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Background

This is a rare disease characterized by the following:

Depressed numbers of circulating T lymphocytes (<300/ul or less than 20%) on more than one occasion of measurement
No laboratory evidence of HIV-1 or HIV-2 infection
Absence of any defined immunodeficiency or therapy associated with depressed levels of CD4+ T lymphocytes

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Differential Diagnosis  
Prognosis and Treatment  
Commonly Used Terms  
Internet Links  


EPIDEMIOLOGY CHARACTERIZATION
AGE RANGE-MEDIAN  


Idiopathic CD4+ T lymphopenia in older persons.

Kaiser FE, Morley JE.

Department of Medicine, St. Louis University School of Medicine, Missouri.

J Am Geriatr Soc 1994 Dec;42(12):1291-4 Abstract quote

OBJECTIVE: Survey of the association of idiopathic CD4+ T cell lymphocytopenia in older persons with protein energy undernutrition and unusual infections/colonizations.

METHOD: Retrospective chart analysis.

RESULTS: Five subjects aged 61 to 87 years, with unusual organisms and/or either marasmus or kwashiorkor, were noted to have absolute CD4+ and CD8+ T cell lymphocytopenia. All were HIV negative.

CONCLUSION: T cell lymphocytopenia may not be a uncommon finding in malnourished older persons, but additional studies to determine its prevalence need to be undertaken. Its role in disease and impact on therapeutic response needs to be further explored.

GEOGRAPHY  
WEST AFRICA  


Idiopathic CD4+ T-lymphocyte depletion in a west African population.

Djomand G, Diaby L, N'Gbichi JM, Coulibaly D, Kadio A, Yapi A, Kanga JM, Boateng E, Diallo K, Kestens L, et al.

Projet RETRO-CI, Centre Hospitalier de Treichville, Abidjan, Cote d'Ivoire.

 

AIDS 1994 Jun;8(6):843-7 Abstract quote

OBJECTIVE: To assess the frequency of CD4+ T-lymphocyte depletion in selected populations in West Africa and to determine whether an association exists between AIDS-like illnesses and CD4+ T-lymphocytopenia in HIV-negative individuals.

DESIGN: Retrospective review of databases and prospective case-control study.

SETTING: Project RETRO-CI, an AIDS research project in Abidjan, Cote d'Ivoire, a University Hospital and tuberculosis treatment and maternal and child health centres in Abidjan.

METHODS: We conducted a retrospective review of CD4+ T-lymphocyte counts performed between 1991 and 1992 on hospitalized medical patients, outpatients with tuberculosis, and women participating in a study of HIV-1 and HIV-2 mother-to-child transmission. A prospective case-control study was conducted in 1992 to examine the relationship between HIV-negative CD4+ T-lymphocyte depletion and wasting syndrome (wasting and chronic diarrhoea and/or chronic fever).

RESULTS: In the retrospective data review, CD4+ T-lymphocyte counts < 300 x 10(6)/l were found in 9.6% of 115 HIV-negative hospitalized patients, in 4.2% of 312 ambulatory tuberculosis patients, and in 0.4% of 263 healthy women after delivery. In the case-control study, no association was found between CD4+ T-lymphocyte depletion in HIV-negative individuals and the presence of wasting syndrome. Increased mortality in HIV-negative individuals was associated with wasting but not with reduced CD4+ T-lymphocyte counts. In contrast, a trend existed for increased mortality with increasingly severe CD4+ T-lymphocyte depletion in HIV-positive patients. Tuberculosis was the most frequently proven or suspected diagnosis in HIV-negative individuals with wasting and CD4+ T-lymphocytopenia.

CONCLUSIONS: In the absence of HIV infection, CD4+ T-lymphocytopenia is uncommon (< 1%) in West African asymptomatic individuals but is more frequent in those with tuberculosis (4%) and hospitalized patients (10%). CD4+ T-lymphocytopenia in HIV-negative individuals was not associated with wasting syndrome or increased mortality. There was no evidence for frequent, clinically relevant immune deficiency other than that associated with HIV infection.

 

DISEASE ASSOCIATIONS CHARACTERIZATION
CHEMOTHERAPY  


CD4+ T-lymphocytopenia in long-term survivors following intensive chemotherapy in childhood cancers.

Azuma E, Nagai M, Qi J, Umemoto M, Hirayama M, Kumamoto T, Hiratake S, Komada Y, Sakurai M.

Department of Pediatrics and Clinical Immunology, Mie University School of Medicine, Tsu, Japan.

Med Pediatr Oncol 1998 Jan;30(1):40-5 Abstract quote

BACKGROUND: It is generally believed the effects of short intensive courses of therapy are rapidly reversible in childhood cancers, and immunologic function following years of maintenance treatment with chemotherapy usually returns to normal by 6 months or less when treatment is terminated. However, we previously demonstrated that dysregulation of immunoglobulins, especially IgD, was observed in long-term survivors following intensive chemotherapy in cancer patients. With regard to cellular immunity, investigators reported that antineoplastic chemotherapy significantly reduces the number of CD4+ T-lymphocytes, and production of newly developing CD4+ T-lymphocytes was inversely related to the patients' age. However, the incidence of CD4+ lymphocytopenia in long-term survivors of childhood cancers is not known.

PROCEDURE: Here, we report the flow cytometric analysis of peripheral blood from long-term survivors who continue complete remission off chemotherapy for more than 5 years.

