Risk factors and preventive interventions for post Covid-19 condition: systematic review

Figures & data

Figure 1. Flow of literature.

Table 1. Summary of characteristics of studies included in key questions 1 and 2.

Characteristics	KQ1 studies (n = 17)	KQ2 studies (n = 18)
Study design (n)	Prospective controlled cohort (14) Retrospective controlled cohort (3)	Pilot RCT (1) Non-randomized experimental design (2) Prospective controlled cohort (2) Prospective uncontrolled cohort (4) Retrospective controlled cohort^a (9)
Country (n)	China (5) Italy (2) Norway (2) Russia (2) Switzerland (2) USA (1) UK (1) Sweden (1) Turkey (1)	China (7) USA (3) Italy (2) India (1) Iran (1) Belgium (1) Norway (1) Spain (1) Switzerland (1)
Population	Sample size, median (range): 540 (304–11,955) Age, median (range)^b: 53.0 (42.7–69.0) Male %, median (range): 49.0 (32.9–65.0)	Sample size, median (range): 82 (10–538) Age, median (range): 57.0 (34.2–70.0) Male %: median (range): 56.5 (36.0–100.0)
Covid-19 ascertainment (n)	≥90% lab-confirmed (12) <90% lab confirmed (4) NR (1)	≥90% lab confirmed (12) <90% lab confirmed (1) NR (5)
Baseline Covid-19 severity (n)	Hospitalized (9) Mixed severity^c (5) Non-hospitalized (3)	Hospitalized (17) Mixed severity (1)
Outcome assessment timing (n)	12–21 weeks (3) ≥22 weeks (14)	12–16 weeks (12) >16 weeks (6)
Risk of bias (n)	Some concerns (11) High (5) Low (1)	Some concerns (6) High (12) Low (0)

Abbreviations: NR: not reported; RCT: randomized controlled trial.

^a These studies were prospective for the authors’ main objective but retrospective for the purposes of this review which analysed data on treatment(s) received during acute illness.

^b Excluding the one study that included children (Osmanov et al.) [40].

^c Studies including hospitalized and non-hospitalized participants.

Table 2. Summary of evidence for associations between risk factors and post Covid-19 condition with moderate or low level of certainty.

