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Taking the Long View: U.S. Scientists Affirm Value of Long Term Research

Note: Yale School of the Environment (YSE) was formerly known as the Yale School of Forestry & Environmental Studies (F&ES). News articles and events posted prior to July 1, 2020 refer to the School's name at that time.

Long-term research has been a primary tool for being able to understand how global changes are happening on the ground, particularly as a result of climate change.

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Harvard study, almost 80 years old, has proved that embracing community helps us live longer, and be happier

Part of the tackling issues of aging series.

A series on how Harvard researchers are tackling the problematic issues of aging.

W hen scientists began tracking the health of 268 Harvard sophomores in 1938 during the Great Depression, they hoped the longitudinal study would reveal clues to leading healthy and happy lives.

They got more than they wanted.

After following the surviving Crimson men for nearly 80 years as part of the Harvard Study of Adult Development , one of the world’s longest studies of adult life, researchers have collected a cornucopia of data on their physical and mental health.

Of the original Harvard cohort recruited as part of the Grant Study, only 19 are still alive, all in their mid-90s. Among the original recruits were eventual President John F. Kennedy and longtime Washington Post editor Ben Bradlee. (Women weren’t in the original study because the College was still all male.)

In addition, scientists eventually expanded their research to include the men’s offspring, who now number 1,300 and are in their 50s and 60s, to find out how early-life experiences affect health and aging over time. Some participants went on to become successful businessmen, doctors, lawyers, and others ended up as schizophrenics or alcoholics, but not on inevitable tracks.

“Loneliness kills. It’s as powerful as smoking or alcoholism.” Robert Waldinger, psychiatrist, Massachusetts General Hospital

During the intervening decades, the control groups have expanded. In the 1970s, 456 Boston inner-city residents were enlisted as part of the Glueck Study, and 40 of them are still alive. More than a decade ago, researchers began including wives in the Grant and Glueck studies.

Over the years, researchers have studied the participants’ health trajectories and their broader lives, including their triumphs and failures in careers and marriage, and the finding have produced startling lessons, and not only for the researchers.

“The surprising finding is that our relationships and how happy we are in our relationships has a powerful influence on our health,” said Robert Waldinger , director of the study, a psychiatrist at Massachusetts General Hospital and a professor of psychiatry at Harvard Medical School . “Taking care of your body is important, but tending to your relationships is a form of self-care too. That, I think, is the revelation.”

Close relationships, more than money or fame, are what keep people happy throughout their lives, the study revealed. Those ties protect people from life’s discontents, help to delay mental and physical decline, and are better predictors of long and happy lives than social class, IQ, or even genes. That finding proved true across the board among both the Harvard men and the inner-city participants.

“The people who were the most satisfied in their relationships at age 50 were the healthiest at age 80,” said Robert Waldinger with his wife Jennifer Stone.

Rose Lincoln/Harvard Staff Photographer

The long-term research has received funding from private foundations, but has been financed largely by grants from the National Institutes of Health, first through the National Institute of Mental Health, and more recently through the National Institute on Aging.

Researchers who have pored through data, including vast medical records and hundreds of in-person interviews and questionnaires, found a strong correlation between men’s flourishing lives and their relationships with family, friends, and community. Several studies found that people’s level of satisfaction with their relationships at age 50 was a better predictor of physical health than their cholesterol levels were.

“When we gathered together everything we knew about them about at age 50, it wasn’t their middle-age cholesterol levels that predicted how they were going to grow old,” said Waldinger in a popular TED Talk . “It was how satisfied they were in their relationships. The people who were the most satisfied in their relationships at age 50 were the healthiest at age 80.”

He recorded his TED talk, titled “What Makes a Good Life? Lessons from the Longest Study on Happiness,” in 2015, and it has been viewed 13,000,000 times.

The researchers also found that marital satisfaction has a protective effect on people’s mental health. Part of a study found that people who had happy marriages in their 80s reported that their moods didn’t suffer even on the days when they had more physical pain. Those who had unhappy marriages felt both more emotional and physical pain.

Those who kept warm relationships got to live longer and happier, said Waldinger, and the loners often died earlier. “Loneliness kills,” he said. “It’s as powerful as smoking or alcoholism.”

According to the study, those who lived longer and enjoyed sound health avoided smoking and alcohol in excess. Researchers also found that those with strong social support experienced less mental deterioration as they aged.

In part of a recent study , researchers found that women who felt securely attached to their partners were less depressed and more happy in their relationships two-and-a-half years later, and also had better memory functions than those with frequent marital conflicts.

