Consistency of inconsistency in long-COVID-19 pain symptoms persistency: A systematic review and meta-analysis

Abstract:

Introduction: Individuals recovering from acute COVID-19 episodes may continue to suffer from various ongoing symptoms, collectively referred to as Long-COVID. Long-term pain symptoms are amongst the most common and clinically significant symptoms to be reported for this post-COVID-19 syndrome.

Objectives: This systematic review and meta-analysis aimed to evaluate the proportions of persisting pain symptoms experienced by individuals past the acute phase of COVID-19 and to identify their associated functional consequences and inflammatory correlates.

Methods: Two online databases were systematically searched from their inception until 31 March 2022. We searched primary research articles in English, which evaluated individuals after laboratory-confirmed COVID-19 acute phase resolution and specifically reported on pain symptoms and their inflammatory and/or functional outcomes.

Results: Of the 611 identified articles, 26 were included, used for data extraction, and assessed for their methodological quality and risk of bias by two independent reviewers. Pain symptoms were grouped under one of six major pain domains, serving as our primary co-outcomes. Proportional meta-analyses of pooled logit-transformed values of single proportions were performed using the random-effects-restricted maximum-likelihood model. An estimated 8%, 6%, 18%, 18%, 17%, and 12% of individuals continued to report the persistence of chest, gastrointestinal, musculoskeletal joint, musculoskeletal muscle, general body, and nervous system-related pain symptoms, respectively, for up to one year after acute phase resolution of COVID-19. Considerable levels of heterogeneity were demonstrated across all results. Functional and quality-of-life impairments and some inflammatory biomarker elevations were associated with the persistence of long-COVID pain symptoms.

Conclusion: This study’s findings suggest that although not well characterized, long-COVID pain symptoms are being experienced by non-negligible proportions of those recovering from acute COVID-19 episodes, thus highlighting the importance of future research efforts to focus on this aspect.

Source: Kerzhner O, Berla E, Har-Even M, Ratmansky M, Goor-Aryeh I. Consistency of inconsistency in long-COVID-19 pain symptoms persistency: A systematic review and meta-analysis. Pain Pract. 2023 Jul 21. doi: 10.1111/papr.13277. Epub ahead of print. PMID: 37475709. https://onlinelibrary.wiley.com/doi/10.1111/papr.13277 (Full study)

The Impact of Post-COVID-19 Syndrome in Adolescents: A Pilot Study

Abstract:

Background: Post-COVID-19 syndrome has emerged as a long-term complication in adults and children; its effect on adolescents’ performance in school is not well studied.

Objectives: To study the physical/psychological impact of prolonged post-COVID-19 symptoms on school performance.

Methods: This is a cross-sectional study using Google Forms, a web-based fully anonymized survey of children in grades 10-12.

Results: The study included 54 students with a mean age of 16 years of whom 32 had COVID-19. Two were hospitalized and 10 had symptoms lasting more than four weeks. Commonly reported chronic symptoms were fatigue and cough. Seven students quit sports; eight had a decrease in their academic performance. Adolescents being infected more than once or not being fully vaccinated were more likely to develop prolonged symptoms and quit sports while academic performance in school was not affected. Three out of 10 (30%) students who had COVID-19 and responded to the questionnaire reported not seeking help.

Conclusion: Post-COVID-19 syndrome is associated with a decline in physical but not mental performance in school. Being infected more than once with SARS-CoV-2 seems to play an important role in the persistence of post-COVID-19 symptoms despite the fact that some adolescents are hesitant to seek medical or psychological care.

Source: El Khoury J, Skoury M, El Khoury MY. The Impact of Post-COVID-19 Syndrome in Adolescents: A Pilot Study. Cureus. 2023 Jun 19;15(6):e40655. doi: 10.7759/cureus.40655. PMID: 37476124; PMCID: PMC10356177. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356177/ (Full text)

Persistent post-COVID-19 neuromuscular symptoms

Abstract:

Neuromuscular symptoms may develop or persist after resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides residual sensorimotor symptoms associated with acute neuromuscular complications of coronavirus disease-2019 (COVID-19), such as Guillain-Barré syndrome, critical illness neuromyopathy, and rhabdomyolysis, patients may report persistent autonomic symptoms, sensory symptoms, and muscle symptoms in the absence of these acute complications, including palpitations, orthostatic dizziness and intolerance, paresthesia, myalgia, and fatigue.

