Post-viral fatigue and COVID-19: lessons from past epidemics

The COVID-19 pandemic, resulting from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has severely impacted the population worldwide with a great mortality rate. The current article reviews the literature on short- and long-term health consequences of prior epidemics and infections to assess potential health complications that may be associated with post-COVID-19 recovery. Past research on post-epidemic and post-infection recovery has suggested that such complications include the development of severe fatigue. Certain factors, such as the severity of infection, in addition to the ‘cytokine storm’ experienced by many COVID-19 patients, may contribute to the development of later health problems. We suggest that the patterns observed in past epidemics and infections may re-occur in the current COVID-19 pandemic. KEYWORDS: Post-infection fatigue, myalgic encephalomyelitis/chronic fatigue syndrome, COVID-19 Current pandemic COVID-19 is a viral infection caused by SARS-CoV-2 that primarily targets the respiratory system, with initial symptoms often including shortness of breath and fever [1]. As of 28 May 2020, there are over 5.5 million confirmed cases of people who have contracted COVID-19 globally and over 353,000 have died [2]. A commonly reported symptom of COVID-19 is fatigue [3], and anecdotal evidence suggests that some people continue to experience severe levels of prolonged fatigue as they recover from this infection. This is not surprising, as post-infectious fatigue has been widely observed across a variety of other viral and non-viral infections [4,5]. We will review evidence of these types of consequences from previous outbreaks and the implications for those with COVID-19. Viral infections Epidemics The most devastating epidemic in modern history was the Spanish Flu of 1918, caused by the A(H1N1) influenza virus [6]. Researchers estimate the global mortality of this pandemic was between 24.7 and 50 million [7]. Of those who survived, some experienced complications during recovery. For example, one report stated that ‘of 1000 cases of influenza, about 200 patients did not fully recover’ and, of these, about 40 remained severely ill [8]. Physical exertion was cited as a factor deterring recovery or even leading to death [9]. Fatigue was one of the most common longer-term consequences of the Spanish Flu. Post-infectious fatigue has also been observed after the onset of other epidemics. In 2003, there was an outbreak of the SARS-CoV virus causing an epidemic SARS. Tansey et al. [10] assessed the health outcomes of recovered patients 3-, 6-, and 12-months after hospital discharge. The researchers found that more than half of their sample experienced fatigue throughout their recovery: 64% reported fatigue at 3-months, 54% at 6-months, and 60% at 12-months. The symptoms often occurred with sleeping difficulties. Additionally, Lam et al. [11] conducted a 4-year follow-up evaluation of people recovering from SARS in Hong Kong and found that 40.3% reported chronic fatigue, and 27.1% qualified for a diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Moldofsky and Patcai [5] also examined people affected by this outbreak approximately 18.9 months after infection onset. While the researchers did not specifically assess ME/CFS in their participants, they did liken many of the post-infection symptoms to ME/CFS. Most notably, many of the patients experienced severe or disabling fatigue, myalgia, and sleep disturbances. In 2009, the influenza A(H1N1) resulted in a pandemic. Magnus et al. [12] studied this pandemic in Norway, and found an ME/CFS incidence rate of 2.08 per 100,000 person-months. Rates were higher for people younger than 30-years old, suggesting that a younger population was more at risk to develop ME/CFS post-infection. The researchers hypothesized that the development of ME/CFS was a reaction to the fever and immune response that was associated with the influenza virus. Post-viral fatigue has also been observed in people recovering from Ebolavirus infection. Wilson et al. [13] estimated that 28% experienced unusual levels of fatigue post-Ebolavirus. Post-Ebola Syndrome shares some common symptomologies with ME/CFS, most notably fatigue, muscle and joint pain, and sleep disturbances. Similarly, Rowe et al. [14] reported that 8.1% of patients reported extreme fatigue while recovering from previous outbreaks of Ebolavirus. In addition, this severe fatigue was also accompanied by myalgia and joint pain. The development of post infectious fatigue has been observed in other studies [4]. Cope et al. [15] found that within 6-months of a generalized viral infection onset, 17.5% of patients developed chronic fatigue. Furthermore, Garcia et al. [16] found that approximately 31% of people recovering from West Nile virus infection experienced chronic fatigue of which 64% qualified for ME/CFS. Non-epidemic post-viral illness Fatigue has also been observed in non-pandemic post-viral infections. For instance, Bogovič et al. [17] found that one third of patients reported persistent fatigue and myalgia while recovering from tick-borne encephalitis. Categorized as post-encephalitis syndrome, these symptoms can persist of many years after infection onset. The Epstein–Barr virus has been the most researched source of