Endocrine, Metabolic and Microbiome Influence on the Post COVID-19 Syndrome

Covid19 Clinical Trial

Official title:

Endocrine, Metabolic and Microbiome Influence on the Post-COVID Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04860869
• Other study ID #: 20-0361
• Status: Completed
• Start date: May 12, 2021
• Est. completion date: May 31, 2022

Study information

• Verified date: August 2022
• Source: The University of Texas Medical Branch, Galveston
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The aim of this study is characterize the endocrine, metabolic and microbiomes of patients with post-COVID syndrome and patients that have recovered from COVID without lingering symptoms.

Description:

The onset of the COVID-19 pandemic has led to a subset of patients that, once recovered from the acute infection, also experience an intractable and debilitating set of lingering symptoms termed post-COVID syndrome. The most common symptoms include anxiety, shortness of breath, continued loss of the sense of smell and taste, loss of appetite with subsequent weight loss, sleep difficulties, severe fatigue, cognitive dysfunction (foggy brain) and increased frailty. These patients frequently present to the emergency room looking for symptom management because they are unable to perform normal activities of daily living and maintain job performance. Thus, it is critical to characterize the baseline endocrine, metabolic, inflammatory and microbiome alterations in the post-COVID syndrome patients to better identify and manage the symptoms to prevent potential long-term health consequences. University of Texas Medical Branch (UTMB) has established a post-COVID clinic for management of these patients, but it is recognized that a more complete clinical picture of the underlying mechanisms driving these lingering symptoms is needed. Persistent and long-lasting health problems are common in patients after COVID-19 infection. In a recent study of patients that had been hospitalized with COVID-19, two months after discharge, 87% reported at least one lingering symptom (joint pain, fatigue, breathing issues, etc), more than 50% reported more than three lingering issues, and over 40% reported a reduction in their of quality of life. Another study found that at 1-month after hospitalization for COVID-19, 74% reported persistent issues related to shortness of breath and a decrease in both physical and mental health. Preliminary data from the UTMB Post-COVID Recovery clinic agree with these two recent reports. In a recent study, 1 1/2 months after COVID-19 diagnosis, patients reported on average 10 of the 18 common symptoms (with 90% having chest pain, 87% dyspnea, 75% fatigue, and 90% with cognitive changes). While the previous studies examined patients that had severe COVID-19 infections, >50% of the patients were never hospitalized, yet have numerous persistent symptoms. This has serious implications for the ability of patients to return to work, downstream effects on mental health due to sometimes drastic lifestyle and work capacity changes, and the ability to engage in activities or hobbies enjoyed prior to COVID-19 illness. Notably, the cluster of symptoms associated with post-COVID syndrome include profound fatigue and cognitive dysfunction, which are strikingly consistent with a syndrome that the investigators clinical research team has described in patients after traumatic brain injury (TBI) designated Brain Injury Associated Fatigue and Altered Cognition (BIAFAC). Over the last 12 months the investigators have reported the characteristics of BIAFAC syndrome. In particular, TBI patients with BIAFAC present with lingering and profoundly debilitating symptoms including severe fatigue, cognitive dysfunction (foggy brain), sleep disturbances, and the inability to perform activities of daily living that persist for years post-injury. Mechanistically the investigators have explored the role of the gut microbiome discovering altered communities in TBI patients in long-term care facilities compared with controls. The investigators also established that many TBI patients with BIAFAC also present with abnormal growth hormone (GH) secretion, and when treated with recombinant GH, a majority of patients have significant improvement of both fatigue and impaired cognition. While studies are underway to understand the details of the mechanism causing BIAFAC and why GH treatment alleviates symptoms in these patients, the investigators are intrigued that the symptom phenotype with post-COVID patients overlaps with many BIAFAC symptoms. It is possible that post-COVID syndrome may be addressed through similar treatment strategies including the potential for prebiotic/probiotic enhancement of microbiome health. In the current pilot proposal, the investigators will characterize the baseline endocrine, metabolic, inflammatory and gut microbiome alterations in post-COVID syndrome patients and patients who recovered without lingering symptoms from COVID infection. These patients will be compared to the investigators extensive database of BIAFAC patients and normal controls. From this critical baseline data, the investigators will develop carefully defined clinical research trials that will test potential treatments for alleviating the syndrome. The investigators hypothesize that an imbalanced endocrine axis stemming from COVID-19 infection leads to metabolic, inflammatory and microbial dysregulation resulting in the onset of persistent post-COVID symptoms. Specific Aims Specific Aim 1: Characterize the baseline physiological measures of endocrine function, metabolism, inflammation, and composition of the gut and nasal microbiome of patients reporting symptoms of post-COVID syndrome. Specific Aim 2: Assess baseline neuropsychological measures of fatigue, sleep, and cognition for patients reporting symptoms of post-COVID syndrome. Specific Aim 3: Correlate physiological and neuropsychological measures of post-COVID patients and compare those measures to the investigators extensive database of BIAFAC patients and normal controls. Specific Aim 4: Characterize the microbiome of patients with post-COVID syndrome and compare to: a)our database of healthy control subjects, b) our database of symptomatic BIAFAC patients, c) new collected samples of patients with a history of COVID who did not develop post-COVID syndrome.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: May 31, 2022
• Est. primary completion date: May 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

