Incidence of Long-term Post-acute Sequelae of SARS-CoV-2 Infection Related to Pain and Other Symptoms: A Living Systematic Review and Meta-analysis
Authors: Hoshijima Hiroshi , Mihara Takahiro , Seki Hiroyuki , Hyuga Shunsuke , Kuratani Norifumi , Shiga Toshiya 
Published: April 2021

AbstractImportancePersistent symptoms are reported in patients who survive the initial stage of COVID-19, often referred to as “long COVID” or “post-acute sequelae of SARS-CoV-2 infection” (PASC); however, evidence on incidence is still lacking, and symptoms relevant to pain are yet to be assessed.ObjectiveTo determine long-term symptoms in COVID-19 survivors after infection.Data SourcesA literature search was performed using the electronic databases PubMed, EMBASE, Scopus, and CHINAL and preprint servers MedRχiv and BioRχiv through January 15, 2021.Study SelectionEligible studies were those reporting patients with a confirmed diagnosis of SARS-CoV-2 and who showed any symptoms persisting beyond the acute phase.Data Extraction and SynthesisIncidence rate of symptoms were pooled using inverse variance methods with a DerSimonian-Laird random-effects model.Main Outcomes and MeasuresThe primary outcome was pain-related symptoms such as headache or myalgia. Secondary outcomes were symptoms relevant to pain (depression or muscle weakness) and symptoms frequently reported (anosmia and dyspnea). Heterogeneity among studies and publication bias for each symptom were estimated. The source of heterogeneity was explored using meta-regression, with follow-up period, age and sex as covariates.ResultsIn total, 35 studies including 18,711 patients were eligible. Eight pain-related symptoms and 26 other symptoms were identified. The highest pooled incidence among pain-related symptoms was chest pain (17%, 95% CI, 12%-25%), followed by headache (16%, 95% CI, 9%-27%), arthralgia (13%, 95% CI, 7%-24%), neuralgia (12%, 95% CI, 3%-38%) and abdominal pain (11%, 95% CI, 7%-16%). The highest pooled incidence among other symptoms was fatigue (45%, 95% CI, 32%-59%), followed by insomnia (26%, 95% CI, 9%-57%), dyspnea (25%, 95% CI, 15%-38%), weakness (25%, 95% CI, 8%-56%) and anosmia (19%, 95% CI, 13%-27%). Substantial heterogeneity was identified (I2, 50-100%). Meta-regression analyses partially accounted for the source of heterogeneity, and yet, 53% of the symptoms remained unexplained.Conclusions and RelevanceThe current meta-analysis may provide a complete picture of incidence in PASC. It remains unclear, however, whether post-COVID symptoms progress or regress over time or to what extent PASC are associated with age or sex.Key PointsQuestionWhat is the incidence rate of long-term post-acute sequelae of SARS-Cov-2 infection related to pain and other symptoms?FindingsIn the current meta-analysis of 35 studies with 18,711 patients, the highest estimated incidence among pain-related symptoms was chest pain (17%), followed by headache (16%), arthralgia (13%), neuralgia (12%) and abdominal pain (11%). That among other symptoms was fatigue (45%), followed by insomnia (26%), dyspnea (25%), weakness (25%) and anosmia (19%).MeaningThese findings suggest that long-term post-acute sequelae of SARS-Cov-2 infection must not be overlooked or underestimated especially when vaccination has become the focus.