“When the study began, nobody cared about empathy or attachment. But the key to healthy aging is relationships, relationships, relationships.” George Vaillant, psychiatrist

“Good relationships don’t just protect our bodies; they protect our brains,” said Waldinger in his TED talk. “And those good relationships, they don’t have to be smooth all the time. Some of our octogenarian couples could bicker with each other day in and day out, but as long as they felt that they could really count on the other when the going got tough, those arguments didn’t take a toll on their memories.”

Since aging starts at birth, people should start taking care of themselves at every stage of life, the researchers say.

“Aging is a continuous process,” Waldinger said. “You can see how people can start to differ in their health trajectory in their 30s, so that by taking good care of yourself early in life you can set yourself on a better course for aging. The best advice I can give is ‘Take care of your body as though you were going to need it for 100 years,’ because you might.”

The study, like its remaining original subjects, has had a long life, spanning four directors, whose tenures reflected their medical interests and views of the time.

Under the first director, Clark Heath, who stayed from 1938 until 1954, the study mirrored the era’s dominant view of genetics and biological determinism. Early researchers believed that physical constitution, intellectual ability, and personality traits determined adult development. They made detailed anthropometric measurements of skulls, brow bridges, and moles, wrote in-depth notes on the functioning of major organs, examined brain activity through electroencephalograms, and even analyzed the men’s handwriting.

Now, researchers draw men’s blood for DNA testing and put them into MRI scanners to examine organs and tissues in their bodies, procedures that would have sounded like science fiction back in 1938. In that sense, the study itself represents a history of the changes that life brings.

6 factors predicting healthy aging According to George Vaillant’s book “Aging Well,” from observations of Harvard men in long-term aging study

Physically active.

Absence of alcohol abuse and smoking

Having mature mechanisms to cope with life’s ups and downs

Healthy weight

Stable marriage.

Psychiatrist George Vaillant, who joined the team as a researcher in 1966, led the study from 1972 until 2004. Trained as a psychoanalyst, Vaillant emphasized the role of relationships, and came to recognize the crucial role they played in people living long and pleasant lives.

In a book called “Aging Well,” Vaillant wrote that six factors predicted healthy aging for the Harvard men: physical activity, absence of alcohol abuse and smoking, having mature mechanisms to cope with life’s ups and downs, and enjoying both a healthy weight and a stable marriage. For the inner-city men, education was an additional factor. “The more education the inner city men obtained,” wrote Vaillant, “the more likely they were to stop smoking, eat sensibly, and use alcohol in moderation.”

Vaillant’s research highlighted the role of these protective factors in healthy aging. The more factors the subjects had in place, the better the odds they had for longer, happier lives.

“When the study began, nobody cared about empathy or attachment,” said Vaillant. “But the key to healthy aging is relationships, relationships, relationships.”

“We want to find out how it is that a difficult childhood reaches across decades to break down the body in middle age and later.” Robert Waldinger

The study showed that the role of genetics and long-lived ancestors proved less important to longevity than the level of satisfaction with relationships in midlife, now recognized as a good predictor of healthy aging. The research also debunked the idea that people’s personalities “set like plaster” by age 30 and cannot be changed.

“Those who were clearly train wrecks when they were in their 20s or 25s turned out to be wonderful octogenarians,” he said. “On the other hand, alcoholism and major depression could take people who started life as stars and leave them at the end of their lives as train wrecks.”

The study’s fourth director, Waldinger has expanded research to the wives and children of the original men. That is the second-generation study, and Waldinger hopes to expand it into the third and fourth generations. “It will probably never be replicated,” he said of the lengthy research, adding that there is yet more to learn.

“We’re trying to see how people manage stress, whether their bodies are in a sort of chronic ‘fight or flight’ mode,” Waldinger said. “We want to find out how it is that a difficult childhood reaches across decades to break down the body in middle age and later.”

Lara Tang ’18, a human and evolutionary biology concentrator who recently joined the team as a research assistant, relishes the opportunity to help find some of those answers. She joined the effort after coming across Waldinger’s TED talk in one of her classes.

“That motivated me to do more research on adult development,” said Tang. “I want to see how childhood experiences affect developments of physical health, mental health, and happiness later in life.”

Asked what lessons he has learned from the study, Waldinger, who is a Zen priest, said he practices meditation daily and invests time and energy in his relationships, more than before.

“It’s easy to get isolated, to get caught up in work and not remembering, ‘Oh, I haven’t seen these friends in a long time,’ ” Waldinger said. “So I try to pay more attention to my relationships than I used to.”

