Chronic Granulomatous Disease Research Articles

Two distinct clinical progressions of P67phox-deficient CGD, both commencing with cervical lymphadenitis.

We present two rare cases of p67phox-deficient chronic granulomatous disease (CGD) caused by compound heterozygous mutations in the NCF2 gene. They developed cervical lymphadenitis as the initial manifestation of CGD but had distinct clinical progressions. Patient 1 presented with aspergillous meningitis, an extremely rare manifestation of neurological involvement in CGD, which has not been reported before. Patient 2 presented with non-infectious inflammatory lymphadenitis is also very rare and has not been reported previously. These cases emphasize the importance of considering p67phox-deficient CGD in children with late-onset invasive fungal infections and non-infectious inflammatory lesions. Additionally, we also reviewed previous reports of Chinese patients with P67phox-Deficient CGD. Our objective is to raise awareness about the clinical, diagnostic, and genetic characteristics of P67phox-deficient CGD in China, to reduce misdiagnosis and improve the management and prognosis of the disease.

Outcomes in hematopoetic cell transplantation in the setting of mold infections in patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a disorder of immunity characterized by phagocyte dysfunction. Mold infections in patients with CGD are often severe and disseminated. We present patient characteristics, microbiological data, and outcomes for 26 patients with CGD who received hematopoietic cell transplantation (HCT) or gene therapy-modified cells (GT) between 2008 and 2019, with proven fungal infection either before or during their transplant. All patients engrafted, and all but one GT recipient had neutrophil recovery and evidence of functional correction. Eighteen patients (69%) are currently alive and 19 patients (73% of total, 90% of patients with repeat imaging performed) had evidence of radiographic improvement. With 3 exceptions, deaths were not principally related to the fungal infection and duration of antecedent infection did not correlate with death. Aspergillus species accounted for the majority of disease (50%), followed by Phellinus species (18%). Osteomyelitis and disseminated disease were common, as only 11 patients (42%) had disease restricted to pneumonia. Triazole therapy was used in all 26 patients, with combination therapy used in 25 (96%). HCT or gene therapy, with appropriate antifungal therapy, are viable therapies for refractory fungal infections in patients with CGD.

Comparison and evaluation of DNA vaccines against Nocardia seriolae infection in largemouth bass (Micropterus salmoides)

Chronic granulomatous diseases caused by Nocardia seriolae have resulted in substantial economic losses for the aquaculture industry. DNA vaccines are considered a promising approach for controlling infectious diseases. To develop effective DNA vaccines against N. seriolae, we selected Ag85L, MmaA4, HspX, Rv3407, and HtpG as candidate antigens. Among these, pcDNA-Ag85L and pcDNA-MmaA4 were the most effective against N. seriolae infection in largemouth bass (Micropterus salmoides), achieving the highest relative percentage survival (RPS) rates of 78.6 % and 92.9 %, respectively. Tissue bacterial loads and histopathological tests revealed a significant reduction in bacterial abundance in the liver, spleen, head kidney, and trunk kidney of the immunised groups compared to that in the control group. Additionally, no distinct pathological changes were observed in the spleen or head kidney tissues. The expression levels of immune-related genes including IL-1β, IL-8, MHCI, MHCII, CD4, and CD8α were significantly upregulated in the pcDNA-Ag85L and pcDNA-MmaA4 immunised groups, thus indicating that the two DNA vaccines mediated immune protection by promoting both humoral and cellular immune responses. Overall, the pcDNA-Ag85L and pcDNA-MmaA4 DNA vaccines demonstrated strong potential for protecting largemouth bass against N. seriolae infection, offering an innovative solution for controlling granulomatous diseases in fish.

High-fidelity PAMless base editing of hematopoietic stem cells to treat chronic granulomatous disease.

