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Vaccine nonresponse during the coronavirus disease 2019 (COVID-19) pandemic has considerable individual and societal risks.To investigate the clinical characteristics of patients with lack of seroconversion after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Demographic and clinical data were collected from 805 patients who had validated antibody assays against the SARS-CoV-2 spike protein at least 14 days after completion of their COVID-19 vaccination. Clinical characteristics from patients with a negative (0.4 U/mL) antibody response were assessed and summarized.A total of 622 (77.3%) patients attained seroconversion as defined by a titer of greater than or equal to 0.4 U/mL, whereas 183 out of 805 (22.7%) patients exhibited no seroconversion after vaccination against SARS-CoV-2. Univariately, older age (P = .02) and male sex were associated with a lower likelihood of seroconversion (P = .003). Therapy with immunosuppressive drugs was noted in 93 (50.8%) of seronegative patients with most (n = 83/93, 89.2%) receiving ongoing immunosuppressive therapy at the time of vaccination. Among the 134 (73.2%) seronegative patients with immunodeficiency, 110 (82.1%) had primary immunodeficiency. Cancer (n = 128, 69.9%), B cell depletion therapy (n = 90/115, 78.3%), and immunosuppressant steroid use (n = 71/93 on immunosuppressants, 76.3%) were the other common characteristics among the vaccine nonresponders. More importantly, our study did not evaluate the actual efficacy of COVID-19 vaccination.Vaccine responses vary by age and sex, with men showing lower rates of seroconversion as compared with women. Primary immunodeficiency along with active malignancy and ongoing immunosuppression with steroids or B cell depletion therapy appeared to be the most common characteristics for those with a lack of vaccine seroconversion after COVID-19 vaccination.

Objective To describe the clinical data from the first 108 patients seen in the Mayo Clinic post–COVID-19 care clinic (PCOCC). Methods After Institutional Review Board approval, we reviewed the charts of the first 108 patients seen between January 19, 2021, and April 29, 2021, in the PCOCC and abstracted from the electronic medical record into a standardized database to facilitate analysis. Patients were grouped into phenotypes by expert review. Results Most of the patients seen in our clinic were female (75%; 81/108), and the median age at presentation was 46 years (interquartile range, 37 to 55 years). All had post-acute sequelae of SARS-CoV-2 infection, with 6 clinical phenotypes being identified: fatigue predominant (n=69), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women, and the dyspnea-predominant phenotype was more common in men. Interleukin 6 (IL-6) was elevated in 61% of patients (69% of women; P=.0046), which was more common than elevation in C-reactive protein and erythrocyte sedimentation rate, identified in 17% and 20% of cases, respectively. Conclusion In our PCOCC, we observed several distinct clinical phenotypes. Fatigue predominance was the most common presentation and was associated with elevated IL-6 levels and female sex. Dyspnea predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were more likely than erythrocyte sedimentation rate and C-reactive protein to be elevated in patients with post-acute sequelae of SARS-CoV-2 infection.

Background The mechanism of coronavirus disease 2019 (COVID-19) vaccine hypersensitivity reactions is unknown. COVID-19 vaccine excipient skin testing has been used in evaluation of these reactions, but its utility in predicting subsequent COVID-19 vaccine tolerance is also unknown. Objective To evaluate the utility of COVID-19 vaccine and vaccine excipient skin testing in both patients with an allergic reaction to their first messenger RNA COVID-19 vaccine dose and patients with a history of polyethylene glycol allergy who have not yet received a COVID-19 vaccine dose. Methods In this multicenter, retrospective review, COVID-19 vaccine and vaccine excipient skin testing was performed in patients referred to 1 of 3 large tertiary academic institutions. Patient medical records were reviewed after skin testing to determine subsequent COVID-19 vaccine tolerance. Results A total of 129 patients underwent skin testing, in whom 12 patients (9.3%) had positive results. There were 101 patients who received a COVID-19 vaccine after the skin testing, which was tolerated in 90 patients (89.1%) with no allergic symptoms, including 5 of 6 patients with positive skin testing results who received a COVID-19 vaccine after the skin testing. The remaining 11 patients experienced minor allergic symptoms after COVID-19 vaccination, none of whom required treatment beyond antihistamines. Conclusion The low positivity rate of COVID-19 vaccine excipient skin testing and high rate of subsequent COVID-19 vaccine tolerance suggest a low utility of this method in evaluation of COVID-19 vaccine hypersensitivity reactions. Focus should shift to the use of existing vaccine allergy practice parameters, with consideration of graded dosing when necessary. On the basis of these results, strict avoidance of subsequent COVID-19 vaccination should be discouraged.

