POSSIBLE ROLE OF PEPTIDE EPITOPES OF COVID-19 BNT-162B2 MRNA VACCINE IN FOMENTING AUTOIMMUNITY: AN IN SILICO ANALYSIS

BackgroundFollowing the launch of the global COVID-19 vaccination campaign, there have been increased reports of autoimmune diseases developing de novo following vaccination. These cases include rheumatoid arthritis, autoimmune hepatitis, immune thrombotic thrombocytopenia, and connective tissue diseases. Nevertheless, COVID-19 vaccines are considered safe for patients with autoimmune diseases and are strongly recommended.ObjectivesThe aim of this in silico analysis is to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most commonly administered COVID-19 vaccines, that could elicit an aberrant adaptive immune response in predisposed individuals.MethodsThe FASTA sequence of the protein encoded by the BNT-162b2 vaccine was retrieved from http://genome.ucsc.edu and used as a key input to the Immune Epitope Database and Analysis Resource (www.iedb.org). Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC ligand assays without MHC restriction were searched and evaluated. HLA-disease associations were screened on the HLA-SPREAD platform (https://hla-spread.igib.res.in) by selecting only positive markers.ResultsA total of 183 epitopes were found, corresponding to 178 SARS-CoV-2 and 5 SARS-CoV spike epitopes, respectively. Results were obtained from 22 T-cell assays, 398 B-cell assays, and 2 MHC ligand assays. Complementary receptors included 1080 T-cell receptors and 0 B-cell receptors.Specifically, the IEDB_epitope:1329790 (NATNVVIKVCEFQFCNDPFLGVYY) was shown to bind to HLA-DRB1*15:02 and HLA-DRB1*15:03 alleles, whereas the IEDB_epitope:1392457 (TKCTLKSFTVEKGIYQTSNFRVQPT) was reported to bind to HLA-DRB1*07:01, HLA-DRB1*03:01, HLA-DRB3*01:01, and HLA-DRB4*01:01 alleles. The HLA alleles detected were found to be positively associated with various immunological disorders (Table 1).Table 1.MHC-restricted epitopes of the BNT-162b2 vaccine and potentially associated immunological conditionsEpitopeAssayMHC moleculeAssociated disease (population)NATNVVIKVCEFQFCNDPFLGVYY + OX(C10)cellular MHC/mass spectrometry ligand presentationHLA-DRB1*15:02Takayasu arteritis (Japanese) Arthritis (Taiwanese) Scleroderma (Japanese) Colitis (Japanese)HLA-DRB1*15:03Systemic lupus erythematosus (Mexican American)TKCTLKSFTVEKGIYQTSNFRVQPT + SCM(K2)as aboveHLA-DRB1*07:01Allergy, hypersensitivity (Caucasian)HLA-DRB1*03:01Type 1 diabetes (African) Sarcoidosis, good prognosis (Finnish)HLA-DRB3*01:01Graves' disease (Caucasian) Thymoma (Caucasian) Sarcoidosis (Scandinavian) Autoimmune hepatitis (Caucasian)HLA-DRB4*01:01Vitiligo (Saudi Arabian)ConclusionSimilar to the SARS-CoV-2 spike protein, the protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals. Genotyping for HLA alleles may help identify at-risk individuals. However, further research is needed to elucidate the underlying mechanisms and potential clinical implications.References[1]Vita R, Mahajan S, Overton JA et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res. 2019 Jan 8;47(D1):D339-D343. doi: 10.1093/nar/gky1006.[2]Dholakia D, Kalra A, Misir BR et al. HLA-SPREAD: a natural language processing based resource for curating HLA association from PubMed s. BMC Genomics 23, 10 (2022). https://doi.org/10.1186/s12864-021-08239-0[3]Parker R, Partridge T, Wormald C et al. Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells. Cell Rep. 2021 May 25;35(8):109179. doi: 10.1016/j.celrep.2021.109179.[4]Knierman MD, Lannan MB, Spindler LJ et al. The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein. Cell Rep. 2020 Dec 1;33(9):108454. doi: 10.1016/j.celrep.2020.108454.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