RESULTS: Six out of 74 long-term survivors (8.1%), showed low CD4+ T-lymphocyte count (<300/mm3). Three of six patients showed continued CD4+ T-lymphocytopenia over a year. In spite of the persistent low levels of CD4+ T cells, these three patients were not susceptible to severe infections.

COMMENT: Intriguingly, in patients with CD4+ T-lymphocytopenia there has been a tendency toward increased numbers of natural killer cells or gamma delta T cells that may be operating as a thymus-independent compensatory mechanism to defend the hosts.

ERYTHRODERMA, ACUTE  


Acute erythroderma as an exclusion criterion for idiopathic CD4+ T lymphocytopenia.

Griffiths TW, Stevens SR, Cooper KD.

Department of Dermatology, University of Michigan Medical Center, Ann Arbor.

Arch Dermatol 1994 Dec;130(12):1530-3 Abstract quote

BACKGROUND: Idiopathic CD4+ T lymphocytopenia is defined as a CD4+ T lymphocytopenia of less than 0.3 x 10(9)/L that is not associated with human immunodeficiency virus, other immunodeficiency, or immunosuppressive therapy. The associated clinical course and laboratory findings are variable. We describe a subset of patients whose peripheral CD4+ T-lymphocytopenia was transient, and suggest a pathomechanism for this phenomenon.

OBSERVATIONS: We describe three patients with cutaneous T-cell lymphoma, atopic dermatitis, or psoriasis in whom acute erythroderma was concomitant with a peripheral CD4+ T lymphocytopenia that normalized after resolution of the erythroderma. Immunoperoxidase staining of skin biopsy specimens and quantitative estimation of CD4+ T lymphocytes in the cutaneous and peripheral blood compartments demonstrated that the peripheral CD4+ T lymphocytopenia in these cases most probably resulted from sequestration of CD4+ T lymphocytes in the skin. The skin of an erythrodermic patient appears capable of sequestering 10(10) to 10(11) CD4+ T lymphocytes, whereas the peripheral blood compartment contains in the range of 10(9) CD4+ T lymphocytes.

CONCLUSIONS: We propose that CD4+ T lymphocytopenia can occur as a result of acute erythroderma of multiple causes and that acute erythroderma associated with transient CD4+ T lymphocytopenia be considered as an exclusion criterion for idiopathic peripheral blood CD4+ T lymphocytopenia.

ESOPHAGITIS  


Bacterial esophagitis associated with CD4+ T-lymphocytopenia without HIV infection. Possible role of corticosteroid treatment.

Richert SM, Orchard JL.

Department of Medicine and Gastroenterology, Mercy Hospital, Pittsburgh, Pennsylvania 15219-5166.

Dig Dis Sci 1995 Jan;40(1):183-5 Abstract quote

Although infectious esophagitis is usually due to infection with Candida, herpes virus, or cytomegalovirus, bacterial esophagitis is occasionally observed. Recently, patients have been reported with CD4+ T-lymphocytopenia without HIV infection. Bacterial esophagitis per se has not been reported in these patients.

We report the case of an 80-year-old patient admitted with a COPD exacerbation after being on chronic steroids. The patient developed esophageal symptoms and was found to have bacterial esophagitis by biopsy. Her CD4+ counts were found to be low, but she denied HIV risk factors and HIV testing was negative. Her CD4+ counts rose into the normal range as her steroids were tapered, and her esophagitis improved on antibiotics.

This case is reported to alert physicians to the possible association of bacterial esophagitis with CD4+ T-lymphocytopenia without HIV infection and to discuss the possible etiological role of corticosteroid treatment.

HEMOPHILIA  


Idiopathic CD4+ T-lymphocytopenia in HIV seronegative men with hemophilia and sex partners of HIV seropositive men. Multicenter Hemophilia Cohort Study.

O'Brien TR, Diamondstone L, Fried MW, Aledort LM, Eichinger S, Eyster ME, Hilgartner MW, White G, Di Bisceglie AM, Goedert JJ.

Viral Epidemiology Branch, National Cancer Institute, Rockville, MD 20852, USA.

Am J Hematol 1995 Jul;49(3):201-6 Abstract quote

Persons with hemophilia or other HIV-1 risk factors may be more likely to have idiopathic CD4+ T-lymphocytopenia (ICL).

We determined the frequency of ICL in prospectively followed cohorts of HIV-1 seronegative hemophilic men and seronegative female sex partners of HIV-1 infected hemophilic men, and examined factors potentially associated with ICL. Seven of 304 (2.3%) seronegative hemophilic men and one of 160 (0.6%) female partners met the ICL definition, but the condition resolved for two of the men and for the sole female partner. All five men with persistent ICL had lymphocytopenia (< 1,200 total lymphocytes/microliters) and < 300 total CD4+ lymphocytes/microliters; only one had a low CD4+ percentage.

On the most recent measurement, 14.5% of the 304 seronegative hemophilic men had lymphocytopenia. Compared with matched hemophilic controls, men with persistent ICL more often had a history of liver disease (3/5 cases, 0/21 controls, P = 0.007) or splenomegaly (3/5 cases, 4/21 controls; P = 0.04), but not severe hemophilia, greater clotting factor concentrate exposure, high alanine aminotransferase levels, hepatitis B virus antigenemia, or detectable hepatitis C virus RNA in plasma. All five cases and 20/21 controls had antibodies to hepatitis C virus present in their serum.

