What we know and don’t know about long COVID

Much about the chronic condition remains unclear nearly 3 years into the pandemic

Authhors:  Daniel de Visé | Oct. 20, 2022 Changing America

Story at a glance

  • The lack of diagnostic tools for long COVID-19 make the condition difficult to conclusively identify or study.

  • Studies place the prevalence of long COVID-19 anywhere between 4 percent and 48 percent of people who have been infected with the virus. 

  • Other aspects of the condition, such as how long symptoms may persist and how common it will be in the future, also remain unclear. 

After two years of research and one of the largest public health campaigns in human history, doctors and scientists don’t yet have a test to detect the mysterious affliction called long COVID-19, let alone a head count of the afflicted. 

Based on the latest wave of studies, long COVID-19 may beset 4 percent of the population who catch the virus, or 14.8 percent, or 48 percent. Its toll on the body spans dozens of possible symptoms, from fatigue to chest pains to fuzzy thinking to hair loss. The symptoms overlap with those seen in scores of other illnesses.  

Many long COVID-19 cases clear up after several months or a year. Some seem to be permanent. Only time will tell. 

“What do we mean when we say long COVID? We’re still figuring it out,” said Dr. Josh Fessel, a senior clinical adviser and COVID-19 specialist at the National Institutes of Health (NIH). Along the way, he said, “we’re learning a lot about what recovery looks like after a significant illness.” 

long COVID-19 study released last week by Scottish researchers raised eyebrows around the globe. Six to 18 months after COVID-19 infection, 48 percent of people surveyed said they had not fully recovered.  

That report is an outlier. The World Health Organization puts the prevalence of long COVID-19 at 10 to 20 percent. Other recent estimates range across the map. An ongoing survey by British health officials, updated in July, found long COVID-19 in only 4 percent of cases. A Canadian government survey, updated this week, found that 14.8 percent of adults with COVID-19 retained symptoms three months after infection. A U.S. government survey, updated this month, found that 30 percent of adults who had the coronavirus believed they had experienced long COVID-19. 

For many Americans, long COVID-19 now looms as a larger worry than acute COVID-19, the first round of disease triggered by the viral invader. Vaccinations and weakening variants have vastly lowered the odds that people without underlying conditions will wind up hospitalized or dead from the acute version of the ailment. 

“People don’t talk about just getting COVID any more,” said Tara Leytham Powell, professor of social work at the University of Illinois. “Long COVID is more of a fear.” 

Ashley Drapeau caught COVID-19 in December 2020. A month later, she said, “it just seemed like it wasn’t getting any better. I was still having shortness of breath. I was having migraines. … Lack of appetite, nausea. It seemed to go on and on.” 

Drapeau took most of 2021 off. Now she’s back at work, running a long COVID-19 program at the George Washington University Center for Integrative Medicine. She’s operating at “about 80 percent.” She has never fully recovered. 

In calculating the prevalence of long COVID-19, researchers struggle to gather basic data. There is no way to conclusively diagnose long COVID-19, so most research relies on self-reported information obtained through surveys. Respondents don’t always know if they had COVID-19. They can only guess.  

“There’s no test. There’s no way to evaluate it,” said Dr. Priya Duggal, an epidemiologist and professor at the Johns Hopkins Bloomberg School of Public Health. “You can only ask people to report it themselves.” 

Duggal works on an ongoing long COVID-19 survey at Johns Hopkins, a project that began with the first reports of lingering illness in the spring of 2020.  

“We expected there would be a long-term consequence,” she said. “We weren’t expecting what we’re seeing now.” 

Hopkins researchers have found that one-third of patients report symptoms of long COVID-19. A much smaller group, around 3 percent, was identified as suffering from severe long COVID-19, “meaning that they can’t function in their day-to-day life,” Duggal said. “They can no longer walk a quarter of a mile, or up a flight of stairs. Can’t do things like vacuum. It affects their ability to do their jobs, take kids to school.”  

Though researchers have not reached consensus on some of the specifics, they generally agree that long COVID-19 is a constellation of symptoms that can endure for months or years after infection, sometimes emerging after an illusory recovery. The most common symptoms seem to be fatigue, shortness of breath and that blurry mental state known as COVID fog. 

Researchers often file long COVID-19 sufferers into two groups. The smaller contingent, perhaps 1 to 5 percent of all coronavirus cases, suffer symptoms so severe that they “can’t live normal lives,” Duggal said. The larger camp of COVID-19 “long-haulers,” somewhere between 5 and 50 percent of all cases, manifest relatively mild symptoms that don’t hinder daily routines of work, school, shopping and sleep.  

Some in that camp may not have long COVID-19 at all.  

In the Scottish study, 91 percent of people who believed they had long COVID-19 reported one or more symptoms associated with the affliction. But at least one of the same symptoms appeared in more than half of the group that had never caught COVID-19.  

Some people confuse essentially random symptoms with resurgent COVID-19, experts say. Others could be coping with the vagaries of recovery from a serious illness. Still others may be fighting symptoms that linger mostly in the mind. 

“A lot of these are symptoms of depression and anxiety,” said Dr. Steven Dubovsky, chairman of psychiatry at the University of Buffalo. “I’m sure there’s a population of people who got sick and stayed sick for complicated psychological reasons. That doesn’t mean they aren’t sick.” 

One problem with diagnosing long COVID-19 lies in the bewildering array of symptoms. One recent Dutch study counted 23. More common: loss of taste and smell, muscle pain, back pain, headache and lethargy. Less common: “heavy arms and legs,” stomach pain, diarrhea and tingling extremities.  

“We talk about long COVID like it’s a thing,” said Fessel of NIH. “And I think the truth is that what we’re learning, and what we’ve had a sense of for a while, is that there are different flavors of long COVID. It seems like there are some people who really have a lot of the fatigue, the cognitive changes. … There are people who don’t have much of that, but they’re really short of breath with activity levels that never used to bother them, and that persists for months. There are people with real high heart rates. All of these fall under the umbrella of long COVID.” 

One uncertainty lies in the very definition of “long.” Some researchers define long COVID-19 as symptoms enduring past three or four weeks. Others draw the line at three months.  

Another imponderable: Fickle public interest in COVID-19 surveys. People who haven’t recovered from the virus may be more likely to answer a long COVID-19 survey than people who have. Educated white women, in particular, seem to answer these surveys at markedly higher rates than people in other demographic groups.  

Not all the news about long COVID-19 is bad. One good tiding: Keeping up with vaccines seems to reduce the chances of contracting long COVID-19.  

U.K. health officials have found encouraging signs that weaker variants, as well, correlate to lower rates of long COVID-19.  

“Our research and other research have found that if you’re fully vaccinated, your risk of having long COVID 12 weeks after an omicron infection is about half what it was with delta,” said Daniel Ayoubkhani, principal statistician at the U.K. Office for National Statistics.  

Other researchers disagree. And even if the rate of long COVID-19 decreases over time, owing to vaccination or milder variants, the sheer number of infections should guarantee a steady stream of long COVID cases for a long time to come. The impact of those cases, on individuals and on society, could be massive. One recent study suggests long COVID-19 may have already sidelined 4 million American workers.  

“That’s over $100 billion a year, in terms of lost wages,” said Drapeau, of George Washington University. “That’s a pretty big deal.”

Post-COVID-19 fatigue: A systematic review

Authors: Jian Joli1Patrizia Buck1Stephan Zipfel1 and Andreas Stengel1,2* Frontiers in Psychiatry

Fatigue is recognized as one of the most commonly presented long-term complaints in individuals previously infected with SARS-CoV-2. This systematic review was performed to describe symptoms, etiology, possible risk factors related to post-COVID-19 fatigue and the therapeutic approaches used for the treatment of post-COVID-19 fatigue. For the systematic literature search the databases PubMed, Web of Science, Cochrane Library, and PsycInfo were used. All articles that met the inclusion criteria were analyzed for demographics, clinical data and treatment. Included were studies which focused on an adult population (18–65 years old); elderly patients and patients with chronic somatic diseases which can also cause fatigue were excluded. We identified 2,851, screened 2,193 and finally included 20 studies with moderate to high methodological quality, encompassing 5,629 participants. Potential risk factors for post-COVID-19 fatigue were old age, female sex, severe clinical status in the acute phase of infection, a high number of comorbidities, and a prediagnosis of depression/anxiety. Lastly, a possible autoimmune etiology was suspected. Several treatment approaches have been tested mostly in small and uncontrolled studies so far: a Chinese herbal formulation improved breathlessness and fatigue. Moreover, molecular hydrogen (H2) inhalation had beneficial health effects in terms of improved physical (6-min walking test) and respiratory function in patients with post-COVID-19. Patients also noticed improvement in fatigue after undergoing hyperbaric oxygen therapy (HBOT) and enhanced external counterpulsation (EECP). Lastly. muscle strength and physical function were improved after undergoing an 8-weeks biweekly physical therapy course including aerobic training, strengthening exercises, diaphragmatic breathing techniques, and mindfulness training. However, larger and controlled studies e.g., investigating the effect of physical and / or psychotherapy for patients with post-COVID-19 fatigue are urgently warranted.

Systematic Review Registration: Unique Identifier: CRD42022320676, https://www.crd.york.ac.uk/PROSPERO/.


Corona virus disease (COVID-19), caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), has led to a global pandemic. From the beginning of the pandemic until today (mid of May 2022), more than 519 million people worldwide have been infected with SARS-CoV-2 according to the world health organization, of whom more than 6 million have died. The corona virus has now spread to more than 190 countries. Currently, the highest numbers of cases are reported in the United States, Brazil, India, Turkey, and Russia. In Europe, Italy, Spain, France, Germany, and the United Kingdom have the highest number of corona virus infections.

