Skip to main content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
BMJ Case Rep. 2009; 2009: bcr08.2008.0803.
Published online 2009 Mar 5. doi: 10.1136/bcr.08.2008.0803
PMCID: PMC3027536
PMID: 21686623
Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

Varicella-zoster virus reactivation during acute enterovirus infection is associated with CD8 lymphocytopenia

Abstract

The trigger or triggers for reactivation of varicella-zoster virus have not been well defined in the medical literature. We investigated the role of enterovirus infections in triggering herpes zoster in five patients and correlated the reactivation with transient CD8 T lymphocyte depletion during the acute enterovirus infection.

BACKGROUND

More than one million cases of herpes zoster occur annually in the USA. Waning immunity to varicella-zoster virus (VZV) has been proposed as the mechanism leading to reactivation. A recently approved zoster vaccine clearly reduced the frequency and severity of zoster in vaccinees as compared with placebo-treated subjects.1 The trigger or triggers for reactivation of VZV have not always been obvious. In recent years, we and others have observed clustering of zoster in patients during or immediately after respiratory and/or gastrointestinal illness. We report the detection of enterovirus in the respiratory secretion and in stools of several patients with clinically diagnosed zoster and discuss the immunologic derangement during acute infection that predisposes to reactivation of VZV.

CASE PRESENTATION

A 35-year-old female with a history of stage II Hodgkin’s lymphoma in remission, developed watery diarrhoea 24 h after eating shellfish. Five days later, the patient developed severe painful blisters and surrounding erythema over her right forehead, which did not respond to cefalexin. She responded to oral valaciclovir after a clinical diagnosis of herpes zoster was made. A perirectal swab was positive for enterovirus RNA by RT-PCR, and the same specimen grew enterovirus in a culture of monkey cells, confirmed by gene sequencing.2 The serotype was not further characterised.

Table 1 summarises the dermatomal distribution of zoster, predisposing factor and the manifestations of enterovirus infection for five patients. The immunologic derangement during acute enteroviral infection leading to reactivation of VZV was investigated by measuring T lymphocyte subsets in patients 1 and 3–5. Patients 1 and 5 had significantly decreased numbers of CD3 and CD4 cells, and all four patients had significantly decreased CD8 cells. These abnormalities returned to normal 6–8 weeks after resolution of the acute infections (data not shown).

Table 1

The clinical presentation, immunologic and virologic studies of patients with acute enterovirus infection complicated with herpes zoster

Patient age/genderNerve distributionPredisposing factorConcurrent illnessWBC/CD3/CD4/CD8 cells*Source of positive enterovirus RNA
35/FV1Prior Hodgkin’s lymphomaDiarrhoea6400/447/320/130Perirectal swab
44/MV1NoneURI/diarrhoeaNDThroat secretions
62/MV1NoneDiarrhoea8400/1024/933/95Perirectal swab
48/FVIINoneBronchitis/diarrhoea5400/718/577/129Perirectal swab
72/FT10NoneBronchitis/diarrhoea6200/500/203/69Throat secretions

Numbers in bold type are below normal range.

*The normal range for white cell count, total lymphocytes, CD3, CD4 and CD8 cells are 4000–10 000, 582–1992, 401–1532, 152–838, respectively. The T lymphocyte panel was performed at Mayo clinic laboratory, Rochester, MN.

F, female; M, male; ND, not done; URI, upper respiratory infection. INVESTIGATIONS

The total CD8 cells of these patients were compared with those of 27 sex- and gender-matched patients with known diagnoses of chronic fatigue syndrome (CFS) associated with chronic enterovirus infections2 that were seen in the clinic during the same period. The means (standard error) of CD8 cells were 106 (15) vs 426 (25) for the two groups, respectively, which was statistically significance (p<0.01, unpaired t test). Enteroviruses were not detected in the peri-rectal swabs taken from 10 CFS patients.

