Long-Covid Risk Factors, Symptoms, and Treatments: New Insights
More than 5 initial symptoms predict long-Covid. And a drug just passed phase III clinical trial for chronic fatigue syndrome.
As with any other systemic disease, Covid-19 may bring systemic complications that may not resolve so soon. We identify them as long-haulers, long-Covid, post-viral Covid-19 syndrome, or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Importantly, a positive SARS-CoV-2 test is not important for long-Covid diagnosis.
We understand what they look like and the probable causes. But how much do we know about its risk factors, namely, what traits make a patient more likely to develop long-Covid, and its potential treatments?
Prevalence and cause
The prevalence of long-Covid depends on the population studied. For example, a study in China detected residual lung abnormalities in 25% of discharged Covid-19 patients in a 3-month follow-up, of whom 31% still had gastrointestinal distress, 18% had headaches, 16% had fatigue, and 15% had dyspnea (shortness of breath).
A study in Italy, on the other hand, followed 179 Covid-19 patients for two months. They uncovered one or two lingering symptoms in 32% of patients and three or more in 55%. Common symptoms were fatigue (53%), dyspnea (43%), joint pain (27%), and chest pain (22%).
Other data from King’s College London that studied over 4000 Covid-19 patients found that 13% of patients had persisting symptoms for at least 28 days, of which over 90% had fatigue and headache. This study further discovered a few risk factors for long-Covid, as discussed below.
Reasons for Covid-19 long-haulers, scientists believe, are due to the residual tissue damage or the aberrant immune responses that persist despite that the coronavirus may no longer be present, or both. More details here:
Risk factors
Two new preprints released in October have tracked a sufficient number of Covid-19 patients to identify the possible risk factors of long-haulers. While preprints have not gone through peer-review yet, these two are from research institutions with a good academic publishing record.
The presence of more than five symptoms during the first week of illness predicted 16.3% of cases [of long-Covid].
Part I: King’s College London
Researchers at King’s College London authored one of the preprints, titled “Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App.” This study is led by Claire J. Steves, an honorary consultant physician in geriatric medicine and deputy director of the Department of Twin Research and Genetic Epidemiology, with over 70 published academic papers.
This study followed 4,182 Covid-19 patients in Sweden, Great Britain, and the U.S. for several months. In the end, they found 13% of patients had symptoms lasting more than 28 days. This number was 4.5% and 2.3% for those suffering symptoms for more than 56 and 95 days, respectively.
The study then pinpointed risk factors that all together could predict 76.7% of long-Covid cases. The researchers also tested their predictive model in another dataset of 2,472 Covid-19 patients, which proved their model’s accuracy and generalizability. Individual risk factors are ranked as follows:
- The old age of 70 years and above predicted 29.2% of cases.
- The presence of more than five symptoms during the first week of illness predicted 16.3% of cases.
- A high body mass index of 27.5 and above predicted 10.3% of cases.
- Horse voice symptoms predicted 4.1% of cases.
- Shortness of breath symptom predicted 3.8% of cases.
- Female sex predicted 3.7% of cases.
- In those aged 70 and above, fever, loss of smell, and comorbidities (particularly heart and lung diseases) were also predictors.
- Socioeconomic status was not a predictor.
Lastly, the authors pointed out their study’s limitations, which include the dominance of females and those younger than 70 years. Data on race were also lacking, preventing risk factor analysis. And data relied on self-reports, which may not be as accurate as doctors’ assessments.
Regardless, both studies identified more than five initial symptoms and shortness of breath as predictors of long-Covid.
Part II: Helix
The second preprint, “Long-term COVID-19 symptoms in a large unselected population,” is from Helix, a population genomics research center in California. This study used survey data from over 20,000 participants of the Helix DNA Discovery and Healthy Nevada Projects. But only 233 people had Covid-19, and most were not tested. Prevalence of long-Covid was 42%, 34%, and 24% after 30, 60, and 90 days, respectively.
This study only found three risk factors of long-Covid: more than five initial symptoms, shortness of breath, and blood type A+. In contrast, sex, BMI, or comorbidities were not associated with long-Covid.
Evidently, this study is weaker than the King’s College London study Dr. Steves led — owing to the smaller sample size while also using self-reports. Regardless, both studies identified more than five initial symptoms and shortness of breath as predictors of long-Covid.
Subtypes and unique symptoms
Another interesting finding from Dr. Steves’s study were the two subtypes of long-Covid. One type is the combo of fatigue, headache, and upper respiratory tract symptoms like shortness of breath, sore throat, persistent cough, or smell loss. The second type is a multi-system complication with ongoing fever and gastrointestinal symptoms.
Although rare, science has recently described new and unique aspects of long-Covid ranging from symptoms of the heart, brain, peripheral nervous system, ear, and skin.
Dr. Steves et al. also noticed a few symptoms unique to long-Covid. Using short-Covid-19 patients as a comparison group, these were cardiac symptoms like palpitations or tachycardia (6.1% vs. 0.5%), concentration or memory problems (4.1% vs. 0.2%), tinnitus and earache (3.6% vs. 0.2%), and peripheral nerve symptoms like prickling or tingling sensation and numbness (2% vs. 0.5%). These differences reached statistical significance (p<0.05), which means that results were not due to random chance.
In a study published this month, Harvard Medical School scientists searched for cases of Covid-19-related skin symptoms in the American Academy of Dermatology and International League of Dermatological Societies databases. They identified 171 such cases from 31 countries. While most skin symptoms lasted less than a month, pernio, chilblains, or redness and swelling of feet or hands—also known as Covid-19 toes — persisted more than 60 days in six cases and more than 130 days in two cases.
Although rare, science has recently described new and unique aspects of long-Covid ranging from symptoms of the heart, brain, peripheral nervous system, ear, and skin.
Possible treatments
At this point, the guidelines for Covid-19 long-haulers include proper sleep, nutrition, and mental health management. Slow and gradual pacing of physical activities is also recommended but should be avoided if symptoms worsen.
According to an unpublished study of 1,600 Covid-19 long-haulers, the self-reported supplements that helped with symptom relieve were vitamin D (500 people), vitamin C (290), zinc (250), magnesium (259), B12 (228), multivitamins (184), turmeric (156), N-acetylcysteine (134), and others. While these are anecdotes, they make sense since proper nutrition is advice for long-Covid recovery. Self-reported prescriptions were heartburn or acid reflux medications (230 people), steroids (221), antihistamines (215), inhalers (196), aspirin (80), ibuprofen (74), and others.
“Rintatolimod is the only drug to have completed successful advanced placebo-controlled clinical trials (Phase II/III) for ME/CFS and is approved for severe ME/CFS in Argentina.”
Long-Covid is a syndrome similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Presently, there are no approved treatments for ME/CFS, but that may soon change. A phase III clinical trial of 75 sufferers of ME/CFS for 2–8 years was published a few days ago. And results found that an immunomodulatory called rintatolimod improved the exercise duration of 51% of patients. In contrast, only 17.6% of the placebo group saw improvement. That is nearly a tripled efficacy in terms of the number of responders.
“Rintatolimod is the only drug to have completed successful advanced placebo-controlled clinical trials (Phase II/III) for ME/CFS and is approved for severe ME/CFS in Argentina,” the authors wrote, which may apply to long-Covid as well. “Covid-19 debilitated patients with “long hauler” post-viral syndrome would benefit from rintatolimod are topics for further investigation.” Rintatolimod is now being investigated for its antiviral potential against Covid-19 in Japan.
