Manish Butte

Nat Rev Gastroenterol Hepatol. 2023 Oct 3. doi: 10.1038/s41575-023-00838-4. Online ahead of print.

ABSTRACT

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis.

PMID:37789059 | DOI:10.1038/s41575-023-00838-4

Indian J Med Res. 2023 Aug;158(2):161-174. doi: 10.4103/ijmr.ijmr_3282_21.

ABSTRACT

BACKGROUND & OBJECTIVES: Accurate diagnosis of immunodeficiencies requires a critical comparison of values with age-matched controls. In India, the existing reference values for rare lymphocyte subsets are currently not available and we rely on the data originating from other countries for the interpretation of the results. Furthermore, there is limited information on normal variation for these rare-subset parameters in Indian children. So, this study aimed to establish normative values for clinically important lymphocyte subsets in Indian children at different age groups.

METHODS: 148 children aged ≥16 yr were enrolled in this study. The study population included 61 per cent males and 39 per cent females and was divided into the following groups: cord blood (n=18), 0-6 months (n=9), 6-12 months (n=13), 1-2 yr (n=19), 2-5 yr (n=27), 5-10 yr (n=25) and 10-16 yr (n=37). The absolute and relative percentage of lymphocytes, T, B, natural killer cell, along with activated, naïve and memory subsets, was determined by flow cytometry.

RESULTS: Median values and the 10^th and 90^th percentiles were obtained for 34 lymphocyte sub-populations. The T and B naïve compartments showed a decreasing trend, whereas memory cells showed an increase with age. The activated T cell subset shows an increasing pattern up to one year and then declines gradually. Double negative T cells are relatively stable. TCRgd+T cell percentage increases with age.

INTERPRETATION & CONCLUSIONS: This single-centre pilot study provides preliminary data that justifies the need for future large-scale multi centric studies to generate a reference range for interpreting extended immunophenotyping profiles in the paediatric age group, making it possible for clinicians to assess the immunological status in inborn errors of immunity, infectious and autoimmune diseases.

PMID:37787259 | DOI:10.4103/ijmr.ijmr_3282_21

Ann Intern Med. 2023 Oct 3. doi: 10.7326/M23-0679. Online ahead of print.

ABSTRACT

BACKGROUND: Previous studies have shown that patients with giant cell arteritis (GCA) who have vascular ¹⁸F-fluorodeoxyglucose (FDG) uptake at diagnosis are at increased risk for thoracic aortic complications.

OBJECTIVE: To measure the association between vascular FDG uptake at diagnosis and the change in aortic dimensions.

DESIGN: Prospective cohort study.

SETTING: University Hospitals Leuven.

PATIENTS: 106 patients with GCA and FDG positron emission tomography (PET) imaging 3 days or less after initiation of glucocorticoids.

MEASUREMENTS: Patients had PET and computed tomography (CT) imaging at diagnosis and CT imaging yearly for a maximum of 10 years. The PET scans were scored 0 to 3 in 7 vascular areas and summed to a total vascular score (TVS). The PET scan results were positive when FDG uptake was grade 2 or greater in any large vessel. The association between vascular FDG uptake and aortic dimensions was estimated by linear mixed-effects models with random intercept and slope.

RESULTS: When compared with patients with a negative PET scan result, those with a positive scan result had a greater increase in the diameter of the ascending aorta (difference in 5-year progression, 1.58 mm [95% CI, 0.41 to 2.74 mm]), the diameter of the descending aorta (1.32 mm [CI, 0.38 to 2.26 mm]), and the volume of the thoracic aorta (20.5 cm³ [CI, 4.5 to 36.5 cm³]). These thoracic aortic dimensions were also positively associated with TVS. Patients with a positive PET scan result had a higher risk for thoracic aortic aneurysms (adjusted hazard ratio, 10.21 [CI, 1.25 to 83.3]).

LIMITATION: The lengthy inclusion and follow-up period resulted in missing data and the use of different PET machines.

CONCLUSION: Higher TVS was associated with greater yearly increase in thoracic aortic dimensions. Performing PET imaging at diagnosis may help to estimate the risk for aortic aneurysm formation.

PRIMARY FUNDING SOURCE: None.

PMID:37782924 | DOI:10.7326/M23-0679

Front Immunol. 2023 Sep 13;14:1211872. doi: 10.3389/fimmu.2023.1211872. eCollection 2023.

ABSTRACT

Many adolescents with immunodeficiency are diagnosed with a comorbid learning disability. The process of transition from paediatric to adult healthcare for these individuals occurs with a range of additional challenges. Due to the lack research available on immunodeficiency specifically, this article addresses a number of recommendations from the research undertaken with individuals with other chronic health conditions and learning disability. The research suggests that for individuals with learning disabilities autonomy and independence needs to be acknowledged despite their perceived need for increased input from parents and medical professionals. Instead, medical professionals could prioritise their relationship with the adolescent patient by ensuring communication needs are met and that a sense of continuity between paediatric and adult services is maintained. Families can be supported through psychological interventions which provide skills to allow family members to empower their young adult with a learning disability. Specific tools to help the transition process run more smoothly are also recommended and have proven to be effective in other parts of the world.

