Correspondence
CD4+ T-Lymphocytopenia without HIV Infection
N Engl J Med 1993; 328:1847-1850June 24, 1993
- Article
To the Editor:
Reports in the February 11 issue of the Journal review the epidemiology of “AIDS” without human immunodeficiency virus (HIV) infection, or idiopathic CD4+ T-lymphocytopenia1-7. Two of these studies report that AIDS is absent and persistent idiopathic CD4+ T-lymphocytopenia is rare in large, prospective studies of seronegative transfusion recipients5 and homosexual men6. Similarly, we have not found persistent idiopathic CD4+ T-lymphocytopenia or AIDS-defining conditions in a seven-year prospective study of 732 men seronegative for HIV type 1. Our study subjects are part of the San Francisco Men's Health Study and San Francisco General Hospital Cohort, and they represent a population-based sample. The sample includes 206 exclusively heterosexual men, providing a basis for comparison between groups with substantially different levels of risk for sexually transmitted infections.
We examined the results of 4217 lymphocyte-subset analyses in 526 homosexual (or bisexual) men and the results of 1454 analyses in 206 heterosexual men, representing more than 4000 person-years of follow-up. Among the homosexual men, 30 of 4217 analyses (0.7 percent) showed a CD4+ count below 300 per cubic millimeter, as compared with 3 of 1454 analyses (0.2 percent) in the heterosexual men. Results in which the CD4+ cell count was less than 20 percent of total T cells were reported in 56 analyses (1.3 percent) in homosexuals and 7 analyses (0.5 percent) in heterosexuals. Nine men met the case definition of idiopathic CD4+ T-lymphocytopenia: three had CD4+ counts below 300 per cubic millimeter on two occasions, and six had counts in which CD4+ cells were less than 20 percent of total T cells on two occasions (eight were homosexual, and one was heterosexual). No subject met the laboratory criteria more than twice, and only four met the criteria on two consecutive biannual examinations. At subsequent visits, all but one had CD4+ counts above 700 per cubic millimeter. This subject had consistently low CD4+ counts (300 to 500 per cubic millimeter), but had no net decline in these values over a seven-year period. These patients with putative cases of idiopathic CD4+ T-lymphocytopenia also had low CD8+ counts (mean, 451 per cubic millimeter, as compared with 763 per cubic millimeter for all other seronegative men), suggesting the occurrence of general lymphopenia rather than the selective loss of CD4+ cells. Finally, no AIDS-defining clinical conditions were observed.
The most likely explanation for cases of transient idiopathic CD4+ T-lymphocytopenia is the broad range of CD4+ counts found in “normal” persons,8 combined with variation in the measurements of lymphocyte subsets and transient perturbations in the number of circulating lymphocytes9,10. These points are illustrated in Figure 1Figure 1
Distribution of CD4+ Counts in HIV-Negative Heterosexual and Homosexual Men in San Francisco., which shows that the distribution of CD4+ counts was virtually identical in 370 seronegative homosexual men (3368 observations) and 206 seronegative heterosexual men (1454 observations) in the San Francisco Men's Health Study. The slightly higher frequency of transient disease in homosexual men may reflect the higher prevalence of other infections that cause temporary perturbations in subsets of circulating lymphocytes. These results suggest that a substantial proportion of cases of HIV-negative idiopathic CD4+ T-lymphocytopenia may occur as the result of the inherent variability in the measurements of T-lymphocyte subsets.10 ReferencesHaynes Sheppard, Ph.D.
California Department of Health Services, Berkeley, CA 94704Warren Winkelstein, M.D.
University of California, Berkeley, CA 94720William Lang, M.D.
California Pacific Medical Center, San Francisco, CA 94115Edwin Charlebois, M.P.H.
