By Dean L. Winslow, MD

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: Researchers reviewed five years of cases at an academic medical center’s pathology department for the use of immunohistochemistry to detect CMV, HSV-1, HSV-2, varicella zoster virus, adenovirus, or polyomavirus. Of 957 cases, 134 were positive. Viral cytopathic effect (CPE) was present on hematoxylin and eosin staining in 75% of the IHC+ cases. No changes in clinical care occurred in any of the IHC+ cases in which viral CPE was absent.

SOURCE: Solomon IH, Hornick JL, Laga AC. Immunohistochemistry is rarely justified for the diagnosis of viral infections. Am J Clin Pathol 2017;147:96-104.

Researchers studied 1,636 viral immunohistochemistry (IHC) stains ordered on 1,099 specimens from 957 cases over a five-year period at an academic center. Three pathologists who were blinded to the results of IHC reviewed the corresponding hematoxylin and eosin (H&E) stained slides. From all specimens, a total of 134 of 1,636 (8.2%) were positive by IHC. Specimens lacking definitive cytomegalovirus (CMV) viral cytopathic effect (CPE) on H&E included 15 (31%) of 49 gastrointestinal specimens, one placenta specimen, two lung specimens, and one buccal mucosal specimen. HSV-1/HSV-2 and varicella zoster virus CPE-negative specimens were seen in three cervical/vaginal and three central nervous system specimens. No cases of adenovirus IHC+ sections were found, which also lacked viral CPE on H&E. Five of 22 (23%) kidney and bladder cases that were IHC+ for polyomavirus lacked distinctive viral CPE. A representative review of 36 cases reported as negative for viral CPE with or without +IHC were confirmed as negative. All cases reported as showing viral CPE were confirmed as positive. Focusing on IHC+/H&E-discrepant cases of CMV infection, all had only rare or single IHC+ cells observed. This discrepancy resulted in either no treatment or continued treatment in a patient with known established CMV infection.


Immunohistochemistry commonly is requested on biopsy specimens obtained from patients who are suspected of having viral infection. While occasionally one sees specimens that are positive by IHC but negative for CPE, this is almost always in cases in which only single or rare IHC+ cells are seen. In addition, in this case series, of the 33 cases from all of the viral infections studied in which IHC was positive without definitive CPE, none resulted in significant change in clinical care.

This paper was interesting because I’ve now encountered several gastroenterologists who aggressively look for concomitant CMV infection in patients with inflammatory bowel disease flares and insist on treating for CMV either before or while giving corticosteroids for the inflammatory bowel disease flare. The study typically cited to justify this practice showed that five of eight patients with even isolated IHC+ cells exhibited worsening symptoms, which seemed to improve with antiviral therapy.1 However, none of the cases in which CMV IHC was positive and viral CPE was negative resulted in a change of treatment. Interestingly, only two of eight patients in the case series had inflammatory bowel disease. One of these patients seemed to improve on valganciclovir, and the other patient with Crohn’s colitis improved without receiving antivirals. Clearly, using antivirals to treat CMV in the setting of inflammatory bowel disease flares is something that should be subjected to a randomized, controlled trial.

In summary, it seems that it is rarely helpful to perform IHC for viral pathogens on biopsy specimens in the absence of viral CPE on H&E examination.


  1. Yan Z, Wang L, Dennis J, et al. Clinical significance of isolated cytomegalovirus-infected gastrointestinal cells. Int J Surg Pathol 2014;22:492-498.