Germline GATA2 deficiency is a pleiotropic condition 1-8 characterized by numerous phenotypes, including monocytopenia, immunodeficiency, microbial susceptibilities, and high rates of myeloid malignancies 1,8. Accurate curation of germline GATA2 variants is critical for patient care and requires well-defined phenotypes associated with GATA2 deficiency. The many phenotypes attributed to the condition render a simple description of GATA2 deficiency difficult, complicating the development of GATA2 variant curation rules. Therefore, the Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) sought to define GATA2 deficiency based on a statistical comparison of phenotype data. To do so, the MM-VCEP systematically analyzed phenotype data and applied statistical comparisons to define the phenotypic features of GATA2 deficiency to inform germline variant curation. The MM-VCEP assembled an international cohort of 339 people with clinically diagnosed GATA2 deficiency from 16 centers in seven countries. The 73 phenotypes of these individuals were compared statistically to those of control participants from the UK Biobank (UKBB). We compared single phenotypes as well as combinations of two, three, and four phenotypes in people with clinically diagnosed GATA2 deficiency to UKBB controls. We defined GATA2 deficiency as any of the 2,903 combinations of two or three phenotypes with log10Odds Ratio ≥3 (OR ≥ 1000). This definition of GATA2 deficiency will inform gene-specific phenotypic criteria used in GATA2 variant curation guidelines that will facilitate standardized variant curation by clinical laboratories worldwide.

We performed a single-center retrospective analysis of chronic granulomatous disease (CGD) autopsy reports to better understand causes of death, end-organ damage, and disease pathophysiology. Forty-four autopsies of CGD patients, including one X-linked female carrier, were performed from February 1990 to June 2025. These cases represent approximately 60% of the CGD deaths over 35 years. There was an increase in age at death over this time, despite a heavy burden of infections. The immediate cause of death was infection n = 30 (68%); Aspergillus species (33%) was the most frequent pathogen. One death was associated with SARS-CoV-2. An aggressive new Aspergillus species, Aspergillus tanneri, and an unidentified Burkholderia species were identified in this cohort.Noninfectious causes of death in 14 patients were associated to accident (1), respiratory failure (2), renal failure (2), surgical complications (1), post-transplant complications (2), cardiovascular complications (2), cerebral infarction (1), Transfusion-Related Acute Lung Injury (TRALI), a serious complication of blood transfusions where the recipient experiences acute lung injury in one case, and one death attributed to metastatic pancreatic ductal adenocarcinoma.A substantial portion had characteristic pigmented-laden macrophages in multiple organs, with a high concentration in the brain parenchyma. Atherosclerotic manifestations were present in a third of the cases. One patient, p22phox, had minimal atherosclerosis manifestations early in life (19 yrs). Lungs and hearts were significantly heavier when compared to norms. Livers were not significantly larger, although there was evidence of underlying inflammatory disease. Periportal inflammation was noted in 19 patients (46%), and nodular regenerative hyperplasia (NRH) was found in 7 (16%). Kidneys were small overall (atrophic), which may be related to drug exposure, specifically amphotericin B. Glomerulosclerosis or chronic renal compromise was found in 17 patients (41%), two of whom were children. Among those with glomerulosclerosis, one had never received amphotericin B. This pathology review shows pigment-laden macrophages across multiple organs not previously recognized, including the brain parenchyma. This is the largest autopsy series known in this population, underscoring the increased survival over time. With fungal infections being the most common cause of death, this emphasizes the importance of antifungal development and definitive cure in this disease.

BACKGROUND:Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and nonimmunologic manifestations. OBJECTIVE:We sought to characterize the spectrum of clinical manifestations, genetics, treatment approaches, and long-term outcomes of patients with STAT3-HIES. METHODS:Clinical features, laboratory findings, treatment, and survival were reviewed in the largest single-center STAT3-HIES cohort (n = 164) prospectively followed under a natural history protocol (NCT00006150). RESULTS:In addition to the classic skin, lung, dental, and musculoskeletal manifestations captured in the 1999 scoring system, we comprehensively characterized disease phenotypes across multiple organ systems, including previously underrecognized features. Lung disease remained the major morbidity with both infectious and parenchymal complications. During longitudinal follow-up, age-related vascular and skeletal degeneration emerged and significantly affected quality of life in patients 45 years and older. No genotype-phenotype correlations were identified. In terms of management, optimal supportive measures, including antimicrobials and immunoglobulin replacement therapy, tailored to disease features and individual risk factors, remained the primary approach. Dupilumab was used primarily for the eczematous dermatitis and demonstrated significant clinical benefit. In highly selected cases (n = 6), allogeneic hematopoietic stem cell transplantation was performed and showed reduction in infection burden. The median overall survival was 55 years-significantly shorter than that of the general United States population-and was not affected by sex, variant location, or proband status. CONCLUSIONS:STAT3-HIES is a multisystem disorder that requires multidisciplinary care. Early diagnosis and supportive measures have altered its natural history. Recognition and improved understanding of the nonimmunologic manifestations of this disorder will further improve patient outcomes.

Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common genetic form of Mendelian susceptibility to mycobacterial disease globally, often presenting as disseminated Bacillus Calmette-Guérin (BCG) infection. In North America, however, where BCG is not used, it manifests with other bacterial or fungal infections, highlighting distinct, sometimes unrecognized, presentations of IL-12Rβ1 deficiency in this geographic area.

Background The transition to adult health care is challenging for adolescents and young adults (AYA) with Chronic Granulomatous Disease (CGD). This pilot study aimed to facilitate the learning of AYA with CGD about their health care and to aid in the development of life skills to enhance self-care. Methods AYA and caregivers (for participants <18 years of age) completed an adapted Transition Readiness Assessment. Educational sessions were held both in person and via telehealth and included virtual meetings with subject matter experts or a designated program mentor. Twenty-five participants were invited, 13 entered the pilot and 8 completed the transition readiness assessment. Results The pilot study was well-received by CGD participants and caregivers. In the future, a larger cohort may provide more data to comment on efficacy and outcome in the AYA population. Conclusion Expansion of an educational transition program for AYA with primary immunodeficiencies (PIDs) might be useful.