COVID Non-Symptomatic controls (nPASC) Inclusion criteria

1. Male or female with a history of COVID with diagnosis confirmed by PCR test.

2. Minimum of 6 months since diagnosis of COVID by PCR test.

3. Ages 18 to 80 years.

4. Participant is willing and able to give informed consent for participation in the study. Exclusion criteria

1. Current COVID infection.

2. Unable to walk unassisted.

3. Significant heart, liver, kidney, blood or respiratory disease as determined by Principal Investigator.

4. Uncontrolled diabetes mellitus.

5. Any history of a recently (12 months) diagnosed cancer other than a skin cancer (excluding melanoma).

6. Current alcohol or drug abuse.

7. History of psychosis.

8. Pregnancy or become pregnant during the trial.

9. Subjects who are being managed with narcotics will be excluded as the effects of central nervous system depressants may interfere with study test results.

10. Other medical condition or medication administration deemed exclusionary by the study investigators. COVID Symptomatic Subjects (PASC)

Inclusion Criteria:

1. Male or female with a history of COVID with diagnosis confirmed by PCR test.

2. Has been seen at UTMB Post COVID clinic.

3. Minimum of 6 months since diagnosis of COVID by PCR test.

4. Ages 18 to 80 years.

5. Score of 3 or higher on any question 1-3 of the Brief Fatigue Inventory (BFI) questionnaire.

6. Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

1. Current COVID infection.

2. Unable to walk unassisted.

3. Significant heart, liver, kidney, blood or respiratory disease.

4. Uncontrolled diabetes mellitus.

5. Any history of a recently (12 months) diagnosed cancer other than a skin cancer (excluding melanoma).

6. Current alcohol or drug abuse.

7. History of psychosis.

8. Pregnancy or become pregnant during the trial.

9. Subjects who are being managed with narcotics will be excluded as the effects of central nervous system depressants may interfere with study test results.

10. Other medical condition or medication administration deemed exclusionary by the study investigators.

Related Conditions & MeSH terms

• COVID-19
• Covid19

Locations

Country	Name	City	State
United States	The University of Texas Medical Branch	Galveston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
The University of Texas Medical Branch, Galveston

