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Unexplained CD4+ T-Lymphocyte Depletion in Persons Without Evident HIV Infection -- United States

Since 1989, 21 persons with unexplained CD4+ T-lymphocyte depletion, but without evident human immunodeficiency virus (HIV) infection, have been described (1-12). These reports included persons who have resided in the United States and six other countries and who sought medical care for conditions often associated with immune deficiency. Some of these cases were also described at the VIII International Conference on AIDS/III STD World Congress in Amsterdam. In addition, CDC has received reports of five persons from three states who have had persistently low CD4+ T-cell levels but who have had no evidence of HIV infection or underlying disease processes or therapies known to be associated with T-cell depletion. In some of these five patients, opportunistic infections were diagnosed that frequently occur in persons with acquired immunodeficiency syndrome (AIDS). This report describes preliminary clinical and laboratory findings from an ongoing investigation by CDC of these five patients.* Patient 1

In March 1991, a 70-year-old man developed Pneumocystis carinii pneumonia that was successfully treated with trimethoprim-sulfamethoxazole. Although serology for HIV antibody was negative, his CD4 count was 50 cells/uL. After this hospitalization, he developed a fungal infection of the groin that was treated with oral ketoconazole and topical antifungal medications. In April 1992, transitional cell carcinoma of the bladder, grade II, was diagnosed. As of July 1992, he was asymptomatic.

His family history and personal history were negative for immunodeficiency disease and for recurrent or unusual infections. His wife, who has remained healthy, is HIV seronegative and has a normal CD4 count. He did not report sexual contact with men or injecting-drug use. In 1987, he received 3 units of whole blood for a bleeding duodenal ulcer; follow-up investigation in 1992 indicated that all three blood donors were HIV type 1 (HIV-1) and HIV type 2 (HIV-2) seronegative, had normal CD4 counts, and were in good health. Patient 2

In October 1984, a 38-year-old male health-care worker developed cryptococcal meningitis that was treated with a full course of amphotericin B and 5-fluorocytosine. In January 1985, he had an episode of localized herpes zoster. In July 1985, symptoms of meningitis recurred. A cryptococcoma was excised from his brain, and he was treated with another course of antifungal therapy. Since this hospitalization, he has been in generally good health except for a nonspecific skin rash that resolved, mild hypertension, and a grand mal seizure for which he takes phenytoin. In December 1987 and December 1988, his CD4 counts were 152 and 84 cells/uL, respectively. An enzyme immunoassay (EIA) test for HIV antibody was negative in April 1989. As of July 1992, he was asymptomatic.

There was no family history or personal history of immunodeficiency or unusual infections. He did not report sexual contact with men or injecting-drug use. He had not received blood transfusions, did not perform invasive procedures, and had no known parenteral or mucous membrane exposure to blood. He reported his spouse was in good health. Patient 3

In October 1989, a 58-year-old woman developed acute cholecystitis and underwent cholecystectomy. She had a prolonged postoperative course complicated by nosocomial pneumonia of undetermined etiology and vaginal candidiasis and recovered with antibiotic therapy. An HIV EIA test was reported as positive during this hospitalization. In December 1989, although HIV serology by EIA was negative, a single p24 band on Western blot was observed; her CD4 count was 86 cells/uL. She remained asymptomatic; when reevaluated in January 1991, HIV serology was negative on two occasions, but her CD4 count remained low (103 cells/uL). As of July 1992, she was asymptomatic.

She had received multiple transfusions for hemorrhage during pregnancy during the 1950s and for menorrhagia in the late 1970s and early 1980s. There was no family history of immunodeficiency or unusual infections. She did not report injecting-drug use. She reported her spouse was in good health. Patient 4

In November 1986, a 45-year-old man received treatment for disseminated molluscum contagiosum. In April 1989, a lung biopsy was performed for evaluation of a mass on chest radiograph. The lesion was consistent with a plaque secondary to asbestosis, although the man had no known history of asbestos exposure. In February and August 1989, HIV EIA serologies were negative; however, CD4 counts were 96 and 68 cells/uL, respectively. As of July 1992, he was asymptomatic.