In this cohort of hemophilic men, ICL was related to lymphocytopenia associated with liver disease rather than selective loss of CD4+ lymphocytes.

HUMAN PAPILLOMAVIRUS INFECTION  


CD4+ T lymphocytopenia with disseminated HPV.

Stetson CL, Rapini RP, Tyring SK, Kimbrough RC.

Department of Dermatology, Texas Tech University, Lubbock, Texas USA; Departments of Dermatology, Microbiology/Immunology and Internal Medicine, UTMB, Galveston, Texas, USA; and Department of Internal Medicine, Texas Tech University, Lubbock, Texas USA.

J Cutan Pathol 2002 Sep;29(8):502-5 Abstract quote

BACKGROUND: There have been several reports of HIV-negative patients with chronic idiopathic CD4+ T lymphocytopenia, the diagnostic criteria for which are: depressed numbers of circulating T lymphocytes (less than 300/ micro l or less than 20%) on more than one occasion; no laboratory evidence of HIV-1 or HIV-2 infection; and the absence of any defined immunodeficiency or therapy associated with depressed levels of CD4+ T lymphocytes.

METHODS: We report a patient with disseminated human papillomavirus infection associated with idiopathic CD4+ T-cell lymphocytopenia. A 50-year-old woman presented to the dermatology clinic with a 10-year history of widespread verrucae involving the skin and the cervix.

RESULTS: Biopsy from the arm revealed a common wart. PCR analysis performed from the paraffin-embedded block was strongly positive for HPV type 2. Other HPV types (including EV-associated HPV 5, 8, 14, 15, 17) were not found. Further laboratory work up revealed T-cell lymphocytopenia, with an absolute CD4 count of 21. HIV tests were repeatedly negative. She was treated with interferon A 8 million units SQ three times per week with partial improvement. The patient underwent a hysterectomy for cervical dysplasia and a vulvectomy for vulvar intraepithelial neoplasia. She developed small-cell lung carcinoma and died.

CONCLUSIONS: The diagnosis of idiopathic CD4+ T-cell lymphocytopenia should be considered in any patient with widespread viral, fungal, or mycobacterial infection whose HIV test is negative, and appropriate evaluation of the absolute CD4+ counts should be performed.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY  


Progressive multifocal leukoencephalopathy and idiopathic CD4+lymphocytopenia: a case report and review of reported cases.

Haider S, Nafziger D, Gutierrez JA, Brar I, Mateo N, Fogle J.

Division of Infectious Diseases, Henry Ford Hospital, Detroit, MI 48202, USA.

Clin Infect Dis 2000 Oct;31(4):E20-2 Abstract quote

Progressive multifocal leukoencephalopathy (PML) is a well recognized demyelinating neurological disorder caused by JC virus. Idiopathic CD4(+) lymphocytopenia (ICL) is a syndrome first described by the Centers for Disease Control and Prevention as a CD4(+) count <300 cells/mm(3) or a CD4(+) count that is <20% of the total T cell count on 2 occasions, with no evidence of human immunodeficiency virus (HIV) infection on testing, and absence of any defined immunodeficiency or therapy that depresses the levels of CD4(+) T cells.

To the best of our knowledge, this is the third reported case of PML and ICL, and also the first reported case of the use of cidofovir to treat PML in a patient not infected with human immunodeficiency virus.

SJOGREN'S SYNDROME  


CD4+ T-lymphocytopenia without HIV infection: increased prevalence among patients with primary Sjogren's syndrome.

Kirtava Z, Blomberg J, Bredberg A, Henriksson G, Jacobsson L, Manthorpe R.

Sjogren's Syndrome Research Centre, Department of Rheumatology, Malmo University Hospital, Sweden.

Clin Exp Rheumatol 1995 Sep-Oct;13(5):609-16 Abstract quote

OBJECTIVE. Primary Sjogren's syndrome (1 degree SS) is an autoimmune disease, usually accompanied by manifest immune hyperactivity. In some cases the disease converts to malignant neoplasia. On the other hand, there are clinical similarities to HIV infection. Since the rare phenomenon of persistent depletion of CD4+ T-lymphocytes in peripheral blood without HIV infection was recently defined as idiopathic CD4+ T-lymphocytopenia (ICL), we have used the ICL criteria to investigate the prevalence of this phenomenon among 1 degree SS patients.

METHODS. During the period 1988-94, 115 caucasian patients (10 males), mean age 57.8 (range 19-82) years, with 1 degree SS were prospectively studied. Lymphocyte subsets were investigated by means of monoclonal antibodies and flow cytometry. For the detection of HIV and HTLV antibodies, we used an enzyme immunoassay (for HIV-1 and HIV-2), Western blot techniques (HIV-1, HIV-2, HTLV-I and HTLV-II), and the polymerase chain reaction procedure (HIV-1, HTLV-I and HTLV-II). HIV antigens were tested for with the HIV-1 p-24 Ag test.

RESULTS. Six patients with 1 degree SS fulfilled the criteria for ICL. While the clinical condition of 5 of those six patients remained stable, one patient developed malignant lymphoma three years after her disease was classified as a case of ICL. The prevalence of ICL among our 115 patients with 1 degree SS was 5.2%, which is significantly higher than the rates reported for any other patient or population group. We have estimated the relative risk of ICL in 1 degree SS patients to vary from 3.4 to 6,000 (P values of 0.0001-0.025).

