Ocular Manifestations in Primary Immunodeficiency Disorders: A Report From the United States Immunodeficiency Network (USIDNET) Registry.

BACKGROUND: Few published studies address eye disease in primary immunodeficiency (PID) despite ocular infections and autoimmune disease being known manifestations of immunodeficient states. OBJECTIVE: Data from the USIDNET Registry provide a resource to study ocular ailments in subjects with PID. METHODS: Ocular manifestations and patient characteristics were determined using data from 4624 patients with PID enrolled in the US Immunodeficiency Network (USIDNET) Registry. RESULTS: A total of 519 (11.2%) patients had recorded ocular diseases. Those with autoinflammatory disorders (n = 4 of 7 [57.1%]), intrinsic and innate immunity defects (n = 9 of 44 [20.5%]), and immune dysregulation (n = 27 of 142 [19.0%]) had the highest percentage of ocular diseases for the PID diagnosis category. Of the 67.6% with infections, 85.5% had conjunctivitis. Bacteria (56.2%) and viruses (27.4%) were the most common microorganisms reported, with Staphylococcus (31.7%), Haemophilus (26.8%), and Streptococcus (22.0%) being the most common bacteria isolated. Those with a history of eye infections had lower immunoglobulin levels, lower CD19 B-cell percentages, and a lower number of protective pneumococcal titers. In patients with noninfectious ocular complications, 30.8% had vision changes, with retina (n = 20 [8.0%]), cataract (n = 16 [6.4%]), and nerve diseases (n = 16 [6.4%]) also being common. Many patients with ocular disease had serious sequelae, with 12.7% undergoing eye surgery and 10.6% having a vision-based disability. CONCLUSIONS: Vision loss and conjunctivitis were the most commonly reported ocular complications and pose large quality-of-life issues. Learning more about ocular disease in PID will increase awareness about the importance of addressing and evaluating for these ailments.

Immunogenicity and tolerability of COVID-19 messenger RNA vaccines in primary immunodeficiency patients with functional B-cell defects.

BACKGROUND: Data on the safety and efficacy of coronavirus disease 2019 (COVID-19) vaccination in people with a range of primary immunodeficiencies (PIDs) are lacking because these patients were excluded from COVID-19 vaccine trials. This information may help in clinical management of this vulnerable patient group. OBJECTIVE: We assessed humoral and T-cell immune responses after 2 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients with PID and functional B-cell defects. METHODS: A double-center retrospective review was performed of patients with PID who completed COVID-19 mRNA vaccination and who had humoral responses assessed through SARS-CoV-2 spike protein receptor binding domain (RBD) IgG antibody levels with reflex assessment of the antibody to block RBD binding to angiotensin-converting enzyme 2 (ACE2; hereafter referred to as ACE2 receptor blocking activity, as a surrogate test for neutralization) and T-cell response evaluated by an IFN-γ release assay. Immunization reactogenicity was also reviewed. RESULTS: A total of 33 patients with humoral defect were evaluated; 69.6% received BNT162b2 vaccine (Pfizer-BioNTech) and 30.3% received mRNA-1273 (Moderna). The mRNA vaccines were generally well tolerated without severe reactions. The IFN-γ release assay result was positive in 24 (77.4%) of 31 patients. Sixteen of 33 subjects had detectable RBD-specific IgG responses, but only 2 of these 16 subjects had an ACE2 receptor blocking activity level of ≥50%. CONCLUSION: Vaccination of this cohort of patients with PID with COVID-19 mRNA vaccines was safe, and cellular immunity was stimulated in most subjects. However, antibody responses to the spike protein RBD were less consistent, and, when detected, were not effective at ACE2 blocking.

Impact of Rapid Transition to Telemedicine-Based Delivery on Allergy/Immunology Care During COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) necessitated wide-scale adoption of telemedicine (TM) and restriction of in-person care. The impacts on allergy/immunology (A/I) care delivery are still being studied. OBJECTIVE: To describe the outcomes of rapid transition to TM-based care (video visit followed by in-person visits dedicated to diagnostic and therapeutic procedures when needed) at an academic A/I practice during COVID-19. METHODS: Demographic data were compared for patients originally scheduled for in-person visits between March 10, 2020, and April 30, 2020, who completed a video visit instead between March 10, 2020, and June 30, 2020, and those who did not. Appointment completion, diagnoses, and drug allergy and skin testing completion were compared for visits between March 10, 2020, and June 30, 2020, and 1 year prior (March 10, 2019-June 30, 2019). RESULTS: Sixty-nine percent (265 of 382) of patients originally scheduled between March 10, 2020, and April 30, 2020, were able to complete video visits. Patients who completed video visits were more likely to be white (52% vs 33%; P < .001), English-speaking (96% vs 89%; P = .01), and privately insured (70% vs 54%; P = .004). With TM-based care compared with in-person care, there were significant decreases in environmental and food skin testing completion rates (91% and 92% in 2019 vs 60% and 64% in 2020, respectively, P < .001). Drug allergy testing completed after internal referral remained low but comparable (51% in 2019 vs 52% in 2020). Transitioning nonprocedural visits to video allowed allergen immunotherapy and biologic injection visits to resume at a volume similar to pre-COVID. No COVID-19 infections resulted from in-clinic exposure. CONCLUSIONS: Although transitioning to TM-based care allowed continued A/I care delivery, strategies are needed to achieve higher testing completion rates and ensure video visits do not exacerbate existing health disparities.