COVID-19 VACCINE PERCEPTION AND HESITANCY AMONG PATIENTS WITH AUTOIMMUNE RHEUMATIC DISEASE (AIRD) IN MALAYSIA

BackgroundPatients with autoimmune rheumatic disease (AIRD) are at risk of severe COVID-19 infection and vaccine has been demonstrated to be able to reduce the severity of infection. Malaysia has a low flu vaccination coverage rate (approximately 3%) and hence it is important to assess the perception and hesitancy of COVID-19 vaccine especially among the vulnerable group.ObjectivesTo study the perception of COVID-19 vaccine and to determine the prevalence of vaccine hesitancy among AIRD patients in Malaysia.MethodsThis was a cross-sectional survey using online Google Forms® that was conducted among adult AIRD patients (18 years and older) from August 2021 until February 2022. Patients were recruited from the outpatient clinics as well as distribution of the survey through social medias. The survey was in English and Malay language. The survey collected data on the socio-demographic background, prior history of other vaccination after the age of 18 and COVID-19 vaccination with reasons of hesitancy, defined as being unsure or unwilling to be vaccinated. The survey also assessed the patients' perception by specifying the level of agreement to COVID-19 vaccine statements using the Likert response scale: 1-Strongly disagree;2- Disagree;3-Neither agree nor disagree;4-Agree;5-Strongly agree.ResultsA total of 162 patients participated in the survey and majority of them were females (87.7%). Our multi-racial cohort consisted of Malay (n=103, 63.5%), followed by Chinese (n=38, 23.5%), Sabahan Bumiputra (n=12, 7.4%) and Indian (n=7, 4.3%). More than half (n=107,66.6%) have not had any history of other vaccination after the age of 18. Only 16.7% (n=27) agreed/strongly agreed that COVID-19 vaccine can be given to patients with co-morbidities and 24.1 (n=39) agreed/strongly agreed that COVID-19 vaccine can be given to patients who have history of allergy to other drugs or food. At the time of the survey, vast majority of the respondents have received at least the 1st dose of Covid-19 vaccine (n=148, 91.4%). A total of 9 (5.6%) patients were hesitant to be vaccinated (6 were unsure and 3 patients were not willing to be vaccinated). The commonest reasons of being unsure or not willing to be vaccinated was worried of the vaccine's adverse effects (66.7%), worried of the blood clot complication (33,3%), worried of disease flare post-vaccine (33,3%), worried of allergic reaction (22.2%), lack of information on the safety of the vaccine in patients with AIRD from government and media (22.2%), face mask and social distancing measures were adequate (22.2%). Statistical analysis revealed that more patients who had vaccine hesitancy were from the lower socioeconomic status (income <1066 Euro/month), 88.9% vs 11.1%, p=0.03 but no association with ethnicity, education status, marital status or place of residence (urban vs rural).ConclusionCOVID-19 vaccine hesitancy is low in Malaysian patients with AIRD but patients with a low socioeconomic status are prone to have vaccine hesitancy. More education on the vaccine's efficacy and safety especially among patients with co-morbidities are warranted.Reference[1]Knowledge, acceptance and perception on COVID-19 vaccine among Malaysians: A web-based survey. Mohamed NA, Solehan HM, Mohd Rani MD, Ithnin M, Che Isahak CI (2021) Knowledge, acceptance and perception on COVID-19 vaccine among Malaysians: A web-based survey. PLOS ONE 16(8): e0256110.Acknowledgements:NIL.Disclosure of InterestsSyahrul Sazliyana Shaharir Speakers bureau: Pfizer,Novartis, Lydia Kamaruzaman: None declared, Theepa Nesam Mariamutu: None declared, Mohd Shahrir Mohamed Said: None declared, Azmawati Mohammed Nawi: None declared, Wan Syamimee Wan Ghazali: None declared, Malehah Mohd Noh: None declared.

PRE-EXPOSURE PROPHYLAXIS OF COVID-19 WITH TIXAGEVIMAB AND CILGAVIMAB IN RHEUMATOLOGIC PATIENTS TREATED WITH RITUXIMAB: DATA FROM A SINGLE-CENTRE COHORT

