Hallie Levine March 14, 2024

About 7% of US adults report having or having had symptoms of long COVID such as fatigue, heart palpitations and/or dizziness. These are three of the 12 symptoms identified as part of the National Institute of Health's RECOVER initiative that can be reliably used to classify someone as having long COVID.

While there is no standard federally approved treatment for long COVID, physicians can recommend several strategies to their patients to help them recover.

The good news is that many people experience improvements in their symptoms over time by adopting these strategies, said Andrew Schamess, MD, an internal medicine physician at the Ohio State University Wexner Medical Center and director of its Post-COVID Recovery Program. 

1. Pace yourself.
Fatigue and postexertional malaise are two of the 12 symptoms used to classify someone as having long COVID. 

"There's mental, or cognitive, fatigue, where people become exhausted after any span of time trying to do complicated cognitive tasks," said Schamess. "There's also general fatigue, or sleepiness, where after a few hours you feel like you could go right back to sleep." 

The third category, he added, is postexertional malaise, where patients are exhausted by exercise, either immediately or up to 24-48 hours later. 

That's where a technique known as "pacing" can help. Pacing is an energy-conservation technique often used among people with other disabling conditions, such as chronic fatigue syndrome, said Ravindra Ganesh, MD, an internal medicine physician at the Mayo Clinic in Minnesota who specializes in long COVID.

"I tell patients that they have to figure out what their energy envelope is, which is the fixed amount of energy that they can use every day without crashing," he said. 

You may be able to handle a daily 30-minute walk, for example, but if you pair it with something cognitively difficult, such as doing your taxes, your fatigue symptoms may flare up. 

"It's hard advice for my patients to follow, as most are real go-getters," he said. "But I point out to them that if they aim to minimize crashes, it will help them make slow progress."

Over time, he said, their energy levels should gradually rise so that they can engage in more and more activity.

2. Follow a plant-based, anti-inflammatory diet.
There's no research to suggest that following a certain eating pattern will help to reverse long COVID, said Ganesh. But in general, he said his patients anecdotally report that they feel better when they limit refined sugar and follow a plant-based diet that can help to lower inflammation in the body. 

"It makes sense, because it prevents dramatic blood glucose changes that can cause their body to crash," he said. He generally recommends an anti-inflammatory diet like the Mediterranean diet, which is rich in fruits, vegetables, whole grains, and monounsaturated fat.

Many people with long COVID take an array of supplements, Ganesh said, although there's little research to suggest that they may help. He does encourage patients to take about 2 g of an omega-3 supplement, such as fish oil, as it may help to reduce inflammation associated with long COVID. 
He also recommends fisetin, a dietary flavonoid found in fruits like strawberries and kiwis. Preliminary research suggests that it may help to combat some of the neurologic damage associated with long COVID. 

"It appears to maintain mitochondrial function and has anti-inflammatory activities," said Ganesh.

3. Modify exercise. 
Most of the time, exercise boosts health and reduces risk for certain diseases. But this strategy may not work for people who have certain symptoms from long COVID, such as postexertional malaise or postural orthostatic tachycardia syndrome (POTS), a condition that causes symptoms such as a fast heart rate, dizziness, and fatigue when transitioning from lying down to standing up. 

"With long-COVID patients, it often has to be symptom-titrated exercise," said Schamess. This means physical activity needs to be constantly monitored and adjusted on the basis of a patient's symptoms. "We need to figure out what they can do that doesn't provoke their symptoms," he explained. 

Schamess often recommends that patients with long COVID, at least initially, focus on exercises in which they are sitting (such as cycling) or prone. 

"The key thing is most people with long COVID can do a lot more exercise in a sitting or lying position than a standing position," he said. "It's baffling to them that they can't walk two blocks but can bike 10 miles." 

For symptoms like fatigue or postexertional malaise, Schamess often refers patients to physical therapy to develop an individualized exercise program. A 2022 study published in Scandinavian Journal of Medicine & Science in Sports found that when long-COVID patients completed an 8-week program of three exercise sessions per week, they experienced significant improvements in quality of life, fatigue, muscle strength, and overall fitness compared with a control group. 

"It's important to make sure that workouts are supervised, so that they can be modified as necessary" said Schamess. 

4. Take steps to improve sleep quality.
A 2023 study published in the Journal of General Internal Medicine found that about 40% of people with long COVID report sleep issues such as insomnia or not feeling refreshed in the morning. 

"Sleep may become challenging, which can be frustrating for a patient with long COVID who desperately needs rest," said Lawrence Purpura, MD, an infectious disease specialist and director of the long COVID clinic at Columbia University Medical Center in New York City.

Some of the simplest ways to improve sleep are common sense; however, these issues never affected the person pre-COVID, so they have to become new habits.

"A lot of my patients with long COVID find that they are more sensitive to caffeine, so they really can't have it anymore later in the day," he said. "The same goes for bright screens" such as those on cell phones, tablets, and e-book readers, he said. "They may find that it's harder for them to fall and stay asleep if they're on their iPhone right before bed. These are all things that may not have been issues before they were diagnosed with long COVID."

Purpura also said that he encourages his patients to practice mindfulness or relaxation exercises before bed, such as deep breathing. One technique he recommends is called box breathing, where the patient inhales for 4 seconds, holds his or her breath for 4 seconds, exhales for 4 seconds, then holds his or her breath again for 4 seconds. Some research suggests that this paced breathing technique, when done for 20 minutes before bed, helps to improve symptoms of insomnia. 

While sleep medications such as zolpidem (Ambien) are often used as short-term relief for insomnia, Schamess said he has not found them particularly helpful for sleep issues that stem from long COVID. 

"They help patients fall asleep but not necessarily stay asleep, which can be an issue for people with long COVID," he said.