CONCLUSION. We suggest that subjects with ICL should be carefully examined for 1 degree SS and, if its presence is confirmed, that they should be followed with regard to the possible complications of this disease, including the development of malignant lymphoma.

SKIN CANCER  


Idiopathic CD4+ T-cell lymphocytopenia with verrucae, basal cell carcinomas, and chronic tinea corporis infection.

Ohashi DK, Crane JS, Spira TJ, Courrege ML.

Campbell University School of Pharmacy.

J Am Acad Dermatol 1994 Nov;31(5 Pt 2):889-91 Abstract quote

Idiopathic CD4+ T lymphocytopenia should be considered in HIV-negative patients with skin lesions commonly associated with HIV infection. Patients with idiopathic CD4+ T lymphocytopenia are presumably rare, often have dermatologic lesions, always have low CD4+ T lymphocyte counts, and lack all evidence of HIV-1 infection.

We describe a young man with verrucae, basal cell carcinomas, chronic tinea corporis, and laboratory evidence supporting a diagnosis of idiopathic CD4+ T lymphocytopenia.

SKIN RASH  

Idiopathic CD4+ lymphocytopenia associated with chronic pruritic papules.

Wakeel RA, Urbaniak SJ, Armstrong SS, Sewell HF, Herriot R, Kernohan N, White MI.

Department of Dermatology, Aberdeen Royal Hospitals NHS Trust, U.K.

Br J Dermatol 1994 Sep;131(3):371-5 Abstract quote

This is a case report and family study of a 65-year-old man with chronic prurigo lesions, in whom we demonstrated a selective deficiency of circulating T-helper/inducer lymphocytes (CD4+), in the absence of any apparent predisposing disease.

He is seronegative for human immunodeficiency virus (HIV types 1 and 2) and human T-cell lymphotropic virus (HTLV-I and HTLV-II), and fulfils the criteria for the syndrome of idiopathic CD4+ T lymphocytopenia. He has an atopic diathesis, has had a severe adult chickenpox infection, chronic staphylococcal infections, tinea pedis and recalcitrant warts. He has also suffered from respiratory infections, for which no specific aetiological agent has been identified.

His peripheral total lymphocyte count has been persistently abnormal since it was first measured in 1969. He has a marked CD4+ T-cell lymphocytopenia. His son, who does not have any skin disorder, has a low CD4+ T-cell count.

TUBERCULOSIS  

 

CD4+ T-lymphocytopenia in severe pulmonary tuberculosis without evidence of human immunodeficiency virus infection.

Pilheu JA, De Salvo MC, Gonzalez J, Rey D, Elias MC, Ruppi MC.

Phthisiopulmonology Division, Dr. Enrique Tornu Hospital, Buenos Aires, Argentina.

Int J Tuberc Lung Dis 1997 Oct;1(5):422-6 Abstract quote

SETTING: A large public hospital in Buenos Aires, Argentina.

OBJECTIVE: To determine the number of blood CD4 and CD8 T-lymphocytes in male human immunodeficiency virus (HIV) negative patients with severe pulmonary tuberculosis.

DESIGN: Seventeen patients with severe pulmonary tuberculosis (SPT), with a mean age of 44.1 years, all HIV negative, had on admission lost 20% or more of their normal weight. Ten male HIV negative pulmonary tuberculosis patients (PT), with a mean age of 25.2 years, in good general condition, acted as a control group. Patients from both groups had a blood CD4/CD8 count before treatment.

RESULTS: In the SPT patients, the CD4/CD8 count before treatment yielded a mean of 341.25 +/- 142.73/ mm3 for CD4 and 259.33 +/- 100.89/mm3 for CD8. Three patients died a few weeks after starting treatment; on admission they had 180,220 and 280 CD4/ mm3, respectively. Patients in good general condition yielded 721.40 +/- 272.20 for CD4 (P < 0.01, t = 4.216) and 416.67 for CD8. At the same time, five normal volunteers, with a mean age of 35.60 +/- 10.45 years, had mean CD4 and CD8 counts of 906 +/- 75.37 and 360 +/- 190.79, respectively.

CONCLUSION: Based on the findings of this study, we feel that it is of value to measure the CD4 and CD8 T-lymphocyte counts in STP patients with a compromised general condition and with significant weight loss at the beginning of treatment. Those patients with a CD4 count of < 300/mm3 have a very poor prognosis and, in addition to the regular antituberculosis drugs, will require intensive care during the first weeks of treatment.

VULVAR INTRAEPITHELIAL NEOPLASIA  


Idiopathic CD4+ T-lymphocytopenia and recurrent vulvar intraepithelial neoplasia.

Park K, Monk BJ, Wilczynski S, Ito JI Jr, Vasilev SA.

Department of Gynecologic Oncology, City of Hope National Medical Center, Durate, California, USA.

Obstet Gynecol 1994 Oct;84(4 Pt 2):712-4 Abstract quote

BACKGROUND: CD4+ T-lymphocytopenia immunodeficiency without human immunodeficiency virus (HIV) infection has been reported recently. The association between immunodeficiency and anogenital neoplasia secondary to human papillomavirus infections is well documented. CASE: A woman with recurrent vulvar intraepithelial neoplasia (VIN) had idiopathic CD4+ T-lymphocytopenia without HIV infection.

