Original Article
Idiopathic CD4+ T-Lymphocytopenia -- An Analysis of Five Patients with Unexplained Opportunistic Infections
N Engl J Med 1993; 328:386-392February 11, 1993
- Abstract
Background
Although patients with idiopathic CD4+ T-lymphocytopenia and serious opportunistic infections have been described previously, the clinical and immunologic features of this condition have not been well defined.
Methods
We studied in detail five patients with idiopathic CD4+ T-lymphocytopenia. The studies included serologic testing, culture, and polymerase chain reaction for the human immunodeficiency virus (HIV) types 1 and 2, serologic testing for the human T-cell lymphotropic virus (HTLV) types I and II, lymphocyte phenotyping, immunoglobulin quantitation, and lymphocyte-transformation assays, as well as attempts to isolate a retroviral agent. The results were compared with those in HIV-infected persons matched for CD4+ T-cell counts and with those in normal controls. We also studied the spouses of patients and the blood donors for one patient.
Results
In these five patients, there was no evidence of either HIV or HTLV infection. All the patients had both low percentages and low counts of CD4+ T cells, with relative increases in percentages, but not counts, of CD8+ cells. Numbers of B cells and natural killer cells were generally normal. As compared with HIV-infected persons, our patients had lower percentages and counts of CD8+ cells and more lymphopenia. CD4+ counts were relatively stable over time. Instead of the high immunoglobulin levels seen in HIV infection, these patients had normal or slightly low levels of immunoglobulins. The lymphocyte-transformation response to mitogens and antigens was depressed. Results in spouses and blood donors were normal.
Conclusions
Idiopathic CD4+ T-lymphocytopenia differs from HIV infection in its immunologic characteristics and in its apparent lack of progression over time. Nothing about the immunologic or viral-culture studies performed in these patients or about their family members or blood donors suggests that a transmissible agent causes this condition.
Media in This Article
Figure 1
Changes over Time in CD4+ T-Cell Counts and Percentages in Five Patients with Idiopathic CD4+ T-Lymphocytopenia.Table 1
Results of the Virologic Studies.Article Activity
- Article
Low CD4+ T-lymphocyte counts are rare in the absence of immunosuppressive therapy or diseases associated with immunodeficiency, most commonly infection with the human immunodeficiency virus (HIV). In recent years, case reports describing persons with unexplained or idiopathic CD4+ T-lymphocytopenia, many of whom had serious opportunistic infections, have appeared in the medical literature1-13. Additional cases were described anecdotally at the Eighth International Conference on AIDS and Third Sexually Transmitted Diseases World Congress in Amsterdam. Since then, three groups have described preliminary findings indicating a possible viral cause for this condition14,15.
Over the past two years, we have studied five persons with idiopathic CD4+ T-lymphocytopenia, which we define as CD4+ T-lymphocyte depletion (absolute CD4+ count, <300 per cubic millimeter, or <20 percent, on more than one occasion), no serologic evidence of HIV infection, and no defined immunodeficiency disease or therapy associated with T-cell depletion. This report describes the preliminary clinical and laboratory findings for these five patients (who are also described in the accompanying article by Smith et al16).
Methods
Study Population
All the patients were referred for the evaluation of unexplained low CD4+ T-lymphocyte counts, and they each consented to participate in a study to evaluate the nature and cause of this abnormality. Laboratory data from patients with HIV infection and comparable CD4+ T-lymphocyte counts, as well as data from normal blood donors matched to the patients for age, race, and sex, were used in the evaluation of the patients.
HIV and HTLV Testing
Serum samples were tested for antibodies to HIV types 1 and 2 with an enzyme immunoassay (Genetic Systems, Seattle). The Western blot assay for HIV-1 was also performed (Biotech/Dupont, Rockville, Md.) and was interpreted according to the criteria of the Association of State and Territorial Public Health Laboratory Directors and the Centers for Disease Control and Prevention (CDC)17. HIV-1 antigen in serum was tested by the p24 antigen assay (Coulter, Hialeah, Fla.). Culture for HIV was performed as described elsewhere18. Cells from two patients (Patients 1 and 3) were also cocultivated with H9 cells and CEM.ss cells (obtained from the AIDS Research and Reference Reagents Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health). The cultures were monitored for the formation of syncytia and for cytotoxicity, and the supernatants were collected for testing for HIV p24 antigen19 and reverse transcriptase activity20. Electron-microscopical analysis of cultured cells was also performed,21 and sections were examined extensively for evidence of virus-like particles. The polymerase chain reaction (PCR) was also used to detect HIV proviral DNA in the patients' mononuclear cells22,23. Serologic testing for the human T-cell lymphotropic virus (HTLV) was performed with a variety of assays, including a Western blot assay containing recombinant envelope proteins (Diagnostic Biotechnology HTLV Blot 2.3, Singapore), a recombinant HTLV type I tax Western blot assay (CDC), and a synthetic-peptide assay for HTLV types I and II (Coulter/IAF Biochem International, Montreal).
Immunologic Studies
Lymphocyte-subgroup analysis was performed as described elsewhere24. Serum levels of IgG, IgA, and IgM were measured by a turbidimetric technique with reagents from Dupont Diagnostics (Wilmington, Del.) and the Discrete Automated Clinical Analyzer IV (Dupont Diagnostics). Lymphocyte-transformation responses were quantitated as described elsewhere25.
Statistical Analysis
The test results for patients with idiopathic CD4+ T-lymphocytopenia, HIV-infected persons matched for CD4+ T-cell counts, and normal blood donors were compared by the Wilcoxon rank-sum test,26 since not all the test indexes were normally distributed. A P value of 0.05 or less was considered to indicate statistical significance, and Bonferroni's correction was applied in order to correct for multiple comparisons.
