Paediatric long COVID & ME/CFS: overlaps & opportunities

Pediatric long COVID and Myalgic Encephalomyelitis/ Chronic Fatigue
Syndrome: overlaps and 0pportunities, by Vikram GR Siberry MS and Peter C Rowe MD in The Pediatric Infectious Disease Journal: February 4, 2022  [doi:10.1097/INF.0000000000003477]

 

Extracts from Commentary:

Zimmermann et al provide a masterful application of Spodick’s exhortation. Their review of the existing evidence regarding long COVID in children enumerates important methodologic challenges in interpreting this literature… Despite such limitations, it is clear that pediatric patients are at risk for prolonged symptoms following acute SARS-CoV-2 infection.

Although many persistent symptoms, such as anosmia, dysgeusia and shortness of breath are unique to the post-COVID state, many other symptoms such as fatigue, cognitive dysfunction, lightheadedness and postexertional malaise overlap with symptoms found in myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

In this commentary, we review case definitions for long COVID and ME/CFS, emphasize recent research findings on the biologic basis of ME/CFS, discuss the overlap with long COVID, and consider opportunities posed by the pandemic to improve the understanding of both conditions.

Overlaps between Long COVID and ME/CFS

The overlap of symptoms between long COVID and ME/CFS is substantial and includes fatigue, postexertional malaise, cognitive impairment, sleep disturbance and lightheadedness. Both conditions are more frequent in females than males. Neither condition can be reliably diagnosed with laboratory findings, although such testing
can help exclude other similar conditions.

Diagnosis for both consists of a thorough history to elicit symptoms along with a full physical exam; to identify orthostatic intolerance, we recommend at least a 10-minute period of orthostatic stress, such as with a passive standing test. Treatment focuses on symptom management.

While no single pharmacologic agent is effective for all long COVID or ME/CFS patients, this should not encourage therapeutic nihilism, as many effective treatments exist for the common features such as orthostatic intolerance, pain, headaches and insomnia.

More work will be needed to identify whether the prevalence of orthostatic intolerance is as high in long COVID as it is in ME/CFS, and whether the risk factors for pediatric ME/CFS (including allergic inflammation, female sex, peak onset in adolescence and heritable risk factors such as joint hypermobility) apply to post-COVID conditions.

Read full article – pdf

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Lessons from ME/CFS for long COVID: “Energy System First Aid” for people with PESE (aka PEM)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID

 

Part 3: “Energy System First Aid” for People With Post Exertional Symptom Exacerbation, by Todd E Davenport, Staci R Stevens, Jared Stevens, Christopher R Snell, J Mark Van Ness in JOSPT, February 16, 2022 [https://doi.org/10.2519/jospt.blog.20220216]

 

Blog post extract:

In a previous post, we demonstrated that the symptoms and physiology of postexertional symptom exacerbation (PESE) are inconsistent with deconditioning. PESE worsens in response to exercise and demonstrates a variable clinical presentation. We will build a clinical rationale for energy system first aid as a place to start helping people with PESE.

Summary

First aid is an important part of rehabilitation. Energy system first aid for people with PESE focuses on helping patients to use the metabolic systems that function well, and to limit the use of the aerobic system that current evidence suggests is functioning abnormally. Working together, patients and clinicians can use widely available tools and simple insights from physiological data to promote improvements in symptoms and functioning.

How to Explain Energy System First Aid to Patients

Recommendations for energy first aid in people with PESE have been made based on symptom acuity and irritability. The energy envelope hypothesis is a patient-friendly way to summarize energy system first aid for patients (FIGURE). A patient’s energy envelope is the physiological capacity for function at any moment in time. Although not curative, people can be coached to stay within their energy envelopes to avoid accessing a dysfunctional aerobic energy system. In turn, adherence to the energy envelope can improve predictability of daily energy level and the capacity for function.5

Heart rate monitoring can be an effective, objective way for patients to monitor the intensity of their daily activities, stay within the energy envelope, and predict PESE before it occurs. The predictive ability of heart rate monitoring is important because of the time delay between an exacerbating activity and resultant PESE.

