| Accepted: 17 October 2022

DOI: 10.1002/jmv.28316

RESEARCH ARTICLE

Clinical features, therapeutic outcomes, and recovery
period of long COVID
Kazuki Takakura1|

Machi Suka2|

Mikio Kajihara3| Shigeo Koido4

1

Department of Internal Medicine,
UnMed Clinic Motomachi, Yokohama,
Kanagawa, Japan

Abstract
To characterize the clinical features of long COVID, 286 patients who received care in2

Department of Public Health andEnvironmental Medicine, The Jikei University
School of Medicine, Tokyo, Japan3

Department of Internal Medicine, Kajihara
Clinic, Hiratsuka, Kanagawa, Japan
4

Department of Internal Medicine, Division of
Gastroenterology and Hepatology, The Jikei
University Kashiwa Hospital, Chiba, Japan
Correspondence
Kazuki Takakura, Department of Internal
Medicine, UnMed Clinic Motomachi 3‐116
Motomachi, Naka‐ku, Yokohama, Kanagawa
231‐0861, Japan.
Email: takakura@unmed-clinic.jp

our outpatient clinic for long COVID from May to December 2021 were surveyed. The
recovery periods of each symptom and the key factors contributing to early recovery
were statistically analysed. The median age of the patients was 35.8 years, with 137
men and 149 women. The median number of symptoms was 2.8. The most frequent
symptoms were respiratory manifestations (52.1%), followed by fatigue (51.4%).
Respiratory symptoms, fatigue, and headache/arthralgia were major complaints in theinitial phase, whereas hair loss was a major complaint in the late phase, suggesting thatthe chief complaint of patients with long COVID may vary temporally. The besttreatment outcome was observed for pulmonary symptoms, and hair loss had theworst outcome. COVID‐19 severity, the number of manifestations, and the delay instarting treatment exerted a negative effect on the recovery period of long COVID. In
addition, the smoking habit was an independent risk factor for slowing the recovery
period from long COVID. This study provides insights into the clinical course of eachmanifestation and therapeutic options with a more certain future of long COVID tomeet the unmet medical needs.
KEYWORDS

herbaceous medication, long COVID, multisystem disorder, persistent symptoms,
recovery period

1| INTRODUCTION

signs and symptoms, such as chronic cough, breathlessness, fatigue,
fever, and headache, with uncertain prospects for unknown periods,

Since the outbreak of COVID‐19 in 2019, several epidemiologicalreliable evidence regarding the clinical features and valid manage-

studies have found that COVID‐19 subsequently causes sequelae,

ment strategies for long COVID are still lacking.

termed long COVID, in a substantial portion of patients.1–3 In a

First, the diagnostic criteria for long COVID differ, depending on

previous study from Italy, some symptoms persisted 60 days after

the country. According to a summary of UK guidelines, long COVID

COVID‐19 onset in 87% of patients.1 Similarly, another large cohort

is separately defined as acute COVID‐19, ongoing symptomatic

study from China also showed that some complaints remain in 76% of

COVID‐19, and post‐COVID‐19 syndrome based on the duration ofpatients with COVID‐19 6 months after onset.4 Although a majority

symptoms for up to 4 weeks, from 4 weeks to up to 12 weeks andof patients with long COVID experience highly variable persistent

more than 12 weeks from the onset of COVID‐19, respectively.5,6This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.
J Med Virol. 2022;e28316.
https://doi.org/10.1002/jmv.28316

wileyonlinelibrary.com/journal/jmv|

1 of 910969071, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmv.28316 by Cochrane Japan, Wiley Online Library on [22/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Received: 6 July 2022

|

TAKAKURA ET AL.

However, the post‐COVID condition is considered in the US

depression, epilepsy, and so forth, as well as a history of smoking

guidelines as persistent symptoms lasting over 4 weeks after thewere similarly recorded based on self‐reported information. For

7,8

first infection.