Case Reports
Patient 1
Patient 1 (Patient 12 in the accompanying report by Smith et al.16) was a 70-year-old white man who presented with Pneumocystis carinii pneumonia in March 1991. He responded well to intravenous treatment with trimethoprim-sulfamethoxazole for two weeks. Serologic testing for HIV antibodies was negative, but a CD4+ lymphocyte count was 19 per cubic millimeter. He had no risk factors for HIV infection other than the receipt of three units of whole blood during duodenal-ulcer surgery in 1987. The blood had been tested for HIV antibodies and was negative. His history was otherwise unremarkable. He had not received any immunosuppressive therapy, except for a three-month course of steroids in 1987.
His family had no history of immunodeficiency disease or of recurrent or unusual infections. His wife and two adult sons were in good health. His travel history included a cruise in the Caribbean in 1980 and a trip to Japan, Hong Kong, and China in 1983.
After his recovery from P. carinii pneumonia, the patient was given oral trimethoprim-sulfamethoxazole daily as prophylaxis against P. carinii pneumonia. His subsequent course was complicated by a fungal infection in the groin, which was treated both topically and with oral ketoconazole and which responded well. In April 1992 a grade II papillary transitional-cell carcinoma of the bladder was diagnosed. The patient had had a workup for hematuria in August 1990 and was said to have had a bladder carcinoma, but this diagnosis was not confirmed at another center in both October 1990 and February 1991. He was treated with four weekly infusions of the bladder with thiotepa. He is asymptomatic at this writing.
Patient 2
Patient 2 (Patient 13 in the report by Smith et al.16) was a 38-year-old white male health care worker who presented in October 1984 with headache and was found to have cryptococcal meningitis. He was treated with amphotericin B. In January 1985, shingles developed in a single dermatome. In July 1985, he had a recurrence of his headaches and was found to have a cryptococcoma with a capsule-deficient Cryptococcus neoformans. The cryptococcoma was excised, and he was treated with a full course of amphotericin B and flucytosine. He has been in good health since, except for a nonspecific maculopapular rash over his trunk and upper extremities in late 1985 and early 1986 and a grand mal seizure in January 1988, for which he has been taking phenytoin. He is asymptomatic as of this writing. His medical history revealed two false positive tests for syphilis in November 1984 and June 1985, but this test was negative on other occasions. He had no history of sexually transmitted diseases.
He has no family history of immunodeficiency or serious infections. His wife and two children are in good health.
Patient 3
Patient 3 (Patient 36 in the report by Smith et al.16) was a 56-year-old white woman who sought treatment for jaundice and fever and was found to have a common-duct stone. She underwent cholecystectomy with removal of the stone but had a prolonged postoperative course. Pneumonia and vaginal candidiasis developed. HIV serologic testing was positive, with confirmation by the Western blot assay. She was treated with ciprofloxacin without antifungal therapy, and her pneumonia and vaginitis resolved. She was referred to a tertiary-care center in December 1989, where repeat HIV serologic tests were negative and the Western blot assay showed reactivity only with p24 antigen. Serologic testing for the HIV p24 antigen was negative. A CD4+ cell count was 86 per cubic millimeter. She was temporarily treated with zidovudine and pyrimethamine-sulfadoxine until the results of the repeat serologic testing became known. In January 1991 she was reevaluated. HIV serologic testing was repeated twice and was negative, although her CD4+ count was still low. She had no risk factors for HIV infection other than a history of multiple blood transfusions for hemorrhage during pregnancies, beginning in 1951, and later for menorrhagia in the late 1970s and early 1980s. She had a hysterectomy in 1985 for cervical carcinoma in situ. Her medical history provided no relevant information.
There was no family history of immunodeficiency or serious infections except for a history of tuberculosis in her father's family. Her husband and two children are in good health at this writing.
Patient 4
Patient 4 (Patient 35 in the report by Smith et al.16) was a 45-year-old white man who sought treatment for molluscum contagiosum on his back, legs, and ankles. The lesions disseminated and were treated by curettage or freezing. In 1989 a chest film revealed a mass, and the findings of a lung biopsy were consistent with the diagnosis of a plaque due to asbestosis. He had no known history of exposure to asbestos. In February 1989, he was tested for HIV antibodies by enzyme immunoassay and was negative, but his CD4+ cell count was 96 per cubic millimeter. HIV serologic testing was repeated six months later and was again negative, but the CD4+ cell count remained low. During the six months before the writing of this account he had fatigue and a 5-lb (2.3 kg) weight loss. His medical history provided no relevant information. He had traveled to Mexico and Japan.
His family has no history of immunodeficiency or serious infections. His wife and son are in good health.
Patient 5
Patient 5 (Patient 11 in the report by Smith et al.16) was a 70-year-old white woman who sought treatment in 1983 for disseminated varicella zoster infection. In 1988 she had fever, cough, and pleuritic chest pain and was found to have extensive mediastinal lymphadenopathy. An open biopsy of a mediastinal mass revealed histoplasmosis. Treatment with a combination of amphotericin B and ketoconazole resulted in the resolution of her lung mass and clinical improvement. A CD4+ count during her hospitalization was 275 per cubic millimeter. Two months later it was 499 per cubic millimeter. She was well until April 1990, when a cough developed; she responded well to treatment for presumptive mycoplasma pneumonia. In April 1991 she had cough, fever, vomiting, and dehydration. Acid-fast bacilli were found in her sputum, which eventually grew Mycobacterium avium complex. At that time her CD4+ count was 199 per cubic millimeter. She responded to treatment with ciprofloxacin, which was stopped after her pulmonary infiltrate cleared. In September 1991 a cough again developed, and although she was afebrile, she had a new pulmonary infiltrate. She was again given ciprofloxacin but did not respond to treatment. Bronchial washings again grew M. avium, and she was given ciprofloxacin, rifampin, and ethambutol. Her cough resolved, but her malaise continued. In January 1992 epigastric distress developed, and she was found to be anemic. A gastrointestinal evaluation found a mass lesion in her stomach with a small ulcer. Biopsy of the mass showed histoplasmosis, and Helicobacter pylori was cultured from the area of the ulcer. She was given fluconazole beginning in March and was also treated for the helicobacter infection. She is asymptomatic at this writing.
