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Journal of Clinical Immunology Feb 2022No rapid diagnostic test exists to screen individuals for primary antibody deficiencies (PAD) at or near the point of care. In settings at risk for polio where live oral...
PURPOSE
No rapid diagnostic test exists to screen individuals for primary antibody deficiencies (PAD) at or near the point of care. In settings at risk for polio where live oral polio vaccine is utilized, undiagnosed PAD patients and cases with delayed diagnosis constitute a potential reservoir for neurovirulent polioviruses, undermining polio eradication. This research aimed to develop a rapid screening test suited for use in resource-limited settings to identify individuals with low immunoglobulin G (IgG) levels, enabling early diagnosis and appropriate treatment.
METHODS
Three prototype tests distinguishing low and normal IgG levels were evaluated with a blinded panel of serum/plasma specimens from 32 healthy controls and 86 primary immunodeficiency-confirmed patients with agammaglobulinemia, common variable immunodeficiency, and hyper-IgM syndrome, including 57 not receiving IgG therapy. Prototype tests were compared to laboratory reference and clinical case definition.
RESULTS
The leading prototype correctly identified 32 of 32 healthy controls. Among primary antibody deficiency patients not receiving IgG treatment, 17 of 19 agammaglobulinemia, 7 of 24 common variable immunodeficiency, and 5 of 14 hyper-IgM were correctly identified by the prototype, with 67% agreement with the reference assay.
CONCLUSION
The Rapid IgG Screen (RIgGS) test can differentiate between low IgG levels associated with agammaglobulinemia and normal IgG antibody levels. Differentiating CVID and hyper IgM was challenging due to the wide range in IgG levels and influence of high IgM. This test can facilitate the identification of patients with primary antibody deficiencies and support polio surveillance initiatives.
Topics: Agammaglobulinemia; Common Variable Immunodeficiency; Diagnostic Tests, Routine; Humans; Point-of-Care Systems; Primary Immunodeficiency Diseases
PubMed: 34839430
DOI: 10.1007/s10875-021-01179-0 -
Neurology(R) Neuroimmunology &... May 2024B-cell-depleting therapies increase the risk of infections and hypogammaglobulinemia. These relationships are poorly understood. The objectives of these analyses were to...
BACKGROUND AND OBJECTIVES
B-cell-depleting therapies increase the risk of infections and hypogammaglobulinemia. These relationships are poorly understood. The objectives of these analyses were to estimate how much of this rituximab-associated infection risk is mediated by hypogammaglobulinemia and to identify other modifiable risk factors in persons with multiple sclerosis (pwMS).
METHODS
We conducted a retrospective cohort study of rituximab-treated pwMS from January 1, 2008, to December 31, 2020, in Kaiser Permanente Southern California. Cumulative rituximab dose was defined as ≤2, >2 and ≤4, or >4 g. Serious infections were defined as infections requiring or prolonging hospitalizations, and recurrent outpatient infections as seeking care for ≥3 within 12 months. Exposures, outcomes, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHRs) were estimated using Andersen-Gill hazards models, and generalized estimating equations were used to examine correlates of IgG values. Cross-sectional causal mediation analyses of rituximab and hypogammaglobulinemia were conducted.
RESULTS
We identified 2,482 pwMS who were treated with rituximab for a median of 2.4 years (interquartile range = 1.3-3.9). The average age at rituximab initiation was 43.0 years, 71.9% were female, 49.7% were White, non-Hispanic patients, and 29.6% had advanced disability (requiring walker or worse). Seven hundred patients (28.2%) developed recurrent outpatient infections, 155 (6.2%) developed serious infections, and only 248 (10.0%) had immunoglobulin G (IgG) < 700 mg/dL. Higher cumulative rituximab dose (>4 g) was correlated with lower IgG levels (Beta = -58.8, < 0.0001, ref ≤2 g) and, in models mutually adjusted for hypogammaglobulinemia, both were independently associated with an increased risk of serious (>4 g, aHR = 1.56, 95% CI 1.09-2.24; IgG < 500, aHR = 2.98, 95% CI 1.56-5.72) and outpatient infections (>4 g, aHR = 1.73, 95% CI 1.44-2.06; IgG < 500 aHR = 2.06, 95% CI 1.52-2.80; ref = IgG ≥ 700). Hypogammaglobulinemia explained at most 17.9% (95% CI -47.2-119%) of serious infection risk associated with higher cumulative rituximab exposure but was not significant for outpatient infections. Other independent modifiable risk factors were advanced physical disability for serious (aHR = 5.51, 95% CI 3.71-8.18) and outpatient infections (aHR = 1.24, 95% CI 1.06-1.44) and COPD (aHR = 1.68, 95% CI 1.34-2.11) and obesity (aHR = 1.25, 95% CI 1.09-1.45) for outpatient infections.