post-viral fatigue. The Epstein–Barr virus is commonly associated with infectious mononucleosis. White et al. [18] found that 9% of participants developed ME/CFS six months after the onset of infectious mononucleosis. Additionally, Buchwald et al. [19] found that 38% of participants failed to recover from infectious mononucleosis at two months after infection onset and 12% did not fully recover at six months. Although this study did not address whether patients met criteria for a ME/CFS diagnosis, the researchers likened symptoms exhibited by non-recovered patients to those of ME/CFS: substantial fatigue, less vitality, lowered physical functioning, worsening pain, and poorer general health. Similarly, Hickie et al. [4] reported a 11% prevalence rate of ME/CFS in people recovering from infectious mononucleosis. In a prospective study, Katz et al. [20] followed 301 adolescent patients (ages 12–18 years) after developing infectious mononucleosis. The incidence rate of ME/CFS was 13% at 6 months, 7% at 12 months, and 4% at 24-months. Utilizing the same cohort, Katz et al. [21] found that participants who developed ME/CFS post-infection demonstrated worse baseline autonomic symptoms than participants who fully recovered. From the same prospective study, Jason et al. [22] found that baseline autonomic symptoms and days spent in bed from the infection, but not psychological measures, were the only significant predictors for the development of ME/CFS after infectious mononucleosis. In a review article, Williams-Harmon, Jason, and Katz [23] found that approximately 1-5% of university students develop infectious mononucleosis annually. As part of a larger ongoing prospective health study, a research group headed by Katz and Jason [24] collected baseline data for approximately 4,500 college students, including self-report measures of fatigue, sleep, and stress, as well as biological measures with blood samples. The researchers followed these students over the course of their academic careers to observe the potential development of infectious mononucleosis. About 5% of the students were diagnosed with infectious mononucleosis. The findings of the study are currently being written up; however, the researchers have reported case studies of two participants. After developing infectious mononucleosis, one participant reported more severe and frequent symptoms (e.g. need to nap, sore throat, etc.) and 6 months later was classified as having ME/CFS. The other participant fully recovered from less symptomatic infectious mononucleosis. This large cohort is currently being re-assessed at a 6-year follow-up for the long-term consequences of infectious mononucleosis, as well as the occurrence of COVID-19. This type of research will provide a unique opportunity as baseline data was collected prior to experiencing either infectious mononucleosis or COVID-19, so this research team might be able to identify predisposing factors for the development of these diseases. Non-viral infections Non-viral causes of fatigue have also been examined, such as Ayres et al. [25] who assessed levels of fatigue five years following Q-fever, a rare bacterial infection caused by Coxiella burnetii. The researchers found that 42.3% of participants exhibited symptoms (e.g. fatigue, joint pain) which qualified for a ME/CFS diagnosis. Non-viral and viral infections were compared in a study by, Hickie et al. [4], who assessed patients recovering from Q fever, Ross River virus, and Epstein Barr virus. Approximately 11% of their sample population met the criteria for ME/CFS six months after being infected. Importantly, the rates of post-infectious fatigue were similar across all three infections. The researchers suggested that severity of an infection is a predictor of post-infectious fatigue. A more recent study of infectious mononucleosis also found that the severity of mononucleosis was predictive of post-infection complications such as fatigue [26]. Lyme disease, caused by the bacteria borreliosis, can become treatment resistant. In 2020, it is predicted that there will be up to 1.9 million cases of post-treatment Lyme disease [27]. a disorder that includes the development of persistent fatigue, musculoskeletal pain, and neurocognitive dysfunction that typically lasts over six months [28]. A meta-analysis found that these symptoms can last for many years and are resistant to antibiotic treatments [29]. While post-treatment Lyme disease syndrome shares many symptoms with ME/CFS, the patterns of these symptoms are different. For instance, Gaudino, Cole, and Krupp [30] found that people with post-treatment Lyme disease demonstrated significantly worse cognitive functions such as verbal memory, verbal fluency, and attention. Community outbreaks of waterborne Giardia lamblia in Norway [31], resulting in giardiasis, have also resulted in long term fatigue. Two years after the outbreak, Mørch et al. [32] found that 41% of people affected by the outbreak reported fatigue. Furthermore, higher risk of fatigue was associated with an increase in age. Naess et al. [33] found that 5% of patients infected with giardiasis never fully recovered, and of these, 60% qualified for ME/CFS. A qualitative study by Stormoken, Jason, and Kirkevold [34] explored reports of fatigue from the giardia outbreak. The researchers found that many participants