April 19, 2023

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Clinical Reports

Update on Vaccine-Derived Poliovirus Outbreaks — Worldwide, January 2021–December 2022
- Circulating vaccine-derived polioviruses (cVDPVs) can emerge and cause paralysis in areas with low population immunity to polioviruses. During January 2021–December 2022, 76 cVDPV type 2 outbreaks occurred in 42 countries. Since 2020, the numbers of paralytic cases and new emergences have declined following the introduction of a safer novel type 2 oral poliovirus vaccine for outbreak control. The number of cVDPV type 1 outbreaks increased during 2021–2022 as COVID-19 pandemic–associated global routine immunization coverage declined. Improving routine immunization coverage, strengthening poliovirus surveillance, and conducting timely and high-quality supplementary immunization activity responses to cVDPV outbreaks in 2023 are necessary to stop cVDPV transmission.
Sleep Disturbance Severity and Correlates in Post-acute Sequelae of COVID-19 (PASC)
- Novel findings include a high prevalence of 41.3% of moderate to severe sleep disturbance in PASC associated with Black race, hospitalization for COVID-19, anxiety severity, and moderate to severe fatigue. There was no significant interaction between anxiety severity and moderate to severe fatigue; further studies are needed to investigate the interplay between mental and sleep disturbances in PASC physiologic pathways. Likewise, there was no association between objective sleep study measures of antecedent sleep apnea and hypoxia with sleep disturbance. With 58% of PASC patients completing PROMIS Sleep Disturbance, our study may suffer from selection bias. However, researchers observed that among patients of Black race who did not complete PROMIS Sleep Disturbance, 60% completed mood and fatigue questionnaires. As such, it is possible that the magnitude of association between Black race and moderate to severe sleep disturbances is even stronger. Study findings emphasize the importance of identification of sleep disturbance in PASC considering its impact on patients’ quality of life, daytime functioning, and medical health status. Results inform risk stratification and highlight the need to elucidate contributions of structural racism and socioeconomic inequities to PASC-related sleep disturbances with the goal of developing interventions to reduce PASC disparities.
Two individuals with potential monkeypox virus reinfection
- These cases represent two potential monkeypox virus reinfections. Following clinical and virological healing of the first episodes, researchers observed high cycle threshold values and short-lasting symptoms for both second episodes, with clinical characteristics consistent with mpox, and detectable neutralizing antibodies. The cycle threshold values were high for new-onset mpox and suggest low viral loads. Possible alternative explanations to reinfection include relapse from tissue reservoirs or sexual contamination. Indeed, potential relapse of infection and persistent monkeypox virus detection have been described previously. The second patient, in particular, had episodes relatively close together, which could indicate recrudescence. However, high cycle threshold values and fast healing could also be linked to presence of neutralizing antibodies. Furthermore, samples from different sites and different time-points (in the second patient) were positive for monkeypox virus, which makes environmental contamination less likely. Both patients had co-infections, which could have caused or exacerbated symptoms, or could have eased reinfection. We isolated and sequenced monkeypox virus from both patients from samples collected during the first episodes. We could not isolate the virus from samples from the second episodes, probably due to low viral loads as indicated by the high cycle threshold values. SARS-CoV-2 could also have had a negative influence. Although genomic data cannot confirm the presence of two distinct viruses, and thus reinfection (in contrast to relapse, which would have presented with the same virus), clinicians need to be aware of potential monkeypox virus reinfections and should investigate with viral culture and sequencing. Furthermore, the potential of monkeypox reinfection has implications for transmission and vaccination policies.
Risk of autoimmune diseases in patients with COVID-19: A retrospective cohort study
- Between January 1st, 2020 and December 31st, 2021, 3,814,479 participants were included in the study (888,463 cases and 2,926,016 controls). After matching, the COVID-19 cohort exhibited significantly higher risks of rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, dermatopolymyositis, systemic sclerosis, Sjögren's syndrome, mixed connective tissue disease, Behçet's disease, polymyalgia rheumatica, vasculitis, psoriasis, inflammatory bowel disease, celiac disease, type 1 diabetes mellitus and mortality. COVID-19 is associated with a different degree of risk for various autoimmune diseases. Given the large sample size and relatively modest effects these findings should be replicated in an independent dataset. Further research is needed to better understand the underlying mechanisms.