BackgroundRheumatologic patients treated with Rituximab (RTX) are at higher risk of severe COVID-19 and death. The B-cell depletive treatment significantly affects B cell functions involved in anti-SARS-CoV-2 response, leading to relevant impacts on the clinical and serological course of infection, long-term immunity, and vaccine responses. In light of these observations, pre-exposure prophylaxis (PrEP) of COVID-19 with Tixagevimab and Cilgavimab (TGM/CGM) was recently approved in Italy for all patients treated with RTX in the previous year, independently of their serological status against SARS-CoV-2.ObjectivesWe aimed to evaluate the efficacy and safety of TGM/CGM in a single-centre cohort of rheumatologic patients treated with RTX.MethodsFrom October 2022, all patients who had been treated with RTX in the previous 12 months and who underwent clinical assessment at our rheumatologic tertiary centre were screened for eligibility to PrEP of COVID-19 with TGM/CGM. According to the indications of the Italian Medicines Agency (AIFA), we excluded subjects with major cardiovascular risk factors and/or coagulation abnormalities;those who reported a previous allergic reaction to any anti-COVID19 vaccine were referred to an allergologist for an evaluation before TGM/CGM administration. Patients who agreed to be treated with TGM/CGM signed an informed consent. Clinical and demographic features were collected at baseline, and follow-up phone assessment was performed the day after and 1 month after TGM/CGM administration, to assess treatment tolerability and new COVID-19- related events. A descriptive analysis was performed.ResultsFrom 1 October 2022 to 31 December 2022, 90 subjects were screened for eligibility to TGM/CGM. Among them, 11 were excluded for contraindications due to comorbidities and 55 refused TGM/CGM administration. Among patients who agreed to receive PrEP of COVID-19, 21 received TGM/CGM before 31 December 2022 and 3 were scheduled for January2023. Patients treated with TGM/CGM had a mean age of 54 years (standard deviation: 17) and 19 (90.5%) were female;9 were affected by rheumatoid arthritis and 12 by other rheumatologic diseases (3 systemic lupus erythematosus, 2 systemic sclerosis, 1 Sjögren syndrome, 1 juvenile idiopathic arthritis, 3 anti-synthetase syndrome, 2 vasculitides). Most of them had completed the vaccination schedule against COVID-19 (19, 90.5%) and 9 (42.8%) reported an infectious event by SARS-CoV-2 in the previous year. One month after TGM/CGM administration, no patient reported adverse events related to TGM/CGM nor COVID-19 related symptoms.ConclusionPrEP of COVID-19 with TGM/CGM was well tolerated in our population of rheumatologic patients treated with RTX in the previous year and no COVID-19 related symptoms were observed in the month of follow-up after TGM/CGM administration. Future observations may provide further data on long-term efficacy of TGM/CGM in preventing COVID-19.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsMaria Manara Speakers bureau: Novartis, Angelini, Consultant of: Lilly, MSD, Manuel Sette: None declared, Laura Giudice: None declared, Martina Biggioggero: None declared, Nicoletta Del Papa Speakers bureau: Janssen, Boehringer-Ingelheim, Actelion, Ennio Giulio Favalli Speakers bureau: AbbVie, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, Consultant of: AbbVie, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, Maria Gerosa: None declared, Francesca Ingegnoli: None declared, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, UCB, Consultant of: AbbVie, Fresenius, Galapagos, Lilly, Novartis, Pfizer, UCB.

ADVERSE EVENTS AFTER VACCINATION FOR SARS-CoV2 IN A CASE SERIES OF FIBROMYALGIA PATIENTS VERSUS HEALTHY CONTROLS

BackgroundFibromyalgia (FM) is a chronic widespread pain syndrome of unknown origin that leads to hypersensitivity for physical, chemical and/or psychic triggers. Vaccination, as an inflammatory stimulus and as a psychologically stressful act, could represent a challenge for these patients.ObjectivesWe aimed to investigate the incidence of adverse reactions after vaccination for Sars-Cov2 in a series of FM patients versus healthy controls.MethodsWe recruited 65 consecutive FM patients classified according to the 2016 ACR diagnostic criteria¹ (M/F: 5/60;mean age 53.6 +/-12.5 years), without other associated rheumatologic conditions, and 65 age/sex-matched healthy controls.All patients filled a questionnaire in order to investigate eventual adverse events occurring up to 6 months after administration of a Sars-Cov2 vaccine. The questionnaire was divided into two parts: the first part included the patient's demographic information, the vaccine type performed and the anamnestic data. In the second part, the individuals described all new symptoms or signs occurred after the first, the second or the third dose of Sars-Cov2 vaccine.ResultsOverall, FM patients reported a higher frequency of adverse events after Sars-Cov2 vaccination in comparison with healthy controls. In particular, 44/65 FM patients vs. 11/65 controls complained of exacerbation of diffuse pain (p<0.001). Fatigue, diarrhea, sweating, tingles, headache, dizziness, transient respiratory discomfort, and paroxysmal vision blurring were also more frequent in FM patients than controls (47/65 vs. 30/65, p=0.004;6/65 vs. 0/65, p=0.028;18/65 vs. 8/65, p=0.047;20/65 vs. 0/65, p<0.001;22/65 vs. 9/65, p=0.013;21/65 vs. 5/65, p<0.001;10/65 vs 1/65, p=0.009;17/65 vs. 2/65, p< 0.001, respectively).No significant difference between FM and the control group as regards fever was reported (24/65 vs. 30/65;p=0.7).Interestingly, swelling at the injection vaccine site was more commonly reported in controls (9/65 vs. 20/65;p=0.034).Finally, one case of Bell's palsy was registered in the FM series while one case of myocarditis in the control group.ConclusionFM patients showed an increased frequency of adverse events to Sars-Cov2 vaccination compared to healthy controls. In particular, all the symptoms reported seemed to be associated with the functional hypersensitivity that characterizes FM.Reference[1]Wolfe F, et Al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016 Dec;46(3):319-329.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Immune-Mediated Organ-Specific Reactions to COVID-19 Vaccines: A Retrospective Descriptive Study.

