Incidence of long-term post-acute sequelae of SARS-CoV-2 infection related to pain and other symptoms: A systematic review and meta-analysis

Abstract:

Background: Persistent symptoms are reported in patients who survive the initial stage of COVID-19, often referred to as “long COVID” or “post-acute sequelae of SARS-CoV-2 infection” (PASC); however, evidence on their incidence is still lacking, and symptoms relevant to pain are yet to be assessed.

Methods: A literature search was performed using the electronic databases PubMed, EMBASE, Scopus, and CHINAL and preprint servers MedRχiv and BioRχiv through January 15, 2021. The primary outcome was pain-related symptoms such as headache or myalgia. Secondary outcomes were symptoms relevant to pain (depression or muscle weakness) and symptoms frequently reported (anosmia and dyspnea). Incidence rates of symptoms were pooled using inverse variance methods with a DerSimonian-Laird random-effects model. The source of heterogeneity was explored using meta-regression, with follow-up period, age and sex as covariates.

Results: In total, 38 studies including 19,460 patients were eligible. Eight pain-related symptoms and 26 other symptoms were identified. The highest pooled incidence among pain-related symptoms was chest pain (17%, 95% confidence interval [CI], 11%-24%), followed by headache (16%, 95% CI, 9%-27%), arthralgia (13%, 95% CI, 7%-24%), neuralgia (12%, 95% CI, 3%-38%) and abdominal pain (11%, 95% CI, 7%-16%). The highest pooled incidence among other symptoms was fatigue (44%, 95% CI, 32%-57%), followed by insomnia (27%, 95% CI, 10%-55%), dyspnea (26%, 95% CI, 17%-38%), weakness (25%, 95% CI, 8%-56%) and anosmia (19%, 95% CI, 13%-27%). Substantial heterogeneity was identified (I2, 50-100%). Meta-regression analyses partially accounted for the source of heterogeneity, and yet, 53% of the symptoms remained unexplained.

Conclusions: The current meta-analysis may provide a complete picture of incidence in PASC. It remains unclear, however, whether post-COVID symptoms progress or regress over time or to what extent PASC are associated with age or sex.

Source: Hoshijima H, Mihara T, Seki H, Hyuga S, Kuratani N, Shiga T. Incidence of long-term post-acute sequelae of SARS-CoV-2 infection related to pain and other symptoms: A systematic review and meta-analysis. PLoS One. 2023 Nov 29;18(11):e0250909. doi: 10.1371/journal.pone.0250909. PMID: 38019841; PMCID: PMC10686440. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10686440/ (Full text)

Molecular Mechanisms Involved in the Occurrence and Progression of Long COVID and Associated Analysis Techniques

Abstract:

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), has emerged as a significant health concern following the COVID-19 pandemic. Molecular mechanisms underlying the occurrence and progression of long COVID include viral persistence, immune dysregulation, endothelial dysfunction, and neurological involvement, and highlight the need for further research to develop targeted therapies for this condition.
While a clearer picture of the clinical symptomatology is shaping, many molecular mechanisms are yet to be unraveled, given their complexity and high level of interaction with other metabolic pathways. This review summarizes some of the most important symptoms and associated molecular mechanisms that occur in long COVID, as well as the most relevant molecular techniques that can be used in understanding the viral pathogen, its affinity towards the host and the possible outcomes of host-pathogen interaction.
Source: Constantinescu-Bercu, A.; Lobiuc, A.; Caliman Sturdza, O.A.; Oita, R.; Iavorschi, M.; Paval, N.; Soldanescu, I.; Dimian, M.; Covasa, M. Molecular Mechanisms Involved in the Occurrence and Progression of Long COVID and Associated Analysis Techniques. Preprints 2023, 2023111865. https://doi.org/10.20944/preprints202311.1865.v1 https://www.preprints.org/manuscript/202311.1865/v1 (Full text available as PDF file)

Long-term neurological dysfunction associated with COVID-19: Lessons from influenza and inflammatory diseases?

Abstract:

As the COVID-19 pandemic persists, SARS-CoV-2 infection is increasingly associated with long-term neurological side effects including cognitive impairment, fatigue, depression, and anxiety, colloquially known as “long-COVID.” While the full extent of long-COVID neuropathology across years or even decades is not yet known, we can perhaps take direction from long-standing research into other respiratory diseases, such as influenza, that can present with similar long-term neurological consequences.

