Respiratory Outcomes at 5-Year Follow-Up in Children with Mannose-Binding Lectin Deficiency: A Retrospective Cohort Study.

OBJECTIVE: Mannose-binding lectin deficiency may predispose children to having increased infection susceptibility. However, there is no conclusive evidence that mannose-binding lectin deficiency is associated with adverse respiratory consequences in children. We aimed to evaluate the effects of mannose-binding lectin deficiency (defined as a level of less than 0.6 mg/L) on clinical, radiological, and microbiological characteristics in children presenting with troublesome respiratory symptoms, as compared to those who are mannosebinding lectin-sufficient. MATERIAL AND METHODS: We conducted a retrospective cohort study to investigate the association between mannose-binding lectin deficiency and respiratory outcomes in children over a period of 10 years in a large teaching hospital. Children presenting with frequent or persistent respiratory symptoms such as a chronic wet cough lasting more than 4 weeks, recurrent lower respiratory tract infections (≥4 infections in a year), or severe respiratory tract infections requiring admission to intensive care or to high dependency unit were included in the study. RESULTS: The study showed no significant difference in clinical outcomes with mannose-binding lectin deficiency and sufficiency. Thirty-two percent of children with mannose-binding lectin deficiency and 30% of those with mannose-binding lectin sufficiency had positive respiratory microbiology. Twenty-three percent of children with mannose-binding lectin deficiency and 24% of those with mannose-binding lectin sufficiency had radiological changes on plain radiographs; also the prevalence of bronchiectasis was similar in both groups. The rates of admission to pediatric intensive care unit were comparable in the 2 groups. CONCLUSIONS: Children with mannose-binding lectin deficiency and sufficiency showed similar clinical, radiological, and microbiological characteristics. Our study suggests that there are no childhood adverse respiratory consequences with mannose-binding lectin deficiency.

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

A case of wild-type rubella-associated cutaneous granuloma in ataxia telangiectasia.

Granulomatous skin disease is known to be associated with various primary immunodeficiencies, including ataxia telangiectasia (AT). Recent reports of persistence of live vaccine strain rubella within such cutaneous granulomas have raised concern regarding the safety of vaccination. Here we report a case of cutaneous granuloma in association with AT, demonstrating wild type, rather than vaccine strain rubella. This supports the persistence of rubella as a causative mechanism, but suggests it is not vaccine strain-specific, and thus may impact the decision of those considering not vaccinating this subset of children.

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK.

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Correct positioning for hip radiographs allows reliable measurement of hip displacement in cerebral palsy.

AIM: The pelvic radiograph in children with cerebral palsy (CP) can inform the degree of hip displacement by calculation of the migration percentage. However, concerns have arisen about the reliability of this measurement. The present study examined the reliability of radiographic assessment of displacement and the importance of positioning and reporting experience. METHOD: Two pelvic radiographs, taken at least an hour apart, were performed in 20 children (total 40 hips) in the standard position by a trained paediatric radiographer. Children (13 males, seven females) were aged 30 months to 10 years with severe bilateral spastic CP in Gross Motor Function Classification System levels IV (n=10) and V (n=10). The migration percentage of each hip was measured on two occasions 3 months apart by two experienced radiologists independently. Comparisons of migration percentage were made in three ways by (1) the same observer at the same time, (2) the same observer 3 months apart, and (3) different observers 3 months apart. RESULTS: Migration percentage (mean [SD]) was (1) 3.2% (3.5), (2) 3.3% (3.2), and (3) 3.7% (3.8) respectively. INTERPRETATION: Reliable measures of migration percentage can be obtained with correct positioning and if reported by suitably experienced radiologists, making this a valid surveillance method. Clinical decisions can be made taking into account an expected error in hip displacement measurements.