It has become increasingly clear that infected patients have symptoms not only in the acute phase, but also after recovery from the initial infection (1). A recent meta-analysis including 4828 patients with post-COVID-19 showed that symptoms and post-acute sequelae of SARS-CoV-2 can persist weeks to months after the infection (2). These patients who reported persistent symptoms have been termed “long haulers” or described as having long COVID, post-acute COVID-19, persistent COVID-19 symptoms, post COVID-19 manifestations, long-term COVID-19 effects, post-acute sequelae of COVID-19 (PASC), or post-COVID-19 syndrome (3). Based on NICE guideline on long COVID (4); long COVID is defined as signs and symptoms that develop during or following an infection consistent with COVID-19 and which continue for more than 4 weeks. NICE recommends using the term post-COVID syndrome from 12 weeks after infection and when symptoms are not explained by an alternative diagnosis. Since in the 20 studies included in our systematic review the symptoms are reported on av-erage 20, 5 weeks after infection, we refer to the symptom(s) – according to the NICE guide-lines as Post-COVID fatigue.

The most prevalent symptoms reported by patients were: fatigue (64%), dyspnea (40%), depression/anxiety (38%), arthralgia (24,3%), headache (21%), and insomnia (20%) (2). Fatigue is a common and debilitating symptom in people with neurological (and oncological) disorders. Despite significant efforts to explain the pathogenic mechanisms of fatigue, current knowledge is limited. This may be because the cause of fatigue often cannot be attributed to a single source. Changes in neurotransmitter levels, inflammation, psychiatric disorders, psychosocial burden, cognitive dysfunction and substrate metabolism/availability are potential contributors to fatigue (5). Post-COVID-19 fatigue is defined as a decrease in physical and/or mental performance resulting from changes in central, psychological and/or peripheral factors resulting from COVID-19 disease (5).

In this systematic review we focused on persistent fatigue after acute COVID-19 infection, defined here as 2 weeks or greater post symptom onset. The review aimed to describe all symptoms related to post-COVID-19 fatigue, its possible etiology and risk factors as well as treatment approaches employed so far.


Data sources and searches

The protocol of this systematic review was registered on the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42022320676). The planning and conduct of this systematic review were carried out following the Cochrane guidelines for Systematic Reviews (6) and the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) criteria catalog (7).

A systematic literature search developed by using the PICO model was conducted on April 14rd 2022 on the following databases: PubMed/Medline, the Cochrane Library, PsycInfo, and Web of Science. There were no reservations related to the status, language or date of publication. The strategies developed and used for each database are presented in the Supplementary material. The following search terms were used: post OR post-infectious OR post-recovery OR postviral OR long OR long-term AND fatigue OR fatigue syndrome OR chronic fatigue AND coronavirus OR COVID-19 OR SARS-CoV-2.

Our search was based on a review question developed according to the PICO scheme i.e., Population (P): Patients, who have undergone a COVID-19 infection and suffer from post-COVID-19 symptoms, Intervention (I): all diagnostic tests (e.g., autonomic testing), interviews, self-reported fatigue tools / assessments / questionnaires, and therapy approaches used for patients with post-COVID-19, Comparison (C): patients, who had COVID-19 infection but no post-COVID-19 symptoms, and Outcome (O): all signs, symptoms, risk factors, pathophysiology related to fatigue after COVID-19 infection.

Criteria for including studies

Original studies focusing on patients with post-COVID-19 fatigue were eligible for inclusion in this systematic review. Post-COVID-19 was initially defined as diagnosis when patients had at least one symptom beyond 2 weeks following acute infection (8). Studies with participants, who were in the acute phase during the study (< 2 weeks after being positive) were excluded. Since in the 20 studies included in our systematic review the symptoms are reported on average 20, 5 weeks after infection, we refer to the symptom(s) – according to the NICE guidelines as post-COVID fatigue.

Included were studies which focused on an adult population (older than 18). Those with data on geriatric patients over 65 years old (due to possible comorbidities in older age which can cause fatigue) and patients with chronic somatic diseases, which can also cause fatigue, were excluded. Only studies which reported cases with confirmed COVID-19 positive testing were included. Cases were defined as confirmed COVID-19 positive if they met one of the following criteria:

– Nasal, nasopharyngeal, oropharyngeal swab or nasotracheal, or blood samples tested positive for SARS-CoV-2 nucleic acid by using real-time reverse-transcriptase polymerase chain reaction assay (RT-PCR).

– A positive SARS-CoV-2 antibody (serology) test.

Studies were considered possibly eligible if they contained data from one or more patients encompassing randomized controlled trials, prospective cohort studies, cross-sectional studies and case reports. Non-original studies (meeting/conference/congress abstracts, notes and narrative reviews), animal studies, articles with non-topic-specific content, editorials, comments, hypotheses, opinions, dissertations, books or letters were excluded from further examination. Reviews, except for narrative reviews, were not generally excluded directly, but rather examined for potentially important primary sources if relevant to the topic. There were no restrictions related to the time of publication and time/duration of follow-up. Articles which met the criteria described above and were written in English were eligible for inclusion.

Screening and full-text review

Before screening, duplicates were removed. This step was performed independently by two investigators (J.J. and P.B.) and the number of titles was compared afterwards. Then, titles and abstracts of identified studies retrieved using the search strategy were independently screened by two investigators (J.J. and P.B.) to identify studies that potentially meet the inclusion criteria mentioned above. The full texts of eligible studies were retrieved and independently assessed for eligibility by the two investigators. Any disagreement between them over the eligibility of particular studies was resolved through discussion with a third investigator (A.S.). The entire screening process is shown in the PRISMA flow diagram (Figure 1).

Figure 1

FIGURE 1. Prisma flow chart.

Data extraction

The following information was extracted: Study data (author, year, country, study design, description of the included population with sample size and characteristics, duration of follow-up, ascertainment of COVID-19 and fatigue), demographic data (age and gender of included population, comorbidities), clinical data (symptoms and signs related to post-COVID-19), laboratory data (C-reactive protein, ferritin, antinuclear antibodies, D-dimer, lactate dehydrogenase, interleukin-6, white blood cells), etiology and possible risk factors (comorbidities, autoimmune diseases, gender, age), diagnostic tests (scales and questionnaires used for identifying fatigue after COVID-19 infection, chest-x-ray, brain MRI, spine MRI, electroencephalogram, autonomic testing, electrocardiogram, blood pressure, heart rate variability, electromyogram), and therapy approaches used for the treatment of post-COVID-19 fatigue.

Assessing the methodological quality or risk of bias of included studies

The risk of bias assessment was performed on the premises of the study design as presented below:

– Randomized clinical trials: Cochrane risk of bias tool (6).

– Case-control study, non-randomized trials: ROBINS-I (9).

– Prevalence cross-sectional study: the Joanna Briggs Institute checklist for prevalence studies.

– Case reports: National Institute of Health quality assessment tool for case series studies.

Two independent investigators (J.J. and P.B.) performed the evaluation and a third investigator (A.S.) was involved in case of dissensus. We judged the quality of studies that used therapeutic interventions using questions such as: Was the intervention well defined? Were there any deviations from the planned intervention?

Analysis of data

The prevalence of fatigue was estimated by dividing the number of patients with fatigue by the total number of patients with COVID-19 in the sample multiplied by 100 to estimate the percentage in each study.

We performed a narrative analysis (qualitative synthesis) to present the frequency of symptoms and signs related to post-COVID-19 fatigue.


Search results

The search strategies retrieved 2,851 records, and 658 duplicates were removed initially. After reading of titles and abstracts (first phase), 1,889 references did not meet the inclusion criteria mentioned above and were excluded. The full texts of the 304 remaining records were read (second phase), 54 studies were excluded because they were not related to topic. Six ongoing studies were excluded. Other exclusion reasons were: non-English articles, age, and no confirmation of COVID-19 by RT-PCR or antibody test. Through the citation search from reviews, no additional studies were included. Finally, 20 studies were included in this systematic review. The PRISMA flow diagram is presented in Figure 1.

The 20 included studies encompass 5 studies that met the inclusion criteria but involved patients with comorbidities to compare this cohort with the fatigued cohort without pre-diagnoses. In one study participants were followed up after a mean duration of recovery from COVID-19 of only 12 days. However, these participants had 2 consecutive negative PCR tests before follow-up.

Characteristics of the included studies

We present the results of the studies in Table 1 including: main characteristics of included studies including country, study design, description of the population, duration of follow-up and methods used for fatigue ascertainment.

Table 1

TABLE 1. Characteristics of the included studies.

The included studies comprised a total sample of 5,629 participants (aged 18 to 65 years). Of the 20 included studies, 3 were prospective cohort studies, 2 were retrospective cohort studies, 3 were cross-sectional studies, 6 were case-control studies, 1 was a randomized single-blind, placebo-controlled study, 2 were observational studies and 3 were case reports. Five studies analyzed data from the US, 2 from Egypt, 4 from Ireland, 2 from Israel, 1 from China, and 1 each analyzed data from Saudi Arabia, Czech Republic, Switzerland, Germany, Canada, and Spain. Study populations ranged from 40 to 1,950 participants; except for the three case reports which analyzed just one patient. The median or mean follow-up periods ranged from 1 to 9 months.

Risk of bias of included studies

The risk of bias was categorized into low risk, some concerns, and high risk. The included studies were evaluated regarding five various forms of bias:

– Bias in selection of participants for the study.

– Bias due to deviations from intended interventions.

– Bias due to missing data.

– Bias in measurement of the outcomes.

– Bias in selection of the reported results.

Ten studies were classified as presenting high quality (low risk), and the remaining 10 as moderate quality (some concerns) data. The reasons for these concerns were as follows: the outcomes were measured via questionnaires or were self-reported by the participants (domain 4: bias in measurement of outcomes). We present the judgments for the bias in Table 2.

Table 2

TABLE 2. Risk of bias assessment.

Results from the included studies

Scales and definition criteria used for identifying post-COVID-19 fatigue

Elanwar et al. (11) defined participants as patients with post-COVID-19 if they were diagnosed with postinfectious fatigue syndrome (PIFS). In order to fulfill the definition of PIFS, patients had to have persistent fatigue for at least 6 months after recovery. Post-COVID-19 fatigue was defined in the other studies by persistent fatigue symptoms at least 6 weeks after recovery or after being negative using RT-PCR test. Kamal et al. (12) did not explain exactly how they defined fatigued patients. In the studies of Ganesh et al. (13) and Graham et al. (10), fatigue domains were assessed using patient-reported outcome measurement information system (PROMIS) with a 5-point Likert scale ranging from 1 = never to 5 = always. El Sayed et al. (14) used the fatigue assessment scale. Elanwar et al. (11), Townsend et al. (1517) used the Chalder fatigue scale providing a total fatigue score from 0-4. Scores of 2 or above are regarded as fatigued.

