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Frontiers in Immunology 2018Most patients with primary antibody deficiency (PAD) suffer from less well-described and understood forms of hypogammaglobulinemia (unclassified primary antibody...
Most patients with primary antibody deficiency (PAD) suffer from less well-described and understood forms of hypogammaglobulinemia (unclassified primary antibody deficiency, unPAD). Because of the moderately decreased immunoglobulin levels compared to CVID, unPAD is generally considered to be clinically mild and not very relevant. To describe our cohort of-mainly-unPAD patients, and to analyze whether subgroups can be identified. Data were prospectively collected (February-2012 to June-2016) as part of a standardized, 1-day Care Pathway for suspected primary immunodeficiency. The TNO-AZL Questionnaire for Health-Related Quality of Life (HRQoL) was part of the pre-first-visit intake procedure. Three hundred and twenty patients were referred to the Care Pathway. Data from 23/27 children and 99/113 adults who were diagnosed with PAD and gave informed consent were available for analysis. 89/99 adults had unPAD, the majority (74%) were female and 44% already showed bronchiectasis. HRQoL was significantly decreased in domains, meaning that a lot of unPAD patients had to cope simultaneously with pain, negative feelings and impairments in cognition, home management tasks, sleep, social interaction, and work. The most prominently impaired HRQoL domain was vitality, indicating these patients feel extremely tired and worn out. These results highlight the need for more attention to the potential patient burden of unPADs. A larger cohort is needed to increase our understanding of unPADs and to analyze whether distinct subgroups can be identified. For now, it is important for the clinician to acknowledge the existence of unPAD and be aware of its potential consequences, in order to timely and appropriately manage its effects and complications.
Topics: Adolescent; Adult; Agammaglobulinemia; Aged; Child; Child, Preschool; Female; Humans; Immunoglobulin G; Immunoglobulin M; Lymphocyte Count; Male; Middle Aged; Quality of Life; Registries; Young Adult
PubMed: 30374358
DOI: 10.3389/fimmu.2018.02384 -
Blood Dec 2017Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a genetic disease characterized by neutropenia, lymphopenia, susceptibility to infections,... (Review)
Review
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a genetic disease characterized by neutropenia, lymphopenia, susceptibility to infections, and myelokathexis, which describes degenerative changes of mature neutrophils and hyperplasia of bone marrow myeloid cells. Some patients present with hypogammaglobulinemia and/or refractory warts of skin and genitalia. Congenital cardiac defects constitute uncommon manifestations of the disease. The disorder, which is inherited as an autosomal dominant trait, is caused by heterozygous mutations of the chemokine receptor CXCR4. These mutations lead to an increased sensitivity of neutrophils and lymphocytes to the unique ligand CXCL12 and to an increased accumulation of mature neutrophils in the bone marrow. Despite greatly improved knowledge of the disease, therapeutic choices are insufficient to prevent some of the disease outcomes, such as development of bronchiectasis, anogenital dysplasia, or invasive cancer. The available therapeutic measures aimed at preventing the risk for infection in WHIM patients are discussed. We critically evaluate the diagnostic criteria of WHIM syndrome, particularly when WHIM syndrome should be suspected in patients with congenital neutropenia and lymphopenia despite the absence of hypogammaglobulinemia and/or warts. Finally, we discuss recent results of trials evaluating plerixafor, a selective antagonist of CXCR4, as a mechanism-oriented strategy for treatment of WHIM patients.