Background: As the vaccination campaign in response to the coronavirus disease 2019 (COVID-19) pandemic continues, concerns with regard to adverse reactions to the vaccine remain. Although immediate hypersensitivity reactions have received much attention, delayed systemic urticarial reactions after vaccination can occur. Objective: To describe the clinical presentation, vaccine excipient skin testing results, and outcomes of subsequent COVID-19 vaccination in patients who experienced delayed systemic urticarial reactions after messenger RNA (mRNA) COVID-19 vaccination. Methods: This was a retrospective case series of 12 patients referred to the Mayo Clinics in Rochester, Minnesota, and Jacksonville, Florida, between January 19, 2021, and April 30, 2021, for evaluation of delayed systemic urticarial reactions after mRNA COVID-19 vaccination. Demographics, medical and allergic history, reaction details, vaccine excipient skin testing results (when performed), and the outcome after subsequent vaccination were collected for each patient. Results: The mean age of the patients was 52 years, all were white, and 9 (75%) were women. Half of the patients had a history of drug allergy, and one had a history of chronic spontaneous urticaria. Seven patients reacted to the Pfizer-BioNTech vaccine and five reacted to the Moderna vaccine. Seven patients developed symptoms between 8 and 24 hours after vaccination. Nine patients required antihistamines for treatment. The median time to symptom resolution was 4 days. Nine patients underwent allergist-directed COVID-19 vaccine excipient skin testing, all of which were negative. Ten patients chose to receive their next mRNA COVID-19 vaccine dose, and four patients experienced recurrent delayed urticaria. Conclusion: Delayed systemic urticarial reactions after mRNA COVID-19 vaccination were not life-threatening, could be treated with antihistamines, and were not predicted with vaccine excipient skin testing. They were not a contraindication to subsequent vaccination, although patients should be counseled with regard to the possibility of recurrence.

Background Myocarditis following coronavirus disease 2019 (COVID-19) mRNA vaccines (Pfizer-BioNTech and Moderna) has been increasingly reported. Incidence rates in the general population are lacking, with pericarditis rather than myocarditis diagnostic codes being used to estimate background rates. This comparison is critical for balancing the risk of vaccination with the risk of no vaccination. Methods A retrospective case series was performed using the Mayo Clinic COVID-19 Vaccine Registry. We measured the incidence rate ratio (IRR) for myocarditis temporally related to COVID-19 mRNA vaccination compared with myocarditis in a comparable population from 2016 through 2020. Clinical characteristics and outcomes of the affected patients were collected. A total of 21 individuals were identified, but ultimately 7 patients met the inclusion criteria for vaccine-associated myocarditis. Results The overall IRR of COVID-19–related myocarditis was 4.18 (95% confidence interval [CI], 1.63–8.98), which was entirely attributable to an increased IRR among adult males (IRR, 6.69; 95% CI, 2.35–15.52) compared with females (IRR 1.41; 95% CI, .03–8.45). All cases occurred within 2 weeks of a dose of the COVID-19 mRNA vaccine, with the majority occurring within 3 days (range, 1–13) following the second dose (6 of 7 patients, 86%). Overall, cases were mild, and all patients survived. Conclusions Myocarditis is a rare adverse event associated with COVID-19 mRNA vaccines. It occurs in adult males with significantly higher incidence than in the background population. Recurrence of myocarditis after a subsequent mRNA vaccine dose is not known at this time., The incidence rate ratio of myocarditis following coronavirus disease 2019 mRNA vaccination is significantly increased for adult males. Most cases occurred within 3 days (range, 1–13) following the second vaccine dose. Cases were mild, and there were no deaths.

Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and was associated with improvement in symptoms.

