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Diseases 2024, 12, 95. https://doi.org/10.3390/diseases12050095 www.mdpi.com/journal/diseases
Review
Long COVID in Children, Adults, and Vulnerable Populations:
A Comprehensive Overview for an Integrated Approach
Valeria Calcaterra 1,2, Sara Zanelli 2, Andrea Foppiani 3,4, Elvira Verduci 2,5, Beatrice Benai 6,7, Roberto Bollina 8,
Francesco Bombaci 9, Antonio Brucato 10, Selene Cammarata 11, Elisa Calabrò 10, Giovanna Cirnigliaro 7,
Silvia Della Torre 8, Bernardo Dell’osso 6,7,12, 13, Chiara Moltrasio 14, Angelo Valerio Marzano 14,15, Chiara Nostro 7,
Maurizio Romagnuolo 14,15, Lucia Troa 10, Valeria Savasi 11,16, Valeria Smiroldo 8 and Gianvincenzo Zuccoi 2,16,*
1 Department of Internal Medicine and Therapeutics, Università degli Sudi di Pavia, 27100 Pavia, Italy;
valeria.calcaterra@unipv.it
2 Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy; zanelli.sara01@gmail.com (S.Z.);
elvira.verduci@unimi.it (E.V.)
3 International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention
Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS),
Università degli Studi di Milano, 20157 Milano, Italy; andrea.foppiani@unimi.it
4 IRCCS Istituto Auxologico Italiano, Department of Endocrine and Metabolic Medicine, Clinical Nutrition
Unit, 20145 Milano, Italy
5 Department of Health Sciences, Università degli Studi di Milano, 20157 Milano, Italy
6 “Aldo Ravelli” Center for Nanotechnology and Neurostimulation, Università degli Studi di Milano,
20157 Milano, Italy; beatrice.benai@asst-f-sacco.it (B.B.); bernardo.dellosso@unimi.it (B.D.)
7 Department of Psychiatry, ASST Fatebenefratelli-Sacco, University of Milano, 20154 Milano, Italy;
giovanna.cirnigliaro@asst-f-sacco.it (G.C.); chiara.nostro@asst-f-sacco.it (C.N.)
8 Department of Medical Oncology, ASST Rhodense, 20024 Milano, Italy; rbollina@asst-rhodense.it (R.B.);
sdellatorre@asst-rhodense.it (S.D.T.); vsmiroldo@asst-rhodense.it (V.S.)
9 Department of Radiology, ASST Fatebenefratelli Sacco, 20154 Milano, Italy;
francesco.bombaci@asst-f-sacco.it
10 Department of Internal Medicine, ASST Fatebenefratelli-Sacco, 20154 Milano, Italy;
antonio.brucato@unimi.it (A.B.); elisa.calabro@asst-f-sacco.it (E.C.); lucia.troa@asst-f-sacco.it (L.T.)
11 Department of Woman, Mother and Neonate, Luigi Sacco Hospital, ASST Fatebenefratelli-Sacco,
20154 Milano, Italy; selene.cammarata@asst-f-sacco.it (S.C.); valeria.savasi@unimi.it (V.S.)
12 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
13 Centro per lo Studio dei Meccanismi Molecolari alla Base delle Patologie Neuro-Psico-Geriatriche,
Università degli Studi di Milano, 20157 Milano, Italy
14 Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy;
chiara.moltrasio@policlinico.mi.it (C.M.); angelo.marzano@unimi.it (A.V.M.);
maurizio.romagnuolo@unimi.it (M.R.)
15 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
16 Department of Biomedical and Clinical Science, Università degli Studi di Milano, 20157 Milano, Italy
* Correspondence: gianvincenzo.zuccoi@unimi.it
Abstract: Long COVID aects both children and adults, including subjects who experienced severe,
mild, or even asymptomatic SARS-CoV-2 infection. We have provided a comprehensive overview
of the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19 symp-
toms in both children and adults, encompassing vulnerable populations, such as pregnant women
and oncological patients. Our objective is to emphasize the critical signicance of adopting an inte-
grated approach for the early detection and appropriate management of long COVID. The incidence
and severity of long COVID symptoms can have a signicant impact on the quality of life of patients
and the course of disease in the case of pre-existing pathologies. Particularly, in fragile and vulner-
able patients, the presence of PASC is related to signicantly worse survival, independent from pre-
existing vulnerabilities and treatment. It is important try to achieve an early recognition and man-
agement. Various mechanisms are implicated, resulting in a wide range of clinical presentations.
Understanding the specic mechanisms and risk factors involved in long COVID is crucial for tai-
loring eective interventions and support strategies. Management approaches involve comprehen-
sive biopsychosocial assessments and treatment of symptoms and comorbidities, such as autonomic
Citation: Calcaterra, V.; Zanelli, S.;
Foppiani, A.; Verduci, E.; Benai, B.;
Bollina, R.; Bombaci, F.; Brucato, A.;
Cammarata, S.; Calabrò, E.; et al.
Long COVID in Children, Adults,
and Vulnerable Populations: A
Co mp re he ns ive Over vie w for an
Integrated Approach. Diseases 2024,
12, 95. hps://doi.org/10.3390/dis-
eases12050095
Academic Editors: Ludovico
Abenavoli and Filippo Lococo
Received: 2 April 2024
Revised: 27 April 2024
Accepted: 3 May 2024
Published: 6 May 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Swierland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Aribution (CC BY) license
(hps://creativecommons.org/license
s/by/4.0/).
Diseases 2024, 12, 95 2 of 54
dysfunction, as well as multidisciplinary rehabilitation. The overall course of long COVID is one of
gradual improvement, with recovery observed in the majority, though not all, of patients. As the
research on long-COVID continues to evolve, ongoing studies are likely to shed more light on the
intricate relationship between chronic diseases, such as oncological status, cardiovascular diseases,
psychiatric disorders, and the persistent eects of SARS-CoV-2 infection. This information could
guide healthcare providers, researchers, and policymakers in developing targeted interventions.
Keywords: long COVID; children; adults; pregnancy; oncological; SARS-CoV-2; post-COVID-19
syndrome; integrated approach
1. Introduction
The COVID-19 pandemic has aected millions of lives globally [1]. Nonetheless,
treatments have been devised over this period, and successful vaccines have been exten-
sively distributed to the population, encompassing both children and adults, safeguard-
ing millions from severe illness and death [2]. Compared to adults, children contract less
frequently Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection,
and among the infected, children have less severe disease [3].
Although vaccination and improved treatment have signicantly impacted on the
severity of acute COVID-19 infection, one in 10 people presents a persistence of symptoms
known as post-COVID-19 syndrome or long COVID [4].
In October 2021, the World Health Organization (WHO) dened long COVID as the
continuation or development of new symptoms 3 months after the initial SARS-CoV-2
infection, with these symptoms lasting for at least 2 months with no other explanation [5].
In February 2022, the National Institute for Health and Care Excellence (NICE) issued
guidelines that characterize long COVID as signs and symptoms that persist or emerge
following acute COVID-19. This encompasses ongoing symptomatic COVID-19 (lasting
from 4 to 12 weeks) and post-COVID-19 syndrome (12 weeks or more) [6].
Long COVID aects both children and adults, including subjects who experienced
severe, mild, or even asymptomatic SARS-CoV-2 infection [7].
The pathogenic mechanisms of long COVID remain not fully understood; moreover,
a multifactorial origin, including an exaggerated immune response, viral persistence,
cross-reactive autoimmune responses, genetics, drugs, and other factors, has been postu-
lated [8]. Being female, of a younger age, belonging to a Black, mixed ethnicity, or other
ethnic minority groups, experiencing socioeconomic deprivation, smoking, a high body
mass index (BMI), and the presence of various comorbidities were associated with an in-
creased risk of long COVID [9]. Long COVID is characterized by a multidimensional
symptomatology (Figure 1) and disability. The predominant symptoms include fatigue,
headache, brain fog, and myalgia. Sequelae were categorized based on the systems or or-
gans involved in respiratory symptoms, residual fatigue, weight loss, neurocognitive se-
quelae, non-respiratory residual organ dysfunction, and others [10,11]. Long COVID
symptoms negatively impact the function, activities, participation, and quality of life of
individuals [12].
There is no specic treatment for long COVID; nutritional support, lifestyle adjust-
ments, and exercise-based therapy are essential parts of the management of this condition
[12]. Considering the diversity of symptoms, the management of patients requires a mul-
tidisciplinary team approach [13], and telemedicine, digital, medical internet, and eHealth
interventions targeting social support have been considered essential for addressing the
long-term negative eects [14].
The early recognition of patients with post-COVID-19 syndrome is essential to un-
dertake a complete and eective diagnostic–therapeutic approach and to guarantee ade-
quate care. Long-term monitoring is mandatory to dene the prevalence of complications
Diseases 2024, 12, 95 3 of 54
post-infection and to understand whether the disease can be considered a long-term risk
condition for health.
In the context of a national project on the integrated approach to post-COVID-19 syn-
drome, we provided a comprehensive overview of the incidence, clinical characteristics,
risk factors, and outcomes of persistent COVID-19 symptoms in both children and adults,
encompassing vulnerable populations, such as pregnant women and oncological patients.
Our objective is to emphasize the critical signicance of adopting an integrated approach
for the early detection and appropriate management of long COVID.
Figure 1. Long COVID symptoms in adults and children (created with Biorender hps://www.bio-
render.com, accessed on 12 March 2024).
2. Methods
We conducted a narrative review examining the multisystemic eects of long COVID
in both children and adults, with a focus on its incidence, clinical characteristics, risk fac-
tors, and outcomes. Our comprehensive, non-systematic literature search was conducted
on PubMed/MEDLINE databases, with a language restriction to English.
The inclusion criteria were: (a) publication date: from January 2020 to February 2024;
(b) age: children (0–18 years old) and adults (>18 years old); and (c) type of article: reviews,
meta-analyses, prospective, retrospective, cross-sectional cohort studies, case–control
studies, clinical practice guidelines, and editorials. Single case reports without a literature
review and articles published as abstracts and non-English-language papers were ex-
cluded.
For the study, we categorized publications by pediatric and adult age groups, organ-
izing them based on dierent organs or systems. The keyword list used for the research,
categorized according to the target population/organ, is detailed in Table 1; the number of
potentially relevant manuscripts and the number of considered manuscripts resulting
from the literature search are also reported.
Diseases 2024, 12, 95 4 of 54
Table 1. List of keywords used in our literature search divided by age and system or organ and respective type and number of articles found.
Population/Organs
Keywords
Number of
Potentially
Relevant
Manuscripts
Number of
Considered
Manuscripts
Number and Type of Articles
Pediatric populations
Pediatrics
Long COVID or Post-COVID-19 syndrome or Post-Acute Sequelae
of COVID-19 syndrome AND Children
Or Adolescents or Pediatric age
98
60
23 reviews
21 cohort studies
7 cross-sectional studies
2 retrospective studies
4 meta-analyses
3 clinical practice guidelines
Adult populations
Neurological and
Psychiatry symptoms
Long COVID and/or post-COVID-19 condition and psychiatric
symptoms
366
35
5 systematic reviews and meta-analyses
22 cohort studies and longitudinal
studies
3 narrative reviews
5 cross-sectional studies
Dermatological
manifestations
Long COVID-19 and skin; long COVID and skin; long COVID
syndrome and skin; cutaneous skin COVID-19; cutaneous long
COVID
50
12
1 systematic review and meta-analysis
4 narrative reviews
7 cohort studies/experimental research
Gastrointestinal
symptoms
Gastrointestinal symptoms of long COVID; long-haul COVID-19
gastrointestinal problems; digestive issues after COVID-19 infection;
post-COVID-19 gut health; persistent gastrointestinal symptoms
following SARS-CoV-2; COVID-19 and chronic digestive disorders;
long COVID and irritable bowel syndrome
86
12
2 narrative reviews
1 systemaic review and meta-analysis
7 cohort studies
2 case–control studies
Lung function
Lung involvement in long COVID; CT findings for long COVID ;
lung function tests in long COVID
32
9
6 restrospective/follow-up, longitudinal
studies
2 reviews
1 cross-sectional study
Cardiovascular
manifestations
Long COVID; myocarditis; cardiovascular outcome for long COVID;
cardiovascular sequelae in long COVID
40
14
2 narrative reviews
7 cohort studies
Diseases 2024, 12, 95 5 of 54
1 meta-analysis
3 observational studies
1 consensus expert opinion
Vulnerable populations
Pregnant women
COVID-19; SARS-CoV-2; pregnancy; long COVID and pregnancy;
long COVID and obstetric complications;
Sequalae; women
90
16
4 systematic reviews and meta-analyses
3 prospective multicenter cohort studies
2 editorials
1 retrospective cohort study
1 cross-sectional retrospective study
2 prospective cohort studies
1 observational prospective study
1 population-based cohort study
1 longitudinal comparative study
Cancer patients
Long COVID AND cancer patients; long COVID AND cancer
60
9
7 retrospective cohort studies
2 ambidirectional cohort studies
Diseases 2024, 12, 95 6 of 54
The term “long COVID” was considered as symptoms persisting beyond the acute
phase of COVID-19; all established denitions of long COVID are permissible, including
proprietary denitions proposed by the study’s authors.
From an initial selection of 8190 papers screened by title/abstract, we proceeded to
evaluate the full texts of potentially relevant articles (n = 822). The authors then reviewed,
analyzed, and discussed the full texts of the relevant papers (n = 167). The reference lists
of all manuscripts were also scrutinized to identify additional pertinent studies. Addition-
ally, pertinent studies discussing pathophysiology and used as part of the general frame-
work of the topic were also considered. The owchart outlining the selection process for
studies and relevant articles considered is schematically depicted in Figure 2.
The resulting draft underwent a through discussion with all co-authors and received
unanimous approval.
Figure 2. Flowchart of the selection process for studies and relevant articles considered.
3. Pathophysiology of Long COVID
The pathophysiology of long COVID is still unclear, but there are several hypotheses
about it. The gateway used by SARS-CoV-2 to invade cells is the Angiotensin Converting
Enzyme-2 (ACE-2) receptor. This is expressed at the epithelium of many organs and thus
can explain the variety of symptoms of long COVID syndrome [15]. A number of factors
can be involved in pathophysiology: chronic organ damage, SARS-CoV-2 persistence in
the organism, dysregulation of the immune system, and thus the persistence of chronic
inammation and autoimmunity. Moreover, lengthy organ recovery time, eects of hos-
pitalization, sequelae of critical illness, post-intensive care syndrome, complications aris-
ing from comorbidities, and adverse medication eects could be implicated [16].
Viral persistence several months after acute infection seems to be a potential mecha-
nism implicated in pathogenesis because of the resulting pathologic inammation [17].
Prolonged exposure to SARS-CoV-2 or its components could indeed exacerbate the im-
mune response with increased levels of proinammatory cytokines, such as IL-6, IL-1β,
and TNF, and these can cause organ damage [18].
As in autoimmune diseases, the dysfunction of T cells can promote long COVID
through autoreactive lymphocytes [19]. Furthermore B cells are involved in pathogenesis;
indeed, in COVID-19 patients, several autoantibodies, such as antiphospholipid autoanti-
bodies [20], can be detected, but also autoantibodies against interferons, neutrophils, con-
nective tissues, cyclic citrullinated peptides, and cell nuclei, were identied in COVID-19
Initialassessm en t
(n =8190)
D ocum ents screened b y
title/abstract
(n =822)
Fu ll text article inclu ded (n =167)
-K ey find in gs
-M eetin g in clusion criteria
-Stud y characteristics
R ecords exclud ed on th e initial
screen of title an d ab stract
(n =7368)
Fu ll text excluded (n=655)
SCREENING
ELIGIBILITY
INCLUDED
In clusion o f
-references on pathophisiology used as
part of the general framework (n= 32)
-reference list of all selected article (n= 67)
Total full text article
includ ed (n =266)
Diseases 2024, 12, 95 7 of 54
patients [21]. These may contribute to typical symptoms of this syndrome, like fatigue,
headache, concentration diculties, and joint pain. Additionally, lymphopenia and hy-
perinammation may contribute to long COVID and the chronic immune activation typ-
ical of this syndrome [22,23].
Moreover, gut microbiota remain signicantly altered after recovery from COVID-19
[24,25], and microbiota dysbiosis is correlated with increased inammatory biomarkers,
which may contribute to persistent symptoms, in particular, gastrointestinal but also neu-
rological ones, given the role of the gut–brain axis in the control of central nervous system
inammation [17].
There is a reduced ability to clear SARS-CoV-2 because of a diminished immunologic
capacity, and so the persistence of the virus seems to have a genetic basis. The result is
excessive proinammatory cytokine production, enhanced by the production of reactive
oxygen species leading to typical long COVID symptomatology [17]. This process can
complement platelet activation and encourage impaired coagulation, enhancing the risk
of microthrombosis in multiple organs [15]. A possible role in the pathogenesis of long
COVID is aributed to perivascular inammation and thromboembolism [26]. More stud-
ies are necessary to investigate a possible pro-brotic state that is already observed in
adult patients.
The evidence concerning long COVID, variants of SARS-CoV-2, and their role in
pathogenesis is limited. Many studies have explored the contribution of genetic factors
associated with severe COVID-19, such as blood group, epigenomic markers, and traits
associated with protection, but the potential contribution of genetic factors to long COVID
is still unexplored [18].
4. Long COVID in Pediatric-Age Patients
Acute SARS-CoV-2 infection is generally mild or asymptomatic in children and ado-
lescents with a low hospitalization and mortality rate [27,28]. The persistence of symp-
toms has been observed in some patients previously infected with SARS-CoV-2, formerly
in adults, and then in the pediatric population [11]. Long COVID syndrome or Post-Acute
Sequelae of COVID-19 Syndrome (PASC) in the pediatric-age population was described
rstly in 2020 by Ludvigsonn et al. in a small group of Swedish children [29], and other
authors reported the presence of PASC in a larger cohort of Australian pediatric COVID-
19 patients [30]. Similarly, an Italian cross-sectional study reported persistent symptoms
in children previously diagnosed with COVID-19 [31].
Long COVID is a multisystemic condition with heterogeneous manifestations involv-
ing cardiovascular, respiratory, neurological, and gastrointestinal systems. While the
symptoms are mostly mild, they still have a signicant impact on the daily functioning,
quality of life, and mental health of the pediatric population. Moreover, distinguishing
functional complaints from post-acute COVID-19 from those caused by social restrictions
remains challenging [32].
Overall, the prevalence of long COVID in children varies from 4% to 66%, depending
on the studies [15,33,34]. This wide variability can be aributed to the heterogeneous char-
acteristics of the selected studies: the dierent sample sizes considered, varying follow-
up durations, and dierent assessment modalities (e.g., telephone survey or clinical ex-
aminations), as well as dierences in the age of enrolled patients. Lopez-Leon et al. de-
scribed in a meta-analysis and systematic review the prevalence of long COVID in 25.24%
of children previously aected by COVID-19, while the prevalence in hospitalized pa-
tients was 29.19% [2]. In a pediatric cohort, Bloise et al. reported that the prevalence of
long-lasting symptoms was around 20% [35], while Miller et al. described a prevalence of
2.6% in a cohort study conducted in England and Wales [36]. In an Italian study on 129
children diagnosed with COVID-19, 42.6% of those patients presented at least one symp-
tom over 60 days after infection [31]. Calcaterra et al. conducted a prospective study in-
volving children who were hospitalized and followed up at 3, 6, and 12 months after dis-
charge [37]. The study showed that 16.5% of the patients reported experiencing at least
Diseases 2024, 12, 95 8 of 54
one symptom indicative of long COVID; these symptoms included weight loss (31.6%),
inappetence (26.3%), chronic cough (21.1%), fatigue (21.1%), as well as sleep disturbances,
wheezing, abdominal pain, and mood disorders (15.8%).
4.1. Risk Factors for Long COVID in Children
There are several risk factors associated with long COVID in children and adoles-
cents: older age, female gender, severe COVID-19, comorbidities such as overweight and
obesity, allergic diseases, and other chronic disorders [2,38].
In a prospective study conducted on 90 children after acute SARS-CoV-2 infection,
several symptoms were more common among older children [39]. Borch et al. demon-
strate in their study that the age distribution of symptoms diers, with older school chil-
dren being more frequently aected compared to younger school and pre-school children
[40].
As for gender, in a cross-sectional study by Berg et al., female children were more
prone to manifest persistent symptoms than males [41]. Long COVID symptoms are more
frequent among female patients, according to Roge et al.’s cohort study [42]. Other studies
do not highlight any gender dierences in pediatric-age patients [43].
As for ethnicity, Rayner et al., in a meta-analysis, identify that the Black race may be
associated with a decreased risk of long COVID in children and adolescents [44], but fur-
ther research is necessary.
The specic SARS-CoV-2 variant is probably another important factor to be consid-
ered. The prevalence of pediatric long COVID should have progressively decreased with
the Omicron variant’s emergence [45]. An Italian prospective study reports in 15/115 pa-
tients long-lasting symptoms, but only four of them were identied with a specic SARS-
CoV-2 variant: three were associated with the Omicron variant and one was linked to the
Delta variant [37]. The prevalence of long COVID seems to be lower in patients infected
with Alpha, Delta, and Omicron variants rather than the ancestral one [46]. In a study, the
Delta variant showed a higher viral load in the respiratory tract of adult patients, and it
could have also had an impact on children and adolescents [47]. Limited evidence exists
about the correlation between symptoms related to long COVID in children and its vari-
ants.
In adult patients, obesity or overweight is described as a long COVID risk factor, and
recently it was also identied by Bloise et al. in pediatric patients [32,35]. Allergic diseases
and long-term conditions could be possible risk factors [48]. Furthermore, respiratory dis-
eases, asthma, and heart disease are risk factors for long COVID in the pediatric popula-
tion [44].
The severity of acute infection and symptom duration have no correlation according
to some studies [31], but other studies report that severity is correlated with the frequency
and duration of sequelae [49]. Children with asymptomatic or paucisymptomatic COVID-
19 could be aected and develop persisting symptoms [31]. An association between longer
hospitalization and more severe persistent symptoms has been reported [33].
The use of COVID-19 vaccines, reducing the incidence and severity of SARS-CoV-2
infection, may also reduce the risk of long COVID [50]; conversely, patients with long
COVID have no signicant improvements of their symptoms after vaccination [51]. A re-
cent, large, retrospective cohort study has shown a moderate protective eect of vaccina-
tions against this syndrome that is stronger in adolescents and wanes over time [52].
The role of genetics is still unclear in the post-COVID-19 condition [18], while studies
have veried the existence of genetic features connected to the high susceptibility and
severity of acute infection [53,54].
Diseases 2024, 12, 95 9 of 54
4.2. Clinical Manifestation of Long COVID in Pediatric-Age Individuals
COVID-19 in children often presents as asymptomatic or with few symptoms. Hos-
pitalization rates are lower compared to adult patients, and life-threatening complications
are infrequent [15].
A long-term consequence of COVID-19 is long COVID, characterized by highly var-
iable intensity and duration. Signs and symptoms in pediatric cases are mostly mild and
closely resemble those described for adults [55]. They can occur alone or in combination,
be intermient or transient, and may change over time or remain constant. Hospitalization
for long COVID symptoms is not usually reported [32].
Long COVID is characterized by multiorgan involvement and highly variable inten-
sity and duration. Symptoms in the pediatric-age population are very similar to those de-
scribed for adults.
In a meta-analysis by Lopez-Leon et al., mood symptoms are described as the most
common (16.5%), in particular, anxiety, depression, sadness, anger, and tension. Further-
more, fatigue (9.66%) and sleep disorders (8.42%), like insomnia, hypersomnia, and poor
sleep quality, are also prevalent. Other frequent symptoms are headaches (7.84%), respir-
atory symptoms (7.62%), sputum production or nasal congestion (7.53%), cognitive symp-
toms (especially reduced concentration, learning diculties, confusion, and memory loss)
(6.27%), inappetence (6.07%), exercise intolerance (5.73%), and altered smell (5.60%),
which includes hyposmia, anosmia, hyperosmia, parosmia, and phantom smell [2].
Gastrointestinal symptoms are possible, but with a low prevalence (<5%). Among
these, abdominal pain is the most frequent manifestation, followed by constipation,
chronic diarrhea, nausea/vomiting, and dysphagia [2,56]. Furthermore, functional gastro-
intestinal disorders, such as irritable bowel syndrome (IBS) and altered bowel motility,
are reported for long COVID syndrome, but the frequency is still not claried [57,58]. Gut
microbiota composition is signicantly altered in patients with COVID-19 [7]. Dysbiosis
is persistent, lasting for at least 14 months [59] because the bowel is a long-term reservoir,
and it could play a central role in the maintenance of symptoms. Lately, the authors also
depicted two rare liver manifestations of long COVID: acute liver injury and hepatitis with
cholestasis [60].
Cardiovascular manifestations of long COVID in children in order of frequency are
orthostatic intolerance [61], exercise intolerance, chest pain, and a variation in heart rate,
while palpitations are less common [2,61–63].
Exertional dyspnea, a persistent cough, and exercise intolerance are the most com-
mon respiratory symptoms in children post-SARS-CoV-2 infection [63]. Esmaeilzadeh et
al. reported a persistent cough and asthma-like symptoms with a prevalence of 41.5% in
a cohort of COVID-19 hospitalized children [64]. While spirometry and plethysmography
are usually normal, abnormality in the six-minute walking test (6MWT) could reveal ex-
ercise intolerance in children aected by long COVID [63]. Even months after acute infec-
tion, irregular pleural lines, B lines, and subpleural consolidations were detected through
lung ultrasounds (LUSs), respectively, in 27.5%, 16.9%, and 8.6% of the cases. Patients
could have ultrasound artifacts and show an improvement with the passage of time from
acute infection [65].
Ear, nose, and throat (ENT) symptoms are possible long COVID presentations at a
pediatric age. A sore throat was described in 2.47% of patients, whilst dysphonia was un-
common [2]. Earache, tinnitus, and vertigo may be present with a prevalence around 3%,
as Lopez-Leon et al. described in their meta-analysis. Buonsenso et al. reported nasal con-
gestion in 12.4% of children with persistent symptoms [31], and in a cohort study, Roge et
al. demonstrated the presence of rhinorrhea in 16.1% of pediatric patients [42]. Olfactory
dysfunction, such as anosmia or dysgeusia, are described in 12.3% of children with post-
COVID-19 syndrome [42]. However, in a prospective cohort study, Osmanov et al. de-
scribed a more rapid improvement of smell disturbances than other symptoms of long
COVID [48].
Diseases 2024, 12, 95 10 of 54
Fatigue and chronic fatigue syndrome (CFS) are common symptoms in children af-
fected by long COVID [66,67]. In an English CLoCK study, fatigue, in addition to concen-
tration problems and headaches, was the most frequent symptom in the case group [28].
In an Italian survey carried out by Buonsenso et al. on 510 children after contracting
COVID-19, their parents reported an impairment in physical activity due to fatigue, and
only 51 patients returned to prior levels of activity [17]. Furthermore, the more physically
active the children were before infection, the more likely they returned to that level. CFS
is associated with a number of viral infections, including SARS-CoV-2, and so it has ac-
quired high epidemiological relevance [67].
Balance problems, like dizziness, are described in children and adolescents, but
merely with a prevalence of 4.4%. Arthralgia and myalgia are also common symptoms,
and Lopez-Leon et al. indicate a prevalence of 3.76% in pediatric patients [2].
About the dermatological symptoms, skin rashes are a possible manifestation of this
condition, with a prevalence of 2.61% [2].
During the COVID-19 pandemic, the isolation, loss of parents or caregivers, increased
stress, and a fear of COVID-19 had a signicant impact on children’s development [68]. A
new onset of psychological problems, like anxiety, depression, irritability, boredom, and
inaention, were displayed by children during this pandemic. Children with behavioral
problems, like autism and aention decit and hyperactivity disorder (ADHD), have a
high probability for worsening symptoms [69].
In an Italian study, parents reported a wide range of neurocognitive symptoms: lack
of concentration, diculty processing/remembering information or understanding in-
structions, short-term memory issues, and struggling to nd the right words [70]. As in
adult patients, visuospatial abilities and executive function are the most often aected
[71]. In the Danish LongCOVIDKidsDK study, headaches and concentration diculties
are the most frequent manifestation in the case group [41]. It is important to highlight the
ongoing development of the nervous system of children and the dierential expression of
cell receptor targets over time with a variable susceptibility to neurological alteration in
post-COVID-19 syndrome [72].
Long COVID symptoms usually disappear spontaneously, leading to a good prog-
nosis [55]. In most patients, long COVID symptoms resolved in the range of 1–5 months
in a minimum of 54–75% of children [40]. In a prospective study, Molteni et al. report a
symptomatic illness lasting 4 weeks or longer in only 4.4% of patients and lasting 8 weeks
or longer in just 1.8% of cases [73].
A follow-up study between 4 and 12 weeks after acute SARS-CoV-2 infection is es-
sential in pediatric cases, particularly in high-risk patients, such as those with asthma,
allergic diseases, obesity, neuropsychiatric disorders, and/or other comorbidities, includ-
ing those who are asymptomatic. Tailored investigations are necessary due to the signi-
cant impact of long COVID on children’s daily lives, especially at home and in school. A
multidisciplinary team is essential due to the involvement of multiple organs. Currently,
there are no dedicated guidelines for treating long COVID in children. Physical rehabili-
tation, symptomatic medication (e.g., paracetamol), and, if necessary, psychological sup-
port could be benecial to these patients. On the other hand, vaccination in children and
adolescents is essential to protect them from the long-term consequences of acute COVID-
19.
In Table 2, a list of the main studies on long COVID on pediatric patients is presented.
Diseases 2024, 12, 95 11 of 54
Table 2. Main studies on long COVID in pediatric-age patients.
First Author; Year of Publication
Study Type
Population
Results
Ashkenazi-Hoffnung et al., 2021 [39]
Prospective cohort study
90
60% symptoms associated with functional impairment
Kikkenborg et al., 2022 [41]
Cross-sectional study
24,315
61.9% long COVID symptoms
Bloise et al., 2022 [35]
Meta-analysis
1413
20% long-term symptoms
Borch et al., 2022 [40]
Cohort study
37,522
Most common symptom is fatigue
Buonsenso et al., 2022 [70]
Cohort study
510
87.4% persistent symptoms
Dennis et al., 2021 [34]
Prospective study
201
60% severe post-COVID-19 syndrome
Parisi et al., 2021 [66]
Cross-sectional survey
267
20% persistent symptoms
Miller et al., 2022 [36]
Cohort study
5032
2.6% persistent symptoms
Molteni et al., 2021 [73]
Prospective cohort study
1734
4.4% long-lasting symptoms
Stephenson et al., 2023 [28]
Prospective cohort study
3395
66.5% symptoms after 3 months
Calcaterra et al., 2024 [37]
Prospective cohort study
167
16.5% reported experiencing at least one symptom
indicative of long COVID
Diseases 2024, 12, 95 12 of 54
5. Long COVID in Adults
5.1. Risk Factors for Long COVID in Adults
Several risk factors are associated with long COVID in adults. First of all, sociodem-
ographic characteristics are involved. According to many studies, the female sex is more
frequently aected by persistent symptoms after SARS-CoV-2 acute infection [9,23]. In a
review, Koch et al. state that female patients are ve-times more likely to develop long
COVID symptoms after discharge than males [74]. Furthermore, an Italian prospective
cohort study on 377enrolled patients revealed a higher risk of being diagnosed with long
COVID in females [75].
Other signicant risk factors include a White ethnicity, which is associated with an
elevated risk of disease [76], and advanced age. Older patients appear to have a higher
likelihood of developing long COVID compared to younger individuals [74,77]. However,
it is important to note that older patients often have pre-existing comorbidities and may
experience a more severe acute infection, which could further increase their risk.
Both current smokers and former smokers also have a higher risk of experiencing
long COVID compared to those who have never smoked [9]. Given that smokers typically
have compromised immune and cardiovascular systems, smoking may potentially con-
tribute to the persistence of symptoms [78].
Pre-existing comorbidities serve as signicant risk factors as well: conditions such as
hypertension, diabetes, chronic kidney disease, cerebrovascular disease, chronic obstruc-
tive pulmonary disease (COPD), or cardiovascular disease may contribute to the onset of
long COVID [77]. Additionally, obesity and overweight are associated with a high disease
risk. A meta-analysis by Tsampasian et al. conrmed that a higher BMI is associated with
a higher risk of developing long COVID [79]. Concerning antecedent allergic diseases, in
a systematic review, Wol et al. reported individuals with asthma and rhinitis may have
a higher risk of long COVID [80]. Lastly, poor mental health (e.g., anxiety and depression)
may also be a signicant risk factor [76].
The severity of acute SARS-CoV-2 infection is also associated with long COVID.
Tsampasian et al., in a recent meta-analysis, report that ICU admission and hospitaliza-
tion, which are indicative of severe disease, are associated with long COVID [79]. Even in
a review by Su et al., critical illness, acute respiratory syndrome, long-term ventilator sup-
port, and multiorgan impairment caused by COVID-19 are considered as risk factors for
post-acute COVID-19 symptoms [81]. Although this syndrome is also described in non-
hospitalized patients with mild acute infections [75], the frequency is lower than in severe
cases.
Chronic diseases, such as diabetes, asthma, and cardiovascular diseases, appear to
have a bidirectional relationship with COVID-19. These comorbidities, prevalent in the
adult population, particularly the elderly, serve as risk factors for both contracting
COVID-19 and experiencing prolonged symptoms following acute SARS-CoV-2 infection.
Furthermore, COVID-19 may exacerbate these pre-existing chronic conditions [82–84].
Data on the prevalence of long COVID in specic chronic disorders remain limited.
Heald et al. found that long COVID was more prevalent in men with type 2 diabetes (T2D)
than in matched non-T2D controls, while the opposite trend was observed for women
with T2D, with similar rates of recorded long COVID for both T2D men and women [85].
Sharif detected a co-prevalence of cardiovascular diseases, diabetes, and long COVID
among 11.9% of patients [86]. Even though Hung et al. described a higher prevalence of
long COVID in adults with asthma compared to the general population [87], the published
data neither conrm nor deny whether long-term COVID-19 symptoms in patients with
an asthma diagnosis dier in strength and frequency from those without an asthma diag-
nosis [88].
Additionally, certain specic populations have been identied as high-risk patients.
Pregnant women, for instance, are considered to be at a heightened risk compared to the
Diseases 2024, 12, 95 13 of 54
non-obstetric population. This is evidenced by an increased incidence of clinical manifes-
tations, severity of symptoms, and associated obstetric morbidity [9].
Similarly, oncology patients have been shown to be more susceptible to acute and
severe COVID-19 infection [89], with a fatality rate estimated at 22.4% among COVID-19
patients with cancer, as opposed to 5.9% in patients without cancer. The systemic immu-
nosuppressive status of cancer patients, whether caused by the disease itself or anticancer
treatment, confers an increased risk of COVID-19 [90]. Simultaneously, the incidence of
post-acute sequelae of SARS-CoV-2 infection, known as COVID-19 long-term eects, has
been described in oncological studies. These studies identied a subgroup of patients with
signicantly worse survival rates. Particularly, patients who experienced one or more
COVID-19 sequelae had signicantly shorter post-COVID-19 survival compared to those
with a complete resolution of symptoms [47].
SARS-CoV-2 variants appear to play a role in determining the risk of long COVID.
The prevalence of long COVID is higher in individuals infected with the historical strain
than posterior variants (e.g., Alpha, Delta, and Omicron) [46]. In particular, the risk seems
to have decreased with the spread of the Omicron variant [81].
5.2. Clinical Manifestation of Long COVID in Adults
5.2.1. Cutaneous Manifestations
Since the beginning of the pandemic, the cutaneous manifestations of COVID-19
have been categorized into six main phenotypes: (1) urticarial rash; (2) conuent erythem-
atous/maculopapular/morbilliform rash; (3) papulo-vesicular exanthem; (4) chilblain-like
acral paern; (5) livedo reticularis/racemosa-like paern; and (6) purpuric vasculitic pat-
tern [91]. However, there have been several reports of a miscellany of other cutaneous
presentations related to COVID-19 that cannot be included in this classication [92–96].
To date, conuent erythematous/maculopapular/morbilliform rashes, urticarial lesions,
cutaneous vasculitis and vasculopathies, and a chilblain-like acral paern are the most
frequently reported COVID-19-associated cutaneous manifestations [97,98].
The pathogenic mechanisms remain incompletely understood, but an immune-me-
diated inammatory response, rather than a direct virus-induced cytopathic eect, has
been suggested [99,100]. Additionally, an ineective immune response to the virus or el-
evated viral loads could be risk factors for the cutaneous transmission of SARS-CoV-2 [99].
The landscape of cutaneous presentations Is likely to evolve due to novel variants of
the virus, as demonstrated for the SARS-CoV-2 Omicron variant [101], and long COVID
syndrome [102]. The published evidence suggests that long COVID patients, even those
who experienced less severe or even asymptomatic diseases, may have a prolonged in-
ammatory response [103], probably coupled with viral reactivation and/or immune
dysregulation able to prevent the resolution of cutaneous manifestations [104]. Recently,
using a murine model, Hussain et al. reported a marked absence of hair follicles, the de-
struction of adipose tissues, and the obliteration of the epidermal layer as long-term post-
COVID-19 cutaneous eects [105].
The complete destruction of hair follicles is thought to be aributable to several fac-
tors, including the direct eect of the virus, the inuence of Transforming Growth Factor-
β (TGF-β) [106], and changes in the androgen receptor content of dermal papilla [107]. It
is noteworthy that Hussain and colleagues [105] demonstrated that treatment with a
newly identied 15-amino-acid synthetic peptide, SPIKENET (SPK), which can prevent
Spike glycoprotein-1 from binding with host receptors and promote an anti-inammatory
response, successfully restored the above-mentioned long COVID dermatologic changes.
This nding suggests that SPK may be considered as a potential therapeutic strategy to
prevent long-term cutaneous alterations caused by SARS-CoV-2, thus ameliorating skin
disease progression related to COVID-19.
McMahon et al. [108], through an international registry for COVID-19 dermatological
manifestations, evaluated the duration of dermatological signs and symptoms of COVID-
Diseases 2024, 12, 95 14 of 54
19 dening “long haulers” [109] as patients with cutaneous presentations persisting for
more than 60 days. In accordance with the UK NICE guidelines [6], only one out of 234
patients included in this registry can now be considered to have had long COVID, expe-
riencing a chilblain-like acral and livedo reticularis paern for over 22 weeks [108]. Sub-
sequently, Tammaro et al. [110] reported a group of adult patients, including both hospi-
talized and non-hospitalized individuals, with cutaneous lesions (mainly a conuent ery-
thematous/maculopapular/morbilliform rash and papulovesicular exanthem) lasting for
more than 26 weeks after the acute peak of COVID-19. Similarly, Förster et al. [111] re-
ported long-term (more than 12 weeks) cutaneous sequelae in 15 out of 127 hospitalized
patients and in 26 out of 588 non-hospitalized subjects. In a Chinese post-acute COVID-
19 study of hospitalized patients conducted by Huang et al. [112], only 47 out of 1655
patients (3%) reported skin rashes 26 weeks after disease onset. On the other hand, signif-
icant hair loss mainly corresponding to telogen euvium, secondary to viral infection
and/or to emotional and physical stress induced by the disease, was a post-discharge per-
sistent symptom reported in 24 of 120 patients (20%), 110 days after hospital discharge
[113].
Interestingly, in a recent study conducted by Grieco et al. [114], the authors investi-
gated cutaneous subjective neurologic symptoms (sNSs) in both subjects with acute
COVID-19 and long COVID syndrome. Six long COVID patients suering from cutaneous
sNSs, evaluated through the Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire,
underwent a histopathological examination of cutaneous areas aected by paroxysmal
diuse burning and itching sensations. It has been hypothesized that the laer, related to
COVID-19 and long COVID as well, may be associated with damage to the cutaneous
neurosensory system with symptoms persisting for months and accompanied by systemic
manifestations, including, among others, asthenia. In the above-mentioned study, histo-
pathological analyses showed the hypertrophy of dermal nerve bers resembling dermal
hyperneury, a rare form of small nerve hypertrophy that aects sensory C bers [115],
and these ndings could explain the dysesthesia experienced by the studied patients. In
addition, electroneurography was also performed on two patients, revealing altered der-
mal A delta and C neuronal bers, although it remains to be claried whether this was
due to the direct action of the virus on the terminal nerve bers or other indirect mecha-
nisms [114].
It can be argued that there is a growing need to reveal the exact mechanisms under-
lying the persistent inammatory response in cutaneous long COVID patients. To date,
there is no specic paern in the acute phase of COVID-19 able to predict the persistence
of long-term lesions or progression to a chronic skin disease. Further investigation is
needed to assess the full clinical spectrum, mechanism, and prognostic signicance of
such cutaneous lesions.
In Table 3, the main selected studies on cutaneous symptoms in adult patients with
long COVID are reported.
Diseases 2024, 12, 95 15 of 54
Table 3. Main selected studies on multisystemic symptoms in adult patients with long COVID.
First Author; Year of
Publication
Study Type
Population
Results
Cutaneous manifestations
McMahon et al., 2021
[108]
Multicenter registry
study
Confirmed or suspected COVID-19 patients with
dermatological manifestations
One patient exibited a chilblain-like acral and livedo reticularis
pattern for over 22 weeks
Tammaro et al., 2021
[110]
Observational study
(cohort study)
Patients with persisting cutaneous lesions that
appeared during the acute peak of COVID-19
Confluent erythematous/maculopapular/morbilliform rash and
papulovesicular exanthem lasted for more than 26 weeks after the
acute peak of COVID-19
Förster et al., 2022
[111]
Observational study
(cohort study)
Patients with a confirmed diagnosis of COVID-19
(both hospitalized and non-hospitalized)
Long-term (more than 12 weeks) cutaneous sequelae in 15 out of 127
hospitalized patients and in 26 out of 588 non-hospitalized subjects
Huang et al., 2021
[112]
Bidirectional cohort
study
Patients with confirmed COVID-19 and discharged
from hospital
3% of patients reported skin rashes 26 weeks after disease onset
Garrigues et al., 2020
[113]
Cohort study
Discharged COVID-19 patients
Hair loss in 20% of patients, 110 days after hospital discharge
Grieco et al., 2022
[114]
Experimental study
COVID-19 and long COVID patients
Hypertrophy of dermal nerve fibers in all long COVID study
patients. In 2 long COVID subjects, we noted an alteration in dermal
A delta and C neuronal fibers
Hussain et al., 2024
[105]
Experimental study
Murine Hepatitis Virus-1 (MHV-1)
Absence of hair follicles, destruction of adipose tissues, and
obliteration of the epidermal layer as long-term skin effects.
SPIKENET peptide able to restore long-term cutaneous changes
Gastrointestinal manifestations
Bogariu et al., 2022
[116]
Narrative review
-
The SARS-CoV-2 virus can affect any part of the digestive system
Choudhury et al.,
2022 [117]
Systematic review
and meta-analysis
50 studies included
GI symptoms were seen in 12% of patients after COVID-19 and 22%
as a result of long COVID. Loss of appetite, dyspepsia, IBS, loss of
taste, and abdominal pain were the 5 most common GI symptoms of
long COVID
Marasco et al., 2023
[118]
Case–control study
883 hospitalized patients
(614 patients with COVID-19 and 269 controls)
Compared with the controls, hospitalized patients with COVID-19
had fewer problems of constipation and hard stools at 12 months
Diseases 2024, 12, 95 16 of 54
after acute infection. Patients with COVID-19 had significantly higher
rates of IBS than controls
Golla et al., 2023 [119]
Case–control study
320 patients with COVID-19 and 2 control groups:
320 healthy spouses/family controls and 280 healthy
COVID-19 serology-negative controls
COVID-19 led to a significantly higher number of new onset PI-
FGID/DGBIs compared with healthy controls at 3 and 6 months of
follow-up
Fernandez-de-las-
Penas et al., 2023
[120]
Cohort study
1266 previously hospitalized COVID-19 survivors
The prevalence of gastrointestinal post-COVID-19 symptoms
fluctuates over the first few years after infection, showing a
progressive decrease
Zhang et al., 2023
[121]
Cohort study
983 antibiotic-naïve patients with mild COVID-19
3-month samples collected from patients with GI symptoms
associated with long COVID showed significant differences, and the
ectopic colonization of the oral cavity by gut microbes was observed
at the 3-month timepoint
Zuo et al., 2023 [122]
Cohort study
Two cohorts of healthy, young, Chinese subjects
(n = 54 and n = 62)
Baseline gut microbiome composition was intricately associated with
different COVID-19 manifestations, particularly GI involvement and
post-COVID-19 lingering symptoms
Plummer et al., 2023
[123]
Narrative review
-
Neurocognitive PACS symptoms may endure because viral damage
to the blood–brain and intestinal barriers could permit an unchecked
flow of harmful substances produced in the gut lumen in the context
of dysbiosis
Elmunzer et al., 2023
[124]
Cohort study
5116 patients
Extended GI manifestations were linked to the severity of GI
symptoms and the extent of psychological trauma associated with the
illness experience
Yagi et al., 2023 [125]
Cohort study
943 COVID-19 patients
6.2% of patients had GI long COVID symptoms; the health-related
QoL parameters in patients with GI long COVID symptoms were
significantly lower than in those without GI long COVID symptoms,
with more varied long COVID symptoms compared to patients
without GI symptoms
Ashktorab et al., 2023
[126]
Cohort study
747 patients with positive SARS-CoV-2 PCR
Dyspeptic symptoms were common GI manifestations in the acute
and post-COVID-19 periods. GI symptoms, abnormal LFTs, and a
history of liver disease during the acute infectious phase associated
with abnormal MoCA and sleep problems during follow-up
Diseases 2024, 12, 95 17 of 54
Ma et al., 2024 [127]
Retrospective cohort
study
COVID-19 group (n = 112,311)
Contemporary (n = 359,671) and historical
comparison groups (n = 370,979)
The risks of developing digestive diseases showed a stepwise
increase with the severity of COVID-19
Neurological and psychiatric manifestations
Akbarialiabad et al.,
2021 [128]
Systematic review
120 publications included
Major mood swings, depression, feelings of loneliness and isolation,
stress and anxiety, and sleep–wake disorders
Alemanno et al., 2021
[129]
Observational study
87 patients
Patients with severe functional impairments were significantly
influenced by cognitive and emotional deficits
Buoite Stella et al.,
2022 [130]
Prospective
observational study
Participants recruited among the post-COVID-19
ambulatory services
Orthostatic intolerance; sudomotor, gastrointestinal, and
pupillomotor abnormalities; decreased tolerance to environmental
conditions; and sexual impairments were commonly reported
Chamberlain et al.,
2021 [131]
Observational study
Survivors of suspected or confirmed COVID-19
recruited from the general population,
predominantly in UK
PTSD symptoms disproportionately elevated in severe forms of
COVID-19 (inpatient admission and ventilation support), compared
with mild COVID-19 forms managed at home
Chaumont et al., 2022
[132]
Multicenter
observational study
Multicenter registry of 222 adult patients
Neuro-COVID-19 carries a high risk of long-term neuropsychiatric
disabilities, e.g., impaired cognition, persistent smell/taste disorders,
memory complaints, anxiety, or depression
Del Brutto et al., 2021
[133]
Longitudinal
prospective study
Stroke- and seizure-free individuals with pre-
pandemic cognitive assessments, normal brain MRI,
and EEG recordings
Cognitive decline among individuals with mild symptomatic SARS-
CoV-2 infections
Del Brutto et al., 2022
[134]
Longitudinal
prospective study
COVID-19 survivors and noninfected individuals
Cognitive decline associated with long COVID may naturally
diminish over time
Fernández-de-las-
Peñas et al., 2022 [46]
Multicenter cohort
study
1969 individuals
Female sex was a risk factor for the development of some long-term
post-COVID-19 symptoms, including mood disorders, e.g., fatigue,
pain, depressive levels, and worse sleep quality
Frontera et al., 2021
[135]
Prospective
observational study
382 hospitalized COVID-19 patients who survived
and had new neurological issues vs. control group
(395 hospitalized COVID-19 survivors without
neurological problems)
Abnormalities in functional outcomes, ADLs, fatigue, abnormal
cognition, anxiety, depression, and sleep occurred in >90% of patients
6 months after hospitalization for COVID-19
Graham et al., 2021
[136]
Prospective study
50 SARS-CoV-2 laboratory-positive patients
50 laboratory-negative with suspected COVID-19
Non-hospitalized long COVID patients experience mainly brain fog
and fatigue that affect their cognition and QoL; among the other
symptoms are headaches; numbness/tingling; dysgeusia; anosmia;
Diseases 2024, 12, 95 18 of 54
myalgia; depression/anxiety; dizziness; pain; insomnia; short-term
memory deficit; blurred vision; tinnitus; and attention deficit
Huang et al., 2021
[112]
Cohort study
1733 patients
Fatigue or muscle weakness, sleep disorders, anxiety, or depression
were commonly reported
Kubota et al., 2023
[137]
Narrative review
-
Fatigue, cognitive impairment, sleep disorders, depression, anxiety,
and PTSD
Lauria et al., 2022
[138]
Single-center study
100 elderly individuals assessed on average 3
months after acute COVID-19
COVID-19 elicits persistent measurable neurocognitive alterations in
the elderly, particularly in the areas of attention and working
memory
Magnúsdóttir et al.,
2022 [139]
Prospective cohort
study
Seven cohorts across six countries (Denmark,
Estonia, Iceland, Norway, Sweden, and the UK)
aged 18 years or older, up to 16 months after a
diagnosis of COVID-19
Individuals diagnosed with COVID-19 showed a higher prevalence
of depressive symptoms and reduced sleep quality, but did not differ
in terms of anxiety symptoms or COVID-19-related distress,
compared to those without a COVID-19 diagnosis
Marchi et al., 2023
[140]
Systematic review
33 reports: 282,711 long COVID patients
Symptoms mostly associated with Long COVID were depression,
anxiety, cognitive and sleep disturbances, and PTSD
Martino et al., 2022
[141]
Prospective
monocentric cohort
study
64 total patients
Reports after 6 months: anxiety (48.5%), depression (56.4%),
persistent fatigue (37.5%), and memory and attention deficits (11%)
Reports after 12 months: anxiety (50%), depression (61%), persistent
fatigue (12.5%), and memory and attention deficits (4.7%)
Mattioli et al., 2021
[142]
Prospective
monocentric
observational study
120 healthcare workers previously affected by
COVID-19
No evidence of neurological deficits or cognitive impairments in this
specific group of patients with mild to moderate COVID-19 4 months
after diagnosis. Severe emotional disturbances in those who had
COVID-19 confirmed
Mazza et al., 2021
[143]
Prospective cohort
study
226 COVID-19 survivors
The following were observed in the sample: persistent depressive
symptomatology, poor performance in at least one cognitive domain
(78%), with impaired executive functions and psychomotor
coordination in 50% and 57% of the sample
PTSD, anxiety, and insomnia decreased during follow-up session
Mazza et al., 2020
[144]
Cohort study
402 patients surviving COVID-19
COVID-19 survivors presented a high prevalence of emergent
psychiatric sequelae (55% of the sample had a pathological score for
at least one disorder) higher than the average incidence of PTSD,
major depression, and anxiety
Diseases 2024, 12, 95 19 of 54
Naik et al., 2021 [145]
Prospective
observational study
1234 patients: median duration of follow-up session
at 91 days
The most common neuro-long COVID symptoms included fatigue,
insomnia, mood disturbances, and anxiety
Nalbandian et al.,
2021 [11]
Narrative review
-
Psychiatric symptoms: anxiety, depression, sleep disturbances, and
PTSD
Natarajan et al.,
2023 [146]
Systematic review
and meta-analysis
36 studies: 11,598 long COVID patients
Mental health symptoms: depression, anxiety, PTSD, and sleep
disturbances
Premraj et al., 2022
[147]
Meta-analysis
18 studies: 10,530 patients
Psychiatric manifestations (sleep disturbances, anxiety, and
depression) are common and increase significantly in prevalence
over time
Pistarini et al., 2021
[148]
Cross-sectional and
exploratory study
40 patients admitted to rehabilitation units
Patients who recovered in COVID-19 and post-COVID-19 functional
rehabilitation units presented with cognitive deficits
Poletti et al., 2022
[149]
Observational study
312 COVID-19 survivors vs. control group
Neuropsychiatric consequences of COVID-19 persistent after hospital
discharge (partial improvement at 6 months). Cognitive impairment,
in association with depression, has a detrimental impact on QoL
Schou et al., 2021
[150]
Systematic review
66 studies: 266,586 participants
Depression/anxiety, PTSD, cognition, fatigue, sleep disturbances, and
psychotic disorders
Seeβle et al., 2021
[151]
Single-center study
96 patients
Reports at 5 months: fatigue, sleep problems, concentration
problems, and headache. Reports at 12 months: fatigue, sleeping
problems, concentration problems, and headache
Tabacof et al., 2022
[152]
Retrospective cross-
sectional
observational study
design
156 patients
(all pre-vaccinations)
Most common long-lasting symptoms were fatigue, brain fog, and
headache; most affected areas included self-care, anxiety/depression,
and usual activities
Taquet et al., 2021
[153]
Cohort study
62,354 patients
Psychiatric diagnosis could be an independent risk factor for COVID-
19
Taquet et al., 2021
[154]
Cohort study
236,379 patients
Significant neurological and psychiatric morbidity in the 6 months
following COVID-19 infection recorded, particularly in severe
COVID-19 cases
Tomasoni et al., 2021
[155]
Cross-sectional study
Patients with documented clinical recovery and
virological clearance after hospitalization for
COVID-19
29% of the patients suffered from anxiety; 11% of the patients
suffered from depression
Diseases 2024, 12, 95 20 of 54
Wong et al., 2023 [78]
Cross-sectional study
2712 patients
Fatigue, cough, sore throat, difficulty concentrating, feeling of
anxiety, myalgia, and arthralgia are the most common, severe long
COVID symptoms
Xiao et al., 2022 [156]
Cross-sectional study
199 patients
Post-hospitalization and psychosocial factors showed a strong
association with depression, anxiety, and post-traumatic growth
Zakia et al., 2023
[157]
Systematic review
23 articles
Anxiety, depression, sleep difficulties, and PTSD symptoms were
prevalent among long COVID participants
Zawilska et al., 2022
[158]
Narrative review
-
Chronic fatigue, cognitive deficits, depression, anxiety, sleep
disturbances, and sensory issues were common symptoms in long
COVID
Pulmonary function and imaging
Mandal et al., 2020
[159]
Cross-sectional study
384
Persisting symptoms and radiological abnormalities in a significant
proportion of subjects
Taquet et al., 2021
[160]
Retrospective cohort
study
273,618
Long COVID clinical features occurred and co-occurred frequently
and showed some specificity to COVID-19, though they were also
observed after influenza
Lewis et al., 2021
[161]
Retrospective
analysis
80
No difference in pulmonary function was detected before and after
COVID-19 infections in non-critically ill patients
Torres-Castro et al.,
2021 [162]
Review and meta-
analysis
380
Impaired lung function was observed in patients post-COVID-19
infection
Han et al., 2021 [163]
Follow-up study
114
Older age, acute respiratory distress syndrome, longer in-hospital
stays, tachycardia, non-invasive mechanical ventilation, and higher
initial chest CT scores are associated with the changes
Cellina et al., 2020
[164]
Pictorial essay
-
Imaging presentations of COVID-19 pneumonia are mostly GGO
Liao et al., 2023 [165]
Follow-up study
273
The most common CT findings were GGO and parenchymal bands at
the 3- and 6-month follow-up sessions
Espallargas et al.,
2021 [166]
Retrospective
analysis
919
Pulmonary embolism in COVID-19 patients might predominantly
affect segmental arteries and the right lung
Cardiological manifestations
Xie et al., 2022 [167]
Cohort study
153,760
Risk and 1-year burden of cardiovascular disease in survivors of
acute COVID-19 are substantial
Diseases 2024, 12, 95 21 of 54
Zuin et al., 2023 [168]
Meta-analysis
20,875,843
Myocarditis represents relatively rare, but important, post-acute
COVID-19 sequelae
Lewek et al., 2021
[169]
Prospective cohort
study
51
Severe cardiovascular complications in 27.5% of hospitalized patients
Ingul et al., 2022 [170]
Multicenter
prospective cohort
study and cross-
sectional case–
control study
204
Mild impairement of right and left ventricular functions at 3 months
after discharge
Bhatia et al., 2023
[171]
Multicenter
observational study
511
3% of athletes demonstrated de-novo ECG changes post-COVID-19
infection, of which 88% were diagnosed with cardiac inflammation
Kim et al., 2020 [172]
Observational study
510
Adverse RV remodeling predicts mortality in COVID-19 patients
Moody et al., 2021
[173]
Prospective cohort
study
79
Ventricular remodeling in 29% of patients after 3 months
Małek et al., 2021
[174]
Retrospective cohort
study
26
Cardiac abnormalities were found in CMR in a small group of
athletes
Starekova et al., 2021
[175]
Prospective cohort
study
145
Low prevalence of myocarditis (1.4%) among athletes recovering
from COVID-19
Ammirati et al., 2020
[176]
Expert consensus
document
-
Diagnosis and management of patients with myocarditis
Strain et al., 2022
[177]
Observational study
900
COVID-19 vaccination may help long COVID patients
Raman et al., 2022
[165]
Narrative review
-
Definition, epidemiology, and pathophysiology of cardiovascular
manifestations of long COVID
Laranjera et al., 2022
[178]
Systematic review of
longitudinal
observational studies
5371
Electrocardiographic abnormalities indicative of myocarditis are
uncommon in young athletes post-COVID-19
Legend: activities of daily living (ADLs); electroencephalogram (EEG); Magnetic Resonance Imaging (MRI); Montreal Cognitive Assessment (MoCA); quality of
life (QoL); post-traumatic stress disorder (PTSD); liver function test (LFT); disorder of gut–brain interaction (DGBI); and post-infection functional gastrointestinal
disorder (PI-FGID).
Diseases 2024, 12, 95 31 of 54
5.2.2. Gastrointestinal Manifestations
Long COVID, characterized by a constellation of persistent symptoms lasting months
after acute COVID-19 infection, is increasingly recognized. Gastrointestinal (GI) compli-
cations are prevalent in long COVID patients, signicantly impacting patient quality of
life.
In a systematic review, Choudhury et al. report, in around 12% of long COVID pa-
tients, the presence of gastrointestinal symptoms [117]. These manifestations could also
occur in adults who experience mild COVID-19; therefore, they are not related to the se-
verity of acute infection. There is no association between gastrointestinal manifestations
in long COVID and ethnicity or sex [179].
There are four potential mechanisms that link the SARS-CoV-2 infection to the late
development of GI symptoms. Firstly, there may be a direct viral impact, as SARS-CoV-2
may infect GI epithelial cells, leading to inammation and tissue damage [116]. Secondly,
viral infection and immune response may alter the gut microbiome
[118,120,122,123,126,127], possibly contributing to other long COVID manifestations, such
as chronic fatigue. Thirdly, the potential consequences of COVID-19-induced systemic in-
ammation are microvascular injury, aecting blood ow and function in the GI tract
[116]. Additionally, damage to the nerves controlling gut function can lead to motility is-
sues and digestive problems [116,118,123,126,127]. Finally, the persistent shedding of vi-
rions from the GI tract is not excluded [180].
The most common GI manifestations include a loss of appetite, diarrhea, abdominal
pain, nausea and vomiting, dyspepsia, and irritable bowel syndrome (IBS) [116,117].
Loss of appetite is frequently present, with the prevalence ranging from 26% to 66.7%,
depending on studies and populations, and contributing to weight loss and nutritional
deciencies [121,124,126,127].
Diarrhea is also recurrently reported (10.4–41.2%); it can be persistent or episodic,
impacting hydration and electrolyte balance [118–120,124,126,127]. Constipation has also
been reported in some cases, occurring in approximately 6.8% of individuals [181].
Abdominal pain (6.7–41%) can be localized or diuse, often linked to altered gut mo-
tility [120,121,124–127].
Nausea and vomiting are also reported (7.7–61.5%), with a signicant impact on daily
life [118–120,124,126,127].
Dyspepsia is reported in fewer cases, suggesting potential changes in gastric func-
tion, although at least one study did not nd signicant dierences in prevalence for con-
trol subjects [118].
Finally, IBS is also present at a higher prevalence compared to the general population
(0.3 vs. 3.2%), suggesting a possible link to COVID-19-induced gut dysbiosis [118].
Researchers found that gut dysbiosis persists for months, also after SARS-CoV-2
clearance, and contributes to long-term symptoms [182]. In particular, the depletion of
commensal anti-inammatory gut bacteria was observed, which correlated with an in-
crease in the C-reactive protein and, consequently, a pro-inammatory state [179].
Specically for GI manifestations, management strategies range from: dietary modi-
cations, with personalized dietary adjustments considering specic symptoms and nu-
tritional needs; probiotics, which may help restore gut microbiota balance and improve
symptoms like diarrhea and bloating; medications, specic medications targeting symp-
toms like diarrhea, constipation, or acid reux; psychological support, stress manage-
ment, and anxiety reduction techniques can positively impact gut function; and emerging
therapies, exploring the potential of fecal microbiota transplantation and neuromodula-
tion for complex cases.
The research priorities regarding the involvement of the GI tract and long COVID are
geared toward understanding the precise mechanisms of GI complications, identifying
risk factors, and developing targeted therapies. In particular, there is a need for the indi-
vidualized management of the symptoms arising, tailoring treatment approaches based
on specic patient proles, and symptom presentations.
Diseases 2024, 12, 95 32 of 54
In Table 3, the main selected studies on GI symptoms in adult patients with long
COVID are reported.
5.2.3. Neurological and Neuropsychiatric Issues
Neurological and neuropsychiatric symptoms are commonly present in long COVID
patients and can last for weeks, even months, after recovery [157].
Neurologically, long COVID is marked by a wide spectrum of symptoms [183,184].
COVID-19 patients frequently exhibit a range of neurological complaints: fatigue, cogni-
tive impairment (brain fog, loss of concentration, or memory issues), headache, sleep dis-
turbances, peripheral neuropathy symptoms (pins and needles, and numbness), dizzi-
ness, orthostatic impairment, delirium (especially in the elderly), mobility impairment,
visual disturbances, mood disorders (depression or anxiety), post-traumatic stress disor-
der (PTSD), and sensory decits, like a loss of smell and taste
[10,129,130,132,133,135,136,138,141,142,145,148,149,151,152,154,183,185,186]. Moreover,
COVID-19 is associated with an elevated risk of developing neurological conditions, in-
cluding Guillain–Barré syndrome, and neurodegenerative diseases, such as Alzheimer’s
[184,187,188].
Neurological and neuropsychiatric complications have varied pathophysiologies, en-
compassing immune dysregulation, glial cell activation leading to neuronal damage, in-
ammation, microvascular thrombosis, iatrogenic eects, and psychosocial impacts of the
infection [11,78,153].
Apart from respiratory symptoms, fatigue and neuropsychiatric symptoms have
been the most frequently reported manifestations of long COVID [78].
Within the symptomatology of long COVID, psychiatric disturbances, along with as-
thenia and intolerance to make an eort, play a primary role in terms of frequency and
the impact on daily life, but also in the professional and familiar dimension [139]. Moreo-
ver, patients experience a heavy sense of stigma, not achieving a clear diagnosis, having
diculties to access specialists’ services, presenting inconsistent criteria for advanced di-
agnostic medical examinations, receiving several referrals to other specialists. As a conse-
quence, a considerable degree of emotional feelings, such as anger, frustration, fear, and
hopelessness, are documented among these patients [128].
The prevalence of psychiatric symptoms following SARS-CoV-2 infection varies sig-
nicantly in dierent studies. Indeed, a study conducted in Italy investigated the preva-
lence of anxiety and depression in individuals with long COVID, obtaining results rang-
ing from 10.4% to 42% [144]. Another study conducted in Wuhan, China, reported a prev-
alence of anxiety, depression, and sleep disturbances of about 25%, six months after the
resolution of acute illness [112]. Finally, a large-scale study in the United States, on 62,354
subjects [153], estimated an incidence of psychiatric disorders at 18.1% [156].
Notably, the prevalence of depression, anxiety, cognitive impairment, PTSD, and
sleep disturbances was much higher among long COVID patients than in the general pop-
ulation [131,140]. Interestingly, all these neuropsychiatric manifestations are more fre-
quent in the long term (six months or more after infection) rather than in the rst three
and six months after acute infection [143,147].
A large number of studies have demonstrated that depression and anxiety are the
most commonly reported psychiatric outcomes among SARS-CoV-2 patients [146,155], es-
pecially among females [120,157].
Among the psychiatric symptoms of long COVID syndrome, the most frequent can
be subdivided into ve clusters.
(1) Depression–anxiety. The severity and duration of the acute phase may correlate
with the development of depressive and anxious symptoms. Other risk factors for the de-
velopment of long-term anxiety–depressive disorders include female gender, the presence
of pre-existing psychiatric disorders, and the persistence of symptoms aributable to this
area one month after infection [150,158]. During the pandemic, females tended to have
Diseases 2024, 12, 95 33 of 54
symptoms of hyperreactivity and negative cognitive and mood disturbances, which con-
sequently could lead to depression onset [157].
(2) PTSD. Risk factors for the development of PTSD include a more severe SARS-
CoV-2 infection, especially with the need for intensive care unit admission, female gender,
and a pre-existing diagnosis of anxiety–depressive disorder [150].
(3) Cognitive disorders. This category includes concentration disorders, short-term
and general memory disorders, reduced aention capacity, language disorders in terms
of uency and encoding, coordination decits, and signs or symptoms of dementia (ac-
cording to the ICD-10 diagnostic criteria). Risk factors include advanced age, the presence
of pre-existing comorbidities, and high severity and duration of the acute phase of
COVID-19 [134,150,158].
(4) Fatigue. This is a condition dened as a reduction in physical and psychological
performances generated by central, psychological, or peripheral changes caused by SARS-
CoV-2 infection. This manifestation often occurs in the acute phase and can persist in the
long term. Risk factors for this condition include female gender and a pre-existing psychi-
atric diagnosis [150].
(5) Sleep disturbances. Sleep alterations seem to be independent of the severity of
COVID-19 infection in the acute phase, which instead seems to be correlated with sleep
disturbances that emerge during follow up. Another risk factor for their development is
the female gender [150]. While the duration of sleep disturbances following COVID-19
remains uncertain, a study revealed that 10% of patients hospitalized for COVID-19 expe-
rienced poor sleep quality, even 12 months after discharge. The link between long COVID
and circadian rhythm disorders has also been elucidated. A retrospective cohort study in
Ukraine found that delayed sleep phase disorders were associated with COVID-19,
whereas advanced sleep phase disorders, irregular sleep phase disorders, and non-24 h
circadian rhythm disorders were not [137].
Long COVID symptoms may either spontaneously resolve or persist, depending on
specic neuropsychiatric symptoms. While there is no established treatment specically
for long COVID, various psychological and pharmacological interventions have been ex-
plored. These include rehabilitation programs for fatigue and cognition, psychological in-
terventions for anxiety, and cognitive processing therapy for PTSD. Most of these treat-
ments have reported signicant improvements, but these results should be considered
preliminary [137].
In Table 3, the main selected studies on psychiatric symptoms in adult patients with
long COVID are summarized.
5.2.4. Pulmonary Function and Imaging
SARS-CoV-2 leads to acute viral respiratory tract infections, including pneumonia.
Following the initial infection with SARS-CoV-2 in the upper respiratory tract, viral rep-
lication persists in the lower airways and alveolar epithelial cells. This triggers a hyper-
inammatory immune response, causing damage to the alveoli and vascular leakage.
Data on the early post-acute COVID-19 phase reveal that up to six months post-in-
fection, COVID-19 patients show a paern of pulmonary restriction and abnormal carbon
monoxide diusion capacity in lung function testing. Similar results were seen 6–12
months after symptom onset in prospective cohort studies [159,160].
Several studies have examined post-COVID-19 pulmonary function tests (PFTs). A
study of 80 patients who underwent both pre-infection and post-infection PFTs showed
no dierence in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1),
FEV1/FVC ratio, and DLCO. However, total lung capacity (TLC) signicantly worsened,
correlating with more severe disease (none of the patients were intubated in this study)
[161]. Other systematic reviews, comprising seven studies, have indicated that reduced
DLCO, restrictive paerns, and obstructive paerns were observed in 39%, 15%, and 7%
of patients, respectively, 3 months after COVID-19 infection [162].
Diseases 2024, 12, 95 34 of 54
Due to severe respiratory inammation and injury, one of the potential manifesta-
tions after COVID-19 is lung brosis caused by the cytokine storm [189].
In a follow-up chest CT study of patients after COVID-19, brotic-like changes were
observed in 35% of the participants. The remaining 65% exhibited either a complete radi-
ologic resolution (38%) or residual ground-glass opacication or interstitial thickening
(27%) [163]. Prospective studies assessing these complications will help identify individ-
uals at the highest risk. Advanced imaging studies, combined with physiological markers,
may uncover previously unknown or underrecognized pathologies. Overall, persistent
ground-glass opacication is the most common radiographic sequela followed by brotic
changes.
Han et al. investigated the characteristics and time course of pulmonary sequelae fol-
lowing recovery from COVID-19 using regular pulmonary function evaluations and CT
scan follow ups. The authors evaluated 67 patients discharged from their hospital with a
three-year post-hospitalization follow up. Follow-up visits consisted of anamnesis, phys-
ical examinations, PFTs, and HRCTs of the chest. Lung function impairment was meas-
ured by performing a pulmonary function test. The recorded parameters included TLC,
FVC, residual volume (RV), FEV1, maximum expiratory ow rate (MEF75/25), FEV1/FVC
ratio, and DLCO measured by means of the single-breath test. DLCO was expressed as a
percentage of predicted normal values and reported as a categorical variable, as dened
by the guidelines of the American Thoracic Society (ATS) and European Respiratory Soci-
ety (ERS). Anomalies were noted as DLCO % predicted with mild reduction (mean value
72% pred) and total lung capacity (TLC) % predicted with mild restrictive lung disease
(mean value 72% pred). The mean value for FEV1/FVC was >70 [163].
Computed tomography is a valuable tool for the diagnosis and the follow up of
COVID-19 pneumonia, and is considered the reference standard for imaging the chest of
patients, providing useful insights into the progression and resolution of the disease [164].
In the early stages of infection, CT scans commonly reveal ground-glass opacities, consol-
idations, and crazy-paving paerns in the lungs. However, as the patients recover, these
ndings may gradually lessen, and signs of improvement, such as decreased opacities and
resolution of lung involvement, may become evident. In the post-acute phase, CT imaging
may still show residual abnormalities, such as brotic changes, which can have implica-
tions for long-term lung function [165]. Additionally, CT scans can help in identifying po-
tential secondary complications, such as pulmonary embolism or bacterial superinfection,
which may arise during the recovery period [166].
In a cohort study, 919 patients underwent chest CT scans during a follow-up period.
A radiological scoring system was used to quantify the presence of typical parenchymal
lung ndings associated with COVID-19 pneumonia. The following alterations have been
evaluated: ground-glass opacities (GGOs), interstitial thickening, consolidation, bronchi-
ectasis, brotic alterations, and honeycombing. Each of the ve lung lobes was evaluated
individually for each of the described alterations and was assigned a score in the range of
0–5 to indicate the percentage of involvement: 0—absence of lesions, 1—alterations in-
volving <5% of the lobe, 2—lesions involving 5–25% of the lobe, 3—lesions involving 25–
50% of the lobe, 4—lesions involving 50–75% of the lobe, and 5—lesions involving >75%
of the lobe. The total CT score for each lung was evaluated by summing the scores of the
individual lobes. Most of the patients presented brotic bands, septal thickening, and
bronchiectasis (52, 38, and 23 patients, respectively). Both lungs were involved with multi-
lobar aection [166].
It is necessary to follow up COVID-19 patients after their recovery through compre-
hensive assessments with a focus on respiratory manifestations and, if necessary, begin
early treatment.
In Table 3, the main selected studies on pulmonary function and imaging in adult
patients with long COVID are summarized.
Diseases 2024, 12, 95 35 of 54
5.2.5. Long COVID and Cardiovascular Diseases
The cardiovascular symptoms of long COVID rank as the third most-frequent mani-
festation of the disease, following neurological and pneumological symptoms. These
symptoms result from various cardiac and extracardiac pathological sequelae, including
residual respiratory abnormalities, pulmonary hypertension, muscular deconditioning,
cytokine dysregulation, left or right ventricular dysfunctions, chronotropic incompetence,
altered parasympathetic tone, and increased heart rate variability [190–193].
Patients who required hospitalization during the acute phase of COVID-19 exhibit
more severe cardiovascular symptoms in long COVID compared to those with mild to
moderate or asymptomatic cases, and with a signicantly higher incidence [167,194–196].
Aected individuals may experience hypotonia, palpitation, chest pain, hyperten-
sion, elevated blood pressure, tachycardia out of proportion to that expected for eort,
and/or drops in oxygen saturation [191]. Several studies have reported cardiac complica-
tions and their prevalence in patients with long COVID. A meta-analysis assessed the risk
of incident myocarditis within 12 months after COVID-19 recovery: over a mean follow
up of 9.5 months, myocarditis occurred in 21/100,000 patients compared with 9/100,000
controls [168].
Another meta-analysis assessed the risk of incident pericarditis within 12 months af-
ter COVID-19 recovery. Over a mean follow up of 9.6 months, pericarditis occurred in
3.4/1000 patients compared with 80/100,000 controls [168]. Delayed-onset myocarditis has
been described after the viral clearance of SARS-CoV-2, probably triggered by immune-
mediated reactions [197], sometimes in the context of the Multisystem Inammatory Syn-
drome in Adults (MIS-A) and Children (MIS-C) [198,199], an uncommon SARS-CoV-2 in-
fection complication, characterized by hyperinammation with cardiovascular involve-
ment [200].
Other cardiac complications and their prevalence in long COVID patients are systolic
or diastolic left ventricular dysfunctions (prevalence: 0.06–35%) [169,170,201], coronary
artery disease (8%) [173], acute myocardial infarction (1.5–8%) [173], heart failure (0.1–2%)
[202], and pulmonary hypertension (10–50%) [203].
Postural Orthostatic Tachycardia Syndrome (POTS) is also described in patients with
long COVID [204–206]. Patients with POTS typically experience a heart rate increase of
more than 30 beats per minute compared to their resting heart rate after standing quietly
for 5–10 min (often exceeding 120 bpm) without orthostatic hypotension. They commonly
report postural symptoms, such as palpitations, dizziness, weakness, fatigue, blurred vi-
sion, and intolerance to exercise [206].
The mechanisms underlying persistent cardiac damage following acute illness are
still not well-understood. One potential explanation is a chronic inammatory response
triggered by lingering viral reservoirs in the heart after the initial infection [207]. Another
mechanism for delayed damage involves an autoimmune response targeting cardiac an-
tigens due to molecular mimicry [208]. A high-throughput proteome analysis by Wang
and colleagues has identied a variety of autoantibodies against humoral and tissue anti-
gens in patients with severe COVID-19 [209–211].
Several longitudinal studies focusing on cytokine proling and proteomics have
shown an increased expression of prothrombotics persisting beyond the acute phase of
infection [212,213]. This is consistent with growing reports of delayed embolic complica-
tions [214–216]. Endothelial dysfunction and its associated complications may also arise
in patients, with evidence of ongoing impairment observed in younger individuals 3–4
weeks after SARS-CoV-2 infection [217,218].
Dierent reports have explored the utility of a 12-lead electrocardiogram (ECG) in
screening patients for post-acute cardiac manifestations [174,175]. Dynamic ECG changes
are common during acute illness, but tend to resolve in the majority of hospitalized pa-
tients by 6 months after acute COVID-19 and often resemble those of risk-factor matched
controls [171,174,175]. However, sinus arrhythmia remains common in the post-acute
Diseases 2024, 12, 95 36 of 54
phase, presenting as transient or sustained episodes of sinus tachycardia or bradycardia
[174,175].
A systematic review of longitudinal observational studies performed on young ath-
letes during post-COVID-19 periods showed that electrocardiographic abnormalities in-
dicative of myocarditis were uncommon [178].
ECG combined with the tilt table test is useful for the diagnosis of POTS [219].
Both transthoracic echocardiography and Cardiac Magnetic Resonance (CMR) play
crucial roles in diagnosing both acute and chronic cardiac conditions.
While endomyocardial biopsy serves as the gold standard for histological evalua-
tions in suspected severe cases [176], CMR oers a non-invasive alternative for assessing
stable cases. CMR provides valuable insights into various pathological processes, such as
myocardial edema, hyperemia, necrosis, and brosis, by detecting changes in the tissue’s
fundamental magnetic properties [176].
Echocardiography is essential for the early detection of cardiac abnormalities in
COVID-19 patients (including suspected myocarditis, Takotsubo syndrome, myocardial
infarction, and pericardial eusion), especially when hemodynamic stability is uncertain
[220]. Right ventricular dilation and dysfunction are the most commonly observed echo-
cardiographic abnormalities with prognostic implications [172,173,221]. As the acute in-
fection subsides [172], most patients show an improvement in right ventricular abnormal-
ities [173]; left ventricular systolic dysfunction is relatively less common [173].
Myocarditis management and treatment of long COVID syndrome depends on the
severity of symptoms, complications, onset, and hemodynamic stability vs. instability. It
is recommended that patients experiencing heart failure as a result of COVID-19 myocar-
ditis should be treated by established medical guidelines. This involves the administration
of ACE inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor neprilysin
inhibitors (ARNi), vasopressors, β-blockers, and diuretics [222]. Usually, patients with
myocarditis and COVID-19 pneumonia who still require supplemental oxygen should re-
ceive corticosteroid treatment [223]. The use of intravenous corticosteroids might be con-
sidered for those with suspected or conrmed COVID-19 myocarditis accompanied by
hemodynamic compromise or MIS-A, a hyperinammatory state characterized by acute
heart failure and cardiogenic shock without sepsis. This approach has been linked to a
favorable prognosis in a small series of cases [224]. The empirical use of immunosuppres-
sive therapy, such as corticosteroids, might also be considered for individuals with bi-
opsy-proven severe myocardial inammatory inltrates or fulminant myocarditis, taking
into account the risk of infection [225].
In regard to pericarditis, the management of this post-COVID-19 manifestation relies
on nonsteroidal anti-inammatory drugs (NSAIDs) that can help alleviate chest pain (e.g.,
ibuprofen, indomethacin, and aspirin) [226]. Low-dose colchicine or prednisone is admin-
istered for persistent chest pain, with a strategy to gradually reduce the dosage, depend-
ing on symptoms and clinical assessments [226]. Low doses of steroids are also used to
relieve the asthenia that many patients report. Anakinra is less used in these forms of per-
icarditis. A low-dose beta-blocker or a non-dihydropyridine calcium-channel blocker can
be introduced and adjusted gradually to reduce the heart rate. This approach may slightly
enhance exercise tolerance, alleviate symptoms, and patients can gradually discontinue
these medications as their tness and activity levels improve. Ivabradine is another option
for those experiencing severe fatigue worsened by beta-blockers and calcium-channel
blockers.
The duration of the therapy is often long, also due to the numerous relapses that
patients experience. The tapering of the therapy should be slow and based on the clinical
response and the symptoms.
For patients experiencing PASC, treatment for cardiac manifestations is primarily
symptomatic, including the use of anti-vasospastic drugs for those with atypical angina
or beta-blockers for palpitations [190]. Treatment strategies for POTS include alpha-1 ag-
onists, steroids, compression garments, and increased uid and salt intake. Non-steroidal
Diseases 2024, 12, 95 37 of 54
anti-inammatory drugs may be employed to manage specic symptoms, such as fever
and pain [23].
Ultimately, the most eective means of preventing severe complications from
COVID-19 is vaccination [227]. The data from an observational study indicate that vac-
cinations may alleviate long COVID symptoms in 56.7% of cases [177].
In Table 3, the main selected studies on cardiovascular diseases in adult patients with
long COVID are summarized.
6. Long COVID in Vulnerable Adults
6.1. Long COVID in Pregnant Women
In the following years, the long-term eects of acute infection have become increas-
ingly important, revealing a wide range of sequelae. Particularly noteworthy is the impact
of long COVID on gynecological and obstetric health, emerging as a growing eld of in-
terest and study in the medical community.
Compared to the non-obstetric population, pregnant women are considered a popu-
lation at risk since the incidence of clinical manifestations, severity of symptoms, and as-
sociated obstetric morbidity seem to be increased [228].
Dierent studies have established a higher incidence of obstetric complications (pre-
term labor, preterm birth, preeclampsia, cesarean delivery, and miscarriage) in patients
with moderate and/or severe infections [229,230], but women in general appear to be sus-
ceptible to prolonged and diversied eects.
The evidence indicates that long COVID disproportionately aects women, with
about twice as many women being impacted compared to men [231]. Additionally,
women before menopause are at a higher risk of long COVID, suggesting a potential role
of sex hormones in the development of this condition [232].
For these reasons, interest in the potential implications of long COVID in gynecology
and obstetrics has signicantly increased, with particular aention on the impact on men-
strual cycles, reproductive health, pregnancy, and maternal well-being. The role of immu-
nological changes and hormonal imbalances is also examined to fully understand how
long COVID may inuence women’s health in various life stages.
6.1.1. Long COVID and Pregnancy
The diagnosis and management of long COVID are challenging, more so in pregnant
women. Given the overlap with normal pregnancy symptoms, women experiencing fa-
tigue and/or shortness of breath may be at an increased risk of worsening in pregnancy,
especially in the third trimester [233].
The impact of COVID-19 infection acquired during pregnancy has been extensively
studied and its eects have been demonstrated, such as a signicant increase in the risk
of preeclampsia [234], elevated maternal and perinatal death rates aligning with each
wave of the pandemic [235], and a higher occurrence of neurodevelopmental disorders in
infants during the initial 12 months after birth for mothers infected during pregnancy
[236]. Although, there is currently no scientically valid literature that oers insights into
the development of the long-term consequences of COVID-19 infection in pregnant
women who have recovered from SARS-CoV-2 infection before or during the early weeks
of pregnancy.
Probably, due to the physiological modications that women experience during the
gestation period, the manifestation of long COVID symptoms may dier from what has
been observed in the general population or in non-pregnant women.
Long COVID in pregnancy represents a multisystem disorder with signicant diag-
nostic challenges, as more than 200 symptoms associated with the disorder can easily be
mistaken for other common conditions.
Limited research has delved into the impact of long COVID on pregnant individuals.
An Ecuadorian cross-sectional survey indicated that pregnant (n = 16) and non-pregnant
Diseases 2024, 12, 95 38 of 54
(n = 231) women with long COVID exhibited similar symptoms, with fatigue, hair loss,
and diculty concentrating being the top-three reported symptoms for both groups [237].
Also, a single-center, cross-sectional, retrospective study on 99 pregnant women who
were polymerase chain reaction (PCR)-positive for COVID-19, conducted by Kandemir,
showed that many women experienced long COVID after suering acute COVID-19 dur-
ing pregnancy, but long COVID prevalence was similar to the general population. In par-
ticular, long COVID correlates with the severity, type, and number of symptoms of acute
COVID-19 [238].
A prospective cohort study involving a longitudinal cohort of ambulatory pregnant
patients in the United States revealed that 25% experienced long COVID symptoms eight
or more weeks after testing positive for SARS-CoV-2 [239].
6.1.2. Post-Viral Fatigue in Pregnant Women
A longitudinal comparative study assessed post-viral fatigue (PVF) following SARS-
CoV-2 infection during pregnancy, revealing a higher prevalence of PVF in women in-
fected during pregnancy. The risk of developing fatigue and its duration increased with
the severity of the infection [240].
However, investigations into how long COVID specically aects pregnancy are still
lacking.
A signicant but relatively small control-matched prospective cohort study con-
ducted in Brazil monitored pregnant women following a positive COVID-19 diagnosis (n
= 84), revealing that 75.9% developed long COVID. This study also highlighted that preg-
nant individuals administered glucocorticoids for treating COVID-19 were at a higher risk
(RR 6.92, 95% CI 1.70–28.07) of persistent fatigue, a pivotal and debilitating symptom as-
sociated with long COVID [241].
A more recent study involved 409 pregnant women diagnosed with acute COVID-
19, with 286 participants followed up for an average of 92 weeks. Among these women,
140 displayed post-COVID-19 symptoms three months after infection, with neurological
(60%) and cutaneous (55%) manifestations being prevalent. The following proles were
identied as having an elevated risk of developing post-COVID-19 conditions: migrant
women born in countries with a lower human development index; multiparous women;
women who contracted COVID-19 during pregnancy, with a higher number of symptoms
and experiencing a greater incidence of moderate and severe symptoms; and women who
required hospitalization due to COVID-19 complications and who were not vaccinated
prior to the onset of the disease. Perinatal outcomes showed no signicant dierences.
Women infected during successive pandemic waves consistently exhibited a de-
crease in the risk of post-COVID-19 conditions. Certain symptoms, especially myalgia
and arthralgia, persisted for an extended period before resolving, and a small but notable
proportion experienced chronic neurological and psycho-emotional symptoms after 90
weeks. In total, 34.2% of obstetric patients with acute COVID-19 displayed symptoms of
post-COVID-19 conditions, highlighting demographic and disease-related risk factors
[242].
6.1.3. Prevention of the Post-COVID-19 Condition in Pregnant Women
One of the potential future consequences of long COVID symptoms in pregnant
women could involve a rise in the frequency of prenatal medical visits, primarily due to
the aftermath experienced by pregnant patients, as previously observed in the Swiss pop-
ulation [243].
This not only places a substantial burden on healthcare systems, but also heightens
the likelihood of pregnant women contracting hospital-associated illnesses, including in-
fections like COVID-19.
Diseases 2024, 12, 95 39 of 54
Consequently, the ongoing implementation of protective measures remains crucial
for pregnant women grappling with long COVID. These measures, including mask usage,
social distancing, and vaccination, stand out as cost-eective and ecient strategies.
Furthermore, the obstetric care for pregnant women dealing with long COVID sequelae should
be personalized to ensure the well-being of both the mother and the fetus [244].
The summary of main studies on long COVID in pregnant women is reported in Table 4.
Diseases 2024, 12, 95 33 of 54
Table 4. Summary of the main studies on long COVID in pregnant women.
First Author, Year
of Publication
Study Type
Population
Results
Sahin et al., 2021
[244]
Review
Pregnant women
SARS-CoV-2 infection can quickly lead to severe disease and higher rates of obstetric
complications
Menges et al., 2021
[243]
Population-based cohort
study
431 adults
A significant proportion of participants experienced longer-term consequences following
SARS-CoV-2 infection
Muñoz-Chápuli
Gutiérrez et al.,
2024 [242]
Observational prospective
study
409 pregnant women
34.2% of obstetric patients presented post-COVID-19 symptoms
Santos et al., 2022
[241]
Prospective cohort study
84 pregnant women
Pregnant women, mildly symptomatic, presented a greater risk of long-term complications,
including ultrasound abnormalities, preterm birth, and postnatal depression
Oliveira et al., 2022
[240]
Longitudinal comparative
study
588 pregnant women
The prevalence and duration of post-viral fatigue are higher in women infected during
pregnancy, increasing with the severity of the infection
Afshar et al., 2020
[239]
Prospective cohort study
991 adults
COVID-19 has a prolonged and nonspecific disease course during pregnancy and in the 6
weeks after pregnancy
Kandemir et al.,
2024 [238]
Single-center, cross-
sectional, retrospective
study
99 pregnant women
Long COVID prevalence was similar to the general population, correlating with severity,
type, and number of symptoms of acute COVID-19
Vásconez-González
et al., 2023 [237]
Cross-sectional
comparative analysis
457 surveys
The most common long COVID symptoms were fatigue, hair loss, and a difficulty
concentrating
Edlow et al., 2022
[236]
Retrospective cohort study
7772 live births, 7466
pregnancies, and 222
births to SARS-CoV-2-
positive mothers
Maternal SARS-CoV-2 infection may be linked to neurodevelopmental sequelae in some
offspring
Abbas-Hanif et al.,
2022 [235]
Editorial
Adults
COVID-19 during pregnancy increases the risk of severe complications for both the mother
and child
Villar et al., 2021
[234]
Multinational cohort study
2130 pregnant women
Consistent association between pregnant individuals with a COVID-19 diagnosis and higher
rates of adverse outcomes
Machado et al.,
2022 [233]
Editorial
Adults
Women with symptoms suggestive of long COVID should have the diagnosis confirmed
and their health optimized before becoming pregnant
Diseases 2024, 12, 95 34 of 54
Sigfrid et al., 2021
[231]
Prospective, multicenter
cohort study
327 hospitalized
participants
Long-term symptoms, new disabilities, increased breathlessness, and reduced quality of life
were noted in young females
Marchand et al.,
2022 [229]
Systematic review and
meta-analysis
754 COVID-19-positive
pregnant women
Pregnant women who test positive for COVID-19 seem to be at a higher risk of lower birth
weights and premature deliveries
Allotey et al., 2020
[228]
Systematic review
67,271 women
Pregnant and recently pregnant women with COVID-19 are more likely to be admitted to
the intensive care unit or require invasive ventilation compared to non-pregnant women of
a reproductive age
Metz et al., 2022
[230]
Retrospective cohort study
14,104 pregnant and
postpartum patients
Among pregnant and postpartum women, SARS-CoV-2 infection was linked to a higher risk
of a combined outcome of maternal mortality or severe morbidity due to obstetric
complications
Diseases 2024, 12, 95 37 of 54
6.2. Long COVID in Cancer Patients
The impact of long COVID on cancer patients adds another layer of complexity. Can-
cer patients, who are often immunocompromised due to their disease and/or treatment,
may face unique challenges when dealing with long COVID. The interplay between the
immune system, the eects of cancer treatments, and the persistent inammatory re-
sponse associated with long COVID can complicate the recovery process for these indi-
viduals. Research has indicated that cancer survivors, particularly those who have under-
gone treatments like chemotherapy or stem cell transplantation, may be at an increased
risk of experiencing prolonged symptoms of fatigue, respiratory issues, cognitive dicul-
ties, and other lingering eects associated with long COVID. The pre-existing vulnerabil-
ities in these patients’ immune systems may contribute to a protracted recovery period.
6.2.1. Epidemiological Data for Cancer Patients
The data available for cancer patients and long COVID are heterogeneous, mainly
due to the dierent populations examined and the period of observation.
Most data, represented in three of the nine studies analyzed, were collected from the
OnCovid European Registry study.
Pinato et al. conducted their analysis on an active European OnCovid registry that
involved 37 institutions across six countries [245]. The data lock for the analysis was 1
March 2021, and only 7% of the patients had at least one dose of the anti-SARS-CoV-2
vaccine. The prevalence of long COVID was 15%. The most common sequelae included
respiratory symptoms (49.6%), residual fatigue (41%), weight loss (5.5%), neurocognitive
symptoms (7.3%), non-respiratory organ dysfunction (1.7%), and other complications
(18.4%). The highest prevalence of sequelae was observed in men compared to women (p
= 0.041), aged 65 years or older, compared with other age groups (p = 0.048); those with
two or more comorbidities compared with one or none (p = 0.0006) had a history of smok-
ing compared with no history (p = 0.0004); those with higher rates of COVID-19 compli-
cations (p < 0.0001), requiring therapy for COVID-19 (p = 0.0002); and requiring hospitali-
zation (p < 0.0001). The distribution of primary tumors was also signicant dierent be-
tween the two groups (p = 0.048) [246].
An updated follow up of the OnCovid registry was conducted by Cortellini et al.,
with a database lock of 2 February 2022 [247]. The prevalence of sequelae from COVID-19
was 16.6%, with 9% having respiratory sequelae, 7% prolonged fatigue, 1.6% weight loss,
2.9% neurocognitive sequelae, and 1.3% reporting other categories of organ dysfunction.
The authors conducted several analyses to evaluate the impact of vaccinations, the Alpha–
Delta phase, and the Omicron phase on the onset of long COVID sequelae and risk factors.
Unvaccinated patients were at a high risk of experiencing COVID-19 sequelae regardless
of the viral strain. When comparing unvaccinated and vaccinated patients, the prevalence
of post-COVID-19 sequelae was higher among current or former smokers. Patients who
received a booster dose and those who received two vaccine doses had a signicantly
lower prevalence of overall COVID-19 sequelae compared to unvaccinated patients.
Thereafter, a long-term follow up on the OnCovid registry was performed with the
aim to describe the prevalence and type of COVID-19 sequelae at 6 and 12 months [248].
The prevalence was 9.8% and 8% at 6 and 12 months, respectively. At the 6-month follow
up, 4.9% had respiratory sequelae, 3.2% fatigue, 2.2% neurocognitive sequelae, and 2.7%
other kinds. At the 12-month follow up, 3% had respiratory sequelae, 3% had fatigue, 1%
had neurocognitive sequelae, and 3% had other types. Patients suering from sequelae
were more likely smokers (p = 0.007) and had a history of complicated COVID-19 (p =
0.0223).
An Italian prospective study on COVID-19 cancer patients collected data on the inci-
dence of long COVID symptoms by a telephonic survey [249]. Twelve patients (12.4%)
reported sequelae, all who were vaccinated with three doses of mRNA vaccines. Speci-
cally, 33.3% reported myalgia, while the majority reported fatigue (58.3%) and brain fog
Diseases 2024, 12, 95 38 of 54
(50%). Only 25% had respiratory symptoms. In the univariate analyses, only the female
sex (p = 0.024), obesity (p = 0.039), and diabetes mellitus (p = 0.014) were shown to relate to
the occurrence of long COVID symptoms.
One-hundred cancer patients receiving care at the University of Texas MD Anderson
Cancer Center were screened by questionnaires for 14 days after COVID-19 infection, then
weekly for three months, and then monthly thereafter [250]. More than half reported
symptoms persisting at least 30 days after the COVID-19 diagnosis. The most commonly
reported symptoms were fatigue (82%), sleep disturbance (78%), myalgia (67%), gastroin-
testinal symptoms (62%), headache (47%), altered smell and taste (47%), dyspnea (47%),
and cough (46%). It is noteworthy that none of these patients were vaccinated.
Another monocenter study involved oncological patients at Guy’s Cancer Center in
London [251]. Patients were contacted by using telephone survey. Symptoms were de-
scribed according NICE guidelines [185] and classied as long COVID if they persisted
over 4 weeks after COVID-19 diagnosis. Half of the patients investigated developed long
COVID. The most frequently reported symptoms by patients included fatigue (78%),
breathlessness (53.7%), cognitive impairment (46.3%), sleep disturbances (39%), loss of
taste (34.1%), and depression (29.3%). Breast, lung, and CNS cancers were the cancer types
most commonly associated with long COVID. There were no signicant dierences ob-
served between the disease stage and the incidence of long COVID.
A retrospective international multicenter study was conducted with the aim to de-
scribe the outcomes of hematological patients infected by SARS-CoV-2, and the authors
reported data on long COVID sequelae [252]. The incidence of post-COVID-19 symptoms
at 3 and 6 months was 7.5% and 9.2%, respectively.
A multicenter retrospective study conducted through a combination of in-person vis-
its, EMR data, and telephone calls documented an incidence of long COVID symptoms in
30% of cancer patients [253]. The incidence at 12 months was lower than 6 months (8.3 vs.
15%). The symptoms were classied as respiratory (cough, shortness of breath, dyspnea,
wheezing, hypoxia, etc.), constitutional (fatigue, weakness, poor appetite, weight loss,
etc.), psychiatric (delirium, brain fog, insomnia, anxiety, etc.), and neurologic (memory
decit, dysgeusia, anosmia, headache, etc.). The most common sequelae at 6 and 12
months were respiratory (2.4% vs. 2.8%), constitutional (12% vs. 2.8%), and psychiatric
(2.4% vs. 2.8%).
An original paper was the result of a longitudinal online survey performed during
the pandemic in a large cohort of cancer patients [254]. Cohort 2 was designed to investi-
gate symptoms lasting more than 6 months, with 37 patients evaluated, 11 of whom were
not vaccinated. The predominant symptoms observed were fatigue at 66%, followed by a
loss of taste or smell at 30%, muscle or joint pain at 28%, dizziness at 23%, and respiratory
symptoms at 19%. Additionally, more than 10% of the patients reported symptoms like
muscle weakness, sleep disturbances, headaches, cough, and palpitations. Those who de-
veloped enduring symptoms were predominantly women (although not signicantly so)
and more commonly had a BMI over 30 or pre-existing conditions, such as hypertension,
cardiovascular disease, or asthma.
6.2.2. Risk Factors of Long COVID in Cancer Patients
Numerous risk factors have been associated with the development and severity of
COVID-19 infection in cancer patients [89,255]. Hospitalization or treatment for acute in-
fection in cancer patients, as well as a previous history of smoking, male sex, higher
comorbidity, and older age, have been considered risks for experiencing PASC, as re-
ported in non-cancer populations [246]. In the only comparative study, no signicant dif-
ference in the prevalence of long COVID was observed between cancer patients and a non-
cancer control cohort in the rst 12 months after infection, despite the dierence in mor-
tality between the two cohorts [253].
Both hematological and solid cancer patients have a similar incidence of COVID-19
sequelae, although hematological patients have reported the highest rates of anticancer
Diseases 2024, 12, 95 39 of 54
treatment modication and discontinuation [246]. In the population studied by Visentin
et al., including patients diagnosed with chronic lymphocytic leukemia (CLL) on active
treatment or who received treatment in the previous 12 months, 16% developed post-
COVID syndrome, consistent with the frequency observed among patients with cancer in
OnCovid studies (15%) [248].
Considering patients without metastatic or advanced disease, as in the study by Cor-
tellini et al., the incidence was 16.6% at the rst follow up at 2.3 months from COVID-19
diagnosis, with no association with oncological features or the receipt of anti-cancer treat-
ment within 4 weeks of COVID-19. In smaller series compared with the non-long COVID
group, the highest rate of long COVID was observed in breast cancer (17% vs. 5.1), lung
cancer (14% vs. 2.6%), and CNS (9.9% vs. 2.6%), without dierences in stage [251]. Only
breast cancer has been conrmed to be associated with long COVID in Lasagna et al.’s
study, where PASC was observed in 12.6% of interviewed patients with solid cancer on
treatment [249]. No association between cancer characteristics (e.g., tumor stage or cancer
treatment) and COVID-19 sequelae was found in the OnCovid Registry [246].
The duration of follow up or the waves analyzed are also important parameters for
the prevalence of long COVID. Cortellini et al. showed 9.8% and 8% sequelae present at 6
and 12 months, respectively, after acute infection [248]. He also demonstrated in another
study that Omicron infection was associated with a reduction in PASC compared with
infections contracted during previous phases of the pandemic (6.2% vs. 16.8%) [247]. This
could explain the wide range of PASC described in literature in both non-cancer and can-
cer patients, respectively, 13–60% and 9.8–60.2% [246,256,257].
6.2.3. Vaccines and Long COVID in Cancer Patients
For the rst time in the analysis of the OnCovid Registry, in 2022, it was documented
that cancer patients with full vaccination were characterized by a lower probability of se-
vere COVID-19 infection and mortality compared to controls. Reduced symptomatic
COVID-19, the need for COVID-19-oriented therapy, complications, hospitalizations due
to COVID-19, and oxygen therapy requirements were observed. Furthermore, the propor-
tion of patients reporting at least one sequela from COVID-19 was signicantly lower in
fully vaccinated patients compared to unvaccinated controls (6.7% vs. 17.2%) [245]. More
recently, it was conrmed by Cortellini et al., based on the OnCovid Registry with a longer
follow-up session, where the data support vaccination as a determinant of the reduction
in PASC, when patients received a booster or two vaccine doses [247].
A higher incidence of long COVID, with 60.2% of patients reporting symptoms at
least 30 days after being diagnosed with COVID-19, has been recorded by Dagher et al. in
the unvaccinated population. The authors analyzed cancer patients followed at the MD
Anderson Cancer Center during the initial period of the COVID-19 pandemic in March
2020; SARS-CoV-2 vaccines were made available only in late 2020 [250]. In contrast, in
CLL-infected patients, there is no protection against PASC with vaccines; nevertheless,
vaccinated individuals had a lower hospitalization rate and beer overall survival than
unvaccinated individuals [252].
6.2.4. Clinical Manifestation of Long COVID in Cancer Patients
While there is certainty about the incidence of PASC in cancer patients, it is more
challenging to accurately gauge the extent of the problem and to beer characterize its
symptoms. As the frequency and presentation of acute COVID-19 signs and symptoms
varied between early and late waves, the same observation applies to SARS-CoV-2 seque-
lae, with inconsistent data across dierent studies [246,254], likely due to various SARS-
CoV-2 variants, patient adherence to shielding measures, and vaccine availability. Simi-
larly, in cancer patients, it can be challenging to dierentiate the origin of some symptoms.
Asthenia, anorexia, and dyspnea are often symptoms related to the disease itself or to
cancer treatments and are unlikely to dier from post-COVID-19 symptoms.
Diseases 2024, 12, 95 40 of 54
In the studies we analyzed, fatigue, headaches, muscle or joint pains, and respiratory
and neurocognitive sequelae were the most prevalent symptoms described, with a wide
range of variability. In Cortellini et al.’s study, a non-metastatic/advanced cohort of pa-
tients showed at least one COVID-19 sequela in 16.6% of patients, including fatigue, neu-
rocognitive, and respiratory sequelae in 7.1%, 3.8%, and 7.6%, respectively [248].
In a smaller population, Lasagna et al. reported fatigue as the main symptom (58%),
followed by brain fog (50%), myalgia (33.3%), and respiratory symptoms (25%) [249]. Fa-
tigue is the symptom most commonly reported as persistent over the long-term follow up.
6.2.5. Long COVID Syndrome and Cancer Outcome
It has been observed that patients experiencing any sequelae from COVID-19 infec-
tion face an increased risk of death because these sequelae can lead to the deferral of on-
cological care.
For patients undergoing cancer treatment at the time of COVID-19 diagnosis, it has
been demonstrated that those who resumed treatment with systemic anticancer therapy
after regimen adjustments had similar post-COVID-19 survival rates to those who re-
sumed or continued their treatment without changes. However, those who permanently
discontinued treatment experienced a signicantly increased risk of death [246]. It is evi-
dent how the persistence of one or more symptoms related to COVID-19 infection can
signicantly inuence the decision and ability to resume cancer treatment. Therefore, it is
essential to provide information and training to healthcare workers to properly recognize
long COVID and collaborate with multidisciplinary teams to oer appropriate medical
and rehabilitation support, thereby improving the patient’s quality of life and promoting
the prompt resumption of cancer programs.
The symptoms reported by patients with long COVID often overlap considerably
with those experienced by cancer survivors and those occurring during chemotherapy,
radiotherapy, targeted therapy, and immunotherapy [11,258]. NICE denes the long-term
eects of COVID-19 syndrome as symptoms that persist or develop after acute COVID-19
infection and cannot be explained by an alternative diagnosis. Therefore, if we analyze the
WHO’s denition of long COVID, which denes sequelae that cannot be aributed to
other causes, it raises the question: “does it also apply to the oncology patient?”.
The summary of the main studies on long COVID in cancer patients is presented in
Table 5.
Diseases 2024, 12, 95 39 of 54
Table 5. Summary of main studies on long COVID in cancer patients.
Authors
Study Design
Population of Interest
Sample Size;
Long COVID
Population
N (%)
Follow-Up
Time
Age, Years
% Female Sex
Outcomes of Interest
Pinato et al., 2021
[246]
Registry study
COVID-19 cancer patients, solid or
hematological malignances (active or
in remission)
1557,
234 (15%)
44 (28–329)
days
<65, 44.9%
≥65, 55.1%
45.5%
Post-COVID-19 sequelae symptom
prevalence,
risk factors
Cortellini et al.,
2023 [247]
Registry study
COVID-19 cancer patients, solid or
hematological malignances (active or
in remission)
1909,
317 (16.6%)
39 (24–68) days
<65, 46.7%
≥65, 53.3%
54%
Post-COVID-19 sequelae symptom
prevalence,
risk factors in vaccinated and
unvaccinated pts
Cortellini et al.,
2022 [248]
Registry study
COVID-19 cancer patients, with the
exclusion of advanced/ metastatic
malignances
186,
18 (9.8%)
100,
8 (8%)
6 months
12 months
<65, 45.2%
≥65, 54.8%
51.6%
Post-COVID-19 sequelae symptom
prevalence at 6 and 12 months, risk
factors
Lasagna et al.,
2023 [249]
Telephone
survey
COVID-19 cancer patients on active
treatment, vaccinated with three
doses of mRNA vaccines
97,
12 (12.4%)
12 weeks
58 (median)
91.7%
Post-COVID-19 sequelae symptom
prevalence and data of patients
treated with early anti-SARS-CoV-2
therapies
Dagher et al.,
2023 [250]
Questionnaire
COVID-19 unvaccinated cancer
patients, solid or hematological
malignances (active or in remission)
312,
188 (60.2%)
14 days
weekly for 3
months
monthly up to
14 months
57,
21–86%
<65, 63%,
≥65, 27%
63%
Post-COVID-19 sequelae symptom
prevalence
Monroy-Iglesias
et al., 2022 [251]
Telephone
survey
COVID-19 cancer patiens, solid or
hematological malignances
80,
41 (51.3%)
Symptoms
occurred/worse
ned 4 weeks
after COVID-
19 diagnosis
<60, 36.6%
>60, 61%
36.6%
Post-COVID-19 sequelae symptom
prevalence,
risk factors
Diseases 2024, 12, 95 40 of 54
Visentin et al.,
2023 [252]
Retrospective
multicenter
study
COVID-19 patients with chronic
lymphocytic leukemia
864,
137 (15.8%)
3 months
6 months
-
-
Overall and symptom prevalence,
risk factors
Fankuchen et al.,
2023 [253]
Cohort study
COVID-19 cancer patients with solid
or hematological malignances and a
matched cohort population
52,
15 (29%)
3 months
6 months
12 months
71,
61–83%
45%
Overall and symptom prevalence
and post-discharge mortality
Hajjaji et al., 2022
[254]
Longitudinal
online Survey
COVID-19 cancer patients with solid
or hematological malignances (active
or in remission)
2116,
37 (1.7%)
16 months
<60, 54%
>60, 46%
81%
Prevalence of long-lasting
symptoms in cancer patients with
mild COVID-19 infection
Diseases 2024, 12, 95 41 of 54
7. Integrated Approach to Long COVID Management
An integrated approach is crucial for long COVID management. A multidisciplinary
team is mandatory because of the multiorgan involvement typical of this condition [15,34].
Fainardi et al. proposed a three-step approach that includes a screening phase, an
assessment phase, and, lastly, a monitoring phase. Firstly, according to NICE recommen-
dations, a questionnaire could be administered to determine the acute phase of the disease
and assess the symptoms of long COVID [185], but currently a specic questionnaire for
children is not available.
We proposed a multidisciplinary questionnaire for both adults (Supplementary Ma-
terials Document S1) and children (Supplementary Materials Document S2) with the aim
of facilitating early recognition and appropriate management. The questionnaires, meant
to be administered by medical personnel, are based on our previous experience of COVID-
19 follow-up sessions at 1 year after infection [259] and the scientic evidence presented
above. The questionnaires investigate the presence of the main symptoms linked to
COVID-19 sequelae and related to pulmonary, neurological, and gastrointestinal symp-
toms, also characterizing patients for previous diseases and conditions, the severity and
treatment received during the acute infection, the overall number of infections, and the
vaccination status at infection. These tools will not only be valuable to identify long
COVID patients, but also highlight the relationship between long COVID syndrome prev-
alence and the factors related to acute infection, and hopefully the protective eect of vac-
cinations.
A physical examination is essential to detect clinical signs, and then appropriate di-
agnostic tests should be chosen.
Nutritional management also has a great relevance. Weight loss or gain should be
carefully monitored, and referrals to dietetics should be made as necessary. Emphasis
should be placed on maintaining a well-balanced diet without excluding any food groups
unless medically indicated. Meals may need to be smaller and more frequent to beer
manage dietary needs. Likewise, the qualitative aspects of the diet and the dietary paern
pursued should be monitored in patients aected by COVID-19. In fact, the consumption
of foods high in saturated fats, sugars, and rened carbohydrates (some typical features
of the Western diet (WD)) contribute to the prevalence of obesity and type 2 diabetes, and
could place individuals at an increased risk of severe COVID-19 pathology and mortality.
WD consumption triggers the innate immune system and inhibits adaptive immunity, re-
sulting in persistent inammation and reduced host protection against viruses. To prevent
long-term consequences from COVID-19, individuals should prioritize healthy eating
habits, consuming high amounts of ber, whole grains, unsaturated fats, and antioxidants
to boost immune function [260]. Dietetic support may be necessary to ensure adequate
calorie intake and meet nutritional requirements. The observed changes in body compo-
sition were also driven by the changes in physical activity habits.
Therefore, the establishment of sedentary habits and COVID-19-related long-term
symptoms may have contributed to the excessive accumulation of fat mass while detri-
mentally aecting lean mass. A sedentary lifestyle is counterproductive, as proper and
tailored exercises stand as a promising, eective therapy for mitigating post-COVID-19
symptoms and helping people in recovering faster and increasing their autonomy, func-
tionality, and quality of life [261]. Thus, to guide the recovery, it may be useful to identify
an early resumption of unstructured physical activity (i.e., walking, cycling, dancing,
playing at the park, and performing housework) alongside targeted nutritional interven-
tion as a useful therapeutical approach to prevent poor nutritional and sedentary habits
resulting in excessive fat mass accumulation. Exercise prescription should be approached
with caution in patients experiencing CFS and post-exertional malaise, as exercise is either
not recommended or considered unhelpful in terms of eectiveness and safety, respec-
tively [262].
Diseases 2024, 12, 95 42 of 54
Well-being and psychological support are essential components of care and should
be tailored to each individual patient.
There is no single diagnostic test for long COVID. Several non-invasive diagnostic
tests could be helpful, such as blood exams, ECG and echocardiography, neurologic eval-
uations, polysomnography, sning test, audiometry, abdominal ultrasound, 6MWT, lung
functioning tests (e.g., spirometry), and LUS [15].
The last phase could be performed as a regular follow up of lung functioning at 3, 6,
and 12 months and a rehabilitation program with light aerobic exercise according to pa-
tients’ abilities.
While several guidelines regarding the management of long COVID have been is-
sued, there still exists a signicant practical gap, and specic treatments have not been
thoroughly reviewed. There is no current eective pharmaceutical treatment for long
COVID syndrome [23]. Medical treatment with paracetamol and non-steroidal anti-in-
ammatory drugs, bronchodilators, or inhaled steroids could be used to manage specic
symptoms.
In patients with persistent and severe mental symptoms, psychological interventions
with psychological support are mandatory [55]. Pediatric patients should be encouraged
to return to school. Providing leers for school to allow for a exible reduced timetable
can often make school aendance more manageable on a consistent basis. Once a man-
ageable baseline timetable has been established, it should be maintained for several weeks
before gradually increasing.
Children with an increased risk of long COVID and their parents or guardians should
be informed about the possibility of developing this condition after the acute infection so
that early interventions can be performed. Long COVID indeed has an important impact
on patients’ quality of life.
Based on our experience [263], telemedicine proves to be a valuable tool for the man-
agement of long COVID. Telemedicine allows for the remote monitoring of vital signs like
oxygen saturation, heart rate, and respiratory rate. This can help healthcare professionals
identify any potential complications early on and prevent the worsening of the condition.
Doctors can conduct consultations remotely, assess symptoms, and recommend treatment
plans for long COVID patients. This can include medications, physical therapy recom-
mendations, or mental health support.
The prognosis for many adults, children, and young people is favorable. Many show
improvements within 6 months of diagnosis, with a notable enhancement between 3 and
6 months.
Currently, there are no eective strategies to prevent the development of long
COVID after acute infection. The only available strategy is to avoid SARS-CoV-2 infection
through vaccination [264].
8. Limitations
Our work certainly has limitations. Firstly, we present a narrative review that, as noted
by Gregory et al. [265], provides a non-systematic overview and analysis of the existing
literature on a specic topic. Due to its non-systematic approach, there are no formally
established guidelines for conducting narrative reviews, which can introduce potential bi-
ases in selection and often results in qualitative syntheses. Consequently, our review meth-
odology possesses inherent limitations. Specically, during the search, all established def-
initions of long COVID were included. By employing more specic and unique denitions,
it might have been possible to identify articles that meet similar criteria and can articulate
more nuanced conclusions.
Secondly, the primary aim of our review was to provide a comprehensive overview of
the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19
symptoms in children, adults, and vulnerable populations, rather than focusing solely on
pathogenetic mechanisms. Consequently, we included a section on pathogenetic mecha-
nisms without conducting a dedicated review on this topic. A more detailed examination
Diseases 2024, 12, 95 43 of 54
of a subset of articles focusing on pathogenic mechanisms could have facilitated the ana-
lytical categorization of associated characteristics, such as the presence or absence of organ
damage requiring treatment, and allowed for comparative analyses.
Finally, we introduce the context of chronic diseases, considering the bidirectional re-
lationship with COVID-19, viewing them more as risk factors. However, dedicated studies
on patients with chronic diseases could be useful in identifying how symptoms may aect
and interfere with these conditions.
9. Conclusions
The outbreak of the pandemic caused by the SARS-CoV-2 virus has necessitated an
incredible eort from medical and scientic resources to address the severe symptoms
induced by acute infection, even leading to death.
In the following years, the long-term eects of acute infection have become increas-
ingly important, revealing a wide range of sequelae, both in children and adults. Long
COVID is a complex multisystem disorder believed to result from a dysregulated immu-
nological response. The incidence and severity of long COVID symptoms can have a sig-
nicant impact on the quality of life of patients and the course of disease in the case of
pre-existing pathologies. Particularly, in vulnerable patients, the presence of PASC is re-
lated to signicantly worse survival independent from pre-existing vulnerabilities and
treatment; it is important try to achieve early recognition and management. Various mech-
anisms are implicated, resulting in a wide range of clinical presentations.
Understanding the specic mechanisms and risk factors involved in long COVID is
crucial for tailoring eective interventions and support strategies. Management ap-
proaches involve comprehensive biopsychosocial assessments and the treatment of symp-
toms and comorbidities, such as autonomic dysfunction, as well as multidisciplinary re-
habilitation. This approach, coupled with aention to symptom management and activity
pacing to achieve functional goals, along with a supported return to education, has proven
eective for most patients. The overall course of long COVID is one of gradual improve-
ment, with recovery observed in the majority, though not all, of patients. Specically, se-
vere fatigue or post-exertional malaise are symptoms that can persist, both in adults and
children [266]. Post-viral fatigue is a common feature observed in both post-COVID-19
and post-EBV conditions. A deeper understanding of post-COVID-19 as a distinct condi-
tion, while acknowledging its similarities with other post-viral syndromes, is essential.
The healthcare burden and socio-economic implications for patients and their families ne-
cessitate additional research and the formulation of suitable healthcare management strat-
egies.
As research on long COVID continues to evolve, ongoing studies are likely to shed
more light on the intricate relationship between chronic diseases, such as oncological sta-
tus, cardiovascular diseases, psychiatric disorders, and the persistent eects of SARS-
CoV-2 infection. This information could guide healthcare providers, researchers, and pol-
icymakers in developing targeted interventions.
Supplementary Materials: The following supporting information can be downloaded at:
hps://www.mdpi.com/article/10.3390/diseases12050095/s1, Document S1: Multidisciplinary ques-
tionnaire for adults; Document S2: Multidisciplinary questionnaire for children.
Author Contributions: Conceptualization, V.C., A.F., E.V. and G.Z.; formal analysis and methodol-
ogy, V.C., S.Z., A.F., E.V., B.B., R.B., F.B., A.B., S.C., E.C., G.C., S.D.T., B.D., C.M., A.V.M., C.N., M.R.,
L.T., V.S. (Valeria Savasi), V.S. (Valeria Smiroldo) and G.Z.; investigation, V.C., S.Z., A.F., E.V., B.B.,
R.B., F.B., A.B., S.C., E.C., G.C., S.D.T., B.D., C.M., A.V.M., C.N., M.R., L.T., V.S. (Valeria Savasi) and
V.S. (Valeria Smiroldo); writing—original draft preparation, V.C., S.Z., A.F., E.V., B.B., R.B., F.B., A.B.,
S.C., E.C., G.C., S.D.T., B.D., C.M., A.V.M., C.N., M.R., L.T., V.S. (Valeria Savasi) and V.S. (Valeria
Smiroldo); writing—review and editing, V.C., A.F., E.V. and G.Z.; supervision, V.C., A.F., E.V. and
G.Z.; funding acquisition, G.Z. All authors have read and agreed to the published version of the
manuscript.
Diseases 2024, 12, 95 44 of 54
Funding: The project received contributions from (1) Bando Cariplo Networking research and train-
ing post-COVID-19 protocol number 2021–4490; (2) HORIZON-HLTH-2021-CORONA-01 CoVICIS,
project number 101046041; and (3) PRIN: progei di ricerca di rilevante interesse nazionale–bando
2022 prot. 20228pnnjl.
Institutional Review Board Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors would like to express their gratitude to Roberto Carlo Rossi, Pres-
ident of the Order of Surgeon and Dentist Physicians of Milan, Italy, as well as to ASST Melegnano,
Milan, Italy, and ASST Valtellina e Alto Lario, Milan, Italy, for their participation in the Bando
Cariplo Networking research and training post-COVID-19.
Conicts of Interest: The authors declare no conicts of interest.
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