Category: Overlapping Illnesses

Early Biological Markers of Post-Acute Sequelae of SARS-CoV-2 Infection

Abstract:

To understand the roles of acute phase viral dynamics and host immune responses in PASC, we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR. Participants self-collected nasal specimens up to 21 times within the first 28 days after symptom onset; Interviewer-administered clinical questionnaires and blood samples were collected at enrollment and days 9, 14, 21, 28, and month 4 and 8 post-symptom.

Defining PASC as the presence of any symptom new or worse since infection reported at their 4-month visit, we compared viral markers (quantity and duration of viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-a, IFN-a, IFN-g, MCP, IP-10, and Spike IgG) over the acute period.

In comparison to those who fully recovered, those who developed PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA, infectious virus, and N-antigen, longer duration of viral shedding, and lower Spike-specific IgG levels within the first 10 days of the acute phase of illness. No significant differences were identified among a panel of host immune markers, though there was a trend toward higher initial levels of certain markers (e.g., MCP-1, IFN-a, and IFN-g) in those who went on to develop PASC.

Early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC. These findings highlight the importance of understanding the early biological markers from acute SARS-CoV-2 infection in the natural history of PASC.

Source: Scott Lu, Michael J. Peluso, David V. Glidden, Michelle C. Davidson, Kara Lugtu, Jesus Pineda-Ramirez, Michel Tassetto, Miguel Garcia-Knight, Amethyst Zhang, Sarah A. Goldberg, Jessica Y. Chen, Maya Fortes-Cobby, Sara Park, Ana Martinez, Matthew So, Aidan Donovan, Badri Viswanathan, Rebecca Hoh, Kevin Donohue, David R. McIlwain, Brice Gaudiliere, Khamal Anglin, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos Petropoulos, Steven G. Deeks, Melissa Briggs-Hagen, Raul Andino, Claire M. Midgley, Jeffrey N. Martin, Sharon Saydah, J. Daniel Kelly. Early Biological Markers of Post-Acute Sequelae of SARS-CoV-2 Infection. medRxiv 2023.07.14.23292649; doi: https://doi.org/10.1101/2023.07.14.23292649 https://www.medrxiv.org/content/10.1101/2023.07.14.23292649v1.full-text (Full text)

Utility of Serum Ferritin for Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Patients with Long COVID

Abstract:

Objective: The most common symptom of post-acute coronavirus disease 2019 (COVID-19) is fatigue, and it potentially leads to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); however, a specific prognosticator is lacking. We aimed to elucidate the clinical characteristics of patients who developed ME/CFS after COVID-19.
Methods: In this retrospective observational study, patients who visited Okayama University Hospital for long COVID between February 2021 and March 2022 were investigated.
Results: Of the 234 patients, 139 (59.4%) had fatigue symptoms. Fifty patients with fatigue symptoms (21.4%) met the criteria for ME/CFS (ME/CFS group), while the other 89 patients did not (non-ME/CFS group); 95 patients had no fatigue complaints (no-fatigue group). Although the patients’ backgrounds were not significantly different between the three groups, the ME/CFS group presented the highest scores on the self-rating symptom scales, including the Fatigue Assessment Scale (FAS), EuroQol, and the Self-Rating Depression Scale (SDS). Furthermore, serum ferritin levels, which were correlated with FAS and SDS scores, were significantly higher in the ME/CFS group (193.0 μg/mL, interquartile range (IQR): 58.8–353.8) than in the non-ME/CFS group (98.2 μg/mL, 40.4–251.5) and no-fatigue group (86.7 μg/mL, 37.5–209.0), and a high serum ferritin level was prominent in female patients. Endocrine workup further showed that the ME/CFS group had higher thyrotropin levels but lower growth hormone levels in serum and that insulin-like growth factor-I levels were inversely correlated with ferritin levels (R = −0.328, p < 0.05).
Conclusions: Serum ferritin level is a possible predictor of the development of ME/CFS related to long COVID, especially in female patients.
Source: Yamamoto Y, Otsuka Y, Tokumasu K, Sunada N, Nakano Y, Honda H, Sakurada Y, Hasegawa T, Hagiya H, Otsuka F. Utility of Serum Ferritin for Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Patients with Long COVID. Journal of Clinical Medicine. 2023; 12(14):4737. https://doi.org/10.3390/jcm12144737 https://www.mdpi.com/2077-0383/12/14/4737 (Full text)

Fatigue presentation, severity, and related outcomes in a prospective cohort following post-COVID-19 hospitalization in British Columbia, Canada

Abstract:

Introduction: Increasing evidence on long-term health outcomes following SARS CoV-2 infection shows post-viral symptoms can persist for months. These symptoms are often consistent with those of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS). The aim of the present study was to examine the prevalence and outcome predictors of post-viral fatigue and related symptoms 3- and 6-months following symptom onset.

