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4 October: CR Top 10 Special
“Long COVID-19” in mild and moderate cases – what do we know?
The profound physical impairments associated with critical COVID-19 illness are well known. Many patients with severe COVID-19, especially older patients and those with ARDS, will suffer long-term complications from an intensive care unit stay and from the effects of the virus on multiple body systems such has the lung, heart, blood vessels and the CNS.
However, there is growing evidence that even in some younger people with non-severe COVID-19 the illness may continue for weeks, even months. The persistent symptoms in these so-called “long haulers” fluctuate and range from severe fatigue, breathlessness, fast heart rate with minimal exertion, chest pain, pericarditis/myocarditis, hoarseness, skin manifestations and hair loss, acquired dyslexia, headaches, memory loss, relapsing fevers, joint pains, and diarrhea. Symptoms may arise through several mechanisms including direct organ damage and involvement of immune function and the autonomic nervous system.
Here we present the Top 10 papers, focusing on post-acute findings in patients with mild-to-moderate COVID-19.
Persistent symptoms, Quality of Life
Carfì A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020 Aug 11;324(6):603-605. PubMed: https://pubmed.gov/32644129. Full-text: https://doi.org/10.1001/jama.2020.12603
In Rome, 143 patients discharged from hospital were assessed after a mean of 60 days after onset of the first COVID-19 symptom. During hospitalization, 73% had evidence of pneumonia but only 15% and 5% received non-invasive or invasive ventilation, respectively. Only 13% were completely free of any COVID-19-related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. Many patients reported fatigue (53%), dyspnea (43%), joint pain (27%) and chest pain (28%). A worsened quality of life was observed among 44% of patients. Main limitations of the study are the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity.
Garrigues E, Janvier P, Kherabi Y, et al. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J Infect. 2020 Aug 25:S0163-4453(20)30562-4. PubMed: https://pubmed.gov/32853602. Full-text: https://doi.org/10.1016/j.jinf.2020.08.029
Same direction: in Paris, persistent symptoms and health-related quality of life were assessed in 120/222 patients discharged from a COVID-19 ward unit, at a mean of 111 days after their admission. The most frequently reported persistent symptoms were fatigue (55%), dyspnea (42%), loss of memory (34%), concentration and sleep disorders (28% and 31%, respectively) and, yes, hair loss (20%). Of note, ward and ICU patients showed no differences with regard to these symptoms. In both groups, EQ-5D (mobility, self-care, pain, anxiety or depression, usual activity) showed a slight difference in pain in the ICU group. The main limitation of the study: a high number of patients could not be reached.
Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation. J Med Virol. 2020 Jul 30. PubMed: https://pubmed.gov/32729939. Full-text: https://doi.org/10.1002/jmv.26368
The Journal of Medical Virology is notorious for publishing any crap. However, even in this journal, you can find something helpful. In this study, 100 survivors discharged from a large University hospital in Leeds, UK were interviewed 29 and 71 days (mean 48 days) after discharge. Among 68 patients who did not need ICU care, new fatigue was the most common symptom (60%, severe in 15%), followed by breathlessness (43%). There was a clinically significant drop in EQ-5D in 46%. However, this was a single point follow-up in hospitalized patients, and results may also be subject to reporting bias. Patients who had “received ward-based care were then selected randomly from the list… until a total of 100 participants had successfully followed up”.
Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network – United States, March-June 2020. MMWR 2020 Jul 31;69(30):993-998. PubMed: https://pubmed.gov/32730238. Full-text: https://doi.org/10.15585/mmwr.mm6930e1
The only US data to date, including a random sample of adults testing positive at an outpatient visit. Telephone interviews were conducted at a median of 16 (14–21) days after the test date. Among 292 respondents, 94% reported experiencing one or more symptoms at the time of testing; 35% of these reported not having returned to their usual state of health by the date of the interview, increasing from 26% (those aged 18–34 years), 32% (35–49 years) to 47% (≥ 50 years). Among respondents reporting cough, fatigue, or shortness of breath at the time of testing, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview.
Crameri GAG, Bielecki M, Züst R, Buehrer TW, Stanga Z, Deuel JW. Reduced maximal aerobic capacity after COVID-19 in young adult recruits, Switzerland, May 2020. Euro Surveill. 2020 Sep;25(36):2001542. PubMed: https://pubmed.gov/32914744. Full-text: https://doi.org/10.2807/1560-7917.ES.2020.25.36.2001542
Probably the best study to date that analyzed physical fitness before and after infection in 199 young, predominantly male military recruits (median age of 21 years). Recruits had had a “baseline” fitness test, performed 3 months prior to a large outbreak in the company. This test included trunk muscle, and upper extremity strength by a progressive endurance run (PER with calculated maximal aerobic capacity VO2 max), prone bridge test and seated shot put test. Baseline fitness values were compared with a fitness test at a median of 45 days (31-58 days) after SARS-CoV-2 diagnosis, Participants were grouped into convalescent recruits with symptomatic COVID-19 (n=68), asymptomatic cases (n=77) and a naive group without symptoms or laboratory evidence of SARS-CoV-2 infection (n=54). Results: neither of the strength tests differed significantly between the groups. However, there was a statistically significant decrease in VO2 max among convalescents compared with naive and asymptomatically infected recruits. Around 19% of the COVID-19 convalescents had a decrease of more than 10% in VO2 max, while none of the naive recruits showed such a decrease. While the overall effect of COVID-19 on VO2 max might be subtle, a significant subset of patients seemed to have lost more than 10% of their initial aerobic capacity.
