- - Empirical evidence published in major academic journals in the past few months is consistent across studies and shows that some COVID-19 survivors have been suffering significant long-term negative impacts.
- - Most of the current studies we identified on the long-term health impact of COVID-19 have small sample size (< 150 subjects). Additionally, the longest follow-up time is 6 months.
- - A recent study published in the Lancet (Huang et al., 2021), following 1733 adult COVID-19 survivors, found that over 75% of the patients reported at least one persisting symptom. Fatigue or muscle weakness was the most commonly reported symptom (63%). Using the EQ-5D-5L questionnaire, the researchers assessed patients’ quality of life outcomes and found that about 27% of the patients felt pain and discomfort, and 23% had depression or anxiety.
- - Huang et al. (2021) also identified significant associations between the disease severity during the acute phase of COVID-19 and the long-term impacts of COVID-19 among survivors. For instance, there was a 4.6 times [OR: 4.60; 95% CI: 1.85 to 11.48; P < 0.05] higher likelihood for patients with a disease severity of 5-6 to develop lung diffusion impairment, compared to COVID-19 survivors with a severity of 3.
- - Future studies should increase sample size, conduct a longer period of follow-up, and focus on the predictors of the long-lasting health effects of COVID-19.
Over a year after the outbreak, COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has resulted in close to 100 million confirmed cases and claimed more than two million lives around the globe (Source).
For patients who have survived COVID-19, many of them might find that their painful suffering was not over. Some symptoms may linger or even recur for some time following recovery. There is a growing concern that SARS-CoV-2 infection might pose long-term negative impacts on the health of recovered patients.
According to the United States Centers for Disease Control and Prevention (US CDC), the most commonly observed persisting symptoms in COVID-19 survivors included fatigue, shortness of breath, cough, joint pain, and chest pain (CDC, 2020). In addition, although relatively rare, a wide range of organ dysfunctions, involving cardiovascular (e.g., inflammation of the heart muscle), neurological (e.g., smell and taste problems, sleep issues, memory problems), pulmonary (e.g., lung dysfunction), renal (e.g., acute kidney injury), and psychiatric (e.g., anxiety and depression) systems, might develop in some cases post-recovery from COVID-19 (CDC, 2020).
As a new disease in human history, COVID-19 brings a great deal of uncertainty for the potential long-lasting health impacts on the survivors of this disease. Having recognized this early in the pandemic, we published an OE Insight in August, 2020 (Long-Term Health Impact of COVID-19: Emerging Updates), in which we aimed to raise awareness among clinicians and researchers alike. We found that the available findings at the time on the long-term impact of SARS-CoV-2 infection were very limited. We also urged the health care community and policy-makers to carry out an extensive “discussion about capacity building to monitor and manage the health of COVID-19 survivors and their healthcare providers – which is of paramount importance given the significant consequences for their physical and mental health”.
Five months have passed since our OE Insight on the long-term impacts of COVID-19. Given the current state of the pandemic, an update on this topic is more relevant than ever. In this OE Original, we examine the recent empirical evidence that has emerged regarding the possible long-term impacts of COVID-19 on recovered patients.
What are the emerging updates on the long-term impact of COVID-19 since August 2020?
On August 11th, 2020, a case series was published in the journal JAMA (Carfì et al., 2020), in which the authors described the persisting COVID-19 symptoms among 143 Italian patients previously discharged from COVID-19 hospitalization (Carfì et al., 2020). At the time of evaluation [mean: 60.3 days; standard deviation (SD): 13.6 after onset of the first COVID-19 symptom], over 87.4% (125/143) of patients still had COVID-19 symptoms. Among them, more than 60% of patients (79/125) reported 3 or more COVID-19-related symptoms. The most frequently reported symptoms included fatigue (53.1%, 76/143), dyspnea (43.4%, 62/143), joint pain (27.3%, 39/143), and chest pain (21.7%, 31/143). The authors also assessed the quality of life (QoL) among these COVID-19 survivors using the EuroQol visual analog scale (EQ-VAS, range: 0 to 100. A higher score indicates a better outcome). A reduction in 10 points was defined as worsened QoL. Carfì et al., (2020) found that about 44.1% (63/143) of patients felt worsened QoL.