Moreover, a certain standard for long COVID iscurrently unavailable in Japan.

the evaluation of therapeutic efficacy, 29 censored patients were
excluded from the analysis. A summary of the data collected from theCompared with the investigations of COVID‐19 itself, the wholestudy patients is presented in Table 1. The study protocol was

picture of long COVID, which is a multisystem disorder after an initialapproved by the ethics committee of UnMed Clinic Motomachi,

severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)

Kanagawa, Japan (authorization number: UM22‐01). The review

infection, is not less well understood. Therefore, the clinical course

board approved and waived the need for written informed consent

of long COVID has been unpredictable, and the ability to obtainfrom the participants due to the retrospective, noninterventional

relevant information regarding suitable approaches and a morenature of this study. We have read the Declaration of Helsinki andcertain future has not been feasible. In addition, the other problems

have followed the recommended guidelines in this study.

of long COVID would be its low awareness and its difficulty inquantitative evaluation because the chief complaints of long COVID
are mainly not objective but subjective symptoms. As a result, long
COVID has already caused an untoward impact on communities,

2.2 | Therapeutic interventions for long
COVID‐related symptoms

such as unfair discrimination from neighbors or retirement from acompany, in addition to medical issues. In summary, an unmet

Because herbaceous medications are generally agents that easily

medical need for a better understanding and characterization of longameliorate a variety of systemic symptoms, including dysautonomia,

COVID outcomes and its multidisciplinary approach certainly exists.

they are actively administered to most patients, depending on the

To date, clinical evidence about the risk of prolongation, themanifestations.

pathological condition, and the effective treatment methods for long

Therapeutic options for long COVID‐related symptoms in our

COVID has been particularly insufficient, even if some reports haveclinic are listed in Table 2. As previously reported, hochuekkito

documented the risks of long COVID appearance from COVID‐19(TJ‐41, 2.5 g three times daily), juzentaihoto (TJ‐48, 2.5 g three times

infection.9–14 In these studies, age, body mass index (BMI), female

daily), and ninjinyoeito (TJ‐108, 3.0 g three times daily) weresex, the severity of COVID‐19, and multiple symptoms at COVID‐19

administered for fatigue, and kakkonto (TJ‐1, 2.5 g three times daily)

onset were indicated as risk factors for long COVID development.

and/or acetaminophen (500 mg orally as needed; not to exceed

Taken together, we thus aimed to assess the profiles, including3000 mg/day) were administered for fever, headache/joint pain,

the clinical courses of each symptom, along with its future

along with some other herbal drugs.15 For smell disorder, tokisha-prediction, the possible risk factors for prolongation, and the

kuyakusan (TJ‐23, 2.5 g three times daily) was prescribed according

specific treatment options in a cohort of patients with long COVID

to the clinical and basic evidence of its effectiveness for olfactory

in a single Japanese medical center. These findings would help todysfunction.16,17 In addition, rikkunshito (TJ‐43, 2.5 g three times

summarize the standardized definition of long COVID and todaily), bukuryoingohangekobokuto (TJ‐116, 2.5 g three times daily),achieve a global consensus.

and hangeshashinto (TJ‐14, 2.5 g three times daily) with a proton
pump inhibitor (esomeprazole 10 mg or vonoprazan 10 mg), as anacid suppressant, and/or a dopamine‐2 receptor antagonist (meto-

2| MATERIALS AND METHODS

2.1| Study design and population

clopramide 100 mg orally as needed) were appropriately administered for digestive manifestations, such as nausea, stomachache,abdominal fullness, diarrhea, constipation.18,19 On the basis of goodresults of a recent clinical trial in the UK, inhaled budesonide was