Variable	Outcome and timing	Baseline severity (no. of studies)	Conclusion*	Certainty^†
Demographic risk factors
Age (continuous)	Non-recovery in children
Age group (ref: <2 yrs)	≥22 weeks	Hospitalized (n = 1)	Small-to-moderate association with more post-Covid condition among children ≥6 vs. <2 years old	Low^a,c
Age (continuous)	Non-recovery
	12–21 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,b
	≥22 weeks	Hospitalized (n = 1)
Age group (18–40 [ref]; 40–60; >60 years)	≥22 weeks	Hospitalized (n = 2)	Little-to-no association	Low^a,c
		Mixed (n = 2)
		Non-hospitalized (n = 2)
Sex (ref: Male)	12–21 weeks	Hospitalized (n = 1)	Small-to-moderate association with more post-Covid condition among females	Moderate^a
	≥22 weeks	Hospitalized (n = 3)
		Mixed (n = 2)
		Non-hospitalized (n = 2)
Age (continuous)	Fatigue
	12–21 weeks	Non-hospitalized (n = 1)	Little-to-no association	Low^a,b
	≥22 weeks	Hospitalized (n = 2)
		Mixed (n = 1)
Sex (ref: Male)	12–21 weeks	Non-hospitalized (n = 1)	Small-to-moderate association with more fatigue among females	Moderate^a
	≥22 weeks	Hospitalized (n = 4)
		Mixed (n = 2)
		Non-hospitalized (n = 1)
BMI (continuous)	12–21 weeks	Non-hospitalized (n = 1)	Little-to-no association	Low^a,b
	≥22 weeks	Mixed (n = 2)
Sex (ref: Male)	Dyspnea
	≥22 weeks	Hospitalized (n = 2)	Small-to-moderate association with more dyspnea among females	Moderate^a
		Mixed (n = 1)
		Non-hospitalized (n = 1)
Age (continuous)	Depression
	≥22 weeks	Hospitalized (n = 2)	Little-to-no association	Low^a,b
Age group (18–39; 40–64; ≥65 years)	≥22 weeks	Mixed (n = 1)	Little-to-no association	Low^a,c
Age group (≥60 vs. <60 years)	Functional incapacity
	12–21 weeks	Hospitalized (n = 2)	Small-to-moderate association with more incapacity in ≥60 vs. <60 years old	Low^a,b
Sex (ref: Male)	12–21 weeks	Hospitalized (n = 1)	Small-to-moderate association with more functional incapacity among females	Low^a,d
	≥22 weeks	Hospitalized (n = 1)
Sex (ref: Male)	Cognitive impairment
	≥22 weeks	Hospitalized (n = 2)	Little-to-no association	Low^A
Race/ethnicity	Return to work
	≥22 weeks	Hospitalized (n = 1)	Small-to-moderate association with less return to work in non-White vs. White people	Low^a,c
Pre-existing conditions
Number of comorbidities (≥1 vs. 0)	Non-recovery
	12–21 weeks	Mixed (n = 1)	Small-to-moderate association with more post-Covid condition among people with ≥1 vs. 0 comorbidities	Moderate^a
	≥22 weeks	Hospitalized (n = 1)
		Mixed (n = 1)
		Non-hospitalized (n = 1)
Diabetes (any)	≥22 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,c
Chronic cardiac disease	≥22 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,c
Hypertension	≥22 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,c
Chronic pulmonary disease	Fatigue
	≥22 weeks	Hospitalized (n = 1)	Small-to-moderate increase with more fatigue among people with chronic pulmonary disease	Low^a,b
		Mixed (n = 1)
Hypertension	≥22 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,b
		Mixed (n = 1)
Rheumatological disorder	≥22 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,b
		Mixed (n = 1)
Chronic pulmonary disease	Dyspnea