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Insulin-Like Growth Factor-1 (IGF1)	Insulin-Like Growth Factor-1 (IGF1) will be measured in serum. Results will be reported in ng/mL.	baseline
Primary	Follicle Stimulating Hormone (FSH)	Follicle Stimulation Hormone (FSH) will be measured in serum. Results will be reported in IU/L.	baseline
Primary	Sex Hormone Binding Globulin (SHBG)	Sex Hormone Binding Globulin (SHBG) will be measured in serum. Results will be reported in nmol/L.	baseline
Primary	Total Testosterone	Total testosterone will be measured in serum of male subjects. Results will be reported in ng/dL.	baseline
Primary	Free Testosterone	Free testosterone will be measured in serum of male subjects. Results will be reported in pg/mL.	baseline
Primary	Prolactin	Prolactin will be measured in serum. Results will be reported in ng/mL.	baseline
Primary	Thyroid Stimulating Hormone (TSH)	Thyroid Stimulating Hormone (TSH) will be measured in serum. Results will be reported in mU/L.	baseline
Primary	C Reactive Protein (CRP)	C Reactive Protein (CRP) will be measured in serum. Results will be reported in mg/L.	baseline
Primary	Vitamin B12	Vitamin B12 will be measured in serum. Results will be reported in pg/mL.	baseline
Primary	Vitamin D	Vitamin D will be measured in serum. Results will be reported in ng/mL.	baseline
Primary	Glucose tolerance as measured by the Oral Glucose Tolerance Test (OGTT) before glucose consumption	Glucose will be measured in serum before (0 minutes) oral consumption of 75g glucose. Glucose will be reported in mmol/L. OGTT will be performed on PASC subjects only.	Before glucose consumption
Primary	Glucose tolerance as measured by the Oral Glucose Tolerance Test (OGTT) 120 minutes after glucose consumption	Glucose will be measured in serum at 120 minutes after oral consumption of 75g glucose. Glucose will be reported in mmol/L. OGTT will be performed on PASC subjects only.	120 minutes after glucose consumption
Primary	Insulin as measured by the Oral Glucose Tolerance Test (OGTT) before glucose consumption	Insulin will be measured in serum before (0 min) oral consumption of 75g glucose. Glucose will be reported in uIUl/L. OGTT will be performed on PASC subjects only.	Before glucose consumption
Primary	Insulin as measured by the Oral Glucose Tolerance Test (OGTT) 120 minutes after glucose consumption	Insulin will be measured in serum at 120 minutes after oral consumption of 75g glucose. Insulin will be reported in uIU/L. OGTT will be performed on PASC subjects only.	120 minutes after glucose consumption
Primary	Glucose derived CO2 as measured by breath during the Oral Glucose Tolerance Test (OGTT) before glucose consumption	Glucose derived CO2 will be measured in breath samples before (0 min) oral consumption of 75g glucose isotopically labeled with 150 mg [U-13C6] glucose.; Glucose-derived breath CO2 data are analyzed by measuring the ratios of 13CO2 to 12CO2 in single breath samples using an UBiT-IR300 infrared spectrophotometer (Otsuka Electronics, Hirakata, Osaka, Japan). The UBIT-IR300 calculates the difference in 13CO2 abundance from the baseline breath sample to each timed sample and expresses this as per mille delta over baseline (‰DOB).; OGTT will be performed on PASC subjects only.	Before glucose consumption
Primary	Glucose derived CO2 as measured by breath during the Oral Glucose Tolerance Test (OGTT) 120 minutes after glucose consumption	Glucose derived CO2 will be measured in breath samples at 120 minutes after oral consumption of 75g glucose isotopically labeled with 150 mg [U-13C6] glucose.; Glucose-derived breath CO2 data are analyzed by measuring the ratios of 13CO2 to 12CO2 in single breath samples using an UBiT-IR300 infrared spectrophotometer (Otsuka Electronics, Hirakata, Osaka, Japan). The UBIT-IR300 calculates the difference in 13CO2 abundance from the baseline breath sample to each timed sample and expresses this as per mille delta over baseline (‰DOB).; OGTT will be performed on PASC subjects only.	120 minutes after glucose consumption
Primary	Characterization of fecal microbiome using molecular methods	Characterization of the fecal microbiome using a commercially available sampling kit and our lab's patented array for PCR.	baseline
Primary	Characterization of oral microbiome using molecular methods	Characterization of the oral microbiome using a commercially available sampling kit and our lab's patented array for PCR.; Oral microbiome will be performed on PASC subjects only.	baseline
Primary	Characterization of nasal microbiome using molecular methods	Characterization of the nasal microbiome using a nasal swab and our lab's patented array for polymerase chain reaction (PCR).; Nasal microbiome will be performed on PASC subjects only.	baseline
Primary	Mobility as measured by the EuroQOL-5 Dimensions	EuroQOL-5 Dimensions (EQ-5D) is a 5 item assessment of health status measuring mobility, self-care, usual activity, discomfort or pain and depression or anxiety.; Mobility subscale is a range of 1-3, with a higher score indicating more dysfunction.	baseline
Primary	Self-care as measured by the EuroQOL-5 Dimensions	EuroQOL-5 Dimensions (EQ-5D) is a 5 item assessment of health status measuring mobility, self-care, usual activity, discomfort or pain and depression or anxiety.; Self-care subscale is a range of 1-3, with a higher score indicating more dysfunction.	baseline
