Leprosy is a chronic granulomatous disease resulting from infection with the unculturable pathogen Mycobacterium leprae. Lepromatous leprosy is the most severe form, typically seen in adults with poor immune response to the bacillus. It is exceptionally rare in young children, specially under 10 years of age due to disease's long incubation period and lower exposure. Early presentation in a child raises question about atypical transmission and host susceptibility. We report a case of a six-year-old boy from Purbadhola, Netrokona, Bangladesh with a four-year history of progressive, asymptomatic erythematous plaques on the left arm and right side of the face. Physical examination revealed well-defined, dry plaques without definitive sensory loss or nerve thickening. Initial differential diagnoses included lupus vulgaris, lepromatous leprosy, and sarcoidosis. Slit skin smear revealed a bacillary index of 1+, suggesting lepromatous leprosy and again we went for skin biopsy for histopathology for any additive diagnosis and it revealed tuberculoid leprosy. The patient was treated with WHO-recommended multibacillary multidrug therapy (rifampicin, dapsone, clofazimine) in collaboration with Damien Foundation. After 4 months, there was marked improvement, with near-complete resolution of skin lesions. This case highlights the diagnostic complexity in pediatric leprosy where clinical, histopathological, and bacteriological findings may not align. It underscores the importance of comprehensive evaluation and the role of slit skin smear in all suspected cases of leprosy especially in children. Early diagnosis and appropriate treatment are crucial to prevent long-term complications and transmission.

Chronic granulomatous disease-related inflammatory bowel disease (CGD-IBD) requires effective and safe therapies, as conventional immunosuppressants increase infection risk. Thalidomide, with anti-inflammatory and immunomodulatory effects, may represent a therapeutic option. This study was conducted to explore the preliminary efficacy and safety of thalidomide for CGD-IBD in a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. Patients were randomized to thalidomide or placebo for a 12-wk blinded phase, followed by a 12-wk extension thalidomide phase. The primary endpoint was achievement of remission or a ≥20-point reduction in the Pediatric Ulcerative Colitis Activity Index. Eight male patients were randomized and analyzed. The primary endpoint was achieved by 1/3 of thalidomide patients versus 0/5 in the placebo group during the blinded phase, and by 5/8 in the extension phase. Secondary endpoints and exploratory endoscopy showed improvements. CGD-related infection rates were comparable before and after treatment. Thalidomide met the prespecified efficacy criterion with an acceptable safety profile in CGD-IBD, suggesting a promising therapeutic option that warrants further clinical studies.

Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy.

Sarcoidosis is a chronic granulomatous disease marked by persistent inflammation and immune cell aggregation, yet its molecular underpinnings remain incompletely understood, hindering the development of effective targeted therapies. Here, we report that deletion of Tsc1 or Tsc2 in mice using a Fsp1-Cre leads to spontaneous formation of sarcoid-like granulomas, driven by hyperactivation of the mTORC1 pathway in fibroblasts and interstitial macrophages. Through inflammatory cytokine/chemokine array, we identified CCL24, a chemokine ligand for CCR3, as a key immunoregulatory molecule downregulated in both our murine model and sarcoid cohort plasma. Mechanistically, mTORC1 suppresses CCL24 expression via aberrant STAT3 signaling in fibroblasts and promotes CCR3 expression in interstitial macrophages, uncovering a novel regulatory axis in granuloma formation and maintenance. Pharmacological inhibition using rapamycin and azithromycin markedly attenuated granuloma burden and normalized CCL24-CCR3 signaling, underscoring the therapeutic relevance of this axis. Together, our study establishes a mechanistic link between mTORC1 activation, CCL24-CCR3 dysregulation, and granuloma persistence, offering not only a new insight into molecular mechanisms in sarcoidosis, but also identifying promising targets for clinical intervention.

IMPACT (Immune Monitoring and Phenotype Assessment of Clinical Trajectory) for Patients with Inborn Errors of Immunity from the Primary Immune Deficiency Treatment Consortium (PIDTC).