	≥22 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,d
		Mixed (n = 1)
Hypertension	≥22 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,c
Number of comorbidities (≥1 vs. none)	Psychopathology (depression/anxiety)
	≥22 weeks	Hospitalized (n = 1)	Little-to-no association	Low^a,d
		Mixed (n = 1)
Rheumatologic disorder	≥22 weeks	Hospitalized (n = 1)	Small-to-moderate association with more psychopathology among people with rheumatologic disorders	Low^a,c
COPD	Cognitive impairment
	≥22 weeks	Hospitalization (n = 1)	Small-to-moderate association with more cognitive impairment among people with COPD	Low^a,c
Hypertension	≥22 weeks	Hospitalization (n = 1)	Little-to-no association (among older adults)	Low^a,c
Acute phase Covid-19 illness severity
Acute Covid-19 severity (severe/critical vs. not)	Non-recovery
	12–21 weeks	Mixed (n = 1)	Small-to-moderate association with more post-Covid condition among people who had severe/critical Covid-19 illness severity in the acute phase	Moderate^a
	≥22 weeks	Mixed (n = 1)
	≥22 weeks	Hospitalized (n = 3)	Little-to-no association	Low^a,c
No. of symptoms (≥1 vs. 0)	≥22 weeks	Mixed (n = 1)	Small-to-moderate association with more post-Covid condition among people who had ≥1 vs. 0 Covid-19 symptoms in the acute phase	Low^a,c
No. of symptoms (ref: ≤ 2 symptoms)	≥22 weeks	Non-hospitalized (n = 1)	Small-to-moderate association with more post-Covid condition among people who had >2 vs. ≤2 symptoms in the acute phase	Low^a,c
Need for hospitalization	12–21 weeks	Mixed (n = 1)	Large association with more post-Covid condition at 12–21 weeks among people who were hospitalized in the acute phase	Low^a,c
	≥22 weeks	Mixed (n = 2)	Small-to-moderate association with more post-Covid condition at ≥22 weeks among people who were hospitalized in the acute phase	Low^a,d
No. of symptoms (ref: 0–5 symptoms)	Fatigue
	12–21 weeks	Non-hospitalized (n = 1)	Small-to-moderate association with more fatigue among people who had >5 vs. ≤5 symptoms in the acute phase	Low^a,c
Acute Covid-19 severity (severe/critical vs. not)	Dyspnea
	≥22 weeks	Hospitalized (n = 2)	Little-to-no association	Moderate^a
Need for hospitalization	≥22 weeks	Mixed (n = 1)	Large association with more dyspnea among people who were hospitalized in the acute phase	Low^a,c
Acute Covid-19 severity (severe/critical vs. not)	Depression
	≥22 weeks	Hospitalized (n = 2)	Small-to-moderate with more psychopathology (depression) among people who had severe/critical Covid-19 illness severity in the acute phase	Low^a,d
Need for intubation	Functional incapacity
	≥22 weeks	Hospitalized (n = 1)	Small-to-moderate association with more functional incapacity among people requiring intubation in the acute phase	Low^a,c
Acute Covid-19 severity (severe/critical vs. no)	Cognitive impairment
	≥22 weeks	Hospitalized (n = 2)	Large association with more cognitive impairment among people who had severe/critical Covid-19 illness severity in the acute phase	Moderate^a
Need for hospitalization	Return to work
	≥22 weeks	Mixed (n = 1)	Large association with less return to work among people who required hospitalization in the acute phase	Low^a,c

