—  BINFORD-DAMMIN SOCIETY OF INFECTIOUS DISEASE PATHOLOGISTS   —

Viral Infections of the Lung


Sherif Zaki
Centers for Disease Control
Atlanta, GA


Many pulmonary infections in man are caused by viruses such as influenza virus, adenovirus, coronavirus, and herpesvirus. Viral infections of the lower respiratory tract occur in both normal and immunocompromised hosts (not mutually exclusive). Table 1 provides a list of the most common viral pathogens observed in these patient populations. Lung may also be involved as part of systemic viral infection as seen for example with poxviridae, parvoviridae, and viral hemorrhagic fevers.

Table 1: Common Viral Infections in Immunocompetent and Immunocompromised Patients

Immunocompetent patients
Influenza viruses
Hantaviruses
Epstein-Barr virus
Adenoviruses

Immunocompromised patients
Herpes simplex viruses
Varicella-zoster virus
Cytomegaloviruses
Measles virus
Adenoviruses


The diagnosis of viral pneumonia, suspected by history and clinical manifestations, also can be supported histopathologically, and the overall pattern of histopathologic lesions may suggest a specific diagnosis. Many viruses can be identified in lung by examining the tissue response and cytopathic changes. Some of these viruses cause recognizable tissue reaction patterns including necrotizing tracheobrochitis, bronchiolitis, and interstitial pneumonia. A summary of the key diagnostic features for the most common viral pathogens that cause a majority of pulmonary infections is provided in Table 2.

Table 2: Diagnostic Features of Viral Pneumonias

Family Virus Inclu- sions Description Tissue Reaction Diagnostic Ultrastructural Features
Adenoviridae Adenovirus Yes Nuclear Necrotizing bronchiolitis; smudge cells; DAD 70-90 nm nucleocapsids (NC) with a dense core are found in cell nuclei, sometimes in paracrystalline arrays.
Bunyaviridae Hantavirus No   Severe edema, early DAD Virions difficult to detect; characteristic NC granulofilamentous inclusions in endothelial cells
Coronaviridae SARS No   Interstitial pneumonia;occasional multinucleation Spherical, enveloped virions, approx. 75, but up to 160 nm in diameter, accumulate in cytoplasmic vesicles, and are often found adherent to the plasma membrane.
Herpesviridae Cyto- megalovirus Yes Nuclear and cytoplasmic Interstitial pneumonia; DAD; cytomegaly 100 nm viral NCS are found in cell nuclei; in cytoplasm, tegument surrounds the nucleocapsids and enveloped virions, 120-200 nm, are found in Golgi cisternae and extracellularly
  Herpes Simplex Yes Nuclear DAD; necrosis and rare multinucleation
  Varicella- zoster Yes Nuclear DAD; necrosis, and rare multinucleation
Ortho- myxoviridae Influenza No   DAD; necrotizing bronchiolitis Filamentous virions, 80-100 nm in diameter, are composed of enveloped, filamentous NCs found budding at the plasma membrane of infectious cells. Cytoplasmic and nuclear NCs are sometime seen.
Para- myxoviridae MeaslesYes Nuclear and cytoplasmic Interstitial pneumonia with multinucleation DAD Paramyxovirinae (measles, nipah, PI) are enveloped, pleomorphic virions, roughly 125-250 nm in diameter, consist of an enveloped aggregation of filamentous NC. The 18 nm wide NCs aligns under plasma membranes as virions bud into extracellular space. Pneumovirinae (RSV, HMPV) are somewhat smaller than Paramyxovirinae, the roughly spherical enveloped particles average 90-130 nm, and contain 14 nm wide NCs.
 Nipah Yes Nuclear and cytoplasmic Interstitial pneumonia with multinucleation and DAD
  Para- influenza (PI) Yes Cytoplasmic DAD; interstitial pneumonia with occasional multinucleation
  Respir- atory syncytial virus (RSV) Yes Cytoplasmic Necrotizing bronchiolitis, interstitial pneumonia with occasional multinucleation
  Human Meta- pneumonia (HMPV)   Recently described; human pathology not yet described

