Clinical features, therapeutic outcomes and recovery period of long COVID

Clinical features, therapeutic outcomes and recovery period of long COVID | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Clinical features, therapeutic outcomes and recovery period of long COVID Kazuki Takakura, Machi Suka, Mikio Kajihara, Shigeo Koido This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1548863/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Dec, 2022 Read the published version in Journal of Medical Virology → Version 1 posted You are reading this latest preprint version Abstract To characterize the clinical features of long COVID, 286 patients who received care in our outpatient clinic for long COVID from May 2021 through 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 the initial phase, whereas hair loss was a major complaint in the late phase, suggesting that the chief complaint of patients with long COVID may vary temporally. The best treatment outcome was observed for pulmonary symptoms, and hair loss had the worst outcome. COVID-19 severity, the number of manifestations and delay in starting treatment exerted a negative effect on the recovery period of long COVID. In addition, a smoking habit was an independent risk factor for slowing the recovery period from long COVID. This study provides insights into the clinical course of each manifestation and therapeutic options with a futuristic overview of long COVID to meet the unmet medical needs. long COVID recovery period persistent symptoms multisystem disorder herbaceous medication Figures Figure 1 Introduction Since the outbreak of COVID-19 in 2019, several epidemiological studies have found that COVID-19 subsequently causes sequelae, termed long COVID, in a substantial portion of patients 1 – 3 . In a previous study from Italy, some symptoms persisted 60 days after COVID-19 onset in 87% of patients 1 . Similarly, another large cohort study from China also showed that some complaints remain in 76% of patients with COVID-19 6 months after onset 4 . Although a majority of patients with long COVID experience highly variable persistent signs and symptoms, such as chronic cough, breathlessness, fatigue, fever, and headache, with uncertain prospects for unknown periods, reliable evidence regarding the clinical features and valid management strategies for long COVID are still lacking. First, the diagnostic criteria for long COVID differ, depending on the country. According to a summary of UK guidelines, long COVID is separately defined as acute COVID-19, ongoing symptomatic COVID-19, and post-COVID-19 syndrome based on the duration of symptoms for up to 4 weeks, from 4 weeks to up to 12 weeks and more than 12 weeks from the onset of COVID-19, respectively 5 , 6 . However, the post-COVID condition is considered in the US guidelines as persistent symptoms lasting over 4 weeks after the first infection 7 , 8 . Moreover, a certain standard for long COVID is currently unavailable in Japan. Compared with the investigations of COVID-19 itself, the whole picture of long COVID, which is a multisystem disorder after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is not less well understood. Therefore, the clinical course of long COVID has been unpredictable, and the ability to obtain relevant information regarding suitable approaches and futuristic overviews has not been feasible. In addition, the other problems of long COVID would be its low awareness and its difficulty of quantitative 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, such as unfair discrimination from neighbours or retirement from a company, in addition to its medical issues. In summary, an unmet medical need for a better understanding and characterization of long COVID outcomes and its multidisciplinary approach certainly exists. To date, clinical evidence about the risk of prolongation, the pathological condition and the effective treatment methods for long COVID has been particularly insufficient, even if some reports have documented the risks of long COVID appearance from COVID-19 infection 9 – 14 . In these studies, age, body mass index (BMI), female sex, severity of COVID-19 and multiple symptoms at COVID-19 onset were indicated as risk factors for long COVID development. Taken together, we thus aimed to assess the profiles, including the clinical courses of each symptom, along with its future prediction, the possible risk factors for prolongation and the specific treatment options in a cohort of patients with long COVID in a single Japanese medical centre. These findings would help to summarize the standardized definition of long COVID and to achieve a global consensus. Results Patient characteristics. Two hundred eighty-six participants with long COVID completed the survey. Twenty-nine patients were excluded from the analysis of therapeutic effects because they were unable to fully follow their clinical courses. The demographic and clinical characteristics of the participants are summarized in Table 1. The median age of the enrolled 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 15.7% overweight. Sixty-four (22.4%) patients were current or former smokers, and 41 (14.3%) participants had any comorbidities, including 16 (5.6%) with respiratory diseases and 12 (4.2%) with metabolic diseases. Overall, 249 (87.1%) were outpatients with a mild illness, and 37 (12.9%) had a moderate (33 patients, 11.5%) or severe (4 patients, 1.4%) disease requiring hospitalization. The median duration from the onset of COVID-19 to initiation of treatment for long COVID was 54.4 (11–254) days. The median number of symptoms was 2.8 (1–9). The most frequent symptoms were respiratory manifestations (149/286, 52.1%), followed by fatigue (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 were ascertained in 30/286 (10.5%) individuals, whereas 34/286 (11.9%) patients presented cognitive disturbances, also called brain fog. Chief complaints may change in the clinical course of long COVID. According to the chi-square test, respiratory