Sarcoidosis is a granulomatous disease with an incidence of up to 18 in 100,000 in some populations. Symptoms range from asymptomatic benign lesions to organ failure, with up to 90% of patients presenting with lung involvement. Sarcoidosis is often a diagnosis of exclusion: inflammation, lymphadenopathy, and sterile granulomata without an identifiable cause. Granuloma formation occurs in primary immunodeficiencies, but the full landscape of these deficiencies and their association with sarcoid is not fully understood. We looked retrospectively at patients initially diagnosed with sarcoidosis referred to the National Institutes of Health (NIH). Many people had refractory inflammation or had a diagnosis of sarcoidosis in the setting of other immune dysfunction such as common variable immunodeficiency (CVID). Within this group of 37 patients with completed whole-genome or whole-exome sequencing, 22 had pathogenic variants, likely pathogenic variants, or variants of unknown significance in relevant candidate genes including SP110, GATA2, NFKBIA, NFKB1, IRF8, CTLA-4, NCF1, SLC26A9, RFX5, MEFV, GFI1, PLCG2, STAT1, BACH2, IKZF3, JAK1, ADCY10, and STXBP2. This study highlights the diseases often gathered under the diagnosis “sarcoid”. Prior studies have highlighted immune dysregulation within multiple pathways, including the interferon-gamma (IFN-γ) response pathway (GATA2, STAT1, NFKBIA, and IRF8), Th17.1 signaling (STAT1 and IRF8), and inflammasome response (IRF8, MEFV, and PLCG2), as being important in granuloma formation. Numerous mutations within this cohort have previously been associated with common immunodeficiencies (RFX5, NFKBIA, SP110, and IKZF3) or predominant antibody deficiencies (NFKB1). This cohort also showed defects of phagocyte number or function (GFI1, NCF1, and GATA2). Within this study, two variants were identified that are not associated with immunodeficiencies, including SLC26A9, an ion transporter for chloride previously identified in atypical cystic fibrosis, and ADCY10, a catalyst for the formation of cAMP. Though it is possible that some of these variants may not be causal or even relevant to the formation of granulomas, this cohort shows how some patients presenting with lymphadenopathy and sterile granulomata in various organs were identified to have Mendelian traits underlying their diagnoses of sarcoidosis. Table 1.Subject IDGenetic Defect IdentifiedAllele Frequency gnomAD v4.1.0Classification (ClinVar)ZygosityCADD ScoreInheritance PatternOrgan InvolvementInfection History1NFKBIA (IkBa) (c.691G>T, p.Asp231Tyr)4.7e-5VUSHet27.3ADCNS, Exocrine, CutaneousNTM, EBV2CTLA4 (c.567+5G>C)0PathogenicHet26ADOcular, LN, Cutaneous, Pulmonary3No defect identifiedOcular, Cutaneous, PulmonaryEBV4NCF1 (p47phox Deficient CGD) (c.75_76del, p.Tyr26fs)8.5e-4PathologicHomo35ARPulmonary, Exocrine, LNS. capitis5No defect identifiedCutaneousSphingomonas paucimobilis6No defect identifiedPulmonaryM. avium8No defect identifiedPulmonary, Neuro, LNJCV9No defect identifiedPulmonarydisseminated M. tilbergii11NCF1 (p47phox Deficient CGD) (c.75_76del, p.Tyr26fs)8.5e-4PathologicHomo38ARPulmonary12NCF1 (p47phox Deficient CGD) (c.75_76del, p.Tyr26fs)8.5e-4PathologicHomo38ARMSK, Ocular, SplenicA. fumigatus141q41 222762100-224070013HetHepatic, PulmonaryS. pneumo1.308 Mb-1.636 Mb LossIFIH1NOD2LRBAFAT4KMT2D15SP110 (c.1428_1429del, p.Tyr476Ter)1.8e-6Not ReportedHet34ARCutaneousM. chelonae16SLC26A9 (c.1459G>A, p.Ala487Thr)6.9e-5Not ReportedHet20.8PulmonaryMAC17GATA2 (c.1021_1024dup, p.Ala342GlyfsTer43)0PathologicHetNAADPulmonary18No defect identifiedPulmonary, Cutaneous19IRF8 (c. 536C>T, p.Ala179Val)6.5e-6VUSHet17.54AR/ADNeuroMAC20No defect identifiedPulmonary, GIMAC23GATA2 (c.1021_1024dup, p.Ala342GlyTer43)0PathogenicHetNAADBM25STXBP2 (c.1001 C>T, p.Pro334Leu)4e-5Likely pathogenicHomo29.9ARHepatic26No defect identifiedPulmonary27No defect identifiedPulmonary28NFKB1 (c.1513A>C, p.Lys505Gln)6.85e-7VUSHet26.2ADPulmonary, Cardiac29RFX5 (c.353+2T>G)1.8e-4Likely pathogenicHet33ARPulmonary, Cutaneous30IKZF3 (c.244G>A, p.Glu82Lys)1.4e-4VUSHet23.6ADHepatic, OcularRecurrent Pneumonia31No defect identifiedPulmonaryEBV32No defect identifiedCardiac33No defect identifiedNeuroVZV34MEFV (c.289C>A, p.Gln97Lys)9.43e-5VUSHet9.8AD/ARPulmonary, Hepatic35GFI1 (c.200G>A, p.Arg67Lys)3.4e-5VUSHet21.2ARPulmonaryAspergillus, pneumocystis36PLCG2 (c.2931C>G, p.Tyr977Ter)6.19e-7VUSHet38ADPulmonary, Splenic, CutaneousRecurrent sinusitis37STAT1 (c.736G>A, p.Ala246Thr)0VUSHet24ADPulmonaryHistoplasmosis38BACH2 (c.2327 C>T, p.Pro776Leu)1.8e-5VUSHet16.9ADPulmonary39No defect identifiedPulmonary40ADCY10 (c.4477del, p.Leu1493SerfsTer24)3e-4PathogenicHet33ADPulmonary41No defect identifiedPulmonary42No defect identifiedCardiac43JAK1 (c.1078C>T, p.Arg360Trp)5.9e-5VUSHet25.1AD/ART1DM, Pulmonary, OcularHistoplasmosis

Clinical Implications Female X-linked chronic granulomatous disease (XL-CGD) carriers may develop severe clinical disease including infections with CGD-defining pathogens and inflammatory disorders. Similar to males with XL-CGD, female carriers warrant ongoing evaluation and prophylaxis where indicated.

