Defining Post-COVID Symptoms (Post-Acute COVID, Long COVID, Persistent Post-COVID): An Integrative Classification. — TEI-tagged view

César Fernández-de-las-PeñaspersName, Domingo Palacios-CeñapersName, Víctor Gómez-MayordomopersName, María L. CuadradopersName, Lidiane L. FlorenciopersName (2021date). “Defining Post-COVID Symptoms (Post-Acute COVID, Long COVID, Persistent Post-COVID): An Integrative Classification..” International Journal of Environmental Research and Public Healthtitle·j.

Object of study — the definition, timeframeterm·key and classificationterm·key of post-COVID symptomsterm·key

Research question — when symptoms after SARS-CoV-2term·key infection should be called post-COVID

Contribution — an integrative, phase-based classificationterm·key of post-COVID symptomsterm·key that includes predisposing factors and hospitalizationterm·key

Full text — tagged

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Defining Post-COVID Symptomsterm·key (Post-Acute COVIDterm·dom, Long COVIDterm·dom, Persistent Post-COVID): An Integrative Classificationterm·key.

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

1. Should Post-COVID Symptomsterm·key Be Considered a New “Syndrometerm·key”?

In 2020, the world suffered the most dramatic and catastrophic experience of the last century due to the pandemic of the coronavirus disease 2019 (COVID-19term·key) caused by SARS-CoV-2term·key. In fact, there has been an unprecedented explosion of research in this area. However, a second pandemic has dramatically emerged, i.e., people suffering from symptoms after SARS-CoV-2term·key infection (“long-haulersterm·dom”) [ 1 ]. Since millions of people have been infected and more will continue to be infected, the number of “long-haulersterm·dom” is dramatically increasing [ 2 ]. Therefore, healthcare professionals and researchers need to identify, classify, and understand the sequelae of COVID-19term·key. Thus, the first step should be an agreement on the terminology [ 3 ]. This is a key issue since “long COVIDterm·dom” is considered the first illness term to have been collectively coined by patients themselves through social media [ 4 ]. This commentary presents three topics related to post-COVID symptomsterm·key, i.e., definition, timeframeterm·key, and syndrometerm·key [ 5 ], which need clarification, and proposes an integrative classificationterm·key for this potential new “syndrometerm·key”.

Although the literature on post-COVID symptomsterm·key is still in its earlier stages, “long-haulersterm·dom” report a plethora of symptoms affecting different systems: neurocognitive post-COVID (brain fog, dizziness, loss of attention, confusion), autonomic post-COVID (chest pain, tachycardia, palpitations), gastrointestinal post-COVID (diarrhea, abdominal pain, vomiting), respiratory post-COVID (general fatigue, dyspnea, cough, throat pain), musculoskeletal post-COVID (myalgias, arthralgias), psychological-related post-COVID (post-traumatic stress disorder, anxiety, depression, insomnia), and other manifestations (ageusia, anosmia, parosmia, skin rashes). In fact, most published studies to date on post-COVID symptomsterm·key have found that 50–70% of hospitalized patients exhibit several post-COVID symptomsterm·key up to 3 months after hospital discharge [ 6 , 7 , 8 , 9 , 10 , 11 ]. Data from non-hospitalized COVID-19term·key patients are scarce and reveal that 50–75% are symptom-free one month after symptom onset [ 12 , 13 ]. It would be expected that post-COVID symptomsterm·key will be different between hospitalized and non-hospitalized patients, but this assumption needs to be confirmed in future studies.

The British Medical Association defines a syndrometerm·key “as a set of medical signs and symptoms which are correlated with each other and associated with a particular disease [ 14 ]. Therefore, the first question arising from this discussion is: should this broad set of post-COVID symptomsterm·key be considered a new “syndrometerm·key”?