5. Consider medications.
No standard drugs or treatments have yet been approved to treat long COVID (although some, like Paxlovid, are in clinical trials). But some medications may help to relieve symptoms, said Ganesh. These include:

• Blood pressure drugs such as beta-blockers now used to treat POTS symptoms
• Nerve-pain medications such as gabapentin or pregabalin. "These can also help with sleep, since patients don't have pain to distract them," said Ganesh.
• Low-dose naltrexone to help with fatigue

"There's not a one-size-fits-all approach to treat long-COVID symptoms," said Ganesh. "You really need to work with the patient and possibly even cycle through several different medications before you find one that helps." 

Ralph Ellis
March 11, 2024 - Medscape

Scientists at the University of California San Francisco have discovered that remnants of the COVID-19 virus can linger in blood and tissue for more than a year after a person is first infected.

In their research on long COVID, the scientists found COVID antigens in the blood for up to 14 months after infection and in tissue samples for more than 2 years after infection.

"These two studies provide some of the strongest evidence so far that COVID antigens can persist in some people, even though we think they have normal immune responses," Michael Peluso, MD, an infectious disease researcher in the UCSF School of Medicine, who led both studies, said in a statement.

Scientists don't know what causes long COVID, in which symptoms of the illness persist months or years after recovery. The most common symptoms are extreme fatigue, shortness of breath, loss of smell, and muscle aches.

The UCSF research team examined blood samples from 171 infected people and found the COVID "spike" protein was still present up to 14 months after infection in some people. The antigens were found more often in people who were hospitalized with COVID or who reported being very sick but were not hospitalized.

Researchers next looked at the UCSF Long COVID Tissue Bank, which contains samples donated by patients with and without long COVID.

They found portions of viral RNA in the tissue up to 2 years after people were infected, though there was no evidence of reinfection. Those viral fragments were found in connective tissue where immune cells are, suggesting that the fragments caused the immune system to attack, according to the researchers.

The UCSF team is running clinical trials to find out if monoclonal antibodies or antiviral drugs can remove the virus.

The findings were presented in Denver this week at the Conference on Retroviruses and Opportunistic Infections.
​
SOURCES:
EurekAlert: "COVID-19 virus can stay in the body more than a year after infection."
University of California San Francisco: "First Tissue Bank May Help Solve Mystery of Long COVID Misery."

Medscape Internal Medicine © 2018  WebMD, LLC 
Cite this article: 'Chronic Fatigue Syndrome' Takes Down Doctors, Too - Medscape - Jun 28, 2018.
A Complex and Poorly Understood Illness
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Gary Solomon, MD, was performing a routine facelift in 2012 when his career-ending event occurred. "For about 10-15 seconds, I kind of spaced out and got lost. No one noticed. I came back to normal, finished the surgery, and quit that day. I realized that I was dangerous and couldn't work anymore."
Solomon, who was then chief of surgery and director of the Wound Healing Center at Long Beach Memorial Medical Center in California, had been ill on and off for about a decade. It all started in 2002, when he developed brachial plexus neuritis that presented with sudden acute shoulder pain and weakness in the upper extremities.
The viral infection resolved in a few months, but he then began experiencing other distressing symptoms: a severe upper respiratory infection that persisted for months, paresthesias, dizziness, gastrointestinal symptoms, and brain fog. He took some time off, but when he returned, he could often only work half-days or needed long breaks to lie down. "It seemed like all my body functions were failing me," says Solomon.
Research on his symptoms pointed him to a complex and poorly understood illness called "chronic fatigue syndrome," now known as "myalgic encephalomyelitis/chronic fatigue syndrome" (ME/CFS). But his neurologist didn't buy it. "He told me, 'We don't believe in this disease.' I thought that was weird, because I'm a pretty straight shooter, and he was somehow implying that I was crazy."
Other Patient Stories
Mark Vink, MD, was a practicing family physician in Amsterdam for 20 years—and before that, a Dutch national field hockey champion—before contracting pneumonia from a patient and then developing ME/CFS. He has been bedridden since 2005, as is 1 in 4 patients with ME/CFS.
"I don't have the muscular strength to sit, stand, or walk, and I suffer from hypersensitivity to light and sound. I spend my days in a dark and quiet room. I also suffer from muscle pain, cognitive dysfunction, et cetera," he says.
Dr X, an internist, had been practicing medicine for 5 years before she became ill. Her case was fairly typical. She'd been in excellent health before experiencing a series of nonspecific, infection-like events over several months. She'd often feel as if she were coming down with the flu, with such symptoms as sore throat, exhaustion, headache, and muscle and joint aches. She worked between episodes until she was no longer able to do so.
Dr Y's illness began before she entered medical school in 1994. Helped by a remission in 1997 that brought her energy levels to "about 80% of normal," she completed several specialty rotations, a residency in anesthesiology, and a fellowship in pain medicine. She accepted a position in another state and relocated with her husband. But, "When I finally started my new job, I knew at the end of day 1 that I could not do it. I had crashed. My remission was over."
 
Diagnosis Based on Symptoms
In 2015, the Institute of Medicine (IOM) published a landmark report intended to encourage physicians to diagnose ME/CFS and address patient symptoms to the best extent possible. The IOM defined ME/CFS as 6 months of unexplained fatigue with substantial functional impairment, postexertional malaise, unrefreshing sleep, and cognitive dysfunction or orthostatic intolerance.[1] The symptoms must be moderate to severe and present at least 50% of the time. The report also proposed a new name for the condition, "systemic exertion intolerance disease," which has not been widely adopted.
 
The IOM clinician guide has not been broadly disseminated in the medical community, but that could soon change. This summer, the Centers for Disease Control and Prevention is expected to revise its information on ME/CFS for healthcare providers to incorporate the IOM diagnostic criteria. In addition, upcoming clinical guidelines are currently in development after an expert clinician summit held earlier this year.
For now, diagnosis is based on patient-reported symptoms because specific diagnostic biomarkers have yet to be identified, but research has been yielding clues.
 