symptoms tended to be a major complaint in the initial phase, followed by fatigue, fever and headache/joint pain, whereas hair loss was the major complaint in the late phase (Table 2). Thus, our clinicians treating patients with long COVID should understand that chief complaint of the patients may vary over time. Additionally, our data revealed no significant relationship between COVID-19 severity and the number of symptoms of long COVID (data not shown). Variation in therapeutic efficacy among long COVID-related symptoms. Compared with previous studies, our data showed that the recovery period of pulmonary manifestations in patients with long COVID was undoubtedly shorten if they used inhaled budesonide 15 – 18 . Using fatigue symptom as the basis for recovery period, pulmonary symptoms presented both a tendency towards early recovery and no treatment resistance in most patients; subsequently, fever and headache/joint pain were comparatively better managed based on the rapid recovery in more patients (Fig. 1 ). 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, which has no effective therapeutic intervention, and smell disorder took second place in slow recovery (Fig. 1 ). Independent risk factors influencing the recovery period of long COVID. As shown in Table 3, the duration of recovery from long COVID was significantly shorter in the mild COVID-19 group than in the moderate/severe COVID-19 group. Considering both our data and previous studies showing a significant difference in the association between COVID-19 severity and long COVID outcomes 12,19−21 , COVID-19 severity undoubtedly exerts a negative effect on COVID-related diseases. Next, we focused on the effects of the number of complaints on the recovery period. Consistent with previous studies describing that multiple symptoms at the onset of COVID-19 were associated with long COVID occurrence 9 , 14 , 22 , our results also revealed that the simple complaint group showed significantly faster improvement from long COVID compared with the multiple complaint group. An undeniable relationship between the number of manifestations and long COVID was observed. Moreover, earlier intervention for long COVID-related symptoms potentially led to more rapid recovery (Table 3). Thus, the sooner patients start treatment, the better the chances of recovery from long COVID. Improvement of long COVID may be delayed by smoking. Strikingly, a smoking habit was an independent risk factor for slowing the recovery period from long COVID, whereas BMI, sex, age and comorbidities were not (Table 4). Since smoking is a well-known major factor exacerbating COVID-19 23–25 , our data support the medical rationale for promoting smoking cessation to prevent not only COVID-19 aggravation but also the delay in long COVID recovery. Increased serum transaminase levels may be a surrogate marker of “fatigue”. Finally, we assessed the relationship between serum transaminase levels and fatigue symptoms in 164 patients from whom blood samples were selectively collected. Interestingly, the correlation between fatigue symptoms and serum alanine aminotransferase (ALT) levels was shown using a chi-square test, although aspartate aminotransferase (AST) levels showed no significant difference (Table 5). Because liver damage may occur during COVID-19 progression, regardless of preexisting liver disease, our finding is consistent with that of a previous study 26 . Namely, increased serum transaminase levels, especially ALT, may provide a convenient indication of fatigue. Discussion To our knowledge, this study is the first to focus on the nature of long COVID-related symptoms and highlight the recovery period of systemic manifestations with prolonged risk factors. As shown in Table 1, sampling of participants in this analysis ensures the validity of this work without any potential problems regarding selection bias. Consistent with previous studies, our data revealed that fatigue and respiratory symptoms are the two leading complaints at almost the same level 27 – 29 . First, our data showed that long COVID has a dynamic nature of changeable manifestations throughout the clinical course in the majority of patients (Table 3), given the depressing impression that the clinical condition continuously improves and worsens over time, and the condition feels permanent. Next, we assessed the therapeutic efficacy for each long COVID-related symptom. Strikingly, the effect of inhaled budesonide on pulmonary symptoms of long COVID contributes substantially to good recovery without any adverse events (Fig. 1 ). Regardless of our data, the use of herbal drugs also depends on the management of long COVID-related manifestations, especially dysautonomia, among the limited therapeutic options (Table 6). As these treatments mainly relieve symptoms rather than cure the disease, herbaceous medications would be a key treatment for this unexplained disease, similar to menopausal syndrome. Our physicians always have difficulty treating brain fog and dysgeusia due to the lack of definitive treatments. Although the efficacy has not been confirmed, we actively recommend that patients with brain fog use some brain-stimulating smartphone applications. 