key: cord-1045567-2hcxp20u
authors: Nguyen, Nhu Ngoc; Hoang, Van Thuan; Dao, Thi Loi; Meddeb, Line; Lagier, Jean-Christophe; Million, Matthieu; Raoult, Didier; Gautret, Philippe
title: Long-term persistence of symptoms of dyspnoea in COVID-19 patients
date: 2021-11-27
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.11.035
sha: 1a3980a791707a2bd49e515d7cfd6958b1d3e353
doc_id: 1045567
cord_uid: 2hcxp20u

nan

Nhu Ngoc Nguyen 1,2 , Van Thuan Hoang 1,2,3 , Thi Loi Dao 1,2,3 , Line Meddeb 2 , Jean-Christophe Lagier 2,4 , Matthieu Million 2,4 , Didier Raoult 2,4 , Philippe Gautret 1,2, * 

Even after recovering from the acute phase of COVID-19, patients may report the persistence of symptoms that have become known as 'long COVID' (Akbarialiabad et al., 2021) . In one meta-analysis of nine studies conducted on 1,816 patients between three weeks and three months after discharge from hospital, the persistence of dyspnoea, chest pain and a cough affected 37%, 16% and 14% of patients, respectively (Cares-Marambio et al., 2021) . These proportions gradually decrease with follow-up time. In a cross-sectional study conducted on 574 patients eight months after recovery, dyspnoea was the most frequent sequelae affecting 29% of patients (Zheng. et al., 2021) . In one prospective cohort study conducted on 588 COVID-19 patients, 14% of patients reported dyspnoea at eight months of follow-up (Soraas et al., 2021) . In this study, we aim to estimate the rate of persistent dyspnoea in French COVID-19 patients, as evaluated at least six months of follow-up and to investigate the risk factors for this persistence.

We identified confirmed COVID-19 patients who reported dyspnoea during the acute phase of the disease from among a cohort of 3,737 patients tested at our institute between 3 March and 27 April 2020 (Lagier et al., 2020) . Patients with pre-existing chronic respiratory diseases and chronic heart disease were excluded from this analysis. Information on demographics, comorbidities, and acute symptoms were retrieved from medical files.

The selected patients were interviewed by telephone and asked to complete a questionnaire on possible persistent dyspnoea. Statistical analysis was performed by R 3.6.1 software (R Core team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, 2020. URL: http://www.r-project.org). Multiple logistic regression model were applied to explore the association between patient characteristics and dyspnoea at the acute phase and at the follow-up time. Variables with p-values < 0.2 in the univariable analysis were included in the multivariable analysis. Of the 3,737 COVID-19 patients, 3,222 had no known chronic respiratory disease and/or chronic heart disease at the time of inclusion and 880/3,222 (27.3%) reported dyspnoea at the acute phase of COVID-19.

Being female or obese and consulting six or more days after the onset of symptoms were independently associated with dyspnoea. Patients with dyspnoea at admission were more likely to receive oxygen therapy. In univariate analysis, hypoxaemia, oxygen saturation 94%, C-reactive protein >5 mg/L, neutrophils >7.5 Giga/L, eosinophils <0.1 Giga/L, lymphocyte <1 Giga/L associated with dyspnoea, but a multivariate analysis was not conducted due to a high proportion of missing information. (Table 1) . Of 880 patients, we randomly selected 838 patients for the telephone interview. Among them, 496/838 (59.2%) answered the questionnaire and 342/838 (40.8%) were lost to follow-up. Patients who responded were significantly less likely to report hypertension, to present severe symptoms, to require oxygen upon inclusion, to undergo prolonged hospitalisation and had lower rates of mortality, as compared with all patients reporting dyspnoea at inclusion (Supplementary Table 1) Among these 496 patients, 123 (24.8%) reported persistent dyspnoea. The duration between the onset of symptoms and the interview was 44.0 ± 10.3 weeks, ranging from 31.6 to 63.1 weeks. Being aged ≥ 45 years old and consulting early during the acute phase (less than six days after the onset of symptoms) were independently associated with persistent dyspnoea (Table 2) .

Lung damage in COVID-19 patients could be explained by various underlying mechanisms, including viral and immune-mediated implications (Liu et al., 2020) , which could cause the persistence of dyspnoea. Dyspnoea is, by nature, a highly subjective experience. Women are more prone to suffer dyspnoea, possibly due to a decreased surface area for pulmonary gas exchange relative to lung size-matched men (Cory et al., 2015) . People who are obese have a decreased functional residual capacity and expiration reserve volume (Parameswaran et al., 2006) . Therefore, it is not surprising that female and obese COVID-19 patients had a higher risk for dyspnoea at admission. We observed that dyspnoea was more frequent in patients consulting more than six days after the onset of symptoms, suggesting that it takes a few days for the virus to provoke such symptoms. The association with a high viral load upon admission suggests a direct cytopathic effect of viruses on lung tissue.

The association of symptom persistence with being older may suggest a lower capacity of cell regeneration due to ageing. We have no hypothesis, however, to explain why early consultation was associated with the persistence of dyspnoea.

The use of the telephone interview has some limitations, including the lack of respiratory functional tests to quantify dyspnoea levels and a lack of information about smoking status. In addition, patients lost to follow-up could potentially include a high proportion of patients who fully recovered their respiratory function. Despites these limitations, our study underlined the high prevalence of the persistence of dyspnoea (24.8%) in COVID-19 patients and its association with older age. Further investigation with a clinical evaluation of respiratory function over time is required in these patients.

This study was approved by the Comité de Protection des Personnes Nord Ouest II (No. 2021-A01183-33) on 22/07/2021.

All authors gave their consent for publication.

All the data for this study will be made available upon reasonable request to the corresponding author.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

None declared. Philippe Gautret is the guarantor for this work. Tomography, C-reactive protein, neutrophil, eosinophil,  3 lymphocyte, D-Dimer, Fibrinogen and Ct <16 were not included in the multivariate due to 4 >5% missing data 5 **only significant results are presented in the multivariate analysis 6 0.14 

A Comprehensive Systematic Scoping Review

Prevalence of potential respiratory symptoms in survivors of hospital admission after coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis

Sex differences in the intensity and qualitative dimensions of exertional dyspnea in physically active young adults

Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis

Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV

Altered respiratory physiology in obesity

Self-reported memory problems eight months after non-hospitalized COVID-19 in a large Cohort

Long-term clinical sequelae and immunological features of COVID-19 survivors: A cross-sectional study in Wuhan

Our thanks go to Yolande Obadia and all the doctors who volunteered to recruit patients by