Background: It remains unclear if asthma is a risk factor associated with worse outcomes among patients with coronavirus disease 2019 (COVID-19). Methods: We performed a comprehensive database search for studies published from January 1, 2019, to October 2, 2020. We included studies that evaluated outcomes among patients with COVID-19 and underlying asthma. Outcomes of interest included the need for hospitalization, length of hospitalization, intensive care unit (ICU) admission, and death. The meta-analysis was conducted by using random-effects methodology. Results: A total of 389 studies were identified through data base searches. After abstract and full-text screening, 16 observational studies with 92,275 patients were included in the analysis. Of the 16 studies, 15 were retrospective and 1 was a prospective cohort study. The average age was 39.6 years, with 48% female patients. Six of the studies included pediatric patients, and one of these studies only evaluated pediatric patients. One study only evaluated pregnant patients. Among patients with COVID-19, the presence of asthma was not associated with any significant increase in risk of hospitalization (odds ratio [OR] 1.46 [95% confidence interval {CI}, 0.29-7.28]), length of hospitalization (1.59 days [‐0.55 to 3.74]), ICU admission (OR 1.65 [95% CI, 0.56-4.17]), or death (OR 0.73 [95% CI, 0.38-1.40]). The overall risk of bias of the included studies was high. Conclusion: Among the patients with COVID-19, asthma did not seem to significantly increase the risk of hospitalization, length of hospitalization, ICU admission, or death.

Antibody responses to pneumococcal polysaccharide vaccination are frequently used as a diagnostic tool for humoral immunodeficiencies, part of the larger collection of inborn errors of immunity. Currently, arbitrary criteria, such as a serotype specific titer of >/= 1.3 µg/mL is most often used as a cut-off for interpretation of pneumococcal antibody responses. The magnitude of the antibody response to each of the 23 serotypes in Pneumovax®, and serotype-specific cut-offs in healthy pneumococcal vaccine-naive adults has not been previously characterized. IgG antibody concentrations were measured prospectively for 23 pneumococcal serotypes pre and 4–6 weeks post-Pneumovax® vaccination in 100 healthy adults, using a multiplex bead-based assay. Antibodies to 19 of 23 serotypes were informative for distinguishing subjects who responded to vaccination, and the serotype threshold was determined to be 9 of 19 serotypes, which characterized an antibody response to pneumococcal vaccination. While this study may facilitate classification of IgG serotype-specific antibody responses post-pneumococcal vaccination in adult patients undergoing diagnostic immunological evaluation for antibody immunodeficiencies or other relevant contexts, additional studies in healthy children and S. pneumoniae protein-conjugate-vaccinated healthy adults will need to be undertaken in the future.

Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID.Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed.We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes.According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (0.05 × 10The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

In 2008, newborn screening (NBS) for severe combined immunodeficiency (SCID) began as a pilot study in Wisconsin and has recently been added to every state's newborn screen panel. The incidence of SCID is estimated at 1 per 58,000 births which may suggest infrequent NBS SCID screen positive results in states with low annual birth rates. In this study, we report our center's experience with NBS positive SCID screen referrals over a 10-year period. A total of 68 full-term newborns were referred to our center for confirmatory testing. Of these referrals, 50% were false positives, 12% were SCID diagnoses, 20% syndromic T cell lymphopenia (TCL) disorders, and 18% non-SCID, non-syndromic TCL. Through collaboration with our newborn screening lab, second-tier targeted gene sequencing was performed for newborns with SCID screen positive results from communities with known founder pathogenic variants and provided rapid genetic confirmation of SCID and non-SCID TCL disorders. Despite extensive genetic testing, two of the eight (25%) identified newborns with SCID diagnoses lacked a definable genetic defect. Additionally, our referrals included ten newborns who were otherwise healthy newborns with idiopathic TCL and varied CD3+ T cell number longitudinal trajectories. Collectively, referrals to our single site over a 10-year period describe a broad spectrum of medically actionable and idiopathic TCL disorders which highlight the importance of clinical immunology expertise in all states, demonstrate efficiencies and challenges for second-tier genetic testing, and further emphasize the need to development standardized evaluation algorithms for non-SCID TCL.