Deleterious mutations in the CYBB gene encoding NOX2 typically cause X-linked recessive chronic granulomatous disease (XR-CGD) by affecting NADPH oxidase-dependent respiratory burst in phagocytes. However, two missense variants (T178P, Q231P) were previously shown to cause isolated Mendelian susceptibility to mycobacterial disease (MSMD) in otherwise healthy males. We describe a novel, private variant in CYBB (c.998C>A, p.S333Y) identified in a male patient with adult-onset disseminated Mycobacterium avium infection. Despite preserved transcript levels, NOX2 protein expression was reduced in the patient's cells. Functionally, an intermediate phenotype was observed, characterized by reduced but not abolished ROS production, with a cell-type specific degree of impairment. This case represents the second report of isolated X-linked recessive MSMD caused by a missense CYBB variant, and the first case presenting in adulthood. Our findings indicate a hypomorphic variant that impairs respiratory burst in a cell type-specific manner, extending previous observations in two kindreds with CYBB-associated MSMD.

The granuloma serves not only as a physical barrier to restrict the dissemination of intracellular pathogens but also functions as a complex immune microenvironment. However, the bioenergetics and regulatory mechanisms maintaining this architecture remain elusive in vertebrates. Here, integrating multi-tissue transcriptomics, single-cell RNA sequencing (scRNA-seq), ultrastructural imaging, and fluorescence in situ hybridization (FISH) in a largemouth bass (Micropterus salmoides)-Nocardia seriolae infection model, we resolved the metabolic and functional landscape of the granuloma. We found that across multiple tissues (head kidney, spleen, liver, kidney), the host initiates a synchronized transcriptional program that promotes macrophage differentiation into specialized epithelioid macrophages (E-Macs). Notably, E-Macs concurrently upregulated specific transporters and metabolic enzymes (e.g., laao, slc6a8), as well as oxidative phosphorylation (OXPHOS) and glycolysis genes, accompanied by mitochondrial proliferation. Functionally, E-Macs shifted from a pro-inflammatory to an immunoregulatory and pro-survival phenotype, characterized by high expression of protease inhibitors (e.g., csta) and anti-apoptotic factors (e.g., bcl2l14, ywhag1). Comparative analysis in zebrafish confirmed these metabolic and regulatory signatures are evolutionarily conserved. In conclusion, this study reveals a host survival strategy of immune regulation underpinned by metabolic adaptation, providing novel perspectives for controlling chronic granulomatous diseases in aquaculture.

Chronic granulomatous disease (CGD) is a primary immunodeficiency marked by defective phagocyte function, predisposing patients to recurrent infections, granuloma formation, and hyperinflammation. Initial diagnosis can be delayed due to nonspecific clinical features, incomplete pathogen detection, and common outpatient antimicrobial use. Plasma microbial cell-free DNA next-generation sequencing (mcfDNA-Seq) is an emerging non-invasive diagnostic tool, but its sensitivity and specificity vary by infection type and host. We report a case of CGD first presenting with concurrent Staphylococcus aureus liver abscess and disseminated Burkholderia cepacia infection, where mcfDNA-Seq contributed to diagnosis and management. An 11-month-old male presented with 17 days of fever, irritability, and bulky cervical lymphadenopathy unresponsive to outpatient antibiotics. Physical exam demonstrated extremity rash, oral ulcers, and bilateral cervical lymphadenopathy. Initial infectious workup was negative including blood and urine cultures, chest radiograph, CMV and EBV serology. Abdominal imaging demonstrated a hepatic abscess, and multiple splenic and hepatic lesions interpreted as granulomas. Culture of liver abscess drainage grew methicillin-resistant S. aureus (MRSA). Fevers and lymphadenopathy continued despite vancomycin, with no evidence of spread or recurrence of MRSA. Rapid resolution of symptoms was achieved after initiating intravenous trimethoprim-sulfamethoxazole and plasma mcfDNA-Seq confirmed presence of Burkholderia cepacia. Subsequent genetic and dihydrorhodamine flow cytometric testing confirmed the suspected diagnosis of CGD. This case highlights the diagnostic challenges associated with CGD and the potential utility of plasma mcfDNA-Seq in this immunocompromised population. It may serve as a less invasive alternative to tissue specimens, particularly when conventional diagnostics are unrevealing. Concurrent infections should be considered during febrile illness in patients with CGD, especially with failure to respond to therapy.