Two hundred eighty‐six patients with previously confirmed

actively used for pulmonary symptoms including cough, sore throat,

SARS‐CoV‐2 infection by polymerase chain reaction(PCR) or

sputum, dyspnea, chest pain with kikyoto (TJ‐138, 2.5 g three times

antigen testing who were diagnosed with long COVID at our clinic

daily), carbocysteine (500 mg three times daily), and ambroxol

between May 2021 and December 2021 were potentially eligiblehydrochloride (15 mg three times daily).20 For sleep disturbance,

for inclusion in this study.

eszopiclone (1, 2, or 3 mg daily) and/or lemborexant (2.5, 5, or 10 mg

Clinical data, such as age, sex, BMI, and COVID‐19 onset, PCR‐

daily), which are independent sleep aids, were palliatively introduced

positive date, consultation day, and laboratory data, including

as needed. As a Japanese study previously successfully managed

aspartate aminotransferase (AST) and alanine aminotransferase

alopecia using saikokaryukotsuboreito (TJ‐12, 2.5 g three times daily),(ALT) levels, of the selected patients, were collected and summarized

this herbal drug was also selected to treat alopecia in the present

in our database designed for this study. In addition, medical histories

study.21 Last, betahistine mesilate (12 mg orally as needed) andof diabetes mellitus, hypertension, hyperlipidemia, migraine, bron-ryokeijyutsukanto (TJ‐39, 2.5 g three times daily) were used to relieve

chial asthma, sleep apnea syndrome, and other conditions suchdizziness symptoms. We were unable to provide appropriate care foras any cancer, Graves' disease, atrial fibrillation, cerebral infarction,

brain fog or dysgeusia.

10969071, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmv.28316 by Cochrane Japan, Wiley Online Library on [22/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

2 of 9

T A B L E 1 Demographic and clinical characteristics of the study
participants
Parameters

Value

Age, mean (SD), years

35.8 (11.8)

TABLE 23 of 9Therapeutic options for long COVID‐related symptoms
Medications

Symptoms

Herbal agents

FatigueNinjinyoeito

Sex, n (%)

The others

JuzendaihotoMen

137 (47.9)

Women

149 (52.1)

Body mass index, n (%)

Hochuekkito
Smell disorder

Tokishakuyakusan

Fever

Kakkonto

Acetaminophen

Headache/
Joint pain

Kakkonto

Acetaminophen

Underweight35 (12.2)

Normal weight

190 (66.4)

Overweight

45 (15.7)

GoreisanMissing

16 (5.6)

ChotosanSmoking habits, n (%)

64 (22.4)

Respiratory
problems

KikyotoBudesonide inhaler

Saibokuto

Carbocysteine

shoseiryuto

Ambroxolhydrochloride

Rikkunshito

Mosapride citrate
hydrateBukuryoingohangekobokuto

Proton pumpinhibitor

Hangeshashinto

scopolamine
butylbromide

Keishikashakuyakuto

Metoclopramide

Daikencyuto

Probiotics

Comorbidities, n (%)
Any

41 (14.3)

Respiratory

16 (5.6)

Metabolic

12 (4.2)

COVID‐19 severity, n (%)
Mild

249 (87.1)

Moderate

33 (11.5)

Severe4 (1.4)Days from COVID‐19 onset to first clinic visit,
mean (SD)Digestive
manifestations

54.4 (41.1)

Symptoms, n (%)
Ramosetronhydrochloride

Fatigue

147 (51.4)

Smell disturbance101 (35.3)

Fever

61 (21.3)

Headache/joint pain

98 (34.3)

Respiratory problems

149 (52.1)

Digestive problems

48 (16.8)

Hair loss

Saikokaryukotsuboreito

Palpitation

31 (10.8)

Dizziness

Ryokeijyutsukanto

Sleep disorder

30 (10.5)

Hair loss

76 (26.6)

Brain fog

34 (11.9)

Dizziness

26 (9.1)

Number of compliants, mean (SD)

2.8 (1.6)

