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Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India.

February 16, 2021 By Manish Butte

Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India.

Front Immunol. 2020;11:612323

Authors: Rawat A, Jindal AK, Suri D, Vignesh P, Gupta A, Saikia B, Minz RW, Banday AZ, Tyagi R, Arora K, Joshi V, Mondal S, Shandilya JK, Sharma M, Desai M, Taur P, Pandrowala A, Gowri V, Sawant-Desai S, Gupta M, Dalvi AD, Madkaikar M, Aggarwal A, Raj R, Uppuluri R, Bhattad S, Jayaram A, Lashkari HP, Rajasekhar L, Munirathnam D, Kalra M, Shukla A, Saka R, Sharma R, Garg R, Imai K, Nonoyama S, Ohara O, Lee PP, Chan KW, Lau YL, Singh S

Abstract
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. Pseudomonas aeruginosa was the commonest bacterial pathogen identified followed by Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae. Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in BTK 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.

PMID: 33584693 [PubMed – in process]

X-Linked Hyper IgM Syndrome Manifesting as Recurrent Pneumocystis jirovecii Pneumonia: A Case Report.

February 16, 2021 By Manish Butte

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X-Linked Hyper IgM Syndrome Manifesting as Recurrent Pneumocystis jirovecii Pneumonia: A Case Report.

J Trop Pediatr. 2020 12 01;66(6):648-654

Authors: Huang SH, Meng XY, Bai ZJ, Li Y, Wu SY

Abstract
We reported a Chinese boy with X-linked hyper IgM (XHIGM) syndrome, manifesting as recurrent and severe pneumonia caused by Pneumocystis jirovecii. His parents were healthy and unrelated. In August 2018, the 5-month-old boy manifested as cough and dyspnea, and then in July 2019, he was admitted because of the same symptoms. Immunological results of the two admissions both showed low IgG, low IgA, normal IgM and high levels of 1,3-β-D-glucan (BDG). Using next-generation sequencing (NGS), great reading counts of P. jirovecii were identified from the deep sputum in both admissions. Caspofungin combined with trimethoprim-sulfamethoxazole were used to anti-infection, and he recovered quickly. Whole-exome sequencing was performed for this family because of immune suppression, the disease-causing gene (exon 10-22 of CD40L) deletion for XHIGM syndrome was identified. NGS is beneficial for etiology diagnosis. Pneumocystis jirovecii pneumonia as an opportunistic infection could be recurrent in patients with XHIGM syndrome.

PMID: 32388558 [PubMed – indexed for MEDLINE]

Advances in Hereditary Angioedema: The Prevention of Angioedema Attacks With Subcutaneous C1-Inhibitor Replacement Therapy.

February 16, 2021 By Manish Butte

Advances in Hereditary Angioedema: The Prevention of Angioedema Attacks With Subcutaneous C1-Inhibitor Replacement Therapy.

J Infus Nurs. 2020 May/Jun;43(3):134-145

Authors: Lumry W, Templeton T, Omert L, Levy D

Abstract
Hereditary angioedema (HAE) is a debilitating condition caused by a functional C1-inhibitor (C1-INH) deficiency and characterized clinically by episodes of subcutaneous or submucosal swelling. C1-INH replacement is highly effective for preventing HAE attacks and can improve health-related quality of life. Once available only for intravenous use, C1-INH is now available as a subcutaneous formulation for self-administration, shown to provide sustained plasma levels of C1-INH and reducing the monthly median HAE attack rate by 95% versus placebo in the phase 3 COMPACT study. Subcutaneously administered C1-INH satisfies multiple unmet needs in the management of patients with HAE.

PMID: 32287168 [PubMed – indexed for MEDLINE]

Not Always (and Only) Heart Failure-A Case Report of Primary Pleural Lymphoma in an Elderly Patient.

February 13, 2021 By Manish Butte

Not Always (and Only) Heart Failure-A Case Report of Primary Pleural Lymphoma in an Elderly Patient.

Clin Pract. 2021 Jan 29;11(1):32-36

Authors: Rabadão T, Naia L, Ferreira F, Teixeira M, Aveiro M, Eulálio M, Silva F

Abstract
Pleural involvement in Non-Hodgkin Lymphoma (NHL) is well documented, but primary pleural lymphomas are extremely rare, occurring mostly in immunosuppressed patients or associated with chronic pleural inflammation. Nevertheless, the pathogenesis and therapeutic approaches to counteract primary pleural lymphomas are still matter of debate. The authors present the clinical case of an 81-year-old female with respiratory and constitutional symptoms. A valvular heart disease and bilateral pleural effusion were known. The study carried out showed a large right pleural effusion; the fluid analysis was compatible with Diffuse Large B-cell Lymphoma (DLBCL), and two lymphomatous masses with pleural origin were found at the ipsilateral hemithorax. Primary pleural lymphoma was considered and chemotherapy was initiated with a good response and evolution. The authors report this remarkable clinical case because of its rarity, its excellent clinical evolution and the absence of an immunodeficiency context.

PMID: 33572698 [PubMed]

A novel activation-induced cytidine deaminase mutation in an adult with hyper-immunoglobulin M syndrome.