X-linked chronic granulomatous disease (X-CGD) is an inborn error of immunity (IEI) resulting from genetic mutations in the cytochrome b-245 beta chain (CYBB) gene. The applicability of base editors (BEs) to correct mutations that cause X-CGD is constrained by the requirement of Cas enzymes to recognize specific protospacer adjacent motifs (PAMs). Our recently engineered PAMless Cas enzyme, SpRY, can overcome the PAM limitation. However, the efficiency, specificity, and applicability of SpRY-based BEs to correct mutations in human hematopoietic stem and progenitor cells (HSPCs) have not been thoroughly examined. Here, we demonstrated that the adenine BE ABE8e-SpRY can access a range of target sites in HSPCs to correct mutations causative of X-CGD. For the prototypical X-CGD mutation CYBB c.676C>T, ABE8e-SpRY achieved up to 70% correction, reaching efficiencies greater than three-and-one-half times higher than previous CRISPR nuclease and donor template approaches. We profiled potential off-target DNA edits, transcriptome-wide RNA edits, and chromosomal perturbations in base-edited HSPCs, which together revealed minimal off-target or bystander edits. Edited alleles persisted after transplantation of the base-edited HSPCs into immunodeficient mice. Together, these investigational new drug-enabling studies demonstrated efficient and precise correction of an X-CGD mutation with PAMless BEs, supporting a first-in-human clinical trial (NCT06325709) and providing a potential blueprint for treatment of other IEI mutations.

Borderline Lepromatous Leprosy Masquerading as Granuloma Annulare: A Case Report

Background: Leprosy is a chronic granulomatous disease caused by Mycobacterium Leprae. Leprosy is a great imitator with its various atypical, unusual and varying clinical presentations which can be confused with many infectious and non-infectious diseases. Case Report: A 46-year-old female presented to the dermatology department with complaints of painful raised lesions over face, upper back, upper limbs, lower legs and feet for 12 months. Clinically suspected as a case of Granuloma annulare. Punch biopsy was taken which revealed epidermis with dermis showing nodules of histiocytes and lymphocytes with grenz zone at the dermoepidermal junction. Acid fast stain and Fite Faraco stain was performed which revealed the presence of leprae bacilli with bacteriological index of 4+. Conclusion: Detailed history taking and correlating clinical picture with morphology is required to diagnose atypical presentations of leprosy. Early diagnosis helps to provide appropriate treatment and thus prevent from devastating complications.

Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements

CRISPR-based genome editing of pseudogene-associated disorders, such as p47phox-deficient chronic granulomatous disease (p47 CGD), is challenged by chromosomal rearrangements due to presence of multiple targets. We report that interactions between highly homologous sequences that are localized on the same chromosome contribute substantially to post-editing chromosomal rearrangements. We successfully employed editing approaches at the NCF1 gene and its pseudogenes, NCF1B and NCF1C, in a human cell line model of p47 CGD and in patient-derived human hematopoietic stem and progenitor cells. Upon genetic engineering, a droplet digital PCR-based method identified cells with altered copy numbers, spanning megabases from the edited loci. We attributed the high aberration frequency to the interaction between repetitive sequences and their predisposition to recombination events. Our findings emphasize the need for careful evaluation of the target-specific genomic context, such as the presence of homologous regions, whose instability can constitute a risk factor for chromosomal rearrangements upon genome editing.

Chronic granulomatous intestinal disease: case report

Chronic intestinal granulomatous disease is a disorder that directly compromises the entire immune system. The estimated incidence is one in a million inhabitants. Among the associated risk factors, the presence of chronic and recurrent infections stands out. In the present case, it is a 39-year-old female patient with a history of intestinal obstruction and endometriosis, who presents abdominal pain in the left abdomen and recurrent abdominal pain without an identifiable cause. Laboratory tests revealed leukocytosis and mild neutrophilia. The tomography showed intestinal dilation at the jejunoileal level without transition zones, and the serological tests were negative. Exploratory laparoscopy was performed and the presence of tumor implants was found in the omentum, extending to the abdominal, uterine, intestinal, and peritoneal regions, as well as sallow fluid at the abdominal level. Tumor markers are normal. Histopathology details fungal colonization with eosinophilic necrosis and presence of granulomas, negative immunohistochemistry for Aspergillus and negative Lowestein-jensen culture. Antifungal and antituberculous treatment was started, with a decrease in symptoms and improvement in the clinical picture.

Multibacillary Leprosy: Presentation of a Clinical Case

Leprosy is an infectious-contagious, chronic granulomatous disease, with a long incubation period (2-21 years), caused by the Mycobacterium leprae complex. It has tropism for skin, mucous membranes of the upper respiratory tract, and peripheral nerves.We present a clinical case of a 24-year-old patient, phototype VI, from the municipality of Huambo, Benfica neighborhood, with a history evolving for about 18 months, without actually making any consultation and with several empirical treatments.

