Manish Butte

JAMA. 2025 Apr 28. doi: 10.1001/jama.2025.2680. Online ahead of print.

ABSTRACT

IMPORTANCE: Non-cystic fibrosis (CF) bronchiectasis is a chronic lung condition caused by permanent bronchial dilatation and inflammation and is characterized by daily cough, sputum, and recurrent exacerbations. Approximately 500 000 people in the US have non-CF bronchiectasis.

OBSERVATIONS: Non-CF bronchiectasis may be associated with prior pneumonia, infection with nontuberculous mycobacteria or tuberculosis, genetic conditions (eg, α1-antitrypsin deficiency, primary ciliary dyskinesia), autoimmune diseases (eg, rheumatoid arthritis, inflammatory bowel disease), allergic bronchopulmonary aspergillosis, and immunodeficiency syndromes (eg, common variable immunodeficiency). Up to 38% of cases are idiopathic. According to US data, conditions associated with non-CF bronchiectasis include gastroesophageal reflux disease (47%), asthma (29%), and chronic obstructive pulmonary disease (20%). The prevalence of non-CF bronchiectasis increases substantially with age (7 per 100 000 in individuals 18-34 years vs 812 per 100 000 in those ≥75 years) and is more common in women than men (180 vs 95 per 100 000). Diagnosis is confirmed with noncontrast chest computed tomography showing dilated airways and often airway thickening and mucus plugging. Initial diagnostic evaluation involves blood testing (complete blood cell count with differential); immunoglobulin quantification testing (IgG, IgA, IgE, and IgM); sputum cultures for bacteria, mycobacteria, and fungi; and prebronchodilator and postbronchodilator spirometry. Treatment includes airway clearance techniques; nebulization of saline to loosen tenacious secretions; and regular exercise, participation in pulmonary rehabilitation, or both. Inhaled bronchodilators (β-agonists and antimuscarinic agents) and inhaled corticosteroids are indicated for patients with bronchiectasis who have asthma or chronic obstructive pulmonary disease. Exacerbations of bronchiectasis, which typically present with increased cough and sputum and worsened fatigue, are associated with progressive decline in lung function and decreased quality of life. Exacerbations should be treated with oral or intravenous antibiotics. Individuals with 3 or more exacerbations of bronchiectasis annually may benefit from long-term inhaled antibiotics (eg, colistin, gentamicin) or daily oral macrolides (eg, azithromycin). Lung transplant may be considered for patients with severely impaired pulmonary function, frequent exacerbations, or both. Among patients with non-CF bronchiectasis, mortality is higher for those with frequent and severe exacerbations, infection with Pseudomonas aeruginosa, and comorbidities, such as chronic obstructive pulmonary disease.

CONCLUSIONS AND RELEVANCE: Non-CF bronchiectasis is a chronic lung condition that typically causes chronic cough and daily sputum production. Exacerbations are associated with progressive decline in lung function and decreased quality of life. Management involves treatment of conditions associated with bronchiectasis, airway clearance techniques, oral or intravenous antibiotics for acute exacerbations, and consideration of long-term inhaled antibiotics or oral macrolides for patients with 3 or more exacerbations annually.

PMID:40293759 | DOI:10.1001/jama.2025.2680

Immunol Allergy Clin North Am. 2025 May;45(2):287-298. doi: 10.1016/j.iac.2025.01.004. Epub 2025 Mar 11.

ABSTRACT

Chronic granulomatous disease (CGD) is a rare primary phagocytic immunodeficiency characterized by recurrent infections due to impaired NADPH oxidase activity. Balancing the need for additional immune suppression with the risk of infection in patients with CGD-associated inflammation can be difficult but increased understanding of the underlying pathophysiology may allow for more targeted and rational therapies. Current treatments for inflammatory complications include glucocorticoids, steroid-sparing immunosuppressive agents, antibiotics, and increasingly the use of targeted biologic agents. However, improved curative therapy strategies for patients with suboptimal donor options are needed and autologous gene therapy remains experimental.

