Tag: long Covid

A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform

Abstract:

Background: Post-acute coronavirus 2019 (COVID-19) syndrome (PACS) is a well-recognized complex systemic disease that is associated with substantial morbidity. There is a paucity of established interventions to treat patients with this syndrome.

Objectives: To systematically review registered trials currently investigating therapeutic modalities for PACS.

Data sources: Search was conducted up to the 16th of September 2022 using the COVID-19 section of the World Health Organization (WHO) Internal Clinical Trials Registry Platform.

Study eligibility criteria, participants, and interventions: Interventional clinical trials of any sample size examining any therapeutic modality targeting persistent symptoms among individuals after diagnosis with COVID-19.

Methods: Data on trial characteristics and intervention characteristics were collected and summarized.

Results: After screening 17125 trials, 388 trials from 42 countries were eligible. 331 trials tested mono-therapeutic strategies, while 39 trials included a combination of interventions. Among the 824 primary outcomes identified, there were more than 300 different outcomes. Rehabilitation was the most employed class of intervention with 169 trials. We encountered 76 trials examining pharmacological agents of various classes with the most common agent being colchicine. Complementary and alternative medicine encompassed 64 trials exploring Traditional Chinese Medicine, Ayurveda, homeopathic medications, naturopathic medications, vitamins, dietary supplements, and botanicals. Psychotherapeutic and educational interventions were also employed with 12 and 4 trials, respectively. Other interventions including transcranial current direct stimulation, transcutaneous auricular vagus nerve stimulation, general electrical stimulation, cranial electrotherapy stimulation, various stem cell interventions, and oxygen therapy interventions were also employed.

Conclusion: We identified 388 registered trials with a high degree of heterogeneity exploring 144 unique interventions for PACS. Most target general alleviation of symptoms. There is a need for further high-quality and methodologically robust PACS treatment trials conducted with standardization of outcomes while following WHO’s recommendation for uniform evaluation and treatment.

Source: Fawzy NA, Shaar BA, Taha R, Arabi TZ, Sabbah BN, Alkodaymi MS, Omrani OA, Makhzoum T, Almahfoudh NE, Al-Hammad QA, Hejazi W, Obeidat Y, Osman N, Al-Kattan KM, Berbari EF, Tleyjeh IM. A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform. Clin Microbiol Infect. 2023 Jan 12:S1198-743X(23)00009-5. doi: 10.1016/j.cmi.2023.01.007. Epub ahead of print. PMID: 36642173; PMCID: PMC9837206. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837206/ (Full text)

Long COVID Symptomatology and Associated Factors in Primary Care Patients: The EPICOVID-AP21 Study

Abstract:

Persistent COVID-19 condition includes a wide variety of symptoms and health problems of indeterminate duration. The present study examined the sociodemographic and clinical characteristics of the population with Long COVID seen in Primary Care using a questionnaire based on the existing scientific literature. It was an observational and descriptive study of the characteristics of the Spanish population with Long COVID over 14 years of age.
The responses were analysed by means of a descriptive analysis of the variables recorded, in addition to a bivariate analysis to determine the existence of a relationship between persistent COVID-19 and variables such as gender, age, vaccination status or concomitant pathology. The results obtained clearly describe the sociodemographic characteristics of the population, highlighting the predominance of female gender and the prevalence of tiredness and fatigue.
Furthermore, relevant information was obtained on the differences in symptomatology according to gender, age, previous pathologies and alterations derived from infection and/or vaccination. These data are important for better detection, diagnosis and treatment of Long COVID and the improvement of the quality of life of this population.
Source: Romero-Rodríguez E, Perula-de-Torres LÁ, González-Lama J, Castro-Jiménez RÁ, Jiménez-García C, Priego-Pérez C, Vélez-Santamaría R, Simón-Vicente L, González-Santos J, González-Bernal JJ. Long COVID Symptomatology and Associated Factors in Primary Care Patients: The EPICOVID-AP21 Study. Healthcare. 2023; 11(2):218. https://doi.org/10.3390/healthcare11020218 https://www.mdpi.com/2227-9032/11/2/218 (Full text)

Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study

Abstract:

Objectives: To determine the clinical sequelae of long covid for a year after infection in patients with mild disease and to evaluate its association with age, sex, SARS-CoV-2 variants, and vaccination status.