These symptoms may be associated with long COVID, also known as post-COVID-19 conditions or postacute sequelae of SARS-CoV-2 infection, which may significantly impact quality of life. Managing these symptoms represents a challenge for health-care providers.

Recent advances have identified small-fiber neuropathy as a potential etiology that may underlie autonomic dysfunction and paresthesia in some long COVID patients. The pathogenic mechanisms underlying myalgia and fatigue remain elusive and need to be investigated. Herein we review the current state of knowledge regarding the evaluation and management of patients with persistent post-COVID-19 neuromuscular symptoms.

Source: Abrams RMC, Zhou L, Shin SC. Persistent post-COVID-19 neuromuscular symptoms. Muscle Nerve. 2023 Jul 19. doi: 10.1002/mus.27940. Epub ahead of print. PMID: 37466117. https://onlinelibrary.wiley.com/doi/10.1002/mus.27940 (Full text)

Plasmapheresis to remove amyloid fibrin(ogen) particles for treating the post‐COVID‐19 condition

Abstract:

Background: The post-COVID-19 condition (PCC) consists of a wide array of symptoms including fatigue and impaired daily living. People seek a wide variety of approaches to help them recover. A new belief, arising from a few laboratory studies, is that ‘microclots’ cause the symptoms of PCC. This belief has been extended outside these studies, suggesting that to recover people need plasmapheresis (an expensive process where blood is filtered outside the body). We appraised the laboratory studies, and it was clear that the term ‘microclots’ is incorrect to describe the phenomenon being described. The particles are amyloid and include fibrin(ogen); amyloid is not a part of a thrombus which is a mix of fibrin mesh and platelets. Initial acute COVID-19 infection is associated with clotting abnormalities; this review concerns amyloid fibrin(ogen) particles in PCC only. We have reported here our appraisal of laboratory studies investigating the presence of amyloid fibrin(ogen) particles in PCC, and of evidence that plasmapheresis may be an effective therapy to remove amyloid fibrin(ogen) particles for treating PCC.

Objectives: Laboratory studies review To summarize and appraise the research reports on amyloid fibrin(ogen) particles related to PCC. Randomized controlled trials review To assess the evidence of the safety and efficacy of plasmapheresis to remove amyloid fibrin(ogen) particles in individuals with PCC from randomized controlled trials.

Search methods: Laboratory studies review We searched for all relevant laboratory studies up to 27 October 2022 using a comprehensive search strategy which included the search terms ‘COVID’, ‘amyloid’, ‘fibrin’, ‘fibrinogen’. Randomized controlled trials review We searched the following databases on 21 October 2022: Cochrane COVID-19 Study Register; MEDLINE (Ovid); Embase (Ovid); and BIOSIS Previews (Web of Science). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress.

Selection criteria: Laboratory studies review Laboratory studies that investigate the presence of amyloid fibrin(ogen) particles in plasma samples from patients with PCC were eligible. This included studies with or without controls. Randomized controlled trials review Studies were eligible if they were of randomized controlled design and investigated the effectiveness or safety of plasmapheresis for removing amyloid fibrin(ogen) particles for treating PCC.

Data collection and analysis: Two review authors applied study inclusion criteria to identify eligible studies and extracted data. Laboratory studies review We assessed the risk of bias of included studies using pre-developed methods for laboratory studies. We planned to perform synthesis without meta-analysis (SWiM) as described in our protocol. Randomized controlled trials review We planned that if we identified any eligible studies, we would assess risk of bias and report results with 95% confidence intervals. The primary outcome was recovery, measured using the Post-COVID-19 Functional Status Scale (absence of symptoms related to the illness, ability to do usual daily activities, and a return to a previous state of health and mind).

