Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection

Key Points Question What are the short-term and long-term postacute sequelae of COVID-19 (PASC) infection? Findings In this systematic review of 57 studies comprising more than 250 000 survivors of COVID-19, most sequelae included mental health, pulmonary, and neurologic disorders, which were prevalent longer than 6 months after SARS-CoV-2 exposure. Meaning These findings suggest that long-term PASC must be factored into existing health care systems, especially in low- and middle-income countries.


Introduction
The global COVID-19 pandemic that began in late 2019 has caused more than 187 million infections and 4 million deaths as of July 10, 2021. 1 Survivors experience long-lasting medical, psychological, and economic consequences, further increasing the disability-adjusted life years lost. 2 Despite current vaccination efforts, 3 the health consequences of COVID-19 remain urgent, with long-term multi-organ system impacts that are yet to be elucidated. With a variety of clinical presentations and degrees of severity in patients, 4 there is a dire need to better understand the lasting and emergent effects of COVID-19.
Frequently reported residual effects from SARS-CoV-2 virus include fatigue, dyspnea, chest pain, persistent loss of taste and/or smell, cognitive changes, arthralgias, and decreased quality of life. Many of these symptoms may result from widespread neuropathological events occurring in major white matter bundle tracts, cortical gray matter, and subcortical gray matter. 5 In a study conducted in the United States by Chopra et al, 6 33% of patients had persistent symptoms at a 60-day follow-up after COVID-19 hospitalization. Similar trends have been observed in Europe. 7 Furthermore, persistent symptoms (>6 weeks) have been reported in 19% of fully vaccinated individuals. 8 However, as the pandemic emerged in 2019, most studies have been limited in the duration of observation, and there has yet to be a consolidation of these trends to portray an overarching evolution of these symptoms from short-term to long-term sequelae following COVID-19 infection.
To our knowledge, short-term and long-term sequelae of COVID-19 have not been systematically evaluated. In this paper, we synthesized the existing literature to estimate the overall and organ system-specific frequency of postacute sequelae of COVID-19 (PASC). We sorted studies into groups that focused on (1) postacute symptoms at 1-month after acute COVID-19 (short term), These categorizations were based on literature reports proposing a framework that COVID-19 infection progresses from an acute infection lasting approximately 2 weeks into a postacute hyperinflammatory illness lasting approximately 4 weeks, until ultimately entering late sequelae. 9,10 As we better understand the disease burden of PASC in COVID-19 survivors, we can develop precise treatment plans to improve clinical care in patients with COVID-19 who are at greatest risk of PASC and establish integrated, evidence-based clinical management for those affected.

Information Source and Search Strategy
The present study has been prospectively registered at PROSPERO (CRD42021239708) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. 11 Studies were selected according to the following criteria: participants, adults and children with a   previous COVID-19 infection; exposure, COVID-19; condition or outcome of interest, frequency of   PASC; study design and context, randomized clinical trials, prospective and retrospective cohort studies, case series with at least 10 patients, and case-control studies. Inclusion criteria included the following: previous COVID-19 diagnosis and reported PASC frequencies.

Data Extraction
Two investigators (D.G. and A.S.) screened titles and abstracts of all identified articles for eligibility.
Full-text articles were screened from eligible studies. Disagreements were resolved by discussion with a third investigator (P.S.). The following information was extracted by 2 investigators (D.G. and A.S.) independently: year of publication, country and time frame of the study, sample size of survivors of COVID-19, number of participants with PASC, mean (SD) or median (IQR) age, percentage male, percentage hospitalized, outcome of interest, time zero (ie, from diagnosis of COVID-19 or hospital discharge), and measurement methods for outcome of interest.

Study Quality Assessment
Two reviewers (D.G. and A.S.) independently assessed the quality of the included studies. The Newcastle-Ottawa Scale (NOS) was used for the quality assessment of the included studies. 12 Based on the NOS criteria, we assigned a maximum of 4 stars for selection, 2 stars for comparability, and 3 stars for exposure and outcome assessment. Studies with fewer than 5 stars were considered low quality; 5 to 7 stars, moderate quality; and more than 7 stars, high quality.

Definition of Short-term, Intermediate-term, and Long-term PASC
The primary outcome was the frequency of PASC, which was defined as the presence of at least 1 abnormality diagnosed by (1) laboratory investigation, (2) radiologic pathology, or (3) clinical signs and symptoms that was present at least 1 month after COVID-19 diagnosis or after discharge from the hospital. We defined short-term PASC as 1 month; intermediate-term, 2 to 5 months; and long-term, as 6 or more months after COVID-19 diagnosis or hospital discharge.

Statistical Analysis
A narrative approach was used to describe the number of studies, proportion male, proportion hospitalized, median or mean age (by study), whether the study was conducted in low-and middleincome countries (median gross national income, Յ$12 535) or high-income countries (median gross national income, Ն$12 536). We did not conduct a meta-analysis due to high heterogeneity in the outcome of interest. We summarized PASC rates descriptively, reporting medians and IQRs. PASC frequencies were summarized as short term, intermediate term, or long term and by organ system. R package ggplot2 was used to display the boxplots. 13 All statistical analyses were performed with R software version 3.6.2 (R Project for Statistical Computing).          Figure 1A is the distribution of studies by country and follow-up time from baseline.