Research Suggests Biomarkers
In 2015, Vink measured and found that his own blood lactate levels were significantly elevated after an exercise challenge that would be considered trivial for healthy people: walking 5-6 yards from his bed to the bathroom, using the toilet, washing his hands, and walking back to bed.[2] Other studiesof patients with ME/CFS have also demonstrated elevated lactate levels.
Vink's conclusion: "In severe ME, both the oxidative phosphorylation and the lactic acid excretion are impaired, and the combination of these two is responsible for the main characteristic of ME: the abnormally delayed muscle recovery after doing trivial things."
Notable recent findings in patients with ME/CFS include alterations in circulating cytokines[3] and other immune markers,[4] metabolic pathway abnormalities consistent with a hypometabolic syndrome,[5] disturbances in fatty acid and lipid metabolism,[6] and evidence of autoimmunity.[7]
Recently launched research efforts funded by the National Institutes of Health (NIH) include an in-house study on postinfectious ME/CFS and a new consortium of collaborative research centers.
The fiscal year 2017 NIH funding of approximately $15 million for ME/CFS research was about double that of previous years,[8] but ME/CFS advocates are now petitioning for much more.
Other research is supported by private funds. The End ME/CFS Project of the Open Medicine Foundation (OMF) is led by Stanford University geneticist Ronald W. Davis, PhD, whose adult son is incapacitated with ME/CFS. The OMF scientific advisory board includes three Nobel laureates.
On May 23, 2018, the OMF announced that it has funded $1.8 million for the establishment of a new ME/CFS Collaborative Research Center at the Harvard Medical School-affiliated hospitals.
Until these efforts bring answers, however, patients will continue to struggle to find physicians who are able to diagnose ME/CFS and help patients manage the illness.
Management and Self-care: Where Are They Now?Today, Solomon runs a nonprofit website called Phoenix Rising, which supports people with ME/CFS. Once an avid skier, he now indulges only once in a while, with the full knowledge that he'll "crash" afterward for days or weeks—the hallmark postexertional malaise associated with ME/CFS. "I call it the price of admission," he says.
Dr X estimates that she is currently functioning at about 30% of where she was before her illness, with postexertional malaise her most disabling symptom. "If I try to exert myself beyond my limits cognitively or physically...I can become sicker immediately or a few hours later and remain sick for several hours or days," she says, noting that by "sicker," she means an exacerbation of all the same flulike symptoms she has had since she first became ill.
As do many patients, Dr X practices "pacing" by monitoring her activity and taking care not to exceed her own threshold for exertion. By doing so, "I still feel sick but am able to get some things done, such as shopping for groceries or reading an article. Most days, I stay home and have to be careful about outings, because they tend to take more energy."
 
Dr Y has been working part-time as a locum tenens since her remission ended 9 years ago. "The days I work are often long. I only allow myself to work 4 days in a row, and after the fourth, I crash hard. It takes me a week or two to recover."
She has told some of her colleagues about her illness, but "I don't think they really grasp how ill I am or how hard it is for me to work. I try very hard not to show it when I'm working."
What Physicians Should Know About ME/CFS
In retrospect, Solomon realized that his mother, who died of complications of Takayasu arteritis—a rare, systemic, inflammatory large-vessel vasculitis—probably also had ME/CFS. He also has a brother with the illness and another brother who died of multiple sclerosis. Solomon admits that before becoming ill himself, he thought that his mother and brother with ME/CFS were "rather histrionic."
He now advises his fellow physicians to listen to their patients and use their general medical knowledge to treat the symptoms. If a patient complains of dizziness, do an orthostatic test. Work with patients to address sleep problems. The disease has no cure, but physicians can validate patients so they don't feel like they're crazy or seek alternative care.
Asked what he would like other physicians to know about ME/CFS, Vink responded "...that this is a debilitating neuroimmune disease, which has got nothing to do with being tired."
Dr X says that in contrast to widespread misconception, "This is not a psychiatric or psychological illness that can be cured by positive thinking or mere deconditioning that can be cured by aerobic exercise." In fact, "incautious exercise or activity can harm patients."
She also points out that patients with ME/CFS are often too ill to leave home, so when they are able to keep medical appointments, it is because they are feeling relatively well and not at their worst.
"Don't judge ME/CFS patients as healthy merely by the way they look or act during a clinic appointment. When you see them...they might look fine or seem normal in their function. What you don't see is the preparation before their appointment [by avoiding prior exertion] and the postexertional symptoms after the visit. So consider asking your patients what happens before and after their visits."
Basic Laboratory Testing Doesn't Tell You Enough
Subsequent test results for Dr Y have revealed Bartonella infection, probable late-stage Lyme disease, mast cell activation syndrome, Lambert-Eaton myasthenic syndrome, and common variable immunodeficiency.
"Many of us have been taught that if the [laboratory results] are normal, the patient is fine. The problem is...our basic labs are...crude instruments. If it weren't for my anemia, if you did a basic [complete blood count] and [basic metabolic panel] on me, you might conclude that I was healthy," she says.
It wasn't until recent years, "as my immune system finally succumbed, that evidence showed up on a [comprehensive metabolic panel]: low protein and low globulin. You have to do much more sophisticated testing, and then all kinds of scary things [might] show up, such as profoundly depressed immune systems, inflammatory markers, and strange autoantibodies. On many patients, a tilt-table test will reveal [postural orthostatic tachycardia syndrome]. But none of this will be evident if you don't suspect and you don't look."
Dr Y doesn't know how much longer she will be able to practice medicine. "But for now, I refuse to let go because my profession gives me fulfillment. When I am working to ease others' pain, I can forget about mine for a little while."
 
The physicians quoted in this article have disclosed norelevant financial relationships.