Severe acute respiratory syndrome coronavirus 2 caused the global COVID-19 pandemic and public health crisis, and it led to the rapid development of COVID-19 vaccines, which can cause rare and typically mild hypersensitivity reactions (HRs). Delayed HRs to COVID-19 vaccines have been reported, and the excipients polyethylene glycol (PEG)2000 and polysorbate 80 (P80) are the suspected culprits. Skin patch tests do not help in diagnosing delayed reactions. We aimed to perform lymphocyte transformation tests (LTT) with PEG2000 and P80 in 23 patients with suspected delayed HRs. Neurological reactions (n = 10) and myopericarditis reactions (n = 6) were the most frequent complications. Seventy-eight percent (18/23) of the study patients were admitted to a hospital ward, and the median time to discharge was 5.5 (IQR, 3-8) days. Some 73.9% of the patients returned to baseline condition after 25 (IQR, 3-80) days. LTT was positive in 8/23 patients (5/10 neurological reactions, 2/4 hepatitis reactions and 1/2 rheumatologic reactions). All myopericarditis cases had a negative LTT. These preliminary results indicate that LTT with PEGs and polysorbates is a useful tool for identifying excipients as causal agents in HRs to COVID-19 vaccines and can play an important role in risk stratification in patients with HRs.

The Prevalence of Immediate Hypersensitivity Reactions to the BNT162b2 mRNA Vaccine against SARS-CoV-2: Data from the Vaccination Campaign in a Large Academic Hospital.

The anti-SARS-CoV-2 vaccination has probably been the most effective tool for preventing the infection and negative outcomes of the COVID-19 disease, and therefore for interrupting the pandemic state. The first licensed SARS-CoV-2 vaccine was BNT162b2, an mRNA vaccine that has been widely used since the earliest stages of the global vaccination campaign. Since the beginning of the vaccination campaign, some cases of suspected allergic reactions to BNT162b2 have been described. Epidemiological data, however, have provided reassuring results of an extremely low prevalence of these hypersensitivity reactions to anti-SARS-CoV-2 vaccines. In this article, we describe the results of a survey carried out through the use of a questionnaire, administered to all the health personnel of our university hospital after the first two doses of the BNT162b2 vaccine, which investigated the development of adverse reactions after a vaccination. We analyzed the responses of 3112 subjects subjected to the first dose of the vaccine; among these, 1.8% developed symptoms compatible with allergic reactions and 0.9% with clinical manifestations of possible anaphylaxis. Only 10.3% of the subjects who had allergic reactions after the first injection experienced similar reactions after the second dose and none of them experienced anaphylaxis. In conclusion, the anti-SARS-CoV-2 vaccination is rarely associated with severe allergic reactions and the second dose of vaccine is safe for this group of patients.

Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions to PEG-containing Covid-19 vaccines: Evidence for immunogenicity of PEG.

A small fraction of recipients who receive polyethylene-glycol (PEG)-containing COVID-19 mRNA-LNP vaccines (Comirnaty and Spikevax) develop hypersensitivity reactions (HSRs) or anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet been proven in humans.We used ELISA for serial measurements of SARS-CoV-2 neutralizing Ab (anti-S) and anti-PEG IgG/IgM Ab levels before and after the first and subsequent booster vaccinations with mRNA-LNP vaccines in a total of 291 blood donors. The HSRs in 15 subjects were graded and correlated with anti-PEG IgG/IgM, just as the anti-S and anti-PEG Ab levels with each other. The impacts of gender, allergy, mastocytosis and use of cosmetics were also analyzed. Serial testing of two or more plasma samples showed substantial individual variation of anti-S Ab levels after repeated vaccinations, just as the levels of anti-PEG IgG and IgM, which were over baseline in 98-99 % of unvaccinated individuals. About 3-4 % of subjects in the strongly left-skewed distribution had 15-45-fold higher values than the median, referred to as anti-PEG Ab supercarriers. Both vaccines caused significant rises of anti-PEG IgG/IgM with >10-fold rises in about âˆ¼10 % of Comirnaty, and all Spikevax recipients. The anti-PEG IgG and/or IgM levels in the 15 vaccine reactors (3 anaphylaxis) were significantly higher compared to nonreactors. Serial testing of plasma showed significant correlation between the booster injection-induced rises of anti-S and anti-PEG IgGs, suggesting coupled anti-S and anti-PEG immunogenicity.Conclusions: The small percentage of people who have extremelevels of anti-PEG Ab in their blood may be at increased risk for HSRs/anaphylaxis to PEGylated vaccines and other PEGylated injectables. This risk might be further increased by the anti-PEG immunogenicity of these vaccines. Screening for anti-PEG Ab "supercarriers" may help predicting reactors and thus preventing these adverse phenomena.