Design: Retrospective nationwide cohort study.

Setting: Electronic medical records from an Israeli nationwide healthcare organisation.

Population: 1 913 234 Maccabi Healthcare Services members of all ages who did a polymerase chain reaction test for SARS-CoV-2 between 1 March 2020 and 1 October 2021.

Main outcome measures: Risk of an evidence based list of 70 reported long covid outcomes in unvaccinated patients infected with SARS-CoV-2 matched to uninfected people, adjusted for age and sex and stratified by SARS-CoV-2 variants, and risk in patients with a breakthrough SARS-CoV-2 infection compared with unvaccinated infected controls. Risks were compared using hazard ratios and risk differences per 10 000 patients measured during the early (30-180 days) and late (180-360 days) time periods after infection.

Results: Covid-19 infection was significantly associated with increased risks in early and late periods for anosmia and dysgeusia (hazard ratio 4.59 (95% confidence interval 3.63 to 5.80), risk difference 19.6 (95% confidence interval 16.9 to 22.4) in early period; 2.96 (2.29 to 3.82), 11.0 (8.5 to 13.6) in late period), cognitive impairment (1.85 (1.58 to 2.17), 12.8, (9.6 to 16.1); 1.69 (1.45 to 1.96), 13.3 (9.4 to 17.3)), dyspnoea (1.79 (1.68 to 1.90), 85.7 (76.9 to 94.5); 1.30 (1.22 to 1.38), 35.4 (26.3 to 44.6)), weakness (1.78 (1.69 to 1.88), 108.5, 98.4 to 118.6; 1.30 (1.22 to 1.37), 50.2 (39.4 to 61.1)), and palpitations (1.49 (1.35 to 1.64), 22.1 (16.8 to 27.4); 1.16 (1.05 to 1.27), 8.3 (2.4 to 14.1)) and with significant but lower excess risk for streptococcal tonsillitis and dizziness. Hair loss, chest pain, cough, myalgia, and respiratory disorders were significantly increased only during the early phase. Male and female patients showed minor differences, and children had fewer outcomes than adults during the early phase of covid-19, which mostly resolved in the late period. Findings remained consistent across SARS-CoV-2 variants. Vaccinated patients with a breakthrough SARS-CoV-2 infection had a lower risk for dyspnoea and similar risk for other outcomes compared with unvaccinated infected patients.

Conclusions: This nationwide study suggests that patients with mild covid-19 are at risk for a small number of health outcomes, most of which are resolved within a year from diagnosis.

Source: Mizrahi B, Sudry T, Flaks-Manov N, Yehezkelli Y, Kalkstein N, Akiva P, Ekka-Zohar A, Ben David SS, Lerner U, Bivas-Benita M, Greenfeld S. Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study. BMJ. 2023 Jan 11;380:e072529. doi: 10.1136/bmj-2022-072529. PMID: 36631153; PMCID: PMC9832503. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832503/ (Full text)

Long COVID in the Older Adult and Vitamin D

Abstract:

Background: The coronavirus COVID-19 strain that emerged in December 2019 continues to produce a widespread and seemingly intractable negative impact on health and longevity and life quality in all parts of the world, especially, among older adults with chronic health conditions.

Objectives: The first aim of this updated review article was to examine, summarize, synthesize, and report on the research base concerning the possible use of vitamin D in the realm of the recently emergent syndrome termed long or post-acute COVID-19 disease. A second was to establish any health associated preventive and intervention recommendations for the older adult with long COVID-19 manifestations, who may yet be susceptible to future COVID-19 variant infections and others.

Methods: To examine the association between vitamin D and long COVID-19 illness manifestations, articles responding to several key words entered into leading data bases were examined: These included the terms: Vitamin D, Long/Post-Acute COVID-19 and/or COVID-19. Databases employed were PUBMED, PubMed Central and Google Scholar. All relevant articles were carefully examined and those meeting the review criteria were carefully read, and described in narrative form.

