Mysterious White Blood Cell Disorder Not Just 'AIDS Without HIV'

Decades after its discovery, the emerging view of idiopathic CD4 lymphocytopenia (ICL) -- popularly dubbed "AIDS without HIV" -- is that it may be more homogeneous than originally thought, despite patients being prone to various cancers and opportunistic infections.

In 91 individuals with this disorder of the immune system, the most common opportunistic infections contracted over 374 person-years of follow-up were related to human papillomavirus (29%), cryptococcosis (24%), molluscum contagiosum (9%), and finally, nontuberculous mycobacterial diseases (5%), reported Andrea Lisco, MD, PhD, of the National Institute of Allergy and Infectious Diseases of the NIH, and co-authors.

Clinical outcomes consistently hinged on CD4+ T-cell counts in these patients, for whom very low cell counts (<100 cells per cubic millimeter) were associated with:

• Increased risk of developing an opportunistic infection (OR 5.3, 95% CI 2.8-10.7)
• Higher risk for developing an invasive cancer (OR 2.1, 95% CI 1.1-4.3)
• Lower likelihood of autoimmunity (OR 0.5, 95% CI 0.2-0.9)

"Although ICL has been consistently described as a heterogenous disorder, we found a rather unifying pattern of clinical presentations of HPV-related diseases, cryptococcosis, cancers, and autoimmunity, a compilation that should trigger an articulated clinical, immunologic, and genetic evaluation," Lisco's group wrote in the New England Journal of Medicine.

"We suspect that ICL may be more homogeneous than originally thought, because our study patients had an overall stable or modestly up-trending T-cell trajectory without a profound effect on mortality (very different from the trajectory in patients with HIV infection) and an apparent lack of a unifying monogenic cause," the authors suggested.

Study participants affected by opportunistic infections were subject to individualized approaches to antimicrobial prophylaxis. Additionally, primary and secondary cancer preventive strategies may be reasonable in the face of the excess cancer in these patients, according to Lisco and colleagues.

Researchers noted that ICL is a relatively rare disease, and its unexplained nature makes research and understanding it all the more difficult. In the over 30 years since the CDC first defined ILC, there is still no concrete explanation for lowered CD4+ T-cells for patients without a human immunodeficiency virus (HIV) diagnosis, nor is there any standard treatment outside antibiotics.

"The consensus had been that ICL represents a heterogeneous disorder and that widespread availability of genomic data would reveal novel mendelian genetic causes. However, the cause of ICL has remained elusive even in infants with lymphopenia that has been diagnosed by means of T-cell receptor excision circle screening, with only 10% currently receiving a specific genetic diagnosis," Lisco's team noted.

The study started out with 108 patients enrolled during an 11-year period. Excluding genetic and acquired causes of CD4 lymphopenia, investigators were left with 91 eligible adults with ICL (median age 48 years, 49% women, 95% white).

ICL was defined as a CD4+ T-cell count of <300 cells per cubic millimeter (or less than 20% of total T lymphocytes) at the screening visit and on at least two previous occasions at least 6 weeks apart in the absence of any disease or therapy that may cause lymphopenia. On average, the cohort had a CD4+ count of 80 cells per cubic millimeter.

At enrollment or during follow-up, 69% of the group experienced one or more infectious complications, and 58% experienced one or more opportunistic infections that were considered clinically significant.

Notably, the COVID-19 pandemic emerged towards the end of the study. By October 2021, 22 patients had received two doses of a SARS-CoV-2 mRNA vaccine, but 36% of them did not show detectable antibodies for the SARS-CoV-2 spike protein. The lack of serologic response was associated with a lower median CD4+ T-cell count at the time of immunization.

By May 2022, ten people had had SARS-CoV-2 infections; all had mild COVID illness that did not require hospitalization, oxygen supplementation, or leave any clinical sequelae.

Study data did not support ICL being tied to a short-term higher risk for death, though the authors cautioned that their sample was small and the follow-up relative short for such an analysis. Another limitation of the study was that the patient population was potentially subject to referral biases.

"Regardless, a national registry would greatly enhance the study of the clinical and epidemiologic features of ICL, including important morbidity and mortality data," Lisco and colleagues urged.

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