Special Issue "Post-COVID Symptoms in Long-Haulers: Definition, Identification, Mechanisms, and Management"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Epidemiology & Public Health".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 12307

Special Issue Editors

Prof. Dr. Domingo Palacios-Ceña
E-Mail Website
Guest Editor
Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, 28922 Alcorcón, Madrid, Spain
Interests: qualitative research; mixed methods; pain; geriatrics; caring science; vulnerable groups; disability and rehabilitation
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Special Issue Information

Dear Colleagues,

SARS-CoV-2, the virus responsible for COVID-19, has spread rapidly across the world in the most unprecedent sanitary outbreak of this century. Current literature about COVID-19 has mainly concentrated on the disease itself and the management of acute cases. Today, the world is in front of a second pandemic associated with COVID-19, the “long-haulers”, individuals who recovered from COVID-19 but develop post-COVID-19 symptoms. The emerging literature supports the presence of several post-COVID-19 symptoms after the acute phase of COVID-19. However, several gaps exist in definitions, identification, timeframe, mechanisms, and treatment strategies for the management of post-COVID-19 symptoms. Better understanding of the underlying mechanisms behind post-COVID-19 symptoms and better identification of timeframes when these symptoms appear will help clinicians to improve future management of this new group of patients. This Special Issue will focus on all these aspects of post-COVID-19 symptomatology, a topic of emerging relevance due to the expected presence of millions of “long-haulers”. We invite researchers/clinicians to submit original articles, systematic reviews, narrative reviews, meta-analysis, case series, cohort, and case–control studies related to proper the identification and management of post-COVID-19 symptoms to this special issue.

Prof. Dr. César Fernández De Las Peñas
Prof. Dr. Domingo Palacios-Ceña
Guest Editors

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Keywords

  • COVID-19
  • symptoms
  • long-COVID
  • pain
  • function
  • fatigue
  • dyspnoea
  • public health

Published Papers (8 papers)