PMID:40287173 | DOI:10.1016/j.iac.2025.01.004

Immunol Allergy Clin North Am. 2025 May;45(2):267-285. doi: 10.1016/j.iac.2025.01.005. Epub 2025 Mar 19.

ABSTRACT

Common Variable Immunodeficiency (CVID) is a prevalent primary immunodeficiency in adults, marked by low immunoglobulin levels and recurrent infections. This review examines the gastrointestinal complications of CVID, including both infectious and non-infectious manifestations. It highlights therapeutic strategies, from antimicrobials to novel biologics, and the role of immune modulation. The review also explores the impact of gut microbiota dysbiosis on CVID pathogenesis and emphasizes the need for personalized treatment approaches and routine cancer screening due to the elevated risk of gastrointestinal malignancy in CVID patients.

PMID:40287172 | DOI:10.1016/j.iac.2025.01.005

BMJ Open. 2025 Apr 25;15(4):e102770. doi: 10.1136/bmjopen-2025-102770.

ABSTRACT

INTRODUCTION: Standard premedication for paclitaxel-based chemotherapy includes dexamethasone and an histamine 1-antagonist to prevent hypersensitivity reactions (HSRs). However, the pharmacological rationale for dexamethasone is limited, and its use is associated with adverse effects such as hyperglycaemia, insomnia and immunodeficiency, negatively impacting health-related quality of life (HRQoL). No clear link has been established between dexamethasone dose, administration route and HSR incidence. Previous studies suggest that discontinuing dexamethasone beyond the second administration does not increase HSR risk. Despite this, dexamethasone remains standard practice. This trial evaluates whether complete omission of dexamethasone as paclitaxel premedication is non-inferior to the standard regimen in preventing clinically relevant HSRs (Common Terminology Criteria for Adverse Events (CTCAE) grade≥3).

METHODS: The DEXASTOP trial is a prospective, multicentre, randomised, non-inferiority study conducted in four hospitals in the Netherlands. 500 adult patients receiving paclitaxel-based chemotherapy for any solid tumour indication will be randomised 1:1 to receive either standard premedication with dexamethasone or an experimental regimen without dexamethasone for up to five paclitaxel administrations. The primary endpoint is the incidence of clinically relevant HSRs (CTCAE grade≥3). Secondary endpoints include the incidence and severity of all-grade HSRs, the number of paclitaxel administrations before the first HSR, dexamethasone-related adverse events, HRQoL and cost-effectiveness from a healthcare and societal perspective.

ETHICS AND DISSEMINATION: This study has been approved by the Erasmus Medical Centre Ethics Committee (reference MEC-2024-0030, protocol version 3, May 2024). Study findings will be published open access in peer-reviewed journals and presented at national and international meetings. Results will be shared with patients, healthcare professionals and the public. Positive outcomes will be implemented in clinical practice, and trial data will be submitted to the EU Clinical Trials Information System for public access.

TRIAL REGISTRATION NUMBER: NCT06118710.

PMID:40280620 | DOI:10.1136/bmjopen-2025-102770

EJHaem. 2025 Apr 24;6(2):e1101. doi: 10.1002/jha2.1101. eCollection 2025 Apr.

ABSTRACT

In patients with X-linked agammaglobulinemia (XLA), serum immunoglobulins are almost completely lacking. The prevalence of autoimmune diseases is low in XLA compared with other primary immunodeficiency diseases because antibodies are absent in XLA. Immune thrombocytopenia (ITP) is considered an antibody-mediated disease characterized by increased platelet destruction, and adult-onset ITP in XLA has not been reported in detail. The case of a 29-year-old Japanese man with XLA and ITP is described. The patient was treated with prednisolone and intravenous immunoglobulins, resulting in rapid improvement of thrombocytopenia. Clinicians should consider co-existing ITP when progressive thrombocytopenia is observed in a patient with XLA.

PMID:40276328 | PMC:PMC12019708 | DOI:10.1002/jha2.1101

J Pediatr Endocrinol Metab. 2025 Apr 25. doi: 10.1515/jpem-2024-0593. Online ahead of print.