February 13, 2021 By Manish Butte

A novel activation-induced cytidine deaminase mutation in an adult with hyper-immunoglobulin M syndrome.

Ann Allergy Asthma Immunol. 2021 02;126(2):199-200

Authors: Mendoza J, Quinn J, Infante A, Nath P, Amornruk N

PMID: 33127529 [PubMed – indexed for MEDLINE]

Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.

February 12, 2021 By Manish Butte

Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.

Blood Adv. 2021 Jan 12;5(1):262-273

Authors: Bakhtiar S, Salzmann-Manrique E, Blok HJ, Eikema DJ, Hazelaar S, Ayas M, Toren A, Goldstein G, Moshous D, Locatelli F, Merli P, Michel G, Öztürk G, Schulz A, Heilmann C, Ifversen M, Wynn RF, Aleinikova O, Bertrand Y, Tbakhi A, Veys P, Karakukcu M, Kupesiz A, Ghavamzadeh A, Handgretinger R, Unal E, Perez-Martinez A, Gokce M, Porta F, Aksu T, Karasu G, Badell I, Ljungman P, Skorobogatova E, Yesilipek A, Zuckerman T, Bredius RRG, Stepensky P, Shadur B, Slatter M, Gennery AR, Albert MH, Bader P, Lankester A

Abstract
Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017. The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively. We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%). The estimate (95% CI) at 3 years for GF- and GVHD-II to IV-free survival as event-free survival (EFS) was 56% (46-69) for the entire cohort; 58% (46-72) and 56% (23-88) for LAD-I and LAD-III, respectively. Grade II to IV acute GVHD was a relevant risk factor for death (hazard ratio 3.6; 95% CI 1.4-9.1; P = .006). Patients’ age at transplant ≥13 months, transplantation from a nonsibling donor, and any serological cytomegalovirus mismatch in donor-recipient pairs were significantly associated with severe acute GVHD and inferior EFS. The choice of busulfan- or treosulfan-based conditioning, type of GVHD prophylaxis, and serotherapy did not impact overall survival, EFS, or aGVHD. An intrinsic inflammatory component of LAD may contribute to inflammatory complications during allo-HSCT, thus providing the rationale for considering anti-inflammatory therapy pretreatment.

PMID: 33570653 [PubMed – as supplied by publisher]

A Large Cohort of RAG1/2-Deficient SCID Patients-Clinical, Immunological, and Prognostic Analysis.

February 12, 2021 By Manish Butte

A Large Cohort of RAG1/2-Deficient SCID Patients-Clinical, Immunological, and Prognostic Analysis.

J Clin Immunol. 2020 01;40(1):211-222

Authors: Greenberg-Kushnir N, Lee YN, Simon AJ, Lev A, Marcus N, Abuzaitoun O, Somech R, Stauber T

Abstract
INTRODUCTION: Severe combined immunodeficiency (SCID) is a fatal disorder resulting from various genetic defects. In the Middle East, where consanguineous marriage is prevalent, autosomal recessive mutations in recombination-activating genes (RAG) are a leading cause of SCID. We present a large cohort of SCID patients due to RAG1 or RAG2 mutations.
METHODS: Twenty-six patients with RAG1 or RAG2 deficiency, diagnosed at Sheba Medical Center, were retrospectively investigated. Clinical presentation, immunologic phenotype, genetic analysis, treatment, and outcome were analyzed.
RESULTS: Majority of patients were referred from the Palestinian Authority. Most patients were males of Muslim Arab descent, 77% were born to consanguineous parents, and 65% had family history of immunodeficiency. Nearly all patients suffered from various infections before turning 2 months old, eight patients (31%) presented with Omenn and Omenn-like syndrome, and three patients (11%) had maternal engraftment. Notably, seven patients (27%) suffered from vaccine-derived infections, including a rare case of measles encephalitis. Nineteen patients underwent hematopoietic stem cell transplantation (HSCT) at a median age of 6 months, with a successful outcome for 72% of them. Genetic analysis revealed 11 different mutations (7 RAG2, 4 RAG1), two of them novel.
CONCLUSIONS: Consanguineous marriages account for a genetic “founder effect.” SCID is a pediatric emergency that dictates immediate precautions and curative treatment with HSCT. Due to lack of newborn screening for SCID within the Palestinian population, most patients in this cohort were diagnosed upon clinical symptoms, which led to a delayed diagnosis, harmful administration of contra-indicated live vaccines, delay in HSCT, and poor outcome.

PMID: 31838659 [PubMed – indexed for MEDLINE]

Prophylactic Antibiotics Versus Immunoglobulin Replacement in Specific Antibody Deficiency.

February 12, 2021 By Manish Butte

Prophylactic Antibiotics Versus Immunoglobulin Replacement in Specific Antibody Deficiency.