Abbreviations: CI: confidence interval; Ref: reference; vs: versus.

*Our conclusions were based on applying thresholds of association. A relative effect (OR/RR) of 0.75–1.49 was considered as little-to-no association, 0.50–0.74 (decrease) and 1.5–1.99 (increase) as small-to-moderate, and <0.50 (decrease) or ≥2.00 (increase) as large effect/association.

^† Assessed using Grading of Recommendations, Assessment, Development and Evaluation. We rated the certainty based on a pooled estimate in case of a meta-analysis or a best estimate of effect/association (relative to the thresholds) across studies based on individual study results considering their sample size and measures of variance in absence of a meta-analysis. Certainty started at high and was rated down by 0, 1, or 2 levels for risk of bias (a), indirectness in outcome (b), inconsistency/lack of consistency (c), and imprecision/ wide confidence intervals (d); capital letters indicate very serious concern.

Table 3. Summary of evidence for preventive interventions for post Covid-19 condition, by timing of implementation and follow-up duration.

Author, country; study design	Intervention/exposure and comparator with sample sizes	Acute phase treatment; Covid-19 illness severity; ≥90% Laboratory confirmed (Y/N)	Outcomes and results	Conclusions (certainty*) Apply to each outcome seperately
Acute-phase interventions with follow-up 12–16 weeks post-Covid 19
Anastasio 2021, Italy Retrospective controlled cohort	Steroid use (n = 42) vs. no steroid use (n = 180)	Hospitalized 100% pneumonia (in analysis) Y	Dyspnea (MMRC scale): positively correlated p = .05	Very uncertain about effects (Very low^a,c)
Qin 2021, China Retrospective controlled cohort	Corticosteroid use (n = 17) vs. no corticosteroid use (n = 64)	Hospitalized Moderate-to-critical Y	Dyspnea: DLCO <80% predicted: IG: 10 (59%) vs. CG: 34 (53%); OR: 1.3 (0.4–3.7), p = .68
Xiong 2021, China Retrospective controlled cohort	Corticosteroid use (n = 138) vs. no corticosteroid use (n = 400)	Hospitalized Moderate-to-critical Y	Fatigue (questionnaire item): IG: 39 (28%) vs. CG: 113 (28%) Dyspnea (post-activity polypnoea item): IG: 34 (25%) vs. CG: 81 (20%); RR 1.29 (0.81–2.03)
Zhao 2020, China Retrospective controlled cohort	Low-dose corticosteroid use (n = 7) vs. no corticosteroid use (n = 48)	Hospitalized Moderate-to-severe Y	Dyspnea: DLCO <80% predicted: IG: 1 (14.3%) vs. CG: 8 (16.7%); RR 0.83 (0.09–7.90)
Gherlone 2021, Italy Retrospective controlled cohort	Antibiotic use (n = 102) vs. no antibiotic use (n = 20)	Hospitalized Moderate-to-critical (25% ICU) Y	Adverse events: association between antibiotic use and salivary gland ectasia: aOR 8.34 (95% CI, 1.47–158.19); p = .049	Very uncertain about effects (Very low^a,b,c,D)
Kataria 2021, India Nonrandomized experimental study (nonconcurrent groups)	Ayurvedic formulation Tinospora cordifolia (Guduchi) and Piper longum (Pippali) twice daily (n = 30) vs. standard care only (n = 30)	Hospitalized Asymptomatic (32%) to moderate (3%) Y	Quality of Life (general health much better now): IG 18 (64.3%) vs. 15 (51.7%): RR, 1.24 [0.79, 1.94] Dyspnea (breathlessness during physical activities): IG 6 (21.4%) vs. CG 3 (10.3%); RR, 2.00 [0.55, 7.22] Functional incapacity (work efficiency limited a lot since discharge): IG 0 vs. CG 0 Fatigue: 1 (5%) vs. CG 6 (26.1%); RR, 0.17 [0.02, 1.30] Sleep disturbances: IG 3 (10.7%) vs. CG 1 (3.4%); RR, 3.00 [0.33, 27.12]	Very uncertain about effects (Very low^a,b,c,d)