Antiviral Therapeutics and Vaccines

FDA Authorizes Changes to Simplify Use of Bivalent mRNA COVID-19 Vaccines.
- The U.S. Food and Drug Administration amended the emergency use authorizations (EUAs) of the Moderna and Pfizer-BioNTech COVID-19 bivalent mRNA vaccines to simplify the vaccination schedule for most individuals. This action includes authorizing the current bivalent vaccines (original and omicron BA.4/BA.5 strains) to be used for all doses administered to individuals 6 months of age and older, including for an additional dose or doses for certain populations. The monovalent Moderna and Pfizer-BioNTech COVID-19 vaccines are no longer authorized for use in the United States.
SARS-CoV-2 neutralizing antibodies after bivalent versus monovalent booster
- The SARS-CoV-2 omicron lineage (B.1.1.529) continues to proliferate and evolve, leading to subvariants adept at evading antibody responses. Bivalent mRNA vaccines expressing both the omicron BA.5 spike and the ancestral D614G spike were introduced in August, 2022 with the goal of boosting waning antibody titres and broadening coverage against emerging SARS-CoV-2 lineages. However, in early 2023, researchers reported that peak serum neutralising antibody (NAb) titres against SARS-CoV-2 variants following a bivalent vaccine booster were similar to peak titres following a monovalent booster. Whether these antibody responses would diverge over time remains unknown. Researchers addressed this question by assessing serum virus-neutralizing titres in 41 participants who received three monovalent mRNA vaccines followed by a bivalent booster, a monovalent booster, or a BA.5 breakthrough infection. Researchers collected serum samples at nearly 1 month and approximately 3 months following the last vaccine dose or breakthrough infection and determined their NAb titres using a pseudovirus neutralization assay against the ancestral D614G strain and a panel of omicron subvariants (BA.2, BA.5, BQ.1·1, and XBB.1·5. Participants who received a monovalent booster were older (mean 55·3 years) than those who received a bivalent booster (mean 37·8 years) or those who had a breakthrough infection (mean 44·0 years. Each cohort exhibited the highest serum NAb titres (ie, the serum dilution at which 50% viral neutralization occurs [ID50]) against D614G and substantially lower titres against the latest omicron subvariants. Consistent with our previous study. There was no significant difference at nearly 1 month after the last booster for the two vaccine cohorts. At approximately 3 months after the last booster there were, again, no statistical differences between the two groups although there was a trend toward higher titres in the bivalent group against omicron lineages (1·4–1·6 times higher; eg, 509 VS 835 against BA.5). The BA.5 breakthrough cohort exhibited significantly higher NAb titres at 3 months against all tested omicron subvariants when compared with both monovalent and bivalent booster cohorts. Over the approximately 2-month follow-up period, mean NAb titres in both vaccine cohorts decreased approximately two-fold (or 50%) against all tested viruses (eg, 1218 to 509 for monovalent cohorts against BA.5 and 1553 to 835 for bivalent cohorts against BA.5, consistent with findings published in 2023. There was no discernible waning of antibody responses in the BA.5 breakthrough infection cases over the same observation period. This finding suggests that vaccine cohorts were not affected by undetected breakthrough infections.
Durability of Bivalent Boosters against Omicron Subvariants
- Effectiveness against infection was higher for the Moderna bivalent vaccine than for the Pfizer–BioNTech bivalent vaccine and higher among previously infected participants than among those with no previous infection. The two types of bivalent boosters were associated with an additional reduction in the incidence of omicron infection among participants who had previously been vaccinated or boosted. Although the two bivalent vaccines were designed to target the BA.4–BA.5 subvariants, they were also associated with a lower risk of infection or severe infection with the BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants. The effectiveness was higher against hospitalization and death than against infection and waned gradually from its peak over time.