University of California, San Francisco, School of Medicine, San Francisco, CA 941431
Smith DK, Neal JJ, Holmberg SD, Centers for Disease Control Idiopathic CD4+ T-Lymphocytopenia Task Force
Full Text | Web of Science | Medline2
Ho DD ,Cao Y ,Zhu T , et al. Idiopathic CD4+ T-lymphocytopenia -- immunodeficiency without evidence of HIV infection. N Engl J Med 1993;328:380-385
Full Text | Web of Science | Medline3
Spira TJ ,Jones BM ,Nicholson JKA , et al. Idiopathic CD4+ T-lymphocytopenia -- an analysis of five patients with unexplained opportunistic infections. N Engl J Med 1993;328:386-392
Full Text | Web of Science | Medline4
Duncan RA ,von Reyn CF ,Alliegro GM ,Toossi Z ,Sugar AM ,Levitz SM . Idiopathic CD4+ T-lymphocytopenia -- four patients with opportunistic infections and no evidence of HIV infection. N Engl J Med 1993;328:393-398
Full Text | Web of Science | Medline5
Aledort LM ,Operskalski EA ,Dietrich SL , et al. Low CD4+ counts in a study of transfusion safety. N Engl J Med 1993;328:441-442
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Vermund SH ,Hoover DR ,Chen K . CD4+ counts in seronegative homosexual men. N Engl J Med 1993;328:442-442
Full Text | Web of Science | Medline7
Fauci AS . CD4+ T-lymphocytopenia without HIV infection -- no lights, no camera, just facts. N Engl J Med 1993;328:429-431
Full Text | Web of Science | Medline8
Reichert T ,DeBruyere M ,Deneys V , et al. Lymphocyte subset reference ranges in adult Caucasians. Clin Immunol Immunopathol 1991;60:190-208
CrossRef | Medline9
Giorgi JV ,Cheng HL ,Margolick JB , et al. Quality control in the flow cytometric measurement of T-lymphocyte subsets: the multicenter AIDS cohort study experience. Clin Immunol Immunopathol 1990;55:173-186
CrossRef | Medline10
Malone JL ,Simms TE ,Gray GC ,Wagner KF ,Burge JR ,Burke DS . Sources of variability in repeated T-helper lymphocyte counts from human immunodeficiency virus type 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J Acquir Immune Defic Syndr 1990;3:144-151
Web of Science | Medline
To the Editor:
In August 1992, after reports of cases of unexplained severe immunodeficiency without evidence of HIV infection, the World Health Organization conducted a retrospective survey to define the epidemiology of this phenomenon further. Thirty-six institutions in 21 countries in Africa, the Americas (outside the United States), Asia, Oceania, Europe, and the Caribbean were asked to complete a detailed case-reporting form for retrospectively identified patients who had clinical signs and symptoms of severe immunodeficiency or CD4+ counts of less than 300 cells per cubic millimeter or of less than 20 percent of total lymphocytes on more than one occasion (if results were available); no known cause of immunodeficiency; and repeatedly negative results for HIV on enzyme-linked immunosorbent assay and at least one supplementary test.
The analysis did not suggest any epidemiologic link among the 49 patients described. Nine resided in France; eight in Australia; six in Zambia; five in Germany; four each in Belgium, Rwanda, and the United Kingdom; three in the Russian Federation; two in Spain; and one each in Denmark, New Zealand, Switzerland, and Ukraine. The patients ranged in age from 16 to 76 years (mean, 43), and there was no clustering in any specific age group. The ratio of male to female patients was 1.9:1; homosexual behavior was reported in 5 of the 28 male patients (18 percent) whose sexual orientation was known; 6 of 40 patients (15 percent) had received at least one blood transfusion; 2 of 41 (5 percent) were injection-drug users; and 1 of 41 (2 percent) had a family member with immunodeficiency or frequent or serious infections. None had hemophilia.
Clinical illness was reported in all patients. The most frequently reported conditions were wasting syndrome (nine patients), extrapulmonary cryptococcosis (seven patients), and atypical mycobacteria, candidiasis, and Kaposi's sarcoma (six patients each). The most recent absolute CD4+ count among the 33 patients for whom counts were reported ranged from 11 to 680 per cubic millimeter (median, 249). One of seven sexual partners (14 percent) of the patients for whom HIV status was reported was HIV-seropositive.
