Proposed subtypes of post‐COVID‐19 syndrome (or long‐COVID) and their respective potential therapies

(A) Non-severe COVID-19 multi-organ sequelae (NSC-MOS) subtype Davis et al.21, 22; retrospective *N = 3762%; 85% were 30–60 years; 79% females; 6- to 7-month post-symptom onset; US, UK and other countries

70%–80% had fatigue and PEM

50%–60% had cognitive impairments and sensorimotor symptoms

30%–50% had insomnia, myalgia, palpitations, dyspnoea, dizziness, joint pain and tachycardia

92% were not hospitalised

Persistent symptoms were not associated with age or sex

Association between persistent symptoms and initial disease severity were not reported (presumably none)

Petersen et al.23; retrospective N = 180; mean age of 40 years; 54% females; 4-month post-symptom onset; Faroe Islands, Denmark

55% had ≥1 persistent symptom

∼30% had fatigue and anosmia

<15% had ageusia, joint pain, rhinorrhoea, dyspnoea, headache, myalgia, nausea, chest tightness, chills, cough and diarrhoea

96% were not hospitalised

Persistent symptoms were associated with older age but not sex, comorbidities or prior hospitalisation

Augustin et al.24; prospective N = 958; median age of 43%; 53.5% females; 4-month (N = 442) and 7-month (N = 353) post-diagnosis or post-symptom onset; Cologne, Germany

28% and 35% had ≥1 persistent symptom at 4- and 7-month, respectively

12% and 15% had anosmia at 4- and 7-month, respectively

11% had ageusia at 4- and 7-month

10% and 15% had fatigue at 4- and 7-month, respectively

9% and 14% had dyspnoea at 4- and 7-month, respectively

<3% had headache, alopecia and diarrhoea at 7-month

97.1% were not hospitalised

Persistent symptoms were associated with female sex, low IgG levels at baseline and ≥5 symptoms during acute COVID-19

Persistent symptoms were not associated with age, comorbidities or initial disease severity

Dennis et al.25; prospective *N = 201; mean age of 45 years; 71% females; median of 140-day post-symptom onset; Oxford and London, UK

99% had ≥4 and 42% had ≥10 persistent symptoms

98% had fatigue

80%–90% had myalgia, dyspnoea and headache

50%–80% had joint pain, cough, chest pain, sore throat, diarrhoea and pain

<50% had wheezing, inability to walk and rhinorrhoea

MRI abnormalities were present in single organ (70%) and multi-organ (29%); i.e., the lungs (33%), heart (32%), pancreas (17%), kidneys (12%), liver (10%), and spleen (6%)

81% were not hospitalised

Persistent symptoms were not associated with age, sex, BMI or prior hospitalisation

MRI abnormalities were associated with prior hospitalisation but not age, sex or BMI

Blomberg et al.26; prospective N = 312; median age of 46 years; 51% females; 6-month post-acute COVID-19; Bergen, Norway

61% had ≥1 persistent symptom

37% had fatigue

20%–30% had concentration impairment, disturbed taste or smell, memory problems and dyspnoea

79% were home-isolated (mild-to-moderate COVID-19)

21% were hospitalised

13% of children (0–15 years; all home-isolated) and 52% of young adults (16–30 years; all home-isolated) developed PCS

Overall persistent symptoms were associated with female sex, ↑ antibody titres and pre-existing lung diseases, but not initial disease severity, age or BMI

Lombardo et al.27; cross-sectional N = 303; median age of 53 years; 54% females; 12-month post-acute COVID-19; Milan, Italy

81% had ≥1 persistent symptom

52% had fatigue

48% had muscle or joint pain

47% had sleep disorders

36% had respiratory, cognitive or neurological disorders

28% had sensory alterations

18% had movement impairments

12% had GI symptoms.

38% were not hospitalised, of which 10% were asymptomatic

62% were hospitalised, of which 35% needed supplemental O2, 38% needed MV and 4% were in ICU

Persistent symptoms were associated with older age and female sex, but not initial disease severity

Seessle et al.28; prospective N = 96; median age of 57 years; 55% females; 12-month post-symptom onset; Heidelberg, Germany

77% had ≥1 persistent symptom

50%–56% had fatigue and reduced exercise capacity

30%–40% had dyspnoea and cognitive impairments

20%–30% had sleep problems, body aches, vertigo, headache, anxiety

10%–20% had anosmia, cough, cold, hair loss and palpitations

<10% had fever, sore throat, vomiting, nausea, diarrhoea and shivering

32% were hospitalised

71% had mild-to-moderate disease

29% had severe-to-critical disease

Persistent symptoms were associated with higher antinuclear antibodies titres and female sex, but not initial disease severity

