Shortly after the first wave of the COVID-19 pandemic, we began to observe that some
patients had persistent symptoms after recovery from the acute infection. These clinical
manifestations could constitute a new post-infectious syndrome, similar to what occurs
in other infections such as those caused by Epstein-Bar, Coxiella burnetti or Lyme
disease.
1
At present it is difficult to distinguish whether these symptoms are related to the
virus itself, to indirect effects of the disease or to the impact of the pandemic
situation. The term #LongCOVID was proposed as a Twitter hashtag in May 2020 by affected
patient groups to define this condition.
Regardless of their relationship to SARS-CoV-2, direct or otherwise, these disorders
have a medium- and long-term health impact. Reports in our country show that only
40% of patients have returned to work 2–3 months after infection.
2
Population-based studies in the United States comparing cohorts of patients hospitalized
for COVID-19 with patients hospitalized for other causes (including cohorts with viral
infections), demonstrate a greater need for subsequent medical care,
3
and even an increase in the frequency of hospital readmission and mortality.
4
With more than 177 million people infected by SARS-CoV-2 worldwide
5
-some 4.5 million in Spain-, even with conservative incidences of these clinical disorders
of 10–20%, we estimate that it could affect some 450,000–900,000 people in our country,
a relevant health problem that requires a response both in scientific and healthcare
terms.
In our opinion, the available evidence is so heterogeneous that its interpretation
is very difficult. With more than 18,000 publications and 22 meta-analyzes,
6
different terms are exchanged in the literature, such as long-COVID, post-acute COVID-19
syndrome or post-COVID conditions, with the absence of a standardized definition,
which implies the inclusion of different clinical features.
In an attempt to standardize terms, CDC and WHO propose the generic use of “post-COVID
conditions” as a broad umbrella for the health consequences that persist 4 weeks after
the acute infection.5, 7 In contrast, the UK National Institute for Health and Care
Excellence (NICE)
8
proposes the term “long-COVID” as an operational definition, which encompasses persistent
symptoms 4 weeks after acute infection in the absence of an alternative aetiological
diagnosis. This term would include the “ongoing symptomatic COVID-19” for signs and
symptoms between 4 and 12 weeks after the acute infection and “post-COVID syndrome”
for persistence of more than 12 weeks.
This definition contributes two relevant points. First of all, the duration of symptoms
of 12 weeks after infection to establish the diagnosis of post-COVID syndrome. In
our experience and in line with the literature, the persistence of symptoms in the
first 4–8 weeks after infection is common and multifactorial, with a tendency to progressive
resolution, so that, although arbitrarily established, the time frame of 12 weeks
allows to outline a more differentiated and COVID-19-related clinical picture. The
second point of interest in this definition is the inclusion of “no alternative diagnosis”.
After COVID-19, the signs and symptoms that these patients manifest, even if they
are new-onset, may be related to other processes, either independent or triggered
by the infection. Identifying these “alternative diagnoses” is essential for the characterisation
of the post-COVID syndrome symptomatology and for the development of the care and
treatment approach.
From a practical point of view, these post-COVID clinical manifestations could be
grouped into the following categories:
1
Sequelae: consequence of established organ damage following acute disease. Thrombotic,
psychiatric, neurological, pulmonary, cardiac, renal and reproductive events are the
most common.9, 10 These manifestations would probably not belong to a post-infectious
syndrome as such, since they reflect an established organ damage related to the pathophysiology
of the acute infection.
2
Derived from the hospitalisation itself, and which would be common with other diseases,
such as post-ICU syndrome, or secondary to prolonged hospitalisation, among which
neuromuscular involvement, fatigue, cognitive or psychiatric disorders stand out.
It is important to point out that isolation measures and the restriction of visits
in this disease can have a greater impact than conventional hospitalization.
3
Decompensation of previous chronic diseases.
4
Onset of a new disease, COVID-19 infection could act as a trigger for other diseases,
whether autoimmune, metabolic or psychiatric.
5
Pharmacological toxicity: although little reported in the literature, it is important
to consider the effects of treatments administered during hospitalisation.
Clinical manifestations that cannot be grouped into these categories and that persist
over time would constitute the “post-COVID syndrome” as a post-infectious syndrome
per se. Defining this symptomatology with the data from the published series is complex,
given that only one third of them include a face-to-face clinical interview, and the
type of assessment performed on patients is very different.
The most common symptomatology, reported by WHO and CDC,5, 7 includes fatigue as the
most characteristic symptom (present in 60–70%), defined as intense tiredness that
interferes with activities of daily living. Of unknown pathophysiology, it has been
compared with myalgic encephalomyelitis or chronic fatigue syndrome. Dyspnoea, with
oximetry, radiological examination and normal respiratory function, frequently associated
with cough and nonspecific chest pain, is characteristic and prolonged over time.
Regarding the neurocognitive area, there is a decrease in the ability to concentrate
(brain fog), memory alterations, headache and persistence of ageusia and anosmia.
Anxiety and depressive symptoms, as well as sleep disturbances, are very common. Other
manifestations are hair loss, arthralgia, myalgia, tachycardia, or gastrointestinal
rhythm disturbances, although more than 50 different symptoms have been described.10,
11, 12, 13
Any patient can develop long COVID, regardless of the severity of the initial infection,
even asymptomatic patients. Although the series are contradictory,
14
it appears that the severity of acute infection may increase the risk. The overlap
of symptoms and the definitions used may explain these discrepancies. Age does not
seem to be a risk factor, but gender does, with a prevalence of women. The association
with co-morbidity, which may act as a confounding factor in the interpretation of
symptoms, is unclear.
15
The influence of new viral variants or vaccination on the incidence, characteristics
or duration of post-COVID syndrome is not determined.
In terms of incidence, our experience shows that approximately half of the nearly
300 patients hospitalised for COVID-19 and systematically evaluated (with clinical,
laboratory, radiological and respiratory function tests), 12–14 weeks after infection
had some of these symptoms, generally mild, but interfering with quality of life.
10
The incidence published in the literature is highly variable and influenced by the
great heterogeneity of the series, making the value of published meta-analyses questionable
6
: from 60 to 80% have been described at 8 weeks after infection16, 17 and from 40
to 50% at 10–14 weeks.18, 19 Recently, a large prospective cohort of more than 1200
patients described the presence of some symptoms in more than 68% and 49% of patients
at 6 and 12 months, respectively.
20
At present there is no clear-cut idea of the prognosis. Some studies report progressive
symptom improvement at follow-ups extended to one year, although with some fluctuating
symptoms.
20
Optimal and systematic management of patients at this time is unclear. Clinical trials
examining medium and long-term results are advisable. Trivialisation by professionals
(medical gaslighting) of these “medically unexplained symptoms” should be avoided,
as it can lead to frustration and loss of trust in the health system by patients.
A comprehensive clinical evaluation, avoiding unnecessary ancillary examinations,
and realistic information to patients can help to minimize this problem. The creation
of support groups and social connection can be useful for the care of these patients.
In the light of the available evidence, and pending the results of future systematised
studies, a reasonable and efficient approach to the challenge that these post-COVID
disorders pose to our national health system should be based on:
1
Establish coordinated clinical pathways in the health system, with integration of
primary care and specialised hospital care resources and the creation of a hospital-based
monographic COVID clinic. Patients with prolonged hospital admission or with suspected
sequelae at discharge would be systematically evaluated in the COVID clinic, with
a follow-up adapted to the needs of each case. Hospitalised patients with no suspected
sequelae but with moderate to severe involvement would be assessed by telephone using
a structured questionnaire 12 weeks after infection; in case of persistent symptoms,
a protocol-based assessment in primary care would be indicated. Based on this assessment,
the patterns for referral to the COVID clinic (either in person or online) or follow-up
in primary care can be agreed upon. Finally, for patients without initial hospital
admission, an evaluation would be carried out in primary care at the request of the
patient.
Coordination between primary care and specialised hospital care, as well as the incorporation
of telemedicine, would allow for efficient care with optimisation of resources.
2
Training of professionals that allows updating the knowledge generated, agreeing on
common clinical protocols and coordinating the different levels of care.
3
Information to patients about post-COVID scenarios. It should include both the description
of the most common symptoms, the warning symptoms or medical consultation, general
measures for symptom control, realistic goals in relation to the prognosis and the
gradual return to an active employment situation.
In terms of prevention, vaccination promotion campaigns could include messages indicating
that preventing COVID-19 also prevents subsequent persistent symptoms with potential
long-term health effects.
21
In conclusion, post-COVID syndrome is a relevant health problem that requires a global
response from society in terms of research, health management and information.
Investment in research, both basic and clinical, with the creation of large inter-hospital
cohorts, as has been done with HIV infection, is a cornerstone. The PHOSP-COVID cohort
22
has been established in the UK and is currently monitoring more than 10,000 patients
after COVID infection. In this sense, the generous involvement of scientific societies
is very important. Simultaneously, an increase in health resources is needed, with
adequate management of these in order to optimise them, guaranteeing the appropriate
care for the population. Dissemination of reliable information to patients and the
population at large that combats the negative effects of misinformation should be
encouraged.
Let us ensure that the aftermath of COVID-19 does not become the “brain fog” of our
national health system in the next decade.
Funding
VII Call for Grants Supporting and Promoting Health Research in Alicante (ISABIAL),
2020.
Conflict of interests
The authors declare no conflicts of interest.