Blood examinations

Palpitation

Saikokeishikankyoto
Orengedokuto

Sleep disorder

Yokukansan

Eszopiclone
Lemborexant

2.3 |Betahistine
mesilate

Outcomes

Primary outcomes were the clinical course with a futuristic overview,
evaluation of the effectiveness of treatment for each manifestation,

AST, mean (U/L) (SD)28.8 (26.0)

and risk factors affecting the recovery period of long COVID. Fatigue,

ALT, mean (U/L) (SD)30.8 (31.8)

smell disturbance, fever, headache/arthralgia, respiratory manifesta-

Note: A summary of qualitative and quantitative variables in the
study. Respiratory = bronchial asthma and sleep apnea syndrome.
Metabolic = hypertension, hyperlipidemia, and diabetes.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate
aminotransferase.

tions, digestive symptoms, circulatory disturbance, sleep disorder,
hair loss, brain fog, and dizziness were separately assessed as distinct
manifestations of long COVID in the analysis. For the validation of
the recovery period, the clinical courses were divided into fourgroups: good (within a month or less), moderate (within 2 months),

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TAKAKURA ET AL.

TAKAKURA ET AL.

slow (within 3 months), and resistance (3 months or more). Clinicalmetabolic diseases. Overall, 249 (87.1%) were outpatients with a mild

outcomes were measured at more than 3 months of follow‐up,

illness, and 37 (12.9%) had a moderate (33 patients, 11.5%) or severe

depending on the condition. The secondary outcome was the(4 patients, 1.4%) disease requiring hospitalization. The median

relationship between serum transaminase levels and fatigue deter-

duration from the onset of COVID‐19 to initiation of treatment formined by measuring blood samples from 164 selected patients.

long COVID was 54.4 (11–254) days. The median number ofsymptoms was 2.8 (1–9). The most frequent symptoms were
respiratory manifestations (149/286, 52.1%), followed by fatigue| Statistical analysis

2.4(147/286, 51.4%), smell disorder (101/286, 35.3%), headache/joint
pain (98/286, 34.3%), and hair loss (76/286, 26.6%). Sleep difficulties

Demographic and clinical data were extracted from electronic

were ascertained in 30/286 (10.5%) individuals, whereas 34/286

medical records. All statistical analyses were performed using(11.9%) patients presented cognitive disturbances, also called brain

SAS version 9.4 (SAS Institute). The χ2 test was used to compare

fog. Fortunately, no serious complications from our treatments were

distributions of categorical variables in Tables 3–6. Significant levels

observed.

were set at p < 0.05. In the comparison of improvement of complaints
after treatment, Bonferroni adjustment was conducted for each test

3.2 | Chief complaints may change in the clinicalcourse of long COVID

separately to consider the number of significant tests undertaken.

3| RESULTS

According to the χ2 test, respiratory symptoms tended to be a majorcomplaint in the initial phase, followed by fatigue, fever, and

3.1| Patient characteristics

headache/joint pain, whereas hair loss was the major complaint in
the late phase (Table 3). Thus, our clinicians treating patients with

Two hundred eighty‐six participants with long COVID completed thelong COVID should understand that the chief complaint of thesurvey. Twenty‐nine patients were excluded from the analysis ofpatients may vary over time. Additionally, our data revealed notherapeutic effects because they were unable to fully follow theirsignificant relationship between COVID‐19 severity and the number

clinical courses. The demographic and clinical characteristics of theof symptoms of long COVID (data not shown).

participants are summarized in Table 1. The median age of theenrolled patients was 35.8 (14–64) years, with 137 (47.9%) men and
149 (52.1%) women. The proportions of different BMI statuses
among patients were 12.2% underweight, 66.4% normal weight, and

3.3 | Variation in therapeutic efficacy among long
COVID‐related symptoms

15.7% overweight. Sixty‐four (22.4%) patients were current orformer smokers, and 41 (14.3%) participants had any comorbidities,

