Studies with objectifiable tests

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study, even of the 439 patients who had not required oxygen in the hospital, 81% reported at least one symptom after 6 months, including 66% fatigue and muscle weakness (Huang 2021). In another large study of 669 patients from Switzerland treated exclusively as outpatients, as many as 32% still had at least one symptom after 6 weeks (Nehme 2020). Long periods of disability are seen even in mild courses (see cases in the box). Of hospitalized patients, almost one-third are unable to work after 3 months (Garrigues 2020, Chopra 2020). The often highly fluctuating course is striking: in a cross-sectional analysis of 70 “long haulers”, the course of symptoms was intermittent in 43% of the cases, alternating symptom-free intervals of a few days or hours with sudden relapses, often worsening after physical or intellectual exercise (SalmonCeron 2020).

A selection of studies that focused on objectifiable tests and parameters is presented below. Again, it is important to consider different follow-up duration, but also the selection of the case population studied. In most studies, there was not only a correlation between the findings and the severity of acute COVID-19 but also a marked improvement over time. However, whether the remaining radiological or pulmonary diffusion abnormalities completely resolve needs to be investigated in future follow-up studies.

Pulmonary function

• Of 145 patients in a prospective study from Germany and Austria (75% hospitalized, 22% in ICU), 41% exhibited persistent symptoms (36% dyspnea) 100 days after COVID-19 onset. CT scans unveiled persistent lung pathologies in 63%, mainly consisting of bilateral ground-glass opacities, without radiological signs of pulmonary fibrosis. However, sequential follow-up evaluations at 60 and 100 days after COVID-19 onset demonstrated a vast improvement of both, symptoms and CT abnormalities over time. One-third displayed an impaired lung function, with a reduced diffusing capacity being the most prominent finding even more than 100 days after COVID-19 diagnosis (Sonnweber 2020). • In the Wuhan cohort, a subgroup was tested for diffusion capacity for carbon monoxide (DLCO) at 6 months of follow-up. A low DLCO (< 80% of predicted) was found in 50% (48/86) and in 29% (66/228) in those

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with and without mechanical ventilation during acute COVID-19, respectively (Huang 2021). • Of 103 consecutively hospitalized patients from Norway (15 ICU cases), about half had exertional dyspnea at three months, a quarter had abnormal CT chest findings, and another quarter had reduced diffusion capacity (Lerum 2020). ICU admission was associated with pathologic CT findings but not with worsened pulmonary function. • Improvement of CT findings in 99% in 124 patients from Nijmwegen,

Netherlands (mostly with mild-moderate disease) after 13 weeks, but residual lesions were seen in 91% of discharged patients, as well as a correlation with diffusion capacity (van den Borst 2020). Cognitive dysfunction was seen in 36%. • In 113 Swiss patients (66 with severe/critical COVID-19), there was a strong association between acute COVID-19 severity and diffusion capacity at 4 months, as well as between duration of mechanical ventilation and lung function (Guler 2021).

Cardiac MRT

• A total of 100 unselected patients (mean age 49 years, 67 outpatients, including 18 asymptomatic cases), received a cardiac MRI 71 (64-92) days after COVID-19 diagnosis (Puntmann 2020). In total, 36% reported persistent shortness of breath and general fatigue. Of note, MRI showed evidence of “cardiac involvement” in 78% and persistent myocardial inflammation in 60%. This was independent of preexisting disease, severity of COVID-19, or time of diagnosis. • In contrast, among 145 young, otherwise healthy students with mildmoderate disease, only two students had an abnormal MRI 14 days after diagnosis (Starekova 2021). • In 26 competitive athletes (14 asymptomatic, 12 mildly ill), a cardiac

MRI was performed 11-53 days after quarantine (Rajpal 2020). Overall, 4/26 (15%) had CMR findings suggestive of myocarditis, and 8/26 (31%) had changes suggestive of previous myocardial injury.

Others

• Physical Fitness: 199 young Swiss recruits had undergone a baseline fitness test (3 months before a major COVID-19 outbreak in the company), including strength measurements and a progressive endurance run. Baseline fitness was compared with a second fitness test performed at a median of 45 days after SARS-CoV-2 diagnosis. Three