Category: Overlapping Illnesses

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS.
New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure.
Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion.
The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance – capillary ischemia-reperfusion – which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.
Source: Wirth, K.J.; Löhn, M. Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome. Preprints 2023, 2023120791. https://doi.org/10.20944/preprints202312.0791.v1  https://www.preprints.org/manuscript/202312.0791/v1 (Full text available as PDF file)

A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial

Abstract:

Background: Post-acute COVID-19 syndrome (PACS) affects over 65 million individuals worldwide but treatment options are scarce. We aimed to assess a synbiotic preparation (SIM01) for the alleviation of PACS symptoms.

Methods: In this randomised, double-blind, placebo-controlled trial at a tertiary referral centre in Hong Kong, patients with PACS according to the US Centers for Disease Control and Prevention criteria were randomly assigned (1:1) by random permuted blocks to receive SIM01 (10 billion colony-forming units in sachets twice daily) or placebo orally for 6 months. Inclusion criterion was the presence of at least one of 14 PACS symptoms for 4 weeks or more after confirmed SARS-CoV-2 infection, including fatigue, memory loss, difficulty in concentration, insomnia, mood disturbance, hair loss, shortness of breath, coughing, inability to exercise, chest pain, muscle pain, joint pain, gastrointestinal upset, or general unwellness. Individuals were excluded if they were immunocompromised, were pregnant or breastfeeding, were unable to receive oral fluids, or if they had received gastrointestinal surgery in the 30 days before randomisation. Participants, care providers, and investigators were masked to group assignment. The primary outcome was alleviation of PACS symptoms by 6 months, assessed by an interviewer-administered 14-item questionnaire in the intention-to-treat population. Forward stepwise multivariable logistical regression was performed to identify predictors of symptom alleviation. The trial is registered with ClinicalTrials.gov, NCT04950803.

Findings: Between June 25, 2021, and Aug 12, 2022, 463 patients were randomly assigned to receive SIM01 (n=232) or placebo (n=231). At 6 months, significantly higher proportions of the SIM01 group had alleviation of fatigue (OR 2·273, 95% CI 1·520-3·397, p=0·0001), memory loss (1·967, 1·271-3·044, p=0·0024), difficulty in concentration (2·644, 1·687-4·143, p<0·0001), gastrointestinal upset (1·995, 1·304-3·051, p=0·0014), and general unwellness (2·360, 1·428-3·900, p=0·0008) compared with the placebo group. Adverse event rates were similar between groups during treatment (SIM01 22 [10%] of 232 vs placebo 25 [11%] of 231; p=0·63). Treatment with SIM01, infection with omicron variants, vaccination before COVID-19, and mild acute COVID-19, were predictors of symptom alleviation (p<0·0036).

Interpretation: Treatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions.

Source: Lau RI, Su Q, Lau ISF, Ching JYL, Wong MCS, Lau LHS, Tun HM, Mok CKP, Chau SWH, Tse YK, Cheung CP, Li MKT, Yeung GTY, Cheong PK, Chan FKL, Ng SC. A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2023 Dec 7:S1473-3099(23)00685-0. doi: 10.1016/S1473-3099(23)00685-0. Epub ahead of print. PMID: 38071990. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00685-0/fulltext (Full text)

Long-term symptom profiles after COVID-19 vs other acute respiratory infections: a population-based observational study (COVIDENCE UK)

Abstract:

Summary:

Background: Long COVID is a well recognised, if heterogeneous, entity. Acute respiratory infections (ARIs) due to other pathogens may cause long-term symptoms, but few studies compare post-acute sequelae between SARS-CoV-2 and other ARIs. We aimed to compare symptom profiles between people with previous SARS-CoV-2 infection, people with previous non-COVID-19 ARIs, and contemporaneous controls, and to identify clusters of long-term symptoms.