Chronic granulomatous intestinal disease: case report

Chronic intestinal granulomatous disease is a disorder that directly compromises the entire immune system. The estimated incidence is one in a million inhabitants. Among the associated risk factors, the presence of chronic and recurrent infections stands out. In the present case, it is a 39-year-old female patient with a history of intestinal obstruction and endometriosis, who presents abdominal pain in the left abdomen and recurrent abdominal pain without an identifiable cause. Laboratory tests revealed leukocytosis and mild neutrophilia. The tomography showed intestinal dilation at the jejunoileal level without transition zones, and the serological tests were negative. Exploratory laparoscopy was performed and the presence of tumor implants was found in the omentum, extending to the abdominal, uterine, intestinal, and peritoneal regions, as well as sallow fluid at the abdominal level. Tumor markers are normal. Histopathology details fungal colonization with eosinophilic necrosis and presence of granulomas, negative immunohistochemistry for Aspergillus and negative Lowestein-jensen culture. Antifungal and antituberculous treatment was started, with a decrease in symptoms and improvement in the clinical picture.

High symptom burden in female X-linked chronic granulomatous disease carriers

High symptom burden in female X-linked chronic granulomatous disease carriers

Unveiling the nerve bumps in Hansen’s arm and forearm

Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae. Intraneural abscess is the rare presentation of leprosy, which poses a diagnostic challenge to the clinician as well as the radiologist. Early identification, diagnosis, and treatment are imperative to reduce the disability. We wish to highlight the features of this rare entity in a 14-year-old male child who presented with painless swelling in arm and forearm.

Dihydrorhodamine-123 flow cytometry method: time for substantial revision in technical procedure.

The dihydrorhodamine 123 assay is generally applied to measure the production of intracellular reactive oxygen species in neutrophils using flow cytometry and is considered a diagnostic evaluation for chronic granulomatous disease. In fact, there is a broad range of variables that can directly or indirectly affect test results, either individually or collectively. It is therefore crucial to identify the ideal requirements to achieve reliable results as well as using these requirements to provide standard operating procedures that should be taken into account. Therefore, we focus on aligning optimum results by comparing preanalytical and analytical phases that influence test results, such as the effect of various anticoagulants, transport and maintaining temperature (24°C or 4°C) of samples, test prime run time, appropriate solution concentrations, and effect of incubation temperature (24°C or 37°C) during the test run.

Inborn errors of immunity and invasive fungal infections: presentation and management.

We review the clinical presentations of invasive fungal infections in a selection of inborn errors of immunity. In addition, we review the particularities of their management, including antifungal therapy, prophylaxis, and immunomodulatory treatments. Patients with chronic granulomatous disease and with signal transducer and activator of transcription 3 (STAT3) deficiency are particularly prone to aspergillosis. Mold-active antifungal prophylaxis should be prescribed to all patients with chronic granulomatous disease, and in patients with STAT3 deficiency and underlying parenchymal lung disease. Invasive fungal infections are rare in patients with STAT1 gain-of-function mutations, while the clinical phenotype of caspase-associated recruitment domain-containing protein 9 deficiency encompasses a wide range of superficial and invasive fungal infections. Most patients with inborn errors of immunity and invasive fungal infections require prolonged durations of antifungals. Hematopoietic stem cell transplantation should be considered early for patients with chronic granulomatous disease, but results have been more mixed for other inborn errors of immunity with active invasive fungal infections. Inborn errors of immunity can confer increased susceptibility to a variety of invasive fungal infections, which can present with specific clinical and radiological features. Management of fungal infections in these patients is often challenging, and relies on a combination of antimicrobial prophylaxis, antifungal treatments, and immunomodulation.

359. INNOVATIVE USE OF WEERDA DIVERTICULOSCOPE FOR REMOVAL OF AN IMPACTED SHARP FOREIGN BODY IN THE CERVICAL OESOPHAGUS MIMICKING MALIGNANCY