Compared with previous studies, our data showed that the recovery

including 16 (5.6%) with respiratory diseases and 12 (4.2%) withperiod of pulmonary manifestations in patients with long COVID was

TABLE 3

Classification of complaints by days from COVID‐19 onset to long COVID treatmentn, %<1 month

Fatigue

7

46.7%

90

60.0%

25

54.3%

25

33.3%

0.002

Smell disturbance

4

26.7%

53

35.3%

14

30.4%

30

40.0%

0.639

Fever

1

6.7%

43

28.7%

11

23.9%

6

8.0%

0.002

Headache/joint pain

5

33.3%

63

42.0%

17

37.0%

13

17.3%

0.003

Respiratory problems

11

73.3%

102

68.0%

20

43.5%

16

21.3%

<0.001

Digestive problems

2

13.3%

28

18.7%

10

21.7%

8

10.7%

0.344

Palpitation

1

6.7%

17

11.3%

5

10.9%

8

10.7%

0.958

Sleep disorder

0

0.0%

18

12.0%

4

8.7%

8

10.7%

0.516

Hair loss

4

26.7%

28

18.7%

12

26.1%

32

42.7%

0.002

Brain fog

0

0.0%

18

12.0%

4

8.7%

12

16.0%

0.298

1

6.7%

15

10.0%

7

15.2%

3

4.0%

0.195

Dizziness

Note: Analyzed by using the χ test.
2

1 month

2 monthsp

3+ months

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4 of 9TABLE 4

5 of 9Comparison of improvement by COVID‐19 severity, number of complaints, and time to start treatment
Severity
MildpOverall (n = 257)

All

Moderate/severe

Good (2 weeks to 1 month)

66

25.7%

62

28.1%

4

11.1%

Moderate (1–2 months)

48

18.7%

44

19.9%

4

11.1%

Slow (2–3 months)

59

23.0%

50

22.6%

9

25.0%

Resistance (3 months–)

84

32.7%

65

29.4%

19

52.8%

Overall (n = 257)

Number of compliant
01Good (2 weeks to 1 month)

31

46.3%

19

36.5%

14

21.9%

2

2.7%

Moderate (1–2 months)

12

17.9%

11

21.2%

13

20.3%

12

16.2%

Slow (2–3 months)

15

22.4%

11

21.2%

19

29.7%

14

18.9%

Resistance (3 months–)

9

13.4%

11

21.2%

18

28.1%

46

62.2%

2

0.019

p

3+

<0.001

Overall (n = 257)

The duration between COVID‐19 onset and start of treatment for long‐COVID<1 month
1 month
2 months
3+ months

Good (2 weeks to 1 month)

4

30.8%

38

28.1%

10

23.8%

14

20.9%

Moderate (1–2 months)

4

30.8%

30

22.2%

1

2.4%

13

19.4%

Slow (2–3 months)

3

23.1%

22

16.3%

11

26.2%

23

34.3%

Resistance (3 months–)

2

15.4%

45

33.3%

20

47.6%

17

25.4%

p
0.014

Note: Analyzed by using the χ2 test.

TABLE 5

Related factors for the recovery time of long COVID
Smoking

Body mass index
NormalweightOverweightp

Underweight

0.021

10

31.3%

49

26.8%

7

16.7%

15.3%

5

15.6%

34

18.6%

9

21.4%

11

18.6%

8

25.0%

46

25.1%

5

11.9%

29

49.2%

9

28.1%

54

29.5%

21

50.0%

Overall (n = 257)

Nonsmoker

SmokerGood (2 weeks to 1 month)

56

28.3%

10

16.9%

Moderate (1–2 months)

39

19.7%

9

Slow (2–3 months)

48

24.2%

Resistance (3 months–)

55

27.8%

Overall (n = 257)

Sex
Men

Good (2 weeks to 1 month)

39

31.0%

27

20.6%

Moderate (1–2 months)

23

18.3%

25

Slow (2–3 months)

