Idiopathic CD4 Lymphocytopenia

By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: A study of 91 adults with idiopathic CD4 lymphocytopenia demonstrated increased risk of cancers and autoimmune disorders, as well as opportunistic infections.

SOURCE: Lisco A, Ortega-Villa AM, Mystakelis H, et al. Reappraisal of idiopathic CD4 lymphocytopenia at 30 years. N Engl J Med 2023;388:1680-1691.

Lisco and colleagues reviewed the experience with adults with idiopathic CD4 lymphocytopenia seen at the National Institutes of Health (NIH) Clinical Center from January 2009 through March 2020. Inclusion required the finding, at a screening visit and again at least six weeks later, of either a CD4+ T-cell count of < 300 cells/mm³ or < 20% of the total T-cell count. Extensive studies were performed to exclude alternative causes, and 17 subjects were excluded initially. Reasons for exclusion included the presence of common variable immunodeficiency, prior receipt of chemotherapy, autoimmune disease, and, in five subjects, inborn errors of immunity. Of the remaining total of 91 subjects, 80 remained in the study through March 2020.

The median age of the 91 patients (88% of whom were white) was 48 years and 49% were women. The median CD4+ and CD8+ T-cell counts at study entry were 80 cells/mm³ and 130 cells/mm³, respectively. In contrast, NK and B cell counts were similar to those in healthy adults. Over the period of observation, the average CD4+ T-cell count, rather dropping as feared, had a minimal increase by a factor of 1.044 each year, while the CD8+ T-cell count increased by a factor of 1.031 per year.

At least one infectious complication occurred in 69%, affecting 58 subjects at enrollment and five during follow-up. Severe human papillomavirus (HPV)-related skin or anogenital diseases were most frequent, occurring in 27 subjects. Cryptococcal infection occurred in 22 patients, 16 of whom had meningoencephalitis and eight patients had molluscum contagiosum. A wide variety of other infections occurred in one to three patients. These included disseminated nontuberculous mycobacterial (NTM) infection, disseminated histoplasmosis, progressive multifocal leukoencephalopathy, cytomegalovirus (CMV) disease, Pneumocystis jirovecii pneumonia (PJP), pulmonary coccidioidomycosis, and pulmonary aspergillosis.

Two-thirds received PJP prophylaxis, while 13% were given azithromycin to prevent NTM infection, and 8% received fluconazole prophylaxis.

Ten patients developed COVID-19, and in each case, the illness was mild and none were hospitalized. Eight of 22 (36%) failed to have a serological response to SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccines.

Cancer occurred in 13 of the patients. In addition to breast, prostate, and thyroid cancers, squamous cell cancers of lung, oral cavity or pharynx, and vulvovaginal occurred. Two patients had non-Hodgkin’s lymphoma and one had Kaposi’s sarcoma. A total of 44 autoimmune diseases were seen in 33 (36%) patients, and among these disorders were psoriasis, autoimmune hemolytic anemia, immune thrombocytopenic purpura, ulcerative colitis, thyroiditis, and lupus.

In comparison to those with a CD4+ T-cell count of 100-300 cells/mm³, those with a CD4+ T-cell count < 100 cells/mm³ had an increased risk of invasive cancer and of opportunistic infections but a reduced risk of autoimmunity.

COMMENTARY

In July 1992, at a time when the country was struggling to understand and manage acquired immunodeficiency syndrome (AIDS), a hallmark of which is loss of CD4+ T-cells, the Centers for Disease Control and Prevention reported five cases of CD4+ T-lymphocytopenia in patients who were not human immunodeficiency virus-infected.¹ I remember that this report, occurring in the midst of uncertainty at the time, created more uncertainty, was disturbing, and caused concern of another epidemic. While scattered reports have continued, there has been no new epidemic, but uncertainty remains because of a lack of understanding of the cause of this disorder. In the experience reported by Lisco and colleagues, despite extensive investigation, its cause remains unknown, although six of 80 subjects who underwent whole exome sequencing (n = 80) or targeted gene panel sequencing (n = 4) were found to have mutations associated with immunodeficiency. These then were excluded from the study.

The lack of severe disease in the 10 patients who developed COVID-19 is encouraging and occurred despite the frequent lack of response to SARS-CoV-2 vaccination. The latter would seem most likely to be due to diminished T-helper function.

The optimal long-term management, a proportion of whom remain indefinitely asymptomatic, remains a matter for discussion and currently should be individualized with dependence on the degree of lymphocytopenia. Patients in the NIH screening were commonly prescribed prophylaxis against PJP and, less often, prophylaxis against NTM or fungi. Regular screening for HPV-related malignancies of the oropharynx and anogenital regions is appropriate.

REFERENCE

Centers for Disease Control (CDC). Unexplained CD4+ T-lymphocyte depletion in persons without evident HIV infection — United States. MMWR Morb Mortal Wkly Rep 1992;41:541-545.