She has no family history of immunodeficiency or serious infections. She is a widow and has two adult children who are in good health.
Results
The results of HIV serologic testing, culture, and PCR are shown in Table 1Table 1
Results of the Virologic Studies.. HIV-1 enzyme immunoassay results were weakly reactive in two patients and negative in three. All the HIV-1 Western blot results were either negative or indeterminate. Reverse transcriptase activity was measured with both manganese and magnesium in cultures from three patients (Patients 2, 3, and 4), and the results were negative in all three. Electron-microscopical examination of cultured cells demonstrated no evidence of viral particles. PCR for HIV-1 was negative in all the patients. None of the patients with idiopathic CD4+ T-lymphocytopenia had antibodies to either HTLV-I or HTLV-II.The results of lymphocyte phenotyping are shown in Table 2Table 2
Results of Lymphocyte-Phenotyping Studies.. When they were first studied at the CDC, none of the patients had anemia, leukopenia, or thrombocytopenia. Three had lymphocytopenia at that time. All had both low percentages and low absolute counts of CD4+ T cells. All had relative increases in the percentage of CD8+ cells, although in all but one patient the absolute counts were in the normal range. All had low ratios of CD4+ cells to CD8+ cells.Lymphocyte-phenotyping data from the patients with idiopathic CD4+ T-lymphocytopenia, normal controls, and HIV-positive persons are shown in Table 3Table 3
Comparison of Lymphocyte-Phenotyping Data among Patients with Idiopathic CD4+ T-Lymphocytopenia (ICL), Normal Controls, and HIV-Infected Persons.. The patients with idiopathic CD4+ T-lymphocytopenia differed from the normal controls in having lower percentages and counts of CD4+ T cells and higher percentages, but not higher counts, of CD8+ cells. The ratio of CD4+ T cells to CD8+ cells was also lower in the patients. As compared with the HIV-infected persons, the patients with idiopathic CD4+ T-lymphocytopenia had lower percentages and counts of both CD8+ cells and T (CD3+) cells. The patients with idiopathic CD4+ T-lymphocytopenia tended more often to have lymphopenia than the normal controls and the HIV-infected persons, whether they were matched for CD4+ count or for the percentage of CD4+ cells.Data were available on the changes in percentages and counts of CD4+ T cells in the patients with idiopathic CD4+ T-lymphocytopenia for periods ranging from 14 to 90 months (Figure 1Figure 1
Changes over Time in CD4+ T-Cell Counts and Percentages in Five Patients with Idiopathic CD4+ T-Lymphocytopenia.). The CD4+ counts changed relatively little over time, and the percentages remained stable in three patients and dropped initially in two.Serum immunoglobulin levels were low in two patients. Patient 1 had an IgG level of 503 mg per deciliter (normal, 568 to 1483) and an IgA level of 32 mg per deciliter (normal, 57 to 414), whereas the IgM level was normal. The IgG and IgA levels became normal in the year preceding the writing of this article. Patient 3 had an IgG level of 470 mg per deciliter. When the levels were compared with those in normal controls and HIV-positive patients (Table 4Table 4
Comparison of Immunoglobulin Levels among Patients with Idiopathic CD4+ T-Lymphocytopenia (ICL), Normal Controls, and HIV-Infected Persons.), the IgG level in the patients with idiopathic CD4+ T-lymphocytopenia was lower than that in the normal controls. The IgA level also tended to be lower, whereas the IgM level was similar. Patients with idiopathic CD4+ T-lymphocytopenia also had significantly lower IgG levels than the HIV-infected patients, and the levels of IgA also tended to be lower.Lymphocyte-transformation responses to mitogens were markedly depressed in all the patients with idiopathic CD4+ T-lymphocytopenia as compared with controls, and only Patient 2 had a response to one of the three soluble antigens tested.
Investigation of the patients' spouses and the blood donors to Patient 1 revealed no abnormalities, either of clinical condition or in the phenotype of the lymphocytes.
Discussion
The most frequent cause of CD4+ T-cell depletion unassociated with immunosuppressive therapy in the United States today is HIV infection. Except for a weakly reactive enzyme immunoassay for HIV in two patients (who had negative or indeterminate Western blot assays), serologic testing, culture, and PCR produced no evidence of infection with either HIV or HTLV in the patients we studied. Moreover, measurements of reverse transcriptase activity (a generic marker for retroviruses) after coculture with normal phytohemagglutinin blasts or cell lines revealed no evidence of any other retroviral agent in these patients. There was no cytopathic effect, and no virus-like particles were detected to suggest the presence of another agent that might be capable of killing CD4+ cells.
