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      Long COVID: current definition

      letter

      , 1 , 2

      Infection

      Springer Berlin Heidelberg

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          Abstract

          Dear Editor We have read with great interest the recent scoping review published in Infection journal by Akbarialiabad et al. [1]. This review covers relevant topics of long COVID such as definition, diagnosis, and treatment. The term long COVID is generally used for describing the presence of symptoms far longer than it would be expected after recovered from SARSCoV-2 infection whereas the term “long-hauler” is proposed for individuals suffering from long COVID. These authors concluded that controversies in long COVID definition impaired proper recognition and management of this condition [1]. In this letter to the Editor, we want to complement the current scoping review based on two integrative models proposed by our research group not included in Akbarialiabad et al. review [1]. Evidence has shown an unprecedent number of studies describing the presence of post-COVID symptoms. These studies have led to different meta-analyses reporting that around 60% of COVID-19 survivors will develop at least one post-COVID symptom after the infection. Some relevant points should be considered from current published meta-analyses: (1) they pooled prevalence rate of post-COVID symptoms without considering the follow-up period after infection (a total prevalence); (2) they also pooled prevalence rates without differentiating hospitalized from non-hospitalized patients; and (3) most of the included studies had follow-up periods ranging from 3 to 12 weeks after the infection. It is currently known that post-COVID symptomatology is highly heterogeneous and more complex than expected, situation which could explain why no consensus in long COVID definition is yet available. Different authors have discussed aspects such as the needed or not of previous positive COVID-19 diagnosis [2] or specific timelines needed for considering symptoms as post-acute or chronic [3]. In a first model, Fernández-de-las-Peñas et al. defined four stages according to the period when a particular post-COVID symptom appears in relation to the acute phase of SARSCoV-2 infection: 1, potentially infection-related symptoms (up to 4–5 weeks after symptoms’ onset), acute post-COVID symptoms (from week 5 to week 12 after symptom’s onset), long post-COVID symptom (from week 12 to week 24 after), and persistent post-COVID symptoms (lasting more than 24 weeks after) [3]. This proposed timeline model integrates considerations appointed by several authors with the inclusion of terms such as post-acute or chronic post-COVID, and also differentiating between hospitalized/non-hospitalized patients or potential asymptomatic patients [3]. With current knowledge, we believe that persistent post-COVID and long-COVID are not appropriate terms to be used [3], and probably the term chronic post-COVID should be considered instead. A second model also proposed by Fernández-de-las-Peñas et al. [4] was centered on the type and nature of any particular post-COVID symptom. In this model, post-COVID symptoms were defined as exacerbated (when a patient suffered from a particular symptom before SARSCoV-2 infection and this symptom worsens after), delayed-onset (a new symptom not experienced by a patient at the acute phase of the infection but appears after a latency period) or persistent (a new symptom experienced by a patient at the acute phase of the infection which persists without pain-free or remission periods) [4]. This model is based on a fluctuating or relapsing nature of post-COVID symptoms. The fluctuating nature of post-COVID symptoms is supported by single studies and also by a meta-analysis showing a decreased prevalence of post-COVID symptoms 30 days after hospitalization/onset, a posterior increase 60 days after but with another decrease > 90 days after [5]. This “roller coaster” of post-COVID symptoms should be longitudinally monitored throughout weeks, months or years after the infection. To conclude this letter, we would like to propose the current long COVID definition considering the timeline when the symptoms appear and/or resolve [3] and the nature of the symptoms [4]: long COVID should be used for defining the presence, in general, of any post-COVID symptom after surpassing the SARSCoV-2 infection (THE condition), and it will consist of two stages: (1) post-acute sequelae of SARSCoV-2 infection” (PASC) or acute post-COVID (from week 5 to week 12 after symptom’s onset), and, (2) chronic post-COVID (lasting more than 12 weeks after). Further, the relapsing feature of post-COVID symptoms should be integrated in this updated definition since it will be relevant to determine the pattern (fluctuating or persisting) and nature (new-onset or exacerbated) of each particular symptom. Therefore, we propose the term long COVID for defining THE condition of suffering post-COVID symptomatology, and post-acute or chronic as the main stages of this fluctuating condition depending on the follow-up period where the symptoms appear.