experienced post-infectious fatigue such as awakening fatigue, which was characterized as prolonged states of being awake but feeling drowsy and unrefreshed. Awakening fatigue can be likened to a vegetative state, or severe unrefreshing sleep also found in patients with ME/CFS. Fatigue has also been widely observed in patients who recovered from dengue fever, caused by the dengue virus [35,36]. Seet, Quek, and Lim [37] found that 24.4% of participants reported significant fatigue post-infection, and many reported symptoms of muscle pain (64.5%) and headaches (77.4%). The categories of symptoms have been classified as post-dengue fatigue syndrome and has been likened to ME/CFS [38]. Common symptoms of post-fatigue dengue syndrome are hallmarks of ME/CFS such as severe (often debilitating) fatigue, muscle pain, joint pain, sore throat, headaches, reduced cognitive function, and tender lymph nodes. Given the ample evidence from previous epidemics, and longitudinal studies of viral and non-viral infections, it is likely some COVID-19 survivors will develop post-viral fatigue and other symptoms. However, it is unclear what factors may contribute to such development, and below we review the evidence involving cytokine responses. Cytokine responses to COVID-19 and post-infectious fatigue Mehta et al. [39] have found that patients who contracted COVID-19 exhibited a ‘cytokine storm.’ Specifically, the researchers found that patients had increased levels of IL-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein-α and tumor necrosis factor-α. The findings suggest a pattern of hyperinflammation which has been associated with complications such as multi-organ failure. Furthermore, COVID-19 infection is associated with a delayed expression of type I interferon (IFN) signaling, which is a crucial part of the innate defense against viral infections. In responses to viral nucleic acid, the subsequent intracellular cascade promotes the synthesis of IFN [40]. It has been hypothesized that this viral IFN production plays a critical aspect in ‘cytokine storm’ found in COVID-19 patients. Several immune factors have also been associated with post-infection fatigue. Utilizing the Dubbo Infection Outcomes study [4], Vollmer-Conna et al. [41] found that post-infection outcomes were impacted by polymorphisms in IFN-γ +874 T/A and the IL-10 −592C/A. These changes were thought to impact the severity of illness and cytokine productions. Using the same cohorot, Piraino, Vollmer-Conna, and Lloyd [42] expanded on these findings. The researchers found associations between single nucleotide polymorphisms in cytokine genes and post-infection complications such as fatigue, pain, neurocognitive difficulties, and mood disturbances Specifically, the associations were found with IL-6, TNF-α, IFN-γ, and IL-10. Furthermore, the researchers found that increased fatigue post-infection was associated with T allele of IFN-γ +874 T/A SNP. Bogovic et al. [17] studied the immune response outcomes of after the onset of tick-borne encephalitis. Many of these patients developed post-encephalitis syndrome, which is characterized by symptoms such as fatigue and myalgia. The researchers found that Th17 expressions were lower in patients who experienced more complications post-infection. The researchers implicate the role of inflammatory immune responses with the development of post-encephalitis syndrome. Cytokine expressions have also been implicated in the development of ME/CFS after infection onset. For instance, Broderick et al. [43] found that the cytokine network structure of people with ME/CFS differed from healthy controls. The researchers found attenuated Th1 and Th17 immune responses in the presence of a Th2 inflammatory milieu. The findings were consistent with processes observed in latent viral infections. Broderick et al. [44] expanded on their results and studied cytokine expressions in participants after infectious mononucleosis. At 24-months post-infection, participants who developed ME/CFS expressed higher levels of IL-2 and IL-6 than participants who fully recovered from infectious mononucleosis. Additionally, the researchers were able to retroactively categorize those with post-infection ME/CFS, from recovered controls, with over 80% accuracy based on levels of IL-2, 6, 8, and 23. Garcia et al. [16] examined cytokine expression in people with post-infection fatigue recovering from West Nile virus. When compared to those who recovered from the viral infection without fatigue, patients with fatigue displayed higher levels IL-2, 6, 12p70, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon-γ (IFN-γ), interferon γ-inducing protein 10 (IP-10). The researchers also found elevated levels of IL-10, IL-8, IL-15, IFN-α, and macrophage inflammatory protein (MIP)-1β; however, this difference was directional but not statistically significant (e.g. p < .10). The findings suggest that after the initial West Nile virus infection, people with post-infection fatigue have elevated levels of both pro-inflammatory and antiviral cytokines. Together with the results from Broderick et al. [43,44], the findings suggest that chronic fatigue after viral infection is related to a miscommunication in the inflammatory response pathways. Concluding remarks Past research has shown that elevated levels of post-infectious fatigue are common