Methods: A prospective cohort of patients hospitalized with Coronavirus disease (COVID-19) (n = 88) were recruited from a Post-COVID-19 Respiratory Clinic (PCRC) in Vancouver, Canada to examine predictors of long-term fatigue and substantial fatigue. Multivariable mixed effects analyses examined the relationship between patient predictors, including pre-existing comorbidities, patient reported outcome measures, and fatigue and substantial fatigue at follow-up.

Results: The number of patients experiencing fatigue or substantial fatigue at 3 months post-infection were 58 (67%) and 14 (16%) respectively. At 6 months these numbers declined to 47 (60%) patients experiencing fatigue and 6 (6%) experiencing substantial fatigue. Adjusted analysis, for sex, age, and time, revealed the number of pre-existing comorbidities to be associated with fatigue (OR 2.21; 95% CI 1.09-4.49; 0.028) and substantial fatigue (OR 1.73; 95% CI 1.06-2.95; 0.033) at 3 months follow-up. Except for shortness of breath, self-care, and follow-up time, all follow-up variables were found to be associated with fatigue and substantial fatigue at 3 months.

Conclusion: Fatigue and substantial fatigue are common after COVID-19 infection but often diminish over time. A significant number of patients continue to exhibit long-term fatigue at 6 months follow-up. Further research is needed to clarify the causality of viral infections in the development and severity of fatigue as a symptom and in meeting post-viral fatigue syndrome or ME/CFS diagnostic criteria.

Source: Magel T, Meagher E, Boulter T, Albert A, Tsai M, Muñoz C, Carlsten C, Johnston J, Wong AW, Shah A, Ryerson C, Mckay RJ, Nacul L. Fatigue presentation, severity, and related outcomes in a prospective cohort following post-COVID-19 hospitalization in British Columbia, Canada. Front Med (Lausanne). 2023 Jun 29;10:1179783. doi: 10.3389/fmed.2023.1179783. PMID: 37457578; PMCID: PMC10344448. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344448/ (Full text)

Carotid body dysregulation contributes to the enigma of long COVID

Abstract:

The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID. During cardiopulmonary exercise testing, the VE/VCO2 slope (a measure of breathing efficiency) was higher in the long COVID group than in the controls, indicating excessive hyperventilation.

The hypoxic ventilatory response, which measures carotid chemoreflex sensitivity, was increased in long COVID participants and correlated with the VE/VCO2 slope, suggesting that excessive hyperventilation may be related to carotid body hypersensitivity. Therefore, the carotid chemoreflex is sensitized in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients.

Source: Ahmed El-Medany, Zoe H Adams, Hazel C Blythe, Katrina A Hope, Adrian H Kendrick, Ana Paula Abdala Sheikh, Julian FR Paton, Angus K Nightingale, Emma C Hart. Carotid body dysregulation contributes to the enigma of long COVID. medRxiv 2023.05.25.23290513; doi: https://doi.org/10.1101/2023.05.25.23290513 https://www.medrxiv.org/content/10.1101/2023.05.25.23290513v1.full-text (Full text)

Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors

Abstract:

In general, an individual who experiences the symptoms of Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2 infection is declared as recovered after 2 weeks. However, approximately 10–20% of these survivors have been reported to encounter long-term health problems, defined as ‘long COVID-19’, e.g., blood coagulation which leads to stroke with an estimated incidence of 3%, and pulmonary embolism with 5% incidence.
At the time of infection, the immune response produces pro-inflammatory cytokines that stimulate stromal cells to produce pro-hepatocyte growth factor (pro-HGF) and eventually is activated into hepatocyte growth factor (HGF), which helps the coagulation process in endothelial and epithelial cells. HGF is a marker that appears as an inflammatory response that leads to coagulation.
Currently, there is no information on the effect of SARS-CoV-2 infection on serum HGF concentrations as a marker of the prognosis of coagulation in long COVID-19 survivors. This review discusses the pathophysiology between COVID-19 and HGF, IL-6, and D-dimer.
Source: Zaira B, Yulianti T, Levita J. Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors. Current Issues in Molecular Biology. 2023; 45(7):5725-5740. https://doi.org/10.3390/cimb45070361 https://www.mdpi.com/1467-3045/45/7/361 (Full text)