All of the scales mentioned above consist of items that measure both the experience of physical and/or mental fatigue and the interference of fatigue on daily activities over the past weeks. Examples of items are: “How often did you feel tired?”, “How often were you too tired to take a bath/shower?”, “I get tired very quickly”, “I don’t do much during the day”, “Physically, I feel exhausted”, “I have problems thinking clearly”, and “Mentally, I feel exhausted”.

In the study of Pang et al. (22) the patients used the Borg scale (39) to grade the level of their fatigue. This is a scale ranging from 0 = nothing at all to 20 = very, very severe (maximal).

Signs and symptoms related to fatigue experienced by participants

The participants reported several symptoms related to fatigue in different proportions. Fatigue (by definition) was always present, anhedonia, brain fog and difficulty concentrating (up to 81%), myalgia (up to 55%), depression/anxiety (up to 47%), insomnia and sleep disturbance (up to 33%), and dementia or loss of memory (up to 32%). A summary of symptoms reported in the included studies is presented in Figure 2.

Figure 2

FIGURE 2. Additional symptoms experienced by patients with post-COVID-19 fatigue (Frequency: from %—to %).

Etiology and risk factors

A total of 7 studies reported aspects that were investigated as potential risk factors for post-COVID-19 fatigue. Kamal (12), Nehme (1), and Townsend (16) described that older and female patients have a higher risk of suffering from fatigue after COVID-19 infection. Kamal (12), El Sayed (14), and Elanwar (11) showed that the longer the duration of the acute phase (or of the disease recovery) and the more severe the disease, the higher the risk of suffering from fatigue. Finally, patients with comorbidities were more affected to have persistent symptoms (12).

Similar to these results, Graham (10) suggested in their study a possible neuropsychiatric vulnerability to becoming long haulers after COVID-19 infection because premorbid depression/anxiety was prevalent in their cohort. Lastly, Townsend (16) found a significant association between pre-existing depression diagnosis and antidepressant use and subsequent development of severe fatigue.

Graham (10) showed that the prevalence of preexisting autoimmune disease and elevated ANA (antinuclear antibodies) in the cohort of participants with post-COVID-19 compared to the general population possibly pointing toward an autoimmune contribution (10). In addition, Ganesh (13) hypothesizes that sex differences in the immune response to COVID-19 may be related to the development of persistent symptoms after COVID-19 infection. Elanwar (11) found higher levels of ferritin in patients with post-COVID-19 fatigue compared to the control group without fatigue. Margalit et al. (18) reported in their study that patients with post-COVID-19 fatigue had more children and lower proportion of hypothyroidism. Lastly, Townsend et al. (15) showed a positive association between fatigue scores and higher vitamin D levels in their cohort. A summary of associated risk factors reported in included studies is presented in Figure 3.

Figure 3

FIGURE 3. Etiology and risk factors of post-COVID-19 fatigue.

Therapeutic approaches

Dayrit et al. (19) presented a case of a 38-year-old female patient who experienced post-COVID-19 sequelae, including fatigue, headache, shortness of breath, and brain fog for 3 months before she underwent enhanced external counterpulsation (EECP) of 1-h sessions, three times per week for 5 weeks. EECP is a non-invasive therapy for patients with chronic stable angina and/or heart failure of ischemic etiology. Standard therapy involves 35 1-h treatments over seven weeks. The patient lies on a treatment table with compression cuffs securely wrapped around the calves, thighs and buttocks. These cuffs induce a sequence of drainage from distal to proximal simultaneously before the onset of diastole and systole. Inflation and deflation are tailored specifically to the patient’s ECG to optimize treatment use. Compression produces pulsating shear stress, this is the same as adjusting Vasodilators (e.g., nitric oxide) and proinflammatory agents (e.g., tumor necrosis factor alpha). This leads to physiological and biochemical changes in the vasculature with the aim to stimulate angiogenesis and increase coronary function (42). Dayrit et al. are the first to use EECP for persistent post-COVID-19 symptoms. After 1 week of treatment, the patient’s brain fog improved. Shortness of breathing improved after 1.5 weeks and the patient reported returning to pre-COVID-19 health and fitness after approximately 5 weeks of EECP treatment. However, this was only one case and a control person was lacking.

Mayer et al. (20) presented another case of a 37-old-year woman who experienced persistent symptoms after COVID-19 infection including dyspnea, headache and cognitive fog. She previously participated in an outpatient physical therapist evaluation, which showed deficits in exercise capacity, reaching 50% of the expected 6-min walk distance for her age (6MWD). Moreover, she had minor reductions in muscle strength and cognitive function. She underwent a physical therapy examination that was based on the guidelines for intensive care unit (ICU) survivors as well as the COVID-19 core outcome measure guidelines from the academies and sections of the American physical therapy association. Subsequently, she participated in an 8-week biweekly physical therapy course that included aerobic training, strengthening exercises, diaphragmatic breathing techniques and mindfulness training. Metabolic equivalent (METS) values for tasks increased as the program progressed. The patient’s muscle strength, physical performance, and physical function improved. The 6MWD increased by 199 m, which is 80% of the predicted distance for her age. However, self-reported quality of life (QoL) scores did not improve. After physical therapy, the patient continued to have migraine, dyspnea, fatigue, and cognitive impairment. Also in this case-report (n = 1) there was no control group.

Bhaiyat et al. (21) reported in a case-report of a 55-year-old healthy man the use of hyperbaric oxygen therapy. The man suffered from persistent symptoms including fatigue, memory problems, low energy, breathlessness and reduced physical fitness, which all started 3 months after the acute infection of COVID-19. He underwent a hyperbaric oxygen therapy that included 60 sessions, 5 days per week, and each session encompassed exposure to 90 min of 100% oxygen at 2 atmosphere absolute with 5-min air breaks every 20 min. The patient noted less fatigue and an improvement in his previous low energy after 15 sessions. Additionally, he reported that his memory and multitasking ability returned to his pre-COVID-19 levels. The baseline brain MRI, prior to therapy showed a global decrease in the brain perfusion which was increased after therapy. However, this was only one case and a control person was lacking.

Pang et al. (22) used a drug called Qingjin Yiqi granules (QJYQ) for 388 patients with post-COVID-19 fatigue for 14 days. QJYQ contains 16 herbs. These herbs are initially extracted with water, followed by concentration and spray-drying to powder, after which excipients are added with the final mixture pelletized by dry granulation method. Each package contains 10 g, equivalent to 52 g of the crude drug. QJYQ has been recommended by the rehabilitation guidelines of integrated medicine for patients with post-COVID-19 in China (4344). In this study, data showed the QJYQ-group was superior to the control group in Borg scale, which was employed to evaluate perceived exertion and fatigue. Improvement in breathlessness and fatigue has been shown. No adverse event related to QJYQ was recorded.

Botek et al. (27) used in their randomized, single-blind, placebo-controlled study molecular hydrogen (H2) as a therapeutic gas for 50 patients with post-COVID-19 with a follow-up of 33 days because it has antioxidative, anti-inflammatory, anti-apoptotic and anti-fatigue properties (4547). The protocol consisted of H2/placebo inhalation, 2 × 60 min/day for 14 days. Results showed that H2 therapy increased 6-min walking distance and improved forced vital capacity (FVC) and forced expiratory volume (FEV1) compared with placebo. These data suggested that H2 inhalation may have beneficial health effects in terms of improved physical and respiratory function in patients with post-COVID-19.


Fatigue was reported as one of the most common persistent symptoms in individuals infected with SARS-CoV-2 before. Persistent fatigue lasting at least 6 months is termed chronic fatigue syndrome (33). This may be observed after several viral and bacterial infections (48). In the included studies of the present systematic review, fatigue was a symptom that either occurred already in the acute phase or developed after recovery from the acute phase of infection. The included studies recruited patients for a maximum of 9 months, with fatigue as persistent symptom. This should be followed up for a longer period to see how long fatigue could persist after the acute infection of COVID-19.

The origin of fatigue can be—based on our current knowledge—explained by a biopsychosocial model of the disease (49). It can be caused by a variety of biological or physical dysfunctions (e.g., genetic factors). In addition, other factors may contribute to the development of fatigue in patients with post-COVID-19 such as cytokines released by SARS-CoV-2 infection that impair psychological defense mechanisms. Also, the prevalence of preexisting autoimmune disease and elevated ANA (antinuclear antibodies) in a cohort of participants with post-COVID-19 compared to the general population suggests the possibility of an autoimmune contribution (10). Lastly, Townsend et al. (17) clearly demonstrated the absence of significant dysautonomia in post-COVID-19 fatigue. Social factors (e.g., socioeconomic status) as well as psychological factors (e.g., emotional stress) can contribute individually or in combination to the development of fatigue (49). Psychological and social factors include experiences of helplessness in illness, avoidance behaviors, financial worries due to unemployment, and loneliness due to limitations in social contacts (49). However, the individual handling of fatigue (motivational factors, coping behavior, sleep habits) also represents an important factor. In our systematic review, a possible link between premorbid depression/anxiety and post-COVID-19 fatigue has been shown (1624). Taken, together, the most predisposing factors of persistent symptoms observed in patients with post-COVID-19 syndrome were old age, female sex, severe clinical status at acute phase, high number of comorbidities, premorbid depression/anxiety, hospital admission and oxygen supplementation at the acute phase (50).

Several non-mutually exclusive hypotheses regarding the pathogenesis of COVID-19 suggest that anti-inflammatory drugs may be beneficial for selected patients (51). Also psychotropic drugs (e.g., selective serotonin reuptake inhibitors) (52) can modulate pro-inflammatory cytokine levels, and may have beneficial effects on mood and cognition in COVID-19 survivors (53). However, data are lacking and the effect of these drugs on patients with post-COVID-19 fatigue should be investigated.