Buonsenso et al.29; cross-sectional; preprint *N = 510; mean age of 10 years; 56% females; mean of 8-month post-symptom onset; UK, US and other countries

87% had tiredness and weakness

70%–80% had fatigue, headache and abdominal pain

50%–60% had PEM, myalgia, joint pain, rashes, irritability and cognitive impairment

40%–50% had palpitations, nausea, diarrhoea, vomiting, sore throat and dizziness

<40% had other symptoms such as cough and flu-like symptoms

All children had ≥1 and 64% had ≥4 health changes since infection in energy levels (83%), mood (59%), sleep (56%), and appetite (50%).

96% were not hospitalised

12% had asymptomatic infection

Association between persistent symptoms and initial disease severity were not reported (presumably none)

Buonsenso et al.30; cross-sectional N = 129; mean age of 11 years; 62% females; 162-day post-diagnosis; Rome, Italy

53% had ≥1 persistent symptom

19% had insomnia

10%–15% had respiratory symptoms, fatigue, myalgia, headache and concentration impairment

<10% had other symptoms, such as joint pain, abdominal pain, skin rashes, palpitations, chest pain, and altered smell and taste

95% were not hospitalised.

26% had asymptomatic infection, of which 27% developed persistent symptoms

Association between persistent symptoms and initial disease severity were not reported (presumably none)

Osmanov et al.31; prospective N = 518; median age of 10 years; 52% females; 8-month post-discharge; Moscow, Russia

24% had ≥1 persistent symptom

11% had fatigue

7% had sleep disturbance

6% had sensory problems

<5% had other symptoms: dyspnoea, altered sense of taste and smell, headache, cough, rash, diarrhoea, hair loss, joint and muscle pain, palpitation and dizziness

37% had moderate disease

2.7% had severe disease

Persistent symptoms were associated with older age and history of allergic diseases

Persistent symptoms were not associated with sex, BMI or initial disease severity

(B) pulmonary fibrosis sequelae (PFS) subtype Raman et al.32; prospective N = 58; mean age of 55 years; 41% females; 2- to 3-month post- discharge; Oxford, UK

MRI abnormalities were present in the lungs (60% of participants), kidneys (29%), heart (26%) and liver (10%)

Morin et al.33; prospective N = 478; mean age of 60 years; 58% females; 4-month post-discharge; le Kremlin-Bicêtre, France

51% had ≥1 persistent symptom

31% had fatigue

10%–20% had memory impairments, dyspnoea, and paraesthesia

In those who attended ambulatory visits (N = 177; mean age of 57 years):

63% had lung CT scan abnormalities

22% had impaired DLCO

19% had pulmonary fibrosis

10% had echocardiography abnormalities

Frija-Masson et al.34; retrospective N = 137; median age of 59 years; 49% females; 3-month post-disease onset; Paris, France Froidure et al.35; retrospective N = 134; median age of 60 years; 41% females; 3-month post-discharge; Brussels, Belgium

35% had dyspnoea

25% had fatigue

10% had dry cough

Mumoli et al.36; retrospective N = 88; mean age of 63 years; 26% females; 3-month post-discharge; Varese, Italy Robey et al.37; retrospective N = 221; mean age of 58 years; 39% females; 4-month post-discharge; Manchester, UK

24% had impaired lung function, most commonly DLCO and FVC

14% had chest CT abnormalities

7% had pulmonary fibrosis via CT

All were hospitalised

76% require supplemental O2

20% were in ICU

Persistent symptoms were associated with pre-existing comorbidities

Chest CT abnormalities and fibrosis were associated with ICU admission

Han et al.38; prospective N = 114; mean age of 54 years; 30% females; 6-month post-symptom onset; Wuhan, China Li et al.39; prospective N = 289; mean age of 44 years; 51% females; 3- to 5-month post-disease onset; Shenzhen, China

10%–20% had cough and fatigue

<10% had dyspnoea, exercise limitation and chest tightness

Pulmonary fibrosis was associated with older age, higher BMI, comorbidities, initial disease severity, and elevated inflammatory biomarkers, but not persistent symptoms or lung function

Liu et al.40; prospective N = 41; mean age of 50 years; 46% females; 7-month post-discharge; Chongqing, China