CONCLUSION: Human papillomavirus-related VIN may be associated with idiopathic CD4+ T-lymphocytopenia.

 

PATHOGENESIS CHARACTERIZATION
APOPTOSIS  


Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia.

Laurence J, Mitra D, Steiner M, Lynch DH, Siegal FP, Staiano-Coico L.

Laboratory of AIDS Virus Research, Cornell University Medical College, New York, New York 10021, USA.

J Clin Invest 1996 Feb 1;97(3):672-80 Abstract quote

Progressive loss of CD4+ T lymphocytes, accompanied by opportunistic infections characteristic of the acquired immune deficiency syndrome, ahs been reported in the absence of any known etiology.

The pathogenesis of this syndrome, a subset of idiopathic CD4+ T lymphocytopenia (ICL), is uncertain. We report that CD4+ T cells from seven of eight ICL patients underwent accelerated programmed cell death, a process facilitated by T cell receptor cross-linking. Apoptosis was associated with enhanced expression of Fas and Fas ligand in unstimulated cell populations, and partially inhibited by soluble anti-Fas mAb. In addition, apoptosis was suppressed by aurintricarboxylic acid, an inhibitor of calcium-dependent endonucleases and proteases, in cells from four of seven patients, The in vivo significance of these findings was supported by three factors: the absence of accelerated apoptosis in persons with stable, physiologic CD4 lymphopenia without clinical immune deficiency; detection of serum antihistone H2B autoantibodies, one consequence of DNA fragmentation, in some patients; and its selectivity, with apoptosis limited to the CD4 population in some, and occurring among CD8+ T cells predominantly in those individuals with marked depletion of both CD4+ T lymphocytes linked to clinical immune suppression have evidence for accelerated T cell apoptosis in vitro that may be pathophysiologic and amenable to therapy with apoptosis inhibitors.


Overexpression of Fas/CD95 and Fas-induced apoptosis in a patient with idiopathic CD4+ T lymphocytopenia.

Roger PM, Bernard-Pomier G, Counillon E, Breittmayer JP, Bernard A, Dellamonica P.

Service des Maladies Infectieuses et Tropicales, Hopital de l'Archet, Nice, France.

Clin Infect Dis 1999 May;28(5):1012-6 Abstract quote

The mechanisms of apoptosis have become better understood, in part with the discovery of Fas/CD95.

We report the case of a patient characterized by a decreased CD4+ T cell count and an overexpression of Fas/CD95 resulting in apoptosis. A 54-year-old man presented with disseminated Mycobacterium xenopi infection. Analysis showed CD4+ T lymphopenia. Tests for human immunodeficiency virus (HIV) types 1 and 2 were negative. We compared the patient with eight healthy controls and five HIV-infected patients in terms of the expression of Fas/CD95 and Fas-mediated apoptosis of peripheral T lymphocytes. The percent of CD95+ cells in lymphocytes was 98% for the patient, and the mean percent of CD95+ cells in lymphocytes +/- SD for HIV-infected patients and healthy controls was 75% +/- 16% and 36% +/- 26%, respectively. The patient had a high level of spontaneous apoptosis, and apoptotic cells were all identified as being CD4+ T cells.

Monoclonal antibodies to CD95 dramatically increased apoptosis of CD4+ T cells exclusively. CD4+ T lymphopenia observed in our patient correlated with an overexpression of Fas together with spontaneous and Fas-induced apoptosis.

p56Lck ACTIVITY  


Defective p56Lck activity in T cells from an adult patient with idiopathic CD4+ lymphocytopenia.

Hubert P, Bergeron F, Ferreira V, Seligmann M, Oksenhendler E, Debre P, Autran B.

Laboratoire d'Immunologie Cellulaire, CNRS UMR 7627, CHU Pitie-Salpetriere, 83 Boulevard de l'Hopital, 75651 Paris Cedex 13, France.

Int Immunol 2000 Apr;12(4):449-57 Abstract quote

Idiopathic CD4(+) lymphocytopenia (ICL) is defined by a stable loss of CD4(+) T cells in the absence of any known cause of immune deficiency. This syndrome is still of undetermined origin. It affects adult patients, some of them displaying opportunistic infections similar to HIV-infected subjects. The hypothesis that the cellular immune defect may be due to biochemical failures of the CD3-TCR pathway is investigated here in a patient associating a severe selective CD4(+) lymphocytopenia with an increased CD8(+) T cell count discovered in the course of a cryptococcal meningitidis. A 40% reduction of T cell proliferation to CD3-TCR stimulation is observed only in the CD4(+) subpopulation. The early CD3-induced protein tyrosine phosphorylations are conserved in both CD4(+) and CD8(+) subsets, and the levels of the T cell protein tyrosine kinases p56(Lck), p59(Fyn) and ZAP-70 are normal.

However, we find a 50% reduction of p56(Lck) kinase activity in the patient's T cells compared to a healthy control donor. p59(Fyn) activity does not appear to be altered. Nevertheless, we do not find any genetic abnormality of p56(Lck). These results thus suggest that a defect of an unknown protein regulating p56(Lck) activity takes place in this patient's T cells.

