Le Infezioni in Medicina, n.

1, 22-29, 2022
doi: 10.53854/liim-3001-3

22 REVIEWS

Long COVID-19 syndrome as a fourth

phase of SARS-CoV-2 infection
Silvia Staffolani, Valentina Iencinella, Matteo Cimatti, Marcello Tavio
Gastroenterological and Transplant Department, S.O.D. Malattie Infettive Emergenti
e degli Immunodepressi, University Hospital “Ospedali Riuniti”, Ancona, Italy

Received 11 February 2022, accepted 22 February 2022

SUMMARY
The SARS-CoV-2 pandemic has affected in the last two high, even if it occurs only in a part of the subjects who
years a large number of subjects, with a high cost in had COVID-19. Therefore, long COVID constitutes
terms of morbidity and mortality. The scientific com- now a major health issue and has to be managed in
munity made progress in understanding risk factors, order to ensure an adequate access to care for all the
pathophysiology, clinical manifestations, diagnosis people that need it.
and treatment of acute SARS-CoV-2 infection. In the “Post COVID” clinics have been created in various
last months, another condition has become evident countries, especially in Europe, for the management of
and caught the attention of the scientific community: people affected by long COVID syndrome. Guidelines
the so-called long COVID syndrome. The pathophysi- have been written to help clinicians. An important role
ology of this condition is not known, even if some hy- in the management of long COVID patients is played
pothesis have been made but not demonstrated yet. by the general practitioner, directly or indirectly linked
Long COVID is characterized by a very heterogeneous to post COVID hospital clinics. The extreme heteroge-
group of subacute and/or chronic symptoms and neity of clinical presentation needs a patient-tailored,
signs that follow the acute phase of SARS-CoV-2 infec- multidisciplinary approach. As NHS guidelines say,
tion and have a very variable duration. The presence the three principal of care for long COVID patients are
of this syndrome in an individual is not dependent personalized care, multidisciplinary support and reha-
from the severity of the acute SARS-CoV-2 infection. bilitation.
Because of the extreme clinical heterogeneity, and also More studies are needed in order to know better the
due to the lack of a shared and specific definition of the pathophysiology of the disease. It is also necessary to
disease, it is very difficult to know the real prevalence create standardized and shared definitions of the dis-
and incidence of this condition. Some risk factors for ease, in order to better understand the epidemiology,
the development of the disease have been identified: the diagnostic criteria and to offer the right treatment
advanced age, elevated body mass index, comorbidi- to all the individuals who need it, without social or
ties, specific symptoms of acute COVID-19 (in particu- economic diffeences.
lar dyspnea), number of symptoms in the acute phase
and female sex. Keywords: Long COVID, post COVID, follow up, CO-
The number of individuals affected by long COVID is VID-19, SARS-CoV-2.

n INTRODUCTION yet. From a pathogenetic point of view, it has not

been convincingly demonstrated that SARS-CoV-2
T he mechanisms leading to the persistence of
symptoms in the absence of chronicization of
the infection, in COVID-19, have not been clarified
infection can become chronic. The set of symptoms
reported by numerous patients with previous
COVID-19, at a variable distance from the acute
infection and when the virus is no longer found
in respiratory secretions, fall within the scope of
Corresponding author post-viral syndromes. These type of syndromes
Marcello Tavio have been studied in the infectious field especially
E-mail: marcello.tavio@ospedaliriuniti.marche.it months after Epstein Barr Virus and Cytomegalo-
 Long COVID-19 syndrome 23

