Post COVID-19 condition and new onset diseases after COVID-19: A rapid review
We aimed to summarise research on the proportion of patients who get long-term symptoms, which long-term symptoms occur after COVID-19, how long the symptoms persist and which patient groups that have the greatest risk of experiencing long-term symptoms.
Most people will experience COVID-19 as a mild and transient disease, although some may experience a prolonged period with symptoms. Long-term and nonspecific symptoms have previously been reported following other viral infections, and after bacterial and parasitic infections. It is also known that people who are admitted to the intensive care unit due to severe lung failure caused by other diseases than COVID-19, can report long-term functional impairments such as impaired cognitive function, mental health problems and reduced lung function after discharge.
We aimed to summarise research on the proportion of patients who get long-term symptoms, which long-term symptoms occur after COVID-19, how long the symptoms persist and which patient groups that have the greatest risk of experiencing long-term symptoms. In addition, we summarise differences in the risk of long-term postinfectious symptoms and new onset diseases between COVID-19 and other respiratory tract infections (RTIs).
This rapid review “Post COVID-19 condition and new onset diseases after COVID-19” is the 4th version replacing our previous report published on February 15th, 2022. In this version we used more stringent inclusion criteria than in previous versions, and we included controlled studies with more than 500 mainly laboratory test positive COVID-19 cases with a follow-up time of six months or longer. We excluded studies mainly reporting on laboratory or radiological finding, uncontrolled studies, and controlled studies that had not been peer-reviewed.
The findings are based on systematic searches in MEDLINE and WHO Global research on coronavirus disease (COVID-19) database on September 19th, 2022, and a network database search in OpenAlex. One researcher screened the search results. Two researchers selected studies for inclusion and summarised study findings.
We present the results narratively given considerable heterogeneity, supplemented by tables and graphics. We plotted effect estimates reported in the included studies without any pooled synthesis.
Characteristics of included studies
The included 14 studies were conducted in the USA n=5, China n=3, Denmark n=3, UK/England n=2, and South Korea n=1. We included ten retrospective cohort studies and four prospective cohort studies. Seven studies used non-COVID-19 controls, while seven studies used patients with other respiratory tract infections, mainly influenza. The median length of follow-up was around 12 months with some studies following participants for up to two years. Follow-up time was measured from hospital discharge, initial symptoms or from positive test for SARS-CoV-2. Number of COVID-19 participants ranged from 1127 to 1 284 437. The participants in most studies were middle-aged, seven studies included populations below 18 and two studies only enrolled children. The sex distribution was mainly balanced, deviating at most by 11%. Patients were mainly sampled during 2020, three studies continued sampling into 2021, and one study into 2022. Follow ups were performed either at clinics, through online/phone/postal surveys, or by assessing register data. Seven studies included a mix of hospitalised and non-hospitalised COVID-19 patients, seven included only hospitalised patients.
Symptoms compared to non-COVID-19 controls
Two studies looked at self-reported long-term symptoms in COVID-19 cohorts compared to non-COVID 19 cohorts. A Danish cohort study found that eighteen symptoms were more common in positive COVID-19 cohorts (mainly non-hospitalised) than among negative controls after 6 to 12 months, including dysosmia, dysgeusia, fatigue, and dyspnoea. The risk differences tended to decrease over time. A Chinese longitudinal cohort study found hospitalised COVID-19 participants had larger risk of experiencing long-term symptoms at 2-years follow-up relative to their spouses (non-COVID-19 controls). COVID-19 participants reported poorer health-related quality of life but also larger improvements over time in numerous symptoms, such as depression, anxiety, and dyspnoea.
New onset diseases after COVID-19 compared to non-COVID-19 controls
Two British retrospective cohort studies and one Chinese prospective cohort study compared long-term symptoms and new onset diseases in hospitalised COVID-19 survivors and non-COVID-19 controls at 12 months or ≤ 315 days. These studies found that COVID-19 survivors had higher risk of neurological and cognitive impairments, including depression, anxiety, and bipolar disorders. Moreover, one study reported that COVID-19 survivors were more than twice as likely to be re-hospitalised or die during the first year after discharge as compared to the general population.