Abstract Background Chronically impacted sharp foreign bodies (FB) of the cervical or upper thoracic oesophagus can present a diagnostic dilemma. Fifty percent of sharp objects tend to lodge in the upper oesophagus and frequently cause perforation. A multidisciplinary approach is warranted. Eventually, surgery by cervical oesophagotomy/thoracotomy may be required. The Weerda diverticuloscope offers excellent endoscopic visibility and access to the lumen of the upper oesophagus allowing for removal of FBs and mitigating risks of a major surgical procedure. Methods We report an interesting case of a 27 year old gentleman being investigated for dysphagia. The patient notes were obtained from the electronic patient records. The radiological images were sourced from the picture archiving and communication system (PACS) and endoscopy from stored images. The patient was radiologically diagnosed as having T4 malignancy but consecutive biopsies suggested Actinomycosis. Patient thereafter recollected having a fist fight and losing his dentures. This triggered the use of the Weerda diverticuloscope, a bivalved rigid diverticuloscope (Karl Storz, Tuttlingen, Germany). It has a distal fibreoptic illumination that is designed for trans-oral stapling of pharyngeal pouches Results Under general anaesthesia, the Weerda diverticuloscope was introduced into the cervical oesophagus. The tips of the jaws positioned just proximal to the embedded dental prosthesis. The diverticuloscope was suspended for stabilisation in the same manner as for endoscopic stapling of a pharyngeal pouch and the jaws were distracted to allow endoscopic access. A 5mm rigid telescope was passed alongside a pair of heavy endoscopic scissors and the prosthesis was divided into 3 parts. The central intraluminal component was removed first using endoscopic forceps, followed by gentle disimpaction and extraction of the remaining two components embedded in the oesophageal wall. Conclusion Foreign bodies in the oesophagus rarely can mimic cancer or chronic granulomatous diseases. A multidisciplinary approach is occassionally recommended in their management. There have been a few published reports of the use of the Weerda diverticuloscope to remove upper oesophageal FBs successfully. It’s use, however, is not often considered routinely. We recommend the use of this technique at centres where expertise in endoscopic management of Zenker’s diverticula is available and when endoscopic retrieval has failed.

Severe clinical phenotypes of heterozygous females with X-linked chronic granulomatous disease

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.

Profile of juvenile systemic lupus erythematosus patients with a special reference to monogenic lupus and lupus nephritis: a cross-sectional study.

To study the clinical, laboratory profile and outcome of juvenile Systemic Lupus Erythematosus (jSLE) patients at a tertiary care centre in South India. A retrospective review of the medical records of all jSLE patients visiting the Pediatric Immunology and Rheumatology Unit, Aster CMI Hospital, India from February 2017 to December 2023 was performed. The clinical characteristics, treatment and outcomes were recorded and tabulated. Seventy patients diagnosed with jSLE were included in the study. The female-to-male ratio was 4.4:1. Mean age at onset and delay in diagnosis were 120.1 (+/- 56.8) and 11.7 (+/- 22.7) months respectively. The median follow-up period was 13 months (range 4, 29 months). Nine patients presented with early onset SLE (< 5 years). Most common manifestations were constitutional symptoms (n = 56), followed by haematologic (n = 55), and mucocutaneous(n = 50) involvement. Immunological workup showed SLE-specific antibody positivity in 38 patients, hypocomplementemia in 40 patients, and anti-phospholipid antibody positivity in 13 patients. Mortality was observed in five patients with LN while there was no mortality in the non-nephritis group (p 0.004). C1q deficiency was the most common cause of monogenic lupus seen in 5/9 patients; protein kinase C delta (PRKCD) defect and chronic granulomatous disease (CYBB mutation) were seen in one patient each. We describe a large cohort of jSLE from Southern India. Lupus nephritis was noted in 35.7% of our cohort and had a direct correlation with mortality. 10% of patients had monogenic lupus. Serious infections were more frequent in patients with monogenic lupus.

Identification of overlapping molecular mechanisms in tuberculosis and sarcoidosis: A bioinformatics approach

