Sequelae, persistent symptomatology and outcomes after COVID-19 hospitalization: the ANCOHVID multicentre 6-month follow-up study

Background Long-term effects of COVID-19, also called Long COVID, affect more than 10% of patients. The most severe cases (i.e. those requiring hospitalization) present a higher frequency of sequelae, but detailed information on these effects is still lacking. The objective of this study is to identify and quantify the frequency and outcomes associated with the presence of sequelae or persistent symptomatology (SPS) during the 6 months after discharge for COVID-19. Methods Retrospective observational 6-month follow-up study conducted in four hospitals of Spain. A cohort of all 969 patients who were hospitalized with PCR-confirmed SARS-CoV-2 from March 1 to April 15, 2020, was included. We collected all the SPS during the 6 months after discharge reported by patients during follow-up from primary care records. Cluster analyses were performed to validate the measures. The main outcome measures were return to the Emergency Services, hospital readmission and post-discharge death. Surviving patients’ outcomes were collected through clinical histories and primary care reports. Multiple logistic regression models were applied. Results The 797 (82.2%) patients who survived constituted the sample followed, while the rest died from COVID-19. The mean age was 63.0 years, 53.7% of them were men and 509 (63.9%) reported some sequelae during the first 6 months after discharge. These sequelae were very diverse, but the most frequent were respiratory (42.0%), systemic (36.1%), neurological (20.8%), mental health (12.2%) and infectious (7.9%) SPS, with some differences by sex. Women presented higher frequencies of headache and mental health SPS, among others. A total of 160 (20.1%) patients returned to the Emergency Services, 35 (4.4%) required hospital readmission and 8 (1.0%) died during follow-up. The main factors independently associated with the return to Emergency Services were persistent fever, dermatological SPS, arrythmia or palpitations, thoracic pain and pneumonia. Conclusions COVID-19 cases requiring hospitalization during the first wave of the pandemic developed a significant range of mid- to long-term SPS. A detailed list of symptoms and outcomes is provided in this multicentre study. Identification of possible factors associated with these SPS could be useful to optimize preventive follow-up strategies in primary care for the coming months of the pandemic. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-021-02003-7.


Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported. Explained in the first 4 paragraphs of the introduction.
Objectives 3 State specific objectives, including any prespecified hypotheses.

Study design 4
Present key elements of study design early in the paper. Presented at the beginning of the methods (study design and setting).
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection. Described at the beginning of the methods (study design and setting).

Participants 6
Give the eligibility criteria, and the sources and methods of selection of participants. Presented at the beginning of the methods (study design and setting).

Variables 7
Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable. We presented all the variables of the study in the "data source and variables" section. We indicated the exposure and outcome variables.  Table S1. We also performed a dendrogram for cluster analysis (figure 1) in order to provide evidence of validity of the information collected.

Bias 9
Describe any efforts to address potential sources of bias. Described in "statistical analyses" section.

Study size 10
Explain how the study size was arrived at. Explained in the methods (a complete cohort of hospitalized patients during the period of recruitment).

Quantitative variables 11
Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why.
Explained in the methods.
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding. Described in "statistical analyses" section.
(b) Describe any methods used to examine subgroups and interactions. Described in "statistical analyses" section.
(c) Explain how missing data were addressed. Explained throughout the manuscript (two variables were not considered for presenting too many missing values: smoking habit and obesity).
If applicable, describe analytical methods taking account of sampling strategy. N/A.
(e) Describe any sensitivity analyses. N/A.

Results
Participants 13* (a) Report numbers of individuals at each stage of study-eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed. Explained in the first paragraph of the "Sociodemographic and clinical variables" section.
(b) Give reasons for non-participation at each stage. We included all hospitalized patients during recruitment (non-participation is not applicable in this study).

(c) Consider use of a flow diagram. N/A
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders. Explained in the first paragraph of the "Sociodemographic and clinical variables" section and in Table 1.
(b) Indicate number of participants with missing data for each variable of interest. Indicated in Table 1 ("Unknown").
Outcome data 15* Cross-sectional study-Report numbers of outcome events or summary measures. Reported in Table 1 (

columns).
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included. Given in Additional File 2: Tables S3 to S5.
(b) Report category boundaries when continuous variables were categorized. Reported in Table 1 (age).
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period. N/A Other analyses 17 Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses. Reported in the "Frequency of SPS during the 6month follow-up" and "Outcomes" sections.

Discussion
Key results 18 Summarise key results with reference to study objectives. Reported in the first paragraph of the Discussion.

Limitations
19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias.

Thoroughly reported in the Limitations subsection.
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence. Reported throughout the Discussion and Conclusion sections.
Generalisability 21 Discuss the generalisability (external validity) of the study results. Reported in the Limitations subsection

Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based. Reported in the "Funding" declaration.