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• Open access
• Published: 09 August 2021

More than 50 long-term effects of COVID-19: a systematic review and meta-analysis

• Sandra Lopez-Leon   ORCID: orcid.org/0000-0001-7504-3441 1 ,
• Talia Wegman-Ostrosky   ORCID: orcid.org/0000-0002-3207-6697 2 ,
• Carol Perelman   ORCID: orcid.org/0000-0002-0111-1154 3 ,
• Rosalinda Sepulveda   ORCID: orcid.org/0000-0003-1146-9552 4 ,
• Paulina A. Rebolledo   ORCID: orcid.org/0000-0002-9808-063X 5 , 6 ,
• Angelica Cuapio   ORCID: orcid.org/0000-0002-9451-1914 7 &
• Sonia Villapol   ORCID: orcid.org/0000-0002-6174-4113 8 , 9  

Scientific Reports volume  11 , Article number:  16144 ( 2021 ) Cite this article

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COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. This systematic review and meta-analysis aims to identify studies assessing the long-term effects of COVID-19. LitCOVID and Embase were searched to identify articles with original data published before the 1st of January 2021, with a minimum of 100 patients. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. PRISMA guidelines were followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included (age 17–87 years). The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.

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Long-COVID in children and adolescents: a systematic review and meta-analyses

A systematic review and meta-analysis, investigating dose and time of fluvoxamine treatment efficacy for COVID-19 clinical deterioration, death, and Long-COVID complications

Long COVID: major findings, mechanisms and recommendations

Introduction.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in China in December 2019. Since then, more than 175 million people worldwide have been infected after a year, and over 3.8 million people have died from the coronavirus disease 2019 (COVID-19) 1 . Although unprecedented efforts from the scientific and medical community have been directed to sequence, diagnose, treat, and prevent COVID-19, individuals' lasting effects after the acute phase of the disease are yet to be revealed.

The terminology has been confusing and not standardized. Different authors have used several terms to describe prolonged symptoms following COVID-19 illness, such as “Long COVID-19”, “post-acute COVID-19”, “persistent COVID-19 symptoms”, “chronic COVID-19”, “post-COVID-19 manifestations”, “long-term COVID-19 effects”, “post COVID-19 syndrome”, “ongoing COVID-19”, “long-term sequelae”, or “long-haulers” as synonyms. Most recently, the term “post-acute sequelae of SARS-CoV-2 infection” (PASC), “long-COVID-19”, and “post-acute COVID-19”, has been utilized 2 .

Symptoms, signs, or abnormal clinical parameters persisting two or more weeks after COVID-19 onset that do not return to a healthy baseline can potentially be considered long-term effects of the disease 3 . Although such alteration is mainly reported in severe and critical disease survivors, the lasting effects also occur in individuals with a mild infection who did not require hospitalization 4 . However, it has not yet been established how sex, gender, age, ethnicity, underlying health conditions, viral dose, or progression of COVID-19 significantly affect the risk of developing long-term effects of COVID-19 5 .

Since first reported, there has been a vast amount of social media patient groups, polls, comments, and scientific articles aiming to describe the chronicity of COVID-19. In parallel, hundreds of scientific publications, including cohorts studying specific effects of the disease and lists of case reports, have been described 6 . However, a broad overview of all the possible longstanding effects of COVID-19 is still needed. Therefore, our study aimed to perform a systematic review and meta-analysis of peer-reviewed studies to estimate the prevalence of all the symptoms, signs, or abnormal laboratory parameters extending beyond the acute phase of COVID-19 reported to date.

Database search strategy

The databases used to identify the studies were LitCOVID 7 , which includes all COVID articles in PubMed and Medline) and Embase. The studies classified in this meta-analysis included those published in the year 2020 (strictly before January 1st, 2021).

The search terms or keywords used were: (COVID-19) OR (COVID) OR (SARS-CoV-2) OR (coronavirus) OR (2019-nCoV) AND (long* OR haulers OR post OR chronic OR term OR complications OR recurrent OR lingering OR convalescent OR convalescence OR persist*. Given that LitCOVID includes all articles from MedLine, in the search in Embase, we excluded the articles from MedLine and those not related to COVID-19. The systematic review followed the Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) guidelines 8 , 9 . The registration of the review protocol was not previously done.