for some survivors of epidemics such as SARS and Ebolavirus [5,13]. Moreover, fatigue has been associated with infections, such as infectious mononucleosis, that occur frequently outside of an epidemic or pandemic scale [45]. These types of outcomes are not limited to just viral infections, but also bacterial infections [4]. Given such evidence, we expect that some survivors of COVID-19 will develop post-infectious fatigue and other complications. There is a need for research to analyze cytokine networks in people who recover from COVID-19 to assess whether the ‘cytokine storm’ experienced during the illness persists and contributes to other complications such as prolonged fatigue. Specifically, researchers might examine cytokines that have been implicated in both post-infectious ME/CFS and COVID-19 such as IL-2, granulocyte-colony stimulating factor, and interferon-γ inducible protein 10 [16,39,43,44]. Currently, there exists a unique opportunity to track how various factors may lead to post-infectious fatigue based on what has been learned from past viral and non-viral epidemics. Our contention that post-infectious fatigue will occur with COVID-19 has been also supported in several recent internet postings regarding surveys by patient organizations. For example, the Body Politic COVID-19 support group [46] collected data on 640 COVID-19 patients experiencing symptoms for over two weeks. At the time of the survey, 91% of respondents reported not being recovered after 40 days of experiencing symptoms. Moreover, 70% of respondents reported developing new symptoms at different stages of the illness. Most alarming, many experienced systemic stigmas from a variety of sources that affected their ability to recover. Other anecdotal reports suggest that, of those who do not fully recover from COVID-19, many experience lingering symptoms of fatigue, muscle ache, cardiac issues, and rashes [47]. Indeed, anecdotal evidence is already suggesting that some recovering from COVID-19 are developing ME/CFS-like symptoms [48]. In another patient derived sample, Petrison [49] suggested that COVID-19 has had prolonged effects in exacerbating symptoms among those with ME/CFS and other mold-related illnesses. Since the start of the epidemic, enough time has not elapsed to study the long-term trajectory of COVID-19, but reports are emerging about the occurrence of serious potentially longer-term health consequences. For example, several patients in Italy have developed Guillain-Barré [50]. There are reports of children developing Kawasaki disease, and other reports of COVID-19 causing lung scarring, blood clots, renal failure, and neurological complications [51]. Shi et al. [52] found 19% of 416 hospitalized COVID-19 patients showed signs of heart damage. These types of findings of COVID-19 reinforce our contention that a portion of survivors will experience a variety of longer-term health complications including post-infectious fatigue. Future research We close this article with a few recommendations for future COVID-19 studies. Given the high rates of COVID-19 mortality among African Americans and Latinx [53], it is important to include ethnically and sociodemographically diverse groups in study samples. It is also of importance to contrast findings from populations from various regions such as North America, South America, Europe, Africa, Asia, and Australia. In addition, researchers should examine co-morbidities and risks that compromise immune function including obesity, diabetes, old age, emphysema, cardiovascular disease, high blood pressure, smoking and vaping tobacco and marijuana products of any sort, and drug use. When possible, it is also optimal to longitudinally follow-up cases to better understand the risk factors for maintenance of fatigue and other symptoms. There is also a need to collect both behavioral and biological data from carefully characterized COVID-19 samples including those who are not symptomatic. Research is needed to assess functioning during the recovery phase post-COVID-19. Such studies might include a full medical and psychiatric assessment, as well as use of standardized and validated measures of critical symptoms such as the severity of infection and autonomic functioning, which have been predictive of post-infection ME/CFS [4,21,22,26]. If possible, data from prospective designs, capturing characteristics of patients prior to infection might provide unique insights into predisposing factors helping to answer why certain individuals have more serious short- and long-term outcomes. These recommendations could help us better understand predisposing factors in the development of COVID-19 and maintenance of symptoms, and thus lay the groundwork for better understanding post-infectious outcomes in a variety of illnesses. Disclosure statement No potential conflict of interest was reported by the author(s). Notes on contributors Mohammed F. Islam has a background in experimental psychology with a focus on human cognition. He is currently studying the factors associated with the development of ME/CFS after infectious mononucleosis in college students. Joseph Cotler earned his Ph.D. in Social Psychology from the University of Birmingham in England. He is currently researching cytokine expressions resulting from ME/CFS. 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