Clinical, imaging, serological, and histopathological features of pulmonary post-acute sequelae after mild COVID-19 (PASC) (preprint)

Background: A significant proportion of patients experience prolonged pulmonary, cardiocirculatory or neuropsychiatric symptoms after Coronavirus disease 2019 (COVID-19), termed post-acute sequelae of COVID (PASC). Lung manifestations of PASC include cough, dyspnea on exertion and persistent radiologic abnormalities and have been linked to viral persistence, ongoing inflammation and immune dysregulation. So far, there is limited data on lung histopathology and tissue-based immune cell subtyping in PASC. Methods: 51 unvaccinated patients (median age, 40 years; 43% female) with a median of 17 weeks (range, 2-55 weeks) after mild SARS-CoV-2 infection (without hospitalization) underwent full clinical evaluation including high-resolution computed tomography (HR-CT) and transbronchial biopsy. We used RT-PCR/FISH and immunohistochemistry (nucleocapsid/spike/CD3/CD4/CD8) for residual SARS-CoV-2 detection and T lymphocyte subtyping, respectively. We assessed interstitial fibrosis and macrophage profiles by transmission electron microscopy (TEM) and immunofluorescence multiplex staining, while cytokine profiling in broncho-alveolar lavage (BAL) fluid was performed by legendplex immunoassay. Results: Dyspnea on exertion was the leading symptom of pulmonary PASC in our cohort. In 16% and 42.9% of patients, FEV1 and MEF50 were [≤]80% and 35.3% showed low attenuation volume (LAV) in >5% of lung area, in line with airflow obstruction. There was a significant correlation between oxygen pulse and time since COVID (p=0.009). Histopathologically, PASC manifested as organizing pneumonia (OP), fibrinous alveolitis and increased CD4+ T cell infiltrate predominantly around airways (bronchiolitis), while the residual virus components were detectable in only a single PASC patient (2%). T cell infiltrates around small airways were inversely correlated with time since COVID, however, this trend failed to reach statistical significance. We identified discrete interstitial fibrosis and a pro-fibrotic macrophage subtype (CD68/CD163/S100A9) as well as significantly elevated interleukin 1{beta} in BAL fluid from PASC patients (p=0.01), but H-scores for fibrotic macrophage population did not correlate with severity of clinical symptoms or T cell infiltration. Interpretation: We show decreased FEV1/MEF50 and increased LAV in line with obstructive lung disease due to CD4+ T cell-predominant bronchiolitis as well as evidence of pro-fibrotic signaling in a subset of unvaccinated PASC patients. Since our results point towards self-limiting inflammation of small airways without detectable viral reservoirs, it remains unclear whether pulmonary symptoms in PASC are SARS-CoV-2-specific or represent a general response to viral infection. Still, evidence of pro-fibrotic signaling should warrant clincal follow-up and further research into possible long-time fibrotic remodeling in PASC patients.

Distinct smell and taste disorder phenotype of post-acute COVID-19 sequelae (preprint)

Background Olfactory dysfunction (OD) often accompanies acute coronavirus disease 2019 (COVID-19) and its sequelae. Herein, we investigated OD during COVID-19 recovery in the context of other symptoms, quality of life, physical and mental health. Methods Symptom recovery patterns were analyzed in a bi-national, ambulatory COVID-19 survey (n = 906, ≥ 90 days follow-up) and a multi-center observational cross-sectional cohort of ambulatory and hospitalized individuals (n = 108, 360 days follow-up) with multi-dimensional scaling, association rule mining and partitioning around medoids clustering. Results Both in the ambulatory collective (72%, n = 655/906) and the cross-sectional ambulatory and hospitalized cohort (41%, n = 44/108) self-reported OD was frequent during acute COVID-19, displayed a slow recovery pace (ambulatory: 28 days, cross-sectional: 90 days median recovery time) and commonly co-occurred with taste disorders. In the ambulatory collective, a predominantly young, female, comorbidity-free group of convalescents with persistent OD and taste disorder (>90 days) was identified. This post-acute smell and taste disorder phenotype was characterized by a low frequency of other leading post-acute symptoms including fatigue, respiratory and neurocognitive complaints. Despite a protracted smell and taste dysfunction, this subset had high ratings of physical performance, mental health, and quality of life. Conclusion Our results underline the clinical heterogeneity of post-acute COVID-19 sequelae calling for tailored management strategies. The persistent smell and taste disorder phenotype may represent a distinct COVID-19 recovery pathway characterized by a good recovery of other COVID-19 related symptoms. Study registration ClinicalTrials.gov: NCT04661462 (ambulatory collective), NCT04416100 (cross-sectional cohort).

Neurological Outcome and Quality of Life Three Months after COVID-19: A Prospective Observational Cohort Study (preprint)

BACKGROUND: Increasing evidence suggests the involvement of the central and peripheral nervous system in patients with coronavirus disease 2019 (COVID-19). Little is known about neurological outcomes and quality of life (QoL) after recovery from acute infection.METHODS: In this prospective, multicentre, observational cohort study we systematically evaluated neurological signs and diseases by detailed neurological examination and a predefined test battery assessing smelling disorders (16-item Sniffin-Sticks-test), cognitive deficits (Montreal Cognitive Assessment), QoL (36-item Short Form), and mental health (Hospital Anxiety and Depression Scale, Post-traumatic Stress Disorder Checklist-5) three months after disease onset.FINDINGS: Of 135 COVID-19 patients included, 31 (23%) required ICU-care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient-care (mild) during acute disease. At three-month follow-up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID-19. These included poly-neuro/myopathy (n=16, 12%), mild encephalopathy (n=2, 2%), parkinsonism (n=1, 1%), orthostatic hypotension (n=1, 1%), Guillain-Barré-Syndrome (n=1, 1%) and ischemic stroke (n=1, 1%). Self-reported hyposmia/anosmia was noted in 23/135 patients (17%), which was significantly lower compared to those documented during acute COVID-19 (44%; p<0·001). Interestingly, objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at three-month follow-up. In ICU patients, encephalopathy significantly improved over time (from 29% (9/31) during acute disease to 3% (1/31) at follow-up, p=0·008). At follow-up, cognitive deficits were apparent in 23% (29/124), and QoL was impaired in 31% (28/90). Assessment of mental health revealed symptoms of depression, anxiety and post-traumatic stress disorders in 11%, 25%, and 11%, respectively.INTERPRETATION: Despite recovery from acute infection, neurological symptoms were prevalent at three-months follow-up. Above all, smelling disorders were persistent in a large proportion of patients. Our results urge for further studies investigating the onset and evolution of neurological diseases following COVID-19 infection to develop strategies for secondary prevention.TRIAL REGISTRATION: ClinicalTrials.gov (NCT04416100)FUNDING: Not applicable.DECLARATION OF INTERESTS: KS reports grants from FWF Austrian Science Fund, grants from Michael J. Fox Foundation, grants from International Parkinson and Movement Disorder Society, personal fees from Teva, personal fees from UCB, personal fees from Lundbeck, personal fees from AOP Orphan Pharmaceuticals AG, personal fees from Abbvie, personal fees from Roche, personal fees from Grünenthal; all outside the submitted work. PM reports grants from TWF (Tyrolean Science Fund), grants from Medtronic, personal fees from Boston Scientific, all outside the submitted work. The other authors have nothing to disclose. All other authors declare no competing interests.ETHICS APPROVAL STATEMENT: The conduct of the study was approved by the local ethics committee (Medical University of Innsbruck, EK Nr: 1103/2020). Written informed consent was obtained from all patients according to local regulations.