2. How Should Post-COVID Symptomsterm·key Be Defined?

“Long COVIDterm·dom” is a general term used for people who have recovered from COVID-19term·key but still exhibit symptoms for far longer than would be expected [ 15 ]. Another definition consists of “not recovering several weeks or months following the start of symptoms that were suggestive of COVID-19term·key, regardless individuals were tested or not” [ 16 ]. The Guideline published by the National Institute for Health and Care Excellenceterm·dom (NICEterm·dom), the Scottish Intercollegiate Guidelines Network, and the Royal College of General Practitioners has defined long COVIDterm·dom as “signs and symptoms developed during or following a disease consistent with COVID-19term·key and which continue for more than four weeks but they are not explained by alternative diagnoses” [ 17 ]. Therefore, the first question to discuss is as follows: is a positive test for SARS-CoV-2term·key or the presence of positive antibodies a prerequisite for the diagnosis? This subject has already been discussed by Raveendran, who proposed three long COVIDterm·dom categories [ 18 ]: Confirmed (positive diagnosis of SARS-CoV-2term·key with real-time reverse transcription-polymerase chain reaction [RT/PCR] and/or positive SARS-CoV-2term·key antibodies testing); Probable (symptoms consistent with COVID-19term·key, with negative RT-PCR and/or antibody test, with or without positive radiological signs but WITH contact with a confirmed/suspected case of COVID-19term·key the previous 2 weeks before the symptom onset); Possible (symptoms consistent with COVID-19term·key, with negative RT-PCR and/or antibody tests, with/without radiological signs but WITHOUT contact with a confirmed or suspected case of COVID-19term·key the previous 2 weeks before the onset of the symptoms) [ 18 ].

This author included two new actors into the equation: the presence of symptoms and the contact with a confirmed/suspected case of COVID-19term·key. Both seem to be conflicting, since almost 40–45% of people infected by the SARS-CoV-2term·key will be asymptomatic [ 19 ]. In addition, the plethora of symptoms produced by COVID-19term·key could also lead to confusion. For instance, the most common symptoms experienced by patients with COVID-19term·key, i.e., fever, fatigue, dyspnea, or productive cough [ 20 ], are also usually reported in other respiratory infections, e.g., community-acquired pneumonia [ 21 ]. Additionally, patients with COVID-19term·key also exhibit non-respiratory symptoms, e.g., neurological symptoms (i.e., headaches, anosmia or ageusia), gastrointestinal symptoms (i.e., diarrhea or vomiting) or dermatological disorders (i.e., hair loss, skin rashes) [ 22 ]. Therefore, “probable” and “possible” categories (based on symptoms “consistent” with COVID-19term·key) seem to be potentially broad and could include people suffering from respiratory infections but not COVID-19term·key. Similarly, the fact that a person has contact with a confirmed/suspected case of COVID-19term·key does not confirm that this individual will be infected, although it is clear that individuals who have unprotected contact with infectious subjects have a significant increase in symptoms [ 23 ]. Similarly, if a contact develops potential symptoms, those symptoms experienced by this subject (if they ever appear) could be a consequence of stress due to exposure and not just are due to SARS-CoV-2term·key infection.

Thus, we propose that determining the prevalence of post-COVID symptomsterm·key should be based on two main premises: 1, there should be a temporal relationship between the symptoms and COVID-19term·key; and 2, symptoms should appear after the SARS-CoV-2term·key infection (new post-COVID symptomsterm·key, not being previously present). These premises are highly important for future research since symptoms usually seen in “long-haulersterm·dom” can also be present in the general population which has been exposed to other infectious agents or to a catastrophic situation, like the current one, and be mostly related to lockdown, unemployment, anxiety, fear, social alarm, or others. Including these “possible” and “probable” cases in current research on post-COVID symptomsterm·key could add heterogeneity and uncertainty to these studies and thus obstruct the generation of future evidence and limit the utility of therapeutic trials. Hence, clinicians and researchers must ascertain if the symptoms are related (or not) to a potential SARS-CoV-2term·key infection [ 24 ]. Nevertheless, it is important to consider that all diagnostic procedures, including RT-PCR, COVID-19term·key antibody tests or radiological imaging, have limitations. For instance, radiological studies (CT scans) are more sensitive than RT-PCR, but they have low specificity [ 25 ]. Similarly, the sensitivity of antibody testing is also low during the first week from symptom onset, but it could be used as a complement to other diagnostic procedures [ 26 ].

Based on these premises, to determine if post-COVID symptomsterm·key are mainly caused by COVID-19term·key, they should appear after a positive diagnosis of SARS-CoV-2term·key infection (timeframeterm·key). However, a prevailing problem is that millions of people can also be infected by COVID-19term·key but never receive a positive COVID-19term·key diagnosis due to the sanitary situation at a particular time. The current challenge would be to identify those individuals developing potential post-COVID symptomsterm·key but without a positive diagnosis, i.e., what Raveendran denominated “probable” or “possible” long COVIDterm·dom [ 18 ].

3. Is There a Timeframeterm·key for Defining Post-COVID Symptomsterm·key?

One of the most important topics that should be clarified is the timeframeterm·key used for the definition of post-COVID symptomsterm·key. Baig proposed that symptoms presenting beyond 3 weeks after the SARS-CoV-2term·key infection should be considered prolonged or persistent [ 27 ]. Halpin et al. proposed the term post-acute COVIDterm·dom (symptoms beyond 3 weeks) and long post-COVID or persistent chronic post-COVID (symptoms beyond 12 weeks) [ 28 ]. The NICEterm·dom guideline proposes the following classificationterm·key: acute COVID-19term·key (symptoms for up to 4 weeks), ongoing symptomatic COVID (symptoms from 4 to 12 weeks), and post-COVID (symptoms developed during or after an infection and continuing for more than 12 weeks) [ 17 ]. In this guideline, the term “long COVIDterm·dom” would comprise both subgroups, ongoing symptomatic COVID and post-COVID syndrometerm·key [ 17 ]. In a subsequent analysis of the NICEterm·dom guideline, Sivan and Taylor proposed the unified definition of long COVIDterm·dom as “signs and symptoms that continue for more than four weeks and can be attributed to COVID-19term·key infection” [ 29 ].

In this equation, the main issue to consider is: once SARS-CoV-2term·key infection has been surpassed, when should symptoms experienced by a patient be called post-COVID? First, it should be noted that around 50% of individuals infected with SARS-CoV-2term·key will exhibit a myriad of symptoms during the infection, the most common being fever, cough, fatigue, dyspnea or cough [ 20 ]. Currently, an improvement of symptoms, particularly fever and respiratory manifestations, is usually considered the beginning of the end of the acute phase. It is commonly accepted that acute SARS-CoV-2term·key infection usually lasts 2–3 weeks, although this timeframeterm·key is mainly based on reports about the incubation period [ 30 ]. Therefore, the first question that researchers should answer is: when can we confirm that a patient has recovered/is free from SARS-CoV-2term·key infection and thus consider the presence of post-COVID symptomsterm·key? It has been found that SARS-CoV-2term·key is detectable up to 30 days after the resolution of symptoms in 10–15% of diagnosed individuals, but apparently without potential clinical relevance [ 31 ]. However, it has been proposed that this prolonged exposition to SARS-CoV-2term·key may be one of the underlying mechanisms of the post-COVID symptomsterm·key. In fact, current evidence supports the presence of psychologic and neuropsychic symptoms, e.g., anxiety, depression, or sleep disorders, in people who deal with COVID-19term·key patients, e.g., healthcare professionals, but also in the general population [ 32 , 33 , 34 , 35 ]. Therefore, some post-COVID-associated symptoms could also be related to the trauma caused by having contracted a potentially fatal infection. Nevertheless, no longitudinal study investigating the evolution of psychological aspects related to COVID-19term·key pandemic has been conducted to date. Finally, we should take into account the fact that 50% of individuals infected with SARS-CoV-2term·key will pass the infection without symptoms [ 19 ]. In this large proportion of COVID-19term·key patients, identification of the infection will be more difficult, and therefore, identifying the development of post-COVID symptomsterm·key will be a challenge. In such a scenario, international efforts by developing mobile phone software (e.g., Mawid, Tabaud, Tawakkalna, Sehha, Aarogya setu, TraceTogether, COVID safe, Immuni, or COVID watch) as methods of quick detection of contacts with COVID-19term·key patients could minimize the number of cases [ 36 ].

The second actor to consider is the relapsing/remitting nature of the symptoms since these individuals exhibit a wide range and fluctuations of post-COVID symptomsterm·key, with gradual improvement in some, but not in others. For instance, several patients can feel they have recovered from the acute infection, but then days or weeks later, they develop (suddenly or progressively) a plethora of symptoms that can be persisting.

4. Integrative Classificationterm·key for Defining Post-COVID Symptomsterm·key Based on the above considerations, we would like to propose the following classificationterm·key for post-COVID symptomsterm·key (pending of validation in future studies). This categorization should be taken as a dynamic and complex process that may integrate potential biological, psychological, and social factors which could predispose or promote the development of post-COVID symptomsterm·key. This classificationterm·key is also conditioned by whether a patient has required hospital admission or not.

Transition Phase: Symptoms potentially associated with acute COVID-19term·key: symptoms up to 4–5 weeks; Phase 1: Acute post-COVID symptomsterm·key: symptoms from week 5 to week 12; Phase 2: Long post-COVID symptomsterm·key: symptoms from week 12 to week 24; Phase 3: Persistent post-COVID symptomsterm·dom: symptoms lasting more than 24 weeks.

The figures graph the classificationterm·key proposed where the time reference point is different depending on whether we are speaking of non-hospitalized (onset of the symptoms, Figure 1 ), hospitalized (hospital discharge, Figure 2 ) or asymptomatic (only positive testing for COVID-19term·key, Figure 3 ) patients, and considering the presence of intrinsic (age, gender, pre-existing comorbidities, epigenetics) and extrinsic factors (biological, psychological, and social), but also hospital factors (days at hospital, Intensive Care Unit (ICU) admission or not, prolonged bedding, adverse events derived from interventions).

As can be seen, in the transition phase, symptoms should be cautiously interpreted as “potentially” related to the SARS-CoV-2term·key infection before being considered post-COVID symptomsterm·key. In order to increase the specificity of the definition of post-COVID symptomsterm·key, potential sequelae related to hospitalizationterm·key (i.e., prolonged bedding, ventilator related barotrauma, critical illness polyneuropathies, etc.) should be first ruled out before establishing the diagnosis. Thus, we also propose a transition phase after hospitalizationterm·key (4–5 weeks after discharge) as a “wash out” period to better define actually related acute post-COVID symptomsterm·key. The duration of this phase will depend on the hospitalizationterm·key time (days, weeks, months) and the “wash out” period.

In this integrative model, we also propose the distinction of “long” (from week 12 to week 24) and “persistent” (from week 24 on) in order to distinguish symptoms with a delayed but progressive improvement, from actual “persistent” symptoms which may have a protracted and refractory course, less probability of spontaneous resolution, and a higher necessity of a multidisciplinary approach.

All these interactions support the proposal of the review by the National Institute for Health Research (NIHR) [ 37 ], which has suggested that people experiencing long COVIDterm·dom may exhibit different syndromesterm·key, such as post-intensive care syndrometerm·key (equivalent to the acute post-COVID phase), post-viral fatigue syndrometerm·key (if fatigue is the predominant post-COVID symptomterm·key), permanent organ damage (an underlying mechanism explaining long-term symptoms), and long-term COVID syndrometerm·key (equivalent to long and persistent post-COVID phases) based on the premise that post-COVID symptomsterm·key range in intensity and duration and are not linear or sequential [ 38 ].

5. Conclusions This commentary proposes a definition of post-COVID symptomsterm·key when they appear after a confirmed diagnosis of SARS-CoV-2term·key infection; however, some exceptions can appear since not all people infected by SARS-CoV-2term·key receive a positive diagnosis. Based on the relapsing/remitting nature of post-COVID symptomsterm·key, we proposed an integrative classificationterm·key integrating potential intrinsic and extrinsic factors and hospitalizationterm·key data which could promote post-COVID symptomsterm·key. The most important topic is to establish the time reference points for defining persistent post-COVID symptomterm·dom. The current discussion should be considered in future studies.