Rituximab is a chimeric monoclonal antibody that is used in a wide variety of conditions, ranging from non-Hodgkin lymphoma to autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. It causes depletion in B cells via antagonism of the CD20 receptor, which is important in initiating B cell cycles and differentiation. The function of CD20 is not entirely known, but it has been shown to be necessary for T-independent B cell immune responses. In some patients, hypogammaglobulinemia develops after rituximab treatment for unclear reasons. We present five cases of patients who received rituximab during their treatment for B cell lymphoma. All of these patients presented with recurrent infections and hypogammaglobulinemia several years after completing chemotherapy, necessitating treatment with immunoglobulin replacement. B cell subset analysis revealed numeric B cell reconstitution; however, when these patients underwent B cell immunophenotyping, it revealed that the class-switched memory B cells (CSMB) (CD27+IgM−IgD−) remained significantly depressed. The low class-switched memory B cells (CD27+IgM−IgD−) may serve as a potential biomarker for the need of continued immunoglobulin replacement therapies.

Hypogammaglobinemia is a well-recognized complication in chronic lymphocytic leukemia (CLL); however, the risk factors that lead to this complication after treatment with anti-CD20 monoclonal antibodies are not well understood. Using the Mayo Clinic CLL database, a retrospective chart review was conducted on patients enrolled between January 1995 and September 2017 who had pre- and post-treatment immunoglobulin values. The relationship between immunoglobulin values prior to treatment as well as post-treatment with clinical variables and overall survival (OS) was evaluated. Hypogammaglobinemia was defined as serum immunoglobulin G (IgG) levels

Underlying lung disease, especially asthma, has recently been found to be associated with a higher risk of hospitalization with coronavirus disease 2019 (COVID-19) infection. Inhaled corticosteroids (ICS) are the most commonly used controller medications in patients with asthma. It is unclear whether ICS use increases the risk for severe COVID-19 infection. At the current time, asthma organizations are still recommending the continued use of ICS and other asthma medications to minimize the risk of uncontrolled asthma. However, for patients with asthma and who have recovered from COVID-19 infection, the timing of resumption of asthma therapy is equally uncertain. Pulmonary function testing and exhaled oral nitric oxide testing are aerosol-generating procedures and are currently being severely restricted at most health-care facilities. We presented a case of a patient with cough-variant asthma who developed severe COVID-19 associated acute respiratory distress syndrome with the need for intubation and prolonged mechanical ventilation. We highlighted the potential utility of using COVID-19 RNA detection as well as immunoglobulin G antibody testing to help guide the timing of resumption of asthma therapy.

This article aims to describe the clinical manifestations and management of COVID-19 in patients with primary and secondary B cell deficient states. We describe the epidemiologic and clinical features as well as unique management paradigm including isolation precautions with COVID-19. We then focus upon primary and secondary preventive approaches including vaccination and pre- as well as post-exposure prophylaxis. Further, we elaborate upon the important disease specific risk factors in these patients and the need to conduct prospective clinical trials to develop individualized management strategies in this population.

This article aims to describe the rationale and utility of immunoglobulin therapies in patients with B-cell immunodeficiency states. We describe the historical perspective, mechanism of actions, and indications for use in this population. We then focus upon management pearls and special considerations for its utility. Finally, we elaborate upon the important economic implications for these patients and the need to develop individualized management strategies in this vulnerable population.

To estimate the incidence of invasive pneumococcal disease (IPD) in the pre-13-valent pneumococcal conjugate vaccine (pre-PCV13; 7-valent pneumococcal conjugate vaccine era, 2002-2010) and post-PCV13 (2011-2018) time periods.Using the Rochester Epidemiology Project, we conducted a population-based cohort study of all IPD cases in Olmsted County, Minnesota, from January 1, 2002, to December 31, 2018.Overall, 187 cases of IPD were identified. The incidence of IPD decreased significantly from 11.1 (95% CI, 9.1 to 13.2) to 5.6 (95% CI, 4.3 to 6.9) per 100,000 person-years when the pre- and post-PCV13 periods (2002-2010 vs 2011-2018) were compared (P.001). Of the 187 patients with IPD, 112 (59.9%) had previously received at least 1 dose of pneumococcal vaccine. Among the IPD cases in the post-PCV13 period, there was an increase in non-PCV13 serotypes, mainly 11A (from 1.0% [1 of 105] to 6.2% [4 of 64]) and 33F (from 2.9% [3 of 105] to 15.6% [10 of 64]), while PCV13/non-7-valent pneumococcal conjugate vaccine serotypes declined from 38.1% (40 of 105) to 15.6% (10 of 64). At 30 days after an IPD diagnosis, the survival rate was 88.8% (95% CI, 84.4% to 93.4%).A marked decline in IPD incidence occurred during the post-PCV13 era. Because of the observed increase in non-PCV13 serotypes, coupled with multiple factors that impact the epidemiology of IPD, ongoing surveillance of patients with IPD, particularly due to non-PCV13 serotypes, is warranted.

