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/gender | Nerve distribution | Predisposing factor | Concurrent illness | WBC/CD3/CD4/CD8 cells* | Source of positive enterovirus RNA |
| 35/F | V1 | Prior Hodgkin’s lymphoma | Diarrhoea | 6400/447/320/130 | Perirectal swab |
| 44/M | V1 | None | URI/diarrhoea | ND | Throat secretions |
| 62/M | V1 | None | Diarrhoea | 8400/1024/933/95 | Perirectal swab |
| 48/F | VII | None | Bronchitis/diarrhoea | 5400/718/577/129 | Perirectal swab |
| 72/F | T10 | None | Bronchitis/diarrhoea | 6200/500/203/69 | Throat 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.
Footnotes
Competing interests: none.
Patient consent: Patient/guardian consent was obtained for publication
