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Clin Exp Immunol. 2021 Jun 1. doi: 10.1111/cei.13626. Online ahead of print.

ABSTRACT

Primary immunodeficiency diseases refer to inborn errors of immunity (IEI) that affect the normal development and function of the immune system. The phenotypic and genetic heterogeneity of IEI have made their diagnosis challenging. Hence, whole-exome sequencing (WES) was employed in this pilot study to identify the genetic etiology of 30 pediatric patients clinically diagnosed with IEI. The potential causative variants identified by WES were validated using Sanger sequencing. Genetic diagnosis was attained in 46.7% (14/30) of the patients and categorized into autoinflammatory disorders (n=3), diseases of immune dysregulation (n=3), defects in intrinsic and innate immunity (n=3), predominantly antibody deficiencies (n=2), combined immunodeficiencies with associated and syndromic features (n=2), and immunodeficiencies affecting cellular and humoral immunity (n=1). Of the 15 genetic variants identified, two were novel variants. Genetic findings differed from the provisional clinical diagnoses in seven cases (50.0%). This study showed that WES enhances the capacity to diagnose IEI, allowing more patients to receive appropriate therapy and disease management.

PMID:34060650 | DOI:10.1111/cei.13626

J Trop Pediatr. 2021 May 17;67(2):fmab031. doi: 10.1093/tropej/fmab031.

ABSTRACT

Mycobacterium abscessus appears to be increasing cause of pulmonary infection in children with underlying risk factors including cystic fibrosis, chronic lung disease and immunodeficiency syndromes. We present a case of pulmonary M. abscessus infection in a pediatric patient with primary ciliary dyskinesia and he was successfully treated with parenteral amikacin, linezolid and oral clarithromycin combined with inhaled amikacin. Clinical improvement was observed after adding inhaled amikacin to the treatment.

PMID:34059924 | DOI:10.1093/tropej/fmab031

J Pediatr Hematol Oncol. 2021 May 31. doi: 10.1097/MPH.0000000000002214. Online ahead of print.

ABSTRACT

Activated PI3 kinase delta syndrome (APDS) is a combined immunodeficiency characterized by recurrent sinopulmonary infections, increased risk of herpesvirus infections, lymphoproliferation, autoimmunity, and increased risk of lymphoid malignancies. Gain-of-function mutations in PIK3CD and PIK3R1 result in increased phosphoinositide-3-kinase-delta activity which causes hyperactivation of lymphocytes and abnormal development and activation of T and B cells. Cytopenias are the most common autoimmune process occurring in patients with APDS and typically occur as a later manifestation of the disease. Here we present a female patient with an early autoimmune hemolytic anemia, hepatosplenomegaly, and frequent infections presenting in infancy, followed by development of significant lymphadenopathy before her diagnosis with APDS type 1. She had significant improvement in her infectious history with immunoglobulin replacement, and control of autoimmune hemolytic anemia with initiation of sirolimus after her diagnosis with APDS type 1. We utilize this case to review the literature on APDS and present the novel finding of early-onset autoimmune disease in the setting of APDS. Autoimmune cytopenias are seen in many primary immunodeficiencies, and workup of autoimmune cytopenias in young patients should include evaluation for underlying immune disorder.

PMID:34054047 | DOI:10.1097/MPH.0000000000002214

J Clin Immunol. 2021 May 29. doi: 10.1007/s10875-021-01053-z. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis.

METHODS: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers.

RESULTS: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG).

CONCLUSIONS: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.

PMID:34052995 | DOI:10.1007/s10875-021-01053-z

Rev Med Interne. 2021 May 26:S0248-8663(21)00458-6. doi: 10.1016/j.revmed.2021.05.009. Online ahead of print.

ABSTRACT

Mucocutaneous fungal infections are common and usually occur in the presence of certain risk factors. However, these infections can occur in patients with no known risk factors. This indicates the presence of an underlying genetic susceptibility to fungi reflecting an innate or adaptive immune deficiency. In this review, we highlight genetic factors that predispose to mucocutaneous fungal infections specially candidiasis and dermatophytosis.

PMID:34052048 | DOI:10.1016/j.revmed.2021.05.009

Clin Exp Immunol. 2021 May 29. doi: 10.1111/cei.13625. Online ahead of print.

ABSTRACT

Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome is an early-onset monogenic inborn error of immunity characterized by multi-organ autoimmune disorders, growth failure and lymphoproliferation. We describe that STAT3 GOF syndrome may be presented with hypogammaglobulinemia and recurrent severe upper and lower respiratory tract infections. In addition, the patient had lymphoproliferation, short stature and interstitial lung disease. Chest CT examinations showed mild bronchiectasis with areas of non-fibrosing alveolar-interstitial disease and maldevelopment of bilateral first ribs. By using Sanger sequencing, we revealed a novel c.508G>C, p.D170H STAT3 variant affecting the coiled coil domain of STAT3. Functional studies confirmed that p.D170H was a GOF variant as showed by increased pSTAT3 and STAT3 transcriptional activity. Our observation suggests that STAT3 GOF syndrome can manifest in early childhood with hypogammaglobulinemia and recurrent severe respiratory tract infections. We suggest that patients with lymphoproliferation, hypogammaglobulinemia and severe, recurrent infections should be screened for STAT3 variants even if autoimmune manifestations are missing.