The changes in lymphocyte populations in these patients differ in nature from those seen in patients with HIV infection who have comparable percentages or counts of CD4+ T cells. In HIV infection lymphocyte levels are maintained at a higher level by the early increase in CD8+ cells in response to the infection27; the patients with idiopathic CD4+ T-lymphocytopenia, who do not have this increase, tend more often to have lymphopenia than comparable HIV-infected persons matched according to percentage of CD4+ T cells. Thus, without a compensatory increase in another cell population, the decrease in the count of CD4+ T cells, which make up the largest single fraction of peripheral-blood lymphocytes, is sufficient to explain the greater lymphocytopenia seen in idiopathic CD4+ T-lymphocytopenia than in HIV infection. The increase in the percentage of CD8+ cells in this syndrome is probably only a reciprocal increase due to the drop in the percentage of CD4+ T cells and similar to the reciprocal increases in the percentages of B cells (CD19+) and natural killer cells (CD3-CD16/56+).
Immunoglobulin levels are usually elevated in patients with HIV infection28. Our patients with idiopathic CD4+ T-lymphocytopenia had either normal or slightly low levels, which, at least in the case of IgG, were lower than those of normal controls. This may also be due to a lack of help from CD4+ T cells in immunoglobulin production in idiopathic CD4+ T-lymphocytopenia without the direct stimulation of such production seen in HIV infection29.
The lack of progressive changes in the CD4+ cell count over time in some of these patients also differs from the invariably progressive drop in counts in HIV infection. Although three of the patients we studied have had low counts for several years, the natural history of this condition is still unknown.
The functional effect of the low CD4+ T-cell counts is evident in the lack of significant response to both nonspecific mitogens and specific soluble antigens in the lymphocyte-transformation assay. In this respect, these patients resemble those with low CD4+ T-cell counts due to HIV infection30.
If HIV is excluded as a cause of the immunodeficiency in these patients, we are left with the challenge of determining the cause. None of these patients have had recent immunosuppressive therapy or disease associated with immunosuppression or immunodeficiency. It has been suggested that this condition might fit into the diagnosis of common variable immunodeficiency31. Although that immunodeficiency is most commonly characterized by recurrent sinopulmonary infections, often with chronic lung disease, and by defective antibody production or hypogammaglobulinemia, it has been diagnosed in a heterogeneous group of imprecisely classified patients32. Patients with common variable immunodeficiency generally have defects in the de-velopment of B cells into immunoglobulin-secreting plasma cells. Some also have depressed lymphocyte responses to mitogen or low CD4+ cell counts33. None of our patients with idiopathic CD4+ T-lymphocytopenia had clinical symptoms suggestive of common variable immunodeficiency, although two had low IgG levels and one had low IgA levels in addition. At least one of these two patients had normal levels of immunoglobulins after the development of opportunistic infection and low CD4+ T-cell counts. Hypogammaglobulinemia may develop due to the loss of CD4+ T cells that assist in B-cell immunoglobulin production34.
The identification of additional patients with idiopathic CD4+ T-lymphocytopenia may reveal that it too is a heterogeneous entity, in which some patients' symptoms or laboratory abnormalities overlap with those seen in common variable immunodeficiency and others belong to other subgroups of idiopathic CD4+ T-lymphocytopenia. At a recent CDC meeting on this subject, three groups described evidence of possible retroviral agents in patients with idiopathic CD4+ T-lymphocytopenia. Since evidence of a novel retrovirus in these patients is not conclusive, nonviral mechanisms affecting CD4+ T-cell counts should also be considered15.
Although three of our patients came from a single state and two were described by a single physician, extensive questioning revealed no apparent connection among these patients. This geographic clustering probably reflects a reporting bias. Studies of the spouses of four of our patients and of the blood donors to one patient revealed no abnormalities in lymphocyte subpopulations. Our search for a possible retroviral agent in this condition was also unrevealing. Together, these findings lead us away from the hypothesis that idiopathic CD4+ T-lymphocytopenia is caused by a transmissible agent.
Persistently low CD4+ T-cell counts are highly unusual24,35. Transiently low counts have been noted in a number of cohort studies of HIV-negative persons: the Multicenter AIDS Cohort Study (Vermund S: personal communication), the CDC San Francisco Cohort Study (Holmberg S: personal communication), the Transfusion Safety Study,36 the New York City Intravenous Drug User Study (DesJarlais D: personal communication), and the New Jersey Intravenous Drug User Study37. Counts have also been reported as being low in several acute infections38,39 and in single cases of cryptococcal meningoencephalitis and disseminated histoplasmosis40,41. Patients 2 and 5, who had cryptococcal meningitis and mediastinal histoplasmosis, respectively, had normal CD4+ T-cell percentages at the time of their initial disease, although the counts were low. In Patient 5 the lymphopenia resolved, but the percentages also subsequently became low. Thus, in some patients, idiopathic CD4+ T-lymphocytopenia may develop consequent to an acute infection, whereas in others the infection is a consequence of the low CD4+ T-cell count.
We have demonstrated major differences in clinical, virologic, and immunologic findings between five patients with idiopathic CD4+ T-lymphocytopenia and patients with HIV infection. Further epidemiologic, immunologic, and virologic studies will aid in the characterization of this newly recognized condition.
Presented in part at the Keystone Symposia on Molecular and Cellular Biology, Keystone, Colo., March 27-April 4, 1992, and the Eighth International Congress of Immunology, Budapest, Hungary, August 23-28, 1992.
The use of trade names is for identification only and does not imply endorsement by the Public Health Service or the Department of Health and Human Services.
We are indebted to the members of the Epidemic Response Laboratory for processing specimens; to Robert C. Hermann, M.D., Gerald Blackburn, D.O., and Neldagae Chisa, M.D., for referring patients; to Marjorie Hubbard, Marianne Simon, Dolly Sinha, Donna Warfield, Cynthia Goldsmith, Judy Petzelt, Charles Schable, Jennifer Rapier, and Martha Monroe for technical assistance; to Ruthie Odum and Fred Ingram for data analysis; to Linda Nealy for assistance in the preparation of the manuscript; to Phyllis Moir for editorial review; and to Steve McDougal, Thomas Hodge, Thomas Folks, Chin-Yih Ou, Harold Jaffe, James Curran, and James Hughes for reviewing the manuscript.