In this review, we highlight commonalities in the neurological impacts of influenza and COVID-19. We first focus on the common potential mechanisms underlying neurological sequelae of long-COVID and influenza, namely (1) viral neurotropism and (2) dysregulated peripheral inflammation. The latter, namely heightened peripheral inflammation leading to central nervous system dysfunction, is emerging as a shared mechanism in various peripheral inflammatory or inflammation-associated diseases and conditions.

We then discuss historical and modern examples of influenza- and COVID-19-associated cognitive impairment, depression, anxiety, and fatigue, revealing key similarities in their neurological sequelae. Although we are learning that the effects of influenza and COVID differ somewhat in terms of their influence on the brain, as the impacts of long-COVID grow, such comparisons will likely prove valuable in guiding ongoing research into long-COVID, and perhaps foreshadow what could be in store for individuals with COVID-19 and their brain health.

Source: Volk P, Rahmani Manesh M, Warren ME, Besko K, Gonçalves de Andrade E, Wicki-Stordeur LE, Swayne LA. Long-term neurological dysfunction associated with COVID-19: Lessons from influenza and inflammatory diseases? J Neurochem. 2023 Nov 28. doi: 10.1111/jnc.16016. Epub ahead of print. PMID: 38014645. https://onlinelibrary.wiley.com/doi/10.1111/jnc.16016 (Full text)

Exploring the Influence of VDR Genetic Variants TaqI, ApaI, and FokI on COVID-19 Severity and Long-COVID-19 Symptoms

Abstract:

There is increasing evidence regarding the importance of vitamin D in the prognosis of coronavirus disease 2019 (COVID-19). Genetic variants in the vitamin D receptor (VDR) gene affect the response to vitamin D and have been linked to various diseases. This study investigated the associations of the major VDR genetic variants ApaI, FokI, and TaqI with the severity and long post-infection symptoms of COVID-19. In total, 100 Jordanian patients with confirmed COVID-19 were genotyped for the VDR ApaI, FokI, and TaqI variants using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
COVID-19 severity, the most commonly reported long-COVID-19 symptoms that lasted for >4 weeks from the onset of infection, and other variables were analyzed according to VDR genetic variants. In this study, ApaI and FokI polymorphisms showed no significant associations with COVID-19 severity (p > 0.05). However, a significant association was detected between the TaqI polymorphism and the severity of symptoms after infection with the SARS-CoV-2 virus (p = 0.04). The wild-type TaqI genotype was typically present in patients with mild illness, whereas the heterozygous TaqI genotype was present in asymptomatic patients.
With regard to long-COVID-19 symptoms, the VDR heterozygous ApaI and wild-type TaqI genotypes were significantly associated with persistent fatigue and muscle pain after COVID-19 (p ˂ 0.05). Most carriers of the heterozygous ApaI genotype and carriers of the wild-type TaqI genotype reported experiencing fatigue and muscle pain that lasted for more than 1 month after the onset of COVID-19. Furthermore, the TaqI genotype was associated with persistent shortness of breath after COVID-19 (p = 0.003). Shortness of breath was more common among individuals with homozygous TaqI genotype than among individuals with the wild-type or heterozygous TaqI genotype.
VDR TaqI is a possible genetic variant related to both COVID-19 severity and long-COVID-19 symptoms among Jordanian individuals. The associations between VDR TaqI polymorphisms and long-COVID-19 symptoms should be investigated in larger and more diverse ethnic populations.
Source: Alhammadin G, Jarrar Y, Madani A, Lee S-J. Exploring the Influence of VDR Genetic Variants TaqI, ApaI, and FokI on COVID-19 Severity and Long-COVID-19 Symptoms. Journal of Personalized Medicine. 2023; 13(12):1663. https://doi.org/10.3390/jpm13121663 https://www.mdpi.com/2075-4426/13/12/1663 (Full text)

SGLT2 Inhibitors in Long COVID Syndrome: Is There a Potential Role?