In September 1992, 21 experts were convened by the World Health Organization in Geneva to review these results and those of the survey conducted by the Centers for Disease Control and Prevention and reported on by Smith and colleagues1,2. The expert panel concluded that there is no evidence that unexplained severe immunodeficiency without HIV infection is epidemic or is caused by a single transmissible agent. The panel concluded that this is not a uniform disease entity, but is due to either primary (in genetically predisposed persons) or secondary (acquired) immunodeficiency. These cases have probably come to attention because of an ascertainment bias resulting from the increased awareness of immunodeficiency and the increased use of lymphocyte phenotyping and other tests to diagnose HIV infection.
2 ReferencesDavid L. Heymann, M.D.
Elizabeth Belsey, Ph.D.
Jose G. Esparza, M.D., Ph.D.
Global Program on AIDS, World Health Organization, 1211 Geneva 27, Switzerland1
Unexplained severe immunosuppression without evidence of HIV infectionWkly Epidemiol Rec 1992;67:309-311
Medline2
Smith DK, Neal JJ, Holmberg SD, Centers for Disease Control Idiopathic CD4+ T-Lymphocytopenia Task Force
Full Text | Web of Science | Medline
To the Editor:
The collection of reports on idiopathic CD4+ T-lymphocytopenia emphasizes the inchoate nature of our understanding of factors affecting CD4+ counts. The diagnosis is predicated on a single immune variable -- a CD4+ count of less than 300 per cubic millimeter -- that is subject to multiple analytic and biologic variances. The same phenomenon is referred to as severe unexplained HIV-seronegative immune suppression by the World Health Organization,1 with the additional requirement of a disease indicative of a cellular immune deficiency. Infections characteristic of stage IV HIV disease may directly influence the production or compartmentalization of T-cell subpopulations2. Idiopathic CD4+ T-lymphocytopenia may represent myriad phenomena with diverse causes, from “physiologic” CD4+ lymphopenia to late manifestations of congenital immune defects. . . .
The search for a new syndrome might be more productive if confined to the small minority of patients at high risk for the acquisition of a sexual or blood-borne pathogen who have immunologic characteristics more typical of HIV disease, such as absolute CD4+ counts below the 95 to 99 percent confidence limits for age- and sex-matched controls, together with CD4+:CD8+ ratios below 1 and an inexorable decline in the CD4+ count. Studies of HIV-seronegative persons at high risk for HIV disease who had HIV-1 proviral DNA detectable with use of the polymerase chain reaction3 support this view.
The failure to detect a lymphocytopathic retrovirus or other microorganism in idiopathic CD4+ T-lymphocytopenia is based on the analysis of a small number of persons who did not fulfill these immunologic criteria and should neither dissuade nor deflect a thorough analysis of patients with T-cell changes that are more characteristic of HIV infection. Preliminary clues to the possible presence of exogenous retroviral activity in a very small number of cases, reported at conferences held by the Centers for Disease Control and Prevention (August 14, 1992) and by the World Health Organization,1 as well as by my group,4 are being analyzed.
4 ReferencesJeffrey Laurence, M.D.
Cornell University Medical College, New York, NY 100211
Unexplained severe immunosuppression without evidence of HIV infectionWkly Epidemiol Rec 1992;67:309-311
Medline2
Laurence J. T cell subsets in health, infectious disease, and idiopathic CD4+ T lymphocytopenia. Ann Intern Med (in press).