Background: There is growing concern about the rising incidence and prevalence of food allergy globally. We previously reported the incidence of food allergy in Olmsted County, Minnesota, between 2002 and 2011. We sought to update the incidence and temporal trends of food allergies in our region through 2018. Methods: By using the Rochester Epidemiology Project, all Olmsted County residents, with an incident diagnosis of food allergy between January 2, 2012, and December 31, 2018, were identified and their medical records were reviewed. These cases were combined with the previously collected incidence cases from January 2, 2002, and December 31, 2011, to understand longitudinal trends in food allergy incidence rates. Results: Over the 17-year study period, 1076 patients (58.0% male patients, 72.1% white) were diagnosed with an incident food allergy. The median (interquartile range) age at first diagnosis was 2.0 years (1.1-8.4 years). The overall annual incidence rate for all ages was 3.9 (95% confidence interval [CI], 3.6‐4.1) per 10,000 person-years and was significantly higher in male than in female patients (4.4 [95% CI, 4.0‐4.7] and 3.3 [95% CI, 3.0‐3.6], respectively; p < 0.001). The most common food allergen was egg in infancy (57.7%), peanuts in ages 1‐4 years (58.3%), tree nuts in ages 5‐18 years (57.4%), and seafood in adults (≥19 years) (45.3%). Conclusion: The incidence of food allergy in Olmsted County steadily increased from 2002 to 2008, then remained relatively stable between the years 2008 and 2013, and again presented a rising trend over the next 5 years until 2018. This warrants further investigations into the effects of changes in guidelines for early introductions of allergenic foods and other factors that affect causality.

Patient satisfaction (PS) surveying has become a commonly used measure of physician performance, but little is known about the impact on pediatricians. To investigate our hypothesis that PS surveys negatively impact pediatricians, we conducted a survey at an academic children’s medical center. Of 155 eligible physicians, 115 responded (response rate 74%). Two-thirds (68%) did not find the PS score report useful and 88% did not feel that PS scores accurately reflect the physician’s clinical ability. A third reported ordering tests, medications, or consultations due to pressure for higher PS scores. In addition, one-third agreed that PS surveys contribute to burnout and make it difficult to practice meaningful medicine. Overall, PS score reporting has a negative impact on pediatricians, especially those who are female, BIPOC (Black, Indigenous, and People of color), subspecialists, younger, and attended non-US medical schools. Further investigation into improved methods for providing feedback to pediatric physicians is warranted.

This is a functional characterization of a novel CYBA variant associated with normal DHR flow cytometry. Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by recurrent bacterial and fungal infections and dysregulated inflammatory responses due to defective phagocytic cell function leading to the formation of granulomas. CGD patients have pathogenic variants in any of the five components of the phagocytic NADPH oxidase, which transfers electrons through the phagosomal membrane and produces superoxide upon bacterial uptake. Here, we report a pediatric female patient with a novel homozygous missense variant (c.293C T, p.(Ser98Leu)) in CYBA, encoding the p22The patient presented with severe recurrent pneumonia. Specific pathogens identified included Burkholderia and Serratia species suggesting neutrophil functional abnormalities; however, the dihydrorhodamine-1,2,3 (DHR) flow cytometric and cytochrome c reduction assays for neutrophil respiratory burst fell within the low side of the normal range. Western blot and flow cytometric analysis of individual NADPH oxidase components revealed reduced levels of p22Although this patient did not exhibit all the classic features of CGD, such as granulomas and skin infections, she had recurrent pneumonias with oxidant-sensitive pathognomonic organisms, resulting in appropriate targeted CGD testing. This case emphasizes the need to contextually interpret laboratory data, especially using clinical findings to direct additional assessments including genetic analysis.