Taken together, these findings reveal p56(Lck) alteration in ICL and confirm the critical role of this kinase in the maintenance of the peripheral CD4(+) T cell subpopulation.

 

LABORATORY/RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  
LABORATORY MARKERS  
BLOOD SCREENING  

Screening of blood donors for idiopathic CD4+ T-lymphocytopenia.

Busch MP, Valinsky JE, Paglieroni T, Prince HE, Crutcher GJ, Gjerset GF, Operskalski EA, Charlebois E, Bianco C, Holland PV, et al.

Irwin Memorial Blood Centers, San Francisco, California.

Transfusion 1994 Mar;34(3):192-7 Abstract quote

BACKGROUND: The recent recognition of idiopathic CD4+ T-lymphocytopenia (ICL) had led to concern that an unknown immunodeficiency virus may be transmissible by transfusion.

STUDY DESIGN AND METHODS: To evaluate the prevalence and significance of low CD4+ values among blood donors, CD4+ data on 2030 blood donors who were negative for antibody to human immunodeficiency virus type 1 (HIV-1) were compiled. Those with CD4+ values below ICL cutoffs (< 300 CD4+ T cells/microL, or < 20% CD4+ T cells) were recalled for follow-up investigations. Serial CD4+ data on 55 homosexual men who seroconverted during prospective follow-up and data on 139 anti-HIV-1-positive blood donors initially evaluated in 1986 were reviewed as well.

RESULTS: Five seronegative donors (0.25%) had absolute CD4+ counts < 300 cells per microL and/or < 20 percent. On follow-up, all five donors had immunologic findings within normal ranges, lacked HIV risk factors, and tested negative for HIV types 1 and 2 and human T-lymphotropic virus type I and II infections by antibody and polymerase chain reaction assays. Four of five donors reported transient illness shortly after their low CD4+ count donations. The median interval from HIV-1 seroconversion to an initial CD4+ value below ICL CD4+ cutoffs was 63 months for infected homosexual men. Of 139 HIV-1-infected blood donors studied 1 to 2 years after seropositive donations, 34 (24%) had CD4+ counts < 300 cells per microL and/or < 20 percent.

CONCLUSION: Low CD4+ counts are rare among anti-HIV-1-negative volunteer blood donors and are generally associated with transient illnesses. If any unknown virus progresses similarly to HIV-1, CD4+ count donor screening would be a poor surrogate for its detection.

LYMPHOCYTE SUBSETS  

Lymphocyte subset diversity in idiopathic CD4+ T lymphocytopenia.

Tassinari P, Deibis L, Bianco N, Echeverria de Perez G.

Instituto de Immunologia, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela.

Clin Diagn Lab Immunol 1996 Sep;3(5):611-3 Abstract quote

The clinical and public health importance of CD4+ T lymphocytopenia without human immunodeficiency virus infection is still unclear. We describe herein two new human immunodeficiency virus-negative patients with low numbers of peripheral CD4+ T cells and opportunistic infections (cerebral toxoplasmosis and tuberculosis plus extrapulmonary histoplasmosis).

The low numbers of CD4+ CD29+ memory cells, the high percentage of gamma delta T-cell receptor cells, and the recovery of CD4+ cells after treatment were remarkable.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  



Unexplained opportunistic infections and CD4+ T-lymphocytopenia without HIV infection. An investigation of cases in the United States. The Centers for Disease Control Idiopathic CD4+ T-lymphocytopenia Task Force.

Smith DK, Neal JJ, Holmberg SD.

Division of HIV/AIDS, Centers for Disease Control and Prevention, Atlanta, GA 30333.

N Engl J Med 1993 Feb 11;328(6):373-9 Abstract quote

BACKGROUND. The clinical and public health importance of recent reports of patients with CD4+ T-lymphocytopenia without human immunodeficiency virus (HIV) infection is unclear. We conducted investigations to determine the demographic, clinical, and immunologic features of patients with idiopathic CD4+ T-lymphocytopenia; whether the syndrome is epidemic or transmissible; and the possible causes.

METHODS. We reviewed 230,179 cases in the Centers for Disease Control and Prevention (CDC) AIDS Reporting System and performed interviews, medical-record reviews, and laboratory analyses of blood specimens from adults and adolescents who met the CDC case definition of idiopathic CD4+ T-lymphocytopenia (< 300 CD4+ cells per cubic millimeter or a CD4+ cell count < 20 percent of total T cells on two occasions and no evidence of infection on HIV testing), their sexual contacts, household contacts, and persons who had donated blood to them.

RESULTS. We interviewed 31 of the 47 patients identified with idiopathic CD4+ T-lymphocytopenia and 23 of their contacts. There were 29 male and 18 female patients, with a mean age of 43 years (range, 17 to 78); 39 were white, 4 were Asian, 2 were Hispanic, and 2 were black. Eighteen patients (38 percent) had one or more risk factors for HIV infection: seven had hemophilia, six had engaged in homosexual sex, six had received blood transfusions, and two had had heterosexual sex partners who were at risk for HIV infection. The other 29 patients (62 percent) had no identified risk factors for HIV infection. Nineteen persons (40 percent) had AIDS-defining illnesses (18 had opportunistic infections), 25 (53 percent) had conditions that were not AIDS-defining, and 3 (6 percent) were asymptomatic. We tested blood from 28 patients: 8 (29 percent) were found to have CD4+ T-lymphocyte counts of less than 300 cells per cubic millimeter, and 6 had CD8+ T-lymphocytopenia (< 250 cells per cubic millimeter). Ten sex partners, three household contacts, and four children of the patients, as well as six persons who had donated blood to the patients, were immunologically and clinically normal.