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          Defining Post-COVID Symptoms (Post-Acute COVID, Long COVID, Persistent Post-COVID): An Integrative Classification

          The pandemic of the coronavirus disease 2019 (COVID-19) has provoked a second pandemic, the “long-haulers”, i.e., individuals presenting with post-COVID symptoms. We propose that to determine the presence of post-COVID symptoms, symptoms should appear after the diagnosis of SARS-CoV-2 infection; however, this situation has some problems due to the fact that not all people infected by SARS-CoV-2 receive such diagnosis. Based on relapsing/remitting nature of post-COVID symptoms, the following integrative classification is proposed: potentially infection related-symptoms (up to 4–5 weeks), acute post-COVID symptoms (from week 5 to week 12), long post-COVID symptoms (from week 12 to week 24), and persistent post-COVID symptoms (lasting more than 24 weeks). The most important topic is to establish the time reference points. The classification also integrates predisposing intrinsic and extrinsic factors and hospitalization data which could promote post-COVID symptoms. The plethora of symptoms affecting multiple systems exhibited by “long-haulers” suggests the presence of different underlying mechanisms.
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            Long COVID-19: Challenges in the diagnosis and proposed diagnostic criteria

            Reports from various parts of the world show that significant proportion of people who recovered from COVID-19 suffers from various health issues which are collectively called “long COVID-19” or post COVID-19 syndrome. The common symptoms include fatigue, breathlessness, cough, joint pain, chest pain, muscle aches, headaches and so on. Even though collectively called long COVID-19, researchers identified that it is a collection of at least 4 distinct clinical entities which are post-intensive care syndrome, post-viral fatigue syndrome, permanent organ damage, and long-term COVID-19 syndrome [1]. In our experience in addition to these we identified that drug related side effects, complications of COVID-19 (like pneumothorax, pneumomediastinum, vascular thrombosis leading to pulmonary thromboembolism, myocardial infarction, stroke etc), post-COVID-19 psychological issues and other infections (bacterial, other viral, fungal or re-infection with SARS-CoV-2 itself) can also cause similar symptoms in COVID-19 recovered patients. Careful evaluation to rule out causes unrelated to COVID-19 is important to offer correct treatment. In people infected with SARS-CoV-2, 80% of infections are mild or asymptomatic, 15% are severe infection and 5% are critical infections [2]. Usually in people with mild disease symptoms resolve within 2 weeks, where as in severe illness it may persist for 3–6 weeks [3]. Presence of long COVID-19 challenges the assumption that “mild” disease recover within 2 weeks [4]. There are lots of challenges in the diagnosis of long COVID-19. Those who had history of typical symptoms of acute COVID-19 with positive throat swab RT-PCR, presenting with long duration symptoms, the diagnosis of long COVID is straight forward. But those with acute COVID-19 symptoms and negative throat swab RT-PCR, presenting with long symptoms pose real challenge in day to day clinical practice. Significant proportions of SARS-CoV-2 infected individuals are asymptomatic. And development of long COVID-19 symptoms in those asymptomatic individuals adds to the diagnostic confusion. Similarly the duration of acute symptoms vary in patients again adding confusion to differentiate acute COVID-19 from long COVID-19. Based on our experience and after reviewing relevant literature, we are proposing criteria for the diagnosis of long COVID-19 (Table 1 ). Table 1 Proposed Diagnostic criteria for Long COVID-19. Table 1 Proposed Diagnostic criteria for Long COVID-19 A. ESSENTIAL CRITERIA (Evidence of preceding infection with SARS-CoV-2 within last 2–4 weeks) Symptomatic Confirmed Clinical features consistent with COVID-19, with positive throat swab RT-PCR Clinical features consistent with COVID-19, with negative throat swab RT- PCR, with positive antibody testing Probable Clinical features consistent with COVID-19, with negative throat swab RT-PCR and antibody testing, with CT thorax or chest X ray consistent with COVID-19 in presence of contact with confirmed or suspected case of COVID-19 within 2 weeks of onset of symptoms Clinical features consistent with COVID-19, with negative throat swab RT-PCR, antibody testing and negative CT thorax and chest X ray in presence of contact with confirmed or suspected case of COVID-19 within 2 weeks of onset of symptoms Possible Clinical features consistent with COVID-19, with negative throat swab RT-PCR and antibody testing, with CT thorax or chest X ray consistent with COVID-19 in the absence of contact with confirmed or suspected case of COVID-19 within 2 weeks of onset of symptoms, in the setting of community transmission Clinical features consistent with COVID-19, with negative throat swab RT-PCR, antibody testing and negative CT thorax and chest X ray in the absence of contact with confirmed or suspected case of COVID-19 within 2 weeks of onset of symptoms, in the setting of community transmission Doubtful Clinical features consistent with COVID-19, with negative throat swab RT-PCR, antibody testing and negative CT thorax and chest X ray in the absence of contact with confirmed or suspected case of COVID-19 within 2 weeks of onset of symptoms in the absence of community transmission Asymptomatic Confirmed Either positive throat swab RT-PCR or positive antibody testing or both Probable Negative throat swab RT-PCR and antibody testing with CT thorax, chest X ray consistent with COVID-19 in presence of contact with confirmed or suspected case of COVID-19 Possible Negative throat swab RT-PCR, antibody testing and negative CT thorax and chest X ray in presence of contact with confirmed or suspected case of COVID-19 Doubtful Negative throat swab RT-PCR, antibody testing and negative CT thorax and chest X ray in the absence of contact with confirmed or suspected case of COVID-19 in the setting of community transmission B.CLINICAL CRITERIA Symptoms of Long COVID-19 Presence of symptoms (new or persistent) like fatigue, breathlessness, cough, joint pain, chest pain, muscle aches, headache and so on which could not be attributed to any other cause C.DURATION CRITERIA Duration In SARS-CoV-2 infected symptomatic individuals, presence of symptoms More than 2 weeks in mild diseaseMore than 4 weeks in moderate/severe illnessMore than 6 weeks in critical illness In SARS-CoV-2 infected asymptomatic individuals, presence of symptoms Appearance of symptoms after 2 weeks of RT-PCR positivityAppearance of symptoms after 1 weeks of antibody positivityAppearance of symptoms after 2 weeks of positive CT thorax or chest X rayAppearance of symptoms after 2 weeks after contact with suspected or positive case of COVID-19Anytime in doubtful cases (Note: Those who did not undergo throat swab RT-PCR or antibody testing also considered as test negative). Clinical criteria (symptoms of Long COVID-19) after defined time period in presence of essential criteria (evidence of preceding SARS-CoV-2 infection) helps to categorise long COVID-19 as confirmed, probable, possible or doubtful long COVID-19 syndrome (Table 2 ). Table 2 Proposed Diagnostic criteria for Long COVID-19. Table 2 Clinical category Clinical features Throat swab RT-PCR SARS-CoV-2 antibody Chest X ray/CT thorax History of contact with confirmed/suspected case of COVID-19 Community spread Clinical status of previous SARS-CoV-2 infection Long COVID-19 symptom duration Symptomatic + + ± ± ± ± Confirmed More than 2 weeks in mild diseaseMore than 4 weeks in moderate/severe illnessMore than 6 weeks in critical illness + - + ± ± ± + - - + + ± Probable + - - - + ± + - - + - + Possible + - - - - + + - - - - - Doubtful Asymptomatic - + ± ± ± ± Confirmed Appearance of symptoms after 2 weeks of positive RT-PCR or 1 week of positive antibody testing - - + ± ± ± - - - + + ± Probable Appearance of symptoms after 2 weeks of positive result or contact - - - - + ± Possible Appearance of symptoms after 2 weeks of contact with positive case - - - - - + Doubtful Anytime
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              Prevalence of Post-COVID-19 Symptoms in Hospitalized and Non-Hospitalized COVID-19 Survivors: A Systematic Review and Meta-Analysis