Role of Vitamin D Supplementation for Symptoms and Lung Function Improvement in Long COVID Patient

Abstract:

Post-Acute COVID-19 Syndrome (PACS) or acute post-COVID-19 syndrome or also known as “Long Covid”, is a collection of persistent symptoms and long-term complications more than four weeks after the onset of initial symptoms. One of the leading causes of these long-term complications is pulmonary fibrosis, with an incidence of almost 25% in patients a year after hospitalization. Vitamin D is an important substance to our body homeostasis and regulation. Vitamin D has pleiotropic effect as pulmonary antifibrosis. This research aims to directly provide vitamin D3 supplements, especially in improving lung function in pulmonary fibrosis patients after COVID-19 infection.

This study was a one-group, quasiexperimental pretest-posttest design conducted at Labuang Baji hospitals in the eastern part of Indonesia. The population of this study was patients post-covid-19 infection with negative PCR results at least three months, had persistent symptoms of covid 19, and a CT scan confirmed pulmonary fibrosis or destroyed lung results. Lung function was measured using spirometry before and after the intervention (Vitamin D3 5000 IU supplementation with a frequency of once per day for two months). This study included 20 cases of Lung Fibrosis post-Covid-19. The majority of respondents were women and between the ages of 40 and 49. Among 20 patients, most of them fatigue or dyspneu or shortness of breath as their main symptoms.

After 2-months supplementation of Vitamin D 5000 IU, number of patients who had shortness of breath and fatigue reduced significantly (From 11 to 3 and from 11 to 2 patients, respectively). 85% of our patient had deficient-insufficient status of vitamin D. We found restrictive pattern as a dominant lung function in our patient. There was significant improvement in lung function status after 2-months vitamin D supplementation (p=0.02). Vitamin D supplementation for Long COVID may have benefit for symptoms and lung function improvement.

Source: Irawaty Djaharuddin, Muzakkir Amir, Jamaluddin Madolangan, Ahmad Fachry Toaha, Muthiah Nur Afifah, Muhammad Zaki Rahmani, Izza fauziah Irfan.Role of Vitamin D Supplementation for Symptoms and Lung Function Improvement in Long COVID Patient. Teikyo Medical Journal. Volume 45, Issue 09, November, 2022 https://www.teikyomedicaljournal.com/volume/TMJ/45/10/role-of-vitamin-d-supplementation-for-symptoms-and-lung-function-improvement-in-long-covid-patient-638db40f96abb.pdf (Full text)

Antihistamines improve cardiovascular manifestations and other symptoms of Long-COVID attributed to Mast Cell Activation

Abstract:

Introduction: Long-COVID is a hardly defined condition and there are no effective therapies. Cardiovascular manifestations of Long-COVID include high heart rate, postural tachycardia, and palpitations. Previous studies have suggested that mast cell activation (MCA) may play a role in the pathophysiology of Long-COVID, including in the mechanisms of its cardiovascular manifestations. The aim of the study was to evaluate the effectiveness of a treatment with blockers of histamine receptors in Long-COVID patients who did not respond to other therapies.

Methods: Fourteen patients (F/M=9/5; 49.5±11.5 years) and 13 controls (F/M=8/5; 47.3±8.0 years) with Long-COVID symptoms attributed to MCA were evaluated. Patients were treated with fexofenadine (180 mg/day) and famotidine (40 mg/day). Fatigue, brain fog, abdominal disorders, and increased heart rate were evaluated in treated and untreated patients at baseline and 20 days later.

Results: Long-COVID symptoms disappeared completely in 29% of treated patients. There was significant improvement in each of the considered symptoms (improved or disappeared) in all treated patients, and the improvement grade was significantly greater in treated patients with respect to controls. No significant differences in the outcomes were observed in the controls.

Our data confirm that histamine receptors blockade may be an effective target to successfully treat long-COVID. Our finding supports the underlying role of MCA in the pathophysiology of Long-COVID.