New onset diseases after COVID-19 compared to other respiratory tract infections
Eight retrospective cohort studies compared long-term symptoms or new onset diseases after COVID-19 with other RTIs. All studies used registered diagnostic codes to extract information on follow-up. A single study used only diagnostic codes registered for re-admission to hospital. Two of the 55 reported diseases were more than twice as likely than the comparator, and only five diseases were less than half as likely among patients with COVID-19 patients compared with other RTIs. Neurological conditions were more common after COVID-19 patients than after other RTIs. Information on mental health consequences was more heterogeneous and without obvious trends in terms of difference between groups. Respiratory illnesses appeared to be slightly less common in COVID-19 patients. Reported cardiovascular diagnostic codes did not show a clear pattern of difference, only two of ten cardiovascular conditions differed: heart failure, and intracerebral and subarachnoid bleeding. Musculoskeletal conditions were less common in two studies for COVID-19 patients. Among the infrequently reported diseases there was more variability. It does not appear like length of follow-up up until 2 years changes the outcomes between COVID-19 and other RTIs.
Overall, adolescent and children appear less affected than older age groups based on studies of participants from during the first pandemic year. Compared with non-COVID-19 controls, children who had COVID-19 had more prevalent long-lasting symptoms, but most symptoms appeared to gradually resolve over time. After 6‐12 months changes to smell and taste, and reduced appetite were more common among covid positive children compared to controls. Data on mental health and functioning were less clear, with a weak tendency towards better health-related quality-of-life scores among children and adolescents in the COVID-19 group.
Predicting factors for long-term symptoms
Factors predicting the risk of new onset disease and long-term symptoms following COVID-19 and other RTI are similar. Important factors are prior comorbidities, female sex, and severity of disease. Middle aged people appear weakly correlated with higher risk of long-term symptoms and new onset diseases whereas the youngest age groups including children appear least affected.
Current evidence suggests that patients who have been hospitalised or undergone non-invasive ventilation due to severe COVID-19 experience similar long-term consequences as patients who have been exposed to similar treatment due to other RTIs. These findings support the current rehabilitation practise of providing similar care to patients post-COVID as after other severe RTIs. Controlled studies also found that most symptoms reported by COVID-19-patients were also reported in the uninfected general population, albeit to a lesser extent. The symptoms that are most specific for COVID-19 seems to be altered smell and taste and neurological diagnoses, although with equally common reporting of dyspnoea and fatigue. Most reported symptoms and new onset diseases are also seen in the follow-up period of other RTIs. Symptom burden appears to decrease over time, but we do not know if or when these symptoms might disappear. The data also reflect that many of the reported symptoms are prevalent in non-infected populations.
Although the evidence base is growing and steadily becomes more trustworthy, some aspects remain uncertain. Our findings continue to reflect long term symptoms in patients who were infected early in the pandemic. New virus variants causing milder disease will likely reduce the overall risk and burden of long-term symptoms. Therapeutic advancements and vaccination impact outcomes and probably lead to milder courses of disease, contributing to a further reduction in the prevalence and burden of long-term symptoms. Studies on consequences of breakthrough infections, and comparative studies on vaccinated versus non vaccinated populations are already pointing in the directions of fewer long-term symptoms. Persons with asymptomatic COVID-19, or those not tested are not well researched.
Severe COVID-19, requiring hospitalisation or intensive care treatment, correlates with more symptoms after six to twelve months. Individuals with COVID-19 appear to experience and get diagnosed with similar conditions as those seen in patients with other severe respiratory tract infections at follow-up, although with some variation and with neurological symptoms standing out as more common after COVID-19. Women have a higher risk for experiencing long-term symptoms than men. Patients who have had mild and moderate COVID-19 (non-hospitalised) report some symptoms beyond six months after infection more often than uninfected persons. The extent of long-term impact of COVID-19 on the quality of life in the general population remains unclear, as most studies included patients with severe COVID-19.