The Burkholderia cepacia complex (Bcc) comprises a diverse group of opportunistic pathogens that are critically relevant to human and animal health. Bcc induces life-threatening infections of the lung in human patients with cystic fibrosis and chronic granulomatous disease and causes mastitis and abscesses in sheep and goats. Therefore, this research aimed to identify the presence of Burkholderia cepacia complex (Bcc) in goats in Bangladesh using serological tests such as the Glanders Rapid Detection Test Kit (GRDTK) and Enzyme-linked immunosorbent assay (ELISA) and molecular tests such as PCR, Sanger sequencing, and phylogenetic analyses. A total of 40 goat blood samples were collected, comprising 30 samples from goats exhibiting a history of abortion accompanied by respiratory symptoms and 10 samples from clinically healthy control goats. Among the 30 samples from symptomatic goats, eight isolates (26.67%) were observed to grow in Luria-Bertani broth, while there was no growth from the control group. Five (62.50%) were found positive for bacterial presence when analyzed using the 16S rRNA gene-specific PCR assay for broth-positive samples. In the Genomix GRDTK and ELISA tests, six isolates were identified as positive for Burkholderia spp. Of the eight broth culture-positive samples, two (25%) were found to be positive by genus-specific PCR using groEL primers and species-specific amplification using zmpA primers. Phylogenetic analysis of positive goat samples confirmed the presence of the Bcc, which showed 100% similarity with the strains from India, Japan, and China. The discovery is the first detection of Bcc in animals in Bangladesh. It raises significant concerns for animal and public health. These findings highlight the critical need for strengthened diagnostic strategies, improved microbiological surveillance, and further research into Bcc’s epidemiology and zoonotic potential within the One Health framework to understand better and mitigate its zoonotic risks.

Chronic granulomatous disease (CGD) is an inborn error of immunity of caused by pathogenic variants of genes encoding components of the phagocyte NADPH oxidase complex, resulting in defective reactive oxygen species production and impaired microbial killing. We conducted a multicenter evaluation of 39 Colombian patients with CGD from 32 unrelated kindreds, describing their clinical, microbiological, and genetic characteristics. Genetic analyses were performed for 31/39 patients and identified variants of the following genes: CYBB (n = 22), CYBA (n = 3), NCF1 (n = 1), NCF2 (n = 1), and NCF4 (n = 4). All but three of the patients had symptoms, the exceptions being individuals with p40 phox deficiency. BCG-related complications occurred in eight patients, pulmonary tuberculosis in four, and Salmonella spp. bacteremia in 12 of 17 patients with Salmonella infections. Colombian patients with CGD had clinical and microbiological profiles similar to those reported across Latin America. The genetic findings broaden the regional variant spectrum and emphasize the need for earlier diagnosis and better access to specialist testing.

Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI) characterized by defective NADPH oxidase activity, leading to severe infections, hyperinflammation, and immune dysregulation. Autoimmune manifestations are increasingly recognized, whereas systemic lupus erythematosus (SLE) with renal involvement is exceedingly rare. We report an 11-year-old boy with X-linked CGD who developed SLE complicated by class IV/V lupus nephritis (LN), presenting with progressive cutaneous lesions, nephrotic-range proteinuria, hypocomplementemia, and high-titer anti-double-stranded DNA antibodies. Renal biopsy confirmed active proliferative and membranous LN. Unlike previously reported cases, the patient was treated with a full induction and maintenance immunosuppressive regimen, including high-dose corticosteroids and MMF, together with careful antimicrobial prophylaxis. The patient achieved complete clinical, renal, and immunological remission without infectious complications. This case highlights the diagnostic and therapeutic challenges of managing LN in CGD and suggests that a full immunosuppressive regimen may lead to favorable outcomes even in this highly vulnerable population.

