Manish Butte

J Allergy Clin Immunol Pract. 2022 May 25:S2213-2198(22)00505-0. doi: 10.1016/j.jaip.2022.05.017. Online ahead of print.

ABSTRACT

Genetic testing is a state-of-the-art and readily accessible diagnostic tool and is increasingly indicated in the evaluation process when relevant and possible, although incorporation of this modality into the daily practice of allergists-immunologists in both academic and nonacademic or community settings is still a challenge. Educational sessions and resources support the use of genetic testing in the diagnosis and management of Primary Immunodeficiency (PID) by both the American Academy of Allergy, Asthma and Immunology, as well as the Clinical Immunology Society. Genetic testing for PID has become much more convenient and affordable over the past decade; allergist-immunologists in private practice are now able to offer patients high-quality and comprehensive genetic testing panels to help diagnose or characterize underlying immune abnormalities among patients with recurrent infections, and even patients with allergic disorder and non-infectious complications. Though genetic testing has not been a commonplace consideration in day-to-day practice for many non-academic specialists, a shift toward adopting this into our standard toolkit should be taking place. Most of the commercial genetic testing is aiming for a panel of genes ranging anywhere from just a few to several hundred, so the specialist can feel comfortable clearly interpreting the data. As the panels are analyzing data from next generation sequencing (NGS) and deletion/duplication assays, this evaluation may need to be repeated when panels expand and include new relevant genes. Ultimately, for undiagnosed cases, whole exome and genome sequencing can be the next step, however, involvement of genetic counsellors may be needed to interpret the data. The value of genetic testing is that it may bring the clinician closer to an accurate diagnosis, therefore we can keep treating our patients more accurately and effectively, which may result in less frequent follow-ups for unresolved or recurrent problems. Additionally, we can then provide patients and their families with important information about the root-cause of their disease state, risks to other family members, and offer genetic counseling services. Genetic testing results may also aid in recognizing when a referral to expert colleagues for more advanced and specialized treatments is indicated.

PMID:35643275 | DOI:10.1016/j.jaip.2022.05.017

Clin Exp Immunol. 2022 Jan 28:uxac008. doi: 10.1093/cei/uxac008. Online ahead of print.

ABSTRACT

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.

PMID:35641155 | DOI:10.1093/cei/uxac008

Ann Allergy Asthma Immunol. 2022 May 28:S1081-1206(22)00492-6. doi: 10.1016/j.anai.2022.05.026. Online ahead of print.

ABSTRACT

BACKGROUND: Vaccine non-response during the COVID-19 pandemic has considerable individual as well as societal risks.

OBJECTIVE: To investigate the clinical characteristics of subjects with lack of seroconversion after SARS-CoV-2 vaccination.

METHODS: Demographic and clinical data were collected from 805 subjects who had a validated antibody assay 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.

RESULTS: 622 (77.3%) subjects attained seroconversion as defined by a titre of ≥0.4 U/mL, while 183/805 (22.7%) subjects showed no seroconversion after SARS-CoV-2 vaccination. Univariately, older age (P = .02) and male sex were associated with a lower likelihood of seroconversion (P = .003). Therapy with immunosuppressive drugs were noted in 93 (50.8%) of seronegative subjects with the majority (n = 83/93, 89.2%) receiving ongoing immunosuppressive therapy at time of vaccination. Among 134 (73.2%) seronegative patients with an immunodeficiency, 110 (82.1%) had a primary immunodeficiency. Cancer (n = 128, 69.9%), B-cell depletion therapy (n = 90/115, 78.3%), and immunosuppressant steroid usage (n = 71/93 on immunosuppressants, 76.3%) were the other common characteristics amongst the vaccine non-responders. Importantly, our study did not evaluate the actual efficacy of COVID-19 vaccination.

CONCLUSION: Vaccine responses vary by age and sex, with males showing lower rates of seroconversion as compared to females. Primary immunodeficiency along with active malignancy and ongoing immunosuppression with steroids and/or B-cell depletion therapy appeared to be the most common characteristics for those with lack of vaccine seroconversion following COVID-19 vaccination.

PMID:35640775 | DOI:10.1016/j.anai.2022.05.026

Medicina (B Aires). 2022;82(3):361-369.