J Clin Immunol. 2020 01;40(1):158-164

Authors: Joud Hajjar, Nguyen AL, Constantine G, Kutac C, Syed MN, Orange JS, Sullivan KE

Abstract
PURPOSE: Prophylactic antibiotics (PA) and immunoglobulin replacement (IGRT) are commonly used in specific antibody deficiency (SAD); however, optimal treatment is not well-established. Our purpose is to compare treatment outcomes with IGRT and/or PA among SAD patients.
METHODS: A retrospective chart review of SAD patients treated at two tertiary centers between January 2012 and May 2017 was performed. Clinical and laboratory data, and rates of infections prior to and after treatment with IGRT or PA were analyzed. Descriptive analyses, between-group comparisons of rates of infection after 1 year of treatment, and a stepwise logistic regression model were employed to explore factors contributing to treatment outcomes.
RESULTS: We identified 65 SAD patients with mean age were 18 years (2-71 years). The baseline mean number of infections in the PA group and IGRT group was 4.71 (SD 3.15) and 7.73 (SD 6.65), respectively. Twenty-nine (44.6%) received IGRT, 7 (10.7%) received PA, 7 (10.7%) received both IGRT and PA, 15 (23.1%) failed PA and switched to IGRT, and 7 did not receive any specific treatment. After 1 year of treatment, the difference in the mean number of infections in PA vs. IGRT was not statistically significant [2.86 (2.73) vs. 4.44 (4.74), p = 0.27]. Reporting autoimmunity increased the odds for persistent infections (OR = 4.29; p = 0.047), while higher IgG levels decreased the odds for persistent infections (OR = 0.68, p = 0.018).
CONCLUSIONS: PA and IGRT are equally effective as first line in preventing infections in SAD patients. However, patients who fail PA would benefit from IGRT.

PMID: 31758281 [PubMed – indexed for MEDLINE]

Rare Infant Case of Pulmonary Aspergilloma Highlighting Common Challenges With Voriconazole Dosing.

February 11, 2021 By Manish Butte

Rare Infant Case of Pulmonary Aspergilloma Highlighting Common Challenges With Voriconazole Dosing.

Pediatr Infect Dis J. 2021 Mar 01;40(3):227-230

Authors: Abo YN, Gwee A, Osowicki J

Abstract
We describe a 6-week-old male-term infant with a pulmonary aspergilloma diagnosed following lobectomy for suspected pleuropulmonary blastoma, with characteristic histopathologic findings and Aspergillus detected by polymerase chain reaction. Intensive testing did not reveal primary or secondary immunodeficiency. During 5 weeks treatment with voriconazole including regular therapeutic drug monitoring and dose adjustment, a level in the target range was never achieved. When the patient developed photosensitivity, treatment was stopped without relapse over 12 months follow-up. Voriconazole dosing is notoriously challenging in children. We review the cumulative published experience with voriconazole use in infants to highlight even greater difficulty in infants. Pulmonary aspergillosis is typically a disease affecting immunocompromised or critically ill patients. In children, it is well described in those with chronic granulomatous disease (CGD) as a complication of immunosuppressive antineoplastic chemotherapy and rarely in extremely- or very-low birthweight premature neonatal intensive care patients. The diagnosis is extremely rare in children without underlying risk factors. To our knowledge, this is the first report of a pulmonary aspergilloma in an immunocompetent infant.

PMID: 33565811 [PubMed – as supplied by publisher]

Lupus manifestations in children with primary immunodeficiency diseases: Comprehensive phenotypic and genetic features and outcome.

February 11, 2021 By Manish Butte

Lupus manifestations in children with primary immunodeficiency diseases: Comprehensive phenotypic and genetic features and outcome.

Mod Rheumatol. 2021 Feb 10;:1-18

Authors: Al-Mayouf SM, Alreefi HA, Alsinan TA, AlSalmi G, AlRowais A, Al-Herz W, Alazami AM, Alsonbul A, Al-Mousa H

Abstract
OBJECTIVES: To report the phenotypic, genetic findings and outcome of children with lupus manifestations associated with primary immunodeficiency diseases (PIDs).
METHODS: Data retrospectively collected on patients with lupus manifestations and PIDs seen between 1998 to 2019. Data comprised the clinical findings and genetic testing, the response to treatment and the accrual damage related to SLE.
RESULTS: A total of 39 patients (22 female) were reviewed. Thirty-four patients had lupus manifestations and six patients with SLE-like. Genetic analysis was performed in 25 patients. Complement deficiency was the most frequent PIDs; 26 patients were C1q deficient, 3 patients had C3 deficiency, 2 patients had C4 deficiency and one patient with heterozygous C8b variant. The other 7 patients had different PIDs genetic defects that include SCID caused by PNP deficiency, CGD, CVID (PIK3CD), IL-2RB mutation, DNase II deficiency, STAT1 mutation, ISG15 mutation and Griscelli syndrome type 3. Mucocutaneous lesions, arthritis and lung involvement were the main clinical features. 84.1% experienced recurrent infections. The mean accrual damage was 2.7 ± 2.2. There were five deaths because of infection.
CONCLUSION: This study suggest that patients with lupus manifestations and early onset disease, family history of SLE or recurrent infections should undergo immunological work-up and genetic testing to rule out PIDs.

PMID: 33563058 [PubMed – as supplied by publisher]