A 10-year-old Guatemalan girl with past medical history of Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) and combined immunodeficiency presented for evaluation of painful intraoral lesions. On examination, she was noted to have multiple, white to flesh-colored, soft, flat-topped papules, and plaques on the buccal and labial mucosa. Human papillomavirus type 13 was detected on PCR with PGMY primers of previously biopsied buccal tissue, confirming a diagnosis of Heck's disease (multifocal epithelial hyperplasia). We present an immunosuppressed, pediatric patient with two rare, virus-associated neoplastic disorders that have not been previously reported to occur in the same individual.

BACKGROUND: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8+ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4+ T cells in disease pathogenesis. OBJECTIVE: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function. METHODS: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4+ T cells and a novel murine disease model caused by overactive PI3K signaling. RESULTS: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH cell function were cell intrinsic. CONCLUSION: Our studies reveal that CD4+ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:144 issue:1 pages:236-253 ispartof: location:United States status: published

Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamon Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counselling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms. This article is protected by copyright. All rights reserved.

ObjectiveTo describe the clinical data from the first 107 patients seen in the Mayo Clinic Post COVID-19 Care Clinic (PCOCC).Patients and MethodsAfter IRB approval, we reviewed the charts of 107 patients seen between January 19, 2021 and April 29, 2021 in the Mayo Clinic Post COVID Care Clinic (PCOCC) in order to describe the first 107 patients treated through the Mayo Clinic PCOCC. Data was abstracted from the electronic medical record into a standardized database to facilitate analysis. Phenotypes of patients seen in the PCOCC clinic were identified by expert review of predominant symptom clusters.ResultsThe majority of patients seen in our clinic were female (75%, 80/107), and the median age at presentation was 47 years (interquartile range [IQR] 37, 55). All had Post Acute Sequelae of SARS-CoV-2 infection (PASC) with six clinical phenotypes being identified – fatigue predominant (n=68), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women (84%, p=0.006) and the dyspnea-predominant phenotype was more common in men (52%, p=0.002). IL-6 was elevated in 61% of patients (69% of women, p=0.0046) which was statistically discordant with elevation in CRP and ESR which was identified in 17% and 20% of cases respectively (pConclusionIn our post COVID clinic, we observed several distinct clinical phenotypes. Fatigue-predominance was the most common presentation and was associated with elevated IL-6 levels and female gender. Dyspnea-predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were significantly elevated in patients with PASC and discordant with ESR and CRP, particularly in those with central sensitization phenotypes.

Background We sought to evaluate the association between vitamin D deficiency and the severity of coronavirus disease 2019 (COVID‐19) infection. Methods Multiple databases from 1 January 2019 to 3 December 2020 were searched for observational studies evaluating the association between vitamin D deficiency and severity of COVID‐19 infection. Independent reviewers selected studies and extracted data for the review. The main outcomes of interest were mortality, hospital admission, length of hospital stay and intensive care unit admission. Results Seventeen observational studies with 2756 patients were included in the analyses. Vitamin D deficiency was associated with significantly higher mortality (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.50–4.05; 12 studies; hazard ratio [HR]: 4.11, 95% CI: 2.40–7.04; 3 studies), higher rates of hospital admissions (OR: 2.18, 95% CI: 1.48–3.21; 3 studies) and longer hospital stays (0.52 days; 95% CI: 0.25–0.80; 2 studies) as compared to nonvitamin D deficient status. Subgroup analyses based on different cut‐offs for defining vitamin D deficiency, study geographic locations and latitude also showed similar trends. Conclusions Vitamin D deficiency is associated with greater severity of COVID‐19 infection. Further studies are warranted to determine if vitamin D supplementation can decrease the severity of COVID‐19.