CDC to Start Tracking Ticks as Diseases Rise
WebMD Health News © 2019
Bara Vaida
March 28, 2019
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The CDC for the first time will be monitoring the nation's tick population and the diseases the pests may be carrying.
The effort comes as the number of people diagnosed with serious diseases caused by things like ticks, fleas, and mosquitoes has more than doubled over the past few decades. Ticks caused the vast majority of those diseases.
Its aim is to assess where Americans might be most likely to get a tick-borne illness.
"For the first time this year, the CDC is funding states to conduct widespread surveillance of ticks and the pathogens they can transmit, in addition to funding human disease surveillance and education and prevention," says Anna Perea of the National Center for Emerging and Zoonotic Infectious Diseases' Division of Vector-Borne Diseases. "Taken together, the data can help define areas where ticks are spreading, the infectious pathogens that they carry, and where risk of tick-borne disease is increasing."
Richard S. Ostfeld, PhD, a disease ecologist with the Millbrook, NY-based Cary Institute of Ecosystem Studies, called the CDC's step "great news."
"The CDC will be able to paint a picture of where risk is occurring, and it will provide us with better data than we have ever had before with geographic coverage of the ticks, where they are moving, and how infection prevalence is changing," he says.
In 2017, the number of tick-borne disease cases reported to the CDC rose 22%, to 59,349. But the number of Americans with tick-related diseases was likely much higher — closer to 300,000 to 400,000 — because not all Lyme disease cases are reported to the CDC, says John Aucott, MD, chairman of a national tick-borne disease working group, supported by the U.S. Department of Health and Human Services.
"It is hard to predict what will happen in any given year, but the long-term trends are obvious," says Aucott, who's also director of the Johns Hopkins Lyme Disease Clinical Research Center. "There are more tick-borne disease [cases] every year."
The most common illness caused by a tick bite is Lyme disease. In 2017, there were 42,743 cases of Lyme disease, up 17% from 2016, according to the CDC. Lyme represented 72% of all tick-borne diseases reported in 2017. Ticks carry other diseases, such as anaplasmosis, ehrlichiosis, Rocky Mountain spotted fever, babesiosis, tularemia and Powassan virus, but these diseases are rarer than Lyme.
Lyme is carried by the blacklegged tick (also called the deer tick) and traditionally was found in the Northeast, mid-Atlantic, North-Central U.S., and parts of Northern California. People living in these regions had been the most at risk of contracting Lyme, says Aucott. Now, the blacklegged tick is found in more than half the country.
"In 1996, we used to say no Lyme disease south of the Potomac [River, which separates Washington, D.C., from Virginia and Maryland]," says Aucott. "But it has moved south. It has spread to west of the Pennsylvania border, and to Michigan and surrounding states."
Ticks are spreading across the country for many reasons, experts say. They include changing land use, destruction of forest, residential building near woods, and the warming climate, says Ostfeld. The institute forecasts how severe tick season will be in the Northeast.
"Traditionally, May has been Lyme disease awareness month in preparation for June [when ticks are at the height of feeding]," he says. "But I have been advocating for Lyme disease awareness month to begin in April because ticks are out in full force in May. People need to be aware, ticks are coming out earlier in the year, advancing the dates of greatest risk."
Ostfeld predicts 2019 will be an "average" to "slightly below average" tick season. Still, he says the risk for becoming ill from Lyme disease is the same as in previous years. His forecast is based on the region's population of white-footed mice, which carry the bacteria that cause Lyme and are a favorite tick host. Ticks need blood to live and tend to feed in May, June, September, and October, making these months among the riskiest times of the year for contracting a tick-borne disease, says Aucott.
This year, public health officials are also warily watching the growing range of a new tick species — the Asian longhorned tick — first reported in New Jersey in 2017. The tick doesn't need a mate to reproduce and has already spread to at least nine states, mostly in the Northeast and mid-Atlantic. Though the tick hasn't yet been found to carry a pathogen dangerous to humans, it has carried potentially deadly diseases in other countries.
"The Asian longhorned tick has everyone very concerned," says E. Oscar Alleyne, DrPH, chief of programs and services for the National Association of County and City Health Officials. The organization represents local health officials charged with disease prevention.
"It is new, invasive, and shouldn't be here...and has the potential to be yet another tick that could wreak devastation," Alleyne says.
Public health officials say the best way to prevent a tick-borne disease is to cut the chances of getting bitten. Here are some of their tips:

• Limit exposure to tall grass, and walk in the center of trails. Ticks hang on to the edge of grass and latch onto your body when you walk by.
• Mow the lawn frequently. Remove leaf litter and tall grass brush from around your home and the edge of your yard.
• When hiking, gardening, and spending time in the outdoors, wear long pants and socks treated with permethrin — a chemical used to treat lice in children — to ward off ticks. Many outdoor companies now sell clothing already treated with this chemical. You may also use a bug repellent like DEET. The CDC has a list of approved insect repellents
• Once you've been outside where ticks might live, do a full body check when you go back inside. Throw your clothing into a dryer turned to high heat for 10 minutes. The dryer will kill the ticks.
• If your pet goes outdoors, use tick collars, spray shampoos, and medications to prevent ticks. Also check your pet for ticks when they return inside. Don't sleep with your pet.

Be aware of what ticks look like so you can detect them. If you find a tick, remove it with tweezers. If you get a rash (and often it won't look like the typical "bull's-eye" rash), call your health care provider right away. If treated early, you can prevent Lyme disease.
SOURCES:
Anna Perea, policy and communications lead, Bacterial Diseases Branch, National Center for Emerging and Zoonotic Infectious Diseases' Division of Vector-Borne Diseases, CDC.
CDC: "Vital Signs: Trends in Reported Vectorborne Disease Cases — United States and Territories, 2004-2016."
CDC: "Lyme Disease Maps: Historical Data."
CDC: "What you need to know about Asian longhorned ticks — A new tick in the United States."
E. Oscar Alleyne, DrPH, chief of programs and services, National Association of County and City Health Officials.
John Aucott, MD, director, Johns Hopkins Lyme Disease Clinical Research Center.
Richard S. Ostfeld, PhD, disease ecologist, Cary Institute of Ecosystem Studies.
 

