Persistent Exertional Intolerance After COVID-19

Abstract:

Background: Some patients with COVID-19 who have recovered from the acute infection after experiencing only mild symptoms continue to exhibit persistent exertional limitation that often is unexplained by conventional investigative studies.

Research question: What is the pathophysiologic mechanism of exercise intolerance that underlies the post-COVID-19 long-haul syndrome after COVID-19 in patients without cardiopulmonary disease?

Study design and methods: This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 patients who recovered from COVID-19 and were without cardiopulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results with those from 10 age- and sex-matched control participants. These data then were used to define potential reasons for exertional limitation in the cohort of patients who had recovered from COVID-19.

Results: The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO2]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4±2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation.

Interpretation: Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.

Source: Singh I, Joseph P, Heerdt PM, Cullinan M, Lutchmansingh DD, Gulati M, Possick JD, Systrom DM, Waxman AB. Persistent Exertional Intolerance After COVID-19: Insights From Invasive Cardiopulmonary Exercise Testing. Chest. 2021 Aug 11:S0012-3692(21)03635-7. doi: 10.1016/j.chest.2021.08.010. Epub ahead of print. PMID: 34389297; PMCID: PMC8354807. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354807/  (Full text)

Experiences Among School Personnel and School Nurses on Educational Adaptations for Students With CFS/ME: A Qualitative Interview Study

Abstract:

Introduction: Chronic fatigue syndrome (CFS/ME) is a disabling disease severely impacting school attendance, education, and social life in young students. Uncertainties surrounding CFS/ME etiology may impact the interpretation of CFS/ME in schools. Thus, school personnel need information from health care providers to make adequate adaptations to education and social life at school for these students.

Objectives: To explore teachers, counselors, and school nurses’ experiences with adapting education for students with CFS/ME aged 13-19 in secondary and high schools.

Design: A qualitative study with focus group interviews and individual interviews performed face-to-face or digitally between November 2020 and March 2021. Data were analyzed using Systematic text condensation.

Participants: Six teachers, two counselors, and four school nurses in secondary and high school participated.

Results: Adapting education for students with CFS/ME was challenging, especially before the students received a diagnosis. The challenges were related to identifying the students’ adaptational needs, maintaining a teacher-student relationship due to school absence, difficulties in maintaining continuity of education, and uncertainty regarding the diagnosis. Successful adaptations were related to quickly reacting to school absence, early referral to educational, psychological services, a close collaboration with the school management, and the development of digital teaching for students with CFS/ME. Interdisciplinary collaboration and a clear, constructive plan with adaptive measures, including maintained teacher-student communication and educational and social adaptations, may be useful in preventing the losses, young people, with CFS/ME experience.

Conclusion: Early interdisciplinary collaboration to adapt education and social life at school for students with CFS/ME, may support teachers, counselors, and school nurses in their efforts to adapt education and prevent losses related to academic and social development in students with CFS/ME.

Source: Similä WA, Rø TB, Nøst TH. Experiences Among School Personnel and School Nurses on Educational Adaptations for Students With CFS/ME: A Qualitative Interview Study. Front Pediatr. 2021 Nov 11;9:756963. doi: 10.3389/fped.2021.756963. PMID: 34858906; PMCID: PMC8632258.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632258/ (Full study)

Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post-Coronavirus Disease

Abstract:

Objectives: The authors used cardiopulmonary exercise testing (CPET) to define unexplained dyspnea in patients with post-acute sequelae of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (PASC). We assessed participants for criteria to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Background: Approximately 20% of patients who recover from coronavirus disease (COVID) remain symptomatic. This syndrome is named PASC. Its etiology is unclear. Dyspnea is a frequent symptom.

Methods: The authors performed CPET and symptom assessment for ME/CFS in 41 patients with PASC 8.9 ± 3.3 months after COVID. All patients had normal pulmonary function tests, chest X-ray, and chest computed tomography scans. Peak oxygen consumption (peak VO2), slope of minute ventilation to CO2 production (VE/VCO2 slope), and end tidal pressure of CO2 (PetCO2) were measured. Ventilatory patterns were reviewed with dysfunctional breathing defined as rapid erratic breathing.

