Correspondence
Primary Human Herpesvirus 6 Infection in an Adult
N Engl J Med 1993; 329:1817-1819December 9, 1993
- Article
To the Editor:
Akashi et al. (July 15 issue)1 reported seroconversion to human herpesvirus 6 (HHV-6) positivity in a patient with an infectious mononucleosis-like syndrome, and Cone et al. (July 15 issue)2 detected high levels of HHV-6 genome in the lungs of recipients of bone marrow transplants who had idiopathic pneumonitis. In neither instance did the data prove that the virus caused the disease being studied. In the first report, the observations could have reflected recurrent HHV-6 infection coincident with signs and symptoms unrelated to the virus1,3. The authors interpreted the serologic findings (IgG seroconversion with no IgM response) as indicating a primary HHV-6 infection, though as they admit, a negative test for specific IgG antibody on immunofluorescence assay does not exclude the possibility of past infection. In addition, specific IgM is more likely to be absent in recurrent than in primary cytomegalovirus infection4 -- a point that is also compatible with the possibility that the HHV-6 infection was recurrent. Were diagnoses of measles, rubella, parvovirus B19, adenovirus, and Toxoplasma gondii infections (possible causes of skin rashes or infectious mononucleosis-like syndromes) completely excluded? Moreover, even if primary HHV-6 infection was the only infection in this patient during the illness, longitudinal studies will be required to prove that the association is causal and does not reflect coincidental asymptomatic primary HHV-6 infection5-7.
Cone et al.2 were more cautious and recognized that the association between severe graft-versus-host disease (GVHD) and high levels of HHV-6 in lung tissues could be the result of the precipitation by GVHD of both lung disease and asymptomatic recurrence of the virus.
It will be difficult to prove that HHV-6 is pathogenic in adults. Analysis of the cellular locus of viral replication, as proposed by Agut,3 was not decisive in the recent immunohistologic study my colleagues and I undertook of pneumonitis in recipients of bone marrow allografts. Using HHV-6-specific monoclonal antibodies, we found viral antigens in pneumocytes8. The number of cells infected with HHV-6 was small, and a few cytomegalovirus-infected cells were also found, but we did not consider that HHV-6 could be excluded as the cause of the lung abnormalities. Cytomegalovirus pneumonitis may arise as a consequence of associated immunopathologic tissue destruction9 or in a setting of preexisting radiation- or chemotherapy-induced lung damage10. If HHV-6-induced lung damage shares one of these pathogenetic mechanisms, extensive lytic infection of pneumocytes or other cells in the lungs might not be necessary for the virus to induce pneumonitis. Conversely, widespread cellular HHV-6 infection does not necessarily imply HHV-6 disease. In the case reported by Akashi et al.,1 the detection of HHV-6 antigens in 32 percent of CD4+ lymphocytes could merely reflect a propensity for viral recurrence to lead to infection of these cells.
Studies purporting to prove that HHV-6 causes a given disease must be scrutinized with great caution. Otherwise, HHV-6 will be considered, like cytomegalovirus, to be the cause of a multitude of clinical symptoms without any certainty that the virus is truly the cause.
10 ReferencesDavid J. Morris, M.D., M.R.C.Path.
University of Manchester, Manchester M13 9PT, United Kingdom1
Akashi K ,Eizuru Y ,Sumiyoshi Y , et al. Severe infectious mononucleosis-like syndrome and primary human herpesvirus 6 infection in an adult. N Engl J Med 1993;329:168-171
Full Text | Web of Science | Medline2
Cone RW ,Hackman RC ,Huang M-LW , et al. Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation. N Engl J Med 1993;329:156-161
Full Text | Web of Science | Medline3
Agut H . Puzzles concerning the pathogenicity of human herpesvirus 6. N Engl J Med 1993;329:203-204
Full Text | Web of Science | Medline4
Stagno S ,Tinker MK ,Elrod C ,Fuccillo DA ,Cloud G ,O'Beirne AJ . Immunoglobulin M antibodies detected by enzyme-linked immunosorbent assay and radioimmunoassay in the diagnosis of cytomegalovirus infections in pregnant women and newborn infants. J Clin Microbiol 1985;21:930-935
Web of Science | Medline5
Morris DJ . Epidemiological evidence is crucial as proof of causation in cytomegalovirus disease. J Infect 1991;23:233-240
CrossRef | Web of Science | Medline6
Morris DJ . Pathogenicity of human herpesvirus 6. Pediatr Infect Dis J 1991;10:957-958
Web of Science | Medline7
Morris DJ . Human herpesvirus-6 and roseola infantum. J Infect Dis 1993;167:772-772
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Pitalia AK, Liu-Yin JA, Freemont JA, Morris DJ, Fitzmaurice RJ. Immunohistopathological detection of human herpesvirus 6 in formalin-fixed paraffin-embedded lung tissue. J Med Virol (in press).