21

16.7%

Resistance (3 months–)

43

34.1%

p

Age
<25

0.068

13

27.1%

39

28.5%

14

19.4%

19.1%

12

25.0%

24

17.5%

12

16.7%

38

29.0%

10

20.8%

32

23.4%

17

23.6%

41

31.3%

13

27.1%

42

30.7%

29

40.3%

Women

25–44

Comorbidities
No

Good (2 weeks to 1 month)

60

27.3%

6

16.2%

Moderate (1–2 months)

42

19.1%

6

16.2%

Slow (2–3 months)

53

24.1%

6

16.2%

Resistance (3 months–)

65

29.5%

19

51.4%

0.151

p

45+

Overall (n = 257)

Note: Analyzed by using the χ2 test.

p

0.564

p

Any

0.068

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TAKAKURA ET AL.

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TAKAKURA ET AL.

undoubtedly shortened if they used inhaled budesonide.22–25 Using

Conversely, hair loss was the worst symptom, with less quick

fatigue symptoms as the basis for comparison of the recovery period,

recovery and more refractory cases, although hair loss tended topulmonary symptoms presented both a tendency towards earlyoccur in the later phase. Brain fog, which has no effective therapeutic

recovery and better therapeutic effect in most patients; subse-

intervention, and smell disorder took second place in slow recovery

quently, fever and headache/joint pain were comparatively well

(Figure 1).

managed based on the rapid recovery in more patients (Figure 1).

TABLE 6

Correlation of fatigue and serum transaminase levels

Overall(n = 164)

AST (IU/L)

Fatigue

–50

50–75

75–

Yes

83

13

9

No

51

8

0

p

0.069

p

ALT (IU/L)
–50

50‐75

75–

83

8

14

51

7

1

3.4 | Independent risk factors influencing therecovery period of long COVID
As shown in Table 4, the duration of recovery from long COVID wassignificantly shorter in the mild COVID‐19 group than in themoderate/severe COVID‐19 group. Considering both our data and0.017

previous studies showing a significant difference in the association
between COVID‐19 severity and long COVID outcomes,12,26–28

Note: Analyzed by using the χ2 test.

COVID‐19 severity undoubtedly exerts a negative effect that cannot

Abbreviations: ALT, alanine aminotransferase; AST, aspartate
aminotransferase.

be ignored. Next, we focused on the effects of the number ofcomplaints on the recovery period. Consistent with previous studies

F I G U R E 1 Therapeutic efficacy among each symptom in long COVID (n = 257). Using fatigue symptoms as the basis for the recovery period,
respiratory symptoms presented both a tendency towards early recovery and no treatment resistance in most patients; subsequently, fever andheadache/arthralgia were comparatively better managed based on the rapid recovery in more patients. Conversely, hair loss was the worst
symptom, with less quick recovery and more refractory cases, although hair loss tended to occur in the later phase. Brain fog and smell disorder
took second place in slow recovery.

10969071, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmv.28316 by Cochrane Japan, Wiley Online Library on [22/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

6 of 97 of 9describing that multiple symptoms at the onset of COVID‐19 werevalidity of this work without any potential problems regarding

associated with long COVID occurrence,9,14,29 our results also

selection bias. Consistent with previous studies, our data revealed

revealed that the simple complaint group showed significantly fasterthat fatigue and respiratory symptoms are the two leading complaints

improvement from long COVID compared with the multiple

at almost the same level.36–38

complaint group. An undeniable relationship between the numberFirst, our data showed that long COVID has a dynamic nature ofof manifestations and long COVID was observed. Moreover, earlierchangeable manifestations throughout the clinical course in theintervention for long COVID‐related symptoms potentially led tomajority of patients (Table 3), given the depressing impression that

more rapid recovery (Table 4). Thus, the sooner patients start

the clinical condition continuously improves and worsens over time,treatment, the better the chances of recovery from long COVID.

