Long COVID: Clinical Framing, Biomarkers, and Therapeutic Approaches
Abstract
:1. Introduction
2. Clinical Framing of Long COVID
3. Long COVID in the Elderly
Source | Study Type | Country | Primary Aim | Sex (% Male) | Age Range (Years) | Total Pts (n) | Results |
---|---|---|---|---|---|---|---|
Daitch et al. [28] | Prospective cohort | Israel, Switzerland, Spain, Italy | To estimate the prevalence of long-COVID symptoms among older adults and to explore independent risk factors for fatigue and dyspnea. | 50.8 | 35–66 | 2333 | Older patients had gone to the recovery clinic about one month earlier than younger participants (p < 0.001) and had higher rates of any symptoms (80.0% vs. 64.2%, p < 0.001). However, age was not an independent predictor of fatigue and dyspnea. |
Tosato et al. [30] | Cross-sectional | Italy | To provide multidisciplinary and individualized follow-up for COVID-19 survivors in the elderly. | 61.6 | 67–80 | 165 | The presence of more symptoms during the acute phase is associated with a higher risk of symptom persistence beyond 2 months after hospital discharge. The presence of fatigue is a major risk factor for symptom persistence. |
Martincheck et al. [34] | Observational retrospective | US | To evaluate the outcome of a COVID-19 outbreak on the weight of older residents in a nursing facility. | 44.0 | 63–86 | 209 | During the acute phase of infection, which lasts about 2 weeks, the patients are likely to lose 5–10% of body weight. |
Paneroni et al. [36] | Cross-sectional | Italy | To evaluate skeletal muscle strength, exercise intolerance, and symptoms in a cohort of patients recovering from COVID-19 pneumonia without preexisting disabilities. | 61.0 | 40–88 | 41 | The strength of the biceps brachii and quadriceps femoris were 69 and 54% of the predicted normal value in 73 and 86% of patients, respectively. The functionality of these large muscle groups was equally impaired. |
Paneroni et al. [37] | Cross-sectional comparative study | Italy | To evaluate whether frail elderly recovering from COVID-19 pneumonia have altered vascular endothelium-dependent responsiveness. | 73.0 | 57–78 | 22 | The peak femoral blood flow was reduced in frail elderly patients at about 100 days after hospitalization for COVID-19 pneumonia |
Douaud et al. [52] | Case control | UK | To investigate the relationship between the use of psychotropic medications and post-COVID incident dementia. | 42.9 | 51.3–81.4 | 785 | Pre-COVID psychotropic medication use was associated with a higher 1-year incidence of dementia, after controlling for patient demographics, characteristics, and severity of acute COVID-19 illness (OR = 3.20, 95% CI: 2.37/4.32). |
4. Sex-Related Differences in Long-COVID
5. Long-COVID Neurological and Psychological Symptoms
6. Long COVID and Cancer
7. Biomarkers for Long-COVID Syndrome
8. Therapeutic Approaches
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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---|---|---|---|---|---|---|---|
Munblit et al. [53] | Longitudinal cohort | Russia | To investigate the incidence of long-term consequences in adults previously hospitalized for COVID-19 and to assess risk factors for long COVID. | 48.8 | 46–66 | 2649 | 47.1% reported persistent dermatological, respiratory, and neurological symptoms. The female sex was associated with all of these manifestations. |
Bai et al. [55] | Prospective cohort | Italy | To investigate the incidence of physical and/or psychological symptoms characterizing the long COVID in women and to determine possible predictors of long COVID. | 63.7 | 49–68 | 377 | 206 out of 377 patients experienced PCS and 81.7% were women. The most reported symptoms were fatigue (39.5%) and dyspnea (28.9%), followed by musculoskeletal pain and cognitive dulling. Female gender, older age, and active smoking were found to be associated with a higher risk of developing long COVID. |
Fernández-de-las-Peñas et al. [56] | Cohort | Spain | To investigate sex differences in post-COVID symptoms. | 53.6 | 45–77 | 1969 | The number of post-COVID manifestations was higher in women than men (p < 0.001), and women were more likely to have 3 or more symptoms (p < 0.001). |
Sigfrid et al. [57] | Prospective cohort | UK | To establish the long-term effects of COVID-19 after hospitalization. | 45.3 | 53.2–69.8 | 327 | Women <50 years old were 5 times less likely to report feeling recovered (OR 5.09, 95% CI 1.64 to 15.74), were more likely to have a greater disability (OR 4.22, 95% CI 1.12 to 15.94), to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31), and to become more breathless (OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. |
Robineau et al. [58] | Cross-sectional | France | To describe the temporal dynamics of COVID-19 long-term effects and the factors useful to predict their resolution. | 73.0 | 38–63 | 3972 | Of 861 patients with persistent symptoms, 75.4% were women, and the female sex was also associated with slower resolution of anosmia, ageusia, and asthenia. |