His family and personal history were negative for immunodeficiency or for recurrent or unusual infections. He did not report sexual contact with men or injecting-drug use; he had not received blood transfusions. His spouse was in good health and had a normal CD4 count. Patient 5

In December 1983, a 70-year-old woman was hospitalized with disseminated cutaneous herpes zoster. In December 1988, she developed fever, cough, and pleurisy. On evaluation, mediastinal lymphadenopathy was found, and histoplasmosis was diagnosed by open lung biopsy. She was treated with amphotericin B and ketoconazole with resolution of both symptoms and lymphadenopathy. Although HIV serology was negative during this hospitalization, a CD4 count was 275 cells/uL. In February 1989, the count was 499 cells/uL.

In April 1991, she developed fever and cough, and a pulmonary infiltrate was indicated on chest radiograph; her CD4 count at that time was 199 cells/uL. Although her symptoms responded to ciprofloxacin, sputum cultures subsequently grew Mycobacterium avium-intracellulare (MAI). In September 1991, her pulmonary symptoms recurred, and a new pulmonary infiltrate was present on chest radiograph; MAI was again cultured from bronchial washings. Her symptoms resolved during treatment with ciprofloxacin, rifampin, and ethambutol. In January 1992, epigastric pain prompted a gastrointestinal evaluation and detection of an ulcerated mass lesion in the stomach. Histoplasmosis was found on biopsy, and Helicobacter pylori was cultured from the lesion. Fluconazole therapy was initiated with good response. As of July 1992, she was asymptomatic.

She had been in excellent health with no family history or personal history of immunodeficiency or unusual infections. She did not report injecting-drug use and had not received a transfusion. Her spouse died in 1984 with atherosclerotic cardiovascular disease and carcinoma of the kidney. Laboratory Findings

Blood samples from each of the five patients have been tested at CDC, and low CD4 counts (less than 300 cells/uL) and negative HIV-1 and HIV-2 serologies (by EIA and Western blot) have been confirmed. Cocultures of peripheral blood mononuclear cells (PBMC) from patients 1-4 with normal PBMC and/or lymphoid cell lines were negative for cytopathicity, syncytia, and the generation of reverse transcriptase activity as measured by standard methods. Human T-cell lymphotropic virus (HTLV)-I and HTLV-II serologies were negative. Neither HIV-1- nor HIV-2-related DNA sequences were detected in blood of patients 1-4 by polymerase chain reaction (PCR). Results of studies of specimens from patient 5 are pending.

Reported by: Div of HIV/AIDS, National Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: The clinical conditions of the patients described in this report vary considerably; however, these cases share three features: 1) persistently low CD4+ T-cell levels; 2) no evidence of HIV infection by serology, culture, or PCR analysis; and 3) infections that prompted physicians to consider HIV infection.

Review of available data on the 26 case-patients (including the five described in this report and 21 reported elsewhere) (1-12) does not indicate an epidemiologic linkage among the cases. Cases of unexplained CD4+ T-cell depletion have been reported from Australia (1), Denmark (2), England (3,4), France (5-7), Germany (8), Spain (9), and the United States (10-12). Of the 26 case-patients, five had received transfusions before onset of illness, five were homosexual men, and the remaining 16 had no known risk factors for HIV infection. In this report, follow-up investigation of the blood donors for patient 1 found that they were HIV-seronegative, immunologically normal, and in good health. Two additional cases reported to CDC have been excluded because CD4+ T-cell depletion may have been related to chemotherapy.

Although infections with HIV-1 or HIV-2 have been associated with immunodeficiency of the type described in these patients, no evidence for infection with either virus has been documented. The cause of CD4+ T-lymphocyte depletion in the patients described in this report and in other reports is unknown; moreover, it is unknown whether these cases represent a single syndrome. However, there are at least two possible hypotheses to explain this abnormality. Persistent CD4+ T-cell depletion may occur in some patients as a response to certain infections or other exposures. Transient CD4+ T-cell depletion has been reported following some infections; whether this persists in some patients is unknown (13,14). Therefore, one possibility is that some or all of these case reports of unexplained CD4+ T-lymphocyte depletion are part of background occurrence that may only now be recognized because of the increased availability of T-cell phenotyping. A second possibility is that some of these cases may represent a different syndrome of immunodeficiency associated with CD4+ T-cell depletion.

Two of the recent preliminary reports of CD4+ T-cell depletion in patients who were HIV-1 and HIV-2 seronegative have suggested the presence of a retrovirus (11,12). The relation of these reports to the immunodeficiency detected in patients described in this and other reports is not known.