Based on the suggested vascular pathophysiology possibly contributing to post-COVID-19 fatigue (54), EECP may be an appropriate treatment for such patients. EECP is a none-invasive treatment for patients with chronic stable angina and/or ischemic heart failure (42). It has also been shown to enhance cerebral blood flow, collateralization in the ischemic regions of the brain, and cognitive function. Improving of the patient’s symptoms in the case-report of Dayrit et al. (19) gives further rise to the hypothesis that post-COVID-19 fatigue may be related to intracerebral hypoperfusion possibly due to COVID-19 associated microemboli (55).

Based on our findings, rehabilitation programs like pulmonary rehabilitation using hyperbaric oxygen therapy or physical therapy including aerobic training, strengthening exercises, diaphragmatic breathing techniques as well as mindfulness training, might represent treatment options in patients with persistent symptoms after COVID-19. Also, a molecular hydrogen (H2) inhalation had beneficial health effects in terms of improved physical (6-min walking test) and respiratory function in patients with post-COVID-19 (27). Other therapeutic options are likely to appear as well and may have been missed here due to the focus on English written literature only. It would be also important to investigate whether (additional) psychotherapeutic approaches such as cognitive behavioral therapy, shown before to be beneficial for patients with long-lasting fatigue after Q-fever (affecting up to 30% of patients after the largest reported outbreak of Q-fever) could be an effective treatment for post-COVID-19 as also suggested by Vink et al. (56), however, actual data are lacking so far. Since most patients with post-COVID-19 fatigue also suffer from brain fog, myalgia, and depression/anxiety, more research including physical and psychological therapy is necessary in order to identify treatment options and ultimately improve the quality of life of patients with post-COVID-19 fatigue.


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Unraveling the Interplay of Omicron, Reinfections, and Long Covid

Authors:  Liz Szabo AUGUST 26, 2022 KHN

The latest covid-19 surge, caused by a shifting mix of quickly evolving omicron subvariants, appears to be waning, with cases and hospitalizations beginning to fall.

Like past covid waves, this one will leave a lingering imprint in the form of long covid, an ill-defined catchall term for a set of symptoms that can include debilitating fatigue, difficulty breathing, chest pain, and brain fog.

Although omicron infections are proving milder overall than those caused by last summer’s delta variant, omicron has also proved capable of triggering long-term symptoms and organ damage. But whether omicron causes long covid symptoms as often — and as severe — as previous variants is a matter of heated study.

Michael Osterholm, director of the University of Minnesota’s Center for Infectious Disease Research and Policy, is among the researchers who say the far greater number of omicron infections compared with earlier variants signals the need to prepare for a significant boost in people with long covid. The U.S. has recorded nearly 38 million covid infections so far this year, as omicron has blanketed the nation. That’s about 40% of all infections reported since the start of the pandemic, according to the Johns Hopkins University Coronavirus Research Center.

Long covid “is a parallel pandemic that most people aren’t even thinking about,” said Akiko Iwasaki, a professor of immunobiology at Yale University. “I suspect there will be millions of people who acquire long covid after omicron infection.”

Scientists have just begun to compare variants head to head, with varying results. While one recent study in The Lancet suggests that omicron is less likely to cause long covid, another found the same rate of neurological problems after omicron and delta infections.

Estimates of the proportion of patients affected by long covid also vary, from 4% to 5% in triple-vaccinated adults to as many as 50% among the unvaccinated, based on differences in the populations studied. One reason for that broad range is that long covid has been defined in widely varying ways in different studies, ranging from self-reported fogginess for a few months after infection to a dangerously impaired inability to regulate pulse and blood pressure that may last years.

Even at the low end of those estimates, the sheer number of omicron infections this year would swell long-covid caseloads. “That’s exactly what we did find in the UK,” said Claire Steves, a professor of aging and health at King’s College in London and author of the Lancet study, which found patients have been 24% to 50% less likely to develop long covid during the omicron wave than during the delta wave. “Even though the risk of long covid is lower, because so many people have caught omicron, the absolute numbers with long covid went up,” Steves said.

recent study analyzing a patient database from the Veterans Health Administration found that reinfections dramatically increased the risk of serious health issues, even in people with mild symptoms. The study of more than 5.4 million VA patients, including more than 560,000 women, found that people reinfected with covid were twice as likely to die or have a heart attack as people infected only once. And they were far more likely to experience health problems of all kinds as of six months later, including trouble with their lungs, kidneys, and digestive system.

“We’re not saying a second infection is going to feel worse; we’re saying it adds to your risk,” said Dr. Ziyad Al-Aly, chief of research and education service at the Veterans Affairs St. Louis Health Care System.

Researchers say the study, published online but not yet peer-reviewed, should be interpreted with caution. Some noted that VA patients have unique characteristics, and tend to be older men with high rates of chronic conditions that increase the risks for long covid. They warned that the study’s findings cannot be extrapolated to the general population, which is younger and healthier overall.

“We need to validate these findings with other studies,” said Dr. Harlan Krumholz, director of the Yale New Haven Hospital Center for Outcomes Research and Evaluation. Still, he added, the VA study has some “disturbing implications.”

With an estimated 82% of Americans having been infected at least once with the coronavirus as of mid-July, most new cases now are reinfections, said Justin Lessler, a professor of epidemiology at the University of North Carolina Gillings School of Global Public Health.

Of course, people’s risk of reinfection depends not just on their immune system, but also on the precautions they’re taking, such as masking, getting booster shots, and avoiding crowds.

New Jersey salon owner Tee Hundley, 43, has had covid three times, twice before vaccines were widely available and again this summer, after she was fully vaccinated. She is still suffering the consequences.

After her second infection, she returned to work as a cosmetologist at her Jersey City salon but struggled with illness and shortness of breath for the next eight months, often feeling like she was “breathing through a straw.”

She was exhausted, and sometimes slow to find her words. While waxing a client’s eyebrows, “I would literally forget which eyebrow I was waxing,” Hundley said. “My brain was so slow.”

When she got a breakthrough infection in July, her symptoms were short-lived and milder: cough, runny nose, and fatigue. But the tightness in her chest remains.

“I feel like that’s something that will always be left over,” said Hundley, who warns friends with covid not to overexert. “You may not feel terrible, but inside of your body there is a war going on.”

Although each omicron subvariant has different mutations, they’re similar enough that people infected with one, such as BA.2, have relatively good protection against newer versions of omicron, such as BA.5. People sickened by earlier variants are far more vulnerable to BA.5.

Several studies have found that vaccination reduces the risk of long covid. But the measure of that protection varies by study, from as little as a 15% reduction in risk to a more than 50% decrease. A study published in July found the risk of long covid dropped with each dose people received.

For now, the only surefire way to prevent long covid is to avoid getting sick. That’s no easy task as the virus mutates and Americans have largely stopped masking in public places. Current vaccines are great at preventing severe illness but do not prevent the virus from jumping from one person to the next. Scientists are working on next-generation vaccines — “variant-proof” shots that would work on any version of the virus, as well as nasal sprays that might actually prevent spread. If they succeed, that could dramatically curb new cases of long covid.

“We need vaccines that reduce transmission,” Al-Aly said. “We need them yesterday.”

New study suggests covid increases risks of brain disorders

Authors: Frances Stead Sellers Fri, August 19, 2022  Washington Post

A study published this week in the Lancet Psychiatry showed increased risks of some brain disorders two years after infection with the coronavirus, shedding new light on the long-term neurological and psychiatric aspects of the virus.

The analysis, conducted by researchers at the University of Oxford and drawing on health records data from more than 1 million people around the world, found that while the risks of many common psychiatric disorders returned to normal within a couple of months, people remained at increased risk for dementia, epilepsy, psychosis and cognitive deficit (or brain fog) two years after contracting covid. Adults appeared to be at particular risk of lasting brain fog, a common complaint among coronavirus survivors.

The study was a mix of good and bad news findings, said Paul Harrison, a professor of psychiatry at the University of Oxford and the senior author of the study. Among the reassuring aspects was the quick resolution of symptoms such as depression and anxiety.

“I was surprised and relieved by how quickly the psychiatric sequelae subsided,” Harrison said.

David Putrino, director of rehabilitation innovation at Mount Sinai Health System in New York, who has been studying the lasting impacts of the coronavirus since early in the pandemic, said the study revealed some very troubling outcomes.

“It allows us to see without a doubt the emergence of significant neuropsychiatric sequelae in individuals that had covid and far more frequently than those who did not,” he said.

Because it focused only on the neurological and psychiatric effects of the coronavirus, the study authors and others emphasized that it is not strictly long-covid research.

“It would be overstepping and unscientific to make the immediate assumption that everybody in the [study] cohort had long covid,” Putrino said. But the study, he said, “does inform long-covid research.”

Between 7 million and 23 million people in the United States have long covid, according to recent government estimates – a catchall term for a wide range of symptoms including fatigue, breathlessness and anxiety that persist weeks and months after the acute infection has subsided. Those numbers are expected to rise as the coronavirus settles in as an endemic disease.

The study was led by Maxime Taquet, a senior research fellow at the University of Oxford who specializes in using big data to shed light on psychiatric disorders.

The researchers matched almost 1.3 million patients with a diagnosis of covid-19 between Jan. 20, 2020, and April 13, 2022, with an equal number of patients who had other respiratory diseases during the pandemic. The data, provided by electronic health records network TriNetX, came largely from the United States but also included data from Australia, Britain, Spain, Bulgaria, India, Malaysia and Taiwan.

The study group, which included 185,000 children and 242,000 older adults, revealed that risks differed according to age groups, with people age 65 and older at greatest risk of lasting neuropsychiatric affects.

For people between the ages of 18 and 64, a particularly significant increased risk was of persistent brain fog, affecting 6.4 percent of people who had had covid compared with 5.5 percent in the control group.

Six months after infection, children were not found to be at increased risk of mood disorders, although they remained at increased risk of brain fog, insomnia, stroke and epilepsy. None of those affects were permanent for children. With epilepsy, which is extremely rare, the increased risk was larger.

The study found that 4.5 percent of older people developed dementia in the two years after infection, compared with 3.3 percent of the control group. That 1.2-point increase in a diagnosis as damaging as dementia is particularly worrisome, the researchers said.