PurposeTo determine the utility of GLILD CT scoring system for assessment of GLILD in patients with CVID to avoid the need for lung biopsy. MethodsThe CT scoring system was developed as a consensus based on review of literature. Two radiologists, blinded to patient clinical information, retrospectively scored CT scans of selected patients with histopathologic diagnosis of GLILD. Discrepancies were settled by a third radiologist. Inter-observer reproducibility was calculated with intra-class correlation coefficients. ResultsWe identified 25 CVID patients with histologically confirmed GLILD (12 male, 13 female). The median age was 38 years (range 12 – 72 years). Inter-observer reproducibility was 0.76 (95% CI 0.53 – 0.89). Splenomegaly/splenectomy and basilar predominant perilymphatic nodules greater than or equal to 4mm have good interobserver agreement in our CT scoring system. Discrepancy between observers occurred most often in differentiating intermediate versus high confidence diagnosis of GLILD as opposed to differentiating between low versus intermediate confidence. ConclusionGLILD CT scoring system of pulmonary disease in CVID patients can stratify patients into categories that may assist in avoiding lung biopsy for diagnosis in a subset of patients.

Live vaccines are contraindicated in patients with severe cellular immunodeficiencies while guidelines regarding the administration of live vaccines in patients with more mild disease are ill-defined. We sought to decipher different parameters used by practicing immunologists for the administration of live vaccines in cellular immunodeficiency patients. A 27-question survey assessing clinical and laboratory threshold parameters used in the administration of live vaccines to immunodeficient patients was distributed to practicing clinicians specializing in immune deficiencies. There were 83 survey respondents, 65% identified as female, and 71% were based in the United States. Allergy / Immunology and Immunodeficiency were the most common identified specialties, accounting for 84% of respondents. Most clinicians did administer live vaccines to patients with humoral (54/67; 80.6%), cellular (41/67; 61.2%), and combined diseases (37/67; 55.2%) . Most clinicians who reported giving live vaccines to patients with immune deficiencies considered a threshold CD4 count of ≥ 400 cells/mm3 (MMR 48/60 [80%], Varicella 42/53 [79%], Rotavirus 40/45 [88.89%]), a CD8 count of ≥ 250 cells/mm3 (MMR 30/39 [76.92%], Varicella 29/37 [78.34%], Rotavirus 27/34 [79.41%]), and normal mitogen function (MMR 44/53 [83.02%], Varicella 40/48 [83.33%], Rotavirus 37/40 [92.5%]). Using these survey results, we propose a treatment threshold of using CD4 count of ≥ 400 cells/mm3, a CD8 count of ≥ 250 cells/mm3, and normal lymphocyte proliferative responses to mitogen. Future studies are needed to determine clinical efficacy and safety using these thresholds.

OBJECTIVE: To determine the trends in testing and incidence of vitamin D deficiency/insufficiency in Olmsted County, Minnesota over a 16-year period. STUDY DESIGN: The Rochester Epidemiology Project (REP) was used to identify Olmsted County, Minnesota residents aged 50 ng/mL. Vitamin D deficiency/insufficiency was defined as a total 25(OH)D level of

BackgroundEvidence suggests the role of an inflammatory storm in COVID-19 complications. Colchicine is an orally administered, anti-inflammatory medication beneficial in gout, pericarditis and coronary disease.MethodsWe performed a randomized, double-blind trial involving non-hospitalized patients with COVID-19 diagnosed by polymerase chain reaction (PCR) testing or clinical criteria. The patients were randomly assigned to receive colchicine (0.5 mg twice daily for 3 days and once daily thereafter) or placebo for 30 days. The primary efficacy endpoint was the composite of death or hospitalization for COVID-19.ResultsA total of 4488 patients were enrolled. The primary endpoint occurred in 4.7% of the patients in the colchicine group and 5.8% of those in the placebo group (odds ratio, 0.79; 95.1% confidence interval (CI), 0.61 to 1.03; P=0.08). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 4.6% and 6.0% of patients in the colchicine and placebo groups, respectively (odds ratio, 0.75; 95% CI, 0.57 to 0.99; P=0.04). In these patients with PCR-confirmed COVID-19, the odds ratios were 0.75 (95% CI, 0.57 to 0.99) for hospitalization due to COVID-19, 0.50 (95% CI, 0.23 to 1.07) for mechanical ventilation, and 0.56 (95% CI, 0.19 to 1.66) for death. Serious adverse events were reported in 4.9% and 6.3% in the colchicine and placebo groups (P=0.05); pneumonia occurred in 2.9% and 4.1% of patients (P=0.02). Diarrhea was reported in 13.7% and 7.3% in the colchicine and placebo groups (PConclusionAmong non-hospitalized patients with COVID-19, colchicine reduces the composite rate of death or hospitalization. (COLCORONAClinicalTrials.govnumber:NCT04322682)