3
Yagi MJ ,Joesten ME ,Wallace J ,Roboz JP ,Bekesi JG . Human immunodeficiency virus type 1 (HIV-1) genomic sequences and distinct changes in CD8+ lymphocytes precede detectable levels of HIV-1 antibodies in high-risk homosexuals. J Infect Dis 1991;164:183-188
CrossRef | Web of Science | Medline4
Laurence J ,Siegal FP ,Schattner E ,Gelman IH ,Morse S . Acquired immunodeficiency without evidence of infection with human immunodeficiency virus types 1 and 2. Lancet 1992;340:273-274
CrossRef | Web of Science | Medline
To the Editor:
Smith and coworkers reported findings on 47 patients with CD4+ T-lymphocytopenia but without HIV infection. One of the patients (Patient 10) was described as having “AIDS dementia,” and another (Patient 19) “HIV encephalopathy.” This progressive syndrome, most commonly referred to as the AIDS dementia complex,1 is thought by most researchers to be unique, both clinically1 and pathologically,2 to patients infected with HIV. The severity of the dementia correlates to some extent with the quantity of HIV recovered from the brain,3 a phenomenon also seen in the vacuolar myelopathy affecting patients with AIDS,4 but the pathogenesis remains uncertain. If these two patients truly had a progressive dementia similar to that seen in AIDS, this would suggest that actual HIV infection of cells in the brain is not required to produce the symptoms and that CD4+ T-lymphocytopenia itself, or the immune dysfunction consequent to it, might be directly responsible for the neurologic damage seen in the AIDS dementia complex. How were the neurologic diagnoses made in these patients? Is more information available regarding their neurologic examination, cerebrospinal fluid analysis, brain imaging, neuropsychological testing, or brain abnormalities that might be useful in determining the nature and extent of their neurologic problems?
4 ReferencesJohn R. Corboy, M.D.
University of Minnesota, Minneapolis, MN 554551
Navia BA ,Jordan BD ,Price RW . The AIDS dementia complex. I. Clinical features. Ann Neurol 1986;19:517-524
CrossRef | Web of Science | Medline2
Navia BA ,Cho E-S ,Petito CK ,Price RW . The AIDS dementia complex. II. Neuropathology. Ann Neurol 1986;19:525-535
CrossRef | Web of Science | Medline3
Spencer DC ,Price RW . Human immunodeficiency virus and the central nervous system. Annu Rev Microbiol 1992;46:655-693
CrossRef | Web of Science | Medline4
Weiser B ,Peress N ,La Neve D ,Eilbott DJ ,Seidman R ,Burger H . Human immunodeficiency virus type 1 expression in the central nervous system correlates directly with extent of disease. Proc Natl Acad Sci U S A 1990;87:3997-4001
CrossRef | Web of Science | Medline
To the Editor:
Inflammatory dermatoses were recorded for 3 of the 47 patients reported on by Smith et al.1,2.; however, insufficient detail is provided to determine whether the patients had erythroderma.
We describe two patients who, with the acute onset of generalized erythroderma, had markedly reduced levels of circulating CD4+ cells. Both fulfilled the current criteria for idiopathic CD4+ T-lymphocytopenia2. The pertinent data are provided in Table 1Table 1
Characteristics of the Two Patients..Neither patient had opportunistic infections or any AIDS-defining illness or was receiving therapy that might decrease lymphocyte subsets, including topical steroids. Both patients tested negative for HIV types 1 and 2, human T-cell lymphotropic virus types I and II, and cytomegalovirus. Immunoglobulin testing in Patient 2 revealed normal levels of IgG, IgA, and IgM. The serum IgE level was elevated (580 IU per milliliter; normal range, 0 to 158) -- a finding characteristic of atopic dermatitis. The CD4+ counts returned to normal in both patients after their dermatoses were controlled.
We believe that the CD4+ T-lymphocytopenia in these two patients may be related to the acute onset of erythroderma and not to the underlying dermatologic condition leading to erythroderma. We have recently evaluated 20 patients with severe, extensive atopic dermatitis3 and 17 patients with cutaneous T-cell lymphoma, 4 of whom had erythroderma at the time of flow cytometric analysis (unpublished data), and all had normal or elevated circulating CD4+ counts. Because in both conditions, the skin is rich in CD4+ lymphocytes, the possibility that T lymphocytes may be sequestered in the skin is intriguing. Whereas this possibility could explain the findings in our patients with acute erythroderma, severe CD4+ T-lymphocytopenia does not occur in patients with indolent dermatoses, on the basis of our flow-cytometric analyses described above and previously published data4,5.
5 ReferencesSeth R. Stevens, M.D.
Tamara W. Griffiths, M.D.
Kevin D. Cooper, M.D.