Methods: COVIDENCE UK is a prospective, population-based UK study of ARIs in adults. We analysed data on 16 potential long COVID symptoms and health-related quality of life (HRQoL), reported in January, 2021, by participants unvaccinated against SARS-CoV-2. We classified participants as having previous SARS-CoV-2 infection or previous non-COVID-19 ARI (≥4 weeks prior) or no reported ARI. We compared symptoms by infection status using logistic and fractional regression, and identified symptom clusters using latent class analysis (LCA).

Findings: We included 10,203 participants (1343 [13.2%] with SARS-CoV-2 infection, 472 [4.6%] with non-COVID-19 ARI). Both types of infection were associated with increased prevalence/severity of most symptoms and decreased HRQoL compared with no infection. Participants with SARS-CoV-2 infection had increased odds of taste/smell problems and hair loss compared with participants with non-COVID-19 ARIs. Separate LCA models identified three symptom severity groups for each infection type. In the most severe groups (including 23% of participants with SARS-CoV-2, and 21% with non-COVID-19 ARI), SARS-CoV-2 infection presented with a higher probability of memory problems, difficulty concentrating, hair loss, and taste/smell problems than non-COVID-19 ARI.

Interpretation: Both SARS-CoV-2 and non-COVID-19 ARIs are associated with a wide range of long-term symptoms. Research on post-acute sequelae of ARIs should extend from SARS-CoV-2 to include other pathogens.

Source: Vivaldi G, Pfeffer PE, Talaei M, et al. Long-term symptom profiles after COVID-19 vs other acute respiratory infections: a population-based observational study (COVIDENCE UK). medRxiv; 2023. DOI: 10.1101/2023.07.06.23292296. https://europepmc.org/article/PPR/ppr687749 (Full text)

Comparison of post-acute sequelae following hospitalization for COVID-19 and influenza

Abstract

Background: Few studies have directly compared the risk and magnitude of post-acute sequelae following COVID-19 and influenza, and most of these studies were conducted before emergence of the Omicron. This study investigated the prevalence of post-COVID conditions and the long-term risk of emergency department (ED) visits, hospitalizations, and deaths in patients with COVID-19 and compared their risk with that of patients with influenza.

Methods: A retrospective study based on the TriNetX databases, a global health research network. We identified patients with COVID-19 and influenza who required hospitalization between January 1, 2022, and January 1, 2023. We compared the risk of developing any post-COVID conditions between the two groups and also analyzed each post-COVID-19 condition and all-cause ED visits, hospitalizations, and deaths in both populations during the follow-up 90-180 days.

Results: Before matching, 7,187 patients with COVID-19 were older (63.9 ± 16.7 vs. 55.4 ± 21.2) and were predominantly male (54.0% vs. 45.4%), and overweight/obese (16.1% vs. 11.2%) than 11,266 individuals with influenza. After propensity score matching, 6,614 patients were identified in each group, resulting in well-balanced baseline characteristics. During follow-up, the COVID-19 group had a higher incidence of any post-COVID-19 condition when compared with the influenza group (17.9% vs. 13.0%), with a hazard ratio (HR) of 1.398 (95% CI, 1.251-1.562). Compared to the influenza group, the COVID-19 group had a significantly higher incidence of abnormal breathing (HR, 1.506; 95% CI, 1.246-1.822), abdominal symptoms (HR, 1.313; HR, 1.034-1.664), fatigue (HR, 1.486; 95% CI, 1.158-1.907), and cognitive symptoms (HR, 1.815; 95% CI, 1.235-2.668). Moreover, the COVID-19 group had a significantly higher risk of the composite outcomes during all-cause ED visits, hospitalizations, and deaths when compared with the influenza group (27.5% vs. 21.7; HR, 1.303; 95% CI, 1.194-1.422).

Conclusions: This study indicates that hospitalized COVID-19 patients are at a higher risk of long-term complications when compared with influenza survivors.

Source: Liu TH, Huang PY, Wu JY, Chuang MH, Hsu WH, Tsai YW, Lai CC. Comparison of post-acute sequelae following hospitalization for COVID-19 and influenza. BMC Med. 2023 Dec 5;21(1):480. doi: 10.1186/s12916-023-03200-2. PMID: 38049876; PMCID: PMC10696681. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696681/ (Full text)

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