virus infections, viruses which however integrate ized for COVID19 reporting symptoms compat-
into the genetic heritage of target cells. ible with Long-COVID syndrome is variable:
Another debated issue is the classification of from 2% of patients 12 weeks after symptoms
“long COVID”. This definition has been used in onset, to 35% 3 weeks after testing and 52% 10
multiple ways across the literature. Greenhalgh et weeks after the onset of symptoms [3-8]. Regard-
al. use the terms ‘post-acute COVID-19’ (from 3 to ing the patients hospitalized for COVID-19, a
12 weeks) and ‘chronic COVID-19’ for symptoms percentage varying between 32,6% and 87% re-
extending beyond 12 weeks [1]. NICE elaborated ports persistence of symptoms for 60 days after
a case definition at three levels [2]: discharge [9-11]. The symptoms most frequently
1) Acute COVID-19: signs and symptoms of CO- described, in order of frequency, are asthenia,
VID-19 for up to 4 weeks. dyspnea, arthralgia and chest pain. Long CO-
2) Ongoing symptomatic COVID-19: signs and VID symptoms seems particularly frequent in
symptoms of COVID-19 from 4 weeks up to 12 patients admitted in intensive care unit. Also the
weeks. paediatric population can develop long COVID
3) Post COVID-19 syndrome: signs and symp- syndrome. According to the scientific literature,
toms that develop during or after an infection a percentage between 4% and 66% has persis-
consistent with COVID-19, continue for more tence of symptoms between 4 and 20 weeks after
than 12 weeks and are not explained by an al- acute infection [12]. In conclusion, it is currently
ternative diagnosis. very difficult to estimate the population affected
In addition to the clinical case definitions, the by long COVID syndrome, both in the court of
term ‘long COVID’ is commonly used to describe patients hospitalized for COVID-19 and in the
signs and symptoms that continue or develop court of patients not hospitalized. The studies
after acute COVID-19. It includes both ongoing conducted are very heterogeneous in terms of di-
symptomatic COVID-19 (from 4 to 12 weeks) and agnostic definition, population, timing and type
post COVID-19 syndrome (12 weeks or more) of of follow-up.
the NICE classification [2].
We conducted a narrative review with the help
n PHYSIOPATHOLOGY
of the literature regarding the essential aspects of
the problem, with particular reference to the epi- The physiopathology of acute SARS-CoV2 has
demiological, clinical and therapeutic data cur- been studied and identified, but the exact reasons
rently available. For this purpose, we analyzed that lead to the persistence of symptoms has to
the available papers in PubMed and the principal be known yet (Figure 1). Some mechanisms have
Guidelines written about these topics. been proposed:
1) Sequelae of organ damage, extent of injury and
time to recovery of each organ system [13].
n EPIDEMIOLOGY
2) Persistence of chronic inflammation or autoan-
The lack of a shared and specific definition of long tibody generation [14, 15].
COVID syndrome makes it difficult to estimate 3) Persistence of virus into the body in people
its incidence and prevalence; according to some with altered immunity, re-infection or relapse
studies, the development of long COVID does not [16].
depend on the severity of the disease and the du- 4) Effect of hospitalization, complications related
ration of symptoms COVID-related [3]. to SARS-Cov2 infection or complications re-
The onset of the syndrome is independent from lated to co-morbidities or adverse effects of
hospitalization for COVID-19, although it is more medications used [17, 18].
frequent in the court of hospitalized patents. The 5) Deconditioning, psychological issues like
studies show variable results. According to some post-traumatic stress [19, 20].
authors, in the non-hospitalized population, 1 in 6) The social and financial impact of COVID-19
5 subjects reports symptoms compatible with also contributes to post COVID issues includ-
long COVID (eg. asthenia, cough and headache) ing psychological ones [7].
5 weeks after the initial infection [4]. For other Persistently elevated inflammatory markers could
studies, the percentage of subjects not hospital- indicate chronic persistence of inflammation [7].
24 S. Staffolani, V. Iencinella, M. Cimatti, et al.

Figure 1 - COVID-19 phases. Three phases has been described in COVID-19 pathophysiology. Phase 1, called “early
stage”, which has a predominant viral replication; it is typically asymptomatic or paucysymptomatic and is highly
contagious. Phase 2, called “pulmonary” phase, characterized by lung viral replication and beginning of possible
radiological findings; phase 3 or “hyperinflammatory phase” in which prevails the action of immune system ruled
by the “cytokine storm”. Recently a fourth phase is being described namely “long COVID” depicted by subacute
to chronic conditions and multiorgan involvement.

However, multiple mechanisms may contribute ed problems are worsened quality of life (44.1%),
to the onset of long COVID [7]. chest pain (21.7%), skin rashes, alopecia, palpita-
tions, loss of smell and taste, anorexia, abdominal
pain and diarrhea [7].
n SYMPTOMS
Researchers identified two main patterns of Respiratory system
symptoms in people with long COVID. The first The two most common symptoms are shortness of
pattern includes symptoms like fatigue, head- breath and dyspnea. In the study of Weerahandi et
ache and upper respiratory complaints (short- al. 74.3% of patients undergoing mechanical venti-
ness of breath, sore throat, persistent cough and lation manifest this type of symptoms. In this pop-
loss of smell). The second one includes systemic ulation, pulmonary fibrosis sequelae (PFS) are also
manifestations like fever and gastroenterological common due to the parenchymal stress produced
symptoms [7]. by mechanical ventilation [22]. Other radiological
abnormalities like bronchiectasis, pulmonary mi-
Generalized symptoms cronodules and pulmonary vascular disease are
The most common symptom is severe fatigue. still evident at radiological instrumental exams
This can be associated to other manifestations like performed 2 to 3 month post-discharge [7].
cervical and axillary lymphadenomegaly, head-
ache, myalgia and arthromyalgia, sore throat, Nervous system
hoarseness and unrefreshing sleep. Raman et al. The emergence of the COVID-19 pandemic has
reported a fatigue frequency of 55% using the Fa- raised many questions around the effects of SARS-
tigue Severity Scale [21]. Other commonly report- CoV-2 on mental health [23]. The increase in inci-
 Long COVID-19 syndrome 25

dence of COVID-19 has been associated with an bidities, asthma and more than five symptoms
increase in prevalence of major depressive disor- in acute phase [3, 28, 29]. Even subjects without
der and anxiety disorder. For both disorders, fe- these risk factors, however, can develop long CO-
males are affected more than males, and younger VID, and long COVID isn’t always related to the
age groups are affected more than older ones. In severity of acute illness [3]. Long COVID symp-
addition, in patients that have been affected by toms overlap with symptoms of other diseases.
COVID the prevalence of fatigue and generalized To date, long COVID is therefore diagnosed when
symptoms are higher than in the healthy popula- the symptoms presented do not have other medi-
tion [7]. Patel V. et al. found that during the CO- cal explanations [2, 3, 26].
VID-19 pandemic the suicide rate increased [23]. The diagnostic workout of the patient suffering
The researchers report other nervous symptoms from long COVID includes a thorough clinical
such as post-traumatic stress disorder following history: information about acute COVID-19 (sus-
severe illness, difficulty concentrating, worsen- pected or confirmed), the nature and severity of
ing of cognitive decline and insomnia/sleep dis- previous and current symptoms, timing and du-
turbance. Other symptoms like headache, “brain ration of symptoms since the start of acute CO-
fog”, vertigo, tremor and paraesthesia are also VID-19, history of other health conditions, exac-
described. Some authors even report the Guillain- erbation of pre-existing conditions [2, 28]. It is
Barré syndrome as a rare but possible complica- important to discriminate which symptoms really
tion of long COVID [24]. need more diagnostic studies, remembering that
some patients can develop psychological prob-
Cardiovascular system lems caused by unnecessary investigations. It is
The postural orthostatic tachycardia syndrome useful to refer to specialized centers patients with
(POTS) is the most common manifestation [25]. suspicion of specific diseases or with disabling
POTS is an autonomic disorder lasting for 6 symptoms, especially psychiatric ones. It is im-
months or more, diagnosed by an increased heart portant to consider possible overlapping with
rate of > 30 beats per minute within 5-10 min of post-traumatic stress syndrome.
standing or upright tilt without orthostatic hy- We report below the diagnostic exams suggested
potension. This increase in heart rate can cause by the majority of studies and guidelines, that
dizziness, palpitations, blurred vision, headache, should be carried out in the post COVID clinics
generalized weakness, exercise intolerance, etc. and services [2, 26, 27, 29]:
[25]. The possible etiologies include dysautono- – blood exams (full blood count, kidney and
mia, hypovolemia, hyperadrenergic stimulation, liver function tests, C-reactive protein, ferritin,
even psychological stress. Most of these clinical BNP, HbA1c and thyroid function tests);
manifestations involve female subjects and are – exercise tolerance tests: evaluate case-by-case
not associated with the severity of acute SARS- risk benefit ratio (e.g. patients with already
CoV2 infection [25]. Less common cardiovascular known cardio-pulmonary disease);
manifestations (usually related to already present – lying and standing blood pressure recording;
comorbidities) are myocardial infarction, myocar- – Chest X-ray by 12 weeks after acute COVID-19
ditis, pericarditis, arrhythmias, cardiac failure and if the person has continuing respiratory symp-
venous thromboembolism. toms. Normal plain chest X-ray does not rule
out lung disease.
Specific diagnostic tools or scores have not be as-
n DIAGNOSIS
sessed yet.
The diagnosis of long COVID is clinical and re- Physicians should be aware that symptoms are
quires a holistic and person-centered approach, as relapsing-remitting and can be absent at the mo-
well as multidisciplinary care [3, 26, 27]. Some au- ment of medical examination.
thors have identified risk factors that can lead to
the persistence of symptoms after acute infection,
n TREATMENT AND PATIENT MANAGEMENT
like older age, severity of acute phase (keeping in
mind that “long COVID” is different from “post- The long COVID and the nature of its symptoms, ex-
ICU syndrome”), obesity, female sex, comor- cept the management of urgent conditions, lead to
26 S. Staffolani, V. Iencinella, M. Cimatti, et al.

the need of a holistic assessment with an approach NHS guidelines propose 3 pathways for the man-
focused on self-management and rehabilitation (in agement of long COVID patients, depending on
NHS guidelines, the three principal of care for long the severity of the acute infection and on whether
COVID patients are personalized care, multidisci- the patient has been hospitalized [31]:
plinary support and rehabilitation, supporting and – People never admitted to hospital with their
enabling self care) [2]. In the last year, post COVID acute illness, but managed independently or
dedicated clinics and outpatient services have been in the community: in this case, the general
created, especially in Europe, in order to take care practitioner is the figure who conducts the
of individuals affected by long COVID. The clini- holistic assessment of the patient and plays
cian leading the long COVID dedicated services a connection role between the patient and
should be a medical doctor with relevant skills and the post COVID services if there is the need
experience, in order to deliver personalized care of further evaluation. This group of patients
and ways to self-manage the symptoms and collab- should have the possibility to access the post
orate with the appropriate specialist support [30]. COVID services like hospitalized ones, if
Beside these services, Authors consider the self- needed [31].
management care an important issue. A possible – People who needed hospitalization for CO-
start point for the patient is keeping a record of his VID-19 should undergo a 12-week post dis-
goals, setting on realistic ones, and of any recovery charge assessment, which include a chest X-
and changes in symptoms to plan a patient-based ray, review of symptoms and consideration
rehabilitation [2]. of further investigations and rehabilitation re-
A multidisciplinary team should tailor support quirements, if the X-ray chest results abnormal
and rehabilitation for the specific patient, includ- or other medical invalidating issues continue.
ing physical, psychological and psychiatric as- If the chest X-ray is normal and there are no
pects of management, and plan how often follow more symptoms, the patient can be discharged
up and monitoring are needed, which healthcare with follow up in community as needed. Some
professionals should be involved and whether people may need clinical evaluation before the
appointments should be carried out in person or scheduled 12 weeks. The timing is based on in-
remotely [2, 30]. The team should include experts dividual needs and is at the discretion of the as-
in treating fatigue, respiratory and other symp- sessing clinician. However, although recovery
toms (breathlessness, de-conditioning, dizziness), time is different for everyone, for many people
in occupational therapy and physiotherapy, in symptoms will resolve by 12 weeks [31].
clinical psychology and psychiatry and rehabilita- – The individuals cared for in an Intensive Care
tion medicine [2]. Speech and language therapists Unit (ICU) or High Dependency Unit setting
should support the rehabilitation of individuals should undergo a post ICU multidisciplinary
who manifested common clinical presentations of clinic reassessment at 4-6 weeks post dis-
post COVID syndrome, including cognitive dis- charge. If continuing to improve, they should
orders (for example brain fog), swallowing, voice be followed as the other hospitalized ones [31]
(included muscle tension dysphonia) and respira- (Figure 2).
tory difficulties. It is important to give the chance The frequency and duration of follow up is cur-
to re-enter rehabilitation services after being dis- rently not defined [2].
charged if symptoms worsen [2]. There is paucity of evidence about when to return
In post COVID clinics, the same healthcare pro- to normal activities. This decision should be pa-
fessional or team should provide continuity of tient-tailored, according to the subject occupation
care, as much as possible. Support groups, social and activities [24]. Some potential risks, including
prescribing, online forums and apps, as the ref- cardiac, pulmonary, and psychiatric, along with
erence clinician, could offer a source of advice the patient’s pre-illness baseline physical status
and support. Support should be offered to people and activities, have to be considered. Salman et al
about the return to education or work, suggesting recommended waiting at least a week after being
for example a phased return. For older people or asymptomatic to resume exercise. Moreover, the
people with complex needs, additional support first 2 weeks of exercise should be minimal exer-
should be considered [2, 30]. tion, with gradual progression. The self-monitor-
 Long COVID-19 syndrome 27

Figure 2 - Long COVID management. Patients affected by long COVID can be managed through three pathways,
depending on the severity of the acute SARS-CoV-2 infection. The main figures that lead the management of the
patients are the general practitioner and the leading physician belonging to the health care centres where the
patient has been hospitalized. If needed (abnormal radiological exams or persistence of symptoms after acute
infections), the patient accesses the post COVID services where a specific patient-tailored treatment is offered.

ing of the signs/symptoms and mood using a di- If patient has respiratory symptoms after 12 weeks
ary is highly recommended in all steps [32]. from acute infections, a chest x ray can be useful
[2]. Mayo clinic suggest the elimination of factors
Specific conditions: Pharmacological and that can exacerbate dyspnea (smoking, pollutants,
rehabilitation treatment extreme temperatures, exercise) [33]. Non-pharma-
Minor symptoms (cough, pain, myalgia): symp- cological strategies include also breathing exercises,
tomatic treatment with paracetamol, cough sup- pulmonary rehabilitation, and postural relief [29].
pressants and oral antibiotics (if secondary bac- Cardiovascular symptoms: Exercise tolerance
terial infection is suspected). Kratum (Mytragina tests for heart rate measuring, while blood pres-
speciosa) has been proposed for patients with sure and heart rate while standing and lying can
contraindications for non-steroidal anti-inflam- be measured if POTS is suspected [2]. ESC recom-
matory drugs [24]. Chest physiotherapy and neu- mends beta-blockers for tachycardia, others sug-
ro rehabilitation are important in patients with gest ivabradin for cardiovascular manifestation of
pulmonary and neuromuscular sequelae. Wors- long COVID [2, 34]. Myocarditis usually resolves
ening of underlying co-morbidities like diabetes, over time, but supportive or immunomodulating
hypertension and cardiovascular illness may oc- drugs can accelerate recovery in some cases [33].
cur in people after SARS-CoV-2 infection, requir- Some authors have also suggested the use of anti-
ing optimization of treatment [29]. coagulants to face the risk connected to the ongo-
Pulmonary symptoms: NICE recommends a mul- ing inflammation [35].
tidisciplinary approach [2]. Breathlessness can be Fatigue, cognitive and neuropsychiatric disor-
investigated with an exercise tolerance test (one- ders: NICE recommends self management and
minute sit and stand test or 6 minutes walking test). support to manage chronic fatigue, because no
28 S. Staffolani, V. Iencinella, M. Cimatti, et al.

specific pharmacologic treatment exists [2]. Cog- [2] National Institute for Health and Care Excellence
nitive behavioral treatment and graded exercise (NICE), Scottish Intercollegiate Guidelines Network
treatment have been suggested [36], but evidenc- (SIGN), Royal College of General Practitioners (RCGP).
es are lacking. Another possible treatment strat- COVID-19 rapid guideline: managing the long-term ef-
fects of COVID-19. NICE. 2022; 1.13.
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