Main results: Laboratory studies review We identified five laboratory studies. Amyloid fibrin(ogen) particles were identified in participants across all studies, including those with PCC, healthy individuals, and those with diabetes. The results of three studies were based on visual images of amyloid fibrin(ogen) particles, which did not quantify the amount or size of the particles identified. Formal risk of bias assessment showed concerns in how the studies were conducted and reported. This means the results were insufficient to support the belief that amyloid fibrin(ogen) particles are associated with PCC, or to determine whether there is a difference in the amount or size of amyloid fibrin(ogen) particles in the plasma of people with PCC compared to healthy controls. Randomized controlled trials review We identified no trials meeting our inclusion criteria.

Authors’ conclusions: In the absence of reliable research showing that amyloid fibrin(ogen) particles contribute to the pathophysiology of PCC, there is no rationale for plasmapheresis to remove amyloid fibrin(ogen) particles in PCC. Plasmapheresis for this indication should not be used outside the context of a well-conducted randomized controlled trial.

Source: Fox T, Hunt BJ, Ariens RA, Towers GJ, Lever R, Garner P, Kuehn R. Plasmapheresis to remove amyloid fibrin(ogen) particles for treating the post-COVID-19 condition. Cochrane Database Syst Rev. 2023 Jul 26;7(7):CD015775. doi: 10.1002/14651858.CD015775. PMID: 37491597; PMCID: PMC10368521. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368521/ (Full text)

Association between duration of SARS-CoV-2 positivity and long COVID

Abstract:

In an observational study, we analyzed 1,293 healthcare workers previously infected with SARS-CoV-2, of which 34.1% developed long COVID. Using a multivariate logistic regression model, we demonstrate that the likelihood of developing long COVID in infected individuals rises with the increasing of duration of infection and that three doses of the BNT162b2 vaccine are protective, even during the Omicron wave.

Source:Chiara Pozzi and others, Association between duration of SARS-CoV-2 positivity and long COVID, Clinical Infectious Diseases, 2023;, ciad434, https://doi.org/10.1093/cid/ciad434 https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciad434/7227950 (Full text available as PDF file)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and COVID-19: is there a connection?

Abstract:

Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic systemic disease that leads to neurological, immunological, autonomic, and energy metabolism dysfunction. COVID-19 has been reported to cause similar symptoms to ME/CFS. The study aims to investigate the prevalence of myalgic encephalomyelitis in patients post-COVID-19 infection by assessing acute and long-term COVID-19 symptoms.

Methods: A cross-sectional questionnaire was developed based on the ME/CFS diagnostic criteria, as specified by the IOM clinical diagnostic criteria, and administered to participants with confirmed COVID-19 who are more than 18 years old and have BMI below 40 Kg/m2. Data from 437 participants were completed.

Results: The current study results revealed that 8.1% of the study participants met the ME/CFS diagnostic criteria. Interestingly, 2.8 of the study participants were classified to have COVID-19 related to ME/CFS. While 4.6% of participants were determined to have disease-related fatigue, 0.7% of participants showed ME/CFS that was not related to COVID-19, and 3.7% of participants were considered to have long COVID-19. Almost one-fourth of the study participants had a family history of ME/CFS. The current study demonstrated that the prevalence of ME/CFS is similar to slightly higher than reported in the literature.

Conclusion: The presence of a relationship between ME/CFS and COVID-19 has been supported by the results of our study. Follow-up of COVID-19 patients is strongly recommended to ensure proper management of ME/CFS symptoms.

Source: Muhaissen SA, Abu Libdeh A, ElKhatib Y, Alshayeb R, Jaara A, Bardaweel SK. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and COVID-19: is there a connection? Curr Med Res Opin. 2023 Jul 28:1-24. doi: 10.1080/03007995.2023.2242244. Epub ahead of print. PMID: 37501626. https://pubmed.ncbi.nlm.nih.gov/37501626/

Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort

Summary:

Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs.

Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677.

Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively).

Interpretation: Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials.

Funding: The study received funding from the Horizon 2020 ORCHESTRA project, grant 101016167; from the Netherlands Organisation for Health Research and Development (ZonMw), grant 10430012010023; from Inserm, REACTing (REsearch & ACtion emergING infectious diseases) consortium and the French Ministry of Health, grant PHRC 20-0424.

