Introduction of Long COVID Center in Ukima Central Hospital
Purpose of Long COVID Center
Long COVID is a disease inducing general fatigue, systematic pain, sleep disturbances, and autonomic nerve disorders etc. after couple of months of initial infection of COVID19. Number of patients with the Long COVID is over 500 thousand in Japan, in which around 30% patients are bedridden.
Our medical group found that patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) as Long COVID accompanied with adrenal insufficiency. Four hundred patients with Long COVID from nationwide had been hospitalized and received adequate doses of hydrocortisone based on the endocrinological examinations, by which 85% of the patients recovered completely.
To rescue the patients with Long COVID, Ukima Central hospital established the Long COVID Center.
Causes of the general fatigue in Long COVID
1. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Infection of corona virus into whole brain
2. Hypothalamic adrenal insufficiency
Infection of corona virus into hypothalamus
Diagnosis criteria of ME/CFS
1. Fatigue at rest
2. Post-exertional fatigue: difficulty of recover taking over 24 hours
3. Sleep disorder: abnormal sleeping rhythm and insomnia
4. Systematic pain: muscle, joint and sever headache
5. Neurological /cognitive manifestations
Confusion
Impairment of concentration and short-term memory consolidation Disorientation
6. Autonomic nerve manifestation
Orthostatic intolerance, Postural orthostatic tachycardia syndrome (POTS), Light and sound- intolerance, Nausea, Irritable bowel syndrome, Urinary frequency
7. Neuroendocrine
Loss of thermostatic stability, Sweating episodes, Cold hand and feet
8. Immune manifestation
New food sensitivities, Medication sensitivities, Chemical sensitivities
From these eight criteria, more than five positive criteria indicate diagnosis of ME/CFS.
Pathogenesis of Long COVID
Mitochondrial energy deficiency of brain cells in ME/CFS
The chronic fatigue in ME/CFS is associated with the mitochondrial energy deficiency of brain cells. In normal brain cells produce enough energy, but brain cells in long COVID produce reduced energy. That is why patients with long COVID become soon sever fatigue after exercise.
Damage of neurotransmitter pathway of brain in long COVID
After corona virus invasion, if serotonin pathway is damaged, patients become depression. If dopamine pathway is damaged, patients become the autonomic nerve dysfunctions as orthostatic hypotension.
Activation of brain microglia in ME/CFS
Here is important mechanisms of long COVID as activation of brain microglia in ME/CFS. After disappear of corona virus, brain microglia cells are activated, which induces central pathogenesis of ME/CFS.
Hypothalamus・Pituitary・Adrenal axis.
Hypothalamus release CRH to stimulates pituitary ACTH and then ACTH stimulates cortisol releasing from adrenal grand. ACTH and Cortisol have circadian rhythm. Levels of blood ACTH and cortisol are highest at early morning and declined to midnight.
Hypothalamic adrenal insufficiency in long COVID.
If corona virus infected into hypothalamus, then hypothalamic CRH and pituitary ACTH levels are decreased, they cannot stimulate enough cortisol generation. Patients with long COVID with low levels of cortisol feels general fatigue, body weight loss and appetite loss.
Hospitalized schedule for long COVID
To investigate profound pathogenesis of general fatigue in patients with long COVID, patients are hospitalized and examined in Long COVID Center of Ukima Central Hospital as following schedule.
Day 1
Brain MRI＋VSRAD analysis
Evaluation of exercise ability by Rehabilitation staff Blood samplings for Hormone circadian rhythm:
Day 2
Blood sampling at 6: 00
Pituitary loading test with GRH, CRH, LHRH and TRH
Day 3
ACTH loading test to investigate adrenal function
Start medicines including hydrocortisone Day 4.
Discharge
Brain MRI findings analyzed by VSRAD in patients with long COVID.
After corona virus infection, VSRAD analysis shows the scattered atrophy of brain tissues including hypothalamus to induce the hypothalamic insufficiency.
Endocrinological grouping for patients with long COVID (n=144)
No abnormality：3
Primary adrenal insufficiency: 1
Pituitary adrenal insufficiency: 0
Hypothalamic adrenal insufficiency：16
ME/CFS:124（86%)
1) No endocrinological abnormality: 23 (16%)
2) Hypothalamic adrenal insufficiency：76 (53%)
3) Pituitary adrenal insufficiency: 2 (0.01%)
4) Primary adrenal insufficiency: 23 (16%)
These data indicate 80% patients with ME/CFS accompanied with adrenal insufficiency.
Circadian rhythms of ACTH and cortisol
ACTH at 6:00 were significantly lower in hypothalamic adrenal insufficiency alone and in hypothalamic adrenal insufficiency with ME/CFS. Cortisol at 6:00 was significantly higher in no endocrinological abnormality than that in another groups.
Response of ACTH and cortisol to CRH loading
There were no differences in responses of ACTH among four groups after CRH loading. Cortisol after CRH loading was significantly lower in primary adrenal insufficiency than no endocrinological abnormality with ME/CFS.
Responses of cortisol to ACTH loading in four groups
Cortisol at 30 and 60 min was significantly lower in primary adrenal insufficiency than another three groups.
Urinary excretion of cortisol for 24 hours in no endocrinological abnormality with ME/CFS was around 70 μg/day. Urinary excretions of cortisol in another three groups were significantly lower than that in no endocrinological abnormality.
Relation between ME/CFS and adrenal insufficiency in the long COVID
Sixty% of patients with ME/CFS are complicated the hypothalamic adrenal insufficiency. Moreover 20% of patients with ME/CFS are complicated the primary adrenal insufficiency.
Rehabilitation program for ME/CFS
1) Evaluation of exercise ability of ME/CFS patients by 6 minutes walking distance
2) Preservation of energy in rehabilitation for ME/CFS
3) Graded exercise therapy (GET) depending on the individual exercise ability
Our established special combination of medicines for ME/CFS For Hypothalamic adrenal insufficiency
●Hydrocortisone：Supplementation based on adrenal insufficiency, Tapering 5mg/6 months
●Saireto (Kanpo) to stimulate hypothalamus
For Mitochondrial energy
●Taurine over 9g/day
●Neuquinon (CoQ10)
●5-Aminolevulinic acid hydrochloride (5-ALA)
For Microglia activation in brain
●Minocycline
●Bucillamine or Iguratimod
For Insomnia and abnormal sleeping rhythm
●SSRI paroxetine to stimulate serotonin in brain.
●Ramelteon to stimulate melatonin.
In Summary
Causes of the general fatigue in patients with long COVID were ME/CFS (77%) and Hypothalamic adrenal insufficiency alone (20%)
ME/CFS accompanied with the hypothalamic adrenal insufficiency (78%) and primary adrenal dysfunction (14%)
Adequate supplementation of hydrocosterone is effective to treat the general fatigue (differed from administration of corticosterone).
Mitochondrial damage is cause of the general fatigue in ME/CFS, for which taurine, CoQ10 and 5-ALA are effectively improved the general fatigue.
Contact us
If you want be examined and treated with our medicines, please contact us to the following address. We welcome inbounds with Long COVID.
Noboru Fukuda
Director of Ukima Central Hospital Ukima Central Hospital,
2-21-19 Akabane Kita, Kita-city, Tokyo 115-0052, Japan
Phone +81-3-3907-8711
E-mail: fukuda.noboru57@gmail.com
http://www.hakueikai.or.jp/ukima/
https://orcid.org/0000-0003-0098-054X