Primary	Usual Activity as measured by the EuroQOL-5 Dimensions	EuroQOL-5 Dimensions (EQ-5D) is a 5 item assessment of health status measuring mobility, self-care, usual activity, discomfort or pain and depression or anxiety.; Usual Activity subscale is a range of 1-3, with a higher score indicating more dysfunction.	baseline
Primary	Discomfort as measured by the EuroQOL-5 Dimensions	EuroQOL-5 Dimensions (EQ-5D) is a 5 item assessment of health status measuring mobility, self-care, usual activity, discomfort or pain and depression or anxiety.; Discomfort subscale is a range of 1-3, with a higher score indicating more dysfunction.	baseline
Primary	Depression/Anxiety as measured by the EuroQOL-5 Dimensions	EuroQOL-5 Dimensions (EQ-5D) is a 5 item assessment of health status measuring mobility, self-care, usual activity, discomfort or pain and depression or anxiety.; Depression/Anxiety subscale is a range of 1-3, with a higher score indicating more dysfunction.	baseline
Primary	Qualify of life as measured by Medical Outcome Study - Short Form 36	Medical Outcome Study - Short Form 36 (MOS-SF-36) is a questionnaire that measures patient self-reported quality of life. Eight subscales are measured including physical function, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional wellbeing, social functioning, pain and general health. Scores for each subscale range from 0 - 100, with 100 being better perceived health and 0 being worst perceived health.	baseline
Primary	Anxiety as measured by the Hospital Anxiety and Depression Scale	Hospital Anxiety and Depression Scale (HADS) is a 14 item assessment which includes 7 questions for anxiety and 7 questions for depression, which are summed separately for a total score for each. HADS classifies scores 0-7 as normal; 8-10 as borderline abnormal (borderline case); 11-21 as abnormal case.	baseline
Primary	Depression as measured by the Hospital Anxiety and Depression Scale	Hospital Anxiety and Depression Scale (HADS) is a 14 item assessment which includes 7 questions for anxiety and 7 questions for depression, which are summed separately for a total score for each. HADS classifies scores 0-7 as normal; 8-10 as borderline abnormal (borderline case); 11-21 as abnormal case.	baseline
Primary	Distress is measured by the Impact of Event Scale	Impact of Event Scale - Revised (IES-R) is a 22-item self-report measure that assesses subjective distress caused by traumatic events. Respondents are asked to identify a specific stressful life event and then indicate how much they were distressed or bothered during the past seven days by each "difficulty" listed. Items are rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely"). The IES-R yields a total score (ranging from 0 to 88) and subscale scores can also be calculated for the Intrusion, Avoidance, and Hyperarousal subscales.	baseline
Primary	Functional Status as measured by Activities of Daily Living	Activities of Daily Living (ADL) (Katz, 1970) is an index to assess functional status of basic activities of independent living. There are six functions measured, bathing, dressing, toileting, transferring, continence and feeding. Summary scores range from 0 (low function, severe functional impairment) to 6 (full function).	baseline
Primary	Independence measured by Instrumental Activities of Daily Living	Instrumental Activities of Daily Living (IADL) (Lawton, 1969) is an instrument to access independent living skills. These skills are considered more complex than the basic activities measured by the Katz ADL scale. There are eight categories, ability to use a telephone, shopping, food preparation, housekeeping, laundry, mode of transportation, responsibility for own medications, ability to handle finances. Summary scores range from 0 (low function, dependent) to 8 (high function, independent).	baseline
Primary	Sleep Quality as measured by Pittsburgh Sleep Quality Index	Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1 month-time interval. Minimum Score = 0 (better); Maximum Score = 21 (worse). Interpretation: Total < 5 associated with good sleep quality. Total > 5 associated with poor sleep quality.	baseline
Primary	Strength as measured by using hand grip dynamometry	Maximum strength will be measured using a hand grip dynamometer.	baseline
Primary	Growth hormone as measured by Glucagon Stimulation Test before glucagon administration	Growth hormone secretion will be measured using the glucagon stimulation test. Serum will be collected for the baseline (time: 0 minutes) to test for levels of human growth hormone. 1 mg glucagon (for subjects over 90 kg, 1.5 mg glucagon) will be injected intramuscularly (IM) in the deltoid muscle of the subject and blood will be drawn at specified time points.; Results will be reported as ng/mL.	Before glucagon administration
Primary	Growth hormone as measured by Glucagon Stimulation Test 90 minutes after glucagon administration	Growth hormone secretion will be measured using the glucagon stimulation test. Serum will be collected at time point 90 minutes after glucagon injection to test for levels of human growth hormone.; Results will be reported as ng/mL.	90 minutes after glucagon administration
Primary	Growth hormone as measured by Glucagon Stimulation Test 120 minutes after glucagon administration	Growth hormone secretion will be measured using the glucagon stimulation test. Serum will be collected at timepoint 120 minutes after glucagon injection to test for levels of growth hormone.; Results will be reported as ng/mL.	120 minutes after glucagon administration
