Opportunistic Viruses

Adeno Adeno Adeno

ADENOVIRAL HEPATITIS

Introduction and Pathophysiology

Adenoviral infection and disease after liver transplantation is largely limited to the pediatric population (1-3), although it occasionally can be seen in adults. The difference in frequency between the two different age populations is presumably related to prior protective immunity, much like the situation seen with CMV, EBV and the other "opportunistic viral infections.. Viral subtypes 1, 2 and 5 have been isolated from the lung, gastrointestinal tract and liver in patients with fever, respiratory distress, diarrhea, and liver dysfunction(1-3). The onset of symptoms attributable to adenoviral infection usually occurs between 1 and 10 weeks after transplantation. Tissue biopsies and histopathological analyses are used to ascertain the diagnosis. Liver involvement with frank hepatitis is most often caused by subtype 5. However, viral subtypes 2, 11 and 16 have been associated with hepatitis in the general population and therefore, could be expected to behave similarly in liver allograft recipients(1-3).

Histopathologic Findings

Some experience is usually required to establish the diagnosis with certainty and therefore, immunohistochemical confirmation of the presence of viral antigens can be very helpful. The most characteristic changes on routine light microscopy, are the presence of "pox-like" granulomas, consisting almost entirely of macrophages, which are spread randomly throughout the parenchyma, encompassing small groups of necrotic hepatocytes (1-3). In other cases, the granulomatoid collections of macrophages are replaced by necrosis that can be rather extensive. Adenoviral inclusions, when identifiable, are often located near the edge of the necrotic zones and/or granulomas. They are characterized by a crowding of chromatin towards the nuclear membrane, imparting a muffin-shape appearance to the nucleus. Immunohistochemical staining are confirmatory. Portal inflammation is variably present, but subendothelial inflammation of portal and/or central veins and bile duct damage are not usually seen.

Differential Diagnosis

The histopathologic differential diagnosis includes deep fungal or mycobacterial infections, CMV and HSV-VZ, ischemic necrosis, and non-specific granulomatoid collections of macrophages, which are not uncommon in liver allograft biopsies. Obvious adenoviral inclusions clinch the diagnosis. However, inclusions are not always identified or easily distinguished from other types of viral inclusions. The granulomas associated with adenovirus consist almost entirely of macrophages, are much larger than the "micro-granulomas" of CMV, and multinucleated giant cells are rare. In contrast, CMV causes cytomegaly of the involved cell, and CMV can produce both eosinophilic intranuclear inclusions surrounded by a clear halo, and basophilic or amphophilic small cytoplasmic inclusions. In contrast, Adenovirus usually does not cause significant cytomegaly. In addition, the infected nuclei are "smudgy-appearing" and there are no cytoplasmic inclusions. The hepatocyte necrosis associated with Adenovirus is generally less than that seen with Herpes Simplex or Varicella-Zoster hepatitis. However, in other cases, the two(Adenovirus and Herpes Simplex or Varicella/Zoster) can appear quite similar.

The zones of ischemic necrosis seen with vascular compromise of one sort or another, can appear similar to the necrosis seen with Adenovirus and HSV-VZ. However, in the former, the necrosis almost always shows a lobular or zonal distribution whereas in the latter, the distribution of necrosis is apparently random. In addition, virally infected cells are usually absent in ischemic damage.

Non-specific granulomatoid collections of macrophages are not infrequent in liver allograft biopsies. However, there usually is little other evidence of tissue damage and the clinical profile is not typical of a viral syndrome. In addition, typical inclusion bodies are not seen.

A not insignificant number of cases will remain where significant pathological changes are seen, but inclusion bodies are not present, or the pathologist is unsure. In such cases, information gained from ancillary studies can provide useful information. For example, microbiologic cultures of the biopsy and negative special stains for granuloma-causing organisms make fungal and mycobacterial infections less likely. The clinical syndrome and findings provide additional useful information. Finally, the presence of Adenoviral antigens confirmed by immunohistochemical staining is confirmatory.

REFERENCES

  1. Koneru B, Jaffe R, Esquivel CO, et al. Adenoviral infections in pediatric liver transplant recipients. JAMA 1987;258(4):489-492.
  2. Michaels MG, Green M, Wald ER, et al. Adenovirus infection in pediatric liver transplant recipients. J Infect Dis 1992;165(1):170-174.
  3. Varki NM, Bhuta S, Drake T, et al. Adenovirus hepatitis in two successive liver transplants in a child. Arch Pathol Lab Med 1990;114(1):106-109.
  4. Reda SS, Demetris AJ, Lee RG, Kusne S, Randhawa P. Adenovirus hepatitis in the adult allograft liver. Transplantation (manuscript submitted).


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Last Modified: Thu Jun 18 10:14:08 EDT 2009