Inclusion and exclusion criteria

The inclusion criteria of the search were as follows: (1) to identify peer-reviewed human studies in English that reported symptoms, signs, or (2) laboratory parameters of patients at a post-COVID-19 stage (assessed 2 weeks or more after initial symptoms) in cohorts of COVID-19 patients. All types of studies, including randomized controlled trials, cohorts, and cross-sectional studies, were analyzed only when the cases (numerator) were part of a COVID-19 cohort (denominator). Titles, abstracts, and full texts of articles were independently screened by two authors (S.L.L. and T.W.O.). The complete article was reviewed in case of a difference of opinion on the inclusion based on title or abstract. Disagreement on the inclusion of a full-text article was discussed with all the authors. We exclude letters, editorials, reviewers, and commentaries. The exclusion criteria were: (1) not written in English; (2) have less than 100 patients included in the study. To estimate the prevalence of long-term erects in patients with COVID-19, we needed to include as a denominator the patients with acute COVID-19 (with and without long-term effects). Therefore, it is not possible to include case studies (usually less than 100 persons). The larger the denominator, the greater the reliability and generalizability of the estimate, and the lower the possibility of bias of including only patients that developed long COVID-19. We also exclude non-English language studies due to a lack of robust resources for accurate translation.

Data extraction and analysis

Data were extracted by five review authors (C.P., A.C., P.R., R.S., S.V.), and each study's quality was assessed using the Health States Quality-Controlled data (QCed) by two review authors independently (S.L.L. and T.W.O.). This index is described and recommended by the MetaXL Guidelines. It is specific to evaluate the quality of studies assessing prevalence. Relevant studies were then subjected to full-text screening by the same reviewers. The descriptive variables extracted were country, setting, follow-up time, the severity of COVID-19, sample size, mean age and percentage of gender, outcomes, and names used to describe the long-term effects of COVID-19 (Supplemental Table S1 ).

All the diseases, disorders, symptoms, signs, and laboratory parameters reported total numbers or percentages were included. Outcomes of interest were blood biomarkers and abnormal chest X-ray/CT reported for patients with SARS-CoV-2 infection in any setting. In addition, we assessed symptoms in several distinct systems; neurological, respiratory, gastrointestinal, cardiac, endocrine, dermatological, hepatic, and renal. When two time points were reported in the study, the outcomes assessed after the most extended follow-up were used.

Statistical analysis

For effects reported only in a single study, the prevalence was estimated by dividing the number of patients with each symptom by the total number of COVID-19 patients in the sample multiplied by 100 to calculate the percentage. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence, which uses a double arcsine transformation 10 . Prevalence with 95% confidence intervals (CI) was presented. Heterogeneity was assessed using I 2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) 2020 guideline was followed. Given the heterogeneity expected, a random-effects model was used. Heterogeneity was assessed using the I 2 statistics. Values of 25%, 50%, and 75% for I 2 represented low, medium, and high heterogeneity. Sensitivity analyses were performed to assess the contribution of each study. Although none of the included definitions, or effects, were pre-specified, all of the effects and definitions were determined via each identified study. Publication bias in the selected study was evaluated by plotting the funnel plot and subsequent analyses. Each study's quality was assessed and described using the MetaXL Guidelines, which is specific to assess the quality of studies assessing prevalence. A description of what was considered is found in Supplemental Table S1 .

The title and abstract of 18,251 publications were screened. Of these, 82 full publications were reviewed for removal of duplication and initial eligibility assessment of title/abstract of all articles based on the eligibility criteria. Nineteen studies were excluded because they involved less than 100 persons. Thus, a total of 15 studies were selected to be analyzed. The process of study selection is presented in Fig.  1 .

Study selection. Preferred items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Out of 15,917 identified studies and after application of the inclusion and exclusion criteria, 15 studies were included in the quantitative synthesis.

Characteristics of the included studies

There were eight studies from Europe and UK, three from the USA, one from Australia, China, Egypt, and Mexico (Table 1 ). The number of patient cohorts that were followed up in the studies ranged from 102 to 44,799. Adults ranging from 17 to 87 years of age were included. The patient follow-up time ranged from 14 to 110 days. Ten studies collected information from the patients using self-reported surveys. Two studies collected data from medical records and three by a clinical evaluation. Six out of the 15 studies included only patients hospitalized for COVID-19. The rest of the studies mixed with mild, moderate, and severe COVID-19 patients. There were no studies with overlapping samples. Two meta-analyses showed low heterogeneity ( I 2  < 25%), two showed medium heterogeneity, and the rest had high ( I 2  > 75%).

The populations were well defined. However, most studies were mixed mild, moderate, and severe patients—none of the studies were stratified by different by severity. The observation period was also well defined. However, none of the studies presented their results as stratified by observation. Therefore, it was impossible to identify the source of heterogeneity and it was not possible to assess how long each symptom lasted. Seven of the studies did not describe the system used to record the symptoms in detail, and most were self-reported retrospectively. A high score was given to the studies that administered an interview, included multi-sites surveys, and reported point prevalence. All of the studies received a score of greater than 8 (out of 11 points).

