and-eosin stain of giant cell pneumonia following measles. A multinucleated cell (center) contains eosinophilic intranuclear inclusions.
High-power hematoxin-and-eosin stain of numerous cells infected with the cytomegalovirus (large cells with enlarged nuclei containing dark-purple intranuclear inclusions surrounded by a clear halo).
High-power hematoxin-and-eosin stained herpes simplexvirus, characterized by "smudgy" degenerating nuclei. Some cells are multinucleated with margination of the chromatin to the periphery of the nuclei and molding of the nuclei to each other.

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Table 1. Diagnostic Techniques Used for Viral Pneumonia

Virus	Viral Culture	Cytologic Evaluation	Rapid Antigen Detection	Gene Amplification
Influenza virus	HA^a, SV^b		IF^c, ELISA^d	RT-PCR^e
Adenovirus	CE^f, 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 FCV^g	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

Table 2. Treatment and Prevention of Common Causes of Viral Pneumonia

Virus	Treatment	Prevention
Influenza virus	Oseltamivir Peramivir Zanamivir	Influenza vaccine^[78] Chemoprophylaxis with: Zanamivir Oseltamivir
Respiratory syncytial virus	Ribavirin	RSV vaccine (adults ≥ 60 y) Palivizumab or nirsevimab (children < 2 y)
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

Table 3. Characteristics of Anti-Influenza Drugs

	Amantadine (Symmetrel)	Rimantadine (Flumadine)	Zanamivir (Relenza)	Oseltamivir (Tamiflu)
Mechanism of action	M2 ion channel blockade inhibits HA^a cleavage beta block RNA encoding, which reduces early viral replication.		Viral NA^b 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: ASA^c, acetaminophen	None	None
Renal clearance	TMP-SMZ^d, triamterene, hydrochlorothiazide, quinine sulfate, quinidine	Cimetidine	None	None
^a HA - Hemagglutinin ^b NA - Neuraminidase ^c ASA - Acetylsalicylic acid ^d TMP-SMZ - Trimethoprim and sulfamethoxazole

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Author

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society

Disclosure: Nothing to disclose.

Coauthor(s)

Arthur Jeng, MD Assistant Professor of Clinical Medicine, University of California at Los Angeles School of Medicine

Arthur Jeng, MD is a member of the following medical societies: Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Nader Kamangar, MD, FACP, FCCP, FCCM Professor of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Chief, Division of Pulmonary and Critical Care Medicine, Vice-Chair, Department of Medicine, Olive View-UCLA Medical Center

Nader Kamangar, MD, FACP, FCCP, FCCM is a member of the following medical societies: Academy of Persian Physicians, American Academy of Sleep Medicine, American Association for Bronchology and Interventional Pulmonology, American College of Chest Physicians, American College of Critical Care Medicine, American College of Physicians, American Lung Association, American Medical Association, American Thoracic Society, Association of Pulmonary and Critical Care Medicine Program Directors, Association of Specialty Professors, California Sleep Society, California Thoracic Society, Clerkship Directors in Internal Medicine, Society of Critical Care Medicine, Trudeau Society of Los Angeles, World Association for Bronchology and Interventional Pulmonology

Disclosure: Nothing to disclose.

Chief Editor

John J Oppenheimer, MD Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA

John J Oppenheimer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, New Jersey Allergy, Asthma and Immunology Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Amgen; GSK; Aquestive; Aimmune<br/>Clinical Adjudication/Data Safety Monitoring Board for AZ, GSK, Abbvie, Sanofi; Executive Editor for Annals of Allergy, Asthma & Immunology; Editor for Medscape; Reviewer for UpToDate; Honoraria from American Board of Allergy and Immunology.

Acknowledgements

Shakeel Amanullah, MD Consulting Physician, Pulmonary, Critical Care, and Sleep Medicine, Lancaster General Hospital

Shakeel Amanullah, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, and Society of Critical Care Medicine