Manish Butte

J Med Case Rep. 2025 Oct 30;19(1):556. doi: 10.1186/s13256-025-05637-w.

ABSTRACT

BACKGROUND: Hyperimmunoglobulin D syndrome is a rare autosomal recessive autoinflammatory syndrome caused by mevalonate kinase enzyme deficiency. It is characterized by recurrent febrile attacks beginning in the first year of life. Treatment is mainly supportive, and there are successful reports of trials of novel therapies such as anakinra and canakinumab.

CASE PRESENTATION: We present a case of a 3-month-old girl from Tanzania, East Africa, who experienced recurrent febrile attacks, sepsis, and anemia since her first week of life. She also exhibited arthritis, generalized lymphadenopathy, urticaria, dermatitis, and failure to thrive. After multiple hospital admissions for similar symptoms, a diagnosis of primary immunodeficiency was considered and genetic testing revealed two heterozygous-like pathogenic variants in the mevalonate kinase gene.

CONCLUSION: This case highlights the importance of clinicians in low-resource settings to have a high index of suspicion for primary immunodeficiencies when managing patients with recurrent febrile infections and to consider genetic studies for accurate diagnosis.

PMID:41168890 | DOI:10.1186/s13256-025-05637-w

Ther Adv Hematol. 2025 Oct 22;16:20406207251388051. doi: 10.1177/20406207251388051. eCollection 2025.

ABSTRACT

BACKGROUND: The therapeutic use of immunoglobulin (IG) is increasing and accounts for the largest expenditure in the Canadian Blood Services budget. However, more granular data on IG utilization is limited.

OBJECTIVE: To describe IG treatment indications, dosing characteristics, and clinical outcomes in patients enrolled in the Ontario IG Treatment (ONIT) program, a government-funded pilot clinical program with a case registry.

METHODS: A longitudinal descriptive study was conducted on ONIT registry participants from June 1, 2020 to March 31, 2024.

RESULTS: Six hundred ninety-three consenting participants were included; 429 (61.9%) were female; median [Q1, Q3] age was 62 [47, 71] years; 47 (6.8%) passed away during the study period. Of 693, 658 (94.9%) were receiving IG treatment: 544 (82.7%) on SCIG and 114 (17.3%) on IVIG. Treatment indications were primary immune deficiency (PID) (299, 43.1%), secondary immune deficiency (SID) (348, 50.2%), and immune-mediated disease (IMD) (46, 6.7%). The median dose was 0.48 [0.42, 0.57] and 0.52 [0.44, 0.64] g/kg/4 weeks, for SCIG and IVIG, respectively. Seventy-three patients transitioned from IVIG to SCIG, with the dose adjusted to clinical response. The IVIG:SCIG conversion ratios were 1:1, 1:0.9, and 1:1.2 for PID, SID, and IMD, respectively. Only 33 (5.0%) stopped IG during the study. There was a 78.4% reduction in infections and over 90% reduction in emergency room visits and hospitalizations in PID and SID. Most patients (89.4%) reported improved health after starting IG therapy.

CONCLUSION: The study provides insights into the current landscape of IG utilization, which may inform health system research and support healthcare delivery planning.

PMID:41164014 | PMC:PMC12559670 | DOI:10.1177/20406207251388051

Folia Med (Plovdiv). 2025 Oct 30;67(5). doi: 10.3897/folmed.67.e142724.

ABSTRACT

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder that is either X-linked or autosomal recessive and is characterized by recurrent infections. The diagnosis is primarily based on the nitroblue tetrazolium dye reduction test. Here, we present the case of a 28-year-old pregnant woman with CGD who was diagnosed before marriage and who presented with recurrent subcutaneous skin and ocular infections. Following treatment with multiple antibacterial agents, including meropenem, her infections resolved, and she gave birth to a healthy baby girl at term. However, the newborn has now started to exhibit similar symptoms to those experienced by her mother. This case highlights the need for further studies on the potential impact of maternal chemotherapy on CGD.

PMID:41163607 | DOI:10.3897/folmed.67.e142724

Cell Biosci. 2025 Oct 29;15(1):149. doi: 10.1186/s13578-025-01490-y.

ABSTRACT

BACKGROUND: Immunoglobulin D (IgD) has historically been considered as a surface marker of mature B cell with its specific function being undefined. Until now, no evidence had been presented to suggest that IgD is also expressed in pro-B cells. This study was designed to elucidate the significance for IgD in early B cell development.

RESULTS: Here we developed a mouse model with a targeted deletion of IgD, and assessed the production of the IgM, IgG and IgA, as well as the generation of the antigen specific antibodies. The findings indicated no significant differences in these Ig levels between wild-type and IgD-deficient mice. However, we observed a notable reduction in the number of mature B cells, which led us to the surprising discovery that this decrease in B cell count begins at the pro-B cell stage. More significantly, we identified that IgD, in its intact tetrameric structure, is expressed in the nucleus of pro-B cells. Functionally, IgD appears to promote the proliferation of pro-B cells. Mechanistically, IgD exhibits a transcription factor-like activity, and directly binds to the promoter region of E2f3, a pro-proliferative transcription factor to drive the expression of E2f3, thereby promoting pro-B cells proliferation.