On August 23rd, 2020, a study in the EClinialMedicine published by the Lancet followed up with 55 COVID-19 survivors and found that persisting symptoms were existing in a number of these COVID-19 survivors without critical cases three months after discharge from the hospital (Zhao et al., 2020). The most common symptom was gastrointestinal symptoms (30.91%, 17/55), followed by headache (18.18%, 10/55), fatigue (16.36%, 9/55), exertional dyspnea (14.55%, 8/55), as well as cough and sputum (1.81%, 1/55). Additionally, using high resolution computed tomography (CT), the authors found that a considerably high proportion of patients showed radiological abnormalities (74.55%, 41/55). Lung dysfunction, mainly referring to abnormal carbon monoxide diffusion capacity, was found in about one-fourth of the patients (25.45%, 14/55). The authors also found an association between urea nitrogen concentration at admission and the presence of CT abnormalities [odds ratio (OR): 7.149; 95% confidence interval (CI): 1.038 to 49.216; P = 0.046]. The measurement of D-dimer levels at admission might also be useful for predicting the impaired diffusion defect in lungs [OR: 1.066, 95% CI: 1.006 to 1.129; P = 0.031].
A study published in Annals of American Thoracic Society on October 17th followed up with 51 recovered patients four weeks after discharge from hospital and compared lung outcomes measured before hospital discharge and at four weeks after discharge (Liu et al., 2020). The chest CT results showed that as opposed to the abnormalities observed before hospital discharge, the lung abnormalities in recovered patients had gradually resolved. For instance, 17.7% (9/51) of patients had focal ground-glass opacity before discharge, while this proportion reduced to 9.8% (5/51) at four weeks after discharge. The proportions of patients with multiple ground-glass opacities, consolidation, and interlobular septal thickening decreased from 80.4% (41/51), 49% (25/51), 80.4% (41/51) before discharge to 23.5% (12/51), 2% (1/51), and 35.3% (18/51) four weeks after discharge, respectively.
Published in the JAMA Cardiology on November 1st, 2020, a cohort study evaluated the outcomes of cardiovascular magnetic resonance imaging (MRI) in 100 German patients who recently recovered from COVID-19 (Puntmann et al., 2020). The median [Interquartile range (IQR)] duration between the positive COVID-19 testing and the cardiovascular MRI examination was 71 (64-92) days. The study showed that 78 of the 100 included patients who recently recovered from COVID-19 (78%) showed abnormal cardiovascular MRI findings regardless of the severity of patients’ COVID-19 presentation, the time since diagnosis of COVID-19, the patients’ pre-existing conditions, and the presence of cardiac symptoms, including myocardial inflammation (which is defined by abnormal myocardial native T1 and T2 measures, 60%, 60/100), myocardial late gadolinium enhancement (32%, 32/100), and pericardial enhancement (22%, 22/100).
Another study, which also investigated the cardiovascular MRI outcomes in athletes recovered from SARS-CoV-2 infection was published in the JAMA Cardiology on the first day of 2021 (Rajpal et al., 2021). Twenty-six competitive college athletes, who had asymptomatic to mild SARS-CoV-2 infection, who were not hospitalized, and who received no anti-COVID-19 therapy, were investigated. The MRI results from 15% of the athletes suggested myocarditis. Over 30% of the athletes (8/26) showed myocardial late gadolinium enhancement without T2 elevation, indicating prior myocardial injury.