CDC and the National Institutes of Health (NIH) are collaborating with physicians, scientists, and public health officials to identify other cases and investigate this problem. NIH will assist in the characterization of the clinical, immunologic, and virologic features by collaborating with investigators and working through its network of grantees and contractors to collect, process, and distribute specimens and reference materials. CDC, in collaboration with NIH, will convene a meeting of investigators and public health officials in mid-August to discuss these cases and epidemiologic and laboratory investigations in progress.

Additional CDC epidemiologic and laboratory investigations regarding these cases are in progress. Health-care providers are requested to report to CDC through the AIDS surveillance section of their local or state health department patients who have 1) CD4+ T-lymphocyte depletion (absolute CD4+ T-cell level less than 300 cells/uL or less than 20% on more than one determination), 2) no serologic evidence of HIV infection, and 3) no defined immunodeficiency or therapy associated with T-cell depletion. Although no cases have been reported in children, HIV-negative pediatric cases with unexplained depletion of CD4 cells (as defined by age-adjusted normal CD4 counts) should also be reported.

Additional information on case reporting is available from the Surveillance Branch, Division of HIV/AIDS, National Center for Infectious Diseases, CDC (telephone (404) 639-2981). Reports of these cases will assist CDC and other public health agencies in developing a more precise case definition to examine this problem and providing a resource for investigators who are conducting etiologic studies. General inquiries about the cases described here as well as on HIV and AIDS should be directed to the CDC National AIDS Hotline, (800) 342-2437.


  1. Gatenby PA. Reduced CD4+ T-cells and candidiasis in absence of HIV infection. Lancet 1989;1:1027-8.

  2. Hansen ER, Lisby S, Baadsgaard O, Ho VC, de Villiers EM, Vejlsgaard GL. Abnormal function of CD4+ helper/inducer T lymphocytes in a patient with widespread human papillomavirus type 3-related infection. Arch Dermatol 1990;126:1604-8.

  3. Pankhurst C, Peakman M. Reduced CD4+ T-cells and severe oral candidiasis in absence of HIV infection. Lancet 1989;1:672.

  4. Jowitt SN, Love EM, Liu Yin JA, Pumphrey RSH. CD4 lymphocytopenia without HIV infection in patient with cryptococcal infection. Lancet 1991;337:500-1.

  5. Cozon G, Greenland T, Revillard JP. Profound CD4+ lymphocytopenia in the absence of HIV infection in a patient with visceral leishmaniasis. N Engl J Med 1990;322:132.

  6. Seligmann M, Aractingi S, Oksenhendler E, Rabian C, Ferchal F, Gonnot G. CD4+ lymphocytopenia without HIV in patient with cryptococcal disease. Lancet 1991;337:57-8.

  7. Gautier V, Chanez P, Vendrell JP, et al. Unexplained CD4-positive T-cell deficiency in non-HIV patients presenting as a Pneumocystis carinii pneumonia. Clin Exp Allergy 1991;21:63-6.

  8. Daus H, Schwarze G, Radtke H. Reduced CD4+ count, infections, and immune thrombocytopenia without HIV infection. Lancet 1989;2:559-60.

  9. Castro A, Pedreira J, Soriano V, et al. Kaposi's sarcoma and disseminated tuberculosis in HIV-negative individual. Lancet 1992;339:868.

  10. Daar ES, Moudgil T, Ho DD. Persistently low T-helper (CD4+) lymphocyte counts in HIV-negative asymptomatic men. Western Society of Clinical Investigation meeting, February 1990.

  11. Gupta S, Ribak CE, Gollapudi S, Kim CH, Salahuddin SZ. Detection of a human intracisternal retroviral particle associated with CD4+ T-cell deficiency. Proc Natl Acad Sci USA (in press).

  12. Laurence J, Siegal FP, Schattner E, Gelman IH, Morse S. Acquired immune deficiency without evidence of infection with human immunodeficiency virus types 1 and 2. Lancet 1992 (in press).

  13. Scalzini A, Castelnuovo F, Puoti M, Cristini G. A case of cryptococcal meningoencephalitis and focal cerebral vasculitis with transient immunodeficiency. Acta Neurol (Napoli) 1990;12:301-4.

  14. Lehmann PF, Gibbons J, Senitzer D, Ribner BS, Freimer EH. T lymphocyte abnormalities in disseminated histoplasmosis. Am J Med 1983;75:790-4.

    • Single copies of this report will be available free until July 31, 1993, from the CDC National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20849-6003.

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