Adrenal Fatigue: 'Just a Myth'?
John Watson 
March 07, 2019
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Fatigue, anxiety and depression,body aches, muscle weakness, mood swings, and trouble concentrating—every clinician has encountered patients presenting with such nonspecific symptoms, a frustrating starting point to any clinical investigation. Depending on the nature of the complaints, physicians may find themselves with thousands of potential culprits to rule out, from the benign to the potentially life-threatening.
Patients suffering from these chronic symptoms may sit through seemingly unending consultations, only to walk away with no satisfying diagnosis. It's a scenario that has long been fertile ground for pseudoscience, which gallantly swoops in to offer certainty in the guise of newly minted conditions.
In endocrinology, this timeworn narrative has seen its most recent occurrence in the emergence of adrenal fatigue, a condition that mainstream medicine almost uniformly agrees does not exist, at least as it's commonly described.
Yet like so many other areas of modern life, scientific certainty has not proven to be the panacea it once was. Adrenal fatigue has been particularly immune to counterarguments, as evidenced by the growing cottage industry of supplements and off-label treatments meant to treat it, despite their carrying very real health risks.
This has led some to question whether simply labeling adrenal fatigue a "myth" is having the unintended effect of making patients feel unheard, pushing them further into the hands of dubious practitioners.
A Diagnosis Out of Step With the Evidence
The diagnosis of adrenal fatigue is attributed to James L. Wilson, DC, ND, PhD, a naturopath and chiropractor who deemed it "the 21st century stress syndrome" in a 2001 book of the same name.
Wilson and others describe adrenal fatigue as a consequence of sustained stress (physical, emotional, or mental), which they posit leads to diminished functioning of the adrenal gland and depleted cortisol levels, resulting in a constellation of symptoms, including exhaustion, impaired concentration, irritability, cravings for salty or sweet food, and fluctuations in sleeping patterns and weight.
A collision of marketing, Internet hype, and vocal backing by alternative medicine practitioners raised the profile of adrenal fatigue, and it wasn't long before endocrinologists were confronted with an increasing number of patients seeking treatment for it.
"I probably heard about it for the first time 10 or 15 years ago," said James W. Findling, MD, clinical professor of medicine and surgery, and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. "I was shocked that the theory was that the adrenal glands could somehow fatigue or become hypoactive due to chronic stress or physical illness, since I was quite aware of the fact that the contrary was true."
As Findling outlined in a 2018 presentation at the Endocrine Society's Clinical Endocrinology Update meeting, adrenal function actually responds to stress by producing more, not less, cortisol, an effect that has been noted in conditions ranging from HIV to post-traumatic stress disorder. In addition, chronic fatigue syndrome (perhaps the most conceptually similar condition) has never been shown to have significant impairment of pituitary adrenal function.
He added that "many endocrinopathies have a variety of nonspecific clinical signs and symptoms, which often puzzle patients and their providers. The nice thing about endocrine disorders, including adrenal insufficiency and thyroid hormone deficiency and excess, is that there are specific and relatively well-defined biochemical markers and tests that can be done that provide evidence of the adequacy of hormone function."
This is not the case with adrenal fatigue, as was reported in a 2016 systematic literature review in which the authors scrutinized nearly 60 studies analyzing cortisol levels and the adrenal axis in this condition. They concluded that the studies offered consistently conflicting results and inappropriate conclusions made on the basis of highly flawed designs that used unsubstantiated cortisol assessments.
The Dangers of Toxic, 'Natural' Treatments
Even as the mainstream endocrinology community has mounted a robust critique of adrenal fatigue's rising profile, debunking the shoddy biology on which it is based in the form of review commentaries and position papers from professional societies, it is commonly accepted that patients diagnosed with this disorder are nonetheless being treated at disconcertingly high numbers.
This can leave patients susceptible to significantly more deleterious symptoms than those for which they originally sought therapy.
The most commonly prescribed treatment for adrenal fatigue is probably corticosteroids, which can provide a false sense of improvement in the short term, with euphoric responses in the wake of its administration.
The trouble comes when corticosteroids are given for chronic conditions, as long-term use, even at moderate doses, has been shown to contribute to a variety of adverse health effects, including psychiatric conditions, ]glaucoma,  metabolic disorders, and cardiovascular diseases.
Findling witnessed the dangers of this off-label intervention firsthand while treating a patient who had received corticosteroids from another practitioner for adrenal fatigue—and developed avascular necrosis of the hip shortly thereafter.
"It illustrates that even relatively low doses of steroids can be quite harmful in normal subjects. It's not innocuous."
Like many, Findling had assumed that the other popular treatment for adrenal fatigue—supplements widely available online and in brick-and-mortar shops—were harmless placebos, but this notion was upended by a publication released last year.
All [tested supplements] contained detectable amounts of the thyroid hormone triiodothyronine (T3), and most at least one steroid hormone.
According to its lead author, Halis Kaan Akturk, MD, assistant professor of medicine and pediatrics at the University of Colorado School of Medicine, the idea for the study came from his own experience treating patients with fatigue.
"The first thing I noticed was that patients presenting with fatigue who were also using some unusual supplements had hormonal abnormalities in their labs," Akturk said. "I suspected that the supplements were the culprit, because after they were discontinued, the labs were normal."
Selecting 12 best-selling supplements from a well-known online website, he and his colleagues set about testing their contents, which were advertised as being "natural" and able to "restore energy," among other nonthreatening claims.
Instead, their research found that all contained detectable amounts of the thyroid hormone triiodothyronine (T3), and most at least one steroid hormone.
Akturk said that although the observed levels of these hormones were relatively low, there were notable variations among the products, and sometimes among the pills contained in a single bottle. He noted that these hormones in excess can cause a host of problems, from heart arrhythmias and fertility issues to a complete shutdown of the adrenal glands, with possibly life-threatening consequences.
 