CONCLUSIONS. This investigation of patients with idiopathic CD4+ T-lymphocytopenia and unexplained opportunistic infections indicates that the disorder is rare and represents various clinical and immunologic states. The investigation of contacts revealed no evidence of a new transmissible agent that causes lymphocytopenia.



Idiopathic CD4+ T-lymphocytopenia--immunodeficiency without evidence of HIV infection.

Ho DD, Cao Y, Zhu T, Farthing C, Wang N, Gu G, Schooley RT, Daar ES.

Aaron Diamond AIDS Research Center, New York.

N Engl J Med 1993 Feb 11;328(6):380-5 Abstract quote

BACKGROUND. The human immunodeficiency virus (HIV), the etiologic agent of the acquired immunodeficiency syndrome (AIDS), infects and depletes CD4+ T lymphocytes. Recently, patients have been described with profound CD4+ T-lymphocytopenia but without evident HIV infection, a condition now termed idiopathic CD4+ T-lymphocytopenia, and a national surveillance network has been set up to investigate such cases.

METHODS. We studied 12 patients with CD4+ T-lymphocytopenia who were referred to us from three U.S. cities. Blood samples were tested for HIV with specific antibody assays, viral cultures, and polymerase-chain-reaction (PCR) techniques.

RESULTS. The patients (10 men and 2 women) ranged in age from 30 to 69 years. Eight had risk factors for HIV infection. The clinical manifestations were heterogeneous: five patients had opportunistic infections, five had syndromes of unknown cause, and two had no symptoms. Two patients died from acute complications of their immunodeficiency. The patients' lowest CD4+ lymphocyte counts ranged from 3 to 308 per cubic millimeter (mean, 149). Three patients had complete or partial spontaneous reversal of the CD4+ T-lymphocytopenia. Concomitant CD8+ T-lymphocytopenia was noted in three patients, and abnormal immunoglobulin levels were found in five. Multiple virologic studies by serologic testing, culture, and PCR were completely negative for HIV in all patients.

CONCLUSIONS. Our 12 patients with idiopathic CD4+ T-lymphocytopenia appear to be epidemiologically, clinically, and immunologically heterogeneous. It is unclear whether this syndrome is new, transmissible, or acquired. Many of the clinical and immunologic features are distinct from those found in AIDS, and our extensive virologic studies found no evidence of HIV infection. The cause of this condition remains unknown.


Idiopathic CD4+ T-lymphocytopenia--an analysis of five patients with unexplained opportunistic infections.

Spira TJ, Jones BM, Nicholson JK, Lal RB, Rowe T, Mawle AC, Lauter CB, Shulman JA, Monson RA.

Immunology Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333.


N Engl J Med 1993 Feb 11;328(6):386-92 Abstract quote

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.



Idiopathic CD4+ T-lymphocytopenia--four patients with opportunistic infections and no evidence of HIV infection.

Duncan RA, von Reyn CF, Alliegro GM, Toossi Z, Sugar AM, Levitz SM.

Evans Memorial Department of Clinical Research, Boston City Hospital, MA 02118.

N Engl J Med 1993 Feb 11;328(6):393-8 Abstract quote

BACKGROUND AND METHODS. We describe four patients without major risk factors for human immunodeficiency virus (HIV) infection, each of whom presented with severe opportunistic infections and was found to have idiopathic CD4+ T-lymphocytopenia. We performed assays to detect the presence of retroviruses and undertook immunophenotyping of subgroups of peripheral-blood lymphocytes.

RESULTS. The opportunistic infections at presentation included Pneumocystis carinii pneumonia, cryptococcal meningitis (two patients, one with concurrent pulmonary tuberculosis), and histoplasma-induced brain abscess. During 10 to 68 months of observation, none of the four patients had evidence of infection with HIV type 1 or 2 or human T-cell lymphotropic virus type I or II on the basis of epidemiologic, serologic, or polymerase-chain-reaction studies or culture, nor was there any detectable reverse transcriptase activity. Although all the patients had severe, persistent CD4+ T-lymphocytopenia (range, 12 to 293 cells per cubic millimeter), the CD4+ cell count progressively declined in only one and was accompanied by multiple opportunistic infections. All four patients had significantly reduced numbers of circulating CD8+ T cells, natural killer cells, or B cells (or all three).

CONCLUSIONS. These four patients had idiopathic CD4+ T-lymphocytopenia with opportunistic infections but no evidence of HIV infection. Instead of the progressive, selective depletion of CD4+ T cells characteristic of HIV infection, some patients with idiopathic immunodeficiency have stable CD4+ cell counts accompanied by reductions in the levels of several other lymphocyte subgroups.

VARIANTS  
ORAL  


Oral manifestations in a patient with idiopathic CD4+ lymphocytopenia.

Reichart PA, Pohle HD, Gelderblom HR.