Source: Elisa Gentilotti, Anna Górska, Adriana Tami, Roy Gusinow, Massimo Mirandola, Jesús Rodríguez Baño, et al. Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort. Lancet,  “eClinicalMedicine” https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00284-5/fulltext (Full text)

Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations

Abstract:

Individuals with SARS-CoV-2 infection can develop symptoms that persist well beyond the acute phase of COVID-19 or emerge after the acute phase, lasting for weeks or months after the initial acute illness. The post-acute sequelae of COVID-19, which include physical, cognitive, and mental health impairments, are known collectively as long COVID or post-COVID-19 condition.

The substantial burden of this multisystem condition is felt at individual, health-care system, and socioeconomic levels, on an unprecedented scale. Survivors of COVID-19-related critical illness are at risk of the well known sequelae of acute respiratory distress syndrome, sepsis, and chronic critical illness, and these multidimensional morbidities might be difficult to differentiate from the specific effects of SARS-CoV-2 and COVID-19.

We provide an overview of the manifestations of post-COVID-19 condition after critical illness in adults. We explore the effects on various organ systems, describe potential pathophysiological mechanisms, and consider the challenges of providing clinical care and support for survivors of critical illness with multisystem manifestations.

Research is needed to reduce the incidence of post-acute sequelae of COVID-19-related critical illness and to optimise therapeutic and rehabilitative care and support for patients.

Source: Parotto M, Gyöngyösi M, Howe K, Myatra SN, Ranzani O, Shankar-Hari M, Herridge MS. Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations. Lancet Respir Med. 2023 Jul 17:S2213-2600(23)00239-4. doi: 10.1016/S2213-2600(23)00239-4. Epub ahead of print. PMID: 37475125. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00239-4/fulltext (Full text)

Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness

Abstract:

Despite advances in the treatment and mitigation of critical illness caused by infection with SARS-CoV-2, millions of survivors have a devastating, post-acute infection syndrome known as long COVID. A large proportion of patients with long COVID have nervous system dysfunction, which is also seen in the distinct but overlapping condition of post-intensive care syndrome (PICS), putting survivors of COVID-19-related critical illness at high risk of long-lasting morbidity affecting multiple organ systems and, as a result, engendering measurable deficits in quality of life and productivity.

In this Series paper, we discuss neurological, cognitive, and psychiatric sequelae in patients who have survived critical illness due to COVID-19. We review current knowledge of the epidemiology and pathophysiology of persistent neuropsychological impairments, and outline potential preventive strategies based on safe, evidence-based approaches to the management of pain, agitation, delirium, anticoagulation, and ventilator weaning during critical illness. We highlight priorities for current and future research, including possible therapeutic approaches, and offer considerations for health services to address the escalating health burden of long COVID.

Source: Pandharipande P, Williams Roberson S, Harrison FE, Wilson JE, Bastarache JA, Ely EW. Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness. Lancet Respir Med. 2023 Jul 17:S2213-2600(23)00238-2. doi: 10.1016/S2213-2600(23)00238-2. Epub ahead of print. PMID: 37475124. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00238-2/fulltext (Full text)

Using Data Science and a Health Equity Lens to Identify Long-COVID Sequelae Among Medically Underserved Populations

Abstract:

Understanding how post-acute COVID-19 syndrome (PACS or long COVID) manifests among underserved populations, who experienced a disproportionate burden of acute COVID-19, can help providers and policymakers better address this ongoing crisis. To identify clinical sequelae of long COVID among underserved populations treated in the primary care safety net, we conducted a causal impact analysis with electronic health records (EHR) to compare symptoms among community health center patients who tested positive (n=4,091) and negative (n=7,118) for acute COVID-19.

We found 18 sequelae with statistical significance and causal dependence among patients who had a visit after 60 days or more following acute COVID-19. These sequelae encompass most organ systems and include breathing abnormalities, malaise and fatigue, and headache. This study adds to current knowledge about how long COVID manifests in a large, underserved population.

Source: Nasir M, Cook N, Parras D, Mukherjee S, Miller G, Ferres JL, Chung-Bridges K. Using Data Science and a Health Equity Lens to Identify Long-COVID Sequelae Among Medically Underserved Populations. J Health Care Poor Underserved. 2023;34(2):521-534. doi: 10.1353/hpu.2023.0047. PMID: 37464515. https://pubmed.ncbi.nlm.nih.gov/37464515/