CONCLUSIONS: Taken together, this novel insight into the physiological significance of IgD in B cell development has important implications for our understanding of immune system function.

PMID:41163050 | DOI:10.1186/s13578-025-01490-y

Ann Clin Microbiol Antimicrob. 2025 Oct 29;24(1):60. doi: 10.1186/s12941-025-00830-7.

ABSTRACT

Inborn errors of immunity (IEIs) are a frequently underdiagnosed group of disorders, with infectious complications posing significant clinical challenges. Recognizing atypical presentations of common infections and the presence of rare opportunistic pathogens can be critical in suspecting an underlying IEI. Among the infectious complications, chronic viral infections are particularly difficult to manage due to limited evidence-based guidelines. Intra-host viral evolution in these patients can lead to treatment resistance and the emergence of novel viral strains, raising concerns about their potential role as reservoirs for mutant viruses. Novel pathogens such as Aichivirus have been identified as significant causes of infection in individuals with IEIs. Furthermore, infections such as talaromycosis, tuberculosis, BCG-related disease, leishmaniasis, and melioidosis may be underrecognized in certain groups of patients with IEIs, largely due to differences in geographic exposure and environmental risk factors. The effects of emerging infections, such as mpox and Middle East respiratory syndrome coronavirus, on individuals with IEIs remain largely unknown. Management strategies for infections in this population include vaccinations, immunoglobulin replacement, and antimicrobial prophylaxis. However, newer higher valency conjugate pneumococcal vaccines may limit the utility of traditional pneumococcal polysaccharide vaccines in assessing immune function. While immunoglobulin replacement is cost-effective, it can interfere with serological diagnostics. Additionally, antimicrobial resistance is a growing issue, emphasizing the need for improved empiric antibiotic strategies and research into optimal treatment durations. This review highlights the key challenges faced by infectious disease clinicians in the care of patients with IEIs.

PMID:41163029 | DOI:10.1186/s12941-025-00830-7

Cancer. 2025 Nov 1;131(21):e70157. doi: 10.1002/cncr.70157.

ABSTRACT

BACKGROUND: Ataxia telangiectasia and Rad3-related (ATR) inhibition with berzosertib potentiates the efficacy of irinotecan in preclinical models. The authors hypothesize that this combination is well tolerated, modulates the DNA damage response to irinotecan, and is associated with clinical activity in advanced solid tumors.

METHODS: In this phase 1 study (NCT02595931), berzosertib 60-270 mg/m² was administered with irinotecan 180 mg/m² every 2 weeks in a 4-week cycle. The primary end point was determination of the maximum tolerated dose and recommended phase 2 dose (RP2D). Antitumor activity, pharmacokinetics, and pharmacodynamics were secondary end points.

RESULTS: Sixty-three patients were enrolled, the majority with colorectal cancer (49%) or pancreatic cancer (21%). Median number of prior lines of therapy was four (range, 2-7). Two dose-limiting toxicities, both febrile neutropenia, occurred among 45 patients treated with berzosertib 270 mg/m² and irinotecan 180 mg/m². The most common treatment-related grade ≥3 toxicities were lymphopenia (30%), neutropenia (29%), and anemia (25%). Two partial responses occurred in patients with pancreatic cancer and ataxia telangiectasia mutated (ATM) alterations: 32% decrease in an ATM E11828/ATM K1109* tumor lasting 15.8 months and 57% decrease in an ATM R3008H/germline ATM R1882* tumor lasting 13.6 months. Induction of DNA damage markers γH2AX and pNBS1 was observed in one tumor biopsy obtained post berzosertib and irinotecan combination treatment compared with post irinotecan alone.

CONCLUSION: Berzosertib 270 mg/m² and irinotecan 180 mg/m² was the RP2D. The combination is associated with manageable side effects and promising disease activity in ATM mutant solid tumors.

PMID:41160399 | DOI:10.1002/cncr.70157

Rev Esp Quimioter. 2025 Oct 24;38 Suppl 1:38-42. doi: 10.37201/req/s01.06.2025. Epub 2025 Oct 24.

ABSTRACT

Primary immunodeficiencies, now referred to as inborn errors of immunity (IEI), are increasingly recognized in adults, not only in the pediatric population. In adults, they may present with recurrent, severe, or unusual infections, but also with autoimmunity, malignancy, allergies, or inflammation, posing a diagnostic challenge. This review is based on clinical experience and the 2022 International Union of Immunological Societies classification. It includes four clinical cases and proposes a practical approach for the evaluation of adults. In the presence of suspected IEI, a stepwise laboratory approach is proposed to facilitate early detection and improve prognosis. Initial screening with basic immunological tests-including complete blood count, immunoglobulin and complement levels, and lymphocyte immunophenotyping-is emphasized. Confirmation of each IEI requires more specific testing, often involving molecular techniques.

PMID:41159229 | DOI:10.37201/req/s01.06.2025

Front Oncol. 2025 Oct 13;15:1668762. doi: 10.3389/fonc.2025.1668762. eCollection 2025.