Results: Data reveal some possible benefits may accrue in the context of COVID-19 illness prevention and rehabilitation by efforts to ensure optimal vitamin D serum levels among high risk, vitamin D deficient, and chronically challenged post-acute COVID-19 older adults.

Conclusion: More rigorous and carefully construed research efforts to examine vitamin D implications and its moderating or mediating role in averting or mitigating long COVID-19 health complications are strongly warranted.

Source: Ray Marks (2023) Long COVID in the Older Adult and Vitamin D. J Gerontol Geriatr Med 9: 155. https://www.heraldopenaccess.us/openaccess/long-covid-in-the-older-adult-and-vitamin-d (Full text)

Clinical Characteristics in the Acute Phase of COVID-19 That Predict Long COVID: Tachycardia, Myalgias, Severity, and Use of Antibiotics as Main Risk Factors, While Education and Blood Group B Are Protective

Abstract:

Background: Risk factors for developing long COVID are not clearly established. The present study was designed to determine if any sign, symptom, or treatment of the acute phase, or personal characteristics of the patient, is associated with the development of long COVID.
Methods: A cohort study was carried out, randomly selecting symptomatic COVID-19 patients and not vaccinated. The severity of the acute illness was assessed through the number of compatible COVID-19 symptoms, hospitalizations, and the symptom severity score using a 10-point visual analog scale.
Results: After multivariate analysis, a severity score ≥8 (RR 2.0, 95%CI 1.1–3.5, p = 0.022), hospitalization (RR 2.1, 95%CI 1.0–4.4, p = 0.039), myalgia (RR 1.9, 95%CI 1.08–3.6, p = 0.027), tachycardia (RR 10.4, 95%CI 2.2–47.7, p = 0.003), and use of antibiotics (RR 2.0, 95%CI 1.1–3.5, p = 0.022), was positively associated with the risk of having long COVID. Higher levels of education (RR 0.6, 95%CI 0.4–0.9, p = 0.029) and type positive B blood group (B + AB, RR 0.44, 95%CI 0.2–0.9, p = 0.044) were protective factors. The most important population attributable fractions (PAFs) for long COVID were myalgia (37%), severity score ≥8 (31%), and use of antibiotics (27%).
Conclusions: Further studies in diverse populations over time are needed to expand the knowledge that could lead us to prevent and/or treat long COVID.
Source: Guzman-Esquivel J, Mendoza-Hernandez MA, Guzman-Solorzano HP, Sarmiento-Hernandez KA, Rodriguez-Sanchez IP, Martinez-Fierro ML, Paz-Michel BA, Murillo-Zamora E, Rojas-Larios F, Lugo-Trampe A, Plata-Florenzano JE, Delgado-Machuca M, Delgado-Enciso I. Clinical Characteristics in the Acute Phase of COVID-19 That Predict Long COVID: Tachycardia, Myalgias, Severity, and Use of Antibiotics as Main Risk Factors, While Education and Blood Group B Are Protective. Healthcare. 2023; 11(2):197. https://doi.org/10.3390/healthcare11020197 https://www.mdpi.com/2227-9032/11/2/197 (Full text)

SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19

Abstract:

Evolution of SARS-CoV-2 in immunocompromised hosts may result in novel variants with changed properties. While escape from humoral immunity certainly contributes to intra-host evolution, escape from cellular immunity is poorly understood. Here, we report a case of long-term COVID-19 in an immunocompromised patient with non-Hodgkin’s lymphoma who received treatment with rituximab and lacked neutralizing antibodies.

Over the 318 days of the disease, the SARS-CoV-2 genome gained a total of 40 changes, 34 of which were present by the end of the study period. Among the acquired mutations, 12 reduced or prevented the binding of known immunogenic SARS-CoV-2 HLA class I antigens. By experimentally assessing the effect of a subset of the escape mutations, we show that they resulted in a loss of as much as ~1% of effector CD8 T cell response. Our results indicate that CD8 T cell escape represents a major underappreciated contributor to SARS-CoV-2 evolution in humans.