9
Grundy JE ,Shanley JD ,Griffiths PD . Is cytomegalovirus interstitial pneumonitis in transplant recipients an immunopathological condition? Lancet 1987;2:996-999
CrossRef | Web of Science | Medline10
Morris DJ . Cytomegalovirus pneumonia -- a consequence of immunosuppression and preexisting lung damage rather than immunopathology? Respir Med 1993;87:345-349
CrossRef | Web of Science | Medline
To the Editor:
Cone et al. report the detection of HHV-6 DNA in lung tissue from recipients of bone marrow transplants who had idiopathic pneumonitis, suggesting a role for HHV-6 in this condition. We are performing a prospective study of HHV-6 and cytomegalovirus in recipients of bone marrow transplants and have detected HHV-6 at autopsy in the lungs of a 44-year-old recipient of an allogeneic graft who was seropositive for both cytomegalovirus and HHV-6 before transplantation and who died of liver failure 78 days after transplantation1. HHV-6 was detected in frozen lung tissue obtained at autopsy both immunohistochemically and by the polymerase chain reaction (PCR). However, there was also strong immunohistochemical and PCR positivity for cytomegalovirus in the lungs and liver, and death was attributed to disseminated cytomegalovirus infection. HHV-6 is genomically and antigenically closely related to cytomegalovirus,2 and coinfection is common. The detection of concurrent infection with HHV-6 and cytomegalovirus in the lungs of our patient supports the report of Carrigan et al.3 of a marrow-graft recipient with interstitial pneumonitis in whom coinfection with cytomegalovirus and HHV-6 was found. Therefore, in immunocompromised patients, studies of HHV-6 infection should be conducted in parallel with investigations for cytomegalovirus. In the presence of overwhelming cytomegalovirus infection, the role of HHV-6 in such patients is unclear, although there is evidence that HHV-6 may be implicated in the pathogenesis of graft-versus-host disease in allograft recipients4 and thus may well be of pathogenic importance after bone marrow transplantation. Cone et al. have detected HHV-6 infection in the absence of cytomegalovirus coinfection in several of their patients with pneumonitis, providing clear evidence implicating HHV-6 in post-transplantation pneumonitis.
4 ReferencesAnne L. Appleton, M.B., Ch.B.
Lisbet Sviland, M.B., B.S., Ph.D.
University of Newcastle-upon-Tyne, Newcastle-upon-Tyne NE1 4LP, United Kingdom1
McCarthy AL ,Malik-Peiris JS ,Taylor CE , et al. Increase in severity of graft versus host disease by cytomegalovirus. J Clin Pathol 1992;45:542-544
CrossRef | Web of Science | Medline2
Lawrence GL ,Chee M ,Craxton MA ,Gompels UA ,Honess RW ,Barrell BG . Human herpesvirus 6 is closely related to human cytomegalovirus. J Virol 1990;64:287-299
Web of Science | Medline3
Carrigan DR ,Drobyski WR ,Russler SK ,Tapper MA ,Knox KK ,Ash RC . Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Lancet 1991;338:147-149
CrossRef | Web of Science | Medline4
Appleton AL ,Sviland L . Pathogenesis of GVHD: role of herpes viruses. Bone Marrow Transplant 1993;11:349-355
Web of Science | Medline
To the Editor:
The two subtypes of HHV-6 (A and B) may be of clinical importance if they are associated with differing pathogenicity1. We describe a 29-year-old man who underwent allogeneic bone marrow transplantation for chronic myelogenous leukemia after receiving total-body irradiation and cyclophosphamide. The bone marrow donor was his father, who had one HLA mismatch and a negative mixed-lymphocyte reaction. On day 12 after bone marrow transplantation, acute (grade IV) graft-versus-host disease developed involving the skin, liver, and gut. Treatment with prednisone, interleukin-2-receptor antibodies, and antilymphocyte globulin brought no clinical improvement. On day 43 clinical and radiologic signs of interstitial pneumonitis developed. The patient died of respiratory failure on day 50.