Read the full blog post

Read Part 1: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity

Read Part 2: Physiological characteristics during acute exercise are abnormal in people with Postexertional Symptom Exacerbation

Read Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation

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Treatment research: …restoration using Naltrexone in natural killer cells of ME/CFS patients

Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients, by Natalie Eaton-Fitch, Stanley Du Preez, Hélène Cabanas, Katsuhiko Muraki, Donald Staines & Sonya Marshall-Gradisnik in Journal of Translational Medicine volume 20, Article number: 94 (2022)

 

Research abstract:

Background:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. While the pathomechanism of ME/CFS remains elusive, reduced natural killer (NK) cell cytotoxic function is a consistent immunological feature. NK cell effector functions rely on long-term sustained calcium (Ca2+) influx.

In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. Specifically, reports of single nucleotide polymorphisms, low surface expression and impaired function of TRPM3 have been reported in NK cells of ME/CFS patients.

It has been reported that mu (µ)-opioid receptor (µOR) agonists, known collectively as opioids, inhibit TRPM3. Naltrexone hydrochloride (NTX), a µOR antagonist, negates the inhibitory action of µOR on TRPM3 function. Importantly, it has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients.

Methods
Live cell immunofluorescent imaging was used to measure TRPM3-dependent Ca2+ influx in NK cells isolated from n = 10 ME/CFS patients and n = 10 age- and sex-matched healthy controls (HC) following modulation with TRPM3-agonist, pregnenolone sulfate (PregS) and TRPM3-antaognist, ononetin. The effect of overnight (24 h) NTX in vitro treatment on TRPM3-dependent Ca2+ influx was determined.

Results
The amplitude (p < 0.0001) and half-time of Ca2+ response (p < 0.0001) was significantly reduced at baseline in NK cells of ME/CFS patients compared with HC. Overnight treatment of NK cells with NTX significantly improved TRPM3-dependent Ca2+ influx in ME/CFS patients. Specifically, there was no significance between HC and ME/CFS patients for half-time response, and the amplitude of Ca2+ influx was significantly increased in ME/CFS patients (p < 0.0001).

Conclusion
TRPM3-dependent Ca2+ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro.

Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS.

Research features: Understanding the intricacies of ion channels in ME/chronic fatigue syndrome – The background to the work of Griffith University’s research into ion channel dysfunction in ME/CFS and their search for treatments.

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Pillow writers: International ME/CFS writers’ group

Writing from our ME lives – the Pillow writers

 

An international group of writers with ME and long COVID invite you to join them.

Pillow writers is a friendly, supportive encouraging space where we share our thoughts on chronic illness, poetry and creative writing.

Find them on Facebook

See the website for:

  • poems
  • haikus
  • art
  • prose
  • the January 2022 Writers Salon

 

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Social research: The circuit of symbolic violence in CFS/ME

The circuit of symbolic violence in chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) (I): A preliminary study, by Xavier Gimeno Torrent in Health Care for Women International Volume 43, 2022 – Issue 1-3

 

Research abstract: 

Objective

How can it be that a disease as serious as CFS affecting such a large number of people could be so unknown to the general population? The answer given to this question is based on Pierre Bourdieu’s analyzes of symbolic violence.

Method

The ‘letters to the editor’ by CFS patients to three national Spanish newspapers were subjected to various qualitative and quantitative analyzes.

Results

Based on the qualitative analyzes and their theoretical interpretation, 13 mechanisms of symbolic violence were identified: non-recognition, institutionalized un-care, condescension, authorized imposition of illegitimate verdicts, delegitimization, disintegration, imposition of discourse, euphemization, silencing, invisibilization, isolation, uncommunication, and self-blaming.

Multiple Correspondence Analysis made it possible to identify that the structural mechanisms (non-recognition, disintegration) were combined with the most symbolic ones, which came to the forefront producing the observed effects of symbolic violence. The 13 clusters obtained in the Agglomerative Hierarchical Clustering confirmed this result.

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Lessons from ME/CFS for Long COVID: Physiological characteristics… are abnormal in people with Postexertional Symptom Exacerbation (aka PEM)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID

Part 2: Physiological characteristics during acute exercise are abnormal in people with Postexertional Symptom Exacerbation, by Todd E Davenport, Staci R Stevens, Jared Stevens, Christopher R Snell, J Mark Van Ness in JOSPT, February 9, 2022 [https://doi.org/10.2519/jospt.blog.20220209]

 

Blog post extract:

In a previous post on the JOSPT Blog, we outlined the connection between postacute sequalae to novel coronavirus (long COVID) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through their common clinical presentation: postexertional symptom exacerbation (PESE). PESE suggests the presence of abnormal physiological responses to exercise/activity. These physiological responses may be measured using cardiopulmonary exercise testing (CPET), which allows for careful characterization of cardiac, pulmonary, and metabolic functioning during exercise. We will review the characteristic findings on CPET in people with PESE.