DISCUSSION
Higher cumulative rituximab doses increase the risk of infections even in this population where 90% of patients maintained normal IgG levels. Clinicians should strive to use minimally effective doses of rituximab and other B-cell-depleting therapies and consider important comorbidities to minimize risks of infections.
Topics: Humans; Female; Male; Rituximab; Agammaglobulinemia; Multiple Sclerosis; Retrospective Studies; Cross-Sectional Studies; Immunoglobulin G; Infections
PubMed: 38507657
DOI: 10.1212/NXI.0000000000200211 -
Journal of Clinical Immunology Apr 2017X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is...
PURPOSE
X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored.
METHODS
We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies.
RESULTS
In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental.
CONCLUSIONS
Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.
Topics: Agammaglobulinemia; Aged, 80 and over; Biomarkers; Gastrointestinal Diseases; Gastrointestinal Tract; Genetic Association Studies; Genetic Diseases, X-Linked; Humans; Immunoglobulin Isotypes; Immunophenotyping; Infant; Lymphocyte Subsets; Male; Mutation; Pedigree; Phenotype
PubMed: 28236219
DOI: 10.1007/s10875-017-0374-x -
Frontiers in Immunology 2023Bruton's tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the gene, which...
BACKGROUND
Bruton's tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.
RESULTS
Twenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were . Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.
CONCLUSION
This report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.
Topics: Male; Pregnancy; Female; Humans; Protein-Tyrosine Kinases; Malaysia; COVID-19; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia
PubMed: 37809070
DOI: 10.3389/fimmu.2023.1252765 -
Arthritis Research & Therapy Jun 2023In Switzerland, rituximab (RTX) is licenced for the treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) but is frequently used off-label to treat...
BACKGROUND
In Switzerland, rituximab (RTX) is licenced for the treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) but is frequently used off-label to treat other auto-immune diseases (AID), especially connective tissue diseases (CTD). We aimed to characterise the use of RTX in AID in a real-life Swiss setting and compare RTX retention rates and safety outcomes between patients treated for RA, CTD and AAV.
METHODS
A retrospective cohort study of patients who started RTX in the Rheumatology Department for RA or AID. The RTX retention rate was analysed using Kaplan-Meier survival curves. Occurrences of serious adverse events (SAE), low IgG levels and anti-drug antibodies (ADA) were reported.
RESULTS
Two hundred three patients were treated with RTX: 51.7% had RA, 29.6% CTD, 9.9% vasculitis and 8.9% other AIDs. The total observation time was 665 patient-years. RTX retention probability at 2 years (95%CI) was similar for RA and CTD 0.65 (0.55 to 0.73), 0.60 (0.47 to 0.72) and lower for vasculitis 0.25 (0.09 to 0.45). Survival curves for RTX retention matched closely (p = 0.97) between RA and CTD patients but were lower for patients with vasculitis due to a higher percentage of induced remission. Patients with vasculitis (95%) and CTD (75%) had a higher rate of concomitant glucocorticoid use than RA (60%). Moderate to severe hypogammaglobulinaemia was observed more frequently in patients with vasculitis (35%) than with RA (13%) or CTD (9%) and was associated with an increased risk of presenting a first infectious SAE (HR 2.01, 95% CI 1.04 to 3.91). The incidence rate of SAE was 23.3 SAE/100 patient-years (36% were infectious). When searched, ADAs were observed in 18% of the patients and were detected in 63% of infusions-related SAE. 10 patients died during RTX treatment and up to 12 months after the last RTX infusion, 50% from infection.
CONCLUSION
RTX retention rates are similar for patients with RA and CTD but lower for those with vasculitis due to more frequent remission. Patients treated with RTX for vasculitis present more SAE and infectious SAE than patients with RA and CTD, potentially due to a higher use of concomitant glucocorticoids and the occurrence of hypogammaglobulinaemia.