Levels of peripheral IL-6 and CD4+and CD8+T cells and their prognostic significance in COVID-19

OBJECTIVE: Chemotherapy -related adverse reactions have been steadily in-creasing in recent years. In patients who develop oxaliplatin-induced hypersensitivity reactions (HSRs), prognosis and quality of life are adversely affected. Proper management of cancer patients enables them to safely receive first-line treatments. This study aimed to assess the risk factors in oxaliplatin-induced HSRs and the effectiveness of the rapid desensitization protocol.PATIENTS AND METHODS: In the study, 57 patients treated with oxaliplatin between October 2019 and August 2020 in the Medical Oncology Department of Elazig City Hospital were retrospectively evaluated. We analyzed patients' clinical histories to reveal any associations with the development of oxaliplatin-induced HSRs. Moreover, we re-evaluated 11 patients with oxaliplatin-induced HSRs through infusion time or desensitization procedures.RESULTS: Of 57 patients treated with oxaliplatin, 11 (19.3%) had HSRs. Patients with HSRs were younger and had higher peripheral blood eosinophil counts than those without HSRs (p=0.004, p=0.020, respectively). Prolongation of the infusion time was effective in the re -ad-ministration of oxaliplatin in six of the hyper-sensitive patients. Rapid desensitization proto-col was performed for a total of 11 cycles in four patients with recurrent HSRs, and their chemo-therapy regimens were successfully completed.CONCLUSIONS: This retrospective study has revealed that younger ages and higher peripheral eosinophil counts could be predictive for oxaliplatin-induced HSR. Furthermore, the study confirms that prolongation of the infusion time and rapid desensitization protocol are effective in patients with HSRs.

Allergic contact stomatitis from homeopathic preparations (Arsenicum Album 30c) used as prophylaxis against COVID 19: A case report

Contact stomatitis or stomatitis venenata is defined as an oral mucosa contact allergy caused by persistent contact with a pathogenic substance. Arsenic album 30 was advised as a 'preventive and prophylactic remedy' against coronavirus disease-19 (COVID-19) by The Ministry of AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy), Government of India. We present a case of a 68-year-old man who suffered ulcers on the left buccal mucosa and tongue after taking arsenic album 30c for 10 days sublingually. This is, to the best of our knowledge, the first recorded incidence of allergic contact stomatitis caused by a homeopathic drug used to treat COVID-19. This case report emphasizes the need for obtaining a history, being aware of the composition of any new items, and reporting allergies or medicines provided to the patient. © 2023 Journal of Indian Academy of Oral Medicine & Radiology ;Published by Wolters Kluwer - Medknow.

A Rare Case of Delayed Hypersensitivity Following COVID-19 Booster Necessitating Treatment With Dupilumab.

Following vaccination, patients can develop symptoms of eczema flare, which could range from mild skin irritation and urticaria to diffuse skin involvement. Delayed immunologic reactions have been described in association with the novel mRNA COVID-19 vaccines and boosters. We report the case of an 83-year-old female who presented with widespread pruritic urticarial indurated papules on the arms, legs, and palms, sparing the face six months following the booster vaccine. She denied constitutional symptoms, new medications, recent illnesses, or new personal care products. Punch biopsy demonstrated acanthosis, spongiosis, and superficial and mild dermal perivascular lymphocytic infiltration with occasional eosinophils compatible with a dermal hypersensitivity reaction. The patient was admitted to the hospital due to the need for systemic steroids as well as IV antibiotics secondary to a superimposed bacterial skin infection in the setting of severe itching and skin injury; she was discharged on oral steroids with follow-up to dermatology and rheumatology. Delayed hypersensitivity reactions typically peak within four days following vaccination and may be observed with COVID-19 vaccines or boosters. However, reports remain limited, and people's history of eczema should not preclude them from receiving a COVID-19 vaccine that is both safe and effective.

Cough desensitization treatment for patients with refractory chronic cough: results of a second pilot randomized control trial.

OBJECTIVE: The purpose of this study was to collect pilot efficacy data on a novel treatment for refractory chronic cough (RCC), which we call cough desensitization treatment (CDT). DESIGN AND METHODS: In this parallel cohort, sham-controlled, randomized controlled trial, 21 adults with RCC were randomly assigned to 12 sessions of either CDT (progressive doses of aerosolized capsaicin while behaviorally suppressing cough; n = 11) or a sham treatment (repeated exposure to aerosolized saline; n = 9). The Leicester Cough Questionnaire (LCQ) was the primary outcome measure. Perceived cough severity with a visual analogue scale and cough challenge testing (for measuring cough-reflex sensitivity) were secondary outcome measures. Data were analyzed with mixed effects linear regression and follow-up contrasts. RESULTS: Results on all measures favored CDT. Excluding one sham participant, whose baseline LCQ scores were deemed unreliable, mean change in LCQ at 3-weeks post treatment was 6.35 and 2.17 in the CDT and sham groups, respectively. There was moderate to strong evidence of a greater improvement in the CDT group in total LCQ score (p = .058) and LCQ Psychological domain (p = .026) and Physical domain (p = .045) scores. Strong evidence was found for a greater reduction in urge-to-cough during CCT in the CDT group (p = .037) and marginal for a reduction in the capsaicin cough-reflex sensitivity (p = .094). There was weak evidence of a greater reduction in cough severity in the CDT group (p = .103). DISCUSSION: Although the study is limited due to the small sample size, the data provide additional evidence supporting further research on CDT. CDT resulted in a greater change in the primary efficacy measure (LCQ) than both pharmaceutical and behavioral treatments currently found in the literature. TRIAL REGISTRATION: This trial (NCT05226299) was registered on Clinicaltrials.gov on 07/02/2022.