Summary

This post reviewed evidence from systems-level physiology that indicates important differences in physiological responses to acute exercise between people with deconditioning compared to people with PESE. Clearly, PESE is not deconditioning. Rather, physiological changes may be related to autonomic dysfunction, as well as direct and indirect effects of pathogenic infection, such as the novel coronavirus infection in long COVID. Insights into the physiology of PESE may be used to evaluate and treat people with long COVID and ME/CFS, as well as shape future rehabilitation research and safe clinical practices.

Read full blog post

Read Part 1: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity

Read Part 3: “Energy System First Aid” for People With Post Exertional Symptom Exacerbation

Read Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation

 

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Case study: ME/CFS post coronavirus disease

Myalgic encephalomyelitis/chronic fatigue syndrome post coronavirus disease 2019, by Yoshiki Kusama, Sadahiro Fukui, Makiko Maruyama, Katsunori Kamimura, Toshiro Maihara in Paediatrics International Vol 64, no. 1 Feb 2022 [doi.org/10.1111/ped.14976]

 

Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been the most impactful infectious disease in the 21st century. The SARS-CoV-2 pandemic significantly increased the number of patients and deaths worldwide. Long-course diseases related to COVID-19, which present with persistent reparatory distress or fatigue (so-called long COVID) have been reported in adult and pediatric patients since the latter half of 2020. Long-COVID is observed as a persistent symptom after the acute phase of the disease.1

Recent research suggested that it can present with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).2 We report a case of long COVID to contribute to the body of knowledge regarding this disease, which has not been well investigated in children.

A 14-year-old boy with well controlled asthma, controlled by a long-acting muscarinic antagonist, long-acting beta-agonist, and corticosteroid inhaler, was admitted to our hospital for severe fatigue and appetite loss. He suffered from COVID-19 diagnosed using reverse transcription polymerase chain reaction 90 days prior to hospitalization. He presented with a low-grade fever, mild cough, dysgeusia, and dysosmia. He was placed under quarantine in a hotel room for 6 days. His low-grade fever and mild cough resolved after 10 days, while the dysgeusia and dysosmia disappeared within a month.

He presented with gradually progressive upper limb muscle weakness, severe fatigue, and difficulty concentrating (so-called “brain fog”) 20 days before hospitalization (70 days after the onset of COVID-19). He was unable to commute to attend junior high school. Three days before hospitalization, the patient did not eat due to appetite loss. He received oral prednisolone (20 mg/day) and Kanpō medicine (Rikkun-shito and Hotyu-ekkito). However, his symptoms were not relieved, and the patient was hospitalized. At the time of hospitalization, he did not present with fever, dyspnea, or desaturation.

Physical examination revealed an upper limb strength of grade 4 on manual muscle testing, but the tendon reflexes or sensory/motor nerve abnormalities were not noted in the extremities. Blood tests revealed normal white blood cell and C-reactive protein levels. Epstein–Barr virus and human immunodeficiency virus antibodies and antinuclear antibodies were not detected. The 10 min standing test revealed an increase of 52 heartbeats after standing at an upright position (from 81 to 133 beats/min). The patient was diagnosed with postural orthostatic tachycardia syndrome (POTS). After the test, the patient complained of worsening fatigue, suggesting post-exertional malaise (PEM), a specific characteristic of ME/CFS. Based on the clinical course and physical examination, the patient was diagnosed with ME/CFS due to long-COVID.

Oral prednisolone was discontinued, while the Kanpō medicine was continued. The patient then developed alopecia. Meanwhile, his muscle weakness and fatigue were alleviated by activity restriction due to hospitalization. On the 14th day of admission, he was discharged because his appetite improved, and he was referred to a hospital that specifically tended to chronic fatigue syndrome patients. Neither brain imaging nor electroencephalography were performed throughout the patient’s hospitalization.