ABSTRACT

OBJECTIVES: Inborn errors of immunity (IEI) are a diverse group of genetically inherited disorders. We aimed to summarize and discuss endocrinopathies in children with IEI.

METHODS: This study included 84 IEI patients evaluated between September 2019 and September 2023.

RESULTS: We found that 15.6 % of the 32 patients with 22q11.2 deletion syndrome had permanent hypoparathyroidism. Hypergonadotropic hypogonadism was identified in one of four female patients with ataxia-telangiectasia (AT) and in all four females with severe congenital neutropenia (SCN) due to HAX1 deficiency. Additionally, hypergonadotropic hypogonadism was observed in one of nine males with common variable immunodeficiency (CVID). Among the CVID patients, one presented with autoimmune thyroiditis (AIT), type 1 diabetes mellitus (T1DM), hypoparathyroidism, and primary adrenal insufficiency. Of the 307 patients followed for selective IgA deficiency (sIgAD), 26 also received care in pediatric endocrinology. Among the sIgAD cases, 3.2 % had AIT and 4.5 % had T1DM. A patient with a STAT1 gain-of-function (GOF) variant was diagnosed with T1DM, AIT, and growth hormone deficiency, while a patient with a novel STAT3-GOF variant developed neonatal DM and interstitial lung disease. When the whole group was evaluated, thyroid disease was the most common endocrinopathy affecting 30.9 % of individuals, followed by DM, which was observed in 20.2 % of cases.

CONCLUSIONS: We have determined that AIT and T1DM were the most prevalent endocrine disorders in IEI patients. Pubertal development and gonadal functions should be monitored in the children with IEI. Early diagnosis and individualized treatment of endocrinopathies are crucial for a better quality of life and reduction of IEI-related complications.

PMID:40270454 | DOI:10.1515/jpem-2024-0593

Ital J Pediatr. 2025 Apr 23;51(1):127. doi: 10.1186/s13052-025-01969-x.

ABSTRACT

BACKGROUND: Necrotizing tonsillitis is rare and may lead to life-threatening upper airway obstruction in children, requiring emergency airway management.

CASE PRESENTATION: An 8-month-old boy presented with unresolved fever and was diagnosed with acute tonsillitis. Despite prior treatment with amoxicillin and paracetamol, the fever persisted, accompanied by leukopenia. Intravenous C-penicillin was initiated, but respiratory distress ensued, necessitating non-invasive ventilatory support and subsequent intubation due to increased stridor. Intubation was challenging due to copious secretions and a floppy epiglottis, but successful intubation was achieved on the second attempt using a C-MAC^® video laryngoscope with a Miller blade size 0. Computed tomography (CT) revealed a large collection with mucosal involvement in the peritonsillar and tonsillar regions, extending to adjacent structures. Direct laryngoscopy, tissue sampling, and multiple surgical debridements were performed as the patient’s condition deteriorated. Perianal excoriation and diarrhea raised suspicion of primary immunodeficiency syndrome. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were isolated from tissue cultures and effectively treated with targeted antibiotics. Serological testing showed positive IgG for herpes simplex virus 1 (HSV-1), while immune deficiency testing indicated a normal immune status, pending genetic testing results. After 21 days of ventilation, the patient was extubated, received non-invasive ventilatory support, and was discharged with oral antibiotics.

CONCLUSION: This case highlights the critical nature of necrotizing tonsillitis, especially in infants with suspected primary immunosuppressive disorders. Early recognition, prompt airway management, and surgical intervention are crucial for optimal outcomes.

PMID:40269922 | DOI:10.1186/s13052-025-01969-x

Hum Mutat. 2025 Apr 15;2025:1725906. doi: 10.1155/humu/1725906. eCollection 2025.