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Research

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Article
Pain Extent Is Not Associated with Sensory-Associated Symptoms, Cognitive or Psychological Variables in COVID-19 Survivors Suffering from Post-COVID Pain
J. Clin. Med. 2022, 11(15), 4633; https://doi.org/10.3390/jcm11154633 - 08 Aug 2022
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Abstract
We aimed to investigate the relationship between pain extent, as a sign of sensitization, and sensory-related, cognitive and psychological variables in hospitalized COVID-19 survivors with post-COVID pain. One hundred and forty-six (67 males, 79 females) previously hospitalized COVID-19 survivors with post-COVID pain completed [...] Read more.
We aimed to investigate the relationship between pain extent, as a sign of sensitization, and sensory-related, cognitive and psychological variables in hospitalized COVID-19 survivors with post-COVID pain. One hundred and forty-six (67 males, 79 females) previously hospitalized COVID-19 survivors with post-COVID pain completed demographic (age, sex, height, weight), sensory-related (Central Sensitization Inventory, Self-Report Leeds Assessment of Neuropathic Symptoms), cognitive (Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia) and psychological (Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index) variables. Pain extent and frequency maps were calculated from pain drawings using customized software. After conducting a correlation analysis to determine the relationships between variables, a stepwise linear regression model was performed to identify pain extent predictors, if available. Pain extent was significantly and weakly associated with pain intensity (r = −0.201, p = 0.014): the larger the pain extent, the lower the pain intensity. No other significant association was observed between pain extent and sensory-related, cognitive, or psychological variables in individuals with post-COVID pain. Females had higher pain intensity, more sensitization-associated symptoms, higher anxiety, lower sleep quality, and higher kinesiophobia levels than males. Sex differences correlation analyses revealed that pain extent was associated with pain intensity in males, but not in females. Pain extent was not associated with any of the measured variables and was also not related to the presence of sensitization-associated symptoms in our sample of COVID-19 survivors with long-term post-COVID pain. Full article
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Article
Neuropsychological Predictors of Fatigue in Post-COVID Syndrome
J. Clin. Med. 2022, 11(13), 3886; https://doi.org/10.3390/jcm11133886 - 04 Jul 2022
Viewed by 782
Abstract
Fatigue is one of the most disabling symptoms in several neurological disorders and has an important cognitive component. However, the relationship between self-reported cognitive fatigue and objective cognitive assessment results remains elusive. Patients with post-COVID syndrome often report fatigue and cognitive issues several [...] Read more.
Fatigue is one of the most disabling symptoms in several neurological disorders and has an important cognitive component. However, the relationship between self-reported cognitive fatigue and objective cognitive assessment results remains elusive. Patients with post-COVID syndrome often report fatigue and cognitive issues several months after the acute infection. We aimed to develop predictive models of fatigue using neuropsychological assessments to evaluate the relationship between cognitive fatigue and objective neuropsychological assessment results. We conducted a cross-sectional study of 113 patients with post-COVID syndrome, assessing them with the Modified Fatigue Impact Scale (MFIS) and a comprehensive neuropsychological battery including standardized and computerized cognitive tests. Several machine learning algorithms were developed to predict MFIS scores (total score and cognitive fatigue score) based on neuropsychological test scores. MFIS showed moderate correlations only with the Stroop Color–Word Interference Test. Classification models obtained modest F1-scores for classification between fatigue and non-fatigued or between 3 or 4 degrees of fatigue severity. Regression models to estimate the MFIS score did not achieve adequate R2 metrics. Our study did not find reliable neuropsychological predictors of cognitive fatigue in the post-COVID syndrome. This has important implications for the interpretation of fatigue and cognitive assessment. Specifically, MFIS cognitive domain could not properly capture actual cognitive fatigue. In addition, our findings suggest different pathophysiological mechanisms of fatigue and cognitive dysfunction in post-COVID syndrome. Full article
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Article
Detection of Male Hypogonadism in Patients with Post COVID-19 Condition
J. Clin. Med. 2022, 11(7), 1955; https://doi.org/10.3390/jcm11071955 - 31 Mar 2022
Cited by 2 | Viewed by 906
Abstract
The pathogenesis and prognosis of post COVID-19 condition have remained unclear. We set up an outpatient clinic specializing in long COVID in February 2021 and we have been investigating post COVID-19 condition. Based on the results of our earlier study showing that “general [...] Read more.
The pathogenesis and prognosis of post COVID-19 condition have remained unclear. We set up an outpatient clinic specializing in long COVID in February 2021 and we have been investigating post COVID-19 condition. Based on the results of our earlier study showing that “general fatigue” mimicking myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the most common symptom in long COVID patients, a retrospective analysis was performed for 39 male patients in whom serum free testosterone (FT) levels were measured out of 61 male patients who visited our clinic. We analyzed the medical records of the patients’ backgrounds, symptoms and laboratory results. Among the 39 patients, 19 patients (48.7%) met the criteria for late-onset hypogonadism (LOH; FT < 8.5 pg/mL: LOH group) and 14 patients were under 50 years of age. A weak negative correlation was found between age and serum FT level (r = −0.301, p = 0.0624). Symptoms including general fatigue, anxiety, cough and hair loss were more frequent in the LOH group than in the non-LOH group (FT ≥ 8.5 pg/mL). Among various laboratory parameters, blood hemoglobin level was slightly, but significantly, lower in the LOH group. Serum level of FT was positively correlated with the levels of blood hemoglobin and serum total protein and albumin in the total population, whereas these interrelationships were blurred in the LOH group. Collectively, the results indicate that the incidence of LOH is relatively high in male patients, even young male patients, with post COVID-19 and that serum FT measurement is useful for revealing occult LOH status in patients with long COVID. Full article
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Article
Cardiopulmonary Exercise Performance and Endothelial Function in Convalescent COVID-19 Patients
J. Clin. Med. 2022, 11(5), 1452; https://doi.org/10.3390/jcm11051452 - 07 Mar 2022
Cited by 2 | Viewed by 878
Abstract
Background: Endothelial dysfunction has been proposed as the common pathogenic background of most manifestations of coronavirus disease 2019 (COVID-19). Among these, some authors also reported an impaired exercise response during cardiopulmonary exercise testing (CPET). We aimed to explore the potential association between endothelial [...] Read more.
Background: Endothelial dysfunction has been proposed as the common pathogenic background of most manifestations of coronavirus disease 2019 (COVID-19). Among these, some authors also reported an impaired exercise response during cardiopulmonary exercise testing (CPET). We aimed to explore the potential association between endothelial dysfunction and the reduced CPET performance in COVID-19 survivors. Methods: 36 consecutive COVID-19 survivors underwent symptom-limited incremental CPET and assessment of endothelium-dependent flow-mediate dilation (FMD) according to standardized protocols. Results: A significantly higher FMD was documented in patients with a preserved, as compared to those with a reduced, exercise capacity (4.11% ± 2.08 vs. 2.54% ± 1.85, p = 0.048), confirmed in a multivariate analysis (β = 0.899, p = 0.038). In the overall study population, FMD values showed a significant Pearson’s correlation with two primary CPET parameters, namely ventilation/carbon dioxide production (VE/VCO2) slope (r = −0.371, p = 0.026) and end-tidal carbon dioxide tension (PETCO2) at peak (r = 0.439, p = 0.007). In multiple linear regressions, FMD was the only independent predictor of VE/VCO2 slope (β = −1.308, p = 0.029) and peak PETCO2 values (β = 0.779, p = 0.021). Accordingly, when stratifying our study population based on their ventilatory efficiency, patients with a ventilatory class III-IV (VE/VCO2 slope ≥ 36) exhibited significantly lower FMD values as compared to those with a ventilatory class I-II. Conclusions: The alteration of endothelial barrier properties in systemic and pulmonary circulation may represent a key pathogenic mechanism of the reduced CPET performance in COVID-19 survivors. Personalized pharmacological and rehabilitation strategies targeting endothelial function may represent an attractive therapeutic option. Full article
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Article
Female Sex Is a Risk Factor Associated with Long-Term Post-COVID Related-Symptoms but Not with COVID-19 Symptoms: The LONG-COVID-EXP-CM Multicenter Study
J. Clin. Med. 2022, 11(2), 413; https://doi.org/10.3390/jcm11020413 - 14 Jan 2022
Cited by 21 | Viewed by 5628
Abstract
This multicenter cohort study investigated the differences between coronavirus disease 2019 (COVID-19) related symptoms and post-COVID symptoms between male and female COVID-19 survivors. Clinical and hospitalization data were collected from hospital medical records in a sample of individuals recovered from COVID-19 at five [...] Read more.
This multicenter cohort study investigated the differences between coronavirus disease 2019 (COVID-19) related symptoms and post-COVID symptoms between male and female COVID-19 survivors. Clinical and hospitalization data were collected from hospital medical records in a sample of individuals recovered from COVID-19 at five public hospitals in Spain. A predefined list of post-COVID symptoms was systematically assessed, but patients were free to report any symptom. Anxiety/depressive levels and sleep quality were also assessed. Adjusted multivariate logistic regressions were used to identify the association of sex with post-COVID related-symptoms. A total of 1969 individuals (age: 61, SD: 16 years, 46.4% women) were assessed 8.4 months after discharge. No overall significant sex differences in COVID-19 onset symptoms at hospital admission were found. Post-COVID symptoms were present in up to 60% of hospitalized COVID-19 survivors eight months after the infection. The number of post-COVID symptoms was 2.25 for females and 1.5 for males. After adjusting by all variables, female sex was associated with ≥3 post-COVID symptoms (adj OR 2.54, 95%CI 1.671–3.865, p < 0.001), the presence of post-COVID fatigue (adj OR 1.514, 95%CI 1.040–2.205), dyspnea (rest: adj OR 1.428, 95%CI 1.081–1.886, exertion: adj OR 1.409, 95%CI 1.109–1.791), pain (adj OR 1.349, 95%CI 1.059–1.720), hair loss (adj OR 4.529, 95%CI 2.784–7.368), ocular problems (adj OR 1.981, 95%CI 1.185–3.312), depressive levels (adj OR 1.606, 95%CI 1.002–2.572) and worse sleep quality (adj OR 1.634, 95%CI 1.097–2.434). Female sex was a risk factor for the development of some long-term post-COVID symptoms including mood disorders. Healthcare systems should consider sex differences in the management of long haulers. Full article
Article
Post-COVID-19 Sydrome and Decrease in Health-Related Quality of Life in Kidney Transplant Recipients after SARS-COV-2 Infection—A Cohort Longitudinal Study from the North of Poland
J. Clin. Med. 2021, 10(21), 5205; https://doi.org/10.3390/jcm10215205 - 08 Nov 2021
Cited by 2 | Viewed by 915
Abstract
Introduction: Patients after SARS-CoV-2 infection frequently face “Post-COVID-19 Syndrome”, defined by symptoms that develop during or after COVID-19, continue for more than 12 weeks, and are not explained by an alternative diagnosis. We aimed to evaluate the presence of post-COVID-19 syndrome and its [...] Read more.
Introduction: Patients after SARS-CoV-2 infection frequently face “Post-COVID-19 Syndrome”, defined by symptoms that develop during or after COVID-19, continue for more than 12 weeks, and are not explained by an alternative diagnosis. We aimed to evaluate the presence of post-COVID-19 syndrome and its predictors in kidney transplant recipients (KTR) 6 months after the disease. Materials and Methods: A total of 67 KTR (38 m) with a mean age of 53.6 ± 14 years, 7.3 ± 6.4 years post-transplant were included in the cohort longitudinal study. Thirty-nine (58.2%) of them were hospitalized, but not one required invasive ventilation therapy. They were interviewed 6 months after being infected, with a series of standardized questionnaires: a self-reported symptoms questionnaire, the modified British Medical Research Council (mMRC) dyspnea scale, EQ-5D-5L questionnaire, and EQ-VAS scale. Results: Post-COVID-19 syndrome was diagnosed in 70.1% of KTR and 26.9% of them reported at least three persistent symptoms. The most common symptoms were fatigue (43.3%), hair loss (31.3%), memory impairment (11.9%), muscle aches, and headaches (11.9%). Dyspnea with an mMRC scale grade of at least 1 was reported by 34.3% patients vs. 14.9% before infection; 47.8% stated that they still feel worse than before the disease. Mean EQ-VAS scores were 64.83 vs. 73.34 before infection. The persistent symptoms are more frequent in older patients and those with greater comorbidity. Conclusions: Persistent symptoms of post-COVID-19 syndrome are present in the majority of KTR, which highlights the need for long-term follow-up as well as diagnostic and rehabilitation programs. Full article
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Review