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 structure changes with larger cognitive decline in 785 UK Biobank participants 30 . However, challenges undoubtedly remain in this area. Similar to an existing study, hair loss occurred as a late-onset symptom, especially in females 3 . This sex difference (data not shown) is probably because women usually have longer hair than men, easily attracting attention to their hair condition. Next, independent risk factors affecting the recovery period from long COVID were evaluated by stratifying patients according to COVID-19 severity, the number of chief complaints and the duration from onset of COVID-19 to therapeutic intervention for long COVID. All of these factors exert a clinical effect on the recovery period of long COVID (Table 3), although the mechanism underlying their effects has not yet been elucidated. Our data suggested that patients with moderate or severe COVID-19 should receive more care for some persistent symptoms, and multiple complaints at long COVID onset are also an unwelcome sign, although the early onset of appropriate treatment might lead to better outcomes of COVID-19 and long COVID. Then, a smoking habit was an independent risk factor for slowing the duration of recovery from long COVID (Table 4), suggesting a need for increased attention to smoking in the whole clinical course of COVID-19. On the other hand, sex (female), older age and the presence of comorbidities were not independent risk factors for prolonged recovery in the analysis (Table 4), although several previous studies presented their negative effects on COVID-19 10,12,19,27,31−34 . Of course, this finding must be confirmed in further studies; however, a prominent result was that smoking exerts a crucial effect on these infectious problems. Finally, we found out the significant relationship between increased serum transaminase, especially ALT and fatigue symptom in long COVID (Table 5). It was an unsurprising result based on a previous report 26 , however ALT level was the only significant abnormal value in blood test of patients with long COVID in the analysis. Taken together, we summarized the features of the changeable clinical course and proposed specific therapeutic options such as using inhaled budesonide and appropriate herbaceous medications 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, our data did not include the most recent COVID-19 variant, “Omicron”. We should always be conscious of the emergence of new variants and adjust to manage them accordingly. Second, the limited sample size and a single study site of the study participants would be potential source of selection bias. Further comprehensive investigations in larger populations will be required to fully understand the clinical profiles of long COVID. Finally, this study did not assess the effect of vaccination, which is a potential confounding factor for long COVID, to prevent an increasingly complex analysis, although a recent study showed the effect of vaccination on changes in symptoms in patients with long COVID 35 . Conclusion Today, we often hear that COVID-19 is just a cold. However, COVID-19 and a common cold or flu are different diseases based on their sequelae; therefore, COVID-19 should be treated as a separate disease that may reduce quality of life for patients, resulting in a decrease in social productivity. Regarding solutions for long COVID, wider recognition and continuous educational activities are equally essential as the elucidation of the pathological mechanism. We would be honoured if our study provides some help to unravel the mechanism of this unexplained disease and meet the unmet medical needs. Methods Study design and population. Two hundred eighty-six patients with previously confirmed SARS-CoV-2 infection by PCR or antigen testing who were diagnosed with long COVID at our clinic between May 2021 and December 2021 were potentially eligible for inclusion in this study. Clinical data, such as age, sex, BMI, and COVID-19 onset, PCR-positive date, consultation day and laboratory data, including AST and ALT levels, of the selected patients were collected and summarized in our database designed for this study. In addition, medical histories of diabetes mellitus, hypertension, hyperlipidaemia, migraine, bronchial asthma, sleep apnoea syndrome, and other conditions, as well as a history of smoking were similarly recorded based on self-reported information. For the evaluation of therapeutic efficacy, 29 censored patients were excluded from the analysis. A summary of the data collected from the study patients is presented in Table 1. The study protocol was approved by the ethics committee of UnMed Clinic Motomachi, Kanagawa, Japan (authorization number: UM22-01). The review board approved and waived the need for written informed consent from the participants due to the retrospective, noninterventional nature of this study. We have read the Declaration of Helsinki and have followed the recommended guidelines in this study. Therapeutic interventions for long COVID-related symptoms. Because herbaceous medications are generally agents that easily ameliorate a variety of systemic symptoms, including dysautonomia, they are actively administered to most patients, depending on the manifestations. Therapeutic options for long COVID-related symptoms in our clinic are listed in Table 6. As previously reported, hochuekkito, juzentaihoto and ninjinyoeito were administered for fatigue, and kakkonto and/or acetaminophen were administered for fever, headache/joint pain, along with some other herbal drugs 36 . For smell disorder, tokishakuyakusan was prescribed according to the clinical and basic evidence of its effectiveness for olfactory dysfunction 37 , 38 . In addition, rikkunshito, bukuryoingohangekobokuto and hangeshashinto with a proton pump inhibitor, as an acid suppressant, and/or a dopamine-2 receptor antagonist were appropriately administered for digestive manifestations, such as nausea, stomachache, abdominal fullness, diarrhoea, constipation 39 , 40 . Based on the good results of a recent clinical trial in the UK, inhaled budesonide was actively used for pulmonary symptoms including cough, sore throat, sputum, dyspnoea, chest pain with kikyoto, carbocysteine and ambroxol hydrochloride 41 . For sleep disturbance, eszopiclone and/or lemborexant, which are independent sleep aids, were palliatively introduced as needed. As a Japanese study previously successfully managed alopecia using saikokaryukotsuboreito, this herbal drug was also selected to treat alopecia in the present study 42 . Last, betahistine mesilate and ryokeijyutsukanto were used to relieve dizziness symptom. We were unable to provide appropriate care for brain fog or dysgeusia. Outcomes. Primary outcomes were the clinical course with a futuristic overview, evaluation of the effectiveness of treatment for each manifestation and risk factors affecting the recovery period of long COVID. Fatigue, smell disturbance, fever, headache/arthralgia, respiratory manifestations, 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 4 groups: good (within a month or less), moderate (within two months), slow (within three months) and resistance (3 months or more). Clinical outcomes were measured at more than 3 months of follow-up, depending on the condition. The secondary outcome was the relationship between serum transaminase levels and fatigue determined by measuring blood samples from 164 selected patients. Statistical analysis. Demographic and clinical data were extracted from electronic medical records. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). The chi-square test was used to compare distributions of categorical variables. Significant levels were set at p < 0.05. In the comparison of improvement of complaints after treatment, Bonferroni adjustment was conducted for each test separately to consider the number of significance tests undertaken. Abbreviations SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 BMI Body mass index AST Aspartate aminotransferase ALT Alanine aminotransferase Declarations Authors’ Contributions KT, MS, MK, and SK conceived the study. KT and MK collected the qualitative data. MS analysed the data. KT wrote the first draft of the manuscript. MS and MK reviewed and provided intellectual input on the draft and contributed to the writing of the manuscript. SK revised the manuscript based on input from MS and MK. All authors reviewed and approved the final version of the manuscript. Funding The authors have not received a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests The authors declare no competing interests. Data accessibility statement Data are available upon reasonable request. References Carfì, A., Bernabei, R. & Landi, F. Persistent Symptoms in Patients After Acute COVID-19. 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Ther. 49 , 1134–1172, doi: 10.1111/apt.15191 (2019). Ding, J. H. et al. Role of gut microbiota via the gut-liver-brain axis in digestive diseases. World J. Gastroenterol. 26 , 6141–6162, doi: 10.3748/wjg.v26.i40.6141 (2020). Ramakrishnan, S. et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med 9 , 763–772, doi: 10.1016/s2213-2600(21)00160-0 (2021). Kawashima, N., Hu, X., Ishikawa, N., Matsuhisa, T. & Sato, J. A combination of herbal formulas, acupuncture, and novel pine-needle stimulation for recurrent alopecia areata: A case report. Medicine (Baltimore) 100 , e26084, doi: 10.1097/md.0000000000026084 (2021). Tables Tables 1 to 6 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Table1to6.docx Cite Share Download PDF Status: Published Journal Publication published 02 Dec, 2022 Read the published version in Journal of Medical Virology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1548863","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":99642908,"identity":"afaa58ee-d899-4cb9-a7bd-80f06121104e","order_by":0,"name":"Kazuki Takakura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYFACNgbGBiDFD+Uw8DEzMBwAs3AAHpgWyQaoFjaitRgcgGkh5Cx79mOJH2e23ZM3vpF7dMOHMgZ5Nnbegwd+MPDl4bSFJ+2w5Ma2YsNtN/LSbs44x2DYxsyXcLCHga0Yt8PSGyQftiUwbruRY3abt+1/Ahszj8FhoPsSG3Bp4X/e/BOoxX7zDKCWv20MRGiRSDsGdFhC4gYJoBZGorTceJZmOeNcQvKMM2/MbvaA/cJjcLDHALdf2PvTjG/2lCXY9rfnmN34AQwxfv4zxh9+VBzDGWK4gMGxBFK1MNSQrmUUjIJRMAqGKwAAcKpT+9gFWCQAAAAASUVORK5CYII=","orcid":"","institution":"UnMed Clinic Motomachi","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Kazuki","middleName":"","lastName":"Takakura","suffix":""},{"id":99642909,"identity":"808e7c96-d4f8-4384-b03c-ec0598803c9e","order_by":1,"name":"Machi Suka","email":"","orcid":"","institution":"The Jikei University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Machi","middleName":"","lastName":"Suka","suffix":""},{"id":99642910,"identity":"a2995c0b-9d37-4c08-8f35-21acbcf3ee39","order_by":2,"name":"Mikio Kajihara","email":"","orcid":"","institution":"Kajihara Clinic","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mikio","middleName":"","lastName":"Kajihara","suffix":""},{"id":99642911,"identity":"3c2ab834-a318-4230-8d03-698352327536","order_by":3,"name":"Shigeo Koido","email":"","orcid":"","institution":"The Jikei University Kashiwa Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shigeo","middleName":"","lastName":"Koido","suffix":""}],"badges":[],"createdAt":"2022-04-12 06:44:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1548863/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1548863/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1002/jmv.28316","type":"published","date":"2022-12-02T13:18:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":20567095,"identity":"f10acb2a-aca8-4648-b215-c8a9f93f0bab","added_by":"auto","created_at":"2022-04-20 17:03:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54854,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTherapeutic efficacy among each symptom in long COVID (n=257)\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eUsing fatigue symptom as the basis for recovery period, respiratory symptoms presented both a tendency towards early recovery and no treatment resistance in most patients; subsequently, fever and headache/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.