Abstract:

The coronavirus disease (COVID)-19 has turned into a pandemic causing a global public health crisis. While acute COVID-19 mainly affects the respiratory system and can cause acute respiratory distress syndrome, an association with persistent inflammatory stress affecting different organ systems has been elucidated in long COVID syndrome (LCS).
Increased severity and mortality rates have been reported due to cardiophysiological and metabolic systemic disorders as well as multiorgan failure in COVID-19, additionally accompanied by chronic dyspnea and fatigue in LCS. Hence, novel therapies have been tested to improve the outcomes of LCS of which one potential candidate might be sodium–glucose cotransporter 2 (SGLT2) inhibitors.
The aim of this narrative review was to discuss rationales for investigating SGLT2 inhibitor therapy in people suffering from LCS. In this regard, we discuss their potential positive effects—next to the well described “cardio-renal-metabolic” conditions—with a focus on potential anti-inflammatory and beneficial systemic effects in LCS. However, potential beneficial as well as potential disadvantageous effects of SGLT2 inhibitors on the prevalence and long-term outcomes of COVID-19 will need to be established in ongoing research.
Source: Zimmermann P, Sourij H, Aberer F, Rilstone S, Schierbauer J, Moser O. SGLT2 Inhibitors in Long COVID Syndrome: Is There a Potential Role? Journal of Cardiovascular Development and Disease. 2023; 10(12):478. https://doi.org/10.3390/jcdd10120478 https://www.mdpi.com/2308-3425/10/12/478 (Full text)

Drawing the Line Between Postacute Sequelae of COVID-19 and Functional Neurologic Disorders A Daunting Clinical Overlap or Irrelevant Conundrum?

Abstract:

Coronavirus disease 2019 (COVID-19) is an acute infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in its multiple variants that classically presents with cough, fatigue, fever, headache, myalgias, and diarrhea. As vaccination becomes widely available and infection rates facilitate herd immunity across the globe, more attention has been given to long-term symptoms that may persist after the index infection, which include impairments in concentration, executive dysfunction, sensory disturbances, depression, anxiety, fatigue, and cough, among other symptoms classified under the umbrella term of postacute sequelae of SARS-CoV-2 infection (PASC).

Functional neurologic disorder (FND), also known as conversion disorder and functional neurologic symptom disorder, refers to the presence of one or more symptoms of altered voluntary motor or sensory function that are incompatible with and not better explained by a known neurological or medical condition that causes significant distress and functional impairment. Although the diagnosis of FND may not require the identification of an underlying psychological stressor, being diagnosed with an FND can worsen stigma and shift attention and resources away from other medical concerns that should be concomitantly addressed.

This review summarizes the literature on the overlapping nature and discrimination of PASC from FND in COVID-19 survivors. Based on this, we develop a treatment framework that targets unique domains of these complex overlapping presentations, following a multidisciplinary approach with an individualized treatment plan inclusive of physical and psychological interventions focused on functional rehabilitation.

Source: Sales, Paulo M.G. MD, MS∗; Greenfield, Melissa J. PsyD∗; Pinkhasov, Aaron MD†; Viswanathan, Ramaswamy MD, DrMedSc‡; Saunders, Ramotse MD§; Huremović, Damir MD, MPP∥. Drawing the Line Between Postacute Sequelae of COVID-19 and Functional Neurologic Disorders: A Daunting Clinical Overlap or Irrelevant Conundrum?. The Journal of Nervous and Mental Disease 211(12):p 882-889, December 2023. | DOI: 10.1097/NMD.0000000000001643 https://journals.lww.com/jonmd/abstract/2023/12000/drawing_the_line_between_postacute_sequelae_of.2.aspx

Long Covid Clinical Severity Types Based on Symptoms and Functional Disability: A Longitudinal Evaluation

Abstract:

Background: Long Covid (LC) is a multisystem clinical syndrome with Functional Disability (FD) and compromised Overall Health (OH). There is a lack of distinct clinical symptom clusters (phenotypes) identified in LC so far but there is emerging information on LC clinical severity types. This study explores the consistency of these clinical severity types over time and the relationship between Symptom Severity (SS), FD, and OH in the context of the clinical severity types in a prospective sample.

Methods: A purposive sample of LC patients recruited to the LOng COvid Multidisciplinary consortium Optimising Treatments and servIces acrOss the NHS (LOCOMOTION) study were assessed using the modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) at two assessment time points. A cluster analysis for clinical severity types was undertaken at both time points using k-means partition using two, three, and four initial clusters and different starting values. Cluster analysis was also carried out to assess the presence of symptom phenotypes (symptom clusters).

Findings: Cross-sectional data was available for 759 patients with 356 patients completing C19-YRSm at the two assessment points. Mean age was 46·8 years (SD = 12·7), 69·4% were females, and median duration of LC symptoms at first assessment was 360 days (IQR 217 to 703 days). Cluster analysis revealed three distinct SS and FD clinical severity types – mild (N=96), moderate (N=422), and severe (N=241) – with no distinct symptom phenotypes. The three-level clinical severity pattern remained consistent over time between the two assessments, with 51% of patients switching the clinical severity type between the assessments. The fluctuation was independent of the LC severity and time between the assessments.