Source Information
From the Immunology Branch, Division of HIV/AIDS (T.J.S., B.M.J., J.K.A.N.), and the Retrovirus (R.B.L., T.R.) and Herpesvirus (A.C.M.) Branches, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta; the Divisions of Allergy, Immunology, and Infectious Diseases, William Beaumont Hospital, Royal Oak, Mich. (C.B.L.); the Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta (J.A.S.); and the University of Arkansas for Medical Sciences, Little Rock (R.A.M.).
Address reprint requests to Dr. Spira at the Division of HIV/AIDS, Mailstop D-08, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333.
- References
References
1
Pankhurst C ,Peakman M . Reduced CD4+ T cells and severe oral candidiasis in absence of HIV infection. Lancet 1989;1:672-672
CrossRef | Web of Science | Medline2
Gatenby PA . Reduced CD4+ T cells and candidiasis in absence of HIV infection. Lancet 1989;1:1027-1028
CrossRef | Web of Science | Medline3
Daus H ,Schwarze G ,Radtke H . Reduced CD4+ count, infections, and immune thrombocytopenia without HIV infection. Lancet 1989;2:559-560
CrossRef | Web of Science | Medline4
Daar ES ,Moudgil T ,Ho DD . Persistently low T-helper (CD4+) lymphocyte counts in HIV-negative asymptomatic men. Clin Res 1990;38:114A-114A abstract.5
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;21:63-66
CrossRef | Web of Science | Medline6
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;322:132-132
Web of Science | Medline7
Hansen ER ,Lisby S ,Baadsgaard O ,Ho VC ,de Villiers E-M ,Vejlsgaard GL . Abnormal function of CD4+ helper/inducer T lymphocytes in a patient with widespread human papillomavirus type 3-related infection. Arch Dermatol 1990;126:1604-1608
CrossRef | Web of Science | Medline8
Seligmann M ,Aractingi S ,Oksenhendler E ,Rabian C ,Ferchal F ,Gonnot G . CD4+ lymphocytopenia without HIV in patient with cryptococcal disease. Lancet 1991;337:57-58
CrossRef | Web of Science | Medline9
Jowitt SN ,Love EM ,Liu Yin JA ,Pumphrey RSH . CD4 lymphocytopenia without HIV infection in patient with cryptococcal infection. Lancet 1991;337:500-501
CrossRef | Web of Science | Medline10
Castro A ,Pedreira J ,Soriano V , et al. Kaposi's sarcoma and disseminated tuberculosis in HIV-negative individual. Lancet 1992;339:868-868
CrossRef | Web of Science | Medline11
Unexplained CD4+ T-lymphocyte depletion in persons without evident HIV infection -- United States
Medline12
Update: CD4+ T-lymphocytopenia in persons without evident HIV infection -- United States
Medline13
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 | Medline14
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 U S A 1992;89:7831-7835
CrossRef | Web of Science | Medline15
Goldsmith MF . Still a mystery but `not likely' a virus. JAMA 1992;268:1235-1236
CrossRef | Web of Science | Medline16
Smith DK, Neal JJ, Holmberg SD, Centers for Disease Control Idiopathic CD4+ T-Lymphocytopenia Task Force
Full Text | Web of Science | Medline17
Interpretation and use of the Western blot assay for serodiagnosis of human immunodeficiency virus type 1 infectionsMMWR Morb Mortal Wkly Rep 1989;38:Suppl S7:1-7
18
Velleca WM, Palmer DF, Feorino PM, et al. Isolation, culture, and identification of human immunodeficiency virus: procedural guide. Rev. ed. Atlanta: Department of Health and Human Services, 1991.
19
Jackson JB . Human immunodeficiency virus type 1 antigen and culture assays. Arch Pathol Lab Med 1990;114:249-253
Web of Science | Medline20
Spira TJ ,Bozeman LH ,Holman RC ,Warfield DT ,Phillips SK ,Feorino PM . Micromethod for assaying reverse transcriptase of human T-cell lymphotropic virus type III/lymphadenopathy-associated virus. J Clin Microbiol 1987;25:97-99
Medline21
Mollenhauer HH . Plastic embedding mixtures for use in electron microscopy. Stain Technol 1964;39:111-114
Web of Science | Medline22
Ou C-Y ,Kwok S ,Mitchell SW , et al. DNA amplification for direct detection of HIV-1 in DNA of peripheral blood mononuclear cells. Science 1988;239:295-297
CrossRef | Web of Science | Medline23
Ou C-Y ,McDonough SH ,Cabanas D , et al. Rapid and quantitative detection of enzymatically amplified HIV-1 DNA using chemiluminescent oligonucleotide probes. AIDS Res Human Retroviruses 1990;6:1323-1329
Web of Science | Medline24
Reichert T ,DeBruyere M ,Deneys V , et al. Lymphocyte subset reference ranges in adult Caucasians. Clin Immunol Immunopathol 1991;60:190-208
CrossRef | Medline25
Rogers MF ,Morens DM ,Stewart JA . et al. National case-control study of Kaposi's sarcoma and Pneumocystis carinii pneumonia in homosexual men. 2. Laboratory results. Ann Intern Med 1983;99:151-158
Web of Science | Medline26
Hollander M, Wolfe DA. Nonparametric statistical methods. New York: John Wiley, 1973:68-9.