Abteilung fur Oralchirurgie und Zahnarztliche Rontgenologie, Charite, Medizinische Fakultat der Humboldt Universitat zu Berlin, Germany.

t J Oral Maxillofac Surg 1996 Aug;25(4):290-2 Abstract quote

A 56-year-old patient with idiopathic CD4+ lymphocytopenia (ICL) is described. In addition to a complex medical history and clinical course, he presented with oral manifestations including episodic erythematous candidiasis, persistent angular cheilitis, lingua exfoliativa areata, and teleangiectasia of facial skin and buccal mucosa.

Light microscopy and transmission electron microscopy (TEM) revealed vascular structures similar to findings in clinically uninvolved oral mucosa of patients with HIV infection. Further observations of patients with ICL are warranted to clarify the significance of oral findings made in the present case.

PEDIATRIC  


CD4+ T lymphocytopenia in children: lack of evidence for a new acquired immunodeficiency syndrome agent.

Lobato MN, Spira TJ, Rogers MF.

Division of HIV/AIDS, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health States Department of Health and Human Services, Atlanta, GA 30333, USA.

Pediatr Infect Dis J 1995 Jun;14(6):527-35 Abstract quote

We investigated children with CD4+ T lymphocytopenia to determine the magnitude and public health impact of this condition and to investigate possible causes. Children < 13 years old with CD4+ T lymphocyte counts below age-adjusted cutoffs (age < 24 months, 1000 cells/microliters; age > or = 24 months, 300 cells/microliters) or < 20% on 2 separate measurements were considered to have CD4+ T lymphocytopenia.

We solicited information from clinicians and public health departments on these children and their families and collected blood for immunologic and retroviral testing. We identified 18 children (10 boys; 14 African-Americans) with a median age of 10 months at their first low CD4+ T lymphocyte measurement. Three children had had opportunistic infections and two still had low CD4+ T lymphocyte counts 5 and 7 years later. Of the 11 children born to human immunodeficiency virus (HIV)-infected mothers 7 were asymptomatic. Specimens from all children were negative for HIV and human T lymphotropic virus antibodies and negative for HIV by culture or polymerase chain reaction. Among 12 families interviewed no other HIV-seronegative family or household member had illnesses suggestive of immunosuppression.

We conclude that negative retroviral tests and lack of illness among their family members do not support the hypothesis that a retrovirus causes CD4+ T lymphocytopenia among these children.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
COMMON VARIABLE IMMUNODEFICIENCY  

CD4+ lymphocytopenia due to common variable immunodeficiency mimicking AIDS.

Kaczmarski RS, Webster AD, Moxham J, Davison F, Sutherland S, Mufti GJ.

Department of Haematological Medicine, King's College School of Medicine and Dentistry, London.

J Clin Pathol 1994 Apr;47(4):364-6 Abstract quote

There are an increasing number of published reports of patients with acquired immunodeficiency without evidence of HIV infection, who have been labelled as having "idiopathic CD4+ lymphocytopenia".

The case is reported here of a young man who presented with Pneumocystis carinii pneumonia (PCP), CD4+ lymphopenia, and hypogammaglobulinaemia attributable to common variable immunodeficiency (CVID). The presentation of this condition, with many of the clinical and laboratory features of AIDS, highlights CVID as a diagnosis to be considered in the differential diagnosis of CD4+ lymphocytopenia.

UREMIA  

Profound reversible CD4+ T lymphocytopenia in a severely uremic patient.

Polsky FI, Dannemann B, Hemmert WH.

Department of Internal Medicine, Utah Valley Regional Medical Center, Provo 84604.

Am J Kidney Dis 1994 Jul;24(1):89-91 Abstract quote

We report a human immunodeficiency virus antibody-negative, profoundly uremic patient who presented with a CD4+ T lymphocyte count of 133/mm3, a CD8+ T lymphocyte count of 77/mm3, and a CD3+ T lymphocyte count of 259/mm3.

These values decrease significantly below reported levels in other lymphopenic uremic patients. High-efficiency chronic hemodialysis resulted in correction of these cytopenias to a normal range within 12 weeks.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSTIC FACTORS  
TREATMENT  
IL-2  


Treatment of idiopathic CD4 T lymphocytopenia with IL-2.

Cunningham-Rundles C, Murray HW, Smith JP.

Department of Medicine, Mount Sinai School of Medicine, Division of Clinical Immunology, New York City, NY 10029, USA

Clin Exp Immunol 1999 May;116(2):322-5 Abstract quote

Idiopathic CD4 T lymphocytopenia (ICL) is an unusual immune defect in which there is an unexplained deficit of CD4 T cells, leading to fungal, parasitic or other serious opportunistic infections.

Current treatment efforts are directed at eliminating infections. Here we describe the use of a novel treatment, subcutaneous polyethylene glycol (PEG)-IL-2 injections, in a woman with this disorder, who had chronic severe mycobacterial disease which led to repeated hospitalizations, and advancing respiratory insufficiency.

For this patient, PEG-IL-2, 50 000 U/m2, has been given by weekly subcutaneous injections for 5.5 years. This treatment has resulted in marked (and still continuing) long-term immunological improvement with normalized T cell functions and increased CD4 cell numbers. She has had substantial clinical improvement with clearing of mycobacterial disease, reducing hospitalizations and improved lung functions. The improvement seen in this patient suggests that low-dose IL-2 is a safe and practical therapy, which might be useful in other subjects with this potentially serious immune defect.

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Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.


Commonly Used Terms

Disorders of White Blood Cells


Last Updated 10/7/2002


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