Background Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation.Methods Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections.Results Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex.Conclusions Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.) Investigators identified autoantibodies against interleukin-23 (with or without anti-interleukin-12) in patients with a variety of opportunistic infections, especially in those with thymoma.

ObjectivePatients with pathogenic variants in the GATA Binding Protein 2 (GATA2), a hematopoietic transcription factor, are at risk for human papillomavirus-related (HPV) anogenital cancer at younger than expected ages. A female cohort with GATA2 haploinsufficiency was systematically assessed by two gynecologists to characterize the extent and severity of anogenital HPV disease, which was also compared with affected males.MethodsA 17-year retrospective review of medical records, including laboratory, histopathology and cytopathology records was performed for patients diagnosed with GATA2 haploinsufficiency followed at the National Institutes of Health. Student’s t-test and Mann-Whitney U test or Fisher’s exact test were used to compare differences in continuous or categorical variables, respectively. Spearman’s rho coefficient was employed for correlations.ResultsOf 68 patients with GATA2 haploinsufficiency, HPV disease was the initial manifestation in 27 (40%). HPV occurred at median 18.9 (15.2-26.2) years in females, and 25.6 (23.4-26.9) years in males. Fifty-two (76%), 27 females and 25 males, developed HPV-related squamous intraepithelial lesions (SIL) including two males with oral cancer. Twenty-one patients developed anogenital high-grade SIL (HSIL) or carcinoma (16 females versus 5 males, (59% versus 20%, respectively, p=0.005) at median 27 (18.6-59.3) years for females and 33 (16.5-40.1) years for males. Females were more likely than males to require >2 surgeries to treat recurrent HSIL (p=0.0009). Of 30 patients undergoing hematopoietic stem cell transplant (HSCT) to manage disease arising from GATA2 haploinsufficiency, 12 (nine females, three males) had persistent HSIL/HPV disease. Of these nine females, eight underwent peri-transplant surgical treatment of HSIL. Five of seven who survived post-HSCT received HPV vaccination and had no or minimal evidence of HPV disease 2 years post-HSCT. HPV disease persisted in two receiving immunosuppression. HPV disease/low SIL (LSIL) resolved in all three males.ConclusionFemales with GATA2 haploinsufficiency exhibit a heightened risk of recurrent, multifocal anogenital HSIL requiring frequent surveillance and multiple treatments. GATA2 haploinsufficiency must be considered in a female with extensive, multifocal genital HSIL unresponsive to multiple surgeries. This population may benefit from early intervention like HSCT accompanied by continued, enhanced surveillance and treatment by gynecologic oncologists and gynecologists in those with anogenital HPV disease.

Chronic granulomatous disease (CGD) is a rare inborn error of immunity, resulting from a defect in nicotinamide adenine dinucleotide phosphate oxidation and decreased production of phagocyte reactive oxygen species. The main clinical manifestations are recurrent infections and chronic inflammatory disorders. Current approaches to management include antimicrobial prophylaxis and control of inflammatory complications. Hematopoietic stem cell transplantation or gene therapy can provide definitive treatment. Gastrointestinal and hepatic manifestations are common in CGD and include structural changes, dysmotility, CGD-associated inflammatory bowel disease, liver abscesses, and noncirrhotic portal hypertension. The findings can be heterogeneous, and the management is complex in light of the underlying immune dysfunction. This review describes the various clinical findings and the latest studies in management of gastrointestinal and hepatic manifestations in CGD, as well as the management experience at the National Institutes of Health.

Background: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments. Objective: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGDIBD. Methods: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium. Results: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD. Conclusion: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets. (J Allergy Clin Immunol 2023;152:1619-33.)

Background: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited. Objectives: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA. Methods: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons. Results: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent >= 1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per mu L for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002). Conclusions: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.

Chronic granulomatous disease (CGD) is a rare immunodeficiency caused by mutations in the NADPH oxidase complex. Dysregulated immune function may cause inflammatory bowel disease (IBD). Patients with CGD-associated IBD may not respond to or may develop serious infections as a result of traditional IBD therapies such as vedolizumab and infliximab. Ustekinumab is approved for use in Crohn’s disease and ulcerative colitis however there is scarce data on its efficacy and safety in CGD. To evaluate the efficacy and safety of ustekinumab for CGD-associated IBD. A retrospective chart review was conducted on CGD patients followed at a single center who had consented to participate in a natural history study. Clinical, laboratory, and endoscopic data were extracted in those that had received ustekinumab for IBD. Eight patients were found. Four were male and four were female. Five were white, one was Asian, one was black, and one was mixed race. Median age at diagnosis of CGD was 3 years (IQR 8) and of IBD was 15.5 years (IQR 20). Median age at initiation of ustekinumab was 27.5 years (IQR 14) and median duration on ustekinumab was 10 months (IQR 7). Six had colonic disease, two had ileocolonic disease, and six had perianal disease. Six failed other biologics (n=5 for vedolizumab, n=1 for infliximab, n=1 for adalimumab). Six patients symptomatically improved whereas two had no improvement. Changes in hemoglobin and C-reactive protein were equivocal. Three patients had improved endoscopic findings, two had unimproved findings, and three patients lacked this data. Overall, four patients achieved clinical remission. However, none of the five patients with endoscopic reevaluation achieved endoscopic remission. Three patients discontinued therapy due to lack of response: two required surgery and one underwent stem cell transplant. Fungal pneumonia (n=2), otitis media (n=1), oral herpes simplex virus 1 (n=1), and viral gastroenteritis (n=1) were reported. One infusion reaction occurred. In our cohort of eight patients with CGD-associated IBD receiving ustekinumab, results were mixed with four patients experiencing some degree of clinical or endoscopic improvement including four who achieved clinical remission. Multiple CGD-related variables may account for the mixed laboratory findings. Four of the five patients with endoscopic reevaluation had pre-existing strictures that would be unlikely to reverse with medical therapy alone. Of these, two had otherwise resolved endoscopic inflammation. Only two patients had no endoscopic improvement. Two serious infections occurred however CGD confers increased infectious susceptibility and no infections lead to discontinuation of therapy. Given these promising results, further formalized study of ustekinumab in CGD-associated IBD is needed.

BACKGROUND: GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations. RESEARCH QUESTION: What are the pulmonary manifestations of GATA2 deficiency? STUDY DESIGN AND METHODS: A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function. RESULTS: Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients. INTERPRETATION: GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by mutations encoding the NADPH oxidase complex.1 Those affected are at increased risk of bacterial and fungal infections and require antimicrobial prophylaxis. Dysregulated inflammation may cause inflammatory bowel disease (IBD), termed CGD-associated IBD or CGD colitis, a distinct entity from Crohn's disease (CD) or ulcerative colitis (UC).

GATA2 deficiency is a bone marrow failure syndrome effectively treated with hematopoietic cell transplantation (HCT), which also addresses the predisposition to many infections (prominently mycobacterial). However, many GATA2-deficient persons who come to HCT also have prevalent and refractory human papilloma virus disease (HPVD), which can be a precursor to cancer. We analyzed 75 HCT recipients for the presence of HPVD to identify patient characteristics and transplantation results that influence HPVD outcomes. We assessed the impact of cellular recovery and iatrogenic post-transplantation immunosuppression, as per protocol (PP) or intensified/prolonged (IP) graft-versus-host disease (GVHD) prophylaxis or treatment, on the persistence or resolution of HPVD. Our experience with 75 HCT recipients showed a prevalence of 49% with anogenital HPVD, which was either a contributing or primary factor in the decision to proceed to HCT. Of 24 recipients with sufficient follow-up, 13 had resolution of HPVD, including 8 with IP and 5 with PP. Eleven recipients had persistent HPVD, including 5 with IP and 6 with PP immunosuppression. No plausible cellular recovery group (natural killer cells or T cells) showed a significant difference in HPV outcomes. One recipient died of metastatic squamous cell carcinoma, presumably of anogenital origin, at 33 months post-transplantation after prolonged immunosuppression for chronic GVHD. Individual cases demonstrate the need for continued aggressive monitoring, especially in the context of disease prevalent at transplantation or prior malignancy. HCT proved curative in many cases in which HPVD was refractory and recurrent prior to transplantation, supporting a recommendation that HPVD should be considered an indication rather than contraindication to HCT, but post-transplantation monitoring should be prolonged with a high level of vigilance for new or recurrent HPVD.

Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID). This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed. Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0–56) years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2–257) days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency. Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.