Nirmatrelvir and risk of hospital admission or death in adults with COVID-19: emulation of a randomized target trial using electronic health records
- In people with SARS-CoV-2 infection who were at risk of developing severe disease, compared with no treatment, nirmatrelvir was associated with a reduced risk of admission to hospital or death at 30 days in people who were not vaccinated, vaccinated, and had received a booster vaccine, and in those with a primary SARS-CoV-2 infection and reinfection.
Evolving Real-World Effectiveness of Monoclonal Antibodies for Treatment of COVID-19
- Treatment guidelines and U.S. Food and Drug Administration emergency use authorizations (EUAs) of monoclonal antibodies (mAbs) for treatment of high-risk outpatients with mild to moderate COVID-19 changed frequently as different SARS-CoV-2 variants emerged. The objective was to evaluate whether early outpatient treatment with mAbs, overall and by mAb product, presumed SARS-CoV-2 variant, and immunocompromised status, is associated with reduced risk for hospitalization or death at 28 days. Early mAb treatment among outpatients with COVID-19 was found to be associated with lower risk for hospitalization or death for various mAb products and SARS-CoV-2 variants.
Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support–Free Days in Patients Hospitalized With COVID-19
- In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19
- COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear. The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 (ANA-COVID-GEAS) was a multicenter, randomized, open-label, 2-group, phase 2/3 clinical trial conducted at 12 hospitals in Spain between May 8, 2020, and March 1, 2021, with a follow-up of 1 month. Participants were adult patients with severe COVID-19 pneumonia and hyperinflammation. Hyperinflammation was defined as interleukin-6 greater than 40 pg/mL, ferritin greater than 500 ng/mL, C-reactive protein greater than 3 mg/dL (rationale, ≥5 upper normal limit), and/or lactate dehydrogenase greater than 300 U/L. Severe pneumonia was considered if at least 1 of the following conditions was met: ambient air oxygen saturation 94% or less measured with a pulse oximeter, ratio of partial pressure O2 to fraction of inspired O2 of 300 or less, and/or a ratio of O2 saturation measured with pulse oximeter to fraction of inspired O2 of 350 or less. Data analysis was performed from April to October 2021. Anakinra was given at a dose of 100 mg 4 times a day intravenously. A total of 179 patients (123 men [69.9%]; mean [SD] age, 60.5 [11.5] years) were randomly assigned to the anakinra group (92 patients) or to the SoC group (87 patients). The proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (64 of 83 patients [77.1%] in the anakinra group vs 67 of 78 patients [85.9%] in the SoC group; risk ratio [RR], 0.90; 95% CI, 0.77-1.04; P = .16). Anakinra did not result in any difference in time to mechanical ventilation (hazard ratio, 1.72; 95% CI, 0.82-3.62; P = .14). There was no significant difference between groups in the proportion of patients not requiring invasive mechanical ventilation up to day 15 (RR, 0.99; 95% CI, 0.88-1.11; P > .99). In this randomized clinical trial, anakinra did not prevent the need for mechanical ventilation or reduce mortality risk compared with standard of care alone among hospitalized patients with severe COVID-19 pneumonia.
Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY): a randomized, controlled, open-label, platform trial
- In patients hospitalized for COVID-19 with clinical hypoxia who required either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared with usual care, which included low-dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalized with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation.