The study’s reliance on a trove of de-identified electronic health data raised some cautions, particularly during the tumultuous time of the pandemic. Tracking long-term outcomes may be hard when patients may have sought care through many different health systems, including some outside the TriNetX network.

“I personally find it impossible to judge the validity of the data or the conclusions when the data source is shrouded in mystery and the sources of the data are kept secret by legal agreement,” said Harlan Krumholz, a Yale scientist who has developed an online platform where patients can enter their own health data.

Taquet said the researchers used several means of assessing the data, including making sure it reflected what is already known about the pandemic, such as the drop in death rates during the omicron wave.

Also, Taquet said, “the validity of data is not going to be better than validity of diagnosis. If clinicians make mistakes, we will make the same mistakes.”

The study follows earlier research from the same group, which reported last year that a third of covid patients experienced mood disorders, strokes or dementia six months after infection with the coronavirus.

While cautioning that it is impossible to make full comparisons among the effects of recent variants, including omicron and its subvariants, which are currently driving infections, and those that were prevalent a year or more ago, the researchers outlined some initial findings: Even though omicron caused less severe immediate symptoms, the longer-term neurological and psychiatric outcomes appeared similar to the delta waves, indicating that the burden on the world’s health-care systems might continue even with less-severe variants.

Hannah Davis, a co-founder of the Patient-Led Research Collaborative, which studies long covid, said that finding was meaningful. “It goes against the narrative that omicron is more mild for long covid, which is not based on science,” Davis said.

“We see this all the time,” Putrino said. “The general conversation keeps leaving out long covid. The severity of initial infection doesn’t matter when we talk about long-term sequalae.

New research provides insight into Long COVID and ME

Authors: University of Otago July 12, 2022: Science Daily

Summary: Researchers have uncovered how post-viral fatigue syndromes, including Long COVID, become life-changing diseases and why patients suffer frequent relapses.

Arising commonly from a viral infection, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), is known to cause brain-centred symptoms of neuroinflammation, loss of homeostasis, brain fog, lack of refreshing sleep, and poor response to even small stresses.

Long-COVID has similar effects on people and is believed to also be caused by neuroinflammation.

Lead author Emeritus Professor Warren Tate, of the University of Otago’s Department of Biochemistry, says how these debilitating brain effects develop is poorly understood.

In a study published in Frontiers in Neurology, he and colleagues from Otago, Victoria University of Wellington and University of Technology Sydney, developed a unifying model to explain how the brain-centred symptoms of these diseases are sustained through a brain-body connection.

They propose that, following an initial viral infection or stressor event, the subsequent systemic pathology moves to the brain vianeurovascular pathways or through a dysfunctional blood-brain barrier. This results in chronic neuroinflammation, leading to a sustained illness with chronic relapse recovery cycles.

The model proposes healing does not occur because a signal continuously cycles from the brain to the body, causing the patient to relapse.

The creation of this model is not only important for the “huge research effort ahead,” but also to provide recognition for ME/CFS and Long COVID sufferers.

“These diseases are very closely related, and it is clear the biological basis of Long COVID is unequivocally connected to the original COVID infection — so there should no longer be any debate and doubt about the fact that post viral fatigue syndromes like ME/CFS are biologically based and involve much disturbed physiology,” Emeritus Professor Tate says.

This work will enable best evidence-based knowledge of these illnesses, and best management practices, to be developed for medical professionals.

“Patients need appropriate affirmation of their biological-based illness and help to mitigate the distressing symptoms of these very difficult life-changing syndromes which are difficult for the patients to manage by themselves.

“This work highlighted that there is a susceptible subset of people who develop such syndromes when exposed to a severe stress, like infection with COVID-19, or the glandular fever virus Epstein Barr, or in some people with vaccination that is interpreted as a severe stress.

“What should be a transient inflammatory/immune response in the body to clear the infection, develop immunity and manage the physiological stress, becomes chronic, and so the disease persists.”

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Story Source:

Materials provided by University of OtagoNote: Content may be edited for style and length.

Journal Reference:

  1. Warren Tate, Max Walker, Eiren Sweetman, Amber Helliwell, Katie Peppercorn, Christina Edgar, Anna Blair, Aniruddha Chatterjee. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote RelapsesFrontiers in Neurology, 2022; 13 DOI: 10.3389/fneur.2022.877772

Researchers are working together to better understand and treat the syndrome


Robin Macnofsky’s first symptoms, in April 2020, were so mild she didn’t take a test for COVID-19, preferring to save it for someone who really needed it.

A few weeks later her chest tightened and her temperature spiked. These ebbed, but an even stronger wave hit: a high fever and exhaustion that left her bedbound in a days-long “zombie sleep.” Macnofsky tested positive for COVID-19 (likely from remaining viral genetic material). Her symptoms endured.

Previously a champion multi-tasker who could split her concentration in four directions, the then-59-year-old could no longer follow the plot of a TV episode or walk her dog. Her temperature waxed and waned.

A realization dawned: The end was nowhere in sight, and no one could tell her why.

Scientists studying the unfamiliar and unfurling COVID-19 pandemic also began to realize that for Macnofsky and many other COVID-19 patients, a long hospital stay or a short, mild illness were not the only outcomes. For some people, mild symptoms, quickly resolved, were just the beginning.

Researchers worldwide, including many at Fred Hutchinson Cancer Research Center and the University of Washington, are working to understand long COVID-19, the long-lasting effects of COVID-19 infection that can affect adults, teens and children. Hutch and UW investigators are building on deep expertise in immunology and infectious diseases like HIV to figure out what causes long COVID-19, who is at risk, and how to treat it. To do so, they’re tackling challenges that range from basic questions about how best to measure symptoms to uncovering the complex immunological interplay that may drive symptoms.

‘Something is different’

In March 2020, Julie Czartoski, a nurse practitioner working with Fred Hutch virology expert and Joel D. Meyers Endowed Chair holder Dr. Julie McElrath, helped McElrath quickly put together a study, the Seattle COVID Cohort Study, to look at COVID-19 in first responders and those infected with SARS-CoV-2, the virus that causes COVID-19. They wanted to know who was getting it, and how badly. Soon they opened the study to others in the community. Luckily, few participants who contracted the coronavirus had symptoms that warranted hospitalization. Most had relatively mild infections that cleared up quickly.

But that wasn’t the end. For many, symptoms persisted, even worsened. Participants reported lingering fevers, new joint pain, exhaustion and brain fog, among a grab bag of other symptoms. When an unexpected number of young, healthy firefighters reported atrial fibrillation — a rapid, abnormal heart rhythm — Czartoski knew something was up.

“It’s not unheard of in young adults, but to have so many was weird,” she said. “I remember texting Julie McElrath and saying, ‘Something is different, because these people are still sick.’”

Because of their fast action and prompt study enrollment, Czartoski and McElrath were early to recognize a truth that would eventually become clear to other scientists: COVID-19 can cast a long shadow.

More research and resources 

Many of the people in McElrath’s study who reported lasting problems had experienced mild, almost cold-like infections with SARS-CoV-2. Very few had been hospitalized.

It takes time to know for sure that a patient is suffering from long COVID-19. A week or two is not long enough to be sure their symptoms won’t clear up soon. Eventually, McElrath and her team found that about 30% of the coronavirus-positive participants in their study had lasting symptoms, or new symptoms attributed to COVID-19, that extended at least 60 days past their initial infection, Czartoski said.

Long COVID-19 dogs some patients, like Macnofsky, much longer, and their symptoms can be severe. After two different week-long hospital stays, in which she underwent terrifying procedures to remove nearly a liter of fluid pressing on her heart and then her lungs, Macnofsky took a leave of absence from her career as a community organizer. By early 2022, she still rations her energy and has yet to regain her prior multi-tasking abilities.

Time defines the syndrome and time challenges those suffering from it and the scientists working to untangle it. Also known as PASC, for post-acute sequelae of SARS-CoV-2 infection, long COVID-19 refers to symptoms that endure long after someone has recovered from their initial coronavirus infection. (The term “sequelae” refers to a disease’s aftereffects.) Symptoms can include fatigue, shortness of breath, brain fog, fever, anxiety and depression. COVID-19 patients who were sick enough to need ICU care may also be dealing with post-ICU syndrome, and it’s not yet clear how their experience will unfold differently from patients who were treated in the ICU for other causes.

For a health problem as mysterious and as complex as long COVID-19, progress requires scientific teamwork.

That’s why, in summer 2021, Dr. Rachel Bender Ignacio reached out to investigators across Fred Hutch and the University of Washington, inviting them to join a long COVID-19 working group to share challenges and solutions, and find collaborators to help investigate specific questions.

As medical director of the Hutch’s COVID-19 Clinical Research Center, or CCRC, Bender Ignacio had a good sense of who at both institutions were treating or studying the syndrome. She was also hearing from CCRC trial participants who had transitioned from acute to long COVID-19 and wanted to know how scientists were addressing it. “I have my ear to the ground,” she said.

Bender Ignacio felt that progress required stronger connections between clinicians and laboratory and translational scientists. Physicians needed a better understanding of the biological mechanisms driving long COVID-19 before they could move proposed treatments into clinical trials, and basic scientists could reveal those mechanisms but needed tissue samples and clinical insights from the people providing patient care.

“Bringing everyone together was the least I could do,” Bender Ignacio said.

The working group she put together is an example of international and multidisciplinary efforts to tackle the challenges that vex investigators studying long COVID-19, including how to best classify and diagnose the syndrome, what’s causing it, and how to treat it. The recently launched National Institutes of Health RECOVER initiative, aimed at understanding PASC, is giving the investigators in the field hope that standards may be forthcoming, said Dr. Eric Chow, a working group member and UW infectious diseases fellow who studies the damage that respiratory viruses can do outside the lungs.

The researchers who joined Bender Ignacio’s collective span disciplines and body systems, including the brain, heart and lungs. They include researchers and clinicians at UW and Harborview Medical Center, which opened one of the nation’s earliest clinics devoted to helping long COVID-19 patients. The working group members bring expertise in long-term complications from viral infections like HIV and influenza, and know how viruses or the immune reaction to them can damage the body. SARS-CoV-2 may be wreaking the most havoc right now, but it’s not the only virus that can upend sufferers’ lives: Many, including Bender Ignacio, have spent their careers studying the long-term effects of HIV.