ABSTRACT

OBJECTIVES: Primary hemophagocytic lymphohistiocytosis (p-HLH), a genetic disorder characterized by hyperinflammation, is associated with high mortality in pediatric hematology. This study investigates laboratory and imaging risk factors for mortality in p-HLH and its subtypes.

METHODS: A retrospective analysis (2012-2024) was conducted on 264 pediatric patients with HLH, categorized into p-HLH and secondary HLH (s-HLH). Five laboratory markers and nine imaging findings were compared between groups and across p-HLH subtypes: familial HLH (F-HLH), immunodeficiency-related HLH (I-HLH), and EBV-driven HLH. Mortality risk factors were analyzed.

RESULTS: The cohort included 264 pediatric patients (median age: 4 years, IQR: 2-7 years, 141 males), with 99 having p-HLH (28 F-HLH, 34 I-HLH, 37 EBV-driven HLH), and 165 having s-HLH (EBV-associated). No significant differences in laboratory parameters were observed between p-HLH and s-HLH. Imaging revealed that p-HLH was associated with less severe ascites, more pronounced hepatomegaly, and greater central nervous system (CNS) involvement than s-HLH. Subgroup analysis showed that F-HLH had more severe CNS involvement, while I-HLH had higher rates of pulmonary complications. Independent mortality risk factors for HLH overall included severe thrombocytopenia (HR = 2.93, 95%CI:1.62-5.30, p < 0.01), CNS involvement (HR = 1.80, 95%CI:1.14-2.84, p = 0.01), and liver/spleen damage (HR = 2.78, 95%CI:1.85-4.18, p < 0.01). For p-HLH, specifically, severe liver/spleen damage (HR = 2.68, 95%CI:1.38-5.21, p < 0.01) and pleural effusion (HR = 3.98, 95%CI:1.20-13.2, p=0.02) were critical factors.

CONCLUSION: No significant differences in mortality risk were found between p-HLH and s-HLH or among p-HLH subtypes. For p-HLH, severe liver/spleen damage and pleural effusion emerged as key mortality predictors.

PMID:41158863 | PMC:PMC12554580 | DOI:10.3389/fonc.2025.1668762

Curr Opin Allergy Clin Immunol. 2025 Dec 1;25(6):455-463. doi: 10.1097/ACI.0000000000001120. Epub 2025 Oct 16.

ABSTRACT

PURPOSE OF REVIEW: Gastric cancer has emerged as a prominent cause of mortality in individuals with primary antibody deficiencies (PAD), especially common variable immunodeficiency (CVID), however its pathogenesis remains still poorly understood. Helicobacter (H.) pylori contributes to gastric cancerrisk in PAD, warranting early detection and eradication strategies. Prevention measures and screening programmes are still debated. This review provides an overview of recent advances in the field and discusses future perspectives.

RECENT FINDINGS: Over the last years, several papers have focused on the epidemiology, pathology, and treatment related to the high incidence and mortality of gastric cancer in PAD. Histological findings support the role of H. pylori as a key contributor, warranting early detection and eradication strategies. Immune dysregulation and genetic susceptibility have also been shown to contribute to the increased risk. H. pylori screening and treatment, along with endoscopic surveillance to identify premalignant and early malignant lesions, are widely recommended. In recent years, a decline in gastric cancer mortality has been observed in patients with CVID, paralleling trends in the general population, reflecting improved H. pylori management and enhanced surveillance.

SUMMARY: Gastric cancer surveillance is a priority in PAD. Further research should clarify pathogenesis, identify reliable biomarkers for risk stratification, and to define optimal surveillance strategies, ultimately improving early diagnosis and survival.

PMID:41158014 | DOI:10.1097/ACI.0000000000001120

Curr Opin Allergy Clin Immunol. 2025 Dec 1;25(6):427-434. doi: 10.1097/ACI.0000000000001115. Epub 2025 Oct 1.

ABSTRACT

PURPOSE OF REVIEW: Previously described as an autosomal recessive form of hyper IgE syndrome, DOCK8 deficiency is now recognized as a combined immunodeficiency, with predominant dermatological manifestations. This review details overlap between DOCK8 deficiency, actin regulator actinopathies, and Tregopathies, and summarizes current treatment experience.

RECENT FINDINGS: Dermatological infection and inflammation are predominant features of DOCK8 deficiency. Previous research demonstrated the importance of the actin defect in contributing to the severe and persistent viral infection that characterizes DOCK8 deficiency. More recent findings have demonstrated a reduction in number and function of regulatory T lymphocytes in the skin of patients with DOCK8 deficiency, which contributes to the severe inflammatory phenotype and may be controlled by treatment with dupilumab. The outcomes of haematopoietic stem cell transplantation are summarized.

SUMMARY: DOCK8 deficiency is a severe inborn error of immunity with features of Tregopathies, actinopathies, and STAT3 signalling defects. Curative treatment with haematopoietic stem cell transplantation should be offered to these patients, and abolishes most of the symptoms, although allergic manifestations may persist.

PMID:41158011 | DOI:10.1097/ACI.0000000000001115