27
Cooper DA ,Tindall B ,Wilson EJ ,Imrie AA ,Penny R . Characterization of T lymphocyte responses during primary infection with human immunodeficiency virus. J Infect Dis 1988;157:889-896
CrossRef | Web of Science | Medline28
Chess Q ,Daniels J ,North E ,Macris NT . Serum immunoglobulin elevations in the acquired immunodeficiency syndrome (AIDS): IgG, IgA, IgM, and IgD. Diagn Immunol 1984;2:148-153
Medline29
Schnittman SM ,Lane HC ,Higgins SA ,Folks T ,Fauci AS . Direct polyclonal activation of human B lymphocytes by the acquired immune deficiency syndrome virus. Science 1986;233:1084-1086
CrossRef | Web of Science | Medline30
Lane HC ,Depper JM ,Greene WC ,Whalen G ,Waldmann TA ,Fauci AS . Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. N Engl J Med 1985;313:79-84
Full Text | Web of Science | Medline31
Kaczmarski RS ,Mufti GJ ,Sutherland S , et al. Idiopathic CD4+ T-lymphocytopenia. Lancet 1992;340:608-608
Web of Science | Medline32
Seligmann M ,Ballet JJ . Diagnosis criteria and classification of human primary defects of humoral immunity. Birth Defects 1983;19:153-160
Medline33
Spickett GP ,Webster AD ,Farrant J . Cellular abnormalities in common variable immunodeficiency. Immunodefic Rev 1990;2:199-219
Medline34
Callard RE. T-cell dependent activation of human B cells. In: Snow EC, ed. T-cell dependent and independent B-cell activation. Boca Raton, Fla.: CRC Press, 1991:139-63.
35
Bofill M ,Janossy G ,Lee CA , et al. Laboratory control values for CD4 and CD8 T lymphocytes: implications for HIV-1 diagnosis. Clin Exp Immunol 1992;88:243-252
CrossRef | Web of Science | Medline36
Aledort LM ,Operskalski EA ,Mosely JW . Low CD4+ counts in a study of transfusion safety. N Engl J Med 1993;328:441-442
Full Text | Web of Science | Medline37
Weiss SH ,Klein CW ,Mayur RK ,Besra J ,Denny TN . Idiopathic CD4+ T-lymphocytopenia. Lancet 1992;340:608-609
Web of Science | Medline38
Shafer RW ,Chirgwin KD ,Glatt AE ,Dahdouh MA ,Landesman SH ,Suster B . HIV prevalence, immunosuppression, and drug resistance in patients with tuberculosis in an area endemic for AIDS. AIDS 1991;5:399-405
CrossRef | Web of Science | Medline39
Williams RC Jr ,Koster FT ,Kilpatrick KA . Alterations in lymphocyte cell surface markers during various human infections. Am J Med 1983;75:807-816
CrossRef | Web of Science | Medline40
Scalzini A ,Castelnuovo F ,Puoti M ,Cristini G . A case of cryptococcal meningoencephalitis and focal cerebral vasculitis with transient immunodeficiency. Acta Neurol (Napoli) 1990;12:301-304
Medline41
Lehmann PF ,Gibbons J ,Senitzer D ,Ribner BS ,Freimer EH . T lymphocyte abnormalities in disseminated histoplasmosis. Am J Med 1983;75:790-794
CrossRef | Web of Science | Medline
- Citing Articles (48)
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Poorvi Dalal, Leah Chernin, David Swender, Haig Tcheurekdjian, Robert Hostoffer. (2011) Histoplasmosis in the olecranon bursa of a patient with idiopathic CD4 lymphocytopenia. Annals of Allergy, Asthma & Immunology 107:6, 543-544
CrossRef2
Carlos Cervera, Francesc Fernández-Avilés, Oscar de la Calle-Martin, Xavier Bosch, Montserrat Rovira, Montse Plana, Asunción Moreno, Felipe García, Jose M. Miró, Antonio Martínez, Teresa Gallart, Enric Carreras, Joan Blade, Jose M. Gatell. (2011) Non-myeloablative hematopoietic stem cell transplantation in the treatment of severe idiopathic CD4+ lymphocytopenia. European Journal of Haematology 87:1, 87-91
CrossRef3
D. Scott-Algara, K. Balabanian, L. A. Chakrabarti, L. Mouthon, F. Dromer, C. Didier, F. Arenzana-Seisdedos, O. Lortholary. (2010) Idiopathic CD4+ T-cell lymphocytopenia is associated with impaired membrane expression of the chemokine receptor CXCR4. Blood 115:18, 3708-3717
CrossRef4
T. Trojan, R. Collins, D. A. Khan. (2009) Safety and efficacy of treatment using interleukin-2 in a patient with idiopathic CD4 + lymphopenia and Mycobacterium avium-intracellulare. Clinical & Experimental Immunology 156:3, 440-445
CrossRef5
Aparna Mukherjee, Rakesh Lodha, S. K. Kabra. (2009) Idiopathic CD4+ T-cell lymphocytopenia. The Indian Journal of Pediatrics 76:4, 430-432
CrossRef6
Yasuaki Yamada, Masahiko Okada, Akira Kamitamari, Hiroyuki Moriuchi, Masanori Yanai, Osamu Hano, Kunihiro Tsukasaki, Kazuto Tsuruda, Hiroo Hasegawa, Katsunori Yanagihara, Shimeru Kamihira. (2009) Multiple Immune Abnormalities in a Patient with Idiopathic CD4+ T-Lymphocytopenia. Internal Medicine 48:22, 1967-1971
CrossRef7