Now the team is bringing their wide-ranging expertise to bear on the many questions of long-haul COVID-19, hoping to surmount its challenges and help patients.

Learning on the fly

Studying a little-understood problem in a rapidly shifting pandemic is incredibly challenging. At the beginning, scientists had no knowledge base to inform their data collection or study design. Every week or month brought new information that forced them to reassess the data they had already collected — and adjust their data-collection methods to incorporate new understanding.

“It’s like building a boat while you’re sailing it,” said working group and CCRC member Dr. James Andrews, a University of Washington rheumatologist who studies how sepsis, particularly severe cases requiring hospitalization, can lead to long-term disability.

The first challenge was realizing that a problem existed. Many of the long-haulers Czartoski interviewed for the Seattle COVID Cohort Study struggled to find help and even recognition of their symptoms, she said.

“In the beginning, a big part of my job was just listening,” Czartoski recalled.

Study participants wept as they described to her their crushing fatigue and debilitating symptoms, and the struggle to get health care providers to understand that their vague-seeming complaints posed a real problem. Macnofsky, too, found it difficult to get help for her constant fever, headaches, fatigue and brain fog.

In the beginning, no one knew what information would be important to understand why these patients were suffering and how to help.

A snapshot of data “is one piece of the whole puzzle,” said Hutch statistician Dr. Zoe Moodie, who helps design and analyze HIV vaccine trials and develops statistical methods to analyze immunological data. “Generally, the more pieces the better, and as time goes go on we learn which are the important pieces.”

Czartoski tackled the problem by collecting everything she could: “Sometimes [a symptom] didn’t seem important, then a week later I’d have five people reporting it.”

And sometimes the information that most impacts a patient’s life can seem negligible when committed to paper, she said. One person’s loss of smell or taste may seem like small potatoes compared to others’ chronic exhaustion and continual fevers. But such seemingly small symptoms can make life and some careers difficult: Firefighters smell phantom burning and parents who can no longer smell a dirty diaper. Once-favorite food now repells.

“And [those symptoms] are really tough on quality of life,” Czartoski noted. Depression can set in, straining a person’s long-term relationships, affecting quality of life and for some, the ability to hold down a job.

Initially, she had a limited systematized questionnaire, and took notes longhand while patients noted every symptom they could think of — whether they knew it related to their COVID-19 or not. As time passed, Czartoski and her colleagues were able to spot common symptoms that they added to an ever-expanding checklist. (Then, they had to get the checklist built into the study records system.)

The working group members brainstorm statistical and analytical strategies that could help, and which take into account the fact that not everyone’s data has been collected in the same way at the same time points during the course of their disease.

Even now, their efforts to untangle long COVID-19 are hampered by what they didn’t know six, 12, 18 months ago, Czartoski said.

“Researchers will ask about blood drawn a year and a half ago: Were they taking Tylenol?” she said. “It could change the immune response, but I don’t know!”

Fred Hutch HIV researchers Dr. Julie McElrath (left) and Dr. Rachel Bender Ignacio (right) are parlaying their expertise in viral infections and clinical trials to help patients suffering from long COVID-19. McElrath gathered a cohort of long-haulers who are helping researchers dig into the immune drivers of PASC. As the CCRC’s medical director, Bender Ignacio helps make crucial connections between basic and translational scientists working in the field.

Photos by Robert Hood / Hutch News Service

Finding the right box

Another major challenge that long COVID-19 researchers face is classification. Many studies are producing data on the syndrome, but if symptoms aren’t collected and classified similarly, trying to compare different studies will be like comparing apples and oranges.

Decisions about how to classify symptoms also affect how patients are grouped together and how the data is analyzed. One big concern: Should patients be grouped by symptom, or should symptoms be grouped by the organs they affect?

It’s a bit of a chicken-and-egg issue, but it gets into the problem of what’s behind long COVID-19 to begin with, said Chow, who began treating Macnofsky after her hospital stay. (The two teamed up to tell Macnofsky’s story in a dual first-person essay published in the scientific journal Open Forum Infectious Diseases.)

“For example, what about fatigue? Do you group everyone with fatigue together? But what if one person’s fatigue is caused by damage to the nervous system, another’s by damage to their heart, and someone else’s by lung damage,” said Chow, who at the start of the pandemic was part of the Centers for Disease Control and Prevention team that went to New York state to confirm COVID-19-associated multisystem inflammatory syndrome in children.

Even in cases where it’s clear the immune system is at fault, fatigue may not have a single cause. Energy-sucking immune activation could explain one person’s fatigue, but post-infection autoimmunity, in which their own tissues are under attack, could be the reason behind another’s, Andrews said.

Trying to find the biological similarities in data taken from these patients would be like trying to compare pages of text written in different languages: more likely to result in gibberish than to identify a helpful pattern.

And sometimes, symptoms may not even be the result of a person’s coronavirus infection. Part of the problem is the often-vague, widely varying collection of symptoms, many of which long COVID-19 shares with other chronic health problems, such as autoimmune diseases or chronic fatigue syndrome. Autoimmune diseases often strike in young adulthood. For some people, SARS-CoV-2 infection and an autoimmune diagnosis are just two pieces of unrelated bad luck.

“In a longitudinal cohort like this, nothing is ever completely clean,” Czartoski said.

Working group members share questions and strategies. Should they classify symptoms by severity score, or follow the CDC’s recommendations to classify symptoms by outcome measures in different areas? Members often draw on their or other members’ expertise in different disciplines, such as adapting questionnaires used by neurologists to assess cognitive difficulties. Czartoski recommended a severity scale long used by HIV researchers to assess how symptoms impact patients’ daily living.

The team also grapples with the challenges of classifying symptoms that may seem focused on a specific organ system, but are actually emblematic of a body-wide problem. Researchers noted that some simplification needs to occur to make it possible to analyze the reams of data that can be collected.

But sometimes it’s unclear what’s causing someone’s symptom — so researchers can’t classify symptoms by underlying cause. What then?

Members also keep an eye on trends in the wider scientific community to see if they can align with areas of growing consensus, the better to compare their results with other studies.

Who’s at risk for symptoms, and how long will they last?

But sorting out the logistical challenges of classification is just the first step. Long COVID-19 researchers want to understand why symptoms develop and who’s at risk. Why do some symptoms affect some patients but not others? Who will have a mild course, and who will suffer greatly? A deeper understanding, they hope, will shed light on why symptoms linger so long for some people, and how to predict how a patient’s experience will unfold.

UW neurologist Dr. Payal Patel is focusing on the cognitive symptoms of PASC.

“I want to know, what is the cause of the symptoms we see in PASC,” said Patel, who studies the continuing effects of infections of the central nervous system, including HIV. “We know PASC affects different organ systems. I’m trying to get a better clinical understanding of how it affects the brain.”

Without this, it’s difficult to give worried patients a clear picture of what they can expect from long COVID. Patel wants to better understand how long such symptoms last, who’s most at risk, and what’s causing them. Is brain fog caused primarily by immune dysfunction? Or could the clotting problems associated with COVID-19 have damaged the cells lining blood vessels in the brain? Patel and a team of scientists have studies underway to answer these questions.

This type of location-specific question can be very difficult to address, Chow noted. It’s relatively easy to take blood samples and look at general patterns of immune cells or antibodies floating through the blood. But what about problems that are occurring at a hard-to-reach spot, like tiny blood vessels in the brain or lungs?

Some working group members focus their research questions on specific areas of the body. With Patel, Andrews is trying to understand who’s most at risk for cognitive and physical impairments after COVID. Some patients’ fatigue is related to muscle wasting, known medically as sarcopenia, and Andrews wants to know what’s behind that and who’s at risk.

Role of the immune system in long COVID-19

Since it became understood that an overactive immune response (known as a “cytokine storm”) lurks behind some of COVID-19’s most dire complications, scientists have begun digging deeper into how the immune system responds to SARS-CoV-2. Macnofsky herself participated in a Benaroya Research Institute study looking at the immune response to the novel coronavirus.

Bender Ignacio’s working group is drawing on the Hutch’s longstanding expertise in immunology and infectious diseases and looking to the immune system for answers.

“We’re studying what natural infection looks like over time,” said Fred Hutch immunologist Dr. Maria Lemos, who studies immune responses in mucosal tissue like vaginal and nasal surfaces, where we first encounter many viruses. “People could have cold symptoms for nine days, then four moths later they’re diagnosed with a lung condition or a heart condition.”

To understand why, she and others on McElrath’s team are mapping the immune response to SARS-CoV-2 infection as it unfolds over months. With collaborators at Emory University in Atlanta, they’re charting the rise and fall of antibodies against the virus and how different immune-cell populations grow, shrink and morph over time.

By describing how these responses differ between people who did and did not develop long COVID-19, the researchers hope to identify key biomarkers, like specific inflammatory proteins, that help predict which patients will have persistent problems. Such biological predictors could help doctors intervene early, either to help connect patients with the right services to help them deal with symptoms, or (once scientists crack this problem) stave it off entirely.

McElrath’s team, with collaborators at Emory University and the Seattle-based Allen Institute for Immunology, has revealed some tantalizing immunological patterns, Lemos said, which the group posted on the preprint server biorxiv.org. The immune trajectory in many long-haulers looks startlingly unlike that seen in people who recover quickly and permanently.

“The alarm system of the immune system doesn’t get turned on as quickly in these people — but surprisingly it seems to remain on for way longer,” Lemos said. They’re currently putting together a paper for peer review at a scientific journal.

On top of this project, Moodie is working with investigators the Allen Institute to identify immunological signatures, including cellular features like proteins and gene expression, that distinguish long COVID-19 from acute COVID-19. Some patients — including Macnofsky — report improvement of symptoms after vaccination for COVID-19, and Moodie and her collaborators want to understand how vaccination may help their bodies resolve their chronic, damaging immune responses.

(Whether prior COVID-19 vaccination helps protect against developing long COVID-19 is still being explored. A recent study in The Lancet suggests that vaccinated people are less likely to have long-lasting symptoms after SARS-CoV-2 infection.)