COVID-19 Incidence and Disease Course Among Patients at an Allergy Department.

Background: Since the coronavirus pandemic in 2020, there is not much reported about the disease course of COVID-19 in patients with allergic diseases. Objectives: The aim of this study was to investigate the cumulative incidence and severity of COVID-19 among patients from the allergy department compared with the general Dutch population and people from their household. Design: We conducted a comparative longitudinal cohort study. Methods: In this study patients of the allergy department were included with their household members as a control group. Data from the beginning of the pandemic were systematically obtained through questionnaires by telephonic interviews and retrieved from electronic patient files between October 15, 2020 and January 29, 2021. Main outcomes were confirmed SARS-CoV-2 infection, disease duration, hospitalization, intensive care admission, and mortality. Questions regarding applied social distancing measures were inventoried as well. Results: Three hundred and eighty nine patients (median age 39.1 (18.7-84.7) years, 69.9% female) and 441 household members (median age 42.0 (18.0-91.5), 44.1% female) were included. The cumulative COVID-19 incidence in patients was higher compared with the general population (10.5% vs 5.6%, P < .001). In total, 41 (10.5%) patients attending the allergy clinic compared to 38 (8.6%) household members were infected with SARS-CoV-2 (P = .407). Median disease duration was 11.0 (0.0-61.0) days in patients compared to 10.5(1.0-232.0) days in household members (P = .996). Conclusion: The cumulative COVID-19 incidence in patients from the allergy cohort was higher compared with the general Dutch population, but similar compared with household members. There was no difference in symptoms, disease duration, or hospitalization rate between the allergy cohort and their household members.

One-year outcomes following rehabilitation for chronic hip-related groin pain: ancillary analysis of a pilot randomized clinical trial

Purpose: Rehabilitation to address modifiable factors associated with chronic hip-related groin pain (CHRGP) may lead to reduced pain and improved function, yet little is known about its effectiveness. We assessed the preliminary effects of two interventions that target two distinct mechanisms, sensory disturbances and abnormal movement patterns. Sensory disturbances such as peripheral and central sensitization may contribute to pain persistence long after initial injury. Joint mobilization (JtMob) may impart a neurophysiological response within the nervous system that results in pain reduction and improved mobility. Abnormal movement patterns may create altered mechanical stresses on hip joint structures, resulting in pain and activity limitations. Movement pattern training (MoveTrain) may improve movement patterns and thus patient function. Method(s): Patients with CHRGP, 18-40, were enrolled. Assessments included self-report questionnaires, clinical exam, and quantitative sensory testing. Outcomes included the Hip disability and Osteoarthritis Outcome Score (HOOS), a patient-reported outcome;frontal plane kinematics of hip, pelvis, and trunk during single leg squat;and pain pressure threshold (PPT) assessed at the anterior groin of the most bothersome hip and dominant thenar eminence (local and generalized pressure hypersensitivity, respectively). Patients were randomized to JtMob or MoveTrain in a 1:1 ratio stratified by sex and HOOS Symptoms. Treatment for both groups included 10 individualized visits over 12 weeks with a trained physical therapist (PT);assessment of patient goals and education which focused on patient-specific tasks reported by the patient to be symptom-producing;instruction in a home exercise program (HEP);and handouts that provided education, description and benefits of assigned treatment and instructions for HEP. The key element of JtMob was PT-provided manual techniques using specific criteria to determine the joint mobilization techniques and parameters used for each patient. The patient's symptom report to each technique was monitored and if indicated, the technique modified according to our outlined procedures. The HEP included flexibility exercises. The key element of MoveTrain was task-specific instruction to correct abnormal movement patterns displayed during daily and patient-specific tasks. For example, hip adduction was minimized during a step descent. The HEP included repeated practice of modified tasks. Task difficulty was progressed based on each patient's performance. Immediately after treatment completion, patients returned for follow up assessment. To assess treatment sustainability after the active treatment phase, we collected HOOS at 6 and 12 months (extended follow-up), and kinematics and PPT at 12 months. Data from patients who provided any data after baseline were analyzed with a repeated measures analysis of variance (RM-ANOVA) with baseline value as a covariate, patient as a random effect, and an autoregressive covariance structure. After adjusting for baseline, the between-group difference in change from post-treatment to each extended follow-up results from pre-planned statistical contrasts in a RM-ANOVA that includes main effects for treatment group, visit and the group by visit interaction. The within-group treatment effect at each extended follow-up was calculated by subtracting the earlier time point from the later follow-up within each treatment group. Dependent samples t-tests were used to assess the degree of within-group change. Result(s): Demographics and outcome data are provided in Tables 1 and 2, respectively. Thirty-three patients with CHRGP were randomized and 29 (88%) provided post-treatment data. Four patients did not complete treatment or post-treatment testing (3 due to COVID pandemic, 1 lost to follow up);6 patients did not complete 12 month laboratory testing (due to pandemic), but did complete 12 month questionnaires. Previously, we reported that both groups reported clinically important improvements in HOOS subscales and MoveTrain group improved hip and pelvis kinematics immediately after treatment compared to baseline. After adjusting for baseline, there were no between-group differences in change in outcomes between post-treatment and extended follow-up when comparing JtMob and MoveTrain, indicating that treatment effects immediately post-treatment were maintained at 12 months after treatment completion. Conclusion(s): Our preliminary findings suggest that 12 weeks of JtMob or MoveTrain, may result in improvements in patient-reported pain and function and these effects may persist 12 months after treatment completion. A future, larger trial to definitively assess the efficacy of JtMob and MoveTrain and identify factors associated with long-term outcomes will improve our ability to develop treatment strategies for people with CHRGP. [Formula presented] [Formula presented]Copyright © 2023