Source: Stanevich OV, Alekseeva EI, Sergeeva M, Fadeev AV, Komissarova KS, Ivanova AA, Simakova TS, Vasilyev KA, Shurygina AP, Stukova MA, Safina KR, Nabieva ER, Garushyants SK, Klink GV, Bakin EA, Zabutova JV, Kholodnaia AN, Lukina OV, Skorokhod IA, Ryabchikova VV, Medvedeva NV, Lioznov DA, Danilenko DM, Chudakov DM, Komissarov AB, Bazykin GA. SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19. Nat Commun. 2023 Jan 10;14(1):149. doi: 10.1038/s41467-022-34033-x. PMID: 36627290; PMCID: PMC9831376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9831376/ (Full text)

The Draft Report by the Institute for Quality and Efficiency in Healthcare Does Not Provide Any Evidence That Graded Exercise Therapy and Cognitive Behavioral Therapy Are Safe and Effective Treatments for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

The German Institute for Quality and Efficiency in Healthcare (IQWiG) recently published its draft report to the government about myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The IQWiG concluded that graded exercise therapy (GET) and cognitive behavioral therapy (CBT) should be recommended in the treatment for mild and moderate ME/CFS based on two CBT and two GET studies. In this article, we reviewed the evidence used by IQWiG to support their claims, because their conclusion is diametrically opposed to the conclusion by the British National Institute for Health and Care Excellence (NICE) in its recently updated ME/CFS guidelines.

Our analysis shows that the trials IQWiG used in support suffered from serious flaws, which included badly designed control groups; relying on subjective primary outcomes in non-blinded studies; alliance and response shift bias, including patients in their trials who did not have the disease under investigation, selective reporting, making extensive endpoint changes and low to very low adherence of treatments.

Our analysis also shows that the report itself used one CBT and one GET study that both examined a different treatment. The report also used a definition of CBT that does not reflect the way it is being used in ME/CFS or was tested in the studies. The report noted that one study used a wrong definition of post-exertional malaise (PEM), the main characteristic of the disease, according to the report. Yet, it ignored the consequence of this, that less than the required minimum percentage of patients had the disease under investigation in that study.

It also ignored the absence of improvement on most of the subjective outcomes, as well as the fact that the IQWiG methods handbook states that one should use objective outcomes and not rely on subjective outcomes in non-blinded studies. The report concluded that both treatments did not lead to objective improvement in the six-minute walk test but then ignored that. The report did not analyze the other objective outcomes of the studies (step test and occupational and benefits status), which showed a null effect.

Finally, the report states that the studies do not report on safety yet assumes that the treatments are safe based on a tendency towards small subjective improvements in fatigue and physical functioning, even though the adherence to the treatments was (very) low and the studies included many patients who did not have the disease under investigation and, consequently, did not suffer from exertion intolerance contrary to ME/CFS patients. At the same time, it ignored and downplayed all the evidence that both treatments are not safe, even when the evidence was produced by a British university.

In conclusion, the studies used by the report do not provide any evidence that CBT and GET are safe and effective. Consequently, the report and the studies do not provide any support for the recommendation to use CBT and GET for ME/CFS or long COVID, which, in many cases, is the same or resembles ME/CFS, after an infection with SARS-CoV-2.

Source: Vink M, Vink-Niese A. The Draft Report by the Institute for Quality and Efficiency in Healthcare Does Not Provide Any Evidence That Graded Exercise Therapy and Cognitive Behavioral Therapy Are Safe and Effective Treatments for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diseases. 2023 Jan 16;11(1):11. doi: 10.3390/diseases11010011. PMID: 36648876; PMCID: PMC9844345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844345/ (Full text)

The Role of Immunity and Inflammation in ME/ CFS and Post-COVID Syndrome: Implications for Treatment

Abstract:

Probably one in seven patients who have experienced acute COVID-19 continue having long-lasting complaints, called post-COVID syndrome or long-COVID, that are similar to those observed in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

There are good reasons to believe that common immunological, epigenetic and inflammatory mechanisms are involved in the pathogenesis both diseases.

To date, various therapeutic approaches have been recommended, but with moderate success. In the present opinion paper, the author weights his clinical experience against data from the literature, and suggests novel approaches.

In addition to general measures and paramedical approaches, food supplementation with a specific nutraceutical can be completed by oral administration of sodium dichloroacetate and Meldonium to optimize glucose metabolism and mitochondrial energy generation.