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Review
Long COVID a New Derivative in the Chaos of SARS-CoV-2 Infection: The Emergent Pandemic?
J. Clin. Med. 2021, 10(24), 5799; https://doi.org/10.3390/jcm10245799 - 11 Dec 2021
Cited by 9 | Viewed by 1576
Abstract
Coronavirus disease 2019 (COVID-19) is a multisystem illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can manifest with a multitude of symptoms in the setting of end-organ damage, though it is predominantly respiratory. However, various symptoms may remain after acute [...] Read more.
Coronavirus disease 2019 (COVID-19) is a multisystem illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can manifest with a multitude of symptoms in the setting of end-organ damage, though it is predominantly respiratory. However, various symptoms may remain after acute SARS-CoV-2 infection, and this condition is referred to as “Long COVID” (LC). Patients with LC may develop multi-organ symptom complex that remains 4–12 weeks after the acute phase of illness, with symptoms intermittently persisting over time. The main symptoms are fatigue, post-exertional malaise, cognitive dysfunction, and limitation of functional capacity. Pediatric patients developed the main symptoms of LC like those described in adults, although there may be variable presentations of LC in children. The underlying mechanisms of LC are not clearly known, although they may involve pathophysiological changes generated by virus persistence, immunological alterations secondary to virus–host interaction, tissue damage of inflammatory origin and hyperactivation of coagulation. Risk factors for developing LC would be female sex, more than five early symptoms, early dyspnea, previous psychiatric disorders, and alterations in immunological, inflammatory and coagulation parameters. There is currently no specific treatment for LC, but it could include pharmacological treatments to treat symptoms, supplements to restore nutritional, metabolic, and gut flora balance, and functional treatments for the most disabling symptoms. In summary, this study aims to show the scientific community the current knowledge of LC. Full article
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Other