The dihydrorhodamine-123 flow cytometry (DHR FC) assay is used to diagnose chronic granulomatous disease (CGD). This study presents the experience of a single center with the DHR FC assay in a large cohort to evaluate its applications and limitations. A total of 179 subjects were included in the study for CGD diagnosis, X-linked CGD (X-CGD) carrier determination, and post-hematopoietic stem cell transplantation (HSCT) chimerism monitoring. We performed the DHR FC assay using a standardized protocol, with additional intracellular myeloperoxidase (MPO) staining for borderline cases. The DHR FC assay demonstrated high diagnostic accuracy. PMA stimulation detected 94% of CGD cases. E. coli stimulation identified all CGD cases, including atypical EROS-deficient (CYBC1) patients (4.3% of the cohort) who exhibited residual reactive oxygen species production (median SI PMA = 40 vs. E. coli = 24). Genetic confirmation revealed that 82% of CGD patients had X-CGD (CYBB), and 18% had autosomal recessive CGD (CYBA/NCF1/NCF2/CYBC1) forms. Borderline results were clarified by MPO staining, which diagnosed three MPO-deficient cases. The assay reliably identified 43 X-CGD carriers out of 45 suspected cases and showed a strong correlation with the real-time quantitative polymerase chain reaction for HSCT chimerism monitoring (r = 0.78, p < 0.0001). The DHR FC assay is a rapid and reliable diagnostic tool for CGD, providing results within hours. Its applications extend to X-CGD carrier detection and post-HSCT chimerism monitoring. Dual-stimulant protocols (PMA + E. coli) and MPO staining enhance diagnostic accuracy. These findings support the use of the DHR FC assay as a versatile and essential tool in CGD management.

Chronic pulmonary aspergillosis (CPA) affects those with underlying lung conditions or mild immunocompromise. Chronic pulmonary aspergillosis carries a poor prognosis in adults. Its pathogenesis remains obscure. We summarize all cases of CPA in children globally. From 6503 screened reports, we reviewed the full text of 604, of which 44 fit the inclusion criteria and an additional 11 other cases with little detail which were included under Supplementary Data. Chronic granulomatous disease and cystic fibrosis cases were excluded. We found 47 well-documented individual cases of CPA in children published from 1963 to 2022. Twenty-two cases were simple aspergillomas, and 11 were chronic cavitary pulmonary aspergillosis. Ages ranged from under 1 year to 17 years old, and 28 (59.8%) were male. Eighteen (38.3%) cases had no reported underlying disease. Underlying diseases included pulmonary tuberculosis (14.9%), Job's Syndrome (10.6%), congenital pulmonary airway malformation (8.5%), allergic bronchopulmonary aspergillosis or asthma (6.4%), pulmonary hydatid cyst (4.3%), bacterial pneumonia with cavitation (4.3%), diabetes mellitus (4.3%), and single cases of pulmonary sequestration or bronchogenic cyst. All cases had either microbiological or immunological evidence of Aspergillus spp. apart from 2 confirmed by histopathology only. Surgical resection only was done in 18 (39.1%) patients, 15 (32.6%) were treated with surgery and antifungal therapy, and 13 (28.3%) were only treated with antifungals; one patient died before intervention. Forty-three cases (91.5%) were alive on hospital discharge, but follow-up was limited, while 2 died. Chronic pulmonary aspergillosis is apparently rare in children but does occur, often with no antecedent condition. Prognosis is good with early diagnosis.

Chronic Granulomatous Disease (CGD) is a defect or abnormality in the immune system that produces severe and persistent signs and symptoms in affected individuals. Phenotypic diversity and genetic heterogeneity exist among patients with inborn errors of immunity (IEI). Symptoms may vary even when the mutations are identical; conversely, patients with different mutations may have similar clinical features. The expression of phenotype may be determined by the gene sequence, epigenetic changes, and sometimes environmental factors. Some of these outcomes are influenced by the individual's past immunological exposure. This study discusses two CGD cases, a father and son; after the diagnosis of CGD in the child and confirmation of the genetic mutation, the same mutation was also identified in the father. Therefore, physicians should have more awareness that a single genetic mutation can have different clinical manifestations.

