Germline mutations in CYBB, the human gene encoding the gp91phox subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This ‘experiment of nature’ indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.

Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

Highlights1. What is already known about this topic? SARS-CoV-2 causes asymptomatic or mild infection in about 80% of humans, while an excessive immune response has killed millions. Differential susceptibility and risk factors became a concern early in the pandemic. Several monogenic defects that involve innate viral sensors or affect interferon response pathways, as well as autoantibodies against type 1 interferons, have been identified in 14% of patients with life-threatening COVID-19. The impact of the novel betacoronavirus infection in patients with known inborn errors of immunity is less clear. Case series and reports from different countries have suggested a minor impact or even a potential protective effect of the IEI for some patients.2. What does this article add to our knowledge? We describe findings and outcomes of COVID-19 in 31 pediatric and adult patients with known IEI from Mexico, 84% of whom survived. Pediatric patients had a higher hospitalization rate. Inpatient mortality was 40%, and ICU mortality was 63%. Six patients died of secondary bacterial infection or uncontrolled systemic inflammation, but not from overwhelming viral infection. One patient with an autoinflammatory disorder under treatment with anakinra had a catastrophic clinical course. Eighty percent of patients received IVIG as part of their treatment for acute SARS-CoV-2 infection.3. How does this study impact current management guidelines? We recommend continued and/or high-dose IVIG in patients with known IEI seeking care for COVID-19. Patients with autoinflammatory disorders, especially those with inflammasome dysregulation, should probably take extreme measures to prevent exposure, while doctors taking care of SARS-CoV-2 infected patients with immune deficiencies must do everything they can to prevent secondary bacterial infections. The high survival of patients with COVID-19 in the context of inborn errors of immunity worldwide (over 80%) might be the result of patientphysician awareness and special care.

Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 ''agreed'' and 38 ''nonagreed'' statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID. (J Allergy Clin Immunol 2019;144:897-905.)

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder characterized by impaired immunity against intracellular pathogens, such as mycobacteria, attenuated Mycobacterium bovis -Bacillus Calmette–Guérin (BCG) vaccine strains, and environmental mycobacteria in otherwise healthy individuals. Retrospective study reviewed the clinical, immunological, and genetic characteristics of patients with MSMD in Mexico. Overall, 22 patients diagnosed with MSMD from 2006 to 2021 were enrolled: 14 males (64%) and eight females. After BCG vaccination, 12 patients (70%) developed BCG infection. Furthermore, 6 (22%) patients developed bacterial infections mainly caused by Salmonella , as what is described next in the text is fungal infections, particularly Histoplasma. Seven patients died of disseminated BCG disease. Thirteen different pathogenic variants were identified in IL12RB1 ( n = 13), IFNGR1 ( n = 3), and IFNGR2 ( n = 1) genes. Interleukin-12Rβ1 deficiency is the leading cause of MSMD in our cohort. Morbidity and mortality were primarily due to BCG infection. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-022-01357-8.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by increased susceptibility to bacteria and fungi since early in life, caused by mutations in any of the five genes coding for protein subunits in NADPH oxidase. X-linked variant CGD can be missed during routine evaluation or present later in life due to hypomorphic mutations and a residual superoxide production. The case of a 10-month-old boy who died of pneumonia is reported. The isolation of Burkholderia cepacia from his lung, together with a marginally low nitroblue tetrazolium reduction assay (NBT), made us suspect and pursue the molecular diagnosis of CGD. A postmortem genetic analysis finally demonstrated CGD caused by a hypomorphic missense mutation with normal gp91phox expression. In a patient being investigated for unusually severe or recurrent infection, a high index of suspicion of immunodeficiency must be maintained.

Mendelian susceptibility to mycobacterial disease (MSMD) is a heterogenous syndrome. The clinical characteristics include repetitive local infection and in some cases dissemination. In this work we analyzed a 5 years old boy with an uncharacterized mycobacterial infection. His parents are first degree cousins. Blood samples were collected and cultured 48 hours with medium, BCG or BCG+IL-12. Supernatants were assayed for IFN-γ by ELISA. PBMC were cultured with PMA-Ionomicyn and IL12R was measured by flow cytometry. We found low production of IFN γ after stimulation with BCG+IL12 that seems to correlate with an IL-12R defect. Flow cytometry showed a decrease of IL-12RB1 expression. Sequencing revealed a point mutation (A182T), which generates E61G change in the extracellular domain. Furthermore, the uncommon clinical features in this case might suggest another primary immunodeficiency.

BackgroundChronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte NADPH oxidase activity. Affected patients display severe, recurrent and multiple infections from the first year of life onwards, in particular caused by various pyogenic bacteria and fungi. Mycobacterial infections have more rarely been reported in these patients.MethodsWe examined the clinical features of mycobacterial disease in 59 CGD patients from 52 kindreds in 16 countries of 4 continents. Tuberculosis or BCG adverse reactions were identified by culture, staining, biopsy, polymerase chain reaction (PCR), and/or by a combination of clinical criteria with response to treatment. CGD was confirmed by NBT, DHR, cytochrome C reduction assay, or a combination of these. Genetic diagnosis was achieved by means of immunoblotting, flow cytometry, PCR and automated gene sequencing.ResultsWe found that mycobacterial infections are fairly common in patients with CGD living in certain regions of the world. Twenty-four patients (45%) had tuberculosis, 43 (80%) presented with adverse effects shortly after Bacille Calmette-Guérin (BCG) vaccination; 12 of the patients (21%) had both tuberculosis infection and BCG adverse reactions. Most patients (93%) had also pyogenic and fungal infections; 7% of them, however, presented solely with mycobacterial disease. Most cases were one-time self-limited localized infections, but recurrence (13 patients, 20%), disseminated disease (18 patients, 30%) and even death (5 patients, 8%) were observed. A recurrent finding was early age of presentation for BCG reaction, with a median of 3 months of age; BCG disease was the first manifestation of immunodeficiency in 60% of these patients.ConclusionsOur study offers compelling evidence for an important susceptibility to mycobacterial diseases in patients with CGD, more easily noticed in countries where tuberculosis is endemic and BCG vaccine mandatory. BCG adverse reactions should raise the suspicion of CGD.