David Barnett, Brooke Walker, Alan Landay, Thomas N. Denny. (2008) CD4 immunophenotyping in HIV infection. Nature Reviews Microbiology 6, S7-S15
CrossRef8
D. I. Zonios, J. Falloon, J. E. Bennett, P. A. Shaw, D. Chaitt, M. W. Baseler, J. W. Adelsberger, J. A. Metcalf, M. A. Polis, S. J. Kovacs, J. A. Kovacs, R. T. Davey, H. C. Lane, H. Masur, I. Sereti. (2008) Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors. Blood 112:2, 287-294
CrossRef9
Dimitrios I. Zonios, Judith Falloon, Chiung-Yu Huang, Doreen Chaitt, John E. Bennett. (2007) Cryptococcosis and Idiopathic CD4 Lymphocytopenia. Medicine 86:2, 78-92
CrossRef10
Seong Gyu Lee, Sung Hwan Byun, Jong Woon Choi, Hyun Soo Kim. (2007) A Case of Idiopathic CD4+ T-lymphocytopenia Associated with Autoimmune Hemolytic Anemia. The Korean Journal of Hematology 42:1, 53
CrossRef11
Ulrich A Walker, Klaus Warnatz. (2006) Idiopathic CD4 lymphocytopenia. Current Opinion in Rheumatology 18:4, 389-395
CrossRef12
K. Hochauf, D. Bandt, C. Pöhlmann, S. Monecke, M. Toma, S. Trautmann. (2005) Fatal varicella zoster virus infection as first manifestation of idiopathic CD4+ T-cell lymphocytopenia. European Journal of Clinical Microbiology & Infectious Diseases 24:10, 706-708
CrossRef13
(2005) The Unturned Stone. New England Journal of Medicine 352:20, 2140-2141
Full Text14
Francisco A. Bonilla, I. Leonard Bernstein, David A. Khan, Zuhair K. Ballas, Javier Chinen, Michael M. Frank, Lisa J. Kobrynski, Arnold I. Levinson, Bruce Mazer, Robert P. Nelson, Jordan S. Orange, John M. Routes, William T. Shearer, Ricardo U. Sorensen. (2005) Practice parameter for the diagnosis and management of primary immunodeficiency. Annals of Allergy, Asthma & Immunology 94:5, S1-S63
CrossRef15
Srdjan Pasic, Predrag Minic, Slobodan Dzudovic, Aleksandra Minic, Bojana Slavkovic. (2005) Idiopathic CD4+ lymphocytopenia and juvenile laryngeal papillomatosis. Pediatric Pulmonology 39:3, 281-283
CrossRef16
Antonella Isgrò, Maria Caterina Sirianni, Claudia Gramiccioni, Ivano Mezzaroma, Alessandra Fantauzzi, Fernando Aiuti. (2005) Idiopathic CD4+ Lymphocytopenia May Be due to Decreased Bone Marrow Clonogenic Capability. International Archives of Allergy and Immunology 136:4, 379-384
CrossRef17
Geoffrey W. Hoffmann. (2004) Proteomic analyser with applications to diagnostics and vaccines. Journal of Theoretical Biology 228:4, 459-465
CrossRef18
S. Marques, P. Marcelino, A. Martins Baptista, F. Aldomiro, J. Ribeiro, J. Malhado. (2002) Pneumocystis carinii Pneumonia in Diabetic Patient. Infectious Diseases in Clinical Practice 11:8, 441-444
CrossRef19
Paula J. Busse, Charlotte Cunningham-Rundles. (2002) Primary leptomeningeal lymphoma in a patient with concomitant CD4+ lymphocytopenia. Annals of Allergy, Asthma & Immunology 88:3, 339-342
CrossRef20
Gerasimos J. Zaharatos, Marcel A. Behr, Michael D. Libman. (2001) Profound T‐Lymphocytopenia and Cryptococcemia in a Human Immunodeficiency Virus–Seronegative Patient with Disseminated Tuberculosis. Clinical Infectious Diseases 33:11, e125-e128
CrossRef21
John A. Van Wagoner, David A. Khan. (2001) Selective CD4+ T cell lymphocytopenia and recalcitrant warts in an 8-year-old child. Annals of Allergy, Asthma & Immunology 87:5, 373-378
CrossRef22
Martin Wilhelm, Florian Weissinger, Volker Kunzmann, Justus G. Muller, John L. Fahey. (2001) Idiopathic CD4+ T Cell Lymphocytopenia Evolving to Monoclonal Immunoglobulins and Progressive Renal Damage Responsive to IL-2 Therapy. Clinical Immunology 99:2, 298-304
CrossRef23
Simona Signorini, Silvia Pirovano, Simona Fiorentini, Roberto Stellini, Valeria Bianchi, Alberto Albertini, Luisa Imberti. (2000) Restriction of T-cell receptor repertoires in idiopathic CD4+ lymphocytopenia. British Journal of Haematology 110:2, 434-437
CrossRef24
Paolo Airò, Arnaldo Caruso, Roberto Stellini, Chiara Antonioli, Fabio Malacarne, Stefano Licenziati, Alberto Albertini, Roberto Cattaneo, Luisa Imberti. (2000) Characterization of γδ T Cells Expressing CD158b, a Killer Cell Inhibitory Receptor, in a Patient with Chronic CD4+ Lymphocytopenia and Disseminated Mycobacterium intracellulare Infection. Clinical Immunology 96:1, 67-75
CrossRef25
Reto Nuesch, Cristina Bellini, Werner Zimmerli. (1999) Pneumocystis carinii Pneumonia in Human Immunodeficiency Virus (HIV)–Positive and HIV‐Negative Immunocompromised Patients. Clinical Infectious Diseases 29:6, 1519-1523
CrossRef26
CUNNINGHAM-RUNDLES, MURRAY, SMITH. (1999) Treatment of idiopathic CD4 T lymphocytopenia with IL-2. Clinical and Experimental Immunology 116:2, 322-325
CrossRef27