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Brief Report
Sensitization-Associated Post-COVID-19 Symptoms at 6 Months Are Not Associated with Serological Biomarkers at Hospital Admission in COVID-19 Survivors: A Secondary Analysis of a Cohort Study
J. Clin. Med. 2022, 11(12), 3512; https://doi.org/10.3390/jcm11123512 - 18 Jun 2022
Cited by 1 | Viewed by 448
Abstract
Individuals who survived coronavirus disease, 2019 (COVID-19), often have symptoms of sensitization, but the extent to which these symptoms relate to serological biomarkers remains unclear. Therefore, this secondary analysis evaluated the association between serological biomarkers at hospital admission with sensitization-associated post-COVID-19 symptoms in [...] Read more.
Individuals who survived coronavirus disease, 2019 (COVID-19), often have symptoms of sensitization, but the extent to which these symptoms relate to serological biomarkers remains unclear. Therefore, this secondary analysis evaluated the association between serological biomarkers at hospital admission with sensitization-associated post-COVID-19 symptoms in a sample of previously hospitalized COVID-19 survivors. Sixty-seven individuals hospitalized due to SARS-CoV-2 infection in one urban hospital of Madrid (Spain) during the first wave of the pandemic were assessed a mean of 6.0 (SD 0.8) months after hospital discharge. The Central Sensitization Inventory (CSI) was used as rough tool to estimate the presence of sensitization-associated post-COVID-19 symptoms (≥40/100 points). Levels of 16 serological biomarkers collected at hospital admission were obtained from medical records. Twenty-four (35.8%) patients reported sensitization-associated post-COVID-19 symptoms (CSI ≥ 40 points). Subjects reporting sensitization-associated symptoms had lower ferritin and hemoglobin levels than those not reporting sensitization-associated post-COVID-19 symptoms; however, these differences were small. We observed significant but small negative associations of the CSI score with ferritin (r: −0.251, p = 0.04) and hemoglobin (r: −0.292, p = 0.017) levels. No other significant difference was found. In conclusion, this secondary analysis did not find significant associations between the investigated serological biomarkers at hospital admission and sensitization-associated post-COVID-19 symptoms at 6 months after hospitalization in COVID-19 survivors. Full article
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