Topics: Humans; Rituximab; Retrospective Studies; Switzerland; Agammaglobulinemia; Arthritis, Rheumatoid; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Connective Tissue Diseases; Antibodies; Glucocorticoids; Treatment Outcome
PubMed: 37264414
DOI: 10.1186/s13075-023-03076-w -
Canadian Medical Association Journal May 1956
Topics: Agammaglobulinemia; gamma-Globulins
PubMed: 13316661
DOI: No ID Found -
British Medical Journal Jul 1955
Topics: Agammaglobulinemia; gamma-Globulins
PubMed: 14378637
DOI: No ID Found -
British Medical Journal Jul 1971
Topics: Agammaglobulinemia; Bone Marrow Transplantation; Female; Humans; Immunity, Cellular; Male; Respiratory Tract Infections; Transplantation, Homologous; gamma-Globulins
PubMed: 4103836
DOI: No ID Found -
Frontiers in Immunology 2020There is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with...
BACKGROUND
There is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with XLA from India.
METHODS
Data on XLA from all regional centers supported by the Foundation for Primary Immunodeficiency Diseases (FPID), USA and other institutions providing care to patients with PIDs were collated. Diagnosis of XLA was based on European Society for Immunodeficiencies (ESID) criteria.
RESULTS
We received clinical details of 195 patients with a provisional diagnosis of XLA from 12 centers. At final analysis, 145 patients were included (137 'definite XLA' and eight 'probable/possible XLA'). Median age at onset of symptoms was 12.0 (6.0, 36.0) months and median age at diagnosis was 60.0 (31.5, 108) months. Pneumonia was the commonest clinical manifestation (82.6%) followed by otitis media (50%) and diarrhea (42%). Arthritis was seen in 26% patients while 23% patients developed meningitis. Bronchiectasis was seen in 10% and encephalitis (likely viral) in 4.8% patients. was the commonest bacterial pathogen identified followed by , and . Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in gene were the most common (36%) followed by frameshift (22%) and nonsense variants (21%). Most pathogenic gene variants (53%) were clustered in the distal part of gene encompassing exons 14-19 encoding for the tyrosine kinase domain. Follow-up details were available for 108 patients. Of these, 12% had died till the time of this analysis. The 5-year and 10-year survival was 89.9% and 86.9% respectively. Median duration of follow-up was 61 months and total duration of follow-up was 6083.2 patient-months. All patients received intravenous immunoglobulin (IVIg) replacement therapy. However, in many patients IVIg could not be given at recommended doses or intervals due to difficulties in accessing this therapy because of financial reasons and lack of universal health insurance in India. Hematopoietic stem cell transplant was carried out in four (2.8%) patients.
CONCLUSION
There was a significant delay in the diagnosis and facilities for molecular diagnosis were not available at many centers. Optimal immunoglobulin replacement is still a challenge.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Arthritis; Child; Child, Preschool; Exons; Female; Genetic Diseases, X-Linked; Genetic Profile; Genetic Variation; Humans; Immunoglobulins, Intravenous; India; Infant; Male; Protein-Tyrosine Kinases
PubMed: 33584693
DOI: 10.3389/fimmu.2020.612323 -
The Netherlands Journal of Medicine Nov 2007In this report we present four patients with reversible hypogammaglobulinaemia who required immunoglobulin substitution for several years. One patient had documented...
In this report we present four patients with reversible hypogammaglobulinaemia who required immunoglobulin substitution for several years. One patient had documented systemic lupus erythematosus (SLE), the other three patients had primary hypogammaglobulinaemia without known cause. Whereas the cessation of azathioprine therapy may have contributed to the recovery in the patient with SLE, the restoration of the immunoglobulin production in the other three patients occurred spontaneously. All four patients were IgA deficient when the hypogammaglobulinaemia was first detected and remained so after IgM and IgG production had recovered. Two of the three patients who also had anti-IgA antibodies started to produce anti-IgA again after stopping the immunoglobulin substitution. We conclude that recovery of hypogammaglobulinaemia is possible but rare. When recovery is suspected, we recommend that immunoglobulin substitution is stopped and the antibody response to vaccination is tested.
Topics: Adolescent; Agammaglobulinemia; Child, Preschool; Female; Humans; IgA Deficiency; Infant; Male; Middle Aged; Risk Factors
PubMed: 18057460
DOI: No ID Found