and the condition feels permanent.
Next, we assessed the therapeutic efficacy for each long COVID‐
related symptom. Strikingly, the effect of inhaled budesonide on

3.5 | Improvement of long COVID may be delayedby smoking

pulmonary symptoms of long COVID contributes substantially togood recovery without any adverse events (Figure 1). Regardless ofour data, the use of herbal drugs also depends on the management ofStrikingly, a smoking habit was an independent risk factor for slowing

long COVID‐related manifestations, especially dysautonomia, among

the recovery period from long COVID, whereas BMI, sex, age, andthe limited therapeutic options (Table 2). Because the maincomorbidities were not (Table 5). Since smoking is a well‐known

application of herbaceous medications is basically alleviating symp-

major factor exacerbating COVID‐19,30–32 our data support thetoms, it can be reliable for unexplained diseases, similar to

medical rationale for promoting smoking cessation to prevent notmenopausal syndrome. Our physicians always have difficulty treating

only COVID‐19 aggravation but also the delay in long COVID

brain fog and dysgeusia due to the lack of definitive treatments.

recovery.

Because this existing condition would obviously affect the recovery
period, the discovery of drugs for these symptoms is urgently
needed. Intriguingly, a recent study from the UK showed brain

3.6 | Increased serum transaminase levels may be asurrogate marker of “fatigue”

structure changes with larger cognitive decline in 785 UK Biobank
participants.39 However, challenges undoubtedly remain in this area.
Similar to an existing study, hair loss occurred as a late‐onset

Finally, we assessed the relationship between serum transaminase

symptom, especially in females.3 This sex difference (data not shown)levels and fatigue symptoms in 164 patients from whom bloodis probably because women usually have longer hair than men, easily

samples were selectively collected in case of blood test consent had

attracting attention to their hair condition.

been given. It is generally accepted that the liver is a major organ in

Next, independent risk factors affecting the recovery period

the pathogenesis of fatigue because it regulates much of the storage,from long COVID were evaluated by stratifying patients according torelease, and production of substrate for energy generation,33 and it

COVID‐19 severity, the number of chief complaints, and the duration

has been reported that ALT activity may be important not only as afrom the onset of COVID‐19 to therapeutic intervention for long

34

COVID. All of these factors exert a clinical effect on the recovery

marker of liver diseases but also as an indicator of general health.

According to Specified Medical Checkups and Specified Healthperiod of long COVID (Table 4), although the mechanism underlying

Guidance in Japan, ALT > 50 is a judgment value of recommendation

their effects has not yet been elucidated. Our data suggested thatfor medical examination. Therefore, we selected the cutoff points

patients with moderate or severe COVID‐19 should receive moreof 50 and 75 IU/L from a clinical perspective. Interestingly, thecare for some persistent symptoms, and multiple complaints at longcorrelation between fatigue symptoms and serum ALT levels was

COVID onset are also an unwelcome sign, although the early onset ofshown using a χ2 test, although AST levels showed no significant

appropriate treatment might lead to better outcomes of COVID‐19

difference (Table 6). Because liver damage may occur during

and long COVID.

COVID‐19 progression, regardless of pre‐existing liver disease, our
35Then, a smoking habit was an independent risk factor for slowing

Namely,the duration of recovery from long COVID (Table 5), suggesting a needincreased serum transaminase levels, especially ALT, may provide afor increased attention to smoking during the whole clinical course

finding is consistent with that of a previous study.
convenient indication of fatigue.

of COVID‐19. On the other hand, sex (female), older age, and thepresence of comorbidities were not independent risk factors forprolonged recovery in the analysis (Table 5), although several previous

4| DISC US SION

studies presented their negative effects on COVID‐19.10,12,26,36,40–43
Of course, this finding must be confirmed in further studies; however,To our knowledge, this study is the first to focus on the nature ofa prominent result was that smoking exerts a crucial effect on theselong COVID‐related symptoms and highlight the recovery period of

infectious problems.

systemic manifestations with prolonged risk factors. As shown in

Finally, we found a significant relationship between increased

Table 1, the sampling of participants in this analysis ensures theserum transaminase, especially ALT, and fatigue symptoms in long

10969071, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmv.28316 by Cochrane Japan, Wiley Online Library on [22/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License|

TAKAKURA ET AL.

|

TAKAKURA ET AL.