Joan Guitart, Mark A. Hurt. (1999) Pleomorphic T-cell Infiltrate Associated With Molluscum Contagiosum. The American Journal of Dermatopathology 21:2, 178-180
CrossRef28
MJBF FLAMINIO, BR RUSH, JH COX, WE MOORE. (1998) CD4+ and CD8+ T- lymphocytopenia in a filly with Pneumocystis carinii pneumonia. Australian Veterinary Journal 76:6, 399-402
CrossRef29
C.M HARDMAN, B.S BAKER, J. LORTAN, J. BREUER, T. SURENTHERAN, A. POWLES, L. FRY. (1997) Active psoriasis and profound CD4 + lymphocytopenia. British Journal of Dermatology 136:6, 930-932
CrossRef30
Joe Venzor, Qiang Hua, Robert B. Bressler, Charles H. Miranda, David P. Huston. (1997) Behçet's-like Syndrome Associated With Idiopathic CD4+ T-Lymphocytopenia, Opportunistic Infections, and a Large Population of TCRαβ+ CD4- CD8- T Cells. The American Journal of the Medical Sciences 313:4, 236-238
CrossRef31
Michael Edmond, Becky Stephenson, Richard Wenzel. (1996) A 31-Year-Old Man With a Multilobar Pulmonary Process. The American Journal of the Medical Sciences 312:5, 235-241
CrossRef32
ROBERT F. GARRY, CÉSAR D. FERMIN, PETER F. KOHLER, M. LOUISE MARKERT, HONG LUO. (1996) Antibodies against Retroviral Proteins and Nuclear Antigens in a Subset of Idiopathic CD4 + T Lymphocytopenia Patients. AIDS Research and Human Retroviruses 12:10, 931-940
CrossRef33
H.A. KURWA, R. MARKS. (1995) Protracted cutaneous disorders in association with low CD4+ lymphocyte counts. British Journal of Dermatology 133:4, 625-629
CrossRef34
U. Wahn. (1995) Evaluation of the child with suspected primary immunodeficiency. Pediatric Allergy and Immunology 6:2, 71-79
CrossRef35
Dianne Vertes, Michael D. Linden, John L. Carey. (1995) Idiopathic CD4 + T-lymphocytopenia: Analysis of a patient with selective IgA deficiency and no evidence of HIV infection. Cytometry 22:1, 40-44
CrossRef36
C WALKER, R MALIK, PJ CANFIELD. (1995) Analysis of leucocytes and lymphocyte subsets in cats with naturally-occurring cryptococcosis but differing feline immunodeficiency virus status. Australian Veterinary Journal 72:3, 93-97
CrossRef37
Vladimir L. Koliadin. (1995) Critical analysis of the current views on the nature of AIDS. Genetica 95:1-3, 71-90
CrossRef38
E. Calderón, B. Sánchez, F. J. Medrano, P. Stiefel, M. Leal. (1995) CD4+ T-lymphocytopenia in the elderly. European Journal of Clinical Microbiology & Infectious Diseases 14:1, 75-77
CrossRef39
Shauna M. Richert, John L. Orchard. (1995) Bacterial esophagitis associated with CD4+ T-lymphocytopenia without HIV infection. Digestive Diseases and Sciences 40:1, 183-185
CrossRef40
Mauro Girotto, Dario Alessandro Verani, Pasquale Paolo Pagliaro. (1994) Idiopathic CD4+ T-lymphocytopenia in blood donors: cohort study. Transfusion 34:10, 935-936
CrossRef41
LaRene Kuller, Raoul E. Benveniste, Che-Chung Tsai, Edward A. Clark, Patricia Polacino, Robin Watanabe, Julie Overbaugh, Michael G. Katze, William R. Morton. (1994) Intrarectal inoculation of macaques by the simian immunodeficiency virus, SIVmne E11S: CD4 + depletion and AIDS. Journal of Medical Primatology 23:7, 397-409
CrossRef42
SCOTT L. GOTTLIEB, PATRICIA L. MYSKOWSKI. (1994) MOLLUSCUM CONTAGIOSUM. International Journal of Dermatology 33:7, 453-461
CrossRef43
Holland, Steven M.Eisenstein, Eli M.Kuhns, Douglas B.Turner, Maria L.Fleisher, Thomas A.Strober, WarrenGallin, John I.. (1994) Treatment of Refractory Disseminated Nontuberculous Mycobacterial Infection With Interferon Gamma: A Preliminary Report. New England Journal of Medicine 330:19, 1348-1355
Full Text44
L.S. Young, L.E.M. Bermudez, C.B. Inderlied. (1994) Practical issues in the antibiotic and immunotherapy of Mycobacterium avium disease in immunocompromised patients. Research in Microbiology 145:3, 206-209
CrossRef45
DeHovitz, Jack A., Feldman, Joseph, Landesman, Sheldon, . (1993) Idiopathic CD4+ T-Lymphocytopenia. New England Journal of Medicine 329:14, 1045-1046
Full Text46
(1993) CD4+ T-Lymphocytopenia without HIV Infection. New England Journal of Medicine 328:25, 1847-1850
Full Text47
Smith, Dawn K.Neal, Joyce J.Holmberg, Scott D.the Centers for Disease Control Idiopathic CD4+ T-Lymphocytopenia Task Force. (1993) Unexplained Opportunistic Infections and CD4+ T-Lymphocytopenia without HIV Infection -- An Investigation of Cases in the United States. New England Journal of Medicine 328:6, 373-379
Full Text48
Fauci, Anthony S., . (1993) CD4+ T-Lymphocytopenia without HIV Infection -- No Lights, No Camera, Just Facts. New England Journal of Medicine 328:6, 429-431
Full Text