\u003c/p\u003e","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-1548863/v1/f998c9a656773cb82fd14cbd.png"},{"id":59496362,"identity":"0f175458-9ee0-4f7f-9af9-6dead43a4f1c","added_by":"auto","created_at":"2024-07-02 13:18:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":528756,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1548863/v1/8b6ef956-b6fc-4592-ad4d-71a95f7da8fa.pdf"},{"id":20567096,"identity":"69dff220-b4bc-4157-be31-54af11802fa0","added_by":"auto","created_at":"2022-04-20 17:03:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33182,"visible":true,"origin":"","legend":"","description":"","filename":"Table1to6.docx","url":"https://assets-eu.researchsquare.com/files/rs-1548863/v1/efa0c248be04af476d3b164d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical features, therapeutic outcomes and recovery period of long COVID","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSince the outbreak of COVID-19 in 2019, several epidemiological studies have found that COVID-19 subsequently causes sequelae, termed long COVID, in a substantial portion of patients \u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. In a previous study from Italy, some symptoms persisted 60 days after COVID-19 onset in 87% of patients \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Similarly, another large cohort study from China also showed that some complaints remain in 76% of patients with COVID-19 6 months after onset \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Although a majority of patients with long COVID experience highly variable persistent signs and symptoms, such as chronic cough, breathlessness, fatigue, fever, and headache, with uncertain prospects for unknown periods, reliable evidence regarding the clinical features and valid management strategies for long COVID are still lacking.\u003c/p\u003e \u003cp\u003eFirst, the diagnostic criteria for long COVID differ, depending on the country. According to a summary of UK guidelines, long COVID is separately defined as acute COVID-19, ongoing symptomatic COVID-19, and post-COVID-19 syndrome based on the duration of symptoms for up to 4 weeks, from 4 weeks to up to 12 weeks and more than 12 weeks from the onset of COVID-19, respectively \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, the post-COVID condition is considered in the US guidelines as persistent symptoms lasting over 4 weeks after the first infection \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Moreover, a certain standard for long COVID is currently unavailable in Japan.\u003c/p\u003e \u003cp\u003eCompared with the investigations of COVID-19 itself, the whole picture of long COVID, which is a multisystem disorder after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is not less well understood. Therefore, the clinical course of long COVID has been unpredictable, and the ability to obtain relevant information regarding suitable approaches and futuristic overviews has not been feasible. In addition, the other problems of long COVID would be its low awareness and its difficulty of quantitative 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, such as unfair discrimination from neighbours or retirement from a company, in addition to its medical issues. In summary, an unmet medical need for a better understanding and characterization of long COVID outcomes and its multidisciplinary approach certainly exists.\u003c/p\u003e \u003cp\u003eTo date, clinical evidence about the risk of prolongation, the pathological condition and the effective treatment methods for long COVID has been particularly insufficient, even if some reports have documented the risks of long COVID appearance from COVID-19 infection \u003csup\u003e\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In these studies, age, body mass index (BMI), female sex, severity of COVID-19 and multiple symptoms at COVID-19 onset were indicated as risk factors for long COVID development.\u003c/p\u003e \u003cp\u003eTaken together, we thus aimed to assess the profiles, including the clinical courses of each symptom, along with its future prediction, the possible risk factors for prolongation and the specific treatment options in a cohort of patients with long COVID in a single Japanese medical centre. These findings would help to summarize the standardized definition of long COVID and to achieve a global consensus.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo hundred eighty-six participants with long COVID completed the survey. Twenty-nine patients were excluded from the analysis of therapeutic effects because they were unable to fully follow their clinical courses. The demographic and clinical characteristics of the participants are summarized in Table\u0026nbsp;1. The median age of the enrolled patients was 35.8 (14\u0026ndash;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 15.7% overweight. Sixty-four (22.4%) patients were current or former smokers, and 41 (14.3%) participants had any comorbidities, including 16 (5.6%) with respiratory diseases and 12 (4.2%) with metabolic diseases. Overall, 249 (87.1%) were outpatients with a mild illness, and 37 (12.9%) had a moderate (33 patients, 11.5%) or severe (4 patients, 1.4%) disease requiring hospitalization. The median duration from the onset of COVID-19 to initiation of treatment for long COVID was 54.4 (11\u0026ndash;254) days. The median number of symptoms was 2.8 (1\u0026ndash;9). The most frequent symptoms were respiratory manifestations (149/286, 52.1%), followed by fatigue (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 were ascertained in 30/286 (10.5%) individuals, whereas 34/286 (11.9%) patients presented cognitive disturbances, also called brain fog.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChief complaints may change in the clinical course of long COVID.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the chi-square test, respiratory symptoms tended to be a major complaint in the initial phase, followed by fatigue, fever and headache/joint pain, whereas hair loss was the major complaint in the late phase (Table\u0026nbsp;2). Thus, our clinicians treating patients with long COVID should understand that chief complaint of the patients may vary over time. Additionally, our data revealed no significant relationship between COVID-19 severity and the number of symptoms of long COVID (data not shown).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVariation in therapeutic efficacy among long COVID-related symptoms.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared with previous studies, our data showed that the recovery period of pulmonary manifestations in patients with long COVID was undoubtedly shorten if they used inhaled budesonide \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Using fatigue symptom as the basis for recovery period, pulmonary symptoms presented both a tendency towards early recovery and no treatment resistance in most patients; subsequently, fever and headache/joint pain were comparatively better managed based on the rapid recovery in more patients (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). 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, which has no effective therapeutic intervention, and smell disorder took second place in slow recovery (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIndependent risk factors influencing the recovery period of long COVID.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in Table\u0026nbsp;3, the duration of recovery from long COVID was significantly shorter in the mild COVID-19 group than in the moderate/severe COVID-19 group. Considering both our data and previous studies showing a significant difference in the association between COVID-19 severity and long COVID outcomes \u003csup\u003e12,19\u0026minus;21\u003c/sup\u003e, COVID-19 severity undoubtedly exerts a negative effect on COVID-related diseases. Next, we focused on the effects of the number of complaints on the recovery period. Consistent with previous studies describing that multiple symptoms at the onset of COVID-19 were associated with long COVID occurrence \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, our results also revealed that the simple complaint group showed significantly faster improvement from long COVID compared with the multiple complaint group. An undeniable relationship between the number of manifestations and long COVID was observed. Moreover, earlier intervention for long COVID-related symptoms potentially led to more rapid recovery (Table\u0026nbsp;3). Thus, the sooner patients start treatment, the better the chances of recovery from long COVID.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImprovement of long COVID may be delayed by smoking.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStrikingly, a smoking habit was an independent risk factor for slowing the recovery period from long COVID, whereas BMI, sex, age and comorbidities were not (Table\u0026nbsp;4). Since smoking is a well-known major factor exacerbating COVID-19 \u003csup\u003e23\u0026ndash;25\u003c/sup\u003e, our data support the medical rationale for promoting smoking cessation to prevent not only COVID-19 aggravation but also the delay in long COVID recovery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIncreased serum transaminase levels may be a surrogate marker of \u0026ldquo;fatigue\u0026rdquo;.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinally, we assessed the relationship between serum transaminase levels and fatigue symptoms in 164 patients from whom blood samples were selectively collected. Interestingly, the correlation between fatigue symptoms and serum alanine aminotransferase (ALT) levels was shown using a chi-square test, although aspartate aminotransferase (AST) levels showed no significant difference (Table\u0026nbsp;5). Because liver damage may occur during COVID-19 progression, regardless of preexisting liver disease, our finding is consistent with that of a previous study \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Namely, increased serum transaminase levels, especially ALT, may provide a convenient indication of fatigue.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this study is the first to focus on the nature of long COVID-related symptoms and highlight the recovery period of systemic manifestations with prolonged risk factors. As shown in Table\u0026nbsp;1, sampling of participants in this analysis ensures the validity of this work without any potential problems regarding selection bias. Consistent with previous studies, our data revealed that fatigue and respiratory symptoms are the two leading complaints at almost the same level \u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFirst, our data showed that long COVID has a dynamic nature of changeable manifestations throughout the clinical course in the majority of patients (Table\u0026nbsp;3), given the depressing impression that the clinical condition continuously improves and worsens over time, and the condition feels permanent.\u003c/p\u003e \u003cp\u003eNext, we assessed the therapeutic efficacy for each long COVID-related symptom. Strikingly, the effect of inhaled budesonide on pulmonary symptoms of long COVID contributes substantially to good recovery without any adverse events (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Regardless of our data, the use of herbal drugs also depends on the management of long COVID-related manifestations, especially dysautonomia, among the limited therapeutic options (Table\u0026nbsp;6). As these treatments mainly relieve symptoms rather than cure the disease, herbaceous medications would be a key treatment for this unexplained disease, similar to menopausal syndrome. Our physicians always have difficulty treating brain fog and dysgeusia due to the lack of definitive treatments. Although the efficacy has not been confirmed, we actively recommend that patients with brain fog use some brain-stimulating smartphone applications. 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 structure changes with larger cognitive decline in 785 UK Biobank participants \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. However, challenges undoubtedly remain in this area. Similar to an existing study, hair loss occurred as a late-onset symptom, especially in females \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. This sex difference (data not shown) is probably because women usually have longer hair than men, easily attracting attention to their hair condition.