COVID (Table 6). It was an unsurprising result based on a previous

CONFLIC T OF INTEREST

report,35 however ALT level was the only significant abnormal value

The authors declare no conflict of interest.

in blood test of patients with long COVID in the analysis.
Taken together, we summarized the features of the changeable

DATA AVAILABILITY STATEMENT

clinical course and proposed specific therapeutic options such as

The data that support the findings of this study are available from theusing inhaled budesonide and appropriate herbaceous medications

corresponding author upon reasonable request.

with a clearer futuristic overview of long COVID in this study.
However, this study has some possible limitations.
First, as the features of long COVID vary based on the variant,

ORC I D
Kazuki Takakura

http://orcid.org/0000-0003-1444-3761

our data did not include the most recent COVID‐19 variant,Machi Suka

“Omicron.” We should always be conscious of the emergence of

Mikio Kajihara

http://orcid.org/0000-0002-3316-1121

new variants and adjust to manage them accordingly. Second, theShigeo Koido

http://orcid.org/0000-0003-0397-4348

http://orcid.org/0000-0003-2125-2218

limited sample size and a single study site of the study participants
would be a potential source of selection bias. A large cohort study in

RE F ER EN CES

the UK demonstrated that the most common comorbidities were1.

depression (22.1%), anxiety (20.3%), asthma (20.1%), eczema(19.5%), and hay fever (18.1%) in a total of 486 149 nonhospitalized2.

long COVID patients including 12.2% of Asian participants.44
Finally, this study did not assess the effect of vaccination which isa potential confounding factor for long COVID, based on the lack ofvaccination data gathering from all included patients. A recent study

3.

from Japan showed the effect of vaccination on changes insymptoms in patients with long COVID 45 and another one from4.

the United States demonstrated that vaccination before COVID‐19
infection confers only partial protection in the postacute phaseof the disease.46 Further comprehensive investigations in larger

5.

populations will be required to fully understand the clinical profilesof long COVID.

5| C ONC LUS I ON

6.

7.

A better understanding of the nature of long COVID can alleviate thephysical and mental state of the patients. Our data underline thedifference in recovery period among symptoms and the impact of a8.
9.

smoking habit on slowing the recovery period from long COVID.
Regarding solutions for long COVID, wider recognition and continuous educational activities are equally essential as the elucidation of10.

the pathological mechanism. We would be honored if our study
provides some help to unravel the mechanism of this unexplained11.

disease and meet the unmet medical needs.
12.

A U T H O R C O N TR I B U T I O N S
Kazuki Takakura, Machi Suka, Mikio Kajihara, and Shigeo Koido

13.

conceived the study. Kazuki Takakura and Mikio Kajihara collected
the qualitative data. Machi Suka analyzed the data. Kazuki Takakura
wrote the first draft of the manuscript. Machi Suka and Mikio

14.

Kajihara reviewed and provided intellectual input on the draft
and contributed to the writing of the manuscript. Shigeo Koido
revised the manuscript based on input from Machi Suka and Mikio
Kajihara. All authors reviewed and approved the final version of themanuscript.

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How to cite this article: Takakura K, Suka M, Kajihara M,
Koido S. Clinical features, therapeutic outcomes, and recovery
period of long COVID. J Med Virol. 2022;e28316.
doi:10.1002/jmv.28316

10969071, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmv.28316 by Cochrane Japan, Wiley Online Library on [22/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License|

TAKAKURA ET AL.