We used PCR to monitor for HHV-6 DNA in blood leukocytes and oral-lavage fluid before and at weekly intervals after bone marrow transplantation2. Positive samples were examined for the HHV-6 subtype by restriction-fragment-length analysis3. HHV-6 could be demonstrated in oral-lavage fluid from the patient before bone marrow transplantation and in donor leukocytes at marrow harvest. Interestingly, the subtypes of HHV-6 differed: the donor harbored subtype A, and the recipient subtype B. After bone marrow transplantation, the recipient was positive for HHV-6 until his death at week 7. He had subtype B until week 6. In the week preceding his death (when the pneumonitis developed), there was a shift in the subtype from B to A -- the donor's subtype. Lung-biopsy specimens could not be analyzed because permission for an autopsy was refused.
Our data indicate that seropositivity for HHV-6 DNA is long lasting and that shifts in the viral subtype may occur and must be considered when HHV-6 infection is related to disease in immunocompromised patients.
3 ReferencesC.A. Schmidt, M.D.
F.F. Wilborn, Ph.D.
W. Siegert, M.D.
Freie Universitat Berlin, 14050 Berlin, Germany1
Agut H . Puzzles concerning the pathogenicity of human herpesvirus 6. N Engl J Med 1993;329:203-204
Full Text | Web of Science | Medline2
Schmidt CA, Oettle H, Neuhaus P, et al. Demonstration of cytomegalovirus by polymerase chain reaction after liver transplantation. Transplantation (in press).
3
Yoshikawa T ,Nakashima T ,Asano Y , et al. Endonuclease analyses of DNA of human herpesvirus-6 isolated from blood before and after bone marrow transplantation. J Med Virol 1992;37:228-231
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Schmidt et al. raise the interesting possibility that HHV-6 type A and HHV-6 type B have different pathogenic potential. We have determined that most of the lung tissues in our cohort were simultaneously infected with both types (unpublished data). The relative pathogenicity of these variants remains unclear.
Appleton and Sviland describe a bone marrow-transplant recipient with cytomegalovirus and HHV-6 lung infections who was similar to one of our patients. These case reports illustrate the difficulty in associating causality with pathogens that persist and recur in the host. Morris cautions that the mere presence of an infectious agent is not sufficient to establish causality. Ironically, very sensitive detection systems, such as PCR, complicate the matter by demonstrating previously unrecognized coinfections. Cytomegalovirus and HHV-6 can persist as apparently asymptomatic infections in immunocompromised hosts, increasing the likelihood that viral replication will be coincidentally associated with disease, regardless of the etiologic relation.
We are gratified that these readers have interpreted our report as evidence of an association between HHV-6 and pneumonia, and not as proof that HHV-6 causes pneumonia. The letter from Morris illustrates that no single report is likely to prove causality between a clinical syndrome and a persisting or reactivating agent. For instance, extensive studies of cytomegalovirus-related pneumonia have still not completely resolved the pathogenic role of the virus.1 One approach to further studies of HHV-6 would be to correlate antiviral therapy with concomitant changes in clinical signs and symptoms. We hope that our report spurs such investigations.
1 ReferencesRichard Cone, M.D., Ph.D.
Lawrence Corey, M.D.