PMID:34050927 | DOI:10.1111/cei.13625

Eur Ann Allergy Clin Immunol. 2021 May 28. doi: 10.23822/EurAnnACI.1764-1489.217. Online ahead of print.

NO ABSTRACT

PMID:34047148 | DOI:10.23822/EurAnnACI.1764-1489.217

Clin Infect Dis. 2021 May 27:ciab495. doi: 10.1093/cid/ciab495. Online ahead of print.

ABSTRACT

BACKGROUND: Serological assays detecting anti-SARS-CoV-2 antibodies are being widely deployed in studies and clinical practice. However, the duration and effectiveness of the protection conferred by the immune response remains to be assessed in population-based samples. To estimate the incidence of newly acquired SARS-CoV-2 infections in seropositive individuals as compared to seronegative controls we conducted a retrospective longitudinal matched study.

METHODS: A seroprevalence survey including a representative sample of the population was conducted in Geneva, Switzerland between April and June 2020, immediately after the first pandemic wave. Seropositive participants were matched one-to-two to seronegative controls, using a propensity-score including age, gender, immunodeficiency, BMI, smoking status and education level. Each individual was linked to a state-registry of SARS-CoV-2 infections. Our primary outcome was confirmed infections occurring from serological status assessment to the end of the second pandemic wave (January 2021).

RESULTS: Among 8344 serosurvey participants, 498 seropositive individuals were selected and matched with 996 seronegative controls. After a mean follow-up of 35.6 (SD 3.2) weeks, 7 out of 498 (1.4%) seropositive subjects had a positive SARS-CoV-2 test, of whom 5 (1.0%) were classified as reinfections. In contrast, the infection rate was higher in seronegative individuals (15.5%, 154/996) during a similar follow-up period (mean 34.7 [SD 3.2] weeks), corresponding to a 94% (95%CI 86% to 98%, P<0.001) reduction in the hazard of having a positive SARS-CoV-2 test for seropositives.

CONCLUSIONS: Seroconversion after SARS-CoV-2 infection confers protection against reinfection lasting at least 8 months. These findings could help global health authorities establishing priority for vaccine allocation.

PMID:34043763 | DOI:10.1093/cid/ciab495

Allergy. 2021 May 26. doi: 10.1111/all.14961. Online ahead of print.

ABSTRACT

Primary antibodydeficiencies (PAD) constitute the majority of all primary immunodeficiency diseases (PID) also termed in born errors of immunity (IEI). This category (PAD) representsaround 52% of all IEI and the proportion overall is still greater given that antibody deficiency is a component of other groups including combined and severe combined immunodeficiencies (SCID), autoinflammatory disorders, diseases of immune dysregulation and other well defined PIDs(1,2). Secondary antibody deficiencies (SAD) represent a larger and expanding number of individuals resulting from the use of a wide range of immunosuppressive therapies, in particular those targeting B cells, and may also result from renal orgastrointestinal immunoglobulin losses, infections, for example HIVormalaria,malnutritionorothers(3).

PMID:34037990 | DOI:10.1111/all.14961

J Clin Immunol. 2021 May 26. doi: 10.1007/s10875-021-00990-z. Online ahead of print.

ABSTRACT

Patients with primary immunodeficiency diseases often require lifelong immunoglobulin (IG) therapy. Most clinical trials investigating IG therapies characterize serum immunoglobulin G (IgG) pharmacokinetic (PK) profiles by serially assessing serum IgG levels. This retrospective analysis evaluated whether steady-state serum IgG trough level measurement alone is adequate for PK assessment. Based on individual patient serum IgG trough levels from two pivotal trials (phase 2/3 European [NCT01412385] and North American [NCT01218438]) of weekly 20% subcutaneous IG (SCIG; Cuvitru, Ig20Gly), trough level-predicted IgG AUC (AUC_τ,tp) were calculated and compared with the reported AUC calculated from serum IgG concentration-time profiles (AUC_τ). In both studies, mean AUC_τ,tp values for Ig20Gly were essentially equivalent to AUC_τ with point estimates of geometric mean ratio (GMR) of AUC_τ,tp/AUC_τ near 1.0 and 90% CIs within 0.80-1.25. In contrast, for IVIG, 10%, mean AUC_τ,tp values were lower than AUC_τ by >20%, (GMR [90% CI]: 0.74 [0.70-0.78] and 0.77 [0.73-0.81] for the two studies, respectively). Mean AUC_τ,tp values calculated for 4 other SCIG products (based on mean IgG trough levels reported in the literature/labels) were also essentially equivalent to the reported AUC_τ (differences <10% for all except HyQvia, a facilitated SCIG product), while differences for IVIG products were >20%. In conclusion, steady-state serum IgG levels following weekly SCIG remain stable, allowing for reliable prediction of AUC over the dosing interval using trough IgG levels. These findings indicate that measuring steady-state serum IgG trough levels alone may be adequate for PK assessment of weekly SCIG.

PMID:34036490 | DOI:10.1007/s10875-021-00990-z