Topics: Agammaglobulinemia; Biomarkers; Child; Child, Preschool; Disease Progression; Female; Humans; Immunologic Deficiency Syndromes; Infections; Neutropenia; Phenotype; Primary Immunodeficiency Diseases; Treatment Outcome; Warts
PubMed: 29066537
DOI: 10.1182/blood-2017-02-708552 -
Frontiers in Bioscience (Elite Edition) Jan 2012Primary immunodeficiency diseases include more than 150 different genetic defects, classified on the basis of the mutations or physiological defects involved. The first... (Review)
Review
Primary immunodeficiency diseases include more than 150 different genetic defects, classified on the basis of the mutations or physiological defects involved. The first immune defects to be well recognized were those of adaptive immunity affecting B cell function and resulting in hypogammaglobulinemia and defects of specific antibody production; more recently, novel defects of innate immunity have been described, some involving Toll-like receptors (TLRs) and their signaling pathways. Furthermore, it is increasingly evident that the innate and adaptive pathways intersect and reinforce each other. B cells express a number of TLRs, which when activated lead to cell activation, up-regulation of co-stimulatory molecules, secretion of cytokines, up-regulation of recombination enzymes, isotype switch and immune globulin production. TLR activation of antigen presenting cells leads to heightened cytokine production, providing additional stimuli for B cell development and maturation. Recent studies have demonstrated that patients with common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) have altered TLR responsiveness. We review TLR defects in these disorders of B cell development, and discuss how B cell gene defects may modulate TLR signaling.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Animals; B-Lymphocytes; Genetic Diseases, X-Linked; Humans; Immunophenotyping; Lymphocyte Activation; Mice; Protein-Tyrosine Kinases; Signal Transduction; Toll-Like Receptors
PubMed: 22202002
DOI: 10.2741/507 -
Current Opinion in Immunology Oct 2009In the past, immunodeficiencies were categorized based on clinical and laboratory findings in the affected patient. Now we are more likely to define them based on the... (Review)
Review
In the past, immunodeficiencies were categorized based on clinical and laboratory findings in the affected patient. Now we are more likely to define them based on the specific gene involved. One might expect this shift to increase the precision and clarity of diagnosis but in the last few years it has become increasingly clear that identification of a mutation in a specific gene may not tell the whole story. Some gene defects may reliably result in clinical disease, others may act as susceptibility factors that are more common in patients with immunodeficiency but can also be found in otherwise healthy individuals. Distinguishing between these two types of gene defects is essential for informative genetic counseling.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; B-Lymphocytes; Diagnosis, Differential; Genetic Counseling; Genetic Diseases, X-Linked; Genetic Predisposition to Disease; Humans; Mutation; Protein-Tyrosine Kinases
PubMed: 19651503
DOI: 10.1016/j.coi.2009.07.003 -
Current Opinion in Hematology Jan 2020WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to...
PURPOSE OF REVIEW
WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. We reviewed clinical manifestations in 24 patients in 9 families to expand understanding of this syndrome.
RECENT FINDINGS
Warts, cellulitis and respiratory infections are common in patients with WHIMs. Less commonly these patients have congenital heart disease, human papilloma virus-associated malignancies (cervical and vulvular) and lymphomas. Hearing loss because of recurrent otitis media is another important complication. Treatment with granulocyte colony-stimulating factor is controversial; this review indicates that it is effective to prevent and treat infections based upon long-term observations of patients enrolled in the Severe Chronic Neutropenia International Registry. Understanding the natural history and diversity of this syndrome are important for ongoing clinical trials of novel agents to treat WHIMs.
SUMMARY
WHIM syndrome has diverse manifestations; some features occur consistently in almost all patients, for example, neutropenia, lymphocytopenia and mild hypogammaglobulinemia. However, the clinical consequences are quite variable across patient cohorts and within families. Each complication is important as a cause for morbidity and a source for patient and family concerns.
Topics: Agammaglobulinemia; Family; Female; Humans; Male; Mutation; Primary Immunodeficiency Diseases; Receptors, CXCR4; Registries; Risk Factors; Warts
PubMed: 31652152
DOI: 10.1097/MOH.0000000000000554 -
CMAJ : Canadian Medical Association... Nov 1987Hypogammaglobulinemia is a feature of several B-cell disorders and is manifested clinically by recurrent infection, most commonly chronic upper and lower respiratory... (Review)
Review
Hypogammaglobulinemia is a feature of several B-cell disorders and is manifested clinically by recurrent infection, most commonly chronic upper and lower respiratory tract disease. Immunoglobulin replacement therapy is available, with at least four different routes of administration. There are as yet no convincing data that allow comparison of the cost-effectiveness of these methods. However, by individualizing therapy for each patient, it is possible to prevent life-threatening acute infections, reduce the severity of chronic upper and lower respiratory tract disease, improve pulmonary function and achieve normal levels of IgG. These are the currently acceptable goals of therapy in patients with hypogammaglobulinemia.
Topics: Agammaglobulinemia; Blood Transfusion; Humans; Immunoglobulins; Infusions, Intravenous; Injections, Intramuscular; Injections, Subcutaneous; Lymphoproliferative Disorders; Plasma
PubMed: 3327579
DOI: No ID Found -
BMC Pediatrics Apr 2022X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in...
BACKGROUND
X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in BTK gene. Usually, XLA patients are not susceptible to respiratory tract infections by viruses and do not present interstitial lung disease (ILD) such as bronchiolitis obliterans (BO) as a consequence of acute or chronic bacterial infections of the respiratory tract. Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder.