Abnormalities of laboratory parameters

Measurable parameters included 6 elevated laboratory parameters. An abnormal chest X-ray/CT was observed in 34% (95% CI 27–42) of the patients. Markers reported to be elevated were D-dimer (20%, 95% CI 6–39), N-terminal (NT)-pro hormone BNP (NT-proBNP), (11%, 95% CI 6–17), C-reactive protein (CRP) (8%, 95% CI 5–12), serum ferritin (8% 95% CI 4–14), procalcitonin (4% 95% CI 2–9) and interleukin-6 (IL-6) (3% 95% CI% 1–7) (Table 2 , Fig.  2 ).

Long-term effects of coronavirus disease 2019 (COVID-19). The meta-analysis of the studies included an estimate for one symptom or more reported that 80% of the patients with COVID-19 have long-term symptoms. CRP C-reactive protein, CT computed tomography, IL-6 Interleukin-6, NT-proBNP (NT)-pro hormone BNP, OCD Obsessive Compulsive Disorder, PTSD Post-traumatic stress disorder. This figure was created using Biorender.com.

Prevalence of long-term effects in COVID-19 patients

We identified a total of 55 long-term effects associated with COVID-19 in the literature reviewed (Table 2 ). Most of the effects correspond to clinical symptoms such as fatigue, headache, joint pain, anosmia, ageusia, etc. In addition, diseases such as stroke and diabetes mellitus were also present. Table 2 presents the prevalence of all the effects that were reported. It was possible to perform 21 meta-analyses. For the rest, the prevalence was estimated using one cohort. The meta-analysis of the studies (n = 7) that included an estimate for one symptom or more reported that 80% (95% CI 65–92) of the patients with COVID-19 have long-term symptoms.

Overall prevalence of most common symptoms

The 5 most common manifestations were fatigue (58%, 95% CI 42–73), headache (44%, 95% CI 13–78), attention disorder (27% 95% CI 19–36), hair loss (25%, 95% CI 17–34), dyspnea (24%, 95% CI 14–36) (Table 2 , Fig.  2 ). Other symptoms were related to lung disease (cough, chest discomfort, reduced pulmonary diffusing capacity, sleep apnea, and pulmonary fibrosis), cardiovascular (arrhythmias, myocarditis), neurological (dementia, depression, anxiety, attention disorder, obsessive–compulsive disorders), and others were unspecific such as hair loss, tinnitus, and night sweat (Table 2 , Fig.  2 , Supplemental Figure S1 ). A couple of studies reported that fatigue was more common in females, and one study reported that post-activity polypnea and alopecia were more common in females 4 , 24 . The rest of the studies did not stratify their results by age or sex.

This systematic review and meta-analysis shows that 80% (95% CI 65–92) of individuals with a confirmed COVID-19 diagnosis continue to have at least one overall effect beyond 2 weeks following acute infection. In total, 55 effects, including symptoms, signs, and laboratory parameters, were identified, with fatigue, anosmia, lung dysfunction, abnormal chest X-ray/CT, and neurological disorders being the most common (Table 1 , Fig.  2 ). Most of the symptoms were similar to the symptomatology developed during the acute phase of COVID-19. However, given that all of the surveys were predefined, there is a possibility that other effects have not yet been identified. In the following paragraphs, we will discuss the most common symptoms to illustrate how complex each one can be. However, further studies are needed to understand each symptom separately and in conjunction with the other symptoms. The five most common effects were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). The recovery from COVID-19 should be more developed than checking for hospital discharge or testing negative for SARS-CoV-2 or positive for antibodies 25 .

Fatigue (58%) is the most common symptom of long and acute COVID-19 23 . It is present even after 100 days of the first symptom of acute COVID-19 4 , 23 . In addition, there are syndromes such as acute respiratory distress syndrome (ARDS), in which it has been observed that after a year, more than two-thirds of patients reported clinically significant fatigue symptoms 26 . The symptoms observed in post-COVID-19 patients, resemble in part the chronic fatigue syndrome (CFS), which includes the presence of severe incapacitating fatigue, pain, neurocognitive disability, compromised sleep, symptoms suggestive of autonomic dysfunction, and worsening of global symptoms following minor increases in physical and/or cognitive activity 27 , 28 , 29 , 30 , 31 . Myalgic encephalomyelitis (ME) or CFS is a complex and controversial clinical condition without established causative factors, and 90% of ME/CFS has not been diagnosed 32 . Possible causes of CFS include viruses, immune dysfunction, endocrine-metabolic dysfunction, and neuropsychiatric factors. The infectious agents related to CFS have been Epstein-Barr virus, cytomegalovirus, enterovirus, and herpesvirus 33 . It is tempting to speculate that SARS-CoV-2 can be added to the viral agents' list causing ME/CFS.