			Pain Frequent headaches: IG 3 (10.7%) vs. CG 3 (10.3%); RR, 1.00 [0.22, 4.54] Chest pain: IG 1 (5%) vs. CG 4 (17.4%); RR, 0.25 [0.03, 2.10] Dyspnea (oxygen support at home): IG 0 vs. CG 0	Very uncertain about effects (Very low^a,c,d)
Feng 2021, China Nonrandomized experimental study	Human umbilical cord mesenchymal stem cells; 1 intravenous delivery (n = 12) vs. standard medical care only (n = 29)	Hospitalized Severe Y	Quality of Life: IG 15.3 ± 3.7 vs. CG 31.9 ± 8.8; MD, −16.60 [−21.23, −11.97] Dyspnea Wheezing: IG 3 (37.5%) vs. 15 (75%); RR, 0.50 [0.20, 1.27] Lung function: FEV1/ FVC ratio <70% IG 1 (12.5%) vs. CG 13 (65%); RR, 0.19 [0.03, 1.24] Adverse events: 0 Serious adverse events: 0	Very uncertain about effects (Very low^a,c,D)
			Fatigue: IG 4 (50%) vs. CG 14 (70%); RR, 0.71 [0.34, 1.51]	Very uncertain about effects (Very low^a,b,c,D)
Jain 2021, U.S. Prospective uncontrolled cohort	Regional in-patient rehabilitation following acute hospitalization	Hospitalized Severe (% ICU NR; 94% required oxygen) NR	Hospital re-admissions (within last 2–3 weeks of follow-up): 0	Very uncertain about effects (Very low^a,c,D)
Acute-phase interventions with follow-up >16 weeks post-Covid 19
Blomberg 2021, Norway Retrospective controlled cohort	Antibiotic use (n = 31) vs. no antibiotic use (n = 262)	Hospitalized or home isolated In hospitalized: 9% on respirator Y	Fatigue (Chalder fatigue scale (score ≥4)): IG 17 (55%) vs. CG 91 (35%); aOR 0.42 (0.10–1.75), p > .05	Very uncertain about effects (Very low^a,c)
Frontera, 2021, US Retrospective controlled cohort	Azithromycin use (n = 246) vs. no azithromycin use (n = 136)	Hospitalized 8.3% ICU Y	All p > .10, unadjusted Functional incapacity: (mRS 3–6): OR 0.398 Functional incapacity (Barthel Index <100): OR 0.078 Cognitive impairment (Telephone Montreal Cognitive Assessment [score < 18]): OR 0.188 Anxiety (subscale of Neuro-QoL [T-score > 50]): OR 0.606 Depression (subscale of Neuro-QoL [T-score > 50]): OR 0.104 Fatigue (subscale of Neuro-QoL [T-score > 50]): OR 0.633 Sleep disturbances (subscale of Neuro-QoL [T-score > 50]): OR 0.819 Return to work: OR 0.458
Frontera, 2021, US Retrospective controlled cohort	Corticosteroid use (n = 101) vs. no corticosteroids (n = 281)	Hospitalized 32% ICU Y	Unless stated, all p > .10 unadjusted; all non-significant with multivariate (data not shown) Functional incapacity: (mRS 3–6): OR 0.13 Functional incapacity (Barthel Index <100): OR 0.480 (0.29–0.80), p = .005 Cognitive impairment (Telephone Montreal Cognitive Assessment [score < 18]): OR 0.98 Anxiety (subscale of Neuro-QoL [T-score > 50]): OR 0.82 Depression (subscale of Neuro-QoL [T-score > 50]): OR 0.37 Fatigue (subscale of Neuro-QoL [T-score > 50]): OR 2.2 (1.3–3.9), p = .004 Sleep disturbances (subscale of Neuro-QoL [T-score > 50]): OR 1.7 (1.0–2.8), p = .064 Return to work (self-report, Yes/No): OR 0.4 (0.2–0.8), p = .008	Very uncertain about effects (Very low^a,c)
Huang 2021, China Retrospective controlled cohort	Corticosteroid use (n = 398) vs. no corticosteroid use (n = 1335)	Hospitalized 4% ICU Y	Dyspnea: (Lung function): aOR 1.18 (0.60–2.34), p = .63
			Anxiety or depression: aOR 1.23 (0.88–1.72), p = .22 Fatigue or muscle weakness: aOR 1.04 (0.77–1.42), p = .78