Treatments for long-haulers?

Macnofsky said she’s recently been helped by six months of weekly pulmonary rehab sessions. It’s possible that early access to rehabilitative therapies could help prevent or alleviate severe long COVID-19 in others.

It is taking time for scientists at the Hutch and elsewhere to get a clear enough picture of what’s driving long COVID-19 to open clinical studies to address patients’ problems, but a few have begun.

The Seattle arm of a multi-center, Phase 2 trial of a drug called RSLV 132, is administered through the CCRC and headed by Andrews. (People interested in participating can contact the CCRC.) Developed by biotech company Resolve Therapeutics, the drug has already shown promise against fatigue in people with autoimmune diseases like Sjögren syndrome, and scientists hope long COVID-19 patients will also benefit.

“One of the exciting things about this study is that it’s taking a targeted therapy approach to treating symptoms,” Andrews said. “It’s targeting the mechanism behind fatigue — chronic inflammation — to see if it helps.”

In addition to testing whether RSLV 132 outperforms a placebo when it comes to alleviating fatigue in long COVID-19 patients, researchers will collect tissue samples that they’ll study to get a better picture of how it might be working (if it does), he said. If it turns out that some patients respond and some don’t, such samples could also help investigators figure out why.

And, if there’s a similar biological process underpinning the fatigue seen in long COVID and other diseases and syndromes, the study could benefit a wide array of patients, Andrews said.

That’s a hope that other members of the working group also harbor. One of the big questions, said Chow, is whether long COVID-19 patients are suffering from the same immunologic problems as patients with chronic fatigue syndrome, autoimmune diseases, or other virus-associated chronic damage. Or is there something unique about the biology behind long COVID-19?

Bender Ignacio sees potential for the close ties between the CCRC and the long COVID-19 working group to help fast-track promising treatments or treatment strategies that emerge from group members’ projects.  

Working toward a more certain future

One thing Chow hopes come from the studies is more predictability. Right now, clinicians struggle to determine whose symptoms will last, and whose will resolve. A better understanding of long COVID-19 subgroups will help clinicians guide patients toward the best therapies for them. Improving doctors’ ability to diagnose and clinically characterize long COVID-19 will also help improve insurance reimbursement, he said. Right now, he stressed the need to recognize and validate what patients with long COVID-19 face.

Macnofsky, who at one point couldn’t take a phone call from a friend without falling back into a zombie sleep, feels fortunate. She joined Facebook groups organized by long COVID-19 sufferers, where many reported not just horrible symptoms but job loss and crushing debt. Macnofsky’s leave of absence from her career was fully supported — emotionally and financially — by her husband. She’s recovered enough now to step back into some job duties, though not at her previous level. But she knows other patients who continue to suffer, with no idea when — or if — their symptoms will ever improve.

On top of everything else, her uncertain future is one of the biggest challenges Macnofsky faces Luckily, she said, her “keep calm and carry on” attitude (and compassionate family) are helping her ride her waves of symptoms.

“There’s a mental health component to being so ill,” Czartoski said. She still encourages patients to treat themselves gently and take it one day at a time. While most will improve with time, a few will worsen — and she still can’t tell someone which patient they’ll be. The answer will only come with more data.

“I’m still collecting everything I can,” Czartoski said.

Who’ll Get Long COVID? Just a Look at a Patient Gives Clues

Authors: Dennis Thompson Jul 19, 2022 The Indiana Gazette

ometimes just looking at a person can give clues to their likelihood of developing long COVID after a bout with the virus.

For example, obese people are five times more likely to suffer long COVID symptoms that persist at least three months after their infection clears, a major new U.S. study finds.

Another risk factor: Experiencing hair loss during COVID-19 illness, the same study found.

Headache and sore throat during infection also greatly increase a person’s risk of long-haul symptoms, the researchers added.

However, the results also showed that other risk factors for COVID-19 infection do not necessarily mean a person will develop long COVID, noted senior researcher Eileen Crimmins, chair of gerontology for the University of Southern California and director of the USC/UCLA Center on Biodemography and Population Health.

“What’s somewhat more interesting are the things that didn’t matter,” Crimmins said. “Gender didn’t predict long COVID. Race/ethnicity didn’t predict long COVID. And having conditions like hypertension [high blood pressure], heart disease, cancer, they didn’t predict long COVID.”

Overall, 23% of people infected with COVID-19 can be expected to develop long-haul symptoms, regardless of whether their infection was severe enough to require hospitalization, Crimmins and her colleagues reported. The study was published online recently in the journal Scientific Reports.

The World Health Organization defines long COVID as symptoms that last 12 weeks or longer after the initial infection has cleared, the researchers said.

“A significant number of people may have trouble working, taking care of their families, doing the things they need to do day-to-day because they’ve had the condition,” Crimmins said. “So, it’s not a nothing disease.”

These numbers are based on the Understanding America Study COVID-19 National Panel, an ongoing regular survey of more than 8,400 U.S. adults.

Starting every two weeks in March 2020, panel members were asked to fill out a questionnaire detailing their health status and any symptoms they might be having.

During the following year, about 10% of total participants reported that they’d been diagnosed with or tested positive for COVID-19.

The researchers focused in on 308 people who had COVID-19 and had reported their health status and symptoms before, during, and at least three months after their initial diagnosis.

What factors influenced the odds of long COVID the most? Obesity increased a person’s risk of long COVID by nearly five and a half times, the results showed. Other prominent risk factors included hair loss during infection, which increased sevenfold the risk of long COVID. Headache and sore throat each increased a person’s risk by more than three times.

It’s likely that obesity and hair loss are both tied to the amount of inflammation a person suffers during their COVID-19 infection, which can wreak havoc on their body’s organs, explained Dr. William Schaffner, medical director of the National Foundation for Infectious Diseases.

“Perhaps obesity allows that inflammation to persist for a longer period of time, therefore resulting in symptoms,” Schaffner said. “Hair loss is kind of new to me, but that’s obviously going to be some sort of symptom that relates somehow to inflammation.”

Surprisingly, age, gender, race, education, smoking, and preexisting health conditions like diabetes or asthma didn’t appear to influence the risk of long COVID.

The most common symptoms people developed during COVID that persisted months later included:

  • Headache (22%)
  • Runny or stuffy nose (19%)
  • Abdominal discomfort (18%)
  • Fatigue (17%)
  • Diarrhea (13%)

The study did not find other symptoms that have been commonly reported by long COVID-19 patients, including brain fog and joint pain, Schaffner noted.

“So there are some things that reinforce what’s in the literature and some other things that are a little different,” Schaffner said.

Despite that, Schaffner praised the study as a “noteworthy addition to the literature” that should help the many long COVID centers that have opened up around the country to deal with this phenomenon.

“The main thing I take away from this is that long COVID is not unusual. In fact, it’s rather common,” Schaffner said. “It’s persistent and it will require a great deal of medical attention going forward. A lot of medical resources will have to be devoted to this, and those resources will largely be outside the hospital, including supportive care, physical therapy and even some psychological support for these patients.”

Crimmins added it could take years, and even decades, to fully understand the long-term effects of COVID-19.

Research into the 1918 influenza pandemic found that fetuses in utero when moms caught the flu had a 25% higher risk of heart disease by the time they were in their 70s, Crimmins noted.

“There are things that may happen in this population to their underlying health that may not be immediately obvious, but could have relatively significant long-term effects,” Crimmins said of long COVID patients.


Scientists propose cause of symptoms, treatment for long COVID-19

Authors: Gary Van Beusekom | News Writer | CIDRAP News   Posted June 10, 2022

Two studies to be presented at upcoming professional society meetings suggest that some long COVID-19 symptoms may be related to the effect of SARS-CoV-2 on the vagus nerve and that the use of enhanced external counterpulsation (EECP)—which increases blood flow—can improve some of those symptoms, respectively.

Long COVID may affect up to 15% of those who survive their infections, causing symptoms such as fatigue, muscle pain, and cognitive problems that linger for months. Neither study has been peer-reviewed, and the second one comes with the added caveat that it was conducted by an EECP provider.

Long COVID, vagus nerve symptoms may overlap

At the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), slated for Apr 23 to 26 in Lisbon, Portugal, a team led by researchers in Spain will discuss the role of the vagus nerve in long COVID, according to an ECCMID news release.

The vagus nerve runs from the brain into the torso, heart, lungs, intestines, and several muscles, including those involved in swallowing. It has a role in heart rate, speech, the gag reflex, the transfer of food from the mouth to stomach, transporting food through the intestines, perspiration, and other bodily functions.

The study authors said that SARS-CoV-2 infection may lead to long COVID symptoms such as dysphonia (voice problems), dysphagia (difficulty swallowing), dizziness, tachycardia (rapid heart rate), orthostatic hypotension (low blood pressure), and diarrhea. Long COVID has been reported to last for months to more than a year.

In the observational study, the researchers evaluated the morphologic and functional aspects of the vagus nerve in 348 patients diagnosed as having long COVID at a Spanish hospital from March to June 2021. Of the 348, 228 (66%) had at least one symptom that could be attributed to vagus nerve dysfunction (VND).

The ongoing study involved the first 22 participants identified as having at least one VND symptom; 91% of them were women, and the median age was 44 years. The most common VND symptoms were diarrhea (73%), tachycardia (59%), dizziness, dysphagia and dysphonia (45% each), and orthostatic hypotension (14%).

Nineteen of 22 participants (86%) had three or more VND symptoms with a median duration of 14 months. Ultrasound examination revealed that at 6 (27%) had alterations of the vagus nerve in the neck, including thickening of the nerve and increased echogenicity, which indicates mild inflammatory changes.

Thoracic ultrasound showed flattened diaphragmatic curves, indicating abnormal breathing, in 10 participants (46%). Ten of 16 patients (63%) had lower maximum inspiration pressures, indicating weakness of the muscles involved in breathing.

Thirteen of 18 patients (72%) had impaired eating and digestive function, including self-reported dysphagia. Among 19 patients assessed for gastric and bowel function, 8 (42%) had impaired ability to move food from the esophagus to the stomach, with 2 of these 8 reporting difficulty swallowing.

