Effect of Vaccination against SARS-CoV-2 on Long COVID-19: A Narrative Review

Abstract:

Vaccines against SARS-CoV-2 have saved millions of lives and played an important role in containing the COVID-19 pandemic. Vaccination against SARS-CoV-2 is also associated with reduced disease severity and, perhaps, with COVID-19 symptom burden.

In this narrative review, we present, in a clinically relevant question-and-answer manner, the evidence regarding the association between vaccination against SARS-CoV-2 and long COVID-19. We discuss how the mechanism of action of vaccines could interplay with the pathophysiology of post-COVID-19 condition.

Furthermore, we describe how specific factors, such as the number of vaccine doses and the type of SARS-CoV-2 variants, may affect post-COVID-19 condition. We also discuss the role of timing for vaccination in relation to the onset of long COVID-19 symptoms, as it seems to affect the frequency and severity of the condition.

Additionally, we describe the potential modifying effect of age, as well as the association of type and level of immune response with long COVID-19. We also describe how system-specific long COVID-19 sequelae, namely neurocognitive-psychologic symptoms and cardiovascular pathology, could be altered by vaccination.

Last, we address the question of whether seasonal influenza vaccination has a meaningful impact on the frequency of long COVID-19.

Source: Tofarides AG, Christaki E, Milionis H, Nikolopoulos GK. Effect of Vaccination against SARS-CoV-2 on Long COVID-19: A Narrative Review. Life (Basel). 2022 Dec 8;12(12):2057. doi: 10.3390/life12122057. PMID: 36556422. https://www.mdpi.com/2075-1729/12/12/2057 (Full text)

The effectiveness of coronavirus disease 2019 (COVID-19) vaccine in the prevention of post-COVID-19 conditions: A systematic literature review and meta-analysis

Abstract:

Background: Although multiple studies have revealed that coronavirus disease 2019 (COVID-19) vaccines can reduce COVID-19-related outcomes, little is known about their impact on post-COVID-19 conditions. We performed a systematic literature review and meta-analysis on the effectiveness of COVID-19 vaccination against post-COVID-19 conditions (ie, long COVID).

Methods: We searched PubMed, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from December 1, 2019, to April 27, 2022, for studies evaluating COVID-19 vaccine effectiveness against post-COVID-19 conditions among individuals who received at least 1 dose of Pfizer/BioNTech, Moderna, AstraZeneca, or Janssen vaccine. A post-COVID-19 condition was defined as any symptom that was present 3 or more weeks after having COVID-19. Editorials, commentaries, reviews, study protocols, and studies in the pediatric population were excluded. We calculated the pooled diagnostic odds ratios (DORs) for post-COVID-19 conditions between vaccinated and unvaccinated individuals. Vaccine effectiveness was estimated as 100% × (1 – DOR).

Results: In total, 10 studies with 1,600,830 individuals evaluated the effect of vaccination on post-COVID-19 conditions, of which 6 studies were included in the meta-analysis. The pooled DOR for post-COVID-19 conditions among individuals vaccinated with at least 1 dose was 0.708 (95% confidence interval (CI), 0.692-0.725) with an estimated vaccine effectiveness of 29.2% (95% CI, 27.5%-30.8%). The vaccine effectiveness was 35.3% (95% CI, 32.3%-38.1%) among those who received the COVID-19 vaccine before having COVID-19, and 27.4% (95% CI, 25.4%-29.3%) among those who received it after having COVID-19.

Conclusions: COVID-19 vaccination both before and after having COVID-19 significantly decreased post-COVID-19 conditions for the circulating variants during the study period although vaccine effectiveness was low.

Source: Marra AR, Kobayashi T, Suzuki H, Alsuhaibani M, Hasegawa S, Tholany J, Perencevich E, Maezato AM, Ricardo VCV, Salinas JL, Edmond MB, Rizzo LV. The effectiveness of coronavirus disease 2019 (COVID-19) vaccine in the prevention of post-COVID-19 conditions: A systematic literature review and meta-analysis. Antimicrob Steward Healthc Epidemiol. 2022 Dec 6;2(1):e192. doi: 10.1017/ash.2022.336. PMID: 36505947; PMCID: PMC9726631. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9726631/ (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown.

Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

Source: Ariza ME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules. 2021 Jan 29;11(2):185. doi: 10.3390/biom11020185. PMID: 33572802; PMCID: PMC7912523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912523/ (Full text)

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial

Abstract:

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis.

A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence.

Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03).