Only certain viruses can cause cytopathic changes that are morphologically distinctive enough to enable the pathologist to recognize a specific diagnosis on routine histologic examination of lung specimens. With the availability of special diagnostic techniques, such as immunohistochemistry (IHC) and in situ hybridization (ISH), many viruses can be detected in formalin-fixed, paraffin-embedded tissue samples even if specific viral inclusions cannot be found in histologic examination of tissue sections. Among the techniques, IHC utilizing specific antibodies can be routinely performed on formalin-fixed tissue and can enhance the pathologist's accuracy in identifying organisms in tissue specimens. Some commercial sources for available antibodies to detect the most prominent viral pathogens are provided in Table 3.

Table 3: Sources for Commercial Immunohistochemical Reagents

Virus Commercial Sources
Adenovirus Chemicon
Cytomegalovirus DAKO
Epstein-Barr DAKO
Herpes Simplex DAKO, Chemicon
Varicella-zoster Chemicon
Measles Chemicon
Parainfluenza Chemicon
Parvovirus Novocastra, Chemicon, DAKO
Respiratory syncytial virus Chemicon

In addition to histologic pattern recognition, IHC, and ISH in tissue, several other diagnostic tests are available to aid the pathologist. Cell culture techniques, serology, polymerase chain reaction (PCR), and electron microscopy (EM) all play vital roles in the diagnosis of these infections.

While histologic techniques can be an excellent means of demonstrating organisms and more sophisticated methods are available using fixed tissue, cultures remain essential for definitive identification of the organism. Samples of all lung tissues should be routinely cultured for organisms when viral pneumonia is suspected. The major advantage of using cell cultures in virologic diagnosis is that it is a non-biased method for screening purposes that doesn't rely on availability of specific antibodies or probes.

Likewise, electron microscopy (EM) offers the same utility as a broad scope diagnostic tool and has been especially critical in outbreaks of unknown etiology. Recently, EM played a critical role during the Nipah virus outbreak in 1999 and more recently, in the early recognition of a novel coronavirus associated with the sudden acute respiratory syndrome (SARS) in 2003. The advantage of this method is that viral particles may be demonstrated directly in clinical material or after amplification in cell culture by negative stain and/or thin section electron microscopy. Like culture, EM is not limited by narrow specificity of reagents or prior clinical bias.

During the course of the talk, an overview of the common pathologic findings present in viral pneumonias will be presented along with discussion of current diagnostic testing modalities. Recent experiences with sudden acute respiratory syndrome (SARS) and influenza associated deaths in the United States among children will be discussed. General and specific references on viral infections are provided.

References

General

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Adenoviridae

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Bunyaviridae

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Coronaviridae

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Herpesviridae

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Orthomyxoviridae

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Paramyxoviridae

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Other Viruses

Viral Hemorrhagic Fevers

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  2. Gubler DJ, Zaki SR. Dengue and other viral hemorrhagic fevers. In: Pathology of Emerging Infections II, Eds. Horsburgh CR, Jr., Nelson AM; American Society for Microbiology, Washington, DC, 1998;43-72.
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  4. Zaki SR, Goldsmith CS. Pathologic features of filovirus infections in humans. In: Current Topics in Microbiology and Immunology (Marburg and Ebola Viruses), Ed. Klenk HD; Springer-Verlag, Berlin, 1998;235:97-116.
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Poxvividae

  1. Guarner J, Johnson BJ, Paddock CD, Shieh WJ, Goldsmith CS, Reynolds MG, Damon IK, Regnery RL, Zaki SR. Pathology of monkeypox in prairie dogs: clues into transmission and pathogenesis. EID 2004 (in press).

Parvovirus

  1. Anderson L, Zaki SR, Török TJ. Parvovirus infections (Erythema infectiosum). In: Volume VIII, Pediatric Infectious Diseases, Ed. Wilfert CM; In: Atlas of Infectious Diseases, Ed. Mandell GL; Current Medicine, Philadelphia, PA 1999; 3.1-3.20.