Introduction Sarcoidosis is a chronic granulomatous disease affecting various organs and systems, most commonly the lungs and lymph nodes, but also the musculoskeletal system (4 – 38% of patients). Ankylosing spondylitis (AS) is the most common type of spondyloarthropathy, predominantly affecting the axial skeleton. It has been reported that AS can occur in patients with sarcoidosis almost two times more frequently than in the general population, we present three case reports of the coexistence of sarcoidosis and AS. Case description The first patient was a 52-year-old man diagnosed with sarcoidosis based on clinical manifestations, radiological findings and lymph node biopsy. Additionally, he suffered from back pain since he was 25 years old and a computed tomography (CT) scan depicted syndesmophytes in his spine and ankylosis of sacroiliac joints. The patient was referred to the rheumatologist, and based on modified New York Criteria, AS with positive HLA-B27 antigen was diagnosed. The patient has been treated with non-steroidal anti-inflammatory drugs (NSAIDs) and sulfasalazine due to an inflammatory bowel disease. The second patient was a 56-year-old man diagnosed with AS with positive HLA-B27 antigen two years prior, treated with NSAIDs and upadacitinib. The patient reported a frequent productive cough, and his chest CT scan revealed enlarged bilateral mediastinal lymph nodes. Pulmonary functional tests were normal, and due to unclear histopathological results, a second lymph node biopsy was performed, and eventually, it confirmed the diagnosis of sarcoidosis. The third patient was a 58-year-old woman also diagnosed with AS with positive HLA-B27 antigen eleven years prior, treated with certolizumab. Additionally, patient reported periodic dyspnoea, and based on a high-resolution CT scan, sarcoidosis was suspected. Lymph node biopsy was performed, and a diagnosis of sarcoidosis was established. The first patient was treated with NSAIDs, the second and third with glucocorticosteroids and NSAIDs, with complete resolution of symptoms and lymphadenopathy in later observation. Conclusions Sarcoidosis and AS coexist, and this phenomenon might be explained by shared pathogenic mechanisms, including Th17 cells, tumour necrosis factor (TNF), interleukin-12 (IL-12), and IL-23 and – at least in some patients – sarcoidosis may occur during anti-TNF treatment. Further studies on this rare but intriguing association should be conducted.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency characterized by impaired phagocytic cells due to mutations in genes encoding the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, leading to recurrent severe infections. In the innate immune system, NETosis, which is a program for the formation of neutrophil extracellular traps (NETs) has been highlighted. Over the past years, NETs have been recognized as being involved in the pathogenesis of immune-mediated inflammatory renal diseases. On the mechanism underlying usual NETosis, reactive oxygen species (ROS) activation by NADPH oxidase (NOX) has been considered to be essential. CGD patients are theoretically unable to form such usual NETosis because of a deficiency of NOX-dependent ROS activation. However, according to previous reports, stimulated neutrophils derived from CGD patients showed NOX-independent unusual NETosis enriched in mitochondrial DNA. The mitochondrial ROS activation on NETosis in CGD was reported to induce an elevated inflammatory response, instead of the usual ROS generation, which might cause autoimmune diseases. We are interested in the renal autoimmune disorder in CGD, especially the inflamed renal disorder caused by unusual mitochondria-rich NETosis in CGD. Indeed, in vivo analysis has revealed severe renal disorder in MRL/lpr lupus-prone mice lacking NOX activity compared to wild-type of MRL/lpr. A few clinical reports showed aggravation of inflamed glomerulonephritis in patients with CGD. Taken together, we presumed that a defect of usual NOX-dependent NETosis might be a clue for aggravated renal disorder in CGD. In the present review, we summarize the features of NETosis in CGD and discuss the aggravation mechanism for renal disorder in CGD by referring to previous reports.

ABSTRACT Eccrine squamous syringometaplasia (ESS) is an uncommon reactive alteration of eccrine ducts, most often reported in oncologic and transplant settings, where it may clinically mimic acute cutaneous graft‐versus‐host disease (GVHD). We describe a 3‐year‐old boy with chronic granulomatous disease who developed a diffuse erythematous eruption 6 weeks after haploidentical hematopoietic stem cell transplantation. Clinically suggestive of acute GVHD, histopathologic examination instead revealed spongiotic dermatitis with prominent squamous metaplasia of eccrine ducts, in the absence of interface dermatitis, keratinocyte apoptosis, or satellitosis, supporting a diagnosis of ESS. The eruption resolved with topical corticosteroids without modification of systemic therapy. We also provide a brief review of Scopus/PubMed‐indexed literature, summarizing reported clinical settings, triggers, histopathologic features, and outcomes. Clinicopathologic correlation is essential in transplant recipients to distinguish ESS from GVHD and to avoid unnecessary escalation of immunosuppression.