The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

Source: Tosato M, Calvani R, Picca A, Ciciarello F, Galluzzo V, Coelho-Júnior HJ, Di Giorgio A, Di Mario C, Gervasoni J, Gremese E, Leone PM, Nesci A, Paglionico AM, Santoliquido A, Santoro L, Santucci L, Tolusso B, Urbani A, Marini F, Marzetti E, Landi F; Gemelli against COVID-19 Post-Acute Care Team. Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial. Nutrients. 2022 Nov 23;14(23):4984. doi: 10.3390/nu14234984. PMID: 36501014; PMCID: PMC9738241. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738241/ (Full text)

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases

Abstract:

Background: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2.

Methods: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein.

Results: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient’s medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein.

Conclusions: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Source: Agrawal S, Farfel JM, Arfanakis K, Al-Harthi L, Shull T, Teppen TL, Evia AM, Patel MB, Ely EW, Leurgans SE, Bennett DA, Mehta R, Schneider JA. Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases. Acta Neuropathol Commun. 2022 Dec 17;10(1):186. doi: 10.1186/s40478-022-01493-7. PMID: 36528671; PMCID: PMC9758667. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9758667/ (Full text)

Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study

Abstract

Background: The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test.

Methods: We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 μg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 μg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 μg/dL and peak ACTH increase <two-fold were assigned to the pituitary disorder (PD) group (n = 15). Inter-group comparisons were performed based on clinical characteristics.

Results: In the CRH challenge test, the peak plasma ACTH levels were significantly lower in the unexplainable-HD group than in the NR group, despite more than two-fold increase compared to basal levels. The increase in serum cortisol was significantly higher in the unexplainable-HD group than in the explainable-HD and PD groups. Although patients in the unexplainable-HD group showed a clear ACTH response in the insulin tolerance test, some patients had peak serum cortisol levels of < 18 μg/dL. Furthermore, attenuated diurnal variations and low normal levels of urinary free cortisol were observed. Most patients in the unexplainable-HD group were young women with chronic fatigue. However, supplementation with oral hydrocortisone at physiological doses reduced fatigue only in some patients.

Conclusions: Patients with unexplainable HD diagnosed by the CRH challenge test had hypothalamic-pituitary-adrenal (HPA) axis dysfunction and some patients had mild central adrenal insufficiency. Hydrocortisone supplementation reduced fatigue only in some patients, suggesting that HPA axis dysfunction may be a physiological adaptation. Further investigation of these patients may help elucidate the pathophysiology of myalgic encephalitis/chronic fatigue syndrome.

Source: Hataya Y, Okubo M, Hakata T, Fujimoto K, Iwakura T, Matsuoka N. Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study. BMC Endocr Disord. 2022 Dec 9;22(1):312. doi: 10.1186/s12902-022-01237-7. PMID: 36494805; PMCID: PMC9733005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733005/ (Full text)

Investigating the neural substrates of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) : a structural and functional MRI study

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by continuous fatigue and has many diagnostic criteria. Cognitive dysfunction affects 86-94% of adults with CFS/ME.

This thesis used MRI applications to investigate brain structure and function in CFS/ME. This thesis hypothesised to find brain volume differences, functional connectivity differences in brain networks, and functional differences measured by Blood Oxygenation Level Dependant (BOLD) signal activation during working memory task performance.

The working memory paradigm was designed to investigate working memory components, processing and storage separately and combined. The relationship between fatigue and performance was assessed. This thesis’s original contribution provides evidence that the salience network might have altered resting-state functional connectivity in CFS/ME in the absence of morphological differences.

The salience network is involved in detecting and integrating salient sensory information; therefore, disruption in this network might disrupt incoming cognitive stimuli and influence other networks’ connectivity, involved in fatigue and impaired memory.

In the more demanding task, participants with CFS/ME were slower and less accurate but used the same working memory network as healthy controls. No brain volume differences, nor atrophy were found. The differences between these findings compared to previous studies might be due to different study designs, analysis methods, sample sizes with different symptoms, including illness duration, physical inactivity and sleep disturbance.

The salience network alteration could potentially have a significant role in CFS/ME, as we cannot determine cause and effect with current experimental design the association with fatigue and other CFS/ME symptoms remains unclear. Using longitudinal studies that account for neurologically relevant confounders are needed in CFS/ME to further investigate the role of salience network.

Source: Almutairi, Basim S. Investigating the neural substrates of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) : a structural and functional MRI study. PhD Thesis, University of Bristol. uk.bl.ethos.866683  https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.866683

What Causes ME/CFS: The Role of the Dysfunctional Immune System and Viral Infections

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigmatic highly disabling and complex long-term condition with a wide range of aetiologies and symptoms.

A viral onset is commonly mentioned by patients and several bodily systems are ultimately disturbed. The parallel with long-covid is clear.