Nine of 19 patients (47%) had gastroesophageal acid reflux, with 4 of these 9 again having problems moving food to the stomach and 3 with hiatal hernia (bulging of the upper stomach through the diaphragm into the chest cavity).

A Voice Handicap Index 30 test (a standard method of measuring voice function) produced abnormal results in 8 of 17 patients (47%), indicating that 7 of the 8 had dysphonia.

“Our findings so far thus point at vagus nerve dysfunction as a central pathophysiological feature of long COVID,” the researchers said in the release.

Improvement in functional scores, fatigue after EECP

In a retrospective study to be presented this week at the American College of Cardiology’s (ACC’s) virtual Cardiovascular Summit, scientists from EECP provider Flow Therapy evaluated the effect of the therapy in 50 COVID-19 survivors, according to an ACC news release. Twenty patients had coronary artery disease (CAD), while 30 did not; average age was 54 years.

EECP uses contracting and relaxing pneumatic cuffs on the calves, thighs, and lower hip area to provide oxygen-rich blood to the heart muscle, brain, and the rest of the body. Each session takes 1 hour, and patients may undergo as many as 35 sessions over 7 weeks.

All patients completed the Seattle Angina Questionnaire-7 (SAQ7), Duke Activity Status Index (DASI), PROMIS Fatigue Instrument, Rose Dyspnea Scale (RDS), and the 6-minute walk test (6MWT) before and after they completed 15 to 35 hours of EECP therapy.

The analysis showed statistically significant improvements in all areas assessed, including 25 more points for health status on the SAQ7 (range, 0 to 100), 20 more points for functional capacity on DASI (range, 0 to 58.2), 6 fewer points for fatigue on PROMIS (range, 4 to 20), 50% lower shortness of breath score on the RDS, and 178 more feet on the 6MWT.

The change from baseline among participants who had long COVID but not CAD was significant for all end points, but there was no difference between long COVID patients with or without CAD.

“Emerging data shows that long COVID is a disease that impacts the health of vessels, also known as endothelial function,” senior author Sachin Shah, PharmD, said in the release. “EECP is a disease-modifying, non-invasive therapy that has previously shown to improve endothelial function in controlled clinical trials.”

Shah said that several study participants weren’t able to work at the beginning of the study. “Remarkably, all patients at this point were able to successfully return back to work after undergoing treatment,” he said. “These patients also showed improvement in ‘brain fog,’ which is a common symptom of long COVID.”

The researchers called for larger studies with a control group receiving sham therapy to validate their findings.

Long COVID symptoms lasted a median of 15 months, Northwestern study finds

Authors: Lisa Schencker, Chicago Tribune May 24, 2022

People with long COVID-19 who visited a Northwestern Medicine clinic were still experiencing symptoms such as headaches, dizziness, fatigue and brain fog for a median of 15 months after first falling ill, despite never needing hospitalization, according to a new Northwestern study.

The study looked at 52 patients who were seen at Northwestern’s Neuro COVID-19 clinic between May 2020 and November 2020, who initially had mild COVID-19 symptoms. Study senior author Dr. Igor Koralnik said the study is the first to look, over such a long time period, at neurological symptoms in people who didn’t need to be hospitalized for COVID-19.

The study was published Tuesday in peer-reviewed journal Annals of Clinical and Translational Neurology.

“It’s important because … long COVID is not going to be going away,” said Koralnik, who is chief of Neuro-infectious Diseases and Global Neurology at Northwestern Medicine and oversees the Neuro COVID-19 Clinic.

Researchers believe long COVID may affect up to 30% of people who get COVID-19, which means an estimated 24 million people in the U.S. may be experiencing lingering symptoms, according to the American Academy of Physical Medicine and Rehabilitation, though some studies have found that being vaccinated may reduce a person’s risk of developing long COVID if they catch COVID-19.

“This is something people need to know about because it impacts a very large population in the U.S.,” Koralnik said.

In the study, there was no significant change in the frequency of patients experiencing symptoms including brain fog, numbness/tingling, headache, dizziness, blurred vision, tinnitus and fatigue, between their first appointments and when they completed questionnaires six to nine months later.

Loss of taste and smell decreased over time, but heart rate and blood pressure variation and gastrointestinal symptoms increased at follow-up.

The average age of the participants was 43, and nearly two-thirds were women. More than two-thirds were vaccinated, but they were vaccinated after they began experiencing COVID-19 symptoms because the vaccines were not yet available when they first got sick. The vaccines did not seem to worsen or improve their cognitive function or fatigue, according to the study.

For the study, researchers reached out to the first 100 non-hospitalized patients who visited the Northwestern clinic, and the 52 studied were those who completed follow-up questionnaires. Those patients had varying experiences with long COVID, with some mainly experiencing loss of taste and/or smell, while others, like Emily Caffee, struggled with a debilitating litany of symptoms.

Caffee said she likely got COVID-19 at the very beginning of the pandemic while traveling for a rowing competition. She had body aches, fatigue, shortness of breath, chest pain and foggy thinking. Though she felt ill, she wasn’t so sick that she had to be hospitalized.

After her initial bout with COVID-19, she returned to her then-job as a physical therapist for Northwestern, but her symptoms soon worsened, to the point that she took a three-month-long medical leave from work, starting in May 2020.

She was plagued by crushing fatigue, brain fog, heart palpitations, vision issues, pain in her legs and neck and unrelenting anxiety — what she called her “buffet of misery.”

“I couldn’t stand for five minutes without getting so dizzy and nauseous I needed to lay down for an hour,” said Caffee, 36, of Wheaton. “If I knew I had to take a shower or follow a recipe or walk downstairs to get the mail, that was it, that was all I could do all day.”

In August 2020, she returned to work, slowly ramping up her hours. By September 2020, when she saw Koralnik, she was feeling about 50% better, she said. Koralnik told her to continue doing what she was doing, slowly resuming her activities, she said.

The feedback was validating, considering that she had previously been told her problems were related to anxiety. She never tested positive for COVID-19, as testing wasn’t yet widespread when she got sick.

“Just hearing from them, from a physician … that what I was going through was real and not just anxiety was key for me,” she said.

Caffee, who now works at PT Solutions in Bloomingdale, said she now feels about 95% back to normal. “This took over two years of my life that I feel was just suffering in so many ways, but I consider myself lucky I’ve come through it without any major complications.”

Like Caffee, about half of the patients in the study never tested positive for COVID-19. But Koralnik said it was important to include them because, like Caffee, many likely had COVID-19, based on their symptoms, before testing was readily available.

“Those patients have experienced a lot of rejection and stigma, and those people are often women in their 40s,” Koralnik said. “There are millions of those people who couldn’t get tested in 2020 yet they continued to have long COVID symptoms.”

Koralnik acknowledges that the study has its limitations. The study is based on just 52 patients, but Koralnik said researchers felt it was important to share what they’ve learned so far, rather than wait longer to study a larger group of people. Also, because the study consists of people who visited the Northwestern clinic and chose to participate in the study, it’s not representative of all people with long COVID who didn’t require hospitalization. About 90% of the study participants were white.

Still, Koralnik said Northwestern has had an open-door policy for its clinic, meaning patients did not need to be referred by other doctors or show proof of insurance. The clinic also has seen people from across the country, by performing both in-person appointments and telehealth visits.

The findings in the new study follow up on a Northwestern study published in March 2021 that found that 85% of people with long COVID-19, who did not require hospitalization, experienced four or more neurological symptoms that impacted their quality of life, and, in some cases, their cognitive abilities.

“This study is the first of its kind that was started in a difficult circumstance, in the lockdown in Chicago, and provides very unique and important data on this population of patients,” Koralnik said. “We hope it’s going to help clinicians take care of those patients and further studies are going to be done.”

Warning to anyone who’s had Covid as scientists discover symptoms that can last for TWO YEARS

Authors: Vanessa Chalmers, Digital Health Reporter May 11 2022  May 12 2022

DOCTORS have discovered the symptoms of Covid that can last for two years or more. 

Their research has shown that half of patients admitted to hospital are still likely to have at least one persistent problem two years later.

The study, published in The Lancet Respiratory Medicine, has the longest follow-up period of patients to date. 

Researchers are only able to analyse what symptoms exist after two years given the coronavirus emerged in late 2019.

So it’s possible problems like fatigue and anxiety could stick around even longer.

Lead author Professor Bin Cao, of the China-Japan Friendship Hospital, China, said: “Our findings indicate that for a certain proportion of hospitalised Covid-19 survivors, while they may have cleared the initial infection, more than two years is needed to recover fully from Covid-19.”

The study involved almost 1,200 patients, aged 57 on average, who were infected with the bug in the early phase of the pandemic.

They had all been treated in Wuhan, China, then assessed six months, 12 months and two years after discharge.

Researchers looked at their walking abilities, mental health, quality of life and more.

Covid patients were generally found to be in poorer health than those in the general population two years after infection.

They reported:

  • Fatigue or muscle weakness (31 per cent of Covid patients compared to five per cent in the general population)
  • Sleep difficulties (51 per cent compared with 14 per cent)
  • Pain or discomfort (23 per cent compared with five per cent)
  • Anxiety or depression (12 per cent compared with five per cent)

Joint pain, palpitations, dizziness, and headaches were also more common among previously hospitalised Covid patients.

Not all of those hospitalised were affected, however.

More than half (55 per cent) of participants had at least one symptom of Covid at two years, and were therefore considered “long Covid” patients.

The researchers then compared the long Covid group with the group of participants who had endured Covid, but gotten better. 

Those with long Covid had more pain (35 per cent vs 10 per cent), and mobility issues (five per cent vs one per cent) than their fully recovered counterparts.

Some 13 per cent showed symptoms of anxiety and 11 per cent depression, compared with three per cent and one per cent in non-long Covid patients, respectively. 

The researchers said it’s not possible to say whether problems like these are specific to Covid, or whether other hospital patients experience them.

Long Covid is defined as someone who still battles symptoms beyond four weeks in the UK.

It may be defined as ongoing Covid (four to 12 weeks), or post-Covid syndrome (more than 12 weeks) by medics.

The symptoms may include fatigue, a cough, breathlessness, muscle or joint pain, loss of taste of smell and brain fog.