\u003c/p\u003e \u003cp\u003eNext, independent risk factors affecting the recovery period from long COVID were evaluated by stratifying patients according to COVID-19 severity, the number of chief complaints and the duration from onset of COVID-19 to therapeutic intervention for long COVID. All of these factors exert a clinical effect on the recovery period of long COVID (Table\u0026nbsp;3), although the mechanism underlying their effects has not yet been elucidated. Our data suggested that patients with moderate or severe COVID-19 should receive more care for some persistent symptoms, and multiple complaints at long COVID onset are also an unwelcome sign, although the early onset of appropriate treatment might lead to better outcomes of COVID-19 and long COVID.\u003c/p\u003e \u003cp\u003eThen, a smoking habit was an independent risk factor for slowing the duration of recovery from long COVID (Table\u0026nbsp;4), suggesting a need for increased attention to smoking in the whole clinical course of COVID-19. On the other hand, sex (female), older age and the presence of comorbidities were not independent risk factors for prolonged recovery in the analysis (Table\u0026nbsp;4), although several previous studies presented their negative effects on COVID-19 \u003csup\u003e10,12,19,27,31\u0026minus;34\u003c/sup\u003e. Of course, this finding must be confirmed in further studies; however, a prominent result was that smoking exerts a crucial effect on these infectious problems.\u003c/p\u003e \u003cp\u003eFinally, we found out the significant relationship between increased serum transaminase, especially ALT and fatigue symptom in long COVID (Table\u0026nbsp;5). It was an unsurprising result based on a previous report \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, however ALT level was the only significant abnormal value in blood test of patients with long COVID in the analysis.\u003c/p\u003e \u003cp\u003eTaken together, we summarized the features of the changeable clinical course and proposed specific therapeutic options such as using inhaled budesonide and appropriate herbaceous medications with a clearer futuristic overview of long COVID in this study. However, this study has some possible limitations.\u003c/p\u003e \u003cp\u003eFirst, as the features of long COVID vary based on the variant, our data did not include the most recent COVID-19 variant, \u0026ldquo;Omicron\u0026rdquo;. We should always be conscious of the emergence of new variants and adjust to manage them accordingly. Second, the limited sample size and a single study site of the study participants would be potential source of selection bias. Further comprehensive investigations in larger populations will be required to fully understand the clinical profiles of long COVID. Finally, this study did not assess the effect of vaccination, which is a potential confounding factor for long COVID, to prevent an increasingly complex analysis, although a recent study showed the effect of vaccination on changes in symptoms in patients with long COVID \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eToday, we often hear that COVID-19 is just a cold. However, COVID-19 and a common cold or flu are different diseases based on their sequelae; therefore, COVID-19 should be treated as a separate disease that may reduce quality of life for patients, resulting in a decrease in social productivity. Regarding solutions for long COVID, wider recognition and continuous educational activities are equally essential as the elucidation of the pathological mechanism. We would be honoured if our study provides some help to unravel the mechanism of this unexplained disease and meet the unmet medical needs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cb\u003eStudy design and population.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTwo hundred eighty-six patients with previously confirmed SARS-CoV-2 infection by PCR or antigen testing who were diagnosed with long COVID at our clinic between May 2021 and December 2021 were potentially eligible for inclusion in this study.\u003c/p\u003e \u003cp\u003eClinical data, such as age, sex, BMI, and COVID-19 onset, PCR-positive date, consultation day and laboratory data, including AST and ALT levels, of the selected patients were collected and summarized in our database designed for this study. In addition, medical histories of diabetes mellitus, hypertension, hyperlipidaemia, migraine, bronchial asthma, sleep apnoea syndrome, and other conditions, as well as a history of smoking were similarly recorded based on self-reported information. For the evaluation of therapeutic efficacy, 29 censored patients were excluded from the analysis. A summary of the data collected from the study patients is presented in Table\u0026nbsp;1. The study protocol was approved by the ethics committee of UnMed Clinic Motomachi, Kanagawa, Japan (authorization number: UM22-01). The review board approved and waived the need for written informed consent from the participants due to the retrospective, noninterventional nature of this study. We have read the Declaration of Helsinki and have followed the recommended guidelines in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTherapeutic interventions for long COVID-related symptoms.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eBecause herbaceous medications are generally agents that easily ameliorate a variety of systemic symptoms, including dysautonomia, they are actively administered to most patients, depending on the manifestations.