Otologic disease among patients with primary ciliary dyskinesia - an international observational study (preprint)

ABSTRACT Importance Otologic disease is common among people with primary ciliary dyskinesia, yet little is known about its spectrum and severity. Objective We characterized otologic disease among participants with primary ciliary dyskinesia using data from the Ear-Nose-Throat Prospective International Cohort of PCD patients (EPIC-PCD). Design Cross-sectional analysis of baseline cohort data. Setting Twelve specialized primary ciliary dyskinesia centers in 10 countries. Participants We prospectively included children and adults with primary ciliary dyskinesia diagnoses, routine ENT examinations, and completed symptom questionnaires at the same visit or within 2 weeks. Exposures Potential risk factors associated with increased risk of ear disease. Main outcomes and measures We describe the prevalence and characteristics of patient-reported otologic symptoms and findings from otologic examinations; we identify potential factors associated with increased risk of ear inflammation and hearing impairment. Results We included 397 (211 males) participants with median age 15 (range 0–73). A total of 204 (51%) reported ear pain, 110 (28%) ear discharge, and 183 (46%) hearing problems. Adults reported ear pain and hearing problems more frequently when compared with children. Otitis media with effusion—usually bilateral—from otoscopy was most common among 121 (32%) of 384 participants. Retracted tympanic membrane and tympanic sclerosis were more commonly seen among adults. Tympanometry was performed on 216 participants and showed pathologic type B results for 114 (53%). Audiometry was performed on 273 participants and showed hearing impairment in at least 1 ear, most commonly mild. Season of visit was the strongest risk factor for problems related to ear inflammation (autumn compared with spring odds ratio, 95% confidence interval: 2.4, 1.5–3.8) and age 30 and older of hearing impairment (age 41–50 compared with age 10 years and younger odds ratio, 95% confidence interval: 3.3, 1.1–9.9). Conclusion and relevance Many people with primary ciliary dyskinesia suffer from ear problems yet frequency varies, highlighting disease expression differences and possible clinical phenotypes. Understanding differences in otologic disease expression and progression during lifetime may inform clinical decisions about follow-up and medical care. We recommend multidisciplinary primary ciliary dyskinesia management includes regular otologic assessments for all ages even without specific complaints. Key Points Question What are the characteristics of otologic disease among patients with primary ciliary dyskinesia (PCD)? Findings Baseline data from a large multicenter cohort of patients with PCD showed frequent reports of ear pain and reduced hearing with age as the main factor associated with hearing impairment. Otitis media with effusion was the most common otoscopic finding; adults often presented with tympanic sclerosis following history of previous ear infections. Meaning Since otologic disease is an important yet underreported part of PCD’s clinical expression, we recommend otologic assessments for all age groups as part of regular clinical follow-up.

Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination (preprint)

While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope (iCope). Pre-existing spike- and iCope-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher IgG titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Abundant spike-specific cross-immunity may be responsible for the unexpectedly high efficacy of current vaccines even with single doses and the high rate of asymptomatic/mild infection courses.

Studying the pathophysiology of coronavirus disease 2019 - a protocol for the Berlin prospective COVID-19 patient cohort (Pa- COVID-19) (preprint)

Purpose Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, in order to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. Methods Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charite - Universitaetsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. Results Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional and health-related quality of life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care (ii) facilitate comprehensive data collection in medical care facilities with varying resources and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. Conclusion We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents.

Presence of SARS-CoV-2 reactive T cells in COVID-19 patients and healthy donors (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a rapidly unfolding pandemic, overwhelming health care systems worldwide1. Clinical manifestations of Corona-virus-disease 2019 (COVID-19) vary broadly, ranging from asymptomatic infection to acute respiratory failure and death2, yet the underlying physiological conditions and mechanisms for this high variability are still unknown. Also, the role of host immune responses in viral clearance and its involvement in pathogenesis remains unresolved. For SARS-CoV (2002/03), however, CD4+ T cell responses are generally associated with positive outcomes3,4, while cellular immune responses to SARS-CoV-2 have not yet been investigated. Here we describe an assay that allows direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood. We demonstrate the presence of S-reactive CD4+ T cells in 83% of COVID-19 patients, as well as in 34% of SARS-CoV-2 seronegative healthy donors, albeit at lower frequencies. Strikingly, in COVID-19 patients S-reactive CD4+ T cells equally targeted both N-terminal and C-terminal parts of S whereas in healthy donors S-reactive CD4+ T cells reacted almost exclusively to the Cterminal part that is a) characterized by higher homology to spike glycoprotein of human endemic "common cold" coronaviruses, and b) contains the S2 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane domain (TM) but not the receptor-binding domain (RBD). S-reactive CD4+ T cells from COVID-19 patients were further distinct to those from healthy donors as they co-expressed higher levels of CD38 and HLA-DR, indicating their recent in vivo activation. Our study is the first to directly measure SARS-CoV-2-reactive T cell responses providing critical tools for large scale testing, in depth epitope mapping and characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of pre-existing SARS-CoV-2-reactive T cells in healthy donors is of high interest but larger scale prospective cohort studies are needed to assess whether their presence is a correlate of protection or pathology. Results of such studies will be key for a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment methods and to support vaccine development.