On January 1st, 2021, the Clinical Microbiology and Infection published a study exploring the clinical sequelae of 538 COVID-19 survivors who have been discharged from hospital for over three months (Xiong et al., 2021). The most common clinical sequelae was general symptoms (referring to the overall discomfort of COVID-19 survivors, including fatigue, sweating, myalgia, arthralgia, chills, limb oedema, and dizziness) seen in 49.6% (267/538) of patients. Other clinical sequelae commonly observed among COVID-19 survivors included respiratory symptoms (e.g., postactivity polypnoea, nonmotor polypnoea, chest distress, chest pain, cough, sputum, and throat pain) (39%, 210/538), alopecia (28.6%, 154/538), psychosocial symptoms (e.g., somnipathy, depression, anxiety, dysphoria, and feelings of inferiority) (22.7%, 122/538), and cardiovascular-related symptoms (e.g., resting heart rate increases, discontinuous flushing, and newly diagnosed hypertension) (13%, 70/538).
On January 16th, 2021, a study done by Huang et al. (2021) following 1733 adult patients recovered from COVID-19 was published in the Lancet. The time from symptom onset to follow-up was about 6 months (median: 186 days, IQR: 175 to 199). Over three-fourth of the patients (1265/1655) reported at least one persisting symptom. Fatigue or muscle weakness was the most commonly reported symptom (63%, 1038/1655), followed by sleep difficulties (26%, 437/1655), hair loss (22%, 359/1655), and smell disorder (11%, 176/1655).
Additionally, Huang et al. (2021) also evaluated the QoL of COVID-19 survivors using the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire. With the EQ-5D-5L questionnaire, authors assessed patients’ QoL from five aspects and found that about 27% (431/1616) of the COVID-19 survivors felt pain and discomfort, 23% (367/1617) of them had depression or anxiety, 7% (113/1622) had problems with walking around, 2% (25/1611) had issues with usual activity, and 1% (11/1622) had difficulties in washing or dishing.
Finally, Huang et al. (2021) determined the association between the disease severity during the acute phase of COVID-19 and the long-term impacts of COVID-19 among survivors. The authors stratified recovered patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5–6. Results after multivariable adjustment showed that recovered patients who had a disease severity of 5-6 were about 3 times [OR: 2.69; 95% CI: 1.46 to 14.96; P < 0.05] and 2 times [OR: 1.77; 95% CI: 1.05 to 2.97; P < 0.05] more likely than patients whose disease severity was 3 to endure muscle weakness/fatigue and to suffer depression or anxiety, respectively. Similarly, there was a 4.6 times [OR: 4.60; 95% CI: 1.85 to 11.48; P < 0.05] higher likelihood for patients with a disease severity of 5-6 to develop lung diffusion impairment, compared to COVID-19 survivors with a severity of 3.
What can we learn from the evidence?
In this OE Original, on top of our previous OE Insight (Long-Term Health Impact of COVID-19: Emerging Updates), we found seven studies published in the past a few months in major academic journals and narratively summarized the empirical evidence on the possible long-term health impacts on COVID-19 patients who survived the disease. Overall, conclusions across the seven studies were fairly consistent. Findings from these studies suggest that COVID-19 survivors might suffer from long-lasting negative impacts of SARS-CoV-2 infection on their physical and mental health as well as their quality of life.
Most of the seven studies had a relatively small sample size, ranging from 26 to 143 (Carfì et al., 2020; Liu et al., 2020; Puntmann et al., 2020; Rajpal et al., 2021; Zhao et al., 2020). Only two studies had a sample size of over 500 (Xiong et al., 2021) and 1700 (Huang et al., 2021), respectively. Studies with a small number of participants are very valuable in the context of fighting against COVID-19 because they can be quick to carry out regarding enrolling patients, reviewing patient records, performing analyses, and conducting surveys. For a new disease like COVID-19, the sooner we gain more knowledge about it the more likely we can have it under control and save more lives.