Results: Eighteen men and 23 women (average age: 45 ± 13 years) were studied. Left ventricular ejection fraction was 59% ± 9%. Peak VO2 averaged 20.3 ± 7 mL/kg/min (77% ± 21% predicted VO2). VE/VCO2 slope was 30 ± 7. PetCO2 at rest was 33.5 ± 4.5 mm Hg. Twenty-four patients (58.5%) had a peak VO2 <80% predicted. All patients with peak VO2 <80% had a circulatory limitation to exercise. Fifteen of 17 patients with normal peak VO2 had ventilatory abnormalities including peak respiratory rate >55 (n = 3) or dysfunctional breathing (n = 12). For the whole cohort, 88% of patients (n = 36) had ventilatory abnormalities with dysfunctional breathing (n = 26), increased VE/VCO2 (n = 17), and/or hypocapnia PetCO2 <35 (n = 25). Nineteen patients (46%) met criteria for ME/CFS.

Conclusions: Circulatory impairment, abnormal ventilatory pattern, and ME/CFS are common in patients with PASC. The dysfunctional breathing, resting hypocapnia, and ME/CFS may contribute to symptoms. CPET is a valuable tool to assess these patients.

Source: Mancini DM, Brunjes DL, Lala A, Trivieri MG, Contreras JP, Natelson BH. Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post-Coronavirus Disease. JACC Heart Fail. 2021 Dec;9(12):927-937. doi: 10.1016/j.jchf.2021.10.002. PMID: 34857177.  https://pubmed.ncbi.nlm.nih.gov/34857177/

Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19

Abstract:

Background and methods: Skeletal muscle-related symptoms are common in both acute Covid-19 and Post-Acute Sequelae of Covid-19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected, and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy and post-viral fatigue syndrome.
Results: Patients with severe Covid-19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fiber atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid-19 include systemic inflammation, disuse, hypoxemia, and malnutrition. These factors also contribute to post-ICU syndrome and ICU-acquired weakness, and likely explain a substantial part of Covid-19-acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure and different factors likely contribute. Direct SARS-CoV-2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study.
Conclusion: Both SARS-CoV-2 specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid 19 and PASC.
Source: Soares, M., Eggelbusch, M., Naddaf, E., Gerrits, K., van der Schaaf, M., van den Borst, B., Wiersinga, W. J., et al. Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19. Journal of Cachexia, Sarcopenia and Muscle. https://doi.org/10.17863/CAM.78509 https://www.repository.cam.ac.uk/handle/1810/331064

Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS.

In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner. Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement. The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor.

In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area. For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis.

Source: Li X, Julin P, Li TQ. Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Tomography. 2021 Nov 1;7(4):675-687. doi: 10.3390/tomography7040056. PMID: 34842817.  https://www.mdpi.com/2379-139X/7/4/56 (Full text)

Intestinal flora and neurological disorders

Abstract:

The human intestinal flora is a highly diverse ecosystem composed of trillions of bacteria. The imbalance of the flora is related to a variety of diseases. The intestinal flora interacts with the nervous system bidirectionally in many ways through the gut-brain axis. It causes neuroimmune inflammatory response, dysfunction of gut mucosa and blood-brain barrier, direct stimulation of the vagus nerve, spinal nerve of the enteric nervous system, and the neuroendocrine hypothalamus-pituitary-adrenal axis, causing neurological disorders. The metabolites of the intestinal microbial community also play a role.

This article summarizes the characteristics of the altered intestinal flora and intervention measures in autism spectrum disorder, multiple sclerosis, Parkinson’s disease, epilepsy, Guillain-Barré syndrome, Alzheimer’s disease, neuromyelitis optica, hepatic encephalopathy, amyotrophic lateral sclerosis, schizophrenia, depression, chronic fatigue syndrome, Huntington’s disease and stroke. The current research on intestinal flora is still in its infancy, and very few studies were carried out on causality and the underlying mechanisms, which prevents the development of precise flora-based clinical intervention measures. It is expected the research on intestinal flora would lead to novel approaches for treatment of some neurological disorders.

Source: Tang Q, Cao L. [Intestinal flora and neurological disorders]. Sheng Wu Gong Cheng Xue Bao. 2021 Nov 25;37(11):3757-3780. Chinese. doi: 10.13345/j.cjb.210253. PMID: 34841782. https://pubmed.ncbi.nlm.nih.gov/34841782/

Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form

Abstract:

Post COVID-19 Syndrome (PCS) is a complex of various symptoms developing a month or more after the acute phase of the disease. The cases of PCS development among patients with asymptomatic/mild forms are frequently reported; however, the pathogenesis of PCS in this group of patients is still not completely clear. The publications about COVID-19 which were published in online databases from December 2019 to September 2021 are analyzed in this review. According to the analysis, PCS develops on average in 30-60% of patients, mainly among women. Fatigue, shortness of breath, cough, and anosmia were reported as the most common symptoms. The possible association between the described PCS symptoms and brain damage was revealed.