Background: Renal malakoplakia is a rare chronic granulomatous inflammatory disorder characterized by defective macrophage function. It typically occurs in immunocompromised patients with recurrent urinary tract infections. We present a case of renal malakoplakia in a diabetic patient who progressed to nephrectomy despite initial conservative management. Case presentation: A 57-year-old female patient with a medical history of insulin-dependent type 2 diabetes mellitus was admitted to the hospital with symptoms including fever, left flank pain, and dysuria. A physical examination revealed a tender left lumbar mass. Laboratory investigations revealed a leukocytosis (16,500/mm³), elevated C-reactive protein (142 mg/L), and preserved renal function. A urine culture revealed the presence of multidrug-resistant Escherichia coli (&gt;106CFU/mL). A subsequent Computed Tomography (CT) scan revealed an enlarged left kidney with a 9 × 6 cm multiloculated subcapsular collection, causing significant parenchymal compression, along with two non-obstructive inferior pole calculi. The initial management strategy encompassed ultrasound-guided percutaneous drainage and targeted antibiotic therapy, with the latter being contingent upon bacterial sensitivities. Notwithstanding the patient’s positive clinical recovery, Technetium-99m Dimercaptosuccinic Acid ((99m)Tc-DMSA) renal scintigraphy performed four weeks after the episode revealed a non-functional left kidney, exhibiting a 15% differential function. Following a multidisciplinary discussion, a total left nephrectomy was performed. A histopathological examination revealed extensive replacement of renal parenchyma by polymorphous inflammatory infiltrate with pathognomonic Michaelis-Gutmann bodies. These bodies are spherical, basophilic, perinuclear inclusions that demonstrate strong positivity for Periodic Acid-Schiff and Perls stains. The postoperative course was complicated by self-limited lymphorrhage. At the 3-month follow-up, the patient reported complete resolution of symptoms and remains under nephrological surveillance. Conclusion: This case underscores the diagnostic challenges posed by renal malakoplakia, a condition that can present with a wide spectrum of mimics, including infectious and neoplastic processes. Early diagnosis and prolonged antibiotic therapy with agents capable of intracellular penetration may preserve renal function; however, nephrectomy remains necessary when irreversible parenchymal damage has occurred. Diabetes mellitus has been identified as a significant risk factor for malakoplakia development through impaired leukocyte function.

Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency with an estimated incidence of 1 in 200,000-250,000 live births caused by defects in the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase complex. NADPH oxidase deficiency leads to an impaired phagocyte respiratory burst and increased susceptibility to recurrent bacterial and fungal infections, with excessive inflammation and granuloma formation. This is a case report of 10‑month‑old infant who initially presented with pneumonia and cervical lymphadenitis. The child had a history of multiple hospital admissions for infections, raising concern for an underlying immunodeficiency. Laboratory evaluation showed an elevated C‑Reactive Protein (CRP) with neutrophil predominance. The tuberculin skin test was positive, while mycobacterial PCR (polymerase chain reaction) was negative. Blood cultures grew Staphylococcus aureus. Cervical lymph node biopsy demonstrated granulomatous inflammation. Functional testing with the Nitroblue Tetrazolium Test (NBT) and Dihydrorhodamine (DHR) flow cytometry revealed a defective oxidative burst. Whole‑exome sequencing identified a CYBB (cytochrome b-245 beta chain) mutation, confirming a diagnosis of X‑linked CGD. The patient’s active infection and inflammatory manifestations were treated successfully. This case highlights the importance of early screening for CGD in infants with recurrent or severe infections, the use of definitive functional and genetic testing for accurate diagnosis, and the timely initiation of antimicrobial prophylaxis to reduce morbidity and mortality

The Nox2 NADPH oxidase regulates neutrophilic inflammation in the oral cavity.