Several neuropsychiatric symptoms have been reported, headache (44%), attention disorder (27%), and anosmia (21%). Other symptoms were reported, which were not included in the publications, including brain fog and neuropathy 34 , 35 . The etiology of neuropsychiatric symptoms in COVID-19 patients is complex and multifactorial. They could be related to the direct effect of the infection, cerebrovascular disease (including hypercoagulation) 36 , physiological compromise (hypoxia), side effects of medications, and social aspects of having a potentially fatal illness 37 . Adults have a double risk of being newly diagnosed with a psychiatric disorder after the COVID-19 diagnosis 37 , and the most common psychiatric conditions presented were anxiety disorders, insomnia, and dementia. Sleep disturbances might contribute to the presentation of psychiatric disorders 38 . Prompt diagnosis and intervention of any neuropsychiatric care is recommended for all patients recovering from COVID-19. An increase in mental health attention models in hospitals and communities is needed during and after the COVID-19 pandemic. Hair loss after COVID-19 could be considered as telogen effluvium, defined by diffuse hair loss after an important systemic stressor or infection. Premature follicular transitions cause it from the active growth phase (anagen) to the resting phase (telogen). It is a self-limiting condition that lasts approximately 3 months, but it could cause emotional distress 39 .

Dyspnea and cough were found in 24% and 19% of patients, respectively (Table 2 , Fig.  2 ). In addition, abnormalities in CT lung scans persisted in 35% of patients even after 60–100 days from the initial presentation. In a follow-up study conducted in China among non-critical cases of hospitalized patients with COVID-19, radiographic changes persisted in nearly two-thirds of patients 90 days after discharge 40 . Although most of the available studies do not include baseline pulmonary dysfunction or radiographic abnormalities, findings indicate improvement or resolution of abnormal CT findings. Previous data from recovered patients with other viral pneumonia 41 , 42 , also found residual radiographic changes. Abnormalities in pulmonary function, such as decreased diffusion capacity for carbon monoxide, were present among 10% of patients in this meta-analysis. Although these findings are not as high as compared to other available studies of survivors with COVID-19 or SARS, where the estimate of lung dysfunction is 53% and 28% respectively 43 , 44 , the reasons behind these differences could be distinct follow-up periods, definitions of pulmonary dysfunction, or characteristics of the patient population. Nevertheless, residual radiographic findings or lung function abnormalities require additional investigation on their clinical relevance and long-term consequences.

The immune-mediated tissue damage in COVID-19 involves cellular and humoral responses, but the immunity to SARS-CoV-2 and the protection to reinfection or a final viral 40 , 45 clearance is unknown. Also, the reason why some patients experience long-term symptoms after COVID-19 is uncertain. This could be partially explained by host-controlled factors that influence the outcome of the viral infection, including genetic susceptibility, age of the host when infected, dose and route of infection, induction of anti-inflammatory cells and proteins, presence of concurrent infections, past exposure to cross-reactive agents, etc. Whether SARS-CoV-2 can cause substantial tissue damage leading to a chronic form of the disease such as the chronic lesions in convalescence observed in other viruses such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), and some herpesviruses is still unknown.

One study was excluded because it did not provide a denominator, and therefore it was not possible to estimate the prevalence 46 . In such a study, the authors performed a survey in a Facebook group of patients who previously had COVID-19 and compared the symptoms of those hospitalized with mild to moderate symptoms. They concluded that both groups had symptoms after 3 months of having COVID-19. Symptoms that were not mentioned in any of the articles we studied include sudden loss of body weight, ear pain, eye problems, sneezing, cold nose, burning feeling in the trachea, dizziness, heart palpitations, pain/burning feeling in the lungs, pain between the shoulder blades, Sicca syndrome, vertigo, body aches, and confusion 3 , 12 .

The results assessed in the present study are in line with the current scientific knowledge on other coronaviruses, such as those producing SARS and MERS, both clinical sharing characteristics with COVID-19, including post symptoms. For example, studies on SARS survivors have shown lung abnormalities months after infection. After a 1-year follow-up, a study showed that 28% of the survivors presented decreased lung function and pulmonary fibrosis signs 44 , 47 , 48 . In addition, MERS survivors showed pulmonary fibrosis (33%) 49 . Regarding psychiatric symptoms, a study reported high levels of depression, anxiety, and post-traumatic stress disorder (PTSD) 37 in the long term in patients previously infected with other coronaviruses.