For sure, some of those in the over-the-counter industry promote adrenal fatigue because it is a money-making tool," he said. "You can sell anything easily in the United States if you use some key catchy words such as 'organic,' 'herbal,' 'natural,' 'plant-based,' etc. It gives a sense of false reassurance."
What Is the Real Diagnosis?
Akturk is adamant that the discussion about adrenal fatigue should not end with telling your patients that it doesn't exist, which he finds to be an ineffective approach.
"I would rather investigate in further detail other explanations for fatigue, such as an organic or other commonly missed cause, like obstructive sleep apnea, depression, or fibromyalgia," he said.
Findling also stressed the importance of taking patient complaints seriously, ruling out possible adrenal dysfunction, pulling them away from potential harmful interventions, and targeting the real source. In his own practice, he has found sleep apnea to be the most common underlying source of these symptoms, particularly in overweight patients.
Rashmi S. Mullur, MD, assistant clinical professor in the division of endocrinology, diabetes, and metabolism at the David Geffen School of Medicine at UCLA, and associate chief of integrative medicine at the VA Greater Los Angeles Healthcare System, has given considerable thought to how to approach patients reporting adrenal fatigue.
Saying 'adrenal fatigue doesn't exist' leaves patients feeling unheard, discounted, and disregarded, even with the best-meaning physicians.
"Patients come to us from an emotional and health-and-wellness point of view; they just want to feel better," she said. "Frankly, if we give them a diagnosis that isn't adrenal fatigue because they have something else truly wrong with them, they wouldn't hold on to the notion [that they have adrenal fatigue]."
Mullur has found that the trouble comes when rounds of initial testing fail to reveal a hormonal abnormality.
"We end up saying, 'Well, there's really nothing hormonally wrong with you.' And not only that, but, 'Adrenal fatigue doesn't exist.' It leaves patients feeling unheard, discounted, and disregarded, even with the best-meaning physicians."
As Mullur detailed in a 2018 commentary in the journal Endocrine Practice, she began to dig deeper with these patients, not just asking them to describe their symptoms but also focusing on the timing of their onset.
"No one just wakes up one morning feeling all of these symptoms. They've been building for a while."
She said that this process has more often than not led such patients to report having had traumatic experiences of various sources. This led her to question whether many of these cases are due to neuronal stress responses.
"There have been a thousand studies on cortisol variations during the day in patients with stress, but unfortunately, none of them are really conclusive," she said. "What we do know is that when a brain experiences chronic trauma and stress, the neurons of the limbic system form alternate pathways. Certain areas of the brain 'hyperreact,' where there is extraneuronal agitation, versus other pathways that are blunted, so they don't respond normally."
Mullur would like to see this hypothesis tested in a structured research study of patients reporting adrenal fatigue, in a partnership between neuropsychiatrists and clinical endocrinologists.
Focusing on the Patient, Not the Myth
Mullur advises endocrinologists to keep in mind the example of chronic fatigue syndrome, a condition that was once similarly discredited but which has since gained acceptance despite continued uncertainty regarding its etiology.
She takes umbrage with the ways in which adrenal fatigue is routinely described in the literature, with titles such as "The Myth of Adrenal Fatigue" and "Adrenal Fatigue Does Not Exist."[3] Although these publications contain nuanced arguments for taking patient symptoms seriously, she is afraid that patients will not get beyond the headlines, which may scare them away—not from self-diagnosing as having adrenal fatigue, but from the medical establishment that is their best chance for real improvement.
"I just wish we wouldn't write things like that. We can write it in a better, more patient-centered, respectful way and say that there isn't a hormonal issue, but it doesn't mean that what the patient is saying doesn't exist. It's having the opposite effect and sending patients away from us," she said. "I'd rather have the difficult conversation and make them feel heard so that they don't feel like they need to go looking for pseudoscience elsewhere."
How long will patients wait before moving on to someone who will give them answers, regardless of their scientific validity?
Clinicians and researchers have a challenging task ahead of them. They will need to continue exposing the unsound foundations of adrenal fatigue and the dangers inherent in its treatment. But to be truly successful in delivering patients from the clutches of pseudoscience, they will need to offer patients clear diagnoses for what's ailing them.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood disease affecting 0.2%–2% of the global population. To gain insight into the pathophysiology of ME/CFS in New Zealand, we examined the transcriptomes of peripheral blood mononuclear cells by RNA-seq analysis in a small well-characterized patient group (10 patients), with age/gender-matched healthy controls (10 control subjects). Twenty-seven gene transcripts were increased 1.5- to sixfold and six decreased three- to sixfold in the patient group (P < 0.01). The top enhanced gene transcripts, IL8, NFΚBIA and TNFAIP3, are functionally related to inflammation, and significant changes were validated for IL8 and NFΚBIA by quantitative polymerase chain reaction (qPCR). Functional network analysis of the altered gene transcripts (P < 0.01) detected interactions between the products related to inflammation, circadian clock function, metabolic dysregulation, cellular stress responses and mitochondrial function. Ingenuity pathway analysis (P < 0.05) provided further insights into the dysfunctional physiology, highlighting stress and inflammation pathways. This analysis provides novel insights into the molecular changes in ME/CFS and contributes to the understanding of the pathophysiological mechanisms of the disease.