Epidemiology

Risk of Death in Patients Hospitalized for COVID-19 vs Seasonal Influenza in Fall-Winter 2022-2023
- There were 8996 hospitalizations (538 deaths [5.98%] within 30 days) for COVID-19 and 2403 hospitalizations (76 deaths [3.16%]) for seasonal influenza. After propensity score weighting, the 2 groups were well balanced (mean age, 73 years; 95% male). The death rate at 30 days was 5.97% for COVID-19 and 3.75% for influenza, with an excess death rate of 2.23% (95% CI, 1.32%-3.13%). Compared with hospitalization for influenza, hospitalization for COVID-19 was associated with a higher risk of death (hazard ratio, 1.61 [95% CI, 1.29-2.02]). The risk of death decreased with the number of COVID-19 vaccinations (P = .009 for interaction between unvaccinated and vaccinated; P < .001 for interaction between unvaccinated and boosted). No statistically significant interactions were observed across other subgroups. This study found that, in a VA population in fall-winter 2022-2023, being hospitalized for COVID-19 vs seasonal influenza was associated with an increased risk of death. This finding should be interpreted in the context of a 2 to 3 times greater number of people being hospitalized for COVID-19 vs influenza in the US in this period. However, the difference in mortality rates between COVID-19 and influenza appears to have decreased since early in the pandemic; death rates among people hospitalized for COVID-19 were 17% to 21% in 2020 vs 6% in this study, while death rates for those hospitalized for influenza were 3.8% in 2020 vs 3.7% in this study. The decline in death rates among people hospitalized for COVID-19 may be due to changes in SARS-CoV-2 variants, increased immunity levels (from vaccination and prior infection), and improved clinical care. The increased risk of death was greater among unvaccinated individuals compared with those vaccinated or boosted—findings that highlight the importance of vaccination in reducing risk of COVID-19 death.
Recent French mpox cluster includes fully vaccinated patients
- French officials recently posted an update on an mpox cluster in the Center-Val de Loire region, with 17 cases reported since the first of the year, including 14 since March 1. All occurred in men who have sex with men who had several partners but didn't attend any common events. Five of the patients had received two mpox vaccine doses in 2022. Also, five had received one smallpox dose during childhood, plus one dose in 2022. Given the high proportion of vaccinated people in the cluster, 59%, Public Health France and its regional partners investigated the development, finding that the proportion of vaccinated cases is higher than the 25% observed at the national level between October and February. In other mpox developments, the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) European regional office yesterday posted a joint update on mpox, which reported 28 new cases from 7 countries since the last update 4 weeks ago. Sixteen of the cases are part of the French cluster. Six were from Spain. Other countries reporting cases are Portugal, the Netherlands, Switzerland, Greece, and Malta.
Epidemiologic and Clinical Features of Mpox-Associated Deaths — United States, May 10, 2022–March 7, 2023
- Severe manifestations of mpox have occurred in the United States, particularly among persons with uncontrolled viral spread resulting from moderately to severely immunocompromising conditions. Thirty-eight mpox-associated deaths occurred in the United States during May 10, 2022–March 7, 2023 (1.3 mpox-associated deaths per 1,000 cases). Most decedents were non-Hispanic Black or African American (87%) persons and cisgender men (95%). Among 24 decedents with HIV for whom data were available, all had advanced HIV, typically with a CD4 count <50. Equitable and early access to prevention and treatment for both mpox and HIV is critical to reducing mpox-related mortality.
SARS-CoV-2 During Omicron Variant Predominance Among Infants Born to People With SARS-CoV-2
- SARS-CoV-2, the virus that causes COVID-19, continues to evolve, resulting in variants with properties that can affect transmissibility and/or severity. The period of Omicron variant predominance has been associated with increased transmissibility but lower severity in the general population. However, studies have shown increases in hospitalizations among infants when comparing the period of Omicron predominance to previous periods. SARS-CoV-2 infection during pregnancy can impart anti–SARS-CoV-2 antibodies to infants, but antibody levels quickly wane during the first 6 months. Analyses of the pre-Omicron period showed low incidence of SARS-CoV-2 infection among infants aged 0 to 6 months born to people with SARS-CoV-2 infection during pregnancy. Infants 0 to 6 months are the only group with no COVID-19 vaccine authorized. The study objective was to understand the rates of SARS-CoV-2 infection before and during the period of Omicron variant predominance among infants born to people with infection during pregnancy and whether the period of maternal infection affects infant susceptibility.