\u003c/p\u003e \u003cp\u003eTherapeutic options for long COVID-related symptoms in our clinic are listed in Table\u0026nbsp;6. As previously reported, hochuekkito, juzentaihoto and ninjinyoeito were administered for fatigue, and kakkonto and/or acetaminophen were administered for fever, headache/joint pain, along with some other herbal drugs \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. For smell disorder, tokishakuyakusan was prescribed according to the clinical and basic evidence of its effectiveness for olfactory dysfunction \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. In addition, rikkunshito, bukuryoingohangekobokuto and hangeshashinto with a proton pump inhibitor, as an acid suppressant, and/or a dopamine-2 receptor antagonist were appropriately administered for digestive manifestations, such as nausea, stomachache, abdominal fullness, diarrhoea, constipation \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Based on the good results of a recent clinical trial in the UK, inhaled budesonide was actively used for pulmonary symptoms including cough, sore throat, sputum, dyspnoea, chest pain with kikyoto, carbocysteine and ambroxol hydrochloride \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. For sleep disturbance, eszopiclone and/or lemborexant, which are independent sleep aids, were palliatively introduced as needed. As a Japanese study previously successfully managed alopecia using saikokaryukotsuboreito, this herbal drug was also selected to treat alopecia in the present study \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Last, betahistine mesilate and ryokeijyutsukanto were used to relieve dizziness symptom. We were unable to provide appropriate care for brain fog or dysgeusia.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOutcomes.\u003c/b\u003e \u003c/p\u003e \u003cp\u003ePrimary outcomes were the clinical course with a futuristic overview, evaluation of the effectiveness of treatment for each manifestation and risk factors affecting the recovery period of long COVID. Fatigue, smell disturbance, fever, headache/arthralgia, respiratory manifestations, 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 4 groups: good (within a month or less), moderate (within two months), slow (within three months) and resistance (3 months or more). Clinical outcomes were measured at more than 3 months of follow-up, depending on the condition. The secondary outcome was the relationship between serum transaminase levels and fatigue determined by measuring blood samples from 164 selected patients.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis.\u003c/h2\u003e \u003cp\u003eDemographic and clinical data were extracted from electronic medical records. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). The chi-square test was used to compare distributions of categorical variables. Significant levels were set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. In the comparison of improvement of complaints after treatment, Bonferroni adjustment was conducted for each test separately to consider the number of significance tests undertaken.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSARS-CoV-2 Severe acute respiratory syndrome coronavirus 2\u003c/p\u003e\n\u003cp\u003eBMI Body mass index\u003c/p\u003e\n\u003cp\u003eAST Aspartate aminotransferase \u003c/p\u003e\n\u003cp\u003eALT Alanine aminotransferase\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eContributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKT, MS, MK, and SK conceived the study. KT and MK collected the qualitative data. MS analysed the data. KT wrote the first draft of the manuscript. MS and MK reviewed and provided intellectual\u0026nbsp;input\u0026nbsp;on the draft and contributed to the writing of the manuscript. SK revised the manuscript based on input from MS and MK. All authors reviewed and approved the final version of the manuscript.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThe authors have not received a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData accessibility statement\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData are available upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCarf\u0026igrave;, A., Bernabei, R. \u0026amp; Landi, F. 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Medicine (Baltimore) \u003cb\u003e100\u003c/b\u003e, e26084, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/md.0000000000026084\u003c/span\u003e\u003cspan address=\"10.1097/md.0000000000026084\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"long COVID, recovery period, persistent symptoms, multisystem disorder, herbaceous medication","lastPublishedDoi":"10.21203/rs.3.rs-1548863/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1548863/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTo characterize the clinical features of long COVID, 286 patients who received care in our outpatient clinic for long COVID from May 2021 through 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 the initial phase, whereas hair loss was a major complaint in the late phase, suggesting that the chief complaint of patients with long COVID may vary temporally. The best treatment outcome was observed for pulmonary symptoms, and hair loss had the worst outcome. COVID-19 severity, the number of manifestations and delay in starting treatment exerted a negative effect on the recovery period of long COVID. In addition, a smoking habit was an independent risk factor for slowing the recovery period from long COVID. This study provides insights into the clinical course of each manifestation and therapeutic options with a futuristic overview of long COVID to meet the unmet medical needs.\u003c/p\u003e","manuscriptTitle":"Clinical features, therapeutic outcomes and recovery period of long COVID","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-20 17:03:38","doi":"10.21203/rs.3.rs-1548863/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6ceea5fe-a200-4c00-85b1-46d2b6e5960e","owner":[],"postedDate":"April 20th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-07-02T13:18:53+00:00","versionOfRecord":{"articleIdentity":"rs-1548863","link":"https://doi.org/10.1002/jmv.28316","journal":{"identity":"journal-of-medical-virology","isVorOnly":true,"title":"Journal of Medical Virology"},"publishedOn":"2022-12-02 13:18:53","publishedOnDateReadable":"December 2nd, 2022"},"versionCreatedAt":"2022-04-20 17:03:38","video":"","vorDoi":"10.1002/jmv.28316","vorDoiUrl":"https://doi.org/10.1002/jmv.28316","workflowStages":[]},"version":"v1","identity":"rs-1548863","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1548863","identity":"rs-1548863","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}