ABSTRACT

Antibody deficiencies (AD) are characterized by low or absent immunoglobulin levels or the inability to develop a specific antibody response. They are classified in primary (PAD) when there is an intrinsic immune defect, or secondary (SAD) to other diseases or drugs. The aim of our study was to review the evolutio n of AD assisted at the Immunology Unit, Hospital Durand between 1982 and 2020, divided into two periods: Period I (1982-2009) and Period II (2010-2020); to evaluate their growth, epidemiologic features and treatment options. A total of 205 patients were identified, 176 (85.8%) with PAD and 29 (14.2%) with SAD. The most frequent PAD were common variable immunodeficiency in 104 (59%) patients, X linked agammaglobulinemia in 17 (9.6%) and selective IgA deficiency in 26 (14.8%). Genetic defects were found in 25 (14.2%) patients with PAD. SAD cases were associated with rituximab in 21 (72.4%) subjects, haematological disease in three (10.2%) and with antiepileptic drugs in other three; 161 (78.5%) patients were treated with immunoglobulins, 140 (87%) PAD y 21 (13%) SAD; 152 (94.4%) received intravenous immunoglobulins and nine (5.6%) subcutaneous immunoglobulins. Thirty (19.7%) patients treated at first with intravenous immunoglobulins changed to subcutaneous formulations. The increase in number of patients between both periods was greater than 250%, and more than 700% in patients added per year. SAD growth was greater than twice times comparing with PAD. By the end of the study 125 patients continued in follow up, 80% PAD y 20% SAD and 14 died.

PMID:35639056

An Pediatr (Engl Ed). 2022 May 28:S2341-2879(22)00048-5. doi: 10.1016/j.anpede.2022.03.002. Online ahead of print.

ABSTRACT

INTRODUCTION: The aim of the study was to assess the incidence of hospital admission due to severe acute respiratory infection by respiratory syncytial virus (RSV-ARI) in children with primary immunodeficiencies (PIDs) and the severity of RSV-ARI in these patients.

METHODS: We conducted a nationwide cross-sectional retrospective and prospective multicentre study in the 2011-2017 period. The study was performed in 15 Spanish hospitals and included children with PID who required hospital admission due to RSV-ARI.

RESULTS: Out of 439 patients with PID followed up at participating hospitals, 13 (3%) required hospital admission due to RSV-ARI. The median age of admitted patients was 1.6 years (interquartile range, 0.5-2.2), and 7 were male. The types of PID most frequently associated with admission due to RSV-ARI were combined immunodeficiency (CID; 4/71; 6%) and CID with associated or syndromic features (CIDwASF; 6/147; 4%). Two of the 13 patients were receiving palivizumab for RSV prophylaxis, and 3 received potentially active therapies against RSV during the hospital stay. Viral coinfection was detected in 6 patients, 5 (39%) developed complications, and 4 (31%) required admission to the paediatric intensive care unit. There were no documented RSV-related deaths.

CONCLUSIONS: In the group of patients with PID, severe RSV infection requiring hospitalization is more frequent in patients with CID and CIDwASF, in whom special efforts should be made to prevent RSV infection. Further studies are needed to confirm these results.

PMID:35637145 | DOI:10.1016/j.anpede.2022.03.002

Front Immunol. 2022 May 13;13:900055. doi: 10.3389/fimmu.2022.900055. eCollection 2022.

ABSTRACT

OBJECTIVES: Ten warning signs of primary immunodeficiency (PID) were suggested by the Jeffrey Modell Foundation (JMF), to increase physician awareness of PID. These warning signs have not yet been evaluated for patients with secondary immunodeficiency (SID). This study investigated whether the 10 warning signs used for the diagnosis of PID were also sufficient for the diagnosis of SID, and explored the possibility of additional signs.

METHODS: This prospective study was conducted between June and December 2020. The mothers of 162 patients with PID and SID, and mothers of 200 healthy children, were asked to complete a questionnaire about family and personal history in addition to the warning signs of PID developed by the JMF. A JMF score was created by giving one point for each “Yes” answer for the 10 warning signs of PID. Medical records of the patients were evaluated for possible additional warning signs for PID and SID.

RESULTS: The JMF scores of the PID (3.36 ± 1.65) and SID (3.72 ± 1.12) groups were significantly higher than the scores of the control group (0.34 ± 0.61) (p < 0.05). A sign for immunological evaluation in two patients without warning signs in the PID group was found to be chronic diarrhea. In addition to the 10 JMF warning signs, we found that consanguinity and a family history of tuberculosis were statistically significant in our PID group, compared with the SID and control groups.

CONCLUSIONS: The JMF warning signs are important for early diagnosis of PID. Our study showed that these signs may also be used for the early diagnosis of SID in patients and, according to our results, in addition to the 10 JMF signs for PID, parental consanguinity, chronic diarrhea, and a family history of tuberculosis may also be considered warning signs for the early diagnosis of PID.

PMID:35634313 | PMC:PMC9136241 | DOI:10.3389/fimmu.2022.900055

Methods Mol Biol. 2022;2453:169-190. doi: 10.1007/978-1-0716-2115-8_11.

ABSTRACT

Inborn errors of immunity (IEI) are genetic defects that can affect both the innate and the adaptive immune system. Patients with IEI usually present with recurrent infections, but many also suffer from immune dysregulation, autoimmunity, and malignancies.Inborn errors of the immune system can cause defects in the development and selection of the B-cell receptor (BCR ) repertoire. Patients with IEI can have a defect in one of the key processes of immune repertoire formation like V(D)J recombination, somatic hypermutation (SHM), class switch recombination (CSR), or (pre-)BCR signalling and proliferation. However, also other genetic defects can lead to quantitative and qualitative differences in the immune repertoire.In this chapter, we will give an overview of protocols that can be used to study the immune repertoire in patients with IEI, provide considerations to take into account before setting up experiments, and discuss analysis of the immune repertoire data using Antigen Receptor Galaxy (ARGalaxy).

PMID:35622327 | DOI:10.1007/978-1-0716-2115-8_11

Clin Immunol. 2022 May 22:109047. doi: 10.1016/j.clim.2022.109047. Online ahead of print.

ABSTRACT

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Treatment for patients who have a monogenic cause of their IBD, often the youngest children, known as very early onset IBD (VEO-IBD), can be different from standard treatment for polygenic cases. Yet, ascertainment of these patients is difficult.

METHODS: We analyzed cases of VEO-IBD to understand the breadth of monogenic etiology and to identify clinical, laboratory, and flow cytometric correlates of this subpopulation.

RESULTS: Genetic causes of very early onset inflammatory bowel disease are highly diverse ranging from pure epithelial defects to classic T cell defects. Flow cytometry, other than testing for chronic granulomatous disease, has a low sensitivity for monogenic etiologies. Poor growth was a clinical feature associated with monogenic causality.

CONCLUSIONS: Genetic testing is, at this moment, the most robust method for the identification of monogenic cases of very early onset IBD.

PMID:35613698 | DOI:10.1016/j.clim.2022.109047

BMJ Case Rep. 2022 May 24;15(5):e248812. doi: 10.1136/bcr-2022-248812.

ABSTRACT

A patient, an adolescent male, presented to us with complaints of recurrent respiratory tract infections since childhood. Differentials considered were cystic fibrosis (CF), bronchial asthma with allergic bronchopulmonary aspergillosis (ABPA), primary ciliary dyskinesia (PCD) and primary immunodeficiency disorders. Sweat chloride test, total IgE and Aspergillus fumigatus specific serum IgE and IgG levels were normal ruling out CF and ABPA. Nasal nitric oxide (NO) screening test showed reduced NO levels, and high-speed video microscopy of nasal scrapings showed stiff beating cilia with reduced ciliary beat frequency confirming the diagnosis of PCD. Immunodeficiency workup showed reduced serum IgG, IgA and IgM, when repeated on two separate occasions when the patient was not harbouring any active infection, suggestive of pan-hypogammaglobulinaemia. Thus, a diagnosis of coexistent PCD and pan-hypogammaglobulinaemia was made. Detection of immunodeficiency disorders is important in patients with PCD as they may benefit from immunoglobulin replacement.

PMID:35609933 | DOI:10.1136/bcr-2022-248812

Orphanet J Rare Dis. 2022 May 23;17(1):210. doi: 10.1186/s13023-022-02365-y.

ABSTRACT

BACKGROUND: In order to facilitate the diagnostic process for adult patients suffering from a rare disease, the Undiagnosed Disease Program (UD-PrOZA) was founded in 2015 at the Ghent University Hospital in Belgium. In this study we report the five-year results of our multidisciplinary approach in rare disease diagnostics.

METHODS: Patients referred by a healthcare provider, in which an underlying rare disease is likely, qualify for a UD-PrOZA evaluation. UD-PrOZA uses a multidisciplinary clinical approach combined with state-of-the-art genomic technologies in close collaboration with research facilities to diagnose patients.

RESULTS: Between 2015 and 2020, 692 patients (94% adults) were referred of which 329 (48%) were accepted for evaluation. In 18% (60 of 329) of the cases a definite diagnosis was made. 88% (53 of 60) of the established diagnoses had a genetic origin. 65% (39 of 60) of the genetic diagnoses were made through whole exome sequencing (WES). The mean time interval between symptom-onset and diagnosis was 19 years. Key observations included novel genotype-phenotype correlations, new variants in known disease genes and the identification of three new disease genes. In 13% (7 of 53), identifying the molecular cause was associated with therapeutic recommendations and in 88% (53 of 60), gene specific genetic counseling was made possible. Actionable secondary findings were reported in 7% (12 of 177) of the patients in which WES was performed.

CONCLUSION: UD-PrOZA offers an innovative interdisciplinary platform to diagnose rare diseases in adults with previously unexplained medical problems and to facilitate translational research.

PMID:35606766 | DOI:10.1186/s13023-022-02365-y