Severe Maternal Morbidity and Mortality of Pregnant Patients With COVID-19 Infection During the Early Pandemic Period in the US
- Among 2,578,095 patients for national estimates included in this study, 5.7% were Asian, 14.7% were Black, 20.6% were Hispanic, and 50.7% were White; the median (IQR) age was 29 (25-33) years. During the 9-month study period, 45 425 (17.6 per 1000) pregnant patients had the diagnosis of COVID-19 at delivery and 1704 hospitals (63.3%) cared for pregnant patients with COVID-19 infection at delivery (median, 15 cases). The top-decile centers by volume had 60 or more COVID-19 cases. In multivariable analysis, younger age, later study period, Black and Hispanic individuals, lower household income, obesity, medical comorbidity, homelessness status, Northeastern region, earlier gestational age, and hospital admission to larger, urban hospitals were the characteristics associated with COVID-19 infection. Pregnant patients with COVID-19 infection at delivery were more likely to develop severe maternal morbidity compared with those without (46.4 vs 18.8 per 1000, adjusted odds ratio [aOR]: 2.60 [95% CI, 2.39-2.82]). Among the individual morbidity indicators, COVID-19 infection was associated with the following outcomes with all aORs greater than 2: increased risk of tracheostomy, respiratory distress syndrome, ventilation, acute myocardial infarction, sepsis, shock, cardiac arrest, and coagulopathy. The mortality risk of pregnant patients with COVID-19 infection at delivery was approximately 14 times higher compared with those without (64.0 vs 4.3 per 100 000 deliveries; aOR, 13.91 [95% CI, 6.36-30.42]. Failure-to-rescue risk following the development of severe maternal morbidity was also increased in pregnant patients with COVID-19 infection at delivery (1.5% vs 0.2%; aOR, 5.56 [95% CI, 2.51-12.30]). Among the pregnant patients with COVID-19 infection who died during the hospital admission, the median time-to-death was 16 days, but this was particularly short in the early period (median 6 days in April to June 2020). The COVID-19 case-fatality rate decreased over time from 232.9 to 79.1 per 100 000 deliveries (P for trend < .001). This national-level analysis found substantial adverse maternal outcomes among pregnant patients with COVID-19 infection at delivery during the early pandemic in the US. Specifically, the odds of severe respiratory complications were increased among pregnant patients with COVID-19 infection at delivery. Greater than 10-fold increased maternal mortality risk associated with COVID-19 infection validates prior investigations with national-level data; moreover, increased failure-to-rescue risk following severe maternal morbidity among patients with COVID-19 adds important information.
Sickness presenteeism in healthcare workers during the coronavirus disease 2019 (COVID-19) pandemic: An observational cohort study
- Sickness presenteeism among healthcare workers (HCW) risks nosocomial infection, but its prevalence among HCW with COVID-19 is unknown. Contemporaneous interviews revealed a sickness presenteeism prevalence of 49.8% among 255 HCW with symptomatic COVID-19. Presenteeism prevalence did not differ among HCW with and without specific COVID-19 symptoms or direct patient care. Sickness presenteeism (working while sick) in healthcare workers (HCWs) likely contributes to nosocomial transmission of respiratory viruses. Studies on laboratory-confirmed influenza in HCW revealed a presenteeism prevalence of 14% to 68%. The risks posed by presenteeism are higher with severe acute respiratory coronavirus virus 2 (SARS-CoV-2) because it is more transmissible and virulent than influenza, yet HCWs with coronavirus disease 2019 (COVID-19) still demonstrate presenteeism. Despite numerous reports of nosocomial outbreaks of COVID-19 linked to symptomatic staff, there have been no systematic studies on the prevalence of presenteeism in HCWs with COVID-19.
Ventilation Improvements Among K–12 Public School Districts — United States, August–December 2022
- To reduce school transmission of SARS-CoV-2, K–12 public school districts implemented ventilation improvements (replacing or upgrading ventilation systems, installing filtration systems, installing ultraviolet germicidal irradiation devices, or improving airflow). Federal funding remains available for ventilation upgrades. None of the ventilation strategies examined was reported by >51% of school districts. Implementation of ventilation improvements varied by school district U.S. Census Bureau region, geographic locale, and poverty level. High-poverty school districts reported implementation of the highest percentage of strategies. Many public school districts have not taken steps to improve school building ventilation. Equitable access and support might be needed to assist school districts in their efforts to prevent respiratory infections through ventilation improvements.
