How immunodeficiency can lead to malignancy

Immunodeficiency, whether acquired in the case of human immunodeficiency virus (HIV) infection or congenital due to inborn errors of immunity (IEIs), presents clinically with not only infection and immune dysregulation but also increased risk of malignancy. The range of malignancies seen is relatively limited and attributable to the particular cellular and molecular defects in each disease. CD4+ T-cell lymphopenia in people living with HIV infection (PLWH) and certain IEIs drive the predisposition to aggressive B-cell non-Hodgkin lymphomas, including certain rare subtypes rarely seen in immunocompetent individuals. PLWH and IEI that lead to profound T-cell lymphopenia or dysfunction also are at risk of cancers related to oncogenic viruses such as Kaposi sarcoma herpesvirus, Epstein-Barr virus, human papillomavirus (HPV), and Merkel cell polyomavirus. IEIs that affect natural killer cell development and/or function heavily predispose to HPV-associated epithelial cancers. Defects in DNA repair pathways compromise T- and B-lymphocyte development during immune receptor rearrangement in addition to affecting hematopoietic and epithelial DNA damage responses, resulting in both hematologic and nonhematologic cancers. Treatment of cancers in immunodeficient individuals should be curative in intent and pursued in close consultation with disease experts in immunology and infectious disease.

Neonatal abstinence syndrome is a potential cause of low TREC copy number

Severe combined immunodeficiency (SCID) is a rare genetic condition characterized by significant T cell lymphopenia and impaired T cell function. Many jurisdictions use the quantitation of T cell receptor excision circles (TRECs) to screen for SCID in newborns, but false positives may be seen in several conditions. We report 3 newborns with neonatal abstinence syndrome who presented with decreased TREC copy number.

996. CD4+ T-Cell Lymphopenia Associated with Frequent Plateletpheresis in Healthy Donors

Background Frequent plateletpheresis using the Time Accel leukoreduction system chamber may result in lymphopenia in healthy donors, with increased donation in the previous year associated with CD4+ T-cell count of less than 200 cells/µL. However, this finding has not been replicated and the clinical significance of plateletpheresis-associated lymphopenia remains unclear. Methods A prospective observational study of healthy plateletpheresis donors aged 18 or older who donated at least once in the previous 365 days was conducted at the Kraft Blood Center at Brigham and Women’s Hospital/Dana Farber Cancer Institute, where the Time Accel system is used exclusively. Blood was drawn immediately before plateletpheresis or at least 2 weeks after the last donation to assess for total lymphocyte and CD4+ T-cell counts. Results A total of 86 participants were enrolled: 23 had 1-5 donations, 36 had 6-19 donations, and 27 had 20-24 donations within the previous 365 days (Figure 1). For the low-, medium-, and high-frequency donation groups, the median age was 53 years (IQR 43-64), 61 years (IQR 53-68), and 61 years (IQR 55-65), respectively. The median total lymphocyte count was 1.5 (IQR 1.3-1.9), 1.2 (IQR 0.9-1.5), 0.8 (IQR 0.6-0.9) 103 cells/µL, and the median CD4+ T-cell count was 648 (IQR 531-843), 525 (IQR 348-698), and 220 (IQR 184-347) cells/µL. CD4+ T-cell counts were < 200 cells/µL in 0/23 (0%), 3/36 (8%), and 9/27 (33%) participants across the three groups. Total lymphocyte and CD4+ T-cell counts were inversely correlated with the number of platelet donations in the prior 365 days, R2 = 0.384 (Fig 2) and 0.402 (Fig 3) respectively. Conclusion Frequent plateletpheresis using Time Accel leukoreduction system chamber is associated with CD4+ T-cell lymphopenia, with counts below 200 cells/µL seen in one third of those who donated 20-24 times in the previous year. Vaccine immunogenicity studies are ongoing to evaluate the clinical significance of this finding. Disclosures Stephen R. Walsh, MDCM, Janssen Vaccines (Scientific Research Study Investigator)Regeneron (Scientific Research Study Investigator)Sanofi Pasteur (Scientific Research Study Investigator)

SARS-CoV-2 may affect the immune response via direct inhibition of T cell receptor: Mechanistic hypothesis and rationale

During co-evolution with their hosts, many viruses have evolved a membrane fusion mechanism to facilitate host cell entry. Examples include human immunodeficiency virus type 1 (HIV-1) and severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2). These viruses can also infect immune cells (e.g., T cells), providing one of the possible mechanisms for the T cell lymphopenia observed in patients with these infections. Previously, we hypothesized and confirmed in vivo that like HIV-1, SARS-CoV-1 can use its fusion domain not only to enter the T cell but also to directly inhibit T cell receptor signaling. Here, based on the analysis of available structural and clinical data, we hypothesize that SARS-CoV-2 may use a similar "disarm the alarm" strategy to suppress immune responses. We also discuss the implications of this hypothesis for better understanding coronavirus disease 2019 (COVID-19) pathology, developing effective COVID-19 vaccines and improving clinical outcomes for COVID-19 patients.

First Year of TREC-Based National SCID Screening in Sweden

Screening for severe combined immunodeficiency (SCID) was introduced into the Swedish newborn screening program in August 2019 and here we report the results of the first year. T cell receptor excision circles (TRECs), kappa-deleting element excision circles (KRECs), and actin beta (ACTB) levels were quantitated by multiplex qPCR from dried blood spots (DBS) of 115,786 newborns and children up to two years of age, as an approximation of the number of recently formed T and B cells and sample quality, respectively. Based on low TREC levels, 73 children were referred for clinical assessment which led to the diagnosis of T cell lymphopenia in 21 children. Of these, three were diagnosed with SCID. The screening performance for SCID as the outcome was sensitivity 100%, specificity 99.94%, positive predictive value (PPV) 4.11%, and negative predictive value (NPV) 100%. For the outcome T cell lymphopenia, PPV was 28.77%, and specificity was 99.95%. Based on the first year of screening, the incidence of SCID in the Swedish population was estimated to be 1:38,500 newborns.

A Rare Presentation of Cryptococcal Meningitis in a Treatment-Native Patient with Sarcoidosis

Cryptococcus neoformans is an encapsulated, yeast-like fungus that commonly lives in the environment due to soil contamination by the faeces of birds, especially pigeons. Cryptococcus is an opportunistic fungal infection frequently diagnosed in immunocompromised patients with HIV, steroid use, malignancy, history of organ transplantation, or, rarely, sarcoidosis. There have been only a few reports of cryptococcus infection in sarcoidosis patients who were not on steroid treatment. Here, we highlight the importance of considering opportunistic fungal infection in asymptomatic treatment-naive sarcoidosis patients. We present a patient with a history of asymptomatic, treatment-naive sarcoidosis who presented with headache and was diagnosed with cryptococcal meningitis in the presence of an idiopathic T-cell lymphopenia.