University of Washington, Seattle, WA 98195Robert Hackman, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 981041
Grundy JE ,Shanley JD ,Griffiths PD . Is cytomegalovirus interstitial pneumonitis in transplant recipients an immunopathological condition? Lancet 1987;2:996-999
CrossRef | Web of Science | Medline
Author/Editor Response
In our report of an infectious mononucleosis-like syndrome induced by HHV-6 type B in a 43-year-old man (Patient 1), the severe skin eruption resembling erythroderma and caused by an infiltration of atypical lymphocytes was striking. We performed in situ hybridization of HHV-6 DNA with a 35S-labeled probe (PstI fragment, pKE-M) and immunohistochemical staining with an HHV-6 monoclonal antibody, OHV-2. Positive staining for OHV-2 (Figure 1Figure 1
HHV-6 Antigen Staining in a Skin-Biopsy Specimen Obtained on the Sixth Day of Hospitalization (x580).) and HHV-6 DNA was seen in the infiltrating lymphocytes. Serologic studies excluded the possibility of an active infection with measles, rubella, parvovirus B19, or toxoplasma. These findings indicate that the skin eruption was due to active HHV-6 type B infection.Two additional patients with heterophil-negative severe infectious mononucleosis-like illness caused by HHV-6 have been seen. One was a 29-year-old man (Patient 2) who reportedly had fulminant hepatitis due to a primary HHV-6 infection,1 and the other (Patient 3) was a 19-year-old woman who was given a diagnosis of HHV-6-induced acute lymphadenitis. HHV-6 was isolated from the blood of Patient 2, and seroconversion of HHV-6 IgG and IgM was evident. Numerous lymphocytes positive for HHV-6 DNA and RNA were seen in lymph nodes from Patient 3, though serologic studies could not be performed. Both patients presented with generalized erythroderma (which closely resembled that observed in Patient 1), marked atypical lymphocytosis, generalized lymphadenopathy, and severe hepatitis after 3 to 10 days of high fever (information concerning Patient 2 was provided by Dr. R. Sobue, Fujita Health University, Aichi, Japan). In all three patients, the erythroderma and hepatitis gradually resolved with intensive care, concomitantly with the disappearance of atypical lymphocytes. Genotyping of HHV-6 in Patients 1 and 3 revealed type B; Patient 2 was not studied. Therefore, we are confident that a primary HHV-6 type B infection can cause a severe infectious mononucleosis-like syndrome in adults, though the possibility of the recurrence of HHV-6 was not completely excluded in these patients.
A longitudinal study is required to clarify the epidemiology of HHV-6, as indicated by Morris. However, serologic data are sometimes confusing; simultaneous elevations in the levels of IgG and IgM antibodies to HHV-6, cytomegalovirus, and other herpesviruses have been reported in similar cases of severe infectious mononucleosis-like illness2. One should exclude the possibility of cross-reacting antibodies or a dual infection of herpesviruses. In situ detection of the virus might help quantify the infected cells and thus identify the virus responsible for the symptoms. In addition, type A and type B HHV-6 have increasingly been shown to have different biologic and epidemiologic characteristics3. Future longitudinal studies of HHV-6 should include genotyping.
3 ReferencesKoichi Akashi, M.D.
Kyushu University, Fukuoka 812, JapanYoshito Eizuru, M.D.
Miyazaki Medical College, Miyazaki 889-16, JapanYoshiaki Sumiyoshi, M.D.
Fukuoka University, Fukuoka 814-01, Japan1
Sobue R ,Miyazaki H ,Okamoto M , et al. Fulminant hepatitis in primary human herpesvirus-6 infection. N Engl J Med 1991;324:1290-1290
Full Text | Web of Science | Medline2
Kirchesch H ,Mertens T ,Burkhardt U ,Kruppenbacher JP ,Hoffken A ,Eggers HJ . Seroconversion against human herpesvirus-6 (and other herpesviruses) and clinical illness. Lancet 1988;2:273-274
CrossRef | Web of Science | Medline3
Salahuddin SZ ,Kelley AS ,Krueger GRF ,Josephs SF ,Gupta S ,Ablashi DV . Human herpesvirus-6 (HHV-6) in diseases. Clin Diagn Virol 1993;1:81-100
CrossRef | Medline
- Citing Articles (1)
Citing Articles
1
Lorraine M. McElhinney, Robert J. Cooper, David J. Morris. (1995) Multiplex polymerase chain reaction for human herpesvirus-6, human cytomegalovirus, and human β-globin DNA. Journal of Virological Methods 53:2-3, 223-233
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