All were hospitalised

63% had moderate; 37% had severe-to-critical disease

Pulmonary fibrosis was associated with older age, impaired lung function, and more severe acute COVID-19

McGroder et al.41; prospective N = 76; mean age of 54 years; 39% females; 4-month post-hospitalisation; New York, US

All were hospitalised and required supplemental O2

42% needed MV

Pulmonary fibrosis was associated with male sex, ↑ duration on MV, and more severe acute COVID-19

(C) Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) subtype Simani et al.42; retrospective N = 120; mean age of 55 years; 33.3% females; 6-month post-discharge; Tehran, Iran

All were hospitalised

8% were in ICU

Persistent symptoms were not associated with sex or comorbidities

Association between persistent symptoms and initial disease severity were not reported (presumably none)

Kedor et al.43; prospective; preprint *N = 42; median age of 36.5 years; 69% females; 6-month post-diagnosis; Berlin, German

90%–100% had fatigue, PEM, cognitive impairment, and headache

All had non-severe (76% mild and 24% moderate) disease

Association between persistent symptoms and initial disease severity were not reported (presumably none)

The ME/CFS group reported more severe fatigue, stress intolerance, more frequent and longer-lasting PEM, and hypersensitivity to noise, light and temperature compared to the non-ME/CFS group

Davis et al.21, 22; retrospective *N = 3762%; 85% were 30–60 years; 79% females; 6- to 7-month post-symptom onset; US, UK, and other countries

70%–80% had fatigue and PEM

50%–60% had cognitive impairments and sensorimotor symptoms

30%–50% had insomnia, myalgia, palpitations, dyspnoea, dizziness, tachycardia and joint pain

92% were not hospitalised

Association between persistent symptoms and initial disease severity were not reported (presumably none)

Gonzalez-Hermosillo et al.44; prospective N = 130; mean age of 51 years; 35% females; 6-month post-discharge; Mexico City, Mexico

88% had ≥1 persistent symptom

53% had short-term memory loss

40%–50% had fatigue, unrefreshing sleep, dyspnoea on effort, tingling, vision focus impairment, and joint pain

30%–40% had concentration impairment, postural dizziness, tachycardia, headache, muscle pain, anxiety and depression

20%–30% had chest pain, constipation, and change in urinary frequency

10%–20% had resting dyspnoea, light sensitivity, dizziness, abdominal pain, diarrhoea, and nausea

<10% had anosmia and ageusia

18%, 15% and 13% had ME/CFS following the 1994 CDC, 2003 CCC, and 2015 IOM criteria, respectively

All were hospitalised

Fatigue was associated with 40–50 years compared to >50 years

Fatigue was not associated with sex (a risk trend towards female sex was present but did not reach statistical significance), initial disease severity, comorbidities, BMI and laboratory biomarkers

Mantovani et al.45; retrospective N = 37; mean age of 52 years; 32% females; >6-month post-SARS-CoV-2 infection; Verona, Italy

27% had ME/CFS-like symptoms of fatigue, sleep disturbances, pain, mood changes, and cognitive complaints, following the 2003 CCC criteria

ME/CFS-like symptoms were not associated with comorbidities, sex, BMI or initial disease severity

ME/CFS-like symptoms were associated with an additional symptom of dyspnoea

Estiri et al.46; retrospective; preprint N = 11,491; age and sex information were not presented; 3- to 9-month post-infection; Massachusetts, US

↑ Risks of alopecia (OR: 3.1), anosmia, dysgeusia, ME/CFS (OR: 2.6), chest pain, palpitations, dyspnoea, pneumonia, and diabetes (OR: 1.3-6) at 3- to 6-month

↑ Risks of anosmia or dysgeusia (OR: 2.1), ME/CFS (OR: 2.0), and dyspnoea (OR: 1.5) at 6-9-month

Note: Risks were compared to matched controls (N = 46,131)

All were not hospitalised

Association between persistent symptoms and initial disease severity were not reported (presumably none)

ME/CFS appeared more often in females and those <65 years

Elanwar et al.47; cross-sectional *N = 46; 76% females; ≥6-month onset of post-COVID-19 fatigue; Beni Suef, Egypt

78% had musculoskeletal pain

76% had orthostatic intolerance

65% had insomnia

26% had sore throat

11% had tender lymph nodes

All met the diagnosis for post-infectious fatigue syndrome

Post-infectious fatigue syndrome was associated with more severe acute COVID-19 and ↑ serum ferritin levels during acute COVID-19

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