              Background : Single studies support the presence of several post-COVID-19 symptoms; however, no meta-analysis differentiating hospitalized and non-hospitalized patients has been published to date. This meta-analysis analyzes the prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized patients recovered from COVID-19 . Methods : MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were searched up to March 15, 2021. Peer-reviewed studies or preprints reporting data on post-COVID-19 symptoms collected by personal, telephonic or electronic interview were included. Methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. We used a random-effects models for meta-analytical pooled prevalence of each post-COVID-19 symptom, and I² statistics for heterogeneity. Data synthesis was categorized at 30days, 60days, and ≥90 days after . Results : From 15,577 studies identified, 29 peer-reviewed studies and 4 preprints met inclusion criteria. The sample included 15,244 hospitalized and 9,011 non-hospitalized patients. The methodological quality of most studies was fair. The results showed that 63.2%, 71.9% and 45.9% of the sample exhibited ≥one post-COVID-19 symptom at 30, 60, or ≥90days after onset/hospitalization. Fatigue and dyspnea were the most prevalent symptoms with a pooled prevalence ranging from 35% to 60% depending on the follow-up. Other post-COVID-19 symptoms included cough (20-25%), anosmia (10-20%), ageusia (15-20%) or joint pain (15-20%). Time trend analysis revealed a decreased prevalence 30days after with an increase after 60days . Conclusion : This meta-analysis shows that post-COVID-19 symptoms are present in more than 60% of patients infected by SARS-CoV‑2. Fatigue and dyspnea were the most prevalent post-COVID-19 symptoms, particularly 60 and ≥90 days after.
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                Author and article information

                Contributors
                cesar.fernandez@urjc.es
                Journal
                Infection
                Infection
                Infection
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0300-8126
                1439-0973
                14 September 2021
                : 1-2
                Affiliations
                [1 ]GRID grid.28479.30, ISNI 0000 0001 2206 5938, Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, , Universidad Rey Juan Carlos (URJC), ; Móstoles, Madrid Spain
                [2 ]GRID grid.28479.30, ISNI 0000 0001 2206 5938, Facultad de Ciencias de La Salud, , Universidad Rey Juan Carlos, ; Avenida de Atenas s/n, 28922 Alcorcón, Madrid Spain
                Article
                1696
                10.1007/s15010-021-01696-5
                8438555
                34519974
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                Correspondence

                Infectious disease & Microbiology

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