BackgroundTuberculosis (TB) and sarcoidosis are chronic granulomatous diseases sharing similar symptoms, immune responses, and radiological characteristics. Transcriptome analysis offers insights into gene expression, regulation, and cellular processes, facilitating the understanding of shared molecular mechanisms. MethodsMicroarray datasets from the NCBI Gene Expression Omnibus (NCBI-GEO) were analysed to identify differentially expressed genes (DEGs) in TB and sarcoidosis compared to controls. DEGs were identified using the GEO2R tool, and subsequent functional enrichment analysis was conducted using EnrichR. Protein-protein interaction (PPI) networks, as well as gene-miRNA and transcription factor-DEG interaction networks, were constructed. In addition, pathway analysis and molecular docking of target proteins were conducted to further elucidate the biological mechanisms involved in both diseases. ResultsFifteen genes, including ANKRD22, BATF2, DHRS9, EPSTI1, ETV7, FCGR1A, FCGR1B, GBP1, GBP5, SERPING1, NELL2, CCR7, PASK, LRRN3, and SLC16A10, were commonly altered in TB and sarcoidosis as compared to controls. Gene network analysis revealed 48.89% co-expression and 26.10% physical interaction between these overlapping genes. PPI networks showed a total of 15 nodes and 28 edges present between the connected proteins (PPI enrichment p-value:<1.0e−16). MiRNAs and transcription factors that exhibited the highest interaction with DEGs included hsa-miR-26a-5p, hsa-miR-16-5p, hsa-miR-335-5p, and EPAS1, HIF1A, KLF2, respectively. Pathway analysis indicated enrichment of IFN gamma signaling in both diseases. Molecular docking revealed weighted scores of −884.4, −851.9, and − 637.1 between three key proteins (PASK-GBP1, PASK-GBP5, and GBP1-GBP5). ConclusionThe shared dysregulated genes in TB and sarcoidosis demonstrate notable co-expression and physical interaction, constituting a PPI network enriched in the IFN-gamma signaling pathway.

Cardiac sarcoidosis presenting as multiple right intra-atrial masses mimicking cardiac tumor

BackgroundCardiac sarcoidosis though in itself, a rare entity, very rarely presents primarily with conduction abnormalities as the primary manifestation in the spectrum of presentations accounted by this chronic granulomatous systemic disease. Sarcoidosis presenting as intra-atrial masses is virtually unheard of.CaseA middle aged female presented with progressive conduction system disease was found to have right atrial masses of unclear etiologic on relevant imaging. Over the course of 3 months she underwent a dual-chamber ICD implant for her eventual complete heart block and a surgical resection following an inconclusive biopsy of the right atrial free wall mass. She was then diagnosed with cardiac sarcoidosis and started on immunosupressants almost instantaneously as a part of her treatment.ConclusionThis is an entirely new and unreported presentation of cardiac sarcoidosis as an intra-atrial mass. Through this case we bring light to cardiac sarcoidosis as a potential differential for intra-cardiac masses and how with available data do we go about treating it.

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

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. 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. 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. 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.

Permissive lung neutrophils facilitate tuberculosis immunopathogenesis in male phagocyte NADPH oxidase-deficient mice.

NADPH oxidase 2 (NOX2) is an enzyme responsible for generating reactive oxygen species, primarily found in phagocytes. Chronic Granulomatous Disease (CGD), along with bacterial infections such as Mycobacterium tuberculosis (Mtb), is a representative NOX2-deficient X-linked disease characterized by uncontrolled inflammation. However, the precise roles of host-derived factors that induce infection-mediated hyperinflammation in NOX2-deficient condition remain incompletely understood. To address this, we compared Mtb-induced pathogenesis in Nox2-/- and wild type (WT) mice in a sex-dependent manner. Among age- and sex-matched mice subjected to Mtb infection, male Nox2-/- mice exhibited a notable increase in bacterial burden and lung inflammation. This was characterized by significantly elevated pro-inflammatory cytokines such as G-CSF, TNF-α, IL-1α, IL-1β, and IL-6, excessive neutrophil infiltration, and reduced pulmonary lymphocyte levels as tuberculosis (TB) progressed. Notably, lungs of male Nox2-/- mice were predominantly populated with CD11bintLy6GintCXCR2loCD62Llo immature neutrophils which featured mycobacterial permissiveness. By diminishing total lung neutrophils or reducing immature neutrophils, TB immunopathogenesis was notably abrogated in male Nox2-/- mice. Ultimately, we identified G-CSF as the pivotal trigger that exacerbates the generation of immature permissive neutrophils, leading to TB immunopathogenesis in male Nox2-/- mice. In contrast, neutralizing IL-1α and IL-1β, which are previously known factors responsible for TB pathogenesis in Nox2-/- mice, aggravated TB immunopathogenesis. Our study revealed that G-CSF-driven immature and permissive pulmonary neutrophils are the primary cause of TB immunopathogenesis and lung hyperinflammation in male Nox2-/- mice. This highlights the importance of quantitative and qualitative control of pulmonary neutrophils to alleviate TB progression in a phagocyte oxidase-deficient condition.