Displayed in
PASC frequencies were stratified and reported by 1 month (short-term), 14

Rates of Clinical Manifestations of PASC
A total of 38 clinical manifestations were assessed. We collapsed these clinical manifestations into categories of (1) organ systems, ie, neurologic, mental health, respiratory, cardiovascular, digestive, dermatologic, and ear, nose, and throat; (2) constitutional symptoms; and (3) functional mobility.

Neurologic Symptoms
Various neurologic symptoms were reported (Figure 2A)

Mental Health Disorders
A variety of standardized instruments were used to assess mental health. These included the Patient Health Questionnaire (PHQ) 2 to screen for depression, the PHQ 9 to evaluate major depressive disorder, the General Anxiety Disorder 7 to assess generalized anxiety disorder, the Hospital Anxiety and Depression Scale to measure symptoms of anxiety and depression, and the PTSD Checklist of DSM-5 and the Impact of Events Scale to assess the presence and severity of posttraumatic stress disorder symptoms. The Pittsburgh Sleep Quality Index questionnaire was used to assess sleep quality and disturbances (Table). Depression or anxiety were reported in 9 studies, and the rates were consistent ( Figure 2B).  Figure 2D).

General and Constitutional Symptoms
Due to their subjective nature and self-reportage of symptoms (Table), general well-being and constitutional symptoms varied widely between studies. In this category, we noted 7 persisting symptoms among survivors of COVID-19 ( Figure 2E). These included fatigue or muscle weakness, by Carvalho-Schneider and colleagues. 14 Except for Glück et al 15 at a 1-month follow-up, the reported fever rates were less than 20%. The high fever rates reported in Glück et al 15 can potentially be explained by unusually high anti-SARS-CoV-2 immunoglobulin G levels in their patient population of frontline health care workers, which was significantly associated with the severity of disease as reported by the authors. Fever rates for the subsequent follow-ups at 3, 5, and more than 6 months after diagnosis were all at 0% in the Glück study. 15 Carvalho-Schneider et al 14 reported a slight increase in unintentional weight loss (defined as a loss of more than or equal to 5% of body weight at baseline) from 9% to 12% at day 30 to day 60 of follow-up, respectively.

Discussion
In this systematic review, we evaluated the temporal progression of clinical abnormalities    73 and autoimmunity 74 as well as neurotropism using a transsynaptic spread mechanism, 5 resulting in hypoxic-or hemorrhagic-driven neuronal apoptosis. 75 Herein, widespread acute injury to cortical/ subcortical and white matter fiber bundles may affect brain function and impede distal brain connectivity, respectively, manifesting in common symptoms, such as those identified in this review.

JAMA Network Open | Infectious Diseases
These symptoms may include headache (ie, encephalopathy), cognitive deficits (ie, widespread neuropathological events), and smell and taste disorders (ie, acute injury to olfactory bulb).
At the forefront of clinical care for acute COVID-19 are multiple guidelines, recommendations, and best practices that have been disseminated and prioritized for prevention and management.
However, no clear guidelines are currently available for postinfectious care or recovery, and there is a notable dearth of information on and strategies about how to assess and manage patients following their acute COVID-19 episode. This is in part due to a high degree of between-study heterogeneity in defining PASC. Indeed, this heterogeneity was evident the present study. We noted varying definitions of time zero, which included symptom onset, COVID-19 diagnosis, hospital admission, or hospital discharge. Furthermore, variations in the specific outcomes of interest and the outcome measurement tools existed, hindering us from pooling the data in a formal meta-analytic model.
SARS-CoV-2 variant types and breakthrough infectivity rates among fully vaccinated individuals will likely modify the manifestations and incidence of PASC further. 8 Our results indicate that clinical management of PASC will require a whole-patient perspective, including management tools like virtual rehabilitation platforms and chronic care for post-acute COVID-19 symptoms in conjunction with the management of preexisting 76,77 or new comorbidities. 78 One-stop multidisciplinary clinics are therefore recommended to avoid multiple referrals to different specialists and encourage comprehensive care. Based on our work and the recent systematic reviews by Nasserie and colleagues, 79 these specialists should include respiratory physicians, cardiologists, neurologists, general physicians (from primary care or rehabilitation medicine), neuropsychologists or neuropsychiatrists, physiotherapists, occupational therapists, speech and language therapists, and dieticians. 80 The clinical and public health implications of our findings are 2-fold. In addition to the life lost from acute COVID-19 illness, many individuals experience disability due to PASC, greatly exacerbating the disease burden. 81 Such a burden is more than enough to overwhelm existing health care system capacities, particularly in resource-constrained settings. Second, predictive models of postacute and chronic COVID-19 sequalae using clinical and laboratory data obtained during the acute phase of COVID-19 are critically needed to inform effective strategies to mitigate or prevent PASC.

Limitations
This study has limitations. First, there is no consensus on the definition of postacute COVID-19. PASC currently has many definitions, including (1) the presence of symptoms beyond 3 weeks from the initial onset of symptoms 78 ; (2) symptoms that develop during or following an infection consistent with COVID-19, continue for more than 4 weeks, and are not explained by an alternative diagnosis 80 ; and (3) signs and symptoms at 12 weeks after infection and beyond. This led to considerable heterogeneity in PASC definitions among the articles synthesized in this systematic review.