We assume the possibility of an alternative course of COVID-19, which develops in genetically predisposed individuals with a stronger immune response, in which it predominantly affects the cells of the nervous system, possibly with the presence of an autoimmune component, which might have similarity with chronic fatigue syndrome or autoimmune disautonomia. Thus, the gender (female) and the presence of anosmia during an asymptomatic or mild course of the disease can be predictive factors for the development of PCS, which can be caused by autoimmune damage to neurons, glia, and cerebral vessels.

Source: Malkova A, Kudryavtsev I, Starshinova A, Kudlay D, Zinchenko Y, Glushkova A, Yablonskiy P, Shoenfeld Y. Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form. Pathogens. 2021 Oct 30;10(11):1408. doi: 10.3390/pathogens10111408. PMID: 34832564. https://pubmed.ncbi.nlm.nih.gov/34832564/

Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder.

Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca2+) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS. TRPM7 is a related channel that is modulated by PIP2 and participates in Ca2+ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown.

This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP2 and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls. The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted.

Source: Du Preez S, Eaton-Fitch N, Cabanas H, Staines D, Marshall-Gradisnik S. Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Int J Environ Res Public Health. 2021 Nov 12;18(22):11879. doi: 10.3390/ijerph182211879. PMID: 34831634. https://pubmed.ncbi.nlm.nih.gov/34831634/

Back to the Future? Immunoglobulin Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

The findings of controlled trials on use of intravenous immunoglobulin G (IV IgG) to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are generally viewed as representing mixed results. On detailed review, a clearer picture emerges, which suggests that the potential therapeutic value of this intervention has been underestimated.

Our analysis is consistent with the propositions that: (1) IgG is highly effective for a proportion of patients with severe and well-characterised ME/CFS; (2) responders can be predicted with a high degree of accuracy based on markers of immune dysfunction. Rigorous steps were taken in the research trials to record adverse events, with transient symptom exacerbation commonly experienced in both intervention and placebo control groups, suggesting that this reflected the impact of participation on people with an illness characterised by post-exertional symptom exacerbation. Worsening of certain specific symptoms, notably headache, did occur more commonly with IgG and may have been concomitant to effective treatment, being associated with clinical improvement.

The findings emerging from this review are supported by clinical observations relating to treatment of patients with severe and very severe ME/CFS, for whom intramuscular and subcutaneous administration provide alternative options. We conclude that: (1) there is a strong case for this area of research to be revived; (2) pending further research, clinicians would be justified in offering a course of IgG to selected ME/CFS patients at the more severe end of the spectrum. As the majority of trial participants had experienced an acute viral or viral-like onset, we further suggest that IgG treatment may be pertinent to the care of some patients who remain ill following infection with SARS-CoV-2 virus.

Source: Brownlie H, Speight N. Back to the Future? Immunoglobulin Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Healthcare (Basel). 2021 Nov 12;9(11):1546. doi: 10.3390/healthcare9111546. PMID: 34828592. https://pubmed.ncbi.nlm.nih.gov/34828592/

Chronic Fatigue Syndrome: A Case Report Highlighting Diagnosing and Treatment Challenges and the Possibility of Jarisch-Herxheimer Reactions If High Infectious Loads Are Present

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-system disease with no cure and no FDA-approved treatment. Approximately 25% of patients are house or bedbound, and some are so severe in function that they require tube-feeding and are unable to tolerate light, sound, and human touch.

The overall goal of this case report was to (1) describe how past events (e.g., chronic sinusitis, amenorrhea, tick bites, congenital neutropenia, psychogenic polydipsia, food intolerances, and hypothyroidism) may have contributed to the development of severe ME/CFS in a single patient, and (2) the extensive medical interventions that the patient has pursued in an attempt to recover, which enabled her to return to graduate school after becoming bedridden with ME/CFS 4.5 years prior.

This paper aims to increase awareness of the harsh reality of ME/CFS and the potential complications following initiation of any level of intervention, some of which may be necessary for long-term healing. Treatments may induce severe paradoxical reactions (Jarisch-Herxheimer reaction) if high infectious loads are present. It is our hope that sharing this case will improve research and treatment options for ME/CFS.

Source: Straub RK, Powers CM. Chronic Fatigue Syndrome: A Case Report Highlighting Diagnosing and Treatment Challenges and the Possibility of Jarisch-Herxheimer Reactions If High Infectious Loads Are Present. Healthcare (Basel). 2021 Nov 10;9(11):1537. doi: 10.3390/healthcare9111537. PMID: 34828583. https://pubmed.ncbi.nlm.nih.gov/34828583/