Management and outcome of COVID-19 in CTLA-4 insufficiency.

Despite the high incidence of COVID-19 worldwide, clinical experience with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in inborn errors of immunity remains limited. Recent studies have shown that patients with defects in type 1 interferon (IFN)-related pathways or those with autoantibodies against type 1 IFNs develop severe COVID-19. We reported the clinical course of 22 patients with CTLA-4 insufficiency and COVID-19 and retrospectively examined autoantibodies against type 1 IFNs at baseline. Data were obtained from the patient interviews and chart reviews. Screening for anti-IFN autoantibodies was performed using a multiplex particle-based assay. Student t test, Mann Whitney, analysis of variance, or χ2 tests were used where appropriate. Twenty-two patients aged from 8 months to 54 years, with genetically confirmed CLTA-4 insufficiency, developed COVID-19 from 2020 to 2022. The most common symptoms were fever, cough, and nasal congestion, and the median duration of illness was 7.5 days. Twenty patients (91%) developed mild COVID-19 and were treated as outpatients. Two patients were hospitalized because of COVID-19 pneumonia but did not require mechanical ventilation. Ten (45%) patients were vaccinated at the time of their first COVID-19 infection. Eleven patients received outpatient treatment with monoclonal antibodies against the SARS-CoV-2 spike protein. During the study period, 17 patients were vaccinated against SARS-CoV-2, with no severe vaccine-related adverse effects. Although median anti-S titers following vaccination or infection were lower in patients receiving immunoglobulin replacement therapy (IGRT) (349 IU/dL) than in those not receiving IGRT (2594 IU/dL; P = .15); 3 of 9 patients on IGRT developed titers >2000 IU/dL. All patients tested negative for autoantibodies against IFN-α, IFN-ß, and IFN-ω at baseline. Most patients with CTLA-4 insufficiency and COVID-19 had nonsevere disease, lacked autoantibodies against type 1 IFNs, and tolerated messenger RNA vaccines with few adverse effects. Whether our findings can be extrapolated to patients receiving CTLA-4-targeting checkpoint inhibitors requires further studies.

Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder.

BACKGROUNDCytotoxic T lymphocyte antigen 4 (CTLA4) is essential for immune homeostasis. Genetic mutations causing haploinsufficiency (CTLA4h) lead to a phenotypically heterogenous, immune-mediated disease that can include neuroinflammation. The neurological manifestations of CTLA4h are poorly characterized.METHODSWe performed an observational natural history study of 50 patients with CTLA4h who were followed at the NIH. We analyzed clinical, radiological, immunological, and histopathological data.RESULTSEvidence for neuroinflammation was observed in 32% (n = 16 of 50) of patients in this cohort by magnetic resonance imaging (MRI) and/or by cerebrospinal fluid analysis. Clinical symptoms were commonly absent or mild in severity, with headaches as the leading complaint (n = 13 of 16). The most striking findings were relapsing, large, contrast-enhancing focal lesions in the brain and spinal cord observed on MRI. We detected inflammation in the cerebrospinal fluid and leptomeninges before the parenchyma. Brain biopsies of inflammatory lesions from 10 patients showed perivascular and intraparenchymal mixed cellular infiltrates with little accompanying demyelination or neuronal injury.CONCLUSIONSNeuroinflammation due to CTLA4h is mediated primarily by an infiltrative process with a distinct and striking dissociation between clinical symptoms and radiological findings in the majority of patients.FUNDINGNIAID, NIH, Division of Intramural Research, NINDS, NIH, Division of Intramural Research, and the National Multiple Sclerosis Society-American Brain Foundation.TRIAL REGISTRATIONClinicalTrials.gov NCT00001355.

Complete Myeloperoxidase Deficiency: Beware the "False-Positive" Dihydrorhodamine Oxidation.

Myeloperoxidase deficiency is the most common inherited phagocyte disorder (1:2000) and causes an abnormal dihydrorhodamine oxidation test, which also is seen in chronic granulomatous disease. A patient with Candida meningitis and low dihydrorhodamine oxidation signal was diagnosed with chronic granulomatous disease but actually had compound heterozygous myeloperoxidase deficiency.

IL2RG reversion event in a common lymphoid progenitor leads to delayed diagnosis and milder phenotype.

Severe combined immunodeficiency (SCID) is most frequently caused by mutations in the cytokine receptor common gamma chain, CD132, encoded by the X-linked gene, IL2RG. Most patients present in the first year of life with failure to thrive, severe, opportunistic infections and absence of CD3+ T cells. We present a patient with pediatric illness and a diagnosis of combined variable immune deficiency (CVID) who was diagnosed at age 23 with an inherited IL2RG mutation causing loss of signal transduction through CD132. His peripheral blood included CD3/CD4 and CD3/CD8 positive cells as well as low levels of CD19+ B cells containing a reversion to the wildtype IL2RG allele. The reversion, which was not present at birth, may account for his mild phenotype and late diagnosis.

Common severe infections in chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades. METHODS: All patients had confirmed diagnoses of CGD, and genotype was determined where possible. Medical records were excerpted into a standard format. Microbiologic analyses were restricted to Staphylococcus, Burkholderia, Serratia, Nocardia, and Aspergillus. RESULTS: Aspergillus incidence was estimated at 2.6 cases per 100 patient-years; Burkholderia, 1.06 per 100 patient-years; Nocardia, 0.81 per 100 patient-years; Serratia, 0.98 per 100 patient-years, and severe Staphylococcus infection, 1.44 per 100 patient-years. Lung infection occurred in 87% of patients, whereas liver abscess occurred in 32%. Aspergillus incidence was 55% in the lower superoxide-producing quartiles (quartiles 1 and 2) but only 41% in the higher quartiles (rate ratio, <0.0001). Aspergillus and Serratia were somewhat more common in lower superoxide producing gp91phox deficiency. The median age at death has increased from 15.53 years before 1990 to 28.12 years in the last decade. Fungal infection carried a higher risk of mortality than bacterial infection and was the most common cause of death (55%). Gastrointestinal complications were not associated with either infection or mortality. CONCLUSIONS: Fungal infections remain a major determinant of survival in CGD. X-linked patients generally had more severe disease, and this was generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality.