Description of BCG and Tuberculosis Disease in a Cohort of 79 Patients with Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by pathogenic variants of genes encoding the enzyme complex NADPH oxidase. In countries where tuberculosis (TB) is endemic and the Bacillus Calmette-Guérin (BCG) vaccine is routinely administered, mycobacteria are major disease-causing pathogens in CGD. However, information on the clinical evolution and treatment of mycobacterial diseases in patients with CGD is limited. The present study describes the adverse reactions to BCG and TB in Mexican patients with CGD. METHODS: Patients with CGD who were evaluated at the Immunodeficiency Laboratory of the National Institute of Pediatrics between 2013 and 2024 were included. Medical records were reviewed to determine the clinical course and treatment of adverse reactions to BCG and TB disease. RESULTS: A total of 79 patients with CGD were included in this study. Adverse reactions to BCG were reported in 55 (72%) of 76 patients who received the vaccine. Tuberculosis was diagnosed in 19 (24%) patients. Relapse was documented in three (10%) of 31 patients with BGC-osis and six (32%) of 19 patients with TB, despite antituberculosis treatment. There was no difference in the frequency of BCG and TB disease between patients with pathogenic variants of the X-linked CYBB gene versus recessive variants. CONCLUSIONS: This report highlights the importance of considering TB in endemic areas and BCG complications in children with CGD to enable appropriate diagnostic and therapeutic approaches to improve prognosis and reduce the risk of relapse.

The Use of Steroids to Treat Hypercalcemia Due to Granulomatous Disease From Disseminated Coccidioidomycosis.

The clinical course and treatment of hypercalcemia from a granulomatous disease in the setting of an infectious etiology, namely disseminated coccidioidomycosis, remains incompletely understood. The mechanism and treatment of hypercalcemia have been documented in most granulomatous disorders, with sarcoidosis being the most well-understood so far. We discuss a case of a patient with a recent diagnosis of disseminated coccidioidomycosis who presented with hypercalcemia despite adequate infection control. The treatment course involved combinatorial-calcitonin, low-dose bisphosphonates, and corticosteroids, which led to a favorable outcome.

Case report and review of literature: IgG4-gastroduodenitis in upper GI Crohn's disease: two separate entities or just a marker of disease severity?

A 20-year-old man was presented with ulcerative gastritis and duodenitis complicated by pyloric stenosis. Helicobacter pylori infection was excluded, and the lesions did not respond to treatment with proton pump inhibitors. No other parts of the intestinal tract showed signs of inflammation. Histopathological review showed signs of chronic inflammation with granuloma formation. A tentative diagnosis of isolated upper gastrointestinal (UGI) Crohn's disease was performed. However, additional work-up revealed significantly positive IgG4 staining as well as elevated IgG4 serum levels. Since granulomatous disease is unlikely in IgG4-related disease, an eventual diagnosis of overlapping IgG4-related disease and Crohn's disease (CD) was performed. Treatment with systemic steroids and anti-TNF in combination with azathioprine led to rapid symptomatic improvement. In this article, we review the available literature on IgG4-related gastroduodenitis, granulomatous gastritis, and upper GI CD. We suggest the possibility that IgG4-infiltration may be a marker of severely active inflammatory bowel disease rather than a separate disease entity.

A Case of Chronic Granulomatous Disease Masquerading As Tubercular Lymphadenitis in an Infant.

Chronic granulomatous disease (CGD) is a rare inborn error of immunity characterized by recurrent fungal and bacterial infections due to defective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. This case report describes an 11-month-old female who was initially diagnosed with tubercular lymphadenitis and presented with fever and bilateral neck swelling. Despite receiving anti-tubercular treatment (ATT) and intravenous antibiotics, the patient experienced recurrent infections and abscesses, prompting further investigation. Laboratory tests revealed normal immunoglobulin levels but abnormal nitroblue tetrazolium (NBT) and dihydrorhodamine (DHR) tests, indicating CGD. Genetic analysis (clinical exome by next-generation sequencing) confirmed a novel NCF2 gene mutation associated with autosomal recessive CGD. This patient was treated with prophylactic antibiotics and antifungals and subsequently underwent successful hematopoietic stem cell transplantation (HSCT). This highlights the diagnostic challenges associated with CGD, particularly in tuberculosis-endemic regions such as India, emphasizing the importance of considering primary immunodeficiency disorders in patients with recurrent infections. Early diagnosis and appropriate treatment, including HSCT, can significantly improve patient outcomes. The patient remained infection-free on prophylactic antimicrobials for 1.5 years post-discharge, demonstrating the potential for a favorable prognosis with timely intervention and comprehensive management.

Causes of Oral Granulomatous Disorders: An Update and Narrative Review of the Literature.

Granulomatous diseases include a diverse range of chronic inflammatory disorders with a wide variety of pathologies and clinical characteristics. In particular, the orofacial region can be affected by granulomatous conditions-whether as an isolated disease or as part of a systemic disorder. Regardless of the nature of the disease or its mechanism of development, precise diagnosis can be challenging, as etiopathogenesis may be driven by several causes. These include reactions to foreign bodies, infections, immune dysregulation, proliferative disorders,, medications, illicit drugs, and hereditary disorders. Granulomas can be identified using histopathological assessment but are not pathognomonic of a specific disease, and therefore require correlation between clinical, serological, radiographical, and histopathological findings. The purpose of this review is to provide a summary of the etiopathogenesis, clinical and histopathologic characteristics, and treatment of oral granulomatous disorders.

Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era.

Chronic granulomatous disease (CGD) is a group of rare primary inborn errors of immunity characterised by a defect in the phagocyte respiratory burst, which leads to severe and life-threatening infective and inflammatory complications. Despite recent advances in our understanding of the genetic and molecular pathophysiology of X-linked and autosomal recessive CGD, and growth in the availability of functional and genetic testing, there remain significant barriers to early and accurate diagnosis. In the current review, we provide an up-to-date summary of CGD pathophysiology, underpinning current methods of diagnostic testing for CGD and closely related disorders. We present an overview of the benefits of early diagnosis and when to suspect and test for CGD. We discuss current and historical methods for functional testing of NADPH oxidase activity, as well as assays for measuring protein expression of NADPH oxidase subunits. Lastly, we focus on genetic and genomic methods employed to diagnose CGD, including gene-targeted panels, comprehensive genomic testing and ancillary methods. Throughout, we highlight general limitations of testing, and caveats specific to interpretation of results in the context of CGD and related disorders, and provide an outlook for newborn screening and the future.

Sarcoidosis versus Granulomatous and Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency: A Comparative Review.

Sarcoidosis and Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) are two rare entities primarily characterised by the development of Interstitial Lung Disease (ILD) in the context of systemic immune dysregulation. These two conditions partially share the immunological background and pathologic findings, with granuloma as the main common feature. In this narrative review, we performed a careful comparison between sarcoidosis and GLILD, with an overview of their main similarities and differences, starting from a clinical perspective and ending with a deeper look at the immunopathogenesis and possible target therapies. Sarcoidosis occurs in immunocompetent individuals, whereas GLILD occurs in patients affected by common variable immunodeficiency (CVID). Moreover, peculiar extrapulmonary manifestations and radiological and histological features may help distinguish the two diseases. Despite that, common pathogenetic pathways have been suggested and both these disorders can cause progressive impairment of lung function and variable systemic granulomatous and non-granulomatous complications, leading to significant morbidity, reduced quality of life, and survival. Due to the rarity of these conditions and the extreme clinical variability, there are still many open questions concerning their pathogenesis, natural history, and optimal management. However, if studied in parallel, these two entities might benefit from each other, leading to a better understanding of their pathogenesis and to more tailored treatment approaches.

[Chest computed tomography manifestations in neonates with chronic granulomatous disease]. / æ–°ç”Ÿå„¿æ ¢æ€§è‚‰èŠ½è‚¿ç— èƒ¸éƒ¨è®¡ç®—æœºæ–­å±‚æ‰«æçš„ç‰¹å¾åˆ†æž.

OBJECTIVES: To study chest computed tomography (CT) manifestations in neonates with chronic granulomatous disease (CGD) to provide clues for early diagnosis of this disease. METHODS: A retrospective analysis was conducted on the clinical data and chest CT scan results of neonates diagnosed with CGD from January 2015 to December 2022 at Anhui Provincial Children's Hospital. RESULTS: Nine neonates with CGD were included, with eight presenting respiratory symptoms as the initial sign. Chest CT findings included: consolidation in all 9 cases; nodules in all 9 cases, characterized by multiple, variably sized scattered nodules in both lungs; masses in 4 cases; cavities in 3 cases; abscesses in 6 cases; bronchial stenosis in 2 cases; pleural effusion, interstitial changes, and mediastinal lymphadenopathy each in 1 case. CT enhancement scans showed nodules and masses with uneven or ring-shaped enhancement; no signs of pulmonary emphysema, lung calcification, halo signs, crescent signs, bronchiectasis, or scar lesions were observed. There was no evidence of rib or vertebral bone destruction. Fungal infections were present in 8 of the 9 cases, including 6 with Aspergillus infections; three of these involved mixed infections with Aspergillus, with masses most commonly associated with mixed Aspergillus infections (3/4). CONCLUSIONS: The primary manifestations of neonatal CGD on chest CT are consolidation, nodules, and/or masses, with Aspergillus as a common pathogen. These features can serve as early diagnostic clues for neonatal CGD.

A rare differential diagnosis of inflammatory bowel disease in a young male patient; a challenging case report.

Background: Chronic granulomatous disease (CGD) is a rare disorder normally diagnosed in infancy. Case presentation: A 27-year-old man admitted with non-specific symptoms of CGD first underwent endoscopy, and colonoscopy procedures as primary evaluation of clinical presentation. Eighteen months after the first admission, he was referred to the emergency department for hematemesis, and critical situations, such as a severe anemic with Hgb= 2.6 mg/dl. As a result of this specific clinical presentation, urgent emergency treatment was performed, and endoscopic examination revealed ulcers and abnormalities in the duodenal bulb and jejunum. Other imaging procedures, such as sonography, and abdominal CT scans, showed splenomegaly. He underwent splenectomy, and after that, endoscopic treatment with balloon TTS dilation was scheduled, but this procedure failed. So, we decided to do a gastro-jujenostomy that alleviated the clinical symptoms. After nine months, he was referred to GOO, and endoscopic evaluation showed giant ulceration with severe stricture in the duodenum, and a polyp in the jejunostomy. Finally, Based on clinical presentation and pathologic evidence of biopsies, the patient approached CGD as the final diagnosis. Conclusion: Step-by-step, rule out of different highly suspicious diseases may result in a definite CGD diagnosis, and rapid management of these patients may increase the chance of survival.

Targeted knock-in of NCF1 cDNA into the NCF2 locus leads to myeloid phenotypic correction of p47 phox -deficient chronic granulomatous disease.

p47 phox -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 (NCF1) gene, resulting in defective NADPH oxidase function in phagocytes. Due to its complex genomic context, the NCF1 locus is not suited for safe gene editing with current genome editing technologies. Therefore, we developed a targeted NCF1 coding sequence knock-in by CRISPR-Cas9 ribonucleoprotein and viral vector template delivery, to restore p47 phox expression under the control of the endogenous NCF2 locus. NCF2 encodes for p67 phox , an NADPH oxidase subunit that closely interacts with p47 phox and is predominantly expressed in myeloid cells. This approach restored p47 phox expression and NADPH oxidase function in p47-CGD patient hematopoietic stem and progenitor cells (HSPCs) and in p47 phox -deficient mouse HSPCs, with the transgene expression following a myeloid differentiation pattern. Adeno-associated viral vectors performed favorably over integration-deficient lentiviral vectors for template delivery, with fewer off-target integrations and higher correction efficacy in HSPCs. Such myeloid-directed gene editing is promising for clinical CGD gene therapy, as it leads to the co-expression of p47 phox and p67 phox , ensuring spatiotemporal and near-physiological transgene expression in myeloid cells.

Cardiac Sarcoidosis: A Comprehensive Clinical Review.

Sarcoidosis is an inflammatory multisystemic disease of unknown etiology characterized by the formation of non-caseating granulomas. Sarcoidosis can affect any organ, predominantly the lungs, lymphatic system, skin and eyes. While > 90% of patients with sarcoidosis have lung involvement, an estimated 5% of patients with sarcoidosis have clinically manifest cardiac sarcoidosis (CS), whereas approximately 25% have asymptomatic, clinically silent cardiac involvement verified by autopsy or imaging studies. CS can present with conduction disturbances, ventricular arrhythmias, heart failure or sudden cardiac death. Approximately 30% of < 60-year-old patients presenting with unexplained high degree atrioventricular (AV) block or ventricular tachycardia are diagnosed with CS, therefore CS should be strongly considered in such patients. CS is the second leading cause of death among patients affected by sarcoidosis after pulmonary sarcoidosis, therefore its early recognition is important, because early treatment may prevent death from cardiovascular involvement. The establishment of isolated CS diagnosis sometimes can be quite difficult, when extracardiac disease cannot be verified. The other reason for the difficulty to diagnose CS is that CS is a chameleon of cardiology and it can mimic (completely or almost completely) different cardiac diseases, such as arrhythmogenic cardiomyopathy, giant cell myocarditis, dilated, restrictive and hypertrophic cardiomyopathies. In this review article we will discuss the current diagnosis and management of CS and delineate the potential difficulties and pitfalls of establishing the diagnosis in atypical cases of isolated CS.

Beyond biopsy for neurosarcoidosis: A review of blood and CSF biomarkers.

Neurosarcoidosis, a rare granulomatous disease, causes inflammation and damage to the central nervous system (CNS). A major diagnostic challenge in neurosarcoidosis is the absence of well-defined biomarkers. The need for biopsy to make the diagnosis can lead to delays and misdiagnosis if histopathology is inaccessible or indeterminate, highlighting the need for more accessible diagnostic indicators. The current gold standard for a "definite" neurosarcoidosis diagnosis requires biopsy of CNS tissue revealing non-caseating granulomas. However, such biopsies are inherently invasive and carry associated procedural risks. Notably, angiotensin-converting enzyme (ACE), commonly associated with systemic sarcoidosis, is recognized as a poor biomarker for neurosarcoidosis due to its lack of accuracy in the context of CNS involvement. Furthermore, imaging in neurosarcoidosis, while widely utilized and important for narrowing the diagnosis, lacks specificity. Decades of research have yielded molecular and immunologic biomarkers-soluble interleukin-2 receptor (IL-2R), serum amyloid A1, the CD4/CD8 ratio, neopterin, interferon-gamma (IFN-γ), and chemokine ligand 2 (CCL2)-that hold potential for improving diagnostic accuracy. However, these biomarkers are not yet established in clinical care as they may be difficult to obtain and are derived from small studies. They also suffer from a lack of specificity against other inflammatory and infectious central nervous system diseases. New biomarkers are needed for use alongside those previously discovered to improve diagnosis of this rare disease. This review synthesizes existing literature on neurosarcoidosis biomarkers, aiming to establish a foundation for further research in this evolving field. It also consolidates information on biomarkers of systemic sarcoidosis such as IL-8 and soluble CD40L that have not yet been studied in neurosarcoidosis but hold potential as markers of CNS disease.

Chronic granulomatous disease: A single-center experience in Central Anatolia.

BACKGROUND: Chronic granulomatous disease (CGD), one of the phagocytic cell defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex in neutrophils. METHODS: The clinical, demographic and laboratory findings of 17 CGD patients who were followed-up between 2002 and 2021 were obtained retrospectively from the records of the patients. RESULTS: The number of male and female patients was 10/7. The median age at diagnosis was 5.3 months (range 4-120) for 3 patients with X-CGD, and 42.4 months (range 8-350) for 14 patients with AR-CGD. We have investigated rare CYBA exon 3-6 deletion in 7 patients and hotspot mutation with delGT at the beginning of exon 2 of NCF1 in 5 patients. The most common clinical findings were pneumonia and lymphadenitis with recurrent fever, respectively (41.2%, 35.3%). A total of 154 microbial infections requiring hospital admission (27 in 3 XL and 127 in 14 AR patients) were detected in the follow-up of the patients and median infection number for a patient was 9 in both groups. Eight of 17 patients had stem cell transplantation and the survival rate was 87.5%. CONCLUSIONS: X-CGD patients are more rapidly recognized by family history and severe infections than those with AR-CGD and early prophylaxis may decrease infectious episodes. We have investigated the large deletion suggesting a possible founder effect for CYBA exon 3-6 deletion in Central Anatolia. Additionally, HSCT transplantation leads to a high survival rate for the patients with CGD.

First Report on Chronic Granulomatous Disease from Nepal and a Review of CYBC1 Deficiency.

Chronic granulomatous disease (CGD) primarily results from inherited defects in components of the nicotinamide adenine dinucleotide phosphate oxidase enzyme complex. These include gene defects in cytochrome B-245/558 subunit α/ß and neutrophil cytosolic factors 1, 2, and 4. Recently, homozygous loss-of-function variants in cytochrome B-245 chaperone 1 gene (CYBC1) have been discovered to cause CGD (CYBC1-CGD). Data on variant-proven CGD from low-income countries, the most underprivileged regions of the world, remain sparse due to numerous constraints. Herein, we report the first cohort of patients with CGD from Nepal, a low-income country in the Himalayas' challenging terrain. Our report includes a description of a new case of CYBC1 deficiency who was first diagnosed with CGD at our center. Only a dozen cases of CYBC1-CGD have been described in the literature thus far which have been reviewed comprehensively herein. Most of these patients have had significant infections and autoimmune/inflammatory manifestations. Pulmonary and invasive/disseminated bacterial/fungal infections were the most common followed by skin and soft-tissue infections. Inflammatory bowel disease (IBD) was the most common inflammatory manifestation (median age at diagnosis: 9 years) followed by episodes of recurrent/prolonged fever. Other autoimmune/inflammatory manifestations reported in CYBC1-CGD include acute pancreatitis, hemophagocytic lymphohistiocytosis, systemic granulomatosis, interstitial lung disease, arthritis, autoimmune hemolytic anemia, uveitis, nephritis, and eczema. Our analysis shows that patients with CYBC1-CGD are at a significantly higher risk of IBD-like illness as compared to other forms of CGD which merits further confirmatory studies in the future.

Immune Thrombocytopenic Purpura (ITP) and Chorioretinopathy in Chronic Granulomatous Disease: A Case Report.

BACKGROUND: Chronic Granulomatous Disease (CGD) is a rare immunodeficiency disorder characterized by impaired phagocytic function, leading to recurrent infections and granuloma formation. Genetic mutations in NADPH oxidase complex components, such as CYBB, NCF1, NCF2, and CYBA genes, contribute to the pathogenesis. This case report explores the possible ocular and hematologic complications associated with CGD. CASE PRESENTATION: A 6-year-old girl with a history of vitrectomy, membranotomy, and laser therapy due to congenital blindness (diagnosed with chorioretinopathy) was referred to the hospital with generalized ecchymosis and thrombocytopenia. Diagnostic workup initially suggested chronic immune thrombocytopenic purpura (ITP). Subsequent admissions revealed necrotic wounds, urinary tract infections, and recurrent thrombocytopenia. Suspecting immunodeficiency, tests for CGD, Nitroblue tetrazolium (NBT) and dihydrorhodamine (DHR) were performed. She had a low DHR (6.7), and her NBT test was negative (0.0%). Her whole exome sequencing results confirmed autosomal recessive CGD with a homozygous NCF1 mutation. CONCLUSION: This case underscores the diverse clinical manifestations of CGD, including recurrent thrombocytopenia and possible early-onset ocular involvement. The diagnostic challenges highlight the importance of a multidisciplinary approach involving hematologists, immunologists, and ophthalmologists for accurate diagnosis and management. The rare coexistence of ITP in CGD emphasizes the intricate link between immunodeficiency and autoimmunity, requiring tailored therapeutic strategies.

A nox2/cybb zebrafish mutant with defective myeloid cell reactive oxygen species production displays normal initial neutrophil recruitment to sterile tail injuries.

Reactive oxygen species are important effectors and modifiers of the acute inflammatory response, recruiting phagocytes including neutrophils to sites of tissue injury. In turn, phagocytes such as neutrophils are both consumers and producers of reactive oxygen species. Phagocytes including neutrophils generate reactive oxygen species in an oxidative burst through the activity of a multimeric phagocytic nicotinamide adenine dinucleotide phosphate oxidase complex. Mutations in the NOX2/CYBB (previously gp91phox) nicotinamide adenine dinucleotide phosphate oxidase subunit are the commonest cause of chronic granulomatous disease, a disease characterized by infection susceptibility and an inflammatory phenotype. To model chronic granulomatous disease, we made a nox2/cybb zebrafish (Danio rerio) mutant and demonstrated it to have severely impaired myeloid cell reactive oxygen species production. Reduced early survival of nox2 mutant embryos indicated an essential requirement for nox2 during early development. In nox2/cybb zebrafish mutants, the dynamics of initial neutrophil recruitment to both mild and severe surgical tailfin wounds was normal, suggesting that excessive neutrophil recruitment at the initiation of inflammation is not the primary cause of the "sterile" inflammatory phenotype of chronic granulomatous disease patients. This nox2 zebrafish mutant adds to existing in vivo models for studying reactive oxygen species function in myeloid cells including neutrophils in development and disease.

Structural basis for EROS binding to human phagocyte NADPH oxidase NOX2.

Essential for reactive oxygen species (EROS) protein is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in EROS is a recently identified cause for chronic granulomatous disease, a genetic disorder with recurrent bacterial and fungal infections. Here, we report a cryo-EM structure of the EROS-NOX2-p22phox heterotrimeric complex at an overall resolution of 3.56Å. EROS and p22phox are situated on the opposite sides of NOX2, and there is no direct contact between them. EROS associates with NOX2 through two antiparallel transmembrane (TM) α-helices and multiple ß-strands that form hydrogen bonds with the cytoplasmic domain of NOX2. EROS binding induces a 79° upward bend of TM2 and a 48° backward rotation of the lower part of TM6 in NOX2, resulting in an increase in the distance between the two hemes and a shift of the binding site for flavin adenine dinucleotide (FAD). These conformational changes are expected to compromise superoxide production by NOX2, suggesting that the EROS-bound NOX2 is in a protected state against activation. Phorbol myristate acetate, an activator of NOX2 in vitro, is able to induce dissociation of NOX2 from EROS with concurrent increase in FAD binding and superoxide production in a transfected COS-7 model. In differentiated neutrophil-like HL-60, the majority of NOX2 on the cell surface is dissociated with EROS. Further studies are required to delineate how EROS dissociates from NOX2 during its transport to cell surface, which may be a potential mechanism for regulation of NOX2 activation.