However, immune dysregulation with impaired NK cell dysfunction and tendency to novel autoimmunity have been frequently reported. These may contribute to reactivation of previous acquired viruses/retroviruses accompanied by impaired endocrine regulation and mitochondrial energy generation.

The unpredictable nature of seemingly unconnected and diverse symptoms that are poorly responsive to several allopathic and alternative therapies then contributes to an escalation of the illness with secondary dysfunction of multiple other systems. Treatment of established ME/CFS is therefore difficult and requires multi-specialty input addressing each of the areas affected by the illness.

Source: Amolak S Bansal, Aletta D Kraneveld, Elisa Oltra and Simon Carding. What Causes ME/CFS: The Role of the Dysfunctional Immune System and Viral Infections. Journal of Immunology and Allergy 2022;3(2):1-15. https://maplespub.co.in/assets/images/files/doc_1663924267.pdf (Full text)

A comparison of health-related factors between patients diagnosed with ME/CFS and patients with a related symptom picture but no ME/CFS diagnosis: a cross-sectional exploratory study

Abstract:

Background: In chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), the capacity for activity and participation is strongly limited. The disease definition is very broad, and considering the lack of evidence for best treatment, it is important to understand what is ME/CFS-specific in the biopsychosocial perspective in comparison with similar syndromes. The objective was to study the difference between those diagnosed with ME/CFS and those with similar symptoms but no ME/CFS diagnosis for self-perceived level of physical activity, work ability, anxiety/depression, and health-related quality of life.

Methods: This was a clinical cross-sectional study with data collected from mailed questionnaires. The following variables were compared between patients diagnosed with ME/CFS (n = 205) and those with similar symptoms but no diagnosis (n = 57); level of physical activity, Work ability index (WAI), Hospital anxiety and depression scale (HAD-A/HAD-D), and RAND-36 Physical functioning, Role limitations due to physical health problems, Role limitations due to personal or emotional problems, Social functioning, Energy/fatigue, Bodily pain, Emotional well-being, and General health perceptions. The Chi-squared test (nominal data), the Mann-Whitney U test, the Student’s t test and regression analysis were used to analyze the data.

Results: The group diagnosed with ME/CFS had a more impaired physical and mental exertion ability as compared to the group that had similar symptoms but was not diagnosed with ME/CFS, shown by a RAND-36 lower index of physical role functioning, social functioning, energy, worse pain and poorer overall health (p ≤ 0.05). In contrast, no significant group differences emerged for weekly level of physical activity, work ability, anxiety/depression, and RAND-36 Emotional role limitation and well-being.

Conclusion: Our results indicate that those with a diagnosis of ME/CFS are characterized by an impaired ability for physical or mental exertion, worse pain, and poorer overall health as compared to individuals with similar symptoms but for whom ME/CFS-diagnosis was not established. The results may be cautiously interpreted as support when focusing on patients’ self-care in terms of management of energy levels. The results must however be verified in future studies.

Source: Bernhoff G, Rasmussen-Barr E, Bunketorp Käll L. A comparison of health-related factors between patients diagnosed with ME/CFS and patients with a related symptom picture but no ME/CFS diagnosis: a cross-sectional exploratory study. J Transl Med. 2022 Dec 9;20(1):577. doi: 10.1186/s12967-022-03769-x. PMID: 36494693; PMCID: PMC9733040. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03769-x (Full text)

ME/CFS and Post-Exertional Malaise among Patients with Long COVID

Abstract:

This study sought to ascertain the prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) among a sample of 465 patients with Long COVID. The participants completed three questionnaires: (1) a new questionnaire measuring both the frequency and severity of 38 common symptoms of COVID and Long COVID, (2) a validated short form questionnaire assessing ME/CFS, and (3) a validated questionnaire measuring post-exertional malaise.
The population was predominantly white, female, and living in North America. The mean duration since the onset of COVID-19 symptoms was 70.5 weeks. Among the 465 participants, 58% met a ME/CFS case definition. Of respondents who reported that they had ME/CFS only 70.57% met criteria for ME/CFS and of those who did not report they had ME/CFS, 29.43% nevertheless did meet criteria for the disease: both over-diagnosis and under-diagnosis were evident on self-report. This study supports prior findings that ME/CFS occurs with high prevalence among those who have persistent COVID-19 symptoms.
Source: Jason LA, Dorri JA. ME/CFS and Post-Exertional Malaise among Patients with Long COVID. Neurology International. 2023; 15(1):1-11. https://doi.org/10.3390/neurolint15010001 https://www.mdpi.com/2035-8377/15/1/1 (Full text)