To assure that future healthcare providers, researchers, and educators recognize the effects of long-term COVID19 that are sex- and age-specific related, it is essential to classify the groups according to such variables to make better decisions about prevention diagnosis and disease management.

Limitations of this systematic review and meta-analyses include the small sample size for some outcomes, making it difficult to generalize these results to the general population. The variation in the definition of some outcomes and markers and the possibility of bias. For example, several studies that used a self-reported questionnaire could result in reporting bias. In addition, the studies were very heterogeneous, mainly due to the follow-up time references and the mixture of patients who had moderate and severe COVID-19. All of the studies assessed had performed their internal pre-definition of symptoms, and therefore there is the possibility that essential outcomes were not reported. Another limitation is that, given that COVID-19 is a new disease, it is impossible to determine how long these effects will last. To decrease heterogeneity and better understand the long-term effects of COVID-19, there is a need for studies to stratify by age, previous comorbidities, the severity of COVID-19 (including asymptomatic), and the duration of each symptom. To determine whether these long-term effects either complicate previous diseases or continue COVID-19, there is a need for prospective cohort studies. The baseline characteristics should be well established. To obtain more accurate meta-analyses, there is an urgent need to have a standard definition of long-COVID-19. Currently, post-COVID-19 symptoms that develop during or after COVID-19 are defined if they continue for ≥ 12 weeks (“long-COVID-19”), and not explained by an alternative diagnosis 2 , 6 , 50 . There is a need to standardize biological measures such as peripheral blood markers of genetic, inflammatory, immune, and metabolic function to compare studies. Besides studying pre-defined symptoms and characteristics, an open question should be included. Proper documentation in medical charts by health care providers and the flexibility and collaboration from the patients to report their symptoms are of equal importance.

More evidence and research from multi-disciplinary teams are crucial to understanding the causes, mechanisms, and risks to develop preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address the after-COVID-19 care. There is a need for more information about prospective studies to better evaluate the natural course of COVID-19 infection and define the long- COVID-19 syndrome. From the clinical point of view, physicians should be aware of the symptoms, signs, and biomarkers present in patients previously affected by COVID-19 to promptly assess, identify and halt long COVID-19 progression, minimize the risk of chronic effects help reestablish pre-COVID-19 health. Management of all these effects requires further understanding to design individualized, dynamic cross-sectoral interventions in Post-COVID-19 clinics with multiple specialties, including graded exercise, physical therapy, frequent medical evaluations, and cognitive behavioral therapy when required 51 , 52 .

Data availability

All data relevant to the study are included in the article or uploaded as supplementary information. In addition, the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Acute respiratory distress syndrome

Credible interval

Coronavirus disease 2019

Chronic fatigue syndrome

C-reactive protein

Computed tomography

Human immunodeficiency virus

Hepatitis C virus

Hepatitis B virus

Interleukin-6

Pro hormone BNP

Myalgic encephalomyelitis

Middle East respiratory syndrome

Obsessive Compulsive Disorder

Post-traumatic stress disorder

Severe acute respiratory syndrome coronavirus 2

Severe acute respiratory syndrome

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This article was funded by Houston Methodist Research Institute (S.V.).

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Lopez-Leon, S., Wegman-Ostrosky, T., Perelman, C. et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep 11 , 16144 (2021). https://doi.org/10.1038/s41598-021-95565-8

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Thursday, May 25, 2023

Large study provides scientists with deeper insight into long COVID symptoms

NIH-funded research effort identifies most common symptoms, potential subgroups, and initial symptom-based scoring system – with aim of improving future diagnostics and treatment.

Initial findings from a study of nearly 10,000 Americans, many of whom had COVID-19, have uncovered new details about long COVID, the post-infection set of conditions that can affect nearly every tissue and organ in the body. Clinical symptoms can vary and include fatigue, brain fog, and dizziness, and last for months or years after a person has COVID-19. The research team, funded by the National Institutes of Health, also found that long COVID was more common and severe in study participants infected before the 2021 Omicron variant.

The study, published in JAMA , is coordinated through the NIH’s Researching COVID to Enhance Recovery (RECOVER) initiative, a nationwide effort dedicated to understanding why some people develop long-term symptoms following COVID-19, and most importantly, how to detect, treat, and prevent long COVID. The researchers hope this study is the next step toward potential treatments for long COVID, which affects the health and wellbeing of millions of Americans.