PMID:37781398 | PMC:PMC10533907 | DOI:10.3389/fimmu.2023.1211872

Front Immunol. 2023 Sep 13;14:1229674. doi: 10.3389/fimmu.2023.1229674. eCollection 2023.

ABSTRACT

BACKGROUND AND AIMS: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder characterized by severe eczema, recurrent infections, and micro-thrombocytopenia. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic option for patients with classic form. The risk of developing post-transplant tumors appears to be higher in patients with WAS than in other inborn errors of immunity (IEIs), but the actual incidence is not well defined, due to the scarcity of published data.

METHODS: Herein, we describe a 10-year-old patient diagnosed with WAS, treated with HSCT in the first year of life, who subsequently developed two rare solid tumors, kaposiform hemangioendothelioma and desmoid tumor. A review of the literature on post-HSCT tumors in WAS patients has been performed.

RESULTS: The patient received diagnosis of classic WAS at the age of 2 months (Zhu score = 3), confirmed by WAS gene sequencing, which detected the nonsense hemizygous c.37C>T (Arg13X) mutation. At 9 months, patient underwent HSCT from a matched unrelated donor with an adequate immune reconstitution, characterized by normal lymphocyte subpopulations and mitogen proliferation tests. Platelet count significantly increased, even though platelet count never reached reference values. A mixed chimerism was also detected, with a residual WASP- population on monocytes (27.3%). The patient developed a kaposiform hemangioendothelioma at the age of 5. A second abdominal tumor was identified, histologically classified as a desmoid tumor when he reached the age of 10 years. Both hematopoietic and solid tumors were identified in long-term WAS survivors after HSCT.

CONCLUSION: Here, we describe the case of a patient with WAS who developed two rare solid tumors after HSCT. An active surveillance program for the risk of tumors is necessary in the long-term follow-up of post-HSCT WAS patients.

PMID:37781361 | PMC:PMC10533990 | DOI:10.3389/fimmu.2023.1229674

Front Oncol. 2023 Sep 13;13:1248964. doi: 10.3389/fonc.2023.1248964. eCollection 2023.

ABSTRACT

BACKGROUND: Common variable immunodeficiency disorders (CVIDs), which are primary immunodeficiencies characterized by the failure of primary antibody production, typically present with recurrent bacterial infections, decreased antibody levels, autoimmune features, and rare atypical manifestations that can complicate diagnosis and management. Although most cases are sporadic, approximately 10% of the patients may have a family history of immunodeficiency. Genetic causes involving genes related to B-cell development and survival have been identified in only a small percentage of cases.

CASE PRESENTATION: We present the case of a family with two brothers who presented with mycosis fungoides as an exclusive symptom of a common variable immunodeficiency disorder (CVID). Whole-exome sequencing of the index patient revealed a pathogenic variant of the NFKB2 gene. Based on this diagnosis and re-evaluation of other family members, the father and brother were diagnosed with this rare immune and preneoplastic syndrome. All CVID-affected family members presented with mycosis fungoides as their only symptom, which is, to the best of our knowledge, the first case to be reported.

CONCLUSION: This case highlights the importance of high-throughput sequencing techniques for the proper diagnosis and treatment of hereditary hematological disorders.

PMID:37781189 | PMC:PMC10534963 | DOI:10.3389/fonc.2023.1248964

J Allergy Clin Immunol Glob. 2022 Sep 2;1(4):322-324. doi: 10.1016/j.jacig.2022.06.004. eCollection 2022 Nov.

ABSTRACT

Chronic granulomatous disease should be considered in adults of any age in the presence of refractory and/or atypical or fulminant pulmonary infections. This case of new large deletions in NCF1 was presented with mulch pneumonitis without a significant history of infections.

PMID:37779538 | PMC:PMC10509940 | DOI:10.1016/j.jacig.2022.06.004

J Allergy Clin Immunol Glob. 2023 Mar 29;2(3):100105. doi: 10.1016/j.jacig.2023.100105. eCollection 2023 Aug.

ABSTRACT

BACKGROUND: Hematopoietic stem cell transplantation in primary immunodeficiency disorders has come a long way since the first transplant in 1968. In India, pediatric stem cell transplantation long-term survival outcomes range from 62.5% to 75%, compared to 90% in high-income countries.

OBJECTIVE: We present single-center data of primary immunodeficiency transplants with immune-reconstitution evaluation after transplantation from a charitable trust hospital.