University of Michigan, Ann Arbor, MI 481091
Smith DK, Neal JJ, Holmberg SD, Centers for Disease Control Idiopathic CD4+ T-Lymphocytopenia Task Force
Full Text | Web of Science | Medline2
Unexplained CD4+ T-lymphocyte depletion in persons without evident HIV infection -- United States
Medline3
Blok B ,Taylor RS ,Gonzalez A , et al. Peripheral blood leukocyte subsets in atopic dermatitis: effect of gamma interferon. J Invest Dermatol 1991;96:604-604 abstract.
Web of Science4
Kang K ,Cooper KD ,Hanifin JM . Thymopoietin pentapeptide (TP-5) improves clinical parameters and lymphocyte subpopulations in atopic dermatitis. J Am Acad Dermatol 1983;8:372-377
CrossRef | Web of Science | Medline5
Horrocks C ,Duncan JI ,Sewell HF ,Ormerod AD ,Thomson AW . Differential effects of cyclosporine A on Langerhans cells and regulatory T-cell populations in severe psoriasis: an immunohistochemical and flow cytometric analysis. J Autoimmun 1990;3:559-570
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Corboy correctly points out that the patients with idiopathic CD4+ T-lymphocytopenia and diagnoses of “AIDS dementia” (Patient 10) and “HIV encephalopathy” (Patient 19) could not have met the standard criteria for these diagnoses because they were not infected with HIV. We reviewed the medical records of Patient 10 as part of our field investigations. He had short-term memory loss and right-sided weakness in March 1989. He was treated with steroids for suspected systemic lupus erythematosus from August through December 1989, although his serologic workup for this disease was nondiagnostic. In August 1992, his CD4+ count, performed by a local laboratory, was 290 per cubic millimeter. When interviewed in September 1992, the patient was not cognitively impaired, and his CD4+ count (737 per cubic millimeter), CD8+ count (807 per cubic millimeter), and absolute lymphocyte count (1755 per cubic millimeter) -- all determined at the Centers for Disease Control and Prevention -- were within normal ranges.
Information about Patient 19 is limited to that reported to the surveillance system by his physician. In March 1989, he had cytomegalovirus retinopathy, presumptively diagnosed Pneumocystis carinii pneumonia, “HIV encephalopathy,” and a CD4+ count of less than 200 per cubic millimeter; his HIV test results were negative. The presence of other serious illnesses when HIV encephalopathy was diagnosed could certainly have accounted for his impaired cognitive function. At the time of his death in December 1990, his CD4+ count remained below 200 per cubic millimeter. We do not know how his neurologic status was originally assessed or whether his condition was progressive.
The medical records of all three patients with inflammatory dermatoses (Patients 9, 20, and 23) were reviewed as part of the field investigations. None contained references to “generalized erythroderma,” as suggested by Stevens et al.
Patient 9 had been given a diagnosis of eczematous dermatitis in the “late 1980s,” but CD4+ counts were not determined. In August and September 1992, her CD4+ counts were 90, 173, and 244 per cubic millimeter on separate determinations.
Patient 20 was given a diagnosis of eczema in May 1989, when his CD4+ counts were 200 and 184 per cubic millimeter on separate occasions, with absolute lymphocytopenia (total lymphocytes, 715 and 683 per cubic millimeter). In August 1992, the CD4+ counts had risen to 288 and 611 per cubic millimeter on separate determinations, with absolute lymphocyte counts of 1051 and 1421 per cubic millimeter, respectively.
Patient 23 was given a diagnosis of psoriasis in 1977. His CD4+ count remained very low from 1983 (52 per cubic millimeter) through August 1992 (131 per cubic millimeter).
The persistence of CD4+ T-lymphocytopenia several years after the initial dermatologic diagnosis suggests that the immunosuppression seen in the patients in our report is unrelated to the acute onset of inflammatory dermatologic disease.
We agree with the conclusions of Heymann et al. based on their review of cases of idiopathic CD4+ T-lymphocytopenia reported to the World Health Organization.
Dawn K. Smith, M.D., M.S., M.P.H.
Joyce J. Neal, Ph.D., M.P.H.
Scott D. Holmberg, M.D., M.P.H.
Centers for Disease Control and Prevention, Atlanta, GA 30333