The National Institute for Health Research in England classified long-COVID into four categories, namely, post-ICU syndrome, long-term organ damage, post-viral syndrome, and an entirely novel syndrome.3 Myalgic encephalomyelitis/chronic fatigue syndrome is typical of post-viral syndromes in adults, and similar cases have also been reported in children.4 Females are more likely to suffer from the disease, but males could also be affected. The exacerbation of symptoms upon exertion is known as PEM; avoiding extensive work is the essential aspect of ME/CFS management.5

In this case, the patient’s muscle fatigue and weakness dramatically improved with activity restriction due to hospitalization. This strategy may be useful for treating the severe exacerbation of ME/CFS. Chronic fatigue syndrome is diagnosed based on the persistence of symptoms for more than 6 months.2 This implies that patients have to wait for 6 months to be diagnosed with ME/CFS. Thus, new diagnostic criteria, specifically for ME/CFS due to COVID, are required to allow early intervention.

Petracek et al. reported that POTS might be an early sign of COVID-induced ME/CFS,4 POTS is considered to be a viable diagnostic criterion. To prepare for a surge of pediatric ME/CFS, the diagnostic and treatment algorithm for the disease should be standardized, and physicians need to know about or recognize the disease.

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Research: Physiological assessment of orthostatic intolerance in CFS

Physiological assessment of orthostatic intolerance in chronic fatigue syndrome by Benjamin H Natelson, Jin-Mann S Lin, Michelle Blate, Sarah Khan, Yang Chen &
Elizabeth R Unger in Journal of Translational Medicine vol 20, no: 95 (2022)

 

Research abstract:

Background
Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis /Chronic Fatigue Syndrome -ME/CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identified in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormality, followed by postural orthostatic tachycardia.

Objective
Evaluate the physiologic response of patients with ME/CFS to a standardized OC.

Design
Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2 ≤ 32 mmHg. Orthostatic tachycardia was heart rate increase ≥ 30 beats per minute compared with resting or ≥ 120 BPM. Orthostatic hypotension was decreased systolic pressure ≥ 20 mmHg from baseline. Tachypnea was respiratory rate of  ≥ 20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2.

Patients
63 consecutive patients fulfilling the 1994 case definition for CFS underwent lean testing at first visit and then annually at visit 2 (n = 48) and 3 (n = 29).

Measures
Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension.

Results
The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not differ between those with and without hypocapnia.

Conclusions
The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormality, hypocapnia, would be missed without capnography.

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Doctors with ME survey health professionals- more training on ME/CFS is needed

Survey: Facilitators to better ME Care

 

The advocacy group Doctors with ME surveyed users of Dr Muirhead’s online ME/CFS training course during 2021.

Results include:

  • 96.1% believe more formal education or training is needed for medical professionals on ME/CFS.
  • 43.6% would like support from a consultant led multidisciplinary team
  • 84.9% believe COVID will bring more cases of ME/CFS.

Read more

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Research: Decreased NO production in endothelial cells… from ME/CFS patients

Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients, by R Bertinat, RVillalobos-Labra, L Hofmann, J Blauensteiner, N Sepúlveda, F Westermeir in Vascular Pharmacology 2022, 106953 [doi.org/10.1016/j.vph.2022.106953]

 

Highlights

  • ME/CFS-plasma reduced the ability of ECs to produce NO.
  • Decreased NO production was linked to higher inhibitory phosphorylation of eNOS at Thr495 at the basal state.
  • We provide new methodological approaches to study in vitro ED in ME/CFS.

 

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED.

Endothelial dysfunction is a type of non-obstructive coronary artery disease (CAD) in which there are no heart artery blockages, but the large blood vessels on the heart’s surface constrict (narrow) instead of dilating (opening).  [Stanford]

In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of either plasma from ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence or presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs.

Our data show that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma.

Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma.

In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease.

Francisco Westermeier says on twitter:

In summary, we expect that our study can:
(1) Provide new perspectives to study endothelial function in ME/CFS.
(2) Improve the diagnosis and stratification of the subset of patients affected by endothelial dysfunction.

Comment on previous research into endothelial dysfunction:

MEA Research Review: Altered Endothelial Function in ME/CFS Blood Plasma

Discussion of results:

ME Research UK: Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients

Cure ME: Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients

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