Activated CD8 T-cell hepatitis in children: a single institution experience

Background: Pediatric acute liver failure is a rare and serious life-threatening situation, principally for the 30 to 50% of children in whom the etiology of their liver failure is unclear or indeterminate. Treating these patients is challenging, requiring constant assessment over time with regular evaluation for possible liver transplantation. Children with pediatric acute liver failure of undetermined etiology have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups. Emerging evidence suggests that a subgroup of patients with indeterminate pediatric acute liver failure have clinical, laboratory, and liver biopsy features of immune dysregulation with a dense infiltration of CD8 T cells. Method(s): In 2022, we received percutaneous liver biopsies from three children with acute hepatic dysfunction that showed an increased number of lymphocytes including CD8 T cells. For each case, routine H&E stains with levels, special stains and immunostains were performed. The first biopsy was from an 18-month-old male who presented with COVID infection, pancytopenia, elevated transaminases, and synthetic liver dysfunction (elevated INR). The second was from a 9-year-old female with a history of elevated liver enzymes with no clear cause. The third case was from a 2-year-old male with elevated liver enzymes, coagulopathy, and cholestasis. Result(s): The three cases showed similar histopathologic findings;an acute liver injury pattern with lobular architectural disarray, giant cell formation, reactive changes, single cell necrosis, cholestasis and marked mixed lymphocytic infiltrates. The infiltrates were predominantly composed of CD8-positive T-lymphocytes with scattered neutrophils, eosinophils and rare plasma cells. Portal areas were mildly expanded with mild bile ductular proliferation and mild to moderate lymphocytic infiltrates. Immunostains for CD8 demonstrated that the infiltrates were predominantly composed of CD8-positive T-lymphocytes. All three patients received steroids and responded to treatment evidenced by normalization of liver enzymes and function. Conclusion(s): Dense hepatic CD8 T-cell infiltration is a major finding inactivated CD8 T-cell hepatitis. However, the percentage distribution of lymphocyte subtypes in the setting of hepatitis is not well established, and CD8 T-cell infiltration has also been described in cases of drug-induced hypersensitivity reactions, viral hepatitis, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome, as well as autoimmune hepatitis. Further investigation is needed to better understand the diagnostic criteria in this disease.

Anaphylaxis to Cyclophosphamide Metabolites during Lymphodepletion for CAR-T Therapy