ABSTRACT

Common variable immunodeficiency (CVID) is the most frequent symptomatic inborn error of immunity (IEI). CVID is genetically heterogeneous and occurs in sporadic or familial forms with different inheritance patterns. Monogenic mutations have been found in a low percentage of patients, and multifactorial or polygenic inheritance may be involved in unsolved patients. In the complex disease model, the epistatic effect of multiple variants in several genes and environmental factors such as infections may contribute. Epigenetic modifications, such as DNA methylation changes, are also proposed to be involved in CVID pathogenesis. In general, the pathogenic mechanism and molecular basis of CVID disease are still unknown, and identifying patterns of association across the genome in polygenic models and epigenetic modification profiles in CVID requires more studies. Here, we describe the current knowledge of the molecular genetic basis of CVID from monogenic, polygenic, and epigenetic aspects.

PMID:40265101 | PMC:PMC12014265 | DOI:10.1155/humu/1725906

BMC Pediatr. 2025 Apr 22;25(1):315. doi: 10.1186/s12887-025-05674-w.

ABSTRACT

BACKGROUND: Leukocyte adhesion deficiency III (LAD III) is a very rare autosomal recessive primary immunodeficiency characterized by recurrent infections without pus formation and bleeding syndrome of Glanzmann-type and life-threatening infections. The main etiology of this condition is variations in the FERMT3 gene, which encodes kindlin-3, an integrin-binding protein. We present a toddler with unique symptom of intestinal perforation followed by prolonged bleeding due to Glanzmann-like thrombasthenia who was diagnosed as LAD-III.

CASE PRESENTATION: This report presents a toddler with leukocyte adhesion deficiency type III (LAD III), who was diagnosed because of protracted surgical wound and gastrointestinal bleeding following surgery for small bowel perforation at the age of 16 months. The patient’s history was positive for febrile episodes after vaccinations, recurrent pulmonary infections, frequent severe epistaxis and ecchymotic purpuric lesions since early infancy. The presence of severe bleeding symptoms encouraged us to consider LAD III. Accordingly, sanger sequencing was performed which identified that the patient was homozygote for mutation in exon 14 of FERMT3 gene, the gene encoding for kindlin-3. Our patient also showed low percentages of CD16 and CD56 on peripheral blood flow cytometry, an unheard finding in LAD type III.

CONCLUSIONS: LAD III should be considered in differential diagnosis of any child with recurrent infections, persistent leukocytosis, and bleeding disorders. This is the first case of LAD III presenting with intestinal perforation. The present case also showed low percentage of natural killer cells which should be followed in further studies.

PMID:40263987 | DOI:10.1186/s12887-025-05674-w

Front Immunol. 2025 Apr 7;16:1521763. doi: 10.3389/fimmu.2025.1521763. eCollection 2025.

ABSTRACT

Cytomegalovirus (CMV) is a major opportunistic pathogen in recipients of solid organ transplantation. Maribavir, a pUL97 protein kinase inhibitor, was approved for the treatment of refractory post-transplant CMV infection in the US in 2021. However, it is rarely used in pediatric patients worldwide. Here, we report the case of a Chinese boy with Schimke’s immune-osseous dysplasia (SIOD) who developed refractory CMV infection after a renal transplantation. An 11-year-old boy was hospitalized with recurrent abdominal and testicular pain 50 days after renal transplantation. Diagnoses included urinary tract infection, epididymitis, CMV viremia, stage 2 chronic kidney disease, and SIOD. After five days of treatment, his pain improved, but he developed persistent fever and shortness of breath. Blood CMV levels rose to 1.64 × 10⁵ copies/ml after one month of ganciclovir treatment. Significant bone marrow suppression was observed after combined treatment with foscarnet. Anti-rejection treatment was discontinued due to compromised immune function. On day 40, maribavir was initiated with parental consent, resulting in undetectable CMV copies within four days. The patient’s clinical status and bone marrow suppression had improved. Continuing maribavir for two weeks led to the disappearance of CMV viremia, no bone marrow suppression, and normal liver and kidney functions. This case demonstrates the successful short-term use of maribavir in the treatment of refractory CMV infection in an immune-deficient child after renal transplantation. Further studies are required to explore the efficacy and safety of maribavir in pediatric patients.

PMID:40260257 | PMC:PMC12009931 | DOI:10.3389/fimmu.2025.1521763