Postviral fatigue syndrome

Postviral Fatigue Syndrome (PVFS) refers to a chronic fatiguing illness which begins after a virus. PVFS has many similarities to myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Since not all cases of ME or CFS are preceded by a viral infection, the term PVFS has become outdated and is nowadays seldom used in scientific literature. As ME expert Peter Behan explained these developments: “It became abundantly, crystal clear that several patients had developed the syndrome, the identical syndrome but they had developed the syndrome not following a viral or other infection but due to their reaction to a particular form of physical or psychological stress.”

Symptoms
By 1990, a group of core and minor symptoms of Postviral Fatigue Syndrome were described:


 * severe fatigue made worse by exercise - now called post-exertional malaise (PEM)
 * persisting or relapsing 'fatigue' or easy fatiguability
 * myalgia (muscle pain)
 * depression, which may be atypical
 * excessive sleep or other sleep disturbance
 * concentration difficulties
 * may or may not follow what appears to be an acute infectious illness, such as a virus, bacteria or parasite infection

Lask and Dillon (1990) also reported:
 * mild fever
 * sore throat
 * sore lymph nodes
 * headaches
 * migratory joint pain
 * light sensitivity
 * forgetfulness
 * irritability

Behan and Behan (1988) also reported:
 * exhaustion
 * emotional lability

Behan et al. (2007) also reported:
 * night sweats (a core symptom)
 * dysequilibrium disorders, e.g. dizziness, balance or gait problems
 * Irritable bowel syndrome

In children, symptoms may include:
 * lethargy
 * headache
 * abdominal pain
 * subjective muscular weakness

These symptoms were altered and adapted over time, with over 20 different sets of diagnostic criteria being published, and psychological symptoms including depression and emotional lability regarded as potential consequences of the illness, rather than diagnostic symptoms.

Diagnostic criteria
The most commonly used diagnostic criteria is the 1994 Fukuda criteria, uses the name chronic fatigue syndrome, and allows for non-viral triggers. This requires at least 6 months of "persistent or relapsing" fatigue which persists despite rest, has a significant impact on daily life, and includes at least four of the following symptoms:
 * post-exertional malaise (PEM) lasting more than 24 hours
 * substantial impairment in short-term memory or concentration
 * sore throat
 * tender lymph nodes
 * muscle pain
 * multi-joint pain without swelling or redness
 * headaches of a new type, pattern, or severity
 * unrefreshing sleep

More recent definitions have emphasized post-exertional malaise rather than fatigue, and used alternative for the illness, including the Systemic Exertion Intolerance Disease (2015) and the International Consensus Criteria for ME (2011).

Viruses
Many different viruses have been reported immediately before the onset of postviral fatigue syndrome, including:
 * Cocksackieviruses
 * Cytomegalovirus
 * Dengue viruses
 * Ebola can cause a post-Ebola syndrome which has similarities
 * Epstein-Barr virus
 * Enