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Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies...
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Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 24670

Special Issue Editor

Prof. Dr. César Fernández De Las Peñas

E-Mail Website
Guest Editor
Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, 28922 Alcorcón, Madrid, Spain
Interests: chronic pain; pain neuroscience education, manual therapy; central nervous system sensitization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The SARS-CoV-2 virus led to a worldwide outbreak of the disease. Current knowledge on SARS-CoV-2 acute infection has dramatically increased. However, healthcare systems and professionals are fighting against a “hidden” and underestimated consequence of the virus: the presence of long-lasting symptoms after acute infection. This condition has been called long COVID or post-COVID-19 syndrome. In fact, “long-haulers” is the term used to refer to subjects who have recovered from SARS-COV-2 infection but have developed post-COVID symptoms. Increasing studies have supported the presence of more than 100 potential symptoms after the acute phase of infection. Although long COVID as a term was proposed in July 2020, a potential consensus on the definition was only reached by the WHO in December 2021. However, several gaps are still present in the research regarding the identification, timeframe, mechanisms, and treatment strategies for the management of post-COVID symptoms. We are pleased to invite you to submit to this Special Issue, “Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications”.

This Special Issue aims to better understand the mechanisms underlying post-COVID-19 symptoms and post-COVID sequelae (associated with real tissue damage) to improve management of these patients. Identification of groups of long haulers according to mechanisms could lead to better treatment approaches. This Special Issue will focus on all these aspects of post-COVID symptoms and sequelae, a topic of emerging relevance due to the presence of millions of “long-haulers”. This is highly relevant since long COVID is independent of the SARS-CoV-2 variant or the implementation of vaccination programs. We invite researchers/clinicians to submit original articles, systematic reviews, narrative reviews, and meta-analysis covering the identification or management of post-COVID subgroups to this Special Issue.

Prof. Dr. César Fernández De Las Peñas
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • COVID-19
  • long-COVID
  • pain
  • function
  • fatigue
  • dyspnoea

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Published Papers (14 papers)

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12 pages, 2141 KiB  
Article
Immunological Similarities and Differences between Post-COVID-19 Lung Sequelae and Idiopathic Pulmonary Fibrosis
by Sara Gangi, Laura Bergantini, Paolo Cameli, Irene Paggi, Marco Spalletti, Fabrizio Mezzasalma, Elena Bargagli and Miriana d’Alessandro
Biomedicines 2024, 12(3), 630; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12030630 - 12 Mar 2024
Viewed by 771
Abstract
Introduction: Pulmonary fibrosis is an irreversible condition that may be caused by known (including viral triggers such as SARS-CoV-2) and unknown insults. The latter group includes idiopathic pulmonary fibrosis (IPF), which is a chronic, progressive fibrosing interstitial pneumonia of unknown cause. The longer [...] Read more.
Introduction: Pulmonary fibrosis is an irreversible condition that may be caused by known (including viral triggers such as SARS-CoV-2) and unknown insults. The latter group includes idiopathic pulmonary fibrosis (IPF), which is a chronic, progressive fibrosing interstitial pneumonia of unknown cause. The longer the insult acts on lung tissue, the lower the probability of a complete resolution of the damage. An emerging clinical entity post-COVID-19 is pulmonary fibrosis (PCPF), which shares many pathological, clinical, and immunological features with IPF. The fibrotic response in both diseases—IPF and PCPF—is orchestrated in part by the immune system. An important role regarding the inhibitory or stimulatory effects on immune responses is exerted by the immune checkpoints (ICs). The aim of the present study was to analyse the similarities and differences between CD4+, CD8+, and NK cells in the peripheral blood of patients affected by fibrotic disease, IPF, and PCPF compared with sarcoidosis patients and healthy controls. The second aim was to evaluate the expression and co-expression of PD-1 and TIGIT on CD4, CD8, and NK cells from our patient cohort. Methods: One hundred and fifteen patients affected by IPF, PCPF, and sarcoidosis at the rare pulmonary disease centre of the University of Siena were enrolled. Forty-eight patients had an IPF diagnosis, 55 had PCPF, and 12 had sarcoidosis. Further, ten healthy controls were enrolled. PCPF patients were included between 6 and 9 months following hospital discharge for COVID-19. The peripheral blood samples were collected, and through flow cytometric analysis, we analysed the expression of CD4, CD8, NK cells, PD-1, and TIGIT. Results: The results show a greater depletion of CD4 and NK cells in IPF patients compared to other groups (p = 0.003), in contrast with CD8 cells (p < 001). Correlation analysis demonstrated an indirect correlation between CD4 and CD8 cells in IPF and sarcoidosis patients (p < 0.001 = −0.87 and p = 0.042; r = −0.6, respectively). Conversely, PCPF patients revealed a direct correlation between CD4 and CD8 cells (p < 0.001; r = 0.90) accentuating an immune response restoration. The expression of PD-1 and TIGIT was abundant on T and NK cell subsets of the two lung fibrotic groups, IPF and PCPF. Analogously, the co-expression of PD-1 and TIGIT on the surfaces of CD4 and CD8 were increased in such diseases. Conclusions: Our study shines a spotlight on the immune responses involved in the development of pulmonary fibrosis, idiopathic and secondary to SARS-CoV-2 infection. We observed a significant imbalance not only in CD4, CD8, and NK blood percentages in IPF and PCPF patients but also in their functional phenotypes evaluated through the expression of ICs. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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16 pages, 1987 KiB  
Article
Pituitary–Adrenal Axis and Peripheral Immune Cell Profile in Long COVID
by Jaume Alijotas-Reig, Ariadna Anunciacion-Llunell, Enrique Esteve-Valverde, Stephanie Morales-Pérez, Sergio Rivero-Santana, Jaume Trapé, Laura González-García, Domingo Ruiz, Joana Marques-Soares and Francesc Miro-Mur
Biomedicines 2024, 12(3), 581; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12030581 - 05 Mar 2024
Viewed by 1252
Abstract
In Long COVID, dysfunction in the pituitary–adrenal axis and alterations in immune cells and inflammatory status are warned against. We performed a prospective study in a cohort of 42 patients who suffered COVID-19 at least 6 months before attending the Long COVID unit [...] Read more.
In Long COVID, dysfunction in the pituitary–adrenal axis and alterations in immune cells and inflammatory status are warned against. We performed a prospective study in a cohort of 42 patients who suffered COVID-19 at least 6 months before attending the Long COVID unit at Althaia Hospital. Based on Post-COVID Functional Status, 29 patients were diagnosed with Long COVID, while 13 were deemed as recovered. The hormones of the pituitary–adrenal axis, adrenocorticotropin stimulation test, and immune cell profiles and inflammatory markers were examined. Patients with Long COVID had significantly lower EuroQol and higher mMRC scores compared to the recovered individuals. Their symptoms included fatigue, myalgia, arthralgia, persistent coughing, a persistent sore throat, dyspnoea, a lack of concentration, and anxiety. We observed the physiological levels of cortisol and adrenocorticotropin in individuals with or without Long COVID. The results of the adrenocorticotropin stimulation test were similar between both groups. The absolute number of neutrophils was lower in the Long COVID patients compared to recovered individuals (p < 0.05). The total count of B lymphocytes remained consistent, but Long COVID patients had a higher percentage of mature B cells compared to recovered participants (p < 0.05) and exhibited a higher percentage of circulating resident memory CD8+ T cells (p < 0.05) and Treg-expressing exonucleases (p < 0.05). Our findings did not identify adrenal dysfunction related to Long COVID, nor an association between adrenal function and clinical symptoms. The data indicated a dysregulation in certain immune cells, pointing to immune activation. No overt hyperinflammation was observed in the Long COVID group. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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15 pages, 1549 KiB  
Article
Red Blood Cell Adenylate Energetics Is Related to Endothelial and Microvascular Function in Long COVID
by Marzena Romanowska-Kocejko, Agata Jędrzejewska, Alicja Braczko, Klaudia Stawarska, Oliwia Król, Marika Frańczak, Gabriela Harasim, Ryszard T. Smoleński, Marcin Hellmann and Barbara Kutryb-Zając
Biomedicines 2024, 12(3), 554; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12030554 - 01 Mar 2024
Viewed by 1679
Abstract
Adenine nucleotides play a critical role in maintaining essential functions of red blood cells (RBCs), including energy metabolism, redox status, shape fluctuations and RBC-dependent endothelial and microvascular functions. Recently, it has been shown that infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [...] Read more.
Adenine nucleotides play a critical role in maintaining essential functions of red blood cells (RBCs), including energy metabolism, redox status, shape fluctuations and RBC-dependent endothelial and microvascular functions. Recently, it has been shown that infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) might lead to morphological and metabolic alterations in erythrocytes in both mild and severe cases of coronavirus disease (COVID-19). However, little is known about the effects of COVID-19 on the nucleotide energetics of RBCs nor about the potential contribution of nucleotide metabolism to the long COVID syndrome. This study aimed to analyze the levels of adenine nucleotides in RBCs isolated from patients 12 weeks after mild SARS-CoV-2 infection who suffered from long COVID symptoms and to relate them with the endothelial and microvascular function parameters as well as the rate of peripheral tissue oxygen supply. Although the absolute quantities of adenine nucleotides in RBCs were rather slightly changed in long COVID individuals, many parameters related to the endothelial and microcirculatory function showed significant correlations with RBC adenosine triphosphate (ATP) and total adenine nucleotide (TAN) concentration. A particularly strong relationship was observed between ATP in RBCs and the serum ratio of arginine to asymmetric dimethylarginine—an indicator of endothelial function. Consistently, a positive correlation was also observed between the ATP/ADP ratio and diminished reactive hyperemic response in long COVID patients, assessed by the flow-mediated skin fluorescence (FMSF) technique, which reflected decreased vascular nitric oxide bioavailability. In addition, we have shown that patients after COVID-19 have significantly impaired ischemic response parameters (IR max and IR index), examined by FMSF, which revealed diminished residual bioavailability of oxygen in epidermal keratinocytes after brachial artery occlusion. These ischemic response parameters revealed a strong positive correlation with the RBC ATP/ADP ratio, confirming a key role of RBC bioenergetics in peripheral tissue oxygen supply. Taken together, the outcomes of this study indicate that dysregulation of metabolic processes in erythrocytes with the co-occurring endothelial and microvascular dysfunction is associated with diminished intracellular oxygen delivery, which may partly explain long COVID-specific symptoms such as physical impairment and fatigue. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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14 pages, 1534 KiB  
Article
Improvement of Symptoms and Cardiac Magnetic Resonance Abnormalities in Patients with Post-Acute Sequelae of SARS-CoV-2 Cardiovascular Syndrome (PASC-CVS) after Guideline-Oriented Therapy
by Mariann Gyöngyösi, Ena Hasimbegovic, Emilie Han, Katrin Zlabinger, Andreas Spannbauer, Martin Riesenhuber, Kevin Hamzaraj, Jutta Bergler-Klein, Christian Hengstenberg, Andreas Kammerlander, Stefan Kastl, Christian Loewe and Dietrich Beitzke
Biomedicines 2023, 11(12), 3312; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11123312 - 14 Dec 2023
Viewed by 1020
Abstract
Cardiac magnetic resonance (CMR) studies reported CMR abnormalities in patients with mild–moderate SARS-CoV-2 infection, suggesting ongoing myocardial inflammation. Patients (n = 278, 43 ± 13 years, 70.5% female) with post-acute sequelae of SARS-CoV-2 cardiovascular syndrome (PASC-CVS) were included prospectively into the Vienna [...] Read more.
Cardiac magnetic resonance (CMR) studies reported CMR abnormalities in patients with mild–moderate SARS-CoV-2 infection, suggesting ongoing myocardial inflammation. Patients (n = 278, 43 ± 13 years, 70.5% female) with post-acute sequelae of SARS-CoV-2 cardiovascular syndrome (PASC-CVS) were included prospectively into the Vienna POSTCOV Registry between March 2021 and March 2023 (clinicaltrials.gov NCT05398952). Clinical, laboratory, and CMR findings were recorded. Patients with abnormal CMR results were classified into isolated chronic pericardial (with/without pleural) effusion, isolated cardiac function impairment, or both (myopericarditis) groups. Medical treatment included a nonsteroidal anti-inflammatory agent (NSAID) for pericardial effusion and a condition-adapted maximal dose of heart failure (HF) treatment. Three months after medical therapy, clinical assessment and CMR were repeated in 82 patients. Laboratory analyses revealed normal hematological, inflammatory, coagulation, and cardiac biomarkers. CMR abnormalities were found in 155 patients (55.8%). Condition-adapted HF treatment led to a significant increase in the left ventricular ejection fraction (LVEF) in patients with initially reduced LVEF (from 49 ± 5% to 56 ± 4%, p = 0.009, n = 25). Low–moderate doses of NSAIDs for 3 months significantly reduced pericardial effusion (from 4/3;5.75/mm to 2/0;3/mm, median/interquartile ranges/p < 0.001, n = 51). Clinical symptoms improved markedly with a decrease in CMR abnormalities, which might be attributed to the maintenance of NSAID and HF medical treatment for PASC-CVS. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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15 pages, 1857 KiB  
Article
Does COVID-19 Infection during Pregnancy Increase the Appearance of Congenital Gastrointestinal Malformations in Neonates?
by Timea Elisabeta Brandibur, Nilima Rajpal Kundnani, Marioara Boia, Daciana Nistor, Daniel Milan Velimirovici, Leonard Mada, Aniko Maria Manea, Eugen Radu Boia, Marioara Nicula Neagu and Calin Marius Popoiu
Biomedicines 2023, 11(12), 3105; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11123105 - 21 Nov 2023
Cited by 1 | Viewed by 1116
Abstract
Background: COVID-19 was an infection that was capable of bringing the entire world to a standstill position within a period of days to months. Despite the advancements in the medical sector, the contagion was difficult to control and costed the lives of millions [...] Read more.
Background: COVID-19 was an infection that was capable of bringing the entire world to a standstill position within a period of days to months. Despite the advancements in the medical sector, the contagion was difficult to control and costed the lives of millions of people worldwide. Many short- and long-term effects are witnessed even to date in people that contracted the disease. Pregnant females had to suffer not only the devastating effects of the virus, but also the psycho-social impact of the lockdown. The impact of COVID-19 infection during pregnancy causing decreased antenatal care or hypoxemic episodes due to severe respiratory distress and whether it could lead to the appearance of congenital gastrointestinal malformation in neonates is still unclear. The aim of our study was to analyze if COVID-19 infection during pregnancy could increase the incidence of gastric malformations in neonates born from these women. Materials and Methods: We sifted the files of all neonates admitted into our hospital between January 2022 and December 2022, and based on inclusion and exclusion criteria, we included the cases having gastrointestinal congenital malformations during the COVID-19 pandemic. We performed a single-center, retrospective, observational descriptive study. We further divided the patients based on the anatomical location of the malformation. We also took down details of the evolution of pregnancy and whether the mother had contracted a SARS-CoV-2 infection during the pregnancy. Details regarding the Apgar score, days of intensive care admission, sex, and nutrition were the key findings studied. Results: A total of 47 neonates were found to have digestive anomalies, among which, based on the anatomical locations, the number of malformation cases found at the level of the esophagus were 15, while 16 occurred at the level of the pylorus; we found 12 cases of malformation of the duodenum, and four cases had malformation of the rectum. Out of these 47 neonates, 38.3% were females and 61.7% were males. A total of 58% were preemies, among which 9% had intra-uterine growth retardation (IUGR), and 42% were full-term newborns, among which 4% had intra-uterine growth retardation (IUGR). A total of 45% of the births were primiparous pregnancies and 55% were from multiparous females. A total of 14 mothers were found to have tested positive for COVID-19 during the course of pregnancy (p-value = 0.23); many had mild symptoms but were not tested. Conclusions: COVID-19 can affect the wellbeing of the pregnant female and their fetus. Larger studies can help gain extensive knowledge as to whether COVID-19 also has the potential to result in congenital gastrointestinal anomalies in children born from COVID-19 positive mothers. In our study, only a few infants born with this pathology were found to be born from COVID-19 positive mothers. Hence, it is difficult to conclude or exclude a direct correlation between the infection and the congenital malformations. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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12 pages, 629 KiB  
Article
Whole-Body Cryostimulation in Post-COVID Rehabilitation for Patients with Obesity: A Multidisciplinary Feasibility Study
by Jacopo Maria Fontana, Angelo Alito, Paolo Piterà, Federica Verme, Stefania Cattaldo, Mauro Cornacchia, Stefania Mai, Amelia Brunani and Paolo Capodaglio
Biomedicines 2023, 11(11), 3092; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11113092 - 18 Nov 2023
Cited by 5 | Viewed by 1133
Abstract
Background: A post-COVID condition can reduce activity and quality of life, resulting in a significant socioeconomic and health burden. Understanding its impact on patients’ health is important for the development of personalized rehabilitation interventions. An independent association between obesity and post-COVID condition was [...] Read more.
Background: A post-COVID condition can reduce activity and quality of life, resulting in a significant socioeconomic and health burden. Understanding its impact on patients’ health is important for the development of personalized rehabilitation interventions. An independent association between obesity and post-COVID condition was found because of complications and comorbidities. Methods: Sixteen patients with obesity and post-COVID symptoms (i.e., dyspnea, pain, poor sleep quality, muscle fatigue), admitted to the Istituto Auxologico Italiano, Piancavallo (VB), Italy, were recruited for a four-week rehabilitation program including conventional exercise therapy, nutritional intervention, psychological support and whole-body cryostimulation (WBC). Results: All participants attended all sessions of the program. Anthropometric data showed statistically significant changes in weight, waist circumference and body mass index. Biochemical analyses showed significant reductions in lipid and inflammatory profiles. There was a significant improvement in physical performance, reduction in pain and improvement in psychological well-being. Conclusion: A multidisciplinary rehabilitation protocol including WBC, designed for patients with obesity and a post-COVID condition, is safe and feasible. The overall improvements demonstrate that multidisciplinary rehabilitation was effective on post COVID patients and suggest that the use of WBC is safe and could play a role as a booster in rehabilitation programs. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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13 pages, 828 KiB  
Article
Severe COVID-19 Illness and α1-Antitrypsin Deficiency: COVID-AATD Study
by Juan Luis Rodríguez Hermosa, Gianna Vargas Centanaro, María Estela González Castro, Marc Miravitlles, Lourdes Lázaro-Asegurado, Beatriz María Jiménez-Rodríguez, Rosanel Amaro Rodríguez, Rosaly Moreno Méndez, María Torres-Duran, José María Hernández-Pérez, Ana María Humanes-Navarro and Myriam Calle Rubio
Biomedicines 2023, 11(2), 516; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11020516 - 10 Feb 2023
Cited by 4 | Viewed by 1556
Abstract
Background: Epidemiologic studies have reported that the geographical distribution of the prevalence of allelic variants of serine protein inhibitor-A1 (SERPINA1) and severe cases of COVID-19 were similar. Methods: A multicenter, cross-sectional, observational study to evaluate the frequency of alpha-1 antitrypsin deficiency (AATD) in [...] Read more.
Background: Epidemiologic studies have reported that the geographical distribution of the prevalence of allelic variants of serine protein inhibitor-A1 (SERPINA1) and severe cases of COVID-19 were similar. Methods: A multicenter, cross-sectional, observational study to evaluate the frequency of alpha-1 antitrypsin deficiency (AATD) in patients with COVID-19 and whether it was associated with having suffered severe COVID-19. Results: 2022 patients who had laboratory-confirmed SARS-CoV-2 infection. Mutations associated with AATD were more frequent in severe COVID versus non-severe (23% vs. 18.8%, p = 0.022). The frequency of Pi*Z was 37.8/1000 in severe COVID versus 17.5/1000 in non-severe, p = 0.001. Having an A1AT level below 116 was more frequent in severe COVID versus non-severe (29.5% vs. 23.1, p = 0.003). Factors associated with a higher likelihood of severe COVID-19 were being male, older, smoking, age-associated comorbidities, and having an A1AT level below 116 mg/dL [OR 1.398, p = 0.003], and a variant of the SERPINA1 gene that could affect A1AT protein [OR 1.294, p = 0.022]. Conclusions: These observations suggest that patients with AATD should be considered at a higher risk of developing severe COVID-19. Further studies are needed on the role of A1AT in the prognosis of SARS-CoV-2 infection and its possible therapeutic role. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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13 pages, 1755 KiB  
Article
Growth Differentiation Factor 15 (GDF-15) Levels Associate with Lower Survival in Chronic Kidney Disease Patients with COVID-19
by Andrea Galassi, Paola Ciceri, Valeria Bono, Lorenza Magagnoli, Matteo Sala, Luisa Artioli, Roberta Rovito, Mohamad Hadla, Vaibhav Yellenki, Antonella D’Arminio Monforte, Camilla Tincati, Mario Cozzolino and Giulia Marchetti
Biomedicines 2022, 10(12), 3251; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10123251 - 14 Dec 2022
Cited by 4 | Viewed by 1922
Abstract
A cytokine storm drives the pathogenesis of severe COVID-19 infection and several biomarkers have been linked to mortality. Chronic kidney disease (CKD) emerged as a risk factor for severe COVID-19. We investigated the association between selected biomarkers and mortality in 77 patients hospitalized [...] Read more.
A cytokine storm drives the pathogenesis of severe COVID-19 infection and several biomarkers have been linked to mortality. Chronic kidney disease (CKD) emerged as a risk factor for severe COVID-19. We investigated the association between selected biomarkers and mortality in 77 patients hospitalized for COVID-19, and whether they differ in patients with eGFR higher and lower than 45 mL/min. The association between patients’ characteristics, plasma biomarkers and mortality was conducted by univariate logistic regression models and independent predictors of mortality were then used to create a multivariate prediction model through Cox regression. Patients with lower eGFR had a significant increase of GDF-15, CD-25 and RAGE, with higher plasma levels in non-survivors and in patients who needed ventilation. At univariate analysis, low and mid-low GDF-15 quartiles (<4.45 ng/mL) were associated with lower mortality risk, while mid-high and high quartiles (>4.45 ng/mL) were associated with higher mortality risk. Independent association between GDF-15 quartiles and mortality risk was confirmed in the Cox model and adjusted for eGFR, age, fever and dyspnea (HR 2.28, CI 1.53–3.39, p < 0.0001). The strength of the association between GDF-15 quartiles and mortality risk increased in patients with lower compared to higher eGFR (HR 2.53, CI 1.34–4.79 versus HR 1.99, CI 1.17–3.39). Our findings may suggest a further investigation of the effect of GDF-15 signaling pathway inhibition in CKD. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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Review

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14 pages, 512 KiB  
Review
Physical Therapies in the Treatment of Post-COVID Syndrome: A Systematic Review
by Juan Carlos Sánchez-García, María Rentero Moreno, Beatriz Piqueras-Sola, Jonathan Cortés-Martín, Antonio Liñán-González, Elena Mellado-García and Raquel Rodriguez-Blanque
Biomedicines 2023, 11(8), 2253; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11082253 - 11 Aug 2023
Viewed by 975
Abstract
Introduction: Several days to months after diagnosis of SARS-CoV-2, 35% of patients have persistent symptoms in high incidence. This is referred to as post-COVID-19 Syndrome. There is a pressing need to find a way to help patients with the manifested symptoms. Objective: To [...] Read more.
Introduction: Several days to months after diagnosis of SARS-CoV-2, 35% of patients have persistent symptoms in high incidence. This is referred to as post-COVID-19 Syndrome. There is a pressing need to find a way to help patients with the manifested symptoms. Objective: To show the different therapies that exist for post-COVID Syndrome and their efficacy. Methodology: A systematic review of the scientific literature was carried out. The data search was carried out in Scopus, PubMed, Cinahl, and Web of Science. Of the 106 articles found, 12 articles were obtained after applying the following eligibility criteria. Results: Interventions related to respiratory musculature and moderate intensity exercise both in supervised face-to-face sessions and in supervised home sessions led patients to a significant improvement in the symptoms presented. Conclusion: Physical therapies significantly reduce fatigue and dyspnea as well as other symptoms related to quality of life. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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24 pages, 1623 KiB  
Review
Efficacy of Pulmonary Rehabilitation in Post-COVID-19: A Systematic Review and Meta-Analysis
by Erika Meléndez-Oliva, Oliver Martínez-Pozas, Juan Nicolás Cuenca-Zaldívar, Jorge Hugo Villafañe, Laura Jiménez-Ortega and Eleuterio A. Sánchez-Romero
Biomedicines 2023, 11(8), 2213; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11082213 - 07 Aug 2023
Cited by 9 | Viewed by 2710
Abstract
Background: This systematic review and meta-analysis examines how pulmonary rehabilitation impacts in patients suffering from subacute and long COVID-19 infections, gauging enhancements in of dyspnea, physical function, quality of life, psychological state (anxiety and depression), and fatigue. Methods: Three electronic databases (PubMed, Web [...] Read more.
Background: This systematic review and meta-analysis examines how pulmonary rehabilitation impacts in patients suffering from subacute and long COVID-19 infections, gauging enhancements in of dyspnea, physical function, quality of life, psychological state (anxiety and depression), and fatigue. Methods: Three electronic databases (PubMed, Web of Science, Cochrane Library) were systematically searched for full-text articles published from inception to January 2023. Randomized, quasi-experimental, and observational studies were included, with adults diagnosed with subacute or long COVID-19 who received pulmonary rehabilitation as intervention. Outcomes related to dyspnea, physical function, quality of life, fatigue, and psychological status were included. Risk of bias was assessed with Cochrane Risk of Bias Tool for Randomized Controlled Trials and Risk of bias in non-randomized studies of intervention. The review was registered before starting in PROSPERO (CRD: 42022373075). Results: Thirty-four studies were included, involving 1970 patients with subacute and long COVID-19. The meta-analysis demonstrated moderate to large effects on dyspnea, physical function, quality of life, and depressive symptoms compared to usual care intervention. No significant differences were found in fatigue compared to usual care, nor in anxiety levels after pulmonary rehabilitation intervention. Conclusions: Pulmonary rehabilitation has the potential to improve health outcomes in patients with subacute and long COVID-19. However, due to the high risk of bias of included studies, conclusions should be taken with caution. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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12 pages, 1394 KiB  
Review
Efficacy of Palmitoylethanolamide and Luteolin Association on Post-Covid Olfactory Dysfunction: A Systematic Review and Meta-Analysis of Clinical Studies
by Anna Paola Capra, Alessio Ardizzone, Lelio Crupi, Fabrizio Calapai, Michela Campolo, Salvatore Cuzzocrea and Emanuela Esposito
Biomedicines 2023, 11(8), 2189; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11082189 - 03 Aug 2023
Cited by 5 | Viewed by 1871
Abstract
Post-Covid Olfactory Dysfunction (PCOD) is characterized by olfactory abnormalities, hyposmia, and anosmia, which are among the most often enduring symptoms in individuals who have recovered from SARS-CoV-2 infection. This disorder has been reported to persist in subsets of patients well after 12 months [...] Read more.
Post-Covid Olfactory Dysfunction (PCOD) is characterized by olfactory abnormalities, hyposmia, and anosmia, which are among the most often enduring symptoms in individuals who have recovered from SARS-CoV-2 infection. This disorder has been reported to persist in subsets of patients well after 12 months following infection, significantly affecting their quality of life. Despite the high prevalence of PCOD among patients who suffered from SARS-CoV-2 infection, specific therapeutic strategies are still limited. Among these, emerging evidence seems to indicate the administration of CoUltraPEALut, a combination of micronized Palmitoylethanolamide (PEA), an endogenous fatty acid amide, and Luteolin, a natural antioxidant flavonoid, as a viable therapy, especially when given as an adjuvant to olfactory training. Based on the above, a systematic review and a meta-analysis of the literature were conducted, with the aim of evaluating the efficacy of CoUltraPEALut as an addition to olfactory training (OT), in treating PCOD symptoms. Pubmed (MEDLINE), Embase (OVID), and Web of Science scientific databases were screened from the inception until 31 May 2023, and a total of 407 articles were recovered; only five of these studies (441 total patients between treated and control groups) were included in the systematic review. CoUltraPEALut demonstrated significant efficacy in the overall recovery of the olfactory function, compared to the conventional therapy, suggesting that it could represent a possible future adjuvant treatment for PCOD. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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12 pages, 705 KiB  
Review
Phenotyping Post-COVID Pain as a Nociceptive, Neuropathic, or Nociplastic Pain Condition
by César Fernández-de-las-Peñas, Jo Nijs, Randy Neblett, Andrea Polli, Maarten Moens, Lisa Goudman, Madhura Shekhar Patil, Roger D. Knaggs, Gisele Pickering and Lars Arendt-Nielsen
Biomedicines 2022, 10(10), 2562; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102562 - 13 Oct 2022
Cited by 17 | Viewed by 4165
Abstract
Pain after an acute Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) condition (post-COVID pain) is becoming a new healthcare emergency. Precision medicine refers to an evidence-based method of grouping patients based on their diagnostic/symptom presentation and then [...] Read more.
Pain after an acute Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) condition (post-COVID pain) is becoming a new healthcare emergency. Precision medicine refers to an evidence-based method of grouping patients based on their diagnostic/symptom presentation and then tailoring specific treatments accordingly. Evidence suggests that post-COVID pain can be categorized as nociceptive (i.e., pain attributable to the activation of the peripheral receptive terminals of primary afferent neurons in response to noxious chemical, mechanical, or thermal stimuli), neuropathic (i.e., pain associated with a lesion or disease of the somatosensory nervous system and limited to a “neuroanatomically plausible” distribution of the system), nociplastic (i.e., pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain), or mixed type (when two pain phenotypes co-exist). Each of these pain phenotypes may require a different treatment approach to maximize treatment effectiveness. Accordingly, the ability to classify post-COVID pain patients into one of these phenotypes would likely be critical for producing successful treatment outcomes. The 2021 International Association for the Study of Pain (IASP) clinical criteria and grading system provide a framework for classifying pain within a precision pain medicine approach. Here we present data supporting the possibility of grouping patients with post-COVID pain into pain phenotypes, using the 2021 IASP classification criteria, with a specific focus on nociplastic pain, which is probably the primary mechanism involved in post-COVID pain. Nociplastic pain, which is usually associated with comorbid symptomology (e.g., poor sleep quality, fatigue, cognitive–emotional disturbances, etc.) and is considered to be more difficult to treat than other pain types, may require a more nuanced multimodal treatment approach to achieve better treatment outcomes. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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9 pages, 293 KiB  
Brief Report
Clinical Variables Related to Functional Capacity and Exertional Desaturation in Patients with COVID-19
by Santiago Larrateguy, Julian Vinagre, Federico Londero, Johana Dabin, Evangelina Ricciardi, Santiago Jeanpaul, Rodrigo Torres-Castro, Rodrigo Núñez-Cortés, Diana Sánchez-Ramírez, Elena Gimeno-Santos and Isabel Blanco
Biomedicines 2023, 11(7), 2051; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11072051 - 20 Jul 2023
Viewed by 1170
Abstract
Impaired functional capacity is one of the most commonly reported consequences among post-COVID-19 patients. This study aimed to analyse the clinical variables related to functional capacity and exertional desaturation in post-COVID-19 patients at the time of hospital discharge. A cross-sectional study was conducted [...] Read more.
Impaired functional capacity is one of the most commonly reported consequences among post-COVID-19 patients. This study aimed to analyse the clinical variables related to functional capacity and exertional desaturation in post-COVID-19 patients at the time of hospital discharge. A cross-sectional study was conducted on patients recovering from COVID-19 pneumonia. The main outcomes measures were functional capacity, assessed using the 1 min sit-to-stand test (1 min STST), and exertional desaturation, defined as a drop of ≥4% in the arterial oxygen saturation. Factors used to characterise the participant outcomes included the use of a high-flow nasal cannula (HFNC), prolonged hospitalisation, occurrence of pulmonary embolism during hospitalisation, and underlying comorbidities. A total of 381 participants (mean age = 53.7 ± 13.2 years, 65.6% men) were included. Participants completed a mean of 16.9 ± 6.2 repetitions in the 1 min STST. Exertional desaturation was observed in 51% of the patients. Higher odds of exertional desaturation were found in the participants who used a HFNC (OR = 3.6; 95%CI: 1.6 to 7.8), were admitted in the hospital >10 days (OR = 4.2; 95%CI: 2.6 to 6.8), and had a pulmonary embolism (OR = 3.5; 95%CI: 2.2. to 5.3). Use of a HFNC (β = −3.4; 95%CI: −5.3 to −1.44), a hospital stay >10 days (β = −2.2; 95%CI: −3.4 to −0.9), and a history of pulmonary embolism (β = −1.4; 95%CI: −2.6 to −0.2) were also negatively associated with the 1 min STST. Most post-COVID-19 patients exhibited reduced functional capacity at the time of hospital discharge, and approximately half had exertional desaturation after the 1 min STST. The use of a HFNC, prolonged hospitalisation and pulmonary embolism were the main clinical variables associated with worse a 1 min STST performance and a higher likelihood of exertional desaturation. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
14 pages, 737 KiB  
Systematic Review
COVID-19 in Pregnant Women, Maternal—Fetal Involvement, and Vertical Mother-to-Child Transmission: A Systematic Review
by Juan Carlos Sánchez-García, Nuria Pilar Carrascosa Moreno, María Isabel Tovar-Gálvez, Jonathan Cortés-Martín, Antonio Liñán-González, Leticia Alvarado Olmedo and Raquel Rodríguez-Blanque
Biomedicines 2022, 10(10), 2554; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102554 - 13 Oct 2022
Cited by 5 | Viewed by 1624
Abstract
Pregnant women are included in the COVID-19 risk groups even if they do not have any pathology. This requires an analysis of research focused on pregnant women to understand the impact of SARS-CoV-2 on their condition. There is also a need to know [...] Read more.
Pregnant women are included in the COVID-19 risk groups even if they do not have any pathology. This requires an analysis of research focused on pregnant women to understand the impact of SARS-CoV-2 on their condition. There is also a need to know whether there is vertical mother-to-child transmission, as well as other consequences in case the pregnant woman is infected and COVID-19 positive. A systematic review was carried out to analyze the existing information on the complications of a pregnant woman infected with the SARS-CoV-2 coronavirus and the possibility of vertical transmission from mother to child, registered in the PROSPERO website and searched in the PubMed, Scopus, CINAHL, and Cochrane Library databases. Finally, 22 articles were included in the review. The review suggests that vertical transmission from mother to child could be exceptionally possible at the time of delivery or breastfeeding, but not through the placenta. It is interesting to point out the good acceptance of vaccination by pregnant women, which may be the reason for the low infectivity. Further research on pregnant women should be carried out to provide evidence on vertical mother-to-child transmission and the role of breast milk in relation to SARS-CoV-2. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications)
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