Frontera 2021, US Retrospective controlled cohort	Hydroxychloroquine use (n = 272) vs. no hydroxychloroquine use (n = 110) Therapeutic anticoagulation use (n = 134) vs. no therapeutic anticoagulation use (n = 248) Zinc use (n = NR) vs. no zinc use (n = NR)	Hospitalized 32.2% ICU, 51.3% neurological COVID-19 disorder Y	Functional incapacity: (mRS 3–6): Hydroxychloroquine: OR 0.98 Therapeutic anticoagulation: OR 0.18 Zinc: OR 0.67 (0.44–1.03), p = .066 Functional capacity (Barthel Index <100): Hydroxychloroquine: OR 0.97 Therapeutic anticoagulation: OR 0.078 Zinc: OR 0.41 Cognitive impairment (Telephone Montreal Cognitive Assessment [score < 18]): Hydroxychloroquine: OR 0.13 Therapeutic anticoagulation: OR 0.99 Zinc: OR 0.52 Anxiety (subscale of Neuro-QoL [T-score > 50]): Hydroxychloroquine: OR 0.95 Therapeutic anticoagulation: OR 0.91 Zinc: OR 0.91 Depression (subscale of Neuro-QoL [T-score > 50]): Hydroxychloroquine: OR 0.50 Therapeutic anticoagulation: OR 0.98 Zinc: OR 0.62 Fatigue (subscale of Neuro-QoL [T-score > 50]): Hydroxychloroquine: OR 0.22 Therapeutic anticoagulation: OR 1.8 (1.1–3.1), p = .022 Zinc: OR 0.27 Sleep disturbances (subscale of Neuro-QoL [T-score > 50]): Hydroxychloroquine: OR 0.52 Therapeutic anticoagulation: OR 1.7 (1.0–2.8), p = .051 Zinc: OR 0.17 Return to work (self-report, Yes/No): Hydroxychloroquine: OR 0.19 Therapeutic anticoagulation: OR 0.31 (0.16–0.60), p = .001 Zinc: OR 2.3 (1.2–4.4), p = .016	Very uncertain about effects (Very low^a,c)
Huang 2021, China Retrospective controlled cohort	Intravenous immunoglobulin use (n = 345) vs. no intravenous immunoglobulin use (n = 1388)	Hospitalized 4% ICU Y	Dyspnea (Lung function): aOR 0.94 (0.49–1.79), p = .85	Very uncertain about effects (Very low^a,c,d)
			Anxiety or depression: aOR 0.77 (0.54–1.10), p = .15 Fatigue or muscle weakness: aOR 0.96 (0.70–1.31), p = .78	Very uncertain about effects (Very low^a,b)
Vetrici 2021, US Pilot RCT	Photobiomodulation adjunctive anti-inflammatory treatment; daily × 4 days (n = 5) vs. standard (supportive) care only (n = 5)	Hospitalized Moderate/severe (0% IV at baseline) Y	Dyspnea (any respiratory symptoms): 0/5 (0%) vs. 4/5 (80%); RR, 0.11 [0.01, 1.64] Treatment-related adverse events: 0/5 vs. NA	Very uncertain about effects (Very low^a,b,c,D)
Wu 2021, China Prospective controlled cohort	Oseltamivir use (n = 53) vs. no oseltamivir use (n = 30) Ganciclovir use (n = 42) vs. no ganciclovir use (n = 41)	Hospitalized Severe illness (0% IV) Y	Dyspnea: DLCO <80% predicted association with Oseltamivir: unadjusted OR 0.75 (95% CI 0.29–1.92) DLCO <80% predicted association with Ganciclovir: unadjusted OR 1.34 (95% CI 0.53–3.38)	Very uncertain about effects (Very low^a,c,d)
Early post-acute interventions with follow-up 12–16 weeks post-Covid 19
Amini 2021, Iran Prospective uncontrolled cohort	Cognitive-motor-therapy for 4 weeks; performed twice per week; measured at baseline (n = 42) and follow-up (n = 42)	Hospitalized Non-severe (COVID-19 symptoms stage 1) NR	Quality of Life: IG (baseline) 47.8 ± 1.6 vs. IG (3 mo) 46.9 ± 1.2; MD 0.86 (p = .006) (<22 pathological symptoms) Cognitive impairment: IG (baseline) 17.9 ± 3.3 vs. IG (3 mo) 19.7 ± 2.2; MD −1.72 (p = .001) (<23 threshold for impairment) *Several subscales of the MMSE were found significant at 3-month follow-up (attention and calculation, recall & action performance, MD range −0.79 to −0.33), all other domains were found to be non-significant (orientation, information encoding, & lingual skills, MD range −0.15 to −0.03). Depressive symptoms: IG (baseline) 8.6 ± 1.7 vs. IG (3 mo) 8.2 ± 1.17 (<6 pathological symptoms) Anxiety symptoms: IG (baseline) 13.7 ± 2.448 vs. IG (3 mo) 12.622 ± 2.292; MD 1.155 (p = .001) (<6 = pathological symptoms) Functional incapacity (each <6 pathological symptoms) Physical symptoms: IG (baseline) 12.66 ± 1.34 vs. IG (3 mo) 11.63 ± 2.31; MD 1.028 (p = .001) Social performance: IG (baseline) 15.05 ± 2.46 vs. IG (3 mo) 14.68 ± 2.41; MD 0.37 (p = .001)	Very uncertain about effects (Very low^a,c,d)