Interpretation: This is the first study in the literature to show the consistency of the three clinical severity types over time with patients also switching between severity types indicating the fluctuating nature of LC.

Source: Sivan, Manoj and Smith, Adam B. and Osborne, Thomas and Goodwin, Madeline and Lawrence, Román Rocha and Baley, Sareeta and Williams, Paul and Lee, Cassie and Davies, Helen and Balasundaram, Kumaran and Greenwood, Darren C., Long Covid Clinical Severity Types Based on Symptoms and Functional Disability: A Longitudinal Evaluation. Available at SSRN: https://ssrn.com/abstract=4642650 or http://dx.doi.org/10.2139/ssrn.4642650 https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4642650 (Full text available as PDF file)

The association of insomnia with long COVID: An international collaborative study (ICOSS-II)

Abstract:

Objective: There is evidence of a strong association between insomnia and COVID-19, yet few studies have examined the relationship between insomnia and long COVID. This study aimed to investigate whether COVID-19 patients with pre-pandemic insomnia have a greater risk of developing long COVID and whether long COVID is in turn associated with higher incident rates of insomnia symptoms after infection.

Methods: Data were collected cross-sectionally (May-Dec 2021) as part of an international collaborative study involving participants from 16 countries. A total of 2311 participants (18-99 years old) with COVID-19 provided valid responses to a web-based survey about sleep, insomnia, and health-related variables. Log-binomial regression was used to assess bidirectional associations between insomnia and long COVID. Analyses were adjusted for age, sex, and health conditions, including sleep apnea, attention and memory problems, chronic fatigue, depression, and anxiety.

Results: COVID-19 patients with pre-pandemic insomnia showed a higher risk of developing long COVID than those without pre-pandemic insomnia (70.8% vs 51.4%; adjusted relative risk [RR]: 1.33, 95% confidence interval [CI]: 1.07-1.65). Among COVID-19 cases without pre-pandemic insomnia, the rates of incident insomnia symptoms after infection were 24.1% for short COVID cases and 60.6% for long COVID cases (p < .001). Compared with short COVID cases, long COVID cases were associated with an increased risk of developing insomnia symptoms (adjusted RR: 2.00; 95% CI: 1.50-2.66).

Conclusions: The findings support a bidirectional relationship between insomnia and long COVID. These findings highlight the importance of addressing sleep and insomnia in the prevention and management of long COVID.

Source: Chen SJ, Morin CM, Ivers H, Wing YK, Partinen M, Merikanto I, Holzinger B, Espie CA, De Gennaro L, Dauvilliers Y, Chung F, Yordanova J, Vidović D, Reis C, Plazzi G, Penzel T, Nadorff MR, Matsui K, Mota-Rolim S, Leger D, Landtblom AM, Korman M, Inoue Y, Hrubos-Strøm H, Chan NY, Bjelajac AK, Benedict C, Bjorvatn B. The association of insomnia with long COVID: An international collaborative study (ICOSS-II). Sleep Med. 2023 Dec;112:216-222. doi: 10.1016/j.sleep.2023.09.034. Epub 2023 Oct 24. PMID: 37922783. https://www.sciencedirect.com/science/article/abs/pii/S1389945723003672

Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

Abstract:

Background Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID.

Methods We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/gender/infection/vaccine-matched patients with long COVID.

Findings Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785.

Conclusions These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID.

Source: Kirsten Baillie, Helen E Davies, Samuel B K Keat, Kristin Ladell, Kelly L Miners, Samantha A Jones, Ermioni Mellou, Erik J M Toonen, David A Price, B Paul Morgan, Wioleta M Zelek. Complement dysregulation is a predictive and therapeutically amenable feature of long COVID.
medRxiv 2023.10.26.23297597; doi: https://doi.org/10.1101/2023.10.26.23297597 https://www.medrxiv.org/content/10.1101/2023.10.26.23297597v1.full-text (Full text)

Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles

Abstract:

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as “long COVID”. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms.

We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues.

In addition, complement system related proteins were more abundant in the serum of patients with PCS, matching observations on the transcriptomic level in the muscle tissue. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

Source: Aschman, T., Wyler, E., Baum, O. et al. Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles. acta neuropathol commun 11, 193 (2023). https://doi.org/10.1186/s40478-023-01662-2 https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-023-01662-2 (Full text)