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Sci Rep. 2018 Jul 3;8(1):10056. doi: 10.1038/s41598-018-28477-9.Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics.  Nagy-Szakal D1, Barupal DK2, Lee B1, Che X1, Williams BL1, Kahn EJR1, Ukaigwe JE1, Bateman L3, Klimas NG4,5, Komaroff AL6, Levine S7, Montoya JG8, Peterson DL9, Levin B10, Hornig M1, Fiehn O11, Lipkin WI12.
After striking that rich vein, the Lipkin group expanded their research effort – incorporating metabolomics for the first time into their studies. (Lipkin and the Simmaron Research Foundation are also currently engaged in the first metabolomics spinal fluid study.) Once again incorporating a wide variety of doctors from different locations (Peterson, Bateman, Klimas, Levine, Montoya) and using a fairly large sample set (n=100) Nagy-Szakal/Lipkin, the Lipkin group fused together blood metabolomic, fecal bacterial metagenomic, and clinical data to paint a new picture of ME/CFS.
The study represented the first attempt to meld two potentially important fields in ME/CFS – metabolomics and gut microbiome findings- together.  Lipkin and Hornig have proposed that the gut issues play an important role in ME/CFS, and several studies have found evidence of dysbiosis (pro-inflammatory gut bacteria) in ME/CFS.  Unutmaz is chasing down a T-cell gut connection, and past studies have suggested that bacterial leakage from the gut could help explain at least some of the post-exertional malaise present.
Given the group’s past gut findings – that significant differences in gut bacteria, immune profiles and possibly energy production exist between ME/CFS + IBS patients and ME/CFS patients without IBS, it made sense for the Lipkin group to once again split the ME/CFS group into subsets with and without IBS and analyze the heck out of them.
Study Results
Energy Production Problems Highlighted
The study confirmed past general findings of decreased levels of phospholipids and sphingomyelins – two important findings by Naviaux- and increased levels of triglycerides (TG’s). (Triglycerides have been associated with metabolic problems and hypothyroidism.)
That both the ME/CFS + IBS group and the ME/CFS without IBS group had reduced levels of metabolites associated with the choline-carnitine energy pathway suggested that both groups had similar core metabolic problems.  (Carnitine participates in the TCA cycle, ATP production and energy metabolism).
More Was Better
The Lipkin group’s decision to integrate metabolomics, microbiome and clinical data worked. Not only did incorporating all this data together illuminate a possibly important subset – the ME/CFS IBS subset – but it also allowed the group to better differentiate ME/CFS patients from controls. It suggested that studies which combine multisystemic data together will do a better job in describing this multisystemic disease.
As with the 2017 study, having or not having IBS was the biggest driver in determining the kind of bacterial profile (and bacterial metabolic pathways) present. This time the study found that the metabolomics of the ME/CFS + IBS group were significantly different from the ME/CFS only group as well. That suggested these two subsets of ME/CFS patients might be quite different indeed.
In contrast to Naviaux, the study did not find a “consistent decrease” in ceramide metabolites – the most commonly disrupted metabolite Naviaux found in his ME/CFS group.  When Lipkin controlled for IBS, he found increased levels of ceramides in the ME/CFS plus IBS group but decreased levels of ceramides in the ME/CFS only group. That suggested that key metabolites in ME/CFS might be different in these two ME/CFS subsets.
Bacterial Toxins Highlighted
Nagy/Lipkin suggested that increased levels of bacterial toxins (IBS connection) in ME/CFS may be triggering an enzyme called sphingomyelinase to produce the ceramides which then may damage the gut lining and possibly interfere with energy production.
Ceramides are waxy fats that figure in a number of processes that may be important in ME/CFS. Not only can they produce many free radicals (reactive oxygen species) that can damage the gut lining (the IBS connection), they can also interfere with electron transport (the energy connection) as well as contribute to insulin and leptin resistance (metabolism issues).
The authors also proposed that the higher mannitol levels found in the ME/CFS could reflect the breakdown of two important barriers in the body: the gut barrier and the blood-brain barrier.
Several studies suggest a breach in the gut barrier could be contributing to systemic inflammation in ME/CFS, and one suggests that exercise may further widen that breach. Several researchers, including Jarred Younger and Avindra Nath, have also postulated that the suspected neuroinflammation in ME/CFS results from immune cells entering the brain through a weakened blood-brain barrier.
The Gut Shines in Distinguishing ME/CFS Patients From Healthy Controls
Interestingly, for all the focus on metabolomics, a network analysis using differences in gut bacterial abundance was better able to distinguish ME/CFS patients from healthy controls than did metabolomic results.
That suggested that gut bacterial differences may be more prominent than metabolomics differences in ME/CFS patients. That was a surprise, and we’ll see how this all turns out. It stands to reason that the closer we get to the core of the problem, the more striking the differences we’ll see between healthy people and people with ME/CFS.  (Will the gut play a bigger role than we thought?)
Possible Treatment Options
The group suggested that their findings, if validated, could present some possible treatment options. They included using SMAse blockers to reduce ceramide levels and giving carnitine supplementation to increase the low levels of metabolites in the choline-carnitine pathway.  One open-label study found that carnitine supplementation helped over half of ME/CFS patients.
Given the unrevealing cytokine data from Lipkin’s cytokine data and his recent turn to metabolomics I asked Lipkin how important a role cytokines were likely to play in future ME/CFS research and treatment. Lipkin felt they may yet play an important role in ME/CFS indeed:
“Cytokine disturbances can result in fatigue, cognitive and other disturbances. The observation that other biomarkers such as metagenomic or metabolomic profiles are highly associated with disease does not diminish their (cytokines) importance. There may be people who would benefit from drugs, including antibody therapies, that modulate cytokine responses.”
Scheibenbogen is pursuing antibody therapies in ME/CFS, and Nancy Klimas is reportedly using Enbrel (etanercept) – a cytokine (TNF) blocker – plus mifepristone in her Gulf War Illness trial. Other biologics are available and more are coming on the market.  Recent findings in POTS suggest that antibody drugs will probably play an important role in that disease as well.
Since the study also found that taking Vit. B supplements was associated with higher levels of pantothenic acid and lower fatigue scores, taking Vit. B supplements may be a good idea.
The 5-MT Question
Decreased levels of 5-MT, a metabolite associated with tryptophan, serotonin and melatonin metabolism could reflect problems with serotonin/melatonin conversion. This finding, however, was confounded by the high use of antidepressants (50% of the ME/CFS group) which could have produced the decrease.
Correlation studies do suggest, though, that low 5-MT levels could contribute to problems with cognition, sleep and fatigue. Larger studies are needed to determine if the low 5-MT levels are associated with those symptoms in ME/CFS – and if they are – if it might be beneficial to modulate that pathway using drugs in ME/CFS.
Next Up for the Simmaron Research Foundation and Ian Lipkin
The next phase in the Simmaron Research Foundation’s ongoing collaboration with Ian Lipkin is an expanded study which will, for the first time in ME/CFS, analyze the metabolomics of ME/CFS patients cerebral spinal fluid. The study, which will also include immune analyses is the third Simmaron/Lipkin CSF study to date. The first two studies found dramatic evidence of immune activation and the presence of a potential new subset.
Lipkin also reported rapid progress from his new NIH research center and a new collaborative effort with ME/CFS researcher and NIH ME/CFS research center leader Derya Unutmaz. The idea of two top labs in the country collaborating in a complementary fashion is an exciting one – one we will hopefully see much more of in this field.