Source: Fabrizio Salvucci, Roberto Codella, ADRIANA COPPOLA, Irene Zacchei, Gabriella Grassi, Maria L. Anti, Nicolita Nitisoara, Livio Luzi, and Carmine Gazzaruso. Antihistamines improve cardiovascular manifestations and other symptoms of Long-COVID attributed to Mast Cell Activation. Front. Cardiovasc. Med. Sec. General Cardiovascular Medicine. Volume 10 – 2023 | doi: 10.3389/fcvm.2023.1202696 https://www.frontiersin.org/articles/10.3389/fcvm.2023.1202696/abstract

Approaches towards menstrual cycle disorder therapy in reproductive-aged women with long COVID

Abstract:

Background. The mirror of a female’s reproductive health is the menstrual cycle. The SARS-CoV-2 pandemic itself acts as a significant stressor. This leads to women’s overall health and life quality disturbance. Moreover, patients struggle with long COVID effects, which is a prolongation of symptoms after recovery. Due to the expression of angiotensin-converting enzyme type 2 receptors in the intestinal mucosa and inflammation, the gastrointestinal (GI) tract is also triggered by the virus.

Objectives. To assess the efficacy of the chosen treatment approach in women with changes in premenstrual syndrome and cyclicity due to long COVID with or without GI symptoms.

Material and methods. A single-centre longitudinal interventional study was organized. Were studied data from the conducted tests (progesterone level, ultrasound follicle scan, etc.) and surveys. Then the effectiveness of the suggested treatment with the use of oral and vaginal forms of progesterone was evaluated. The study was held in the Kyiv City Center of Reproductive and Perinatal Medicine (Ukraine) from January to June 2021.

Results. On average 78% patients without GI symptoms experienced relief after 3 months and 89% patients after 6 months of suggested treatment. 71% patients with GI symptoms experienced improvement after 3 and 87% of them after 6 months. The vaginal progesterone had better results compared to oral form. Averagely 6–8% experienced side effects (nausea, hypotension, less compliance) due to progesterone intake. The vaginal micronised progesterone also presented better results than oral with fewer side effects compared to the total number of participants.

Conclusions. The proposed approach has shown particular correction of the menstrual cycle disturbances in women with long COVID. Vaginal micronized progesterone offers more promising outcomes in patients with GI symptoms and disrupted absorption, compared to the oral form.
Further investigation is required for a more reasonable conclusion.

Source: Kaminskyi, V., Serbeniuk, A., & Kumpanenko, Y. (2023). Approaches towards menstrual cycle disorder therapy in reproductive-aged women with long COVID. REPRODUCTIVE ENDOCRINOLOGY, (68), 44–47. https://doi.org/10.18370/2309-4117.2023.68.44-47 http://reproduct-endo.com/article/view/284093

Long COVID: An approach to clinical assessment and management in primary care

Abstract:

Long COVID is an emerging public health threat, following swiftly behind the surges of acute infection over the course of the COVID-19 pandemic. It is estimated that there are already approximately 100 million people suffering from Long COVID globally, 0.5 million of whom are South African, and for whom our incomplete understanding of the condition has forestalled appropriate diagnosis and clinical care. There are several leading postulates for the complex, multi-mechanistic pathogenesis of Long COVID. Patients with Long COVID may present with a diversity of clinical phenotypes, often with significant overlap, which may exhibit temporal heterogeneity and evolution.

Post-acute care follow-up, targeted screening, diagnosis, a broad initial assessment and more directed subsequent assessments are necessary at the primary care level. Symptomatic treatment, self-management and rehabilitation are the mainstays of clinical care for Long COVID. However, evidence-based pharmacological interventions for the prevention and treatment of Long COVID are beginning to emerge. This article presents a rational approach for assessing and managing patients with Long COVID in the primary care setting.

Source: Perumal R, Shunmugam L, Naidoo K. Long COVID: An approach to clinical assessment and management in primary care. S Afr Fam Pract (2004). 2023 Jun 23;65(1):e1-e10. doi: 10.4102/safp.v65i1.5751. PMID: 37427773; PMCID: PMC10331047. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331047/ (Full text)

Long COVID, the Brain, Nerves, and Cognitive Function

Abstract:

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms.
Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies.
This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored.
Source: Reiss AB, Greene C, Dayaramani C, Rauchman SH, Stecker MM, De Leon J, Pinkhasov A. Long COVID, the Brain, Nerves, and Cognitive Function. Neurology International. 2023; 15(3):821-841. https://doi.org/10.3390/neurolint15030052 https://www.mdpi.com/2035-8377/15/3/52 (Full text)