Benzakour 2021; Switzerland Prospective uncontrolled cohort (pre-post)	Screening and treatment for psychiatric symptoms (n = 109; 64 follow-up)	Hospitalized 16.5% ICU (in n = 64 with CoviCare follow-up data) NR	PTSD: T0: 15 (14.6%) vs. T1: 7 (10.6%) Depressive symptoms: T0: 20 (18.5%) vs. T1; 6 (10.0%) Anxiety symptoms: T0: 17 (15.7%) vs. T1 6 (10.0%)	Very uncertain about effects (Very low^a,c,d)
Li 2021, China Retrospective controlled cohort	Chinese medicine for 28 days after discharge; 2 different oral formula twice daily, depending on type of syndrome (pathogen residue or qi and yin deficiency) (n = 64) vs. Western medicine or no medicines (n = 32)	Hospitalized All severities (22% severe or critical) Y	Fatigue Dyspnea Insomnia Pain: Chest tightness No significant difference in the improvement rates of symptoms, including fatigue, between the two groups (p > .05)	Very uncertain about effects (Very low^a,b,c,d)
Martin 2021, Belgium Prospective controlled cohort	Telerehabilitation programme videoconferencing; supervised by a physiotherapist; home–based individual and group 50-min endurance and strength exercises 2/week for 6 week with 2–3/week unsupervised (n = 14) vs. patients refusing programme (n = 13)	Hospitalized Severe or critical illness (22% ICU)	Dyspnea: Sit-to-stand (< 50th %ile): IG pre 14/14 (100%) vs. post 13/14 (93%) vs. CG pre 13/13 (100%) vs. post 13/13 (100%); RR, 0.93 [0.77, 1.13] Change since baseline in dyspnea after sit-to-stand: IG 2.5 (−2–7) vs. CG 2.0 (0–6); p = .56 Adverse events: none reported	Very uncertain about effects (Very low^a,c,D)
Early post-acute interventions with follow-up >16 weeks post-Covid 19
Meije 2021, Spain Prospective uncontrolled cohort	Outpatient assessment with referrals (standard follow-up protocol checklist of symptoms and adverse events, medical history, physical examination, laboratory testing including chest x-ray) medical follow-up as required (50.3% patients; 27.1% to pulmonologist) (n = 294)	Hospitalized Variable severity (1% IV; ICU 8.9%) N	At post discharge assessment vs. 7 mo follow-up: Proportion with persistent symptoms: 228 (77.6%) vs. 147 (50%) Pain: Migraine 19 (6.5%) vs. 12 (4.1%) Chest pain 30 (10.2%) vs. 8 (2.7%) Psychopathology: Need for psychological medication 35 (11.9%) vs. 30 (10.2%) Fear of relapse 68 (23.1%) vs. 86 (29.3%)	Very uncertain about effects (Very low^a,c)
			Dyspnea: 88 (29.9%) vs. 28 (9.5%) Insomnia: 62 (21.1%) vs. 54 (18.4%) Functional disability: 60 (20.4%) vs. 57 (19.4%)	Very uncertain about effects (Very low^a,b,c)

Abbreviations: CG: control group; DLCO: diffusing capacity of the lungs for carbon monoxide; ICU: intensive care unit; IG: intervention group; IV: invasive ventilation; MD: mean difference; MMRC: modified Medical Research Council dyspnea scale; MMSE: mini mental state examination; mRC: modified Rankin Scale; NR: not reported; OR: odds ratio; QoL: quality of life; RR: relative risk; vs.: versus.

*Assessed using GRADE. Certainty was rated down by 0, 1, or 2 levels for risk of bias (a), indirectness in outcome (b), inconsistency/lack of consistency (c), and imprecision/ wide confidence intervals (d); capital letters indicates very serious concern. The certainty rating applies similarly to each outcome within each row.

Data availability statement

All of the data extracted for this review are included in the manuscript and associated supplementary files.