Source | Study Type | Country | Primary Aim | Sex (% Male) | Age Range (Years) | Total Pts (n) | Results |
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Liu et al. [64] | RCT | China | To investigate the long-term effects on cognitive function and to determine related risk factors in patients who recovered from COVID-19 | 47.95 | 66–75 | 1539 | Patients with severe COVID-19 have greater cognitive decline than patients with non-severe COVID-19. [dementia: 25 vs. 9, p < 0.001; MCI: 60 vs. 63, p < 0.001] and controls [dementia: 25 vs. 0, p < 0.001; MCI: 60 vs. 20, p < 0.001)]. |
Liu et al. [65] | RCT | China | To assess cognitive changes in elderly PCS patients over 1 year. | 48.05 | 66–74 | 3233 | Higher incidence of cognitive decline in PCS patients compared with uninfected controls. Patients with severe COVID-19 have a higher risk of early- (OR: 4.87; 95% CI, 3.30–7.20), late- (OR: 7.58; 95% CI, 3.58–16.03), and progressive-onset cognitive decline (OR: 19.00; 95% CI, 9.14–39.51) than controls. |
Davis et al. [66] | Multicenter observational | 56 countries | To analyze the neurological and neuropsychiatric symptoms course and severity over time in COVID-19 survivors. | 19.1 | >18 | 3762 | Of 3762 patients, 85% had cognitive dysfunction that peaked 4 months after the onset of COVID-19 symptoms and memory impairment, altered attention, executive functioning, problem-solving, and decision-making. |
Frontera et al. [68] | Observational | US | To identify clinically important phenotypes of patients with PCS and to assess associations of these phenotypes with their functional status and quality of life. | 64 | 53–73 | 242 | More than 100 patients were divided into three main symptom groups: with continuous symptoms (most commonly headache), with many relevant symptoms (including high levels of anxiety and depression); reporting shortness of breath, headache, and cognitive symptoms. |
Rass et al. [70] | Observational | Austria | To describe the natural course of neurological manifestations over 1 year in PCS patients. | 59 | 47–64 | 81 | The prevalence of memory and concentration difficulties of 23% and 18% was found at 3 months and 1 year after acute COVID-19, respectively. The most frequent symptoms at the 1-year follow-up were fatigue, difficulty in concentration, sleep disturbance, myalgia, limb weakness, headache, altered sensitivity, and hyposmia. |
Zhou et al. [71] | Observational | China | To study the clinical characteristics of patients recovered from COVID-19 at 3 months post-discharge. | 19.5 | 51.50–64 | 72 | Significant serum amyloid levels were found in COVID-19 survivors at 3 months. |
Fischer et al. [73] | Observational | US | To describe the clinical characteristics and functional status of COVID-DoC patients at 3 and 6 months after discharge. | 41.7 | 55–76.3 | 12 | At 3 months, the median scores of GOSE and DRS were 3 and 7, respectively; at 6 months, the median scores of GOSE and DRS were 4 and 3. Functional and structural brain connectivity of COVID-DoC patients, undergoing MRI, were decreased compared with healthy controls, and structural connectivity was comparable to that in patients with severe TBI. |
Source | Study Type | Country | Primary Aim | Sex (% Male) | Age (Years) | Total Pts (n) | Type of Cancer (%) | Results |
---|---|---|---|---|---|---|---|---|
Pinato et al. [91] | Retrospective registry study | Belgium, France, Germany, Italy, Spain UK | To evaluate the prevalence and impact of COVID-19 sequelae in cancer patients, following recovery from SARS-CoV-2 infection. | 48.2 | ≥18 | 1557 | Breast (43.7) GI (34.6) GU (40.6) Hematological (27.5) Thoracic (28.1) Others (25.5) Missing (0) | 234 (15%) patients reported COVID-19 sequelae. Sequelae were associated with sex, age, number of comorbidities, and smoking status. The risk of death from sequelae in cancer patients increased compared to noncancer patients (HR 1.80 [95%CI 1.18–2.75]). |
Dagher et al. [92] | Observational retrospective | US | To describe long-term effects from COVID-19 recovery in cancer patients. | NA | 18–86 | 312 | NA | Long COVID-19 can persist up to 14 months after acute disease and occurs in up to 60% of cancer patients. Long COVID-19 effects included fatigue, sleep disturbances, myalgia, gastrointestinal symptoms, dyspnea, and cough (82%, 78%, 67%, 61%, 47%, and 46%, respectively). The persistence of symptoms was higher in women than in men (63% vs. 37%, p = 0.036). |