Primary	Growth hormone as measured by Glucagon Stimulation Test 150 minutes after glucagon administration	Growth hormone secretion will be measured using the glucagon stimulation test. Serum will be collected at timepoint 150 minutes after glucagon injection to test for levels of growth hormone.; Results will be reported as ng/mL.	150 minutes after glucagon administration
Primary	Growth hormone as measured by Glucagon Stimulation Test 180 minutes after glucagon administration	Growth hormone secretion will be measured using the glucagon stimulation test. Serum will be collected at timepoint 180 minutes after glucagon injection to test for levels of growth hormone.; Results will be reported as ng/mL.	180 minutes after glucagon administration
Primary	Basal Metabolic rate as measured by Resting Energy Expenditure	Resting Energy Expenditure will be measured by capturing the expired breath of subjects while at rest with a metabolic cart over a 30 minute time period. Data from the first 5 minutes will be discarded and the remaining 25 minutes of data will be averaged to calculate the resting energy expenditure. Data will be reported as kilocalories/day; Procedure will be performed on PASC subjects only.	baseline
Primary	Cortisol as measured by the adrenocorticotropic hormone stimulation test (ACTH) before cortrosyn administration	Cortisol secretion will be measured using the ACTH stimulation test. Serum will be collected for the baseline (time: 0 minutes) to test for levels of cortisol. 0.25 mg Cortrosyn will be administered and additional serum (3.5 mL) will be collected at specified time points.; Results will be reported as ug/dL. Procedure will be performed on PASC subjects only.	Before Cortrosyn administration
Primary	Cortisol as measured by the adrenocorticotropic hormone stimulation test (ACTH) 30 minutes after cortrosyn administration	Cortisol secretion will be measured using the ACTH stimulation test. Serum will be collected at time point 30 minutes after Cortrosyn administration to test for levels of cortisol. Procedure will be performed on PASC subjects only.; Results will be reported as ug/dL.	30 minutes after Cortrosyn administration
Primary	Cortisol as measured by the adrenocorticotropic hormone stimulation test (ACTH) 60 minutes after cortrosyn administration	Cortisol secretion will be measured using the ACTH stimulation test. Serum will be collected at time point 60 minutes after Cortrosyn administration to test for levels of cortisol.; Results will be reported as ug/dL. Procedure will be performed on PASC subjects only.	60 minutes after Cortrosyn administration
Primary	Cognitive Function as measured by Montreal Cognitive Assessment	The Montreal Cognitive Assessment (MoCA) will be used to assess cognition.; The Montreal Cognitive Assessment (MoCA) is a rapid assessment of cognition. The MoCA consists of 9 questions with the following subcategories: visuospatial/executive, naming, memory, language, abstraction, delayed recall and orientation. The MoCA has been used extensively to detect cognitive impairment in many conditions, including head trauma. Version 7.1 will be used. Scores range from 0 to 30, higher score being a better outcome.	baseline
Primary	Walking as measured by 6 minute walk test	Walking performance will be assessed in subjects during 6 minutes of walking in long corridor hallways. This is a standard test of walking performance that has been validated in similar studies. Subjects will be asked to walk at a 100% effort. Results will be reported as total distance traveled in meters (m). Procedure will be performed on PASC subjects only.	baseline
Primary	Fatigue as measured by the Multidimensional Fatigue Symptom Inventory	Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) from the Moffitt Cancer Center, University of South Florida The MFSI-SF is a 30 question assessment designed to assess the principal manifestations of fatigue.; There 5 subscales used to calculate a total score. The subscales are: General Fatigue, Physical Fatigue, Emotional Fatigue, Mental Fatigue, and Vigor (an estimate of the patient's energy level). The total score is calculated with the equation: (general + physical + emotional + mental) - vigor = total score.; The range of the total score is -24 to 96, with the higher the number meaning more fatigue.	baseline
Primary	Symptoms of Growth Hormone Deficiency measured by the questionnaire Quality of Life - Assessment of Growth Hormone Deficiency in Adults	Symptoms of growth hormone deficiency will be measured using the Quality of Life - Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). This 25-item questionnaire measures specific symptoms associated with growth hormone deficiency, with a score range of 0 to 25, with a higher score indicating worse symptoms.	baseline
Primary	Depression measured by the Beck Depression Inventory-II	The Beck Depression Inventory- II (BDI-II) assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of "3" indicating a severe symptoms and a score of "0" indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: =13 = minimal; 14-19 = mild; 20-28 = moderate; = 29 = severe.	baseline
Primary	Gastrointestinal Health measured by the Gastrointestinal Symptom Rating Scale	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome).	baseline