“Americans living with long COVID want to understand what is happening with their bodies,” said ADM Rachel L. Levine, M.D., Assistant Secretary for Health. “RECOVER, as part of a broader government response, in collaboration with academia, industry, public health institutions, advocacy organizations and patients, is making great strides toward improving our understanding of long COVID and its associated conditions.”

Researchers examined data from 9,764 adults, including 8,646 who had COVID-19 and 1,118 who did not have COVID-19. They assessed more than 30 symptoms across multiple body areas and organs and applied statistical analyses that identified 12 symptoms that most set apart those with and without long COVID: post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic cough, chest pain, and abnormal movements.

They then established a scoring system based on patient-reported symptoms. By assigning points to each of the 12 symptoms, the team gave each patient a score based on symptom combinations. With these scores in hand, researchers identified a meaningful threshold for identifying participants with long COVID. They also found that certain symptoms occurred together and defined four subgroups or “clusters” with a range of impacts on health.

Based on a subset of 2,231 patients in this analysis who had a first COVID-19 infection on or after Dec. 1, 2021, when the Omicron variant was circulating, about 10% experienced long-term symptoms or long COVID after six months. The results are based on a survey of a highly diverse set of patients and are not final. Survey results will next be compared for accuracy against an array of lab tests and imaging.

To date, more than 100 million Americans have been infected with SARS-CoV-2, the virus that causes COVID-19. As of April, the federal government’s Household Pulse survey estimates that about 10% of adults infected with the virus continue to experience and suffer from the many symptoms termed together as long COVID. Patients and researchers have identified more than 200 symptoms associated with long COVID.

“This study is an important step toward defining long COVID beyond any one individual symptom,” said study author Leora Horwitz, M.D., director of the Center for Healthcare Innovation and Delivery Science, and co-principal investigator for the RECOVER Clinical Science Core, at NYU Langone Health. “This approach — which may evolve over time — will serve as a foundation for scientific discovery and treatment design.” The researchers explain studying the underlying biological mechanisms of long COVID is central to advancing informed interventions and identifying effective treatment strategies.

In addition to establishing the scoring system, the researchers found that participants who were unvaccinated or who had COVID-19 before the Omicron strain emerged in 2021 were more likely to have long COVID and more severe cases of long COVID. Further, reinfections were also linked to higher long COVID frequency and severity, compared to people who only had COVID-19 once.

“While the score developed in this study is an important research tool and early step toward diagnosing and monitoring patients with long COVID, we recognize its limitations,” said David C. Goff, M.D., Ph.D., director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute, part of NIH. Goff serves as an epidemiology lead for NIH RECOVER. “All patients suffering from long COVID deserve the attention and respect of the medical field, as well as care and treatment driven by their experiences. As treatments are developed, it will be important to consider the complete symptom profile.”

The ongoing RECOVER research serves as the foundation for planned clinical trials, whose interventions are rooted in many of the symptoms outlined in this study. RECOVER clinical trials are expected to begin enrolling patient participants in 2023.

This research was funded by NIH agreements OT2HL161841 , OT2HL161847 , and OT2HL156812 . Additional support came from grant R01 HL162373 . For more information on RECOVER, visit https://recovercovid.org .                                                                 

About RECOVER : The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) Initiative is a $1.15 billion effort, including support through the American Rescue Plan Act of 2021, that seeks to identify how people recuperate from COVID-19, and who are at risk for developing post-acute sequelae of SARS-CoV-2 (PASC). Researchers are also working with patients, clinicians, and communities across the United States to identify strategies to prevent and treat the long-term effects of COVID – including long COVID. For more information, please visit recovercovid.org .

HHS Long COVID Coordination : This work is a part of the National Research Action Plan (opens pdf), a broader government-wide effort in response to the Presidential Memorandum directing the Secretary for the Department of Health and Human Services to mount a full and effective response to long COVID. Led by Assistant Secretary for Health Admiral Rachel Levine, the Plan and its companion Services and Supports for Longer-term Impacts of COVID-19 (opens pdf) report lay the groundwork to advance progress in the prevention, diagnosis, treatment, and provision of services for individuals experiencing long COVID.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Thaweethai T, Jolley SE, Karlson EW, et al. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection.  JAMA.  Published online May 25, 2023. doi: 10.1001/jama.2023.8823

Change Note

On May 31, 2023, a statistic in the seventh paragraph on the percentage of adults continuing to experience symptoms of COVID-19 was updated from 6% to 10%.

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