Lipkin and Unutmaz are merging their respective strengths in a collaboration – something we could use much more of in ME/CFS.
We are completing analysis of saliva, blood, and feces for bacteria, viruses and fungi from ME/CFS and control subjects using powerful new sequencing methods. This will be the largest and most comprehensive study to date on the microbiome in ME/CFS. We will soon begin metabolomic, proteomic, and transcriptomic analyses of ME/CFS and control subjects before and after exercise. We are deeply grateful to the patients who are contributing to this work despite the implications for their health. They are true heroes.
We have begun a new collaboration with Derya Unutmaz and Jackson Laboratories that builds on the complementary expertise of our teams in cellular immunology and molecular microbiology and biochemistry.
Dana March and Tony Komaroff are building an app to help ME/CFS subjects and their caregivers track their status. We have had great support in this effort from people in the community.
Conclusions
In the past three years Lipkin’s identified three potential subsets (early/late duration patients, the “Peterson subset”, ME/CFS + IBS subset) and his explorations into the ME/CFS IBS subset continues to reap dividends.
His metabolomic study found signs of energy production problems in all ME/CFS patients, but when Lipkin separated out the ME/CFS + IBS patients, he found altered, even at times opposite metabolic findings that could suggest a different source of fatigue was present in the ME/CFS + IBS patients. His earlier study suggested more severe energy production problems may be present in ME/CFS patients with IBS.
The importance of the gut bacteria in ME/CFS perhaps rose to a new level of significance when a network analysis found larger differences in gut bacteria than metabolites. Lipkin’s ability to better differentiate ME/CFS patients from healthy controls using gut bacteria, metabolomic and clinical data suggests that large studies which tie together multiple systems will be the most helpful.
In short, the latest study from the Lipkin group indicates that the gut does matter in ME/CFS and that in those with gut problems it may matter more than we think.
The Simmaron Research Foundation and Lipkin are employing metabolomics in the study of cerebral spinal fluid for the first time, and Lipkin has launched a new collaborative ME/CFS effort with fellow NIH ME/CFS Research Center leader Derya Unutmaz.
 ​

Rich Haridy   July 10th, 2018

• A new blood metabolic profile for chronic fatigue syndrome may be a step towards a tool to help diagnose the disorder

 

• In the world of medicine there are still many biological mysteries yet to be solved. Chronic fatigue syndrome (CFS) is one of those big unsolved mysteries but a team from Columbia University is bringing us closer to understanding this elusive disorder, finding a specific metabolic fingerprint for the condition that could lead to a new diagnostic tool for doctors.

 

• Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a controversial condition identified by a variety of symptoms, from severe fatigue and muscle pain, to allergies, depression and impaired memory. Other than targeting specific symptoms, there is no effective treatment for CFS, and despite a growing body of strong physiological evidence, some in the medical community still persist in labeling it a psychological condition.
• Last year, a team of researchers from the Center for Infection and Immunity at Columbia University's Mailman School of Public Health revealed sufferers of CFS displayed microbiome profiles that were unique to the disorder. Compared to a healthy control group, the researchers found that CFS patients could be identified by having abnormally high levels of certain bacteria in the gut.
• Following on from that research the team moved to studying the particular blood metabolite profile of CFS patients and analyzed plasma samples from 50 CFS sufferers compared to 50 healthy control subjects. Over 500 different metabolic biomarkers were examined and the researchers homed in on several that were significantly altered in relation to the healthy control group. 
• When a predictive model was generated to diagnose CFS using these blood biomarkers the researchers reached an accuracy rate of over 80 percent. A comprehensive model was then generated combining the metabolic markers and the previously studied microbiome markers. This model could accurately predict the presence of CFS with 84 percent certainty.
• "This is a strong predictive model that suggests we're getting close to the point where we'll have lab tests that will allow us to say with a high level of certainty who has this disorder," says Dorottya Nagy-Szakal, first author on the new study.
• Other than offering a pathway towards a much-needed diagnostic tool for the disorder, it's hoped this research will lead to a better understanding of what causes this devastating condition. One outcome the researchers suggest is that animal models be developed that simulate these same metabolic and microbiome footprints. If those animals subsequently display CFS symptoms and behaviours it means that those specific parameters are playing a causal role in the disorder. 
• "We're getting close to the point where we can develop animal models that will allow us to test various hypotheses, as well as potential therapies, says W. Ian Lipkin, director of the Center for Infection and Immunity. "For instance, some patients might benefit from probiotics to retune their gastrointestinal microflora or drugs that activate certain neurotransmitter systems."​