Sharafeldin et al. [93] | Retrospective cohort study | US | To describe characteristics of long COVID in cancer patients. | 39.6 | 54–72 | 1700 (1066 controls) | Skin (21.9) Breast (17.7) Prostate (8.3) Lymphoma (8.0) Leukemia (5.7) | Characteristics were (i) median age of 64 years (range: 54–72 years), (ii) female sex (60.4%), (iii) non-Hispanic white ethnicity (76.8%), (iv) current or former smokers (41.1%), (v) more comorbidities (OR = 4.3, [95%CI 2.9–6.2], p < 0.0001), and (vi) more likely to be hospitalized for COVID-19 (OR = 1.3, [95%CI 1.0–1.7], p = 0.05) compared with non-cancer subjects. |
Source | Study Type | Country | Primary Aim | Sex (% Male) | Age Range (Years) | Total Pts (n) | Tested Dietary Supplement(s) | Results |
---|---|---|---|---|---|---|---|---|
Kharaeva et al. [153] | RCT | Russia | To alleviate PCS symptoms | 49.7 | 35–69 | 213 (25 controls) | Fermented Carica papaya 14 mg per os and fermented Morinda citrifolia 14 mg per os Duration: 20 days | At 20 days, self-reported clinical symptoms as well as IL-6, IL-8, and nitric oxide metabolites diminished in PCS patients receiving supplementation compared to placebo. The PMNs capacity to phagocyte, AOA, and ATP content remarkably increased in the supplemented group compared to placebo. |
Rossato et al. [154] | Open-label observational trial | Italy | To improve the general health status especially the PCS-related chronic fatigue | 39.3 | 35–62 | 201 | Vitamins D, H, B1, B3, B7, C, E 87 mg, minerals (e.g., iron, magnesium, zinc, selenium) 204 mg, amino acids (e.g., arginine, carnitine) 1.5 g, and Panax ginseng and Eleutherococcus senticosus extracts 150 mg, once daily per os Duration: 28 days | The scores on quality of life, health status, FACIT-Fatigue and mental fatigue significantly improved after the first 14 days and at 28 days. |
Naureen et al. [155] | Pilot observational study | Italy | To diminish perceived PCS-related fatigue | 47.5 | 28–76 | 40 (20 controls) | Vitamin C 160 mg; acetyl-L-carnitine 150 mg; hydroxytyrosol/olive polyphenols, 100 mg; thiamine 12.5 mg; vitamin B6, 5 mg; folic acid 0.2 mg; vitamin D3 0.025 mg; and vitamin B12. 0.005 mg, once daily per os Duration: 15 days | At 15 days, self-perceived energy doubled (+123%) and fatigue and tension levels halved (−51% and −48%, respectively) in the supplemented compared with the unsupplemented group. |
Tosato et al. [156] | RCT | Italy | To increase physical performance, endothelial function and decrease persistent PCS-related fatigue | 34.8 | 50.5 (median) | 46 | L-arginine, 1.66 g + liposomal vitamin C, 500 mg, BID, per os Duration: 28 days | At 28 days, 6 min walk distance, handgrip strength, and FMD increased significantly while self-reported fatigue was significantly lower in PCS patients belonging to the supplemented group compared with those receiving the placebo. |
Belcaro et al. [157] | Pilot observational study | Italy | To ameliorate endothelial function, microcirculation inflammatory markers, and oxidative stress in PCS patients | NA | 35–70 | 60 | Pinus pinaster extract, 50 mg, 3 times a day (total 150 mg), per os Duration: 90 days | FMD, reactive finger hyperemia, ankle swelling rate, and renal cortical flow velocity improved significantly in the supplemented group after 1 month and after 3 months compared with controls. High-sensitivity CRP (hs-CRP), plasma Il-6 levels and oxidative stress markers decreased significantly over 3 months in the supplemented group. Questionnaire scores on quality of life, mood and fatigue, and Karnofsky scale performance index improved significantly in the supplemented group compared with controls after 1 and 3 months. |
Bove et al. [158] | Pilot observational study | Italy | To improve cognitive function and psychosocial parameters in PCS patients | NA | 65–68 | 40 | Bacopa monnieri extract, 320 mg; L-theanine, 100 mg; Crocus sativus L. extract Saffron, 30 mg; vitamin B6, 9.5 mg; vitamin D, 25 µg; copper, 2 mg; biotin, 450 µg; folic acid, 400 µg; and vitamin B12, 33 µg, 1 capsule/day per os Duration: 90 days | After 90 days, functional status, assessed by the MMSE and PCFS scale, and major psychological disorders improved significantly. |
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Conti, V.; Corbi, G.; Sabbatino, F.; De Pascale, D.; Sellitto, C.; Stefanelli, B.; Bertini, N.; De Simone, M.; Liguori, L.; Di Paola, I.; et al. Long COVID: Clinical Framing, Biomarkers, and Therapeutic Approaches. J. Pers. Med. 2023, 13, 334. https://doi.org/10.3390/jpm13020334
Conti V, Corbi G, Sabbatino F, De Pascale D, Sellitto C, Stefanelli B, Bertini N, De Simone M, Liguori L, Di Paola I, et al. Long COVID: Clinical Framing, Biomarkers, and Therapeutic Approaches. Journal of Personalized Medicine. 2023; 13(2):334. https://doi.org/10.3390/jpm13020334
Chicago/Turabian StyleConti, Valeria, Graziamaria Corbi, Francesco Sabbatino, Domenico De Pascale, Carmine Sellitto, Berenice Stefanelli, Nicola Bertini, Matteo De Simone, Luigi Liguori, Ilenia Di Paola, and et al. 2023. "Long COVID: Clinical Framing, Biomarkers, and Therapeutic Approaches" Journal of Personalized Medicine 13, no. 2: 334. https://doi.org/10.3390/jpm13020334