CASE PRESENTATION
We report two pediatric cases from male siblings with X-Linked Agammaglobulinemia and bronchiolitis obliterans, a phenotype not often observed in XLA phenotype. The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751G>A(p.Gly584Glu) in BTK gene of both patients. We also identified a gain-of-function mutation in TGFβ1 (rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGFβ1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment.
CONCLUSIONS
Our report illustrates a possible role for WES in patients with known inborn errors of immunity, but uncommon clinical presentations, providing a personalized understanding of genetic basis, with possible implications in the identification of potential treatments, and prognosis for patients and their families.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Bronchiolitis Obliterans; Child; DNA Mutational Analysis; Genetic Diseases, X-Linked; Humans; Male; Mutation; Siblings
PubMed: 35382780
DOI: 10.1186/s12887-022-03245-x -
Journal of Clinical Immunology Aug 2014In the past, XLA was described as associated with several inflammatory conditions, but with adequate immune globulin treatment, these are presumed to have diminished....
PURPOSE
In the past, XLA was described as associated with several inflammatory conditions, but with adequate immune globulin treatment, these are presumed to have diminished. The actual prevalence is not known.
METHODS
A web-based patient survey was conducted December 2011- February 2012. Respondents were recruited from the Immune Deficiency Foundation (IDF) patient database, online patient discussion forums and physician recruitment of patients. The questionnaire was developed jointly by IDF and by members of the USIDNET-XLA Disease Specific Working Group. Information regarding inflammatory conditions in patients with XLA was also obtained from the United States Immune Deficiency Network (USIDNET) Registry.
RESULTS
Based on 128 unique patient survey responses, the majority of respondents (69%) reported having at least one inflammatory symptom, with 53% reporting multiple symptoms. However, only 28% had actually been formally diagnosed with an inflammatory condition. Although 20% reported painful joints and 11% reported swelling of the joints, only 7% were given a diagnosis of arthritis. Similarly, 21% reported symptoms of chronic diarrhea and 17% reported abdominal pain, however only 4% had been diagnosed with Crohn's disease. Data from the USIDNET Registry on 149 patients with XLA, revealed that 12% had pain, swelling or arthralgias, while 18% had been diagnosed with arthritis. Similarly, 7% of these patients had abdominal pain and 9% chronic diarrhea.
CONCLUSIONS
Although patients with XLA are generally considered to have a low risk of autoimmune or inflammatory disease compared to other PIDD cohorts, data from this patient survey and a national registry indicate that a significant proportion of patients with XLA have symptoms that are consistent with a diagnosis of arthritis, inflammatory bowel disease or other inflammatory condition. Documented diagnoses of inflammatory diseases were less common but still increased over the general population. Additional data is required to begin implementation of careful monitoring of patients with XLA for these conditions. Early diagnosis and proper treatment may optimize clinical outcomes for these patients.
Topics: Adolescent; Adult; Agammaglobulinemia; Arthritis; Autoimmunity; Child; Child, Preschool; Crohn Disease; Data Collection; Female; Genetic Diseases, X-Linked; Humans; Infant; Inflammation; Inflammatory Bowel Diseases; Male; Middle Aged; Prevalence; Surveys and Questionnaires; United States; Young Adult
PubMed: 24909997
DOI: 10.1007/s10875-014-0056-x -
Blood Advances Apr 2024Immunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological... (Randomized Controlled Trial)
Randomized Controlled Trial
Immunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, we enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. Participants allocated to antibiotics were allowed to crossover after grade ≥3 infections. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. Between August 2017 and April 2019, 63 patients were randomized: 42 to antibiotics and 21 to immunoglobulin. Proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm (Fisher exact test P=.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, P=.65). Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections. Our findings support the feasibility of progressing to a phase 3 trial. Trial registration #ACTRN12616001723471.
Topics: Humans; Agammaglobulinemia; Anti-Bacterial Agents; Doxycycline; Hematologic Neoplasms; Immunoglobulins; Feasibility Studies
PubMed: 38592710
DOI: 10.1182/bloodadvances.2023011231 -
The Pan African Medical Journal 2014
Review
Topics: Agammaglobulinemia; Humans; IgA Deficiency; IgG Deficiency; Immunity, Humoral; Immunologic Deficiency Syndromes
PubMed: 25489366
DOI: 10.11604/pamj.2014.18.272.4061