Perceived Versus Actual Aeroallergen Sensitization in Urban Children.

BACKGROUND: Individuals often report allergy to specific aeroallergens, but allergy testing can reveal disparate sensitization. OBJECTIVE: To characterize the agreement between perceived and actual sensitization to individual aeroallergens in an urban pediatric population. METHODS: A total of 253 children were enrolled from pediatric clinics in New York, NY. Detailed questionnaires regarding perceived sensitization and serum specific IgE measurements to 10 common aeroallergens were completed. Agreement between perceived and actual sensitization (sIgE ≥ 0.35 kUA/L) to individual aeroallergens was assessed by Cohen's kappa. Multivariable logistic regression models adjusted for potential confounders were used to test for associations between perceived and actual sensitization. RESULTS: A total of 161 (63.6%) of 253 children reported perceived sensitization to 1 or more aeroallergen, and 203 (80.2%) were actually sensitized to 1 or more aeroallergen. Agreement between perceived and actual aeroallergen sensitization was fair for most aeroallergens, with greatest agreement for cat dander (κ, 0.42; 95% CI, 0.32-0.53) and dust (κ, 0.32; 95% CI, 0.20-0.44). Models adjusted for potential confounders showed nearly 6-fold odds of sensitization to cat dander given perceived cat allergy (adjusted odds ratio, 5.82; 95% CI, 2.91-11.64), and over 2-fold odds of sensitization to Dermatophagoides pteronyssinus, Dermatophagoides farinae, dog dander, or grass pollen given perceived sensitization to their respective allergens. Among children with no perceived sensitization, actual sensitization ranged from 5.4% to 30.4%, and was more common for indoor versus outdoor allergens, including cockroach. CONCLUSIONS: Children who perceive allergen sensitization to cat, dog, dust, or grass are likely to demonstrate actual sensitization to these individual allergens. Children with no perceived sensitization to allergens are nonetheless frequently sensitized.

Prenatal Diet and the Development of Childhood Allergic Diseases: Food for Thought.

PURPOSE OF REVIEW: The development of allergic disease is shaped by genetics and the environment, including diet. Many studies suggest a role for maternal diet during pregnancy. In this article, we discuss potential mechanisms by which specific nutrients, particular foods, and dietary patterns may influence allergic disease development and review studies examining the relationship between prenatal diet and the risk of childhood allergy. RECENT FINDINGS: The combination of in utero exposures and genetic predisposition may contribute to the development of allergic disease by altering immune and organ development. Inflammation predominates in the first and third trimesters whereas the second trimester is characterized by anti-inflammatory and Th2 immune responses. Maternal dietary exposures during pregnancy may interact with inherited genetic risk factors influence immune system development. There are varied results regarding the impact of maternal prenatal diet on the development of childhood allergies. Well-designed randomized controlled studies are needed to clarify this area.

Evaluation of Lymphoproliferative Disease and Increased Risk of Lymphoma in Activated Phosphoinositide 3 Kinase Delta Syndrome: A Case Report With Discussion.

Activated phosphoionositide-3 kinase delta syndrome (APDS) is a rare disorder caused by activating mutations in phosphoionositide 3-kinase delta (PI3Kδ). This syndrome usually presents in childhood with recurrent sinopulmonary infections and immune deficiency as is seen in the case discussed in this report. Patients with APDS also experience other complications including lymphoid hyperplasia, autoimmunity, increased susceptibility to herpes viruses, especially Epstein-Barr virus and cytomegalovirus, and an increased incidence of B-cell lymphoma. The clinical implications for lymphoid hyperplasia and lymphoma are profound and frequently, it is challenging to distinguish between the two. This case report is of a young girl with a mutation in PIK3CD, the gene encoding the catalytic subunit of PI3Kδ, who presents with asymmetrical cervical lymphadenopathy and parotid swelling. After little improvement in lymphadenopathy on antibiotics, an excisional biopsy of a cervical lymph node was obtained which was initially concerning for lymphoma. This case recounts the clinical decisions made to evaluate this lymphadenopathy and concern for malignancy due to the increased incidence of B-cell lymphoma in this population. It was concluded after careful evaluation of her lymph node histology and cytometry, bone marrow biopsy, and CSF studies that her findings were consistent with lymphoid hyperplasia and not lymphoma and she was treated with rituximab. This case highlights the many comorbidities present in patients with this disease and the current treatments for complications in patients with APDS, including new targeted therapies.

