The COVID-19 pandemic may no longer be a global public health emergency, but millions continue to struggle with the aftermath: Long COVID. New research and clinical anecdotes suggest that certain individuals are more likely to be afflicted by the condition, nearly 4 years after the virus emerged.
People with a history of allergies, anxiety or depression, arthritis, and autoimmune diseases and women are among those who appear more vulnerable to developing long COVID, said doctors who specialize in treating the condition.
Many patients with long COVID struggle with debilitating fatigue, brain fog, and cognitive impairment. The condition is also characterized by a catalog of other symptoms that may be difficult to recognize as long COVID, experts said. That's especially true when patients may not mention seemingly unrelated information, such as underlying health conditions that might make them more vulnerable. This makes screening for certain conditions and investigating every symptom especially important.
The severity of a patient's initial infection is not the only determining factor for developing long COVID, experts said.
"Don't judge the person based on how sick they were initially," said Mark Bayley, MD, medical director of the Toronto Rehabilitation Institute at University Health Network and a professor with the Temerty Faculty of Medicine at the University of Toronto. "You have to evaluate every symptom as best you can to make sure you're not missing anything else."
Someone who only had a bad cough or felt really unwell for just a few days and recovered but started feeling rotten again later — "that's the person that we are seeing for long COVID," said Bayley.
While patients who become severely sick and require hospitalization have a higher risk of developing long COVID, this group size is small compared with the much larger number of people infected overall. As a result, despite the lower risk, those who only become mild to moderately sick make up the vast majority of patients in long COVID clinics.
A small Northwestern Medicine study found that 41% of patients with long COVID never tested positive for COVID-19 but were found to have antibodies that indicated exposure to the virus.
Doctors treating patients with long COVID should consider several risk factors, specialists said. They include:
- A history of asthma, eczema, or allergies
- Signs of autonomic nervous system dysfunction
- Preexisting immune system issues
- Chronic infections
- Diabetes
- Being slightly overweight
- A preexisting history of anxiety or depression
- Joint hypermobility (being "double-jointed" with pain and other symptoms)
Screening for Allergies
Alba Azola, MD, assistant professor of Physical Medicine and Rehabilitation at Johns Hopkins Medicine, said a history of asthma, allergies, and eczema and an onset of new food allergies may be an important factor in long COVID that doctors should consider when evaluating at-risk patients.
It is important to identify this subgroup of patients because they respond to antihistamines and mast cell stabilizers, which not only relieve their allergy symptoms but may also help improve overall fatigue and their tolerance for basic activities like standing, Azola said.
A recently published systemic review of prospective cohort studies on long COVID also found that patients with preexisting allergic conditions like asthma or rhinitis may be linked to a higher risk of developing long COVID. The authors cautioned, however, that the evidence for the link is uncertain and more rigorous research is needed.
"It stands to reason that if your immune system tends to be a bit hyperactive that triggering it with a virus will make it worse," said Bayley.
Signs of Dysautonomia, Joint Hypermobility
Patients should also be screened for signs and symptoms of dysautonomia, or autonomic nervous system disorder, such as postural orthostatic tachycardia syndrome (POTS) or another type of autonomic dysfunction, doctors said.
"There's a whole list because the autonomic nervous system involves every part of your body, every system," Azola said.
Issues with standing, vision, digestion, urination, and bowel movement, for example, appear to be multisystemic problems but may all be linked to autonomic dysfunction, she explained.
Patients who have POTS usually experience a worsening of symptoms after COVID infection, Azola said, adding that some patients may have even assumed their pre-COVID symptoms of POTS were normal.
She also screens for joint hypermobility or hypermobile Ehlers-Danlos syndrome, which affects connective tissue. Research has long shown a relationship between autonomic dysfunction, mast cell activation syndrome (repeated severe allergy symptoms that affect multiple systems), and the presence of hypermobility, Azola said. She added that gentle physical therapy can be helpful for patients with hypermobility issues.
Previous studies before and during the pandemic have also found that a substantial subset of patients with myalgic encephalomyelitis/chronic fatigue syndrome, which shares many similarities with long COVID, also have connective tissue/hypermobility disorders.
Depression, Anxiety, and Female Patients
People with a preexisting history of anxiety or depression also appear to be at a higher risk for long COVID, Bayley said, noting that patients with these conditions appear more vulnerable to brain fog and other difficulties brought on by COVID infection. Earlier research found biochemical evidence of brain inflammation that correlates with symptoms of anxiety in patients with long COVID.
"We know that depression is related to neurotransmitters like adrenaline and serotonin," Bayley said. "The chronic inflammation that's associated with COVID — this will make people feel more depressed because they're not getting the neurotransmitters in their brain releasing at the right times."
It may also put patients at a risk for anxiety due to fears of post-exertional malaise (PEM), where symptoms worsen after even very minor physical or mental exertion and can last days or weeks.
"You can see how that leads to a bit of a vicious cycle," said Bayley, explaining that the cycle of fear and avoidance makes patients less active and deconditioned. But he added that learning to manage their activity can actually help mitigate PEM due to the anti-inflammatory effects of exercise, its positive impact on mood, and benefits to the immune and cardiovascular systems.
Meanwhile, a number of epidemiologic studies have found a higher prevalence of long COVID among women. Perimenopausal and menopausal women in particular appeared more prone, and at least one study reported that women under 50 years were five times more likely to develop post-COVID symptoms than men.
A recent small UK study that focused on COVID-19 hospitalizations found that women who had lower levels of inflammatory biomarkers at admission were more likely to experience certain long-term symptoms like muscle ache, low mood and anxiety, adding to earlier research linking female patients, long COVID, and neuropsychiatric symptoms.
History of Immune Dysfunction, Diabetes, Elevated Body Mass Index (BMI)
Immune dysfunction, a history of recurrent infections, or chronic sinus infections are also common among patients under Azola and her team's care. Those who have arthritis or other autoimmune diseases such as lupus also appear more vulnerable, Bayley said, along with patients who have diabetes or a little overweight.
Recent research out of the University of Queensland found that being overweight can negatively affect the body's immune response to the SARS-CoV-2 virus. Blood samples collected 13 months after infection, for example, found that individuals with a higher BMI had lower antibody activity and a reduced percentage of relevant B cells that help build antibodies to fight the virus. Being overweight did not affect the antibody response to the COVID-19 vaccines, however, giving further support for vaccination over infection-induced immunity as an important protective factor, researchers said.
Narrowing the Information Gap
The latest Centers for Centers for Disease Control and Prevention's Household Pulse Survey estimates that 14% of all American adults have had long COVID at some point, with > 5% of the entire adult population currently experiencing long COVID. With millions of Americans affected, experts and advocates highlight the importance of bridging the knowledge gap with primary care doctors.
Long COVID specialists said understanding these connections helps guide treatment plans and manage symptoms, such as finding the right medications, improving tolerance, optimizing sleep, applying cognitive strategies for brain fog, dietary changes, respiratory exercises to help with shortness of breath, and finding the fine line between what causes PEM and what doesn't.
"Whenever you see a disease like this one, you always have to ask yourself, is there an alternative way of looking at this that might explain what we're seeing?" said Bayley. "It remains to be said that all bets are still open and that we need to continue to be very broad thinking about this."
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