However, there are limitations for studies with small sample sizes. For example, from the point of view of a statistician, Ersbøll et al. (2003) pointed out that small sample size could undermine data quality with regard to clinical examination results. Clinical examinations are conducted by clinical practitioners with a subjective opinion, meaning that every clinical practitioner may have their own “sensitivity (ability to assess true positive) and specificity (ability to assess true negative)” (Ersbøll et al., 2003). If some clinical examination results were misclassified by clinical practitioners, it will pose a relatively large effect on the accuracy of the conclusion from a small study. A solution to this problem is that researchers can compare the evaluation results between two independent clinical examiners or compare repeated evaluations from one single examiner (Ersbøll et al., 2003). Among the five small studies summarized in this OE Original, only a few of them (Liu et al., 2020; Puntmann et al., 2020; Zhao et al., 2020) clearly addressed the limitation by involving two or more clinical examiners to reach agreement on patients’ results. Therefore, future studies with large sample sizes or small studies addressing the limitations bright by a small sample are needed.
Additionally, the time of evaluation among included studies also varies: Rajpal et al. (2021) examined the athletes between 11 and 53 days after recommended quarantine; Liu et al. (2020) followed up with COVID-19 survivors at four weeks after discharge from hospital; Carfì et al. (2020), Zhao et al. (2020), Puntmann et al. (2020), and Xiong et al. (2021) measured outcomes on recovered patients from two up to three months after hospital discharge. The longest time of evaluation came from Huang et al. (2021), which was 6 months (Huang et al., 2021). It still remains unclear what the clinical sequelae would be for a period longer than 6 months. For the SARS outbreak which occurred in 2003, researchers have been following the survivors for 15 years and still found some abnormalities among the SAR patients (Zhang et al., 2020). Researchers interested in the long-term health impact of COVID-19 should keep following COVID-19 survivors for years.
Finally, based on the current evidence, we can be relatively certain about the existence of the long-lasting health impact of COVID-19. Future research could focus more on the predictors of such long-term effects. As Huang et al. (2021) did in their study, which determined the association between the disease severity during the acute phase of COVID-19 and the long-term impacts of COVID-19 among survivors. Identifying these predictors would be extremely valuable because we can recognize the high probability of the long-term negative impacts occurring in some individuals more than others, and intervene as soon as possible for early prevention.
Empirical evidence published in major academic journals is consistent across studies and shows that some COVID-19 survivors have suffered significant long-term negative impacts on their health, such as lung dysfunction, cardiovascular abnormalities, reduced quality of life, muscle weakness/fatigue, gastrointestinal symptoms, depression and anxiety and so on. More studies with a larger sample size, conducting a longer period of follow-up, and focusing on the predictors of the long-lasting health effects of COVID-19 are required in the future.
Carfì, A., et al. (2020). Persistent Symptoms in Patients After Acute COVID-19. JAMA, 324(6), 603-605. doi:10.1001/jama.2020.12603
CDC. (2020, Nov 13, 2020). Long-Term Effects of COVID-19. Retrieved from https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html
Ersbøll, A. K., et al. (2003). Epidemiological studies based on small sample sizes--a statistician's point of view. Acta Vet Scand Suppl, 98, 127-140.
Huang, C., et al. (2021). 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. The Lancet, 397(10270), 220-232. doi:10.1016/S0140-6736(20)32656-8
Liu, C., et al. (2020). Chest Computed Tomography and Clinical Follow-Up of Discharged Patients with COVID-19 in Wenzhou City, Zhejiang, China. Ann Am Thorac Soc, 17(10), 1231-1237. doi:10.1513/AnnalsATS.202004-324OC
National Institute of Health (NIH). (2020, Dec 17, 2020). Clinical Spectrum of SARS-CoV-2 Infection. Retrieved from https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/
Puntmann, V. O., et al. (2020). Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol, 5(11), 1265-1273. doi:10.1001/jamacardio.2020.3557
Rajpal, S., et al. (2021). Cardiovascular Magnetic Resonance Findings in Competitive Athletes Recovering From COVID-19 Infection. JAMA Cardiol, 6(1), 116-118. doi:10.1001/jamacardio.2020.4916
Xiong, Q., et al. (2021). Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study. Clinical Microbiology and Infection, 27(1), 89-95. doi:10.1016/j.cmi.2020.09.023
Zhang, P., et al. (2020). Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study. Bone Research, 8(1), 8. doi:10.1038/s41413-020-0084-5
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