Zhao YM, Shang YM, Song WB, et al. Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. EClinicalMedicine. 2020 Aug;25:100463. PubMed: https://pubmed.gov/32838236. Full-text: https://doi.org/10.1016/j.eclinm.2020.100463
In 55 survivors from 3 tertiary hospitals of Henan Province, China with mostly moderate COVID-19 (14 requiring additional oxygen but no mechanical ventilation), pulmonary function tests and HRCT scan of the thorax were performed 3 months after discharge. Although all 55 patients had returned to their original work, the presenting symptoms included gastrointestinal symptoms (31%), headache (18%), fatigue (16%) and exertional dyspnea (15%). Of note, radiological abnormalities were detected in 71% and residual abnormalities of pulmonary function were observed in 25%, mostly demonstrated diffusion reductions.
Zhang P, Li J, Liu H, et al. 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 Res. 2020 Feb 14;8:8. PubMed: https://pubmed.gov/32128276. Full-text: https://doi.org/10.1038/s41413-020-0084-5
Is this what we can expect in a decade? The authors have performed a long-term follow-up study on the lungs of 80 SARS patients (all HCW). In 2018, 15 years after being infected, pulmonary interstitial damage and functional decline caused by SARS mostly recovered, with a greater extent of recovery within 2 years after rehabilitation. However, the number of patients with impaired FEF25%–75% values was 40% (16/52) 15 years after infection, and 38% had a reduced diffusion capacity.
Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of Cardiovascular Magnetic Resonance (CMR) Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020 Jul 27:e203557. PubMed: https://pubmed.gov/32730619. Full-text: https://doi.org/10.1001/jamacardio.2020.3557
The best study to date on cardiac issues, including 100 COVID-19 patients at a mean age of 49 years. The median time between diagnosis and CMR was 71 (64-92) days. Most patients had recovered at home (n=67), with only minor or moderate (n=49) or without any symptoms (n=18). Compared with pre-COVID-19 status, 36% reported ongoing shortness of breath and general exhaustion, of whom 25 noted symptoms during less-than-ordinary daily activities, such as a household chore. CMR revealed cardiac involvement in 78% and ongoing myocardial inflammation in 60%, independent of preexisting conditions, severity of COVID-19 or from the time of diagnosis. The authors concluded that “participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup”.
Rajpal S, Tong MS, Borchers J, et al. Cardiovascular Magnetic Resonance Findings in Competitive Athletes Recovering From COVID-19 Infection. JAMA Cardiol. 2020 Sep 11:e204916. PubMed: https://pubmed.gov/32915194. Full-text: https://doi.org/10.1001/jamacardio.2020.4916
A comprehensive CMR examination in 26 competitive athletes, among them 14 asymptomatic and 12 with only mild symptoms. CMR was performed 11-53 days after recommended quarantine. In total 4/26 (15%) had CMR findings suggestive of myocarditis and 8/26 (31%) exhibited changes suggestive of prior myocardial injury. In 7/12 of patients with pathological findings, CMR had been performed at least three weeks after the positive SARS-CoV-2 test result.
Lu Y, Li X, Geng D, et al. Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study. EClinicalMedicine. 2020 Aug;25:100484. PubMed: https://pubmed.gov/32838240. Full-text: https://doi.org/10.1016/j.eclinm.2020.100484
Magnetic Resonance Imaging (MRI) in 60 COVID-19 patients (47 classified as mild), performed at a mean of 97 days from symptom onset. Compared with 39 age- and sex-matched non-COVID-19 volunteers, recovered COVID-19 patients showed volumetric and micro-structural abnormalities that were detected mainly in the central olfactory cortices and partially in the white matter in the right hemisphere. According to the authors, these abnormalities might cause long-term burden to COVID-19 patients after recovery.
Taken together, clinical data is still scarce. However, it is dismissive to solely attribute persisting symptoms after mild or moderate COVID-19 to anxiety or to depression or to label them as anecdotal. “COVID-19 long haulers” are no hypochondriacs. There is an urgent need to quantify long-term complications properly and accurately, including non-hospitalized patients with mild disease. Several prospective studies are underway, and we will keep you updated. In the meantime, read these 10 additional references.
Five good reviews and perspectives
Alwan NA, Attree E, Blair JM, et al. From doctors as patients: a manifesto for tackling persisting symptoms of covid-19. BMJ. 2020 Sep 15;370:m3565. PubMed: https://pubmed.gov/32933949. Full-text: https://doi.org/10.1136/bmj.m3565
Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute covid-19 in primary care. BMJ. 2020 Aug 11;370:m3026. PubMed: https://pubmed.gov/32784198. Full-text: https://doi.org/10.1136/bmj.m3026
Marshall M. The lasting misery of coronavirus long-haulers. Nature. 2020 Sep;585(7825):339-341. PubMed: https://pubmed.gov/32929257. Full-text: https://doi.org/10.1038/d41586-020-02598-6
Rubin R. As Their Numbers Grow, COVID-19 “Long Haulers” Stump Experts. JAMA. 2020 Sep 23. PubMed: https://pubmed.gov/32965460. Full-text: https://doi.org/10.1001/jama.2020.17709
Yelin D, Wirtheim E, Vetter P, et al. Long-term consequences of COVID-19: research needs. Lancet Infect Dis. 2020 Oct;20(10):1115-1117. PubMed: https://pubmed.gov/32888409. Full-text: https://doi.org/10.1016/S1473-3099(20)30701-5
Five impressive case reports
Alwan NA. Track COVID-19 sickness, not just positive tests and deaths. Nature. 2020 Aug;584(7820):170. PubMed: https://pubmed.gov/32782377. Full-text: https://doi.org/10.1038/d41586-020-02335-z
Crosby SS. My COVID-19. Ann Intern Med. 2020 Aug 11. PubMed: https://pubmed.gov/32777184. Full-text: https://doi.org/10.7326/M20-5126