Risk factors and vectors for SARS-CoV-2 household transmission: a prospective, longitudinal cohort study
- In this longitudinal cohort study, during the pre-alpha (September to December, 2020) and alpha (B.1.1.7; December, 2020, to April, 2021) SARS-CoV-2 variant waves, researchers prospectively recruited contacts from households exposed to newly diagnosed COVID-19 primary cases, in London, UK. To maximally capture transmission events, contacts were recruited regardless of symptom status and serially tested for SARS-CoV-2 infection by RT-PCR on upper respiratory tract (URT) samples and, in a subcohort, by serial serology. Contacts' hands, primary cases' hands, and frequently-touched surface-samples from communal areas were tested for SARS-CoV-2 RNA. SARS-CoV-2 URT isolates from 25 primary case-contact pairs underwent whole-genome sequencing (WGS). From Aug 1, 2020, until March 31, 2021, 620 contacts of PCR-confirmed SARS-CoV-2-infected primary cases were recruited. 414 household contacts (from 279 households) with available serial URT PCR results were analysed in the full household contacts' cohort, and of those, 134 contacts with available longitudinal serology data and not vaccinated pre-enrolment were analysed in the serology subcohort. Household infection rate was 28·4% (95% CI 20·8–37·5) for pre-alpha-exposed contacts and 51·8% (42·5–61·0) for alpha-exposed contacts (p=0·0047). Primary cases' URT RNA viral load did not correlate with transmission, but was associated with detection of SARS-CoV-2 RNA on their hands (p=0·031). SARS-CoV-2 detected on primary cases' hands, in turn, predicted contacts' risk of infection (adjusted relative risk [aRR]=1·70 [95% CI 1·24–2·31]), as did SARS-CoV-2 RNA presence on household surfaces (aRR=1·66 [1·09–2·55]) and contacts' hands (aRR=2·06 [1·57–2·69]). In six contacts with an initial negative URT PCR result, hand-swab (n=3) and household surface-swab (n=3) PCR positivity preceded URT PCR positivity. WGS corroborated household transmission. Presence of SARS-CoV-2 RNA on primary cases' and contacts' hands and on frequently-touched household surfaces associates with transmission, identifying these as potential vectors for spread in households.
Definition of Post–COVID-19 Condition Among Published Research Studies
- Among 7087 studies, researchers excluded 6792 that were not relevant to PCC (eg, SARS-CoV-2 vaccines, commentary, systematic review, and full articles in languages other than English). The remaining 295 studies were included, consisting of 2 randomized clinical trials (0.7%), 134 cohort studies (45.4%), 66 cross-sectional studies (22.4%), 13 case-control studies (4.4%), 45 case reports or case series (15.3%), and 35 studies using other designs (11.9%) (Figure 1). Of these, 167 studies (56.6%) were conducted in European countries. Researchers found that only 102 studies (34.6%) used 1 of the 3 organizational definitions for their studies (NICE: 56, WHO: 31, and CDC: 15). A total of 193 studies (65.4%) did not follow any of the 3 definitions for PCC and 6 studies were submitted for publication before NICE released their PCC definition (ie, before December 18, 2020). Of 193 studies that did not follow any of 3 definitions, 129 studies (66.8%) used their own definitions for PCC (eg, presence of chronic symptoms that last >5 months or after 2 weeks of SARS-CoV-2 infection), while 64 studies (33.2%) did not define PCC. Researchers found substantial heterogeneity in defining PCC in the published studies, with almost two-thirds (65.4%) not complying with the definitions from the NICE, CDC, or WHO. This study highlights major issues in comparing interventions and outcomes between these reported studies in PCC due to differences in definition. The differences also result in considerable variation when translating findings into clinical management and cost-effectiveness assessments of interventions in patients with PCC. The clinical management of PCC must be evidence-based and include a personalized approach. A clearer definition of PCC is timely so that clinical trial evidence can reliably be applied to clinical management and the well-being of patients with PCC can be improved.