DISCUSSION

Acute enterovirus infections clearly preceded the reactivation of VZV in these cases, as documented by the finding of enteroviral RNA in the stool or throat secretion but not in 10 control subjects.

Lymphocytopenia has been reported in children with acute enterovirus infection.3 In our patients, predominant depletion of CD8 lymphocyte was seen in all four patients and yet reduction of total T lymphocytes and CD4 lymphocytes were seen in only two. The CD8 lymphocyte counts of the patients with zoster were significantly lower than the values observed in CFS patients seen during the same period. The improvement of lymphocyte counts after the acute enterovirus infection excluded pre-existing lymphocytopenia in these patients.

The most important factor that predisposes to the development of herpes zoster is a decline or suppression of VZV-specific cellular immunity.4 Development of chickenpox in utero and before 2 months of age predisposes to pediatric herpes zoster. Older age, white race, immunosuppression, autoimmune diseases, trauma and surgery are other known risk factors for adult cases of shingles.5,6 The frequency of herpes zoster and recurrences are more common in HIV-positive patients with CD4 lymphocyte counts of less than 100 cells per cubic millimetre than in patients with counts above 500.5,6 The role of CD8 lymphocytes has not been clearly investigated in this or other patient populations.

The mechanism for the depletion of circulating CD8 T cells is not clear, although enteroviruses are known to infect T and B lymphocytes in vitro.3 CD8 cells are thought to constitute one of the main effector arms in the immune response and to be responsible for viral clearance and protection on re-exposure.7 A depletion of total CD8 cells and likely the VZV-specific CD8 lymphocyte subpopulation could reactivate underlying dormant VZV infection. Acute enterovirus infection, which affects more than 50 million people yearly in the United States,8 may be an important trigger of herpes zoster.

LEARNING POINTS

  • Herpes zoster can occur during and following acute enterovirus infection.
  • The mechanism of varicella-zoster virus reactivation is transient decrease of CD8 T lymphocytes.
  • Acute enterovirus infection may be an important trigger of herpes zoster.

Footnotes

Competing interests: none.

Patient consent: Patient/guardian consent was obtained for publication

REFERENCES

1. Oxman MN, Levine MJ, Johnson MS, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352: 2271–84 [PubMed] [Google Scholar]
2. Chia J, Chia A. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Path 2008; 61: 43–8 [PubMed] [Google Scholar]
3. Dommergues MA, Harzic M, Gobert ME, et al. Seasonal outbreak of enteroviral meningitis during summer 2005: experience of a French paediatric unit. Arch Paediatric 2007; 14: 964–70 [PubMed] [Google Scholar]
4. Burke BL, Steele RW, Beard OW, et al. Immune response to varicella zoster in the aged. Arch Intern Med 1982; 142: 291–3 [PubMed] [Google Scholar]
5. Engels EA, Rosenberg PS, Biggar RJ. Zoster incidence in human immunodeficiency virus-infected haemophiliacs and homosexual men, 1984–1997. District of Columbia Gay Cohort Study; multicenter Haemophilia Cohort Study. J Infect Dis 1999; 180:1784–9 [PubMed] [Google Scholar]
6. Harpaz R, Ortega-Sanchez IR, Seward JF; Centers for Disease Control and Prevention Prevention of herpes zoster. Recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep Early Release 2008 (RR-5); 57: 1–30 [PubMed] [Google Scholar]
7. Vossen MT, Biezeveld MH, de Jong MD, et al. Absence of circulating natural killer and primed CD8+ cells in life-threatening varicella. J Infect Dis 2005; 191: 198–206 [PubMed] [Google Scholar]
8. Oberste MS, Pallansch M. Establishing evidence for enterovirus infection in chronic diseases. Ann N Y Acad Sci 2003; 1005: 23–31 [PubMed] [Google Scholar]

Articles from BMJ Case Reports are provided here courtesy of BMJ Publishing Group