The long-term clinical outcomes of SARS-CoV-2 infection in people with mild disease in Israel

By Neha MathurReviewed by Danielle Ellis, B.Sc.Jan 16 2023

In a recent study published in the BMJ, researchers conducted a nationwide study in Israel to determine the post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [PASC], a year after mild coronavirus disease 2019 (COVID-19).

They evaluated the correlation of PASC occurrence with age, gender, infecting SARS-CoV-2 variants, and vaccination status of the study cohort. Additionally, they assessed the differences in PASC symptoms between vaccinated and unvaccinated recovered individuals.

Background

Acute COVID-19 might be asymptomatic to mild or manifest as a multi-organ affecting syndrome in the long term, colloquially referred to as Long COVID. Though its definition is still evolving, it is the persistence of COVID-19-related symptoms beyond four weeks from the primary diagnosis. Non-standardized study designs and poor-quality data have prevented scientific studies from adequately assessing the prevalence of long COVID and monitoring its clinical manifestations.

It is crucial to determine the magnitude and severity of PASC and its persistent and delayed symptoms to provide effective treatment and prevent adverse events in an increasing number of patients. Equally important is to delineate it from infections with other pathogens and assess whether vaccination protects against PASC.

About the study

In the present retrospective study, researchers screened electronic health records from the comprehensive database of Maccabi Healthcare Services (MHS) in Israel. It covers longitudinal medical data of over 2.5 million Israeli people from outpatient clinics, including their COVID-19 diagnoses, outcomes, recovery, and post-recovery follow-up. In fact, 76% of MHS members also underwent at least one reverse transcription-polymerase chain reaction (RT-PCR) test during the study duration.

The researchers compared incidence rates of several COVID-19-related outcomes in the short and long term, including symptoms, the occurrence of new chronic diseases, new acute symptoms, and infectious diseases. The team classified these outcomes as recurrent and first-time events and assessed the time a patient experienced them. The study analyses also covered around ten extremely rare adverse events.

The team calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for the COVID-19-positive vs. negative controls during three time periods, 30 to 90, 30 to 180, and 180 to 360 days from primary diagnosis using inverse propensity score weighting Cox regression model. Similarly, they computed HRs with 95% CIs of vaccinated vs. unvaccinated patients for each COVID-19 outcome. Plus, the team assessed possible effect modifications in the model reflecting HRs stratified by age and gender. Finally, they applied false discovery rate (FDR) correction within each study objective, taking 0.05 as the cut-off for significance.

Study findings

The study population comprised all Israeli people who had a positive RT-PCR test at least once since March 2020 but did not seek hospitalization in the succeeding month. The study analysis showed a heightened risk for several health issues after mild COVID-19 varying with age, gender, and vaccination status. Moreover, the risk was more pronounced during the first six months after COVID-19 diagnosis but declined later.

Children had an increased risk of fewer health outcomes during the early phase, which returned to baseline in the late phase. Most health outcomes persisted six months after COVID-19 in the 41-60 years subgroup. Moreover, the risk of five outcomes remained markedly higher throughout the year after mild COVID-19.

Though patients in the other age subgroups had fewer health outcomes reported, the subpopulation of >60 years had many persistent symptoms, resulting in hospitalization. However, only dyspnoea remained significantly higher in the late period in this subpopulation.

Compared to negative controls, the risk of 13 outcomes was significantly higher in patients testing RT-PCR-positive for COVID-19. The study analysis also showed that within a year of the first COVID-19 diagnosis, the risk for many of them decreased and declined to levels observed among negative controls. Together, these findings showcased the long-term presence and presentation of COVID-19, relevant for clinicians who need to improve care for such patients.

The most common persistent symptoms documented a year after mild COVID-19 were anosmia, dysgeusia, impaired cognitive functions, weakness, dizziness, dyspnoea, and streptococcal tonsillitis. The authors found that previous studies that followed patients for shorter periods shorter also recorded some of these symptoms repeatedly among their study population.

Of particular interest was the prevalence of respiratory tract infections and the increased risk for streptococcal tonsillitis up to a year after mild COVID-19. Although a direct causal link might be missing, increased susceptibility to bacterial infection after COVID-19 is worrisome. It might be due to poor immunity that makes people, especially children, more susceptible to viral infections, such as adenovirus-caused conjunctivitis. Social distancing among infected patients may reduce the associations between COVID-19 and later incidences of infectious diseases. Studies must further investigate whether an increased risk of streptococcal tonsillitis and conjunctivitis represent immunological health outcomes inherent to COVID-19.

Furthermore, the study results indicated no marked differences in health outcomes due to infecting the SARS-CoV-2 variant. They remained the same for the wild-type strain and the Alpha variant and wild-type and Delta variant up to a year after infection, in both early and late periods. However, there is also a need to assess the effect of the Delta and the Omicron variants on long-term health outcomes. Here it is also important to note that the absolute risk difference might still vary across SARS-CoV-2 variants.

In Israel, the BNT162b2 COVID-19 vaccine was the most widely administered and markedly reduced COVID-19 cases and related hospitalizations and death. Per the study analysis, vaccination with BNT162b2 before breakthrough infection partially reduced the risk of PASC, with reduced risk for dyspnoea in the first three months.

Conclusions

To summarize, the study results showed that many health outcomes arose after mild COVID-19 and persisted for several months but returned to normal within a year. Thus, the mild disease did not lead to any chronic long-term health complications in most of Israel's population.

Moreover, mild COVID-19 led to a minimal burden on healthcare providers due to PASC in Israel. Most importantly, vaccinations reduced the risk of lingering dyspnoea in vaccinated patients with breakthrough infection compared with unvaccinated people.