Alternatively, intravenous infusions with magnesium salt and multivitamins can be completed with glutathione, m-tranexamic acid, and cultured stem cells.

Preliminary results of an open-label, prospective, two-centre trial suggest more than four in five patients benefit from combined oral and infusion therapy with significantly diminished fatigue and improved well-being.

Monoclonal antibodies in “biologicals”, blocking the effects of cytokines, and “small molecules” with Janus kinase inhibiting activity may offer novel opportunities by focusing on both immunologic and inflammation targets. A pilot trial with, in particular, one of the Janus kinase inhibitors could be considered.

Source: Comhaire F. The Role of Immunity and Inflammation in ME/CFS and Post-COVID Syndrome: Implications for Treatment. MedLife Clinics 2022, Volume 4 (2), Article 1043 http://www.medtextpublications.com/open-access/the-role-of-immunity-and-inflammation-in-me-cfs-and-1254.pdf (Full text)

Toxin-like Peptides from the Bacterial Cultures Derived from Gut Microbiome Infected by SARS-CoV-2—New Data for a Possible Role in the Long COVID Pattern

Abstract:

It has been 3 years since the beginning of the SARS-CoV-2 outbreak, however it is as yet little known how to care for the acute COVID-19 and long COVID patients. COVID-19 clinical manifestations are of both pulmonary and extra-pulmonary types. Extra-pulmonary ones include extreme tiredness (fatigue), shortness of breath, muscle aches, hyposmia, dysgeusia, and other neurological manifestations.
In other autoimmune diseases, such as Parkinson’s disease (PD) or Alzheimer’s Disease (AD), it is well known that role of acetylcholine is crucial in olfactory dysfunction. We have already observed the presence of toxin-like peptides in plasma, urine, and faecal samples from COVID-19 patients, which are very similar to molecules known to alter acetylcholine signaling.  After observing the production of these peptides in bacterial cultures, we have performed additional proteomics analyses to better understand their behavior and reported the extended data from our latest in vitro experiment.
It seems that the gut microbiome continues to produce toxin-like peptides also after the decrease of RNA SARS-CoV-2 viral load at molecular tests. These toxicological interactions between the gut/human microbiome bacteria and the virus suggest a new scenario in the study of the clinical symptoms in long COVID and also in acute COVID-19 patients. It is discussed that in the bacteriophage similar behavior, the presence of toxins produced by bacteria continuously after viral aggression can be blocked using an appropriate combination of certain drugs.
Source: Brogna C, Cristoni S, Brogna B, Bisaccia DR, Marino G, Viduto V, Montano L, Piscopo M. Toxin-like Peptides from the Bacterial Cultures Derived from Gut Microbiome Infected by SARS-CoV-2—New Data for a Possible Role in the Long COVID Pattern. Biomedicines. 2023; 11(1):87. https://doi.org/10.3390/biomedicines11010087 https://www.mdpi.com/2227-9059/11/1/87 (Full text)

Long COVID: an estrogen-associated autoimmune disease?

Introduction:

Some people who have had severe to a moderate or mild form of COVID-19 disease may suffer from variable and debilitating symptoms for many months after the initial infection. This condition is commonly called “Long COVID”. An exact definition is missing, but symptoms with a duration of more than 2 months are typically considered as Long COVID. The condition is characterized by long-term sequelae and can involve a range of symptoms such as persistent fatigue, headache, shortness of breath, anosmia, muscle weakness, fever, cognitive dysfunction (brain fog), tachycardia, intestinal disorders, and skin manifestations. Long COVID syndrome bears a similarity to the post-infectious syndromes that followed the outbreaks of chikungunya and Ebola.

In general, women appear to be twice as likely to develop Long COVID as men, but only until around age 60, when the risk level becomes similar. In addition to being a woman, older age and a higher body mass index also seem to be risk factors for having Long COVID.

Source: Ortona E, Buonsenso D, Carfi A, Malorni W; Long Covid Kids study group. Long COVID: an estrogen-associated autoimmune disease? Cell Death Discov. 2021 Apr 13;7(1):77. doi: 10.1038/s41420-021-00464-6. PMID: 33850105; PMCID: PMC8042352.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042352/ (Full text)