Background: As the global COVID-19 pandemic has unfolded, there has been much debate surrounding the optimal management of patients with asthma who are at risk of or contract COVID-19, whether asthma and steroids are risk factors for severe COVID-19, and how transmissible the virus is among children. Objective: The objective of this study is to provide allergists and other clinicians with pearls pertaining to the management of patients with asthma in the setting of the COVID-19 pandemic and to provide some information regarding the risk of transmission among the pediatric population. Methods: Utilizing the case of one of our own patients with asthma who developed COVID-19 as context, we review the recent literature discussing the risk of COVID-19 in patients with asthma, the management of asthma medications in the time of the pandemic, and the risk of viral transmission. Results: Despite initial reports that asthma was a risk factor for developing severe COVID-19, subsequent investigation has shown that this is likely not true. Additionally, the use of systemic or inhaled glucocorticoids does not appear to increase the risk of severe COVID-19, but there is no evidence guiding the use of biologic therapy. There is conflicting evidence regarding the ability of children to transmit the virus. Conclusion: We provide pearls that asthma does not appear to be associated with an increased risk of COVID-19 and continued use of inhaled corticosteroids appears to be safe. While there is no evidence guiding the use of biologic therapies, a recent position paper suggests that they should be continued unless a patient contracts COVID-19, at which point they should be held until clinical recovery occurs.

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study’s objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913

Norovirus is an emerging pathogen causing gastroenteritis. We sought to identify factors associated with clinical outcomes in a cohort of patients with laboratory-confirmed norovirus infection. We performed a retrospective chart review of patients with positive norovirus polymerase chain reaction in stool between October 1, 2015, and May 31, 2016. 128 unique patients were identified during the study period, 64 of whom had immune deficiency, of which only 3 patients had a primary immune deficiency (common variable immune deficiency), while 61 patients had a secondary immune deficiency. 50% of patients with immune deficiency were hospitalized as compared to only 30% of the non–immune-deficient cohort (odds ratio: 2.1 (1.1–4.18, P =0.04). One-third (32.8%) of the patients had a polymicrobial stool infection, and 21.1% had concurrent Clostridium difficile infection. Initial mean total leukocyte count was higher in the hospitalized group at 8.40×109/L versus 6.31×109/L in the nonhospitalized group ( P =0.049). All 13 patients presenting with fever had symptomatic resolution ( P =0.002). The presence of C. difficile infection was correlated with persistent symptoms (OR 2.30 [0.95–5.58], P =0.067). The overall mortality rate among our cohort was 3.13% (4 patients). All deceased patients had secondary immune deficiency, and none had C. difficile coinfection. Presence of an immune deficiency increases the risk of hospitalization with norovirus infection. Absence of fever is associated with lower resolution and possibly may contribute to a persistent infectious state. Presence of concomitant C. difficile infection is correlated with a lower overall mortality rate.

We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant. We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis. Based on the WES result, we developed a novel flow cytometric panel for rapid assessment of DNA repair defects using blood samples. We also performed whole transcriptome sequencing (WTS) on fibroblast RNA from the patient and father for abnormal transcript analysis. WES revealed a pathogenic paternally inherited indel in ATM. We used the flow panel to assess several proteins in the DNA repair pathway in lymphocyte subsets. The patient had absent phosphorylation of ATM, resulting in absent or aberrant phosphorylation of downstream proteins, including γH2AX. However, ataxia-telangiectasia (AT) is an autosomal recessive condition, and the abnormal functional data did not correspond with a single ATM variant. WTS revealed in-frame reciprocal fusion transcripts involving ATM and SLC35F2 indicating a chromosome 11 inversion within 11q22.3, of maternal origin. Inversion breakpoints were identified within ATM intron 16 and SLC35F2 intron 7. We identified a novel ATM-breaking chromosome 11 inversion in trans with a pathogenic indel (compound heterozygote) resulting in non-functional ATM protein, consistent with a diagnosis of AT. Utilization of several molecular and functional assays allowed successful resolution of this case.

Introduction: Asthma is one of the most common airway diseases that nearly all pediatricians will encounter in their clinical practice. Using spirometry to compare a patient’s forced expiratory vol...