Linkage of posterior amorphous corneal dystrophy to chromosome 12q21.33 and exclusion of coding region mutations in KERA, LUM, DCN, and EPYC.

PURPOSE: To identify the genetic basis of posterior amorphous corneal dystrophy (PACD) segregating in a large pedigree. METHODS: The authors performed clinical evaluation of a previously unreported pedigree with PACD, light and electron microscopic examination of an excised corneal button, genomewide linkage analysis, fine mapping linkage and haplotype analysis, and screening of four candidate genes (KERA, LUM, DCN, and EPYC). RESULTS: Twenty-one participants were determined to be affected based on the presence of characteristic clinical features of PACD; 15 affected and 39 unaffected individuals from a single pedigree enrolled in the study and provided DNA for analysis. Histopathologic examination of an excised corneal specimen from an affected individual demonstrated disorganized stromal lamellae and stromal staining with colloidal iron. Genomewide analysis demonstrated significant evidence of linkage to chromosome region 12q21.33 and evidence suggestive of linkage to chromosome region 8q22.3. Fine mapping of the chromosome 12 locus confirmed significant linkage; the largest multipoint log odds ratio score was 5.6 at D12S351. The linkage support interval was approximately 3.5 Mb (3.5 cM) in length between flanking markers D12S1812 and D12S95, roughly the entire chromosome band 12q21.33. No coding region mutations were identified in four candidate genes-KERA, LUM, DCN, EPYC-located in the chromosome 12 linkage support interval. CONCLUSIONS: Linkage and haplotype analyses identified 12q21.33 as a locus for PACD. However, no mutations were identified in the candidate genes (KERA, LUM, DCN, EPYC) within this region.

Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval.

PURPOSE: Posterior polymorphous corneal dystrophy (PPCD) is an autosomal-dominant disorder of the corneal endothelium associated with visually significant corneal edema and glaucoma. Statistical genetic analysis of 4 families with PPCD has demonstrated linkage to a 2.4 cM common support interval on chromosome 20 bordered by the markers D20S182 and D20S139. We sought to identify the genetic basis of PPCD linked to chromosome 20 (PPCD1) by screening the 26 positional candidate genes between these markers in a family previously mapped to the PPCD1 region. METHODS: The coding regions of the 26 positional candidate genes mapped to the common PPCD1 support interval were amplified and sequenced in affected and unaffected individuals from a family previously linked to the PPCD1 locus. Nine other genes positioned just outside of the common PPCD1 support interval but within the autosomal-dominant congenital hereditary endothelial dystrophy interval were also screened. RESULTS: Four DNA sequence variants in 3 of the positional candidate genes demonstrated complete segregation with the affected phenotype: p.Thr109Thr (rs6111803) in OVOL2, p.Arg56Gln (novel variant-RPSnovel) in RPS19P1, and p.Thr85Thr (rs1053834) and p.Pro99Ser (rs1053839) in C20orf79. Each of these 4 sequence variants demonstrated significant linkage with the affected phenotype in this family (P = 2.5 x 10 for RPSnovel, rs1053834 and rs1053839; P = 8.6 x 10 for rs6111803). However, we also identified each of these 4 sequence variants in > or = affected control individuals. The haplotype on which the disease-causing mutation is segregating was found to have a population frequency of 4.2% in the CEPH HapMap trios. Although a number of other previously described and novel single nucleotide polymorphisms were identified in the 35 positional candidate genes located within the PPCD1 and congenital hereditary endothelial dystrophy intervals, none segregated with the affected phenotype. CONCLUSIONS: We report the absence of a presumed pathogenic coding region mutation in the common PPCD1 support interval. Although minor alleles of 4 single nucleotide polymorphisms were identified that segregated with the affected phenotype, the relatively high frequency of each minor allele in the general population indicates that none is a candidate for the causal variant for PPCD. Instead, the causal variant is most likely a coding region deletion or a variant in a noncoding region of the PPCD1 common support interval.