METHODS: Retrospective data of children transplanted for primary immunodeficiency disorders from March 2019 to March 2022 in a newly established transplant unit were collected. Data of pretransplant infections and comorbidities, surveillance for carbapenem-resistant Enterobacteriaceae, transplant characteristics, donor source, graft-versus-host disease, posttransplant infections, immune reconstitution, overall survival at 1 year, and immunodeficiency-free survival were collated.

RESULTS: Twenty-one patients underwent transplantation for primary immunodeficiency disorders. The median age at transplantation was 3 years and 5 months (range, 7 months to 17 years). Seventy-five percent of the cohort had organ involvement, with lung being the most common organ involved, followed by central nervous system. Fifty-two percent of children had peritransplant infections, with most of them recognized at the pretransplant assessment. Among 20 of 21 children with engraftment, 94% had complete chimerism initially, with 33% developing mixed chimerism over time. The median duration of immunosuppression was 3 months after transplantation, and only 1 child required systemic graft-versus-host disease treatment for more than a year. Immune-reconstitution showed good T-cell recovery at 3 months and naive T-cell production at 6 months. There was no regimen-related or sepsis-related mortality. Overall survival of the cohort was 95% at 1-year follow-up. Immunodeficiency-free survival was 86% after a median follow-up of 20 months.

CONCLUSIONS: Immunodeficiency-free and graft-versus-host disease-free survival can be achieved in the majority of children with primary immunodeficiencies using enhanced supportive care and the latest transplantation algorithms.

PMID:37779531 | PMC:PMC10509861 | DOI:10.1016/j.jacig.2023.100105

J Clin Immunol. 2023 Sep 29. doi: 10.1007/s10875-023-01572-x. Online ahead of print.

ABSTRACT

PURPOSE: To assess the pharmacokinetics (PK) of subcutaneous immunoglobulin (SCIG) and hyaluronidase-facilitated SCIG (fSCIG) therapy across body mass index (BMI) and age categories in patients with primary immunodeficiency diseases (PIDD) previously treated with intravenous immunoglobulin (IVIG).

METHODS: Using our previously published integrated population PK model based on data from eight clinical trials, simulations were conducted to examine the effects of BMI and age on serum immunoglobulin G (IgG) PK after administration of SCIG 0.15 g/kg weekly or fSCIG 0.6 g/kg every 4 weeks in patients switching from stable IVIG. Patients were assumed to have baseline IgG trough concentrations of 7 g/L (hypothetical protective threshold).

RESULTS: Mean steady-state serum IgG trough values (C_min,ss or trough) increased with BMI and age. Mean C_min,ss was 18% (SCIG) and 16% (fSCIG) higher in the obese than the healthy BMI group. Pediatric patients aged < 18 years had 8-22% (SCIG) and 4-20% (fSCIG) lower mean C_min,ss values than adults, with the youngest group (2- < 6 years) having the lowest C_min,ss. All patients across populations maintained C_min,ss IgG concentrations of ≥ 7 g/L after switching to SCIG or fSCIG.

CONCLUSION: Both SCIG and fSCIG successfully maintained trough values at or above the hypothetical protective threshold after switching from stable IVIG, irrespective of BMI or age. Differences in trough values between BMI groups and age groups (≤ 22%) may not warrant SCIG or fSCIG dose adjustments based on BMI or age alone; instead, the dosing paradigm should be guided by prior IVIG dose, individual IgG monitoring, and clinical findings.

PMID:37773562 | DOI:10.1007/s10875-023-01572-x

J Asthma Allergy. 2023 Sep 22;16:997-1006. doi: 10.2147/JAA.S418996. eCollection 2023.

ABSTRACT

INTRODUCTION: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders, common variable immunodeficiency disorder (CVID) and X-linked agammaglobulinemia (XLA) are PIDs related to B-cell defect, characterized by reduced levels of immunoglobulins and immune dysregulation. Infections are the most common clinical manifestations, while underlying autoimmune and inflammatory conditions are present in some patients with CVID and XLA, leading to clinical misdiagnosis and diagnostic delay. Chronic diarrhea in patients with CVID and XLA, particularly complicated malabsorption and protein-energy malnutrition, is responsible for poor prognostic outcomes.

METHODS: In this study, we described three PID adult patients (two with CVID and one with XLA) who presented with varying degrees of chronic diarrhea, weight loss, and protein-energy malnutrition. We suggest that villous blunting of the small intestine under capsule endoscopy may be an endoscopic feature of PID-related enteropathy, thus highlighting the application of capsule endoscopy in patients with CVID and XLA presenting with chronic diarrhea.

CONCLUSION: We also summarize regular Ig supplementation is the basic treatment for CVID and XLA patients, proper enteral nutrition and probiotic therapy can be explored to use to alter gut microbiota and modulate intestinal immune response. However, vedolizumab is not helpful to PID-related enteropathy therapy, as it exacerbates the inflammatory response in extra-intestinal organs and ultimately causes poor clinical outcomes.

PMID:37772267 | PMC:PMC10522781 | DOI:10.2147/JAA.S418996