Background: Cyclophosphamide (Cy) is used in hematopoietic stem cell transplant (HSCT) preparative regimens and lymphodepletion for chimeric antigen receptor T-cell (CAR-T) therapy. We describe a case of cyclophosphamide hypersensitivity in a pediatric patient during CAR-T therapy. Case description: A 13 year old boy was diagnosed with very high risk ALL in 2015 and had 2 isolated CNS relapses treated with intensified chemotherapy (chemo) and cranial radiation (1st relapse) and Blinatumomab with intrathecal (IT) chemo followed by sibling donor HSCT (2nd relapse). At age 19, and 18 months after HSCT, he had a 3rd CNS relapse treated with IT chemo and referral for CAR-T therapy. At our center, leukapheresis and CAR-T production (Novartis) were performed. Later, during lymphodepletion with fludarabine (Flu) and Cy, physiologic replacement hydrocortisone (HC) was briefly held to prevent interference with CAR-T function. After 3 days of Flu/Cy, he developed fever and hypotension requiring inotropic support. Hypotension and fever resolved with stress dose HC and antibiotics and was attributed to culture-negative sepsis and adrenal crisis. CAR-T infusion was subsequently delayed by skin GVHD requiring glucocorticoids and COVID-19 infection treated with convalescent plasma and nirmatrelvir/ritonavir. Physiologic HC replacement was continued when he was re-admitted for CAR-T therapy, but he again developed fever, diffuse erythema and shock in hours following the first dose of Cy necessitating stress dose HC, antibiotics, inotropes, and mechanical ventilation. Negative blood cultures and ongoing physiologic HC replacement suggested an alternative explanation for shock. Case reports of anaphylaxis to Cy metabolites implicated Cy as the causative agent so it was discontinued. After recovery, CAR-T cells were infused without complications. In the following weeks, he had no evidence of recurrent leukemia but was persistently pancytopenic. A sibling donor stem cell boost was proposed but the patient accepted only palliative care. He had several opportunistic infections before succumbing to E. coli sepsis. Discussion(s): The first episode of shock was initially attributed to adrenal crisis and sepsis, although no organism was identified. The second episode appeared anaphylactic in timing and clinical presentation with adequate HC replacement and negative cultures, suggesting Type I hypersensitivity. The patient previously received Cy uneventfully before HSCT, suggesting that the donor-derived immune system was the source of new Cy hypersensitivity. Onset of anaphylaxis within hours rather than minutes after Cy administration supports hypersensitivity to Cy metabolites rather than to the drug itself. This case highlights the importance of consideration of sensitivity to Cy metabolites as well as acquired donor-specific allergy even when alternative explanations are likely.Copyright © 2023 American Society for Transplantation and Cellular Therapy

Mental health outcomes in patients discharged after COVID-19 hospitalization: the case report of a male nurse in the context of occupational surveillance program of health care workers

This case study draws attention on mental health sequelae that emerged in the context of the COVID-19 outbreak after recovery from hospitalization, even in subjects without personal psychiatric history. The case involves a 65-year-old male shift nurse who took SARS-COV-2 infection through a co-worker and that had been hospitalized for interstitial pneumonia from April 6 to April 17. After recovery, he developed psychiatric symptoms overlapping between different dimensions of psychiatric disorders and started to be followed by the Occupational Health Department of a Major University Hospital in central Italy. He reported a score of 28 at the Peritraumatic Distress Inventory and of 39 at the Self-Rating Anxiety State. He was treated with a combination therapy of SSRI and NaSSA antidepressants with clinical remission. In this case study, authors discuss the possible overlapping role of post-traumatic stress and anxiety symptoms in patients discharged after COVID-19 hospitalization that may deserve appropriate classification, treatment and follow up with the future goal to refine clinical management of post and long COVID syndromes of subjects who present low abnormalities in other specialty investigations.Copyright © 2022 EDIZIONI MINERVA MEDICA.

Moisture damage and fungal contamination in buildings are a massive health threat - a surgeon's perspective.

OBJECTIVES: Indoor air toxicity is of major public health concern due to the increase in humidity-induced indoor mould exposure and associated health changes. The objective is to present evidence for the causality of health threats and indoor mould exposure. METHODS: PubMed search on the following keywords: dampness, mould, indoor air quality, public health, dampness, and mould hypersensitivity syndrome, sick building syndrome, and building-related illness as well as information from the health authorities of Bavaria and North Rhine-Westphalia, the Center of Disease Control (CDC), World Health Organisation (WHO), and guidelines of professional societies. RESULTS: The guidelines of professional societies published in 2017 are decisive for the assessment of the impact of mould pollution caused by moisture damage on human health and for official regulations in Germany. Until 2017, a causal connection between moisture damage and mould exposure could usually only be established for pulmonary diseases. The health risk of fungal components is apparent as documented in the fungal priority pathogens list (FPPL) of the WHO. Since 2017, studies, especially in Scandinavia, have proved causality between moisture and mould exposure not only for pulmonary diseases but also for extrapulmonary diseases and symptoms. This was made possible by new test methods for determining the toxicity of fungal components in indoor air. Environmental medical syndromes, e.g., dampness and mould hypersensitivity syndrome (DMHS), sick building syndrome (SBS), building-related symptoms (BRS), and building-related illness (BRI), and fungal pathogens, e.g., Aspergillus fumigatus, pose a major threat to public health. CONCLUSION: There is evidence for the causality of moisture-induced indoor moulds and severe health threats in these buildings. According to these findings, it is no longer justifiable to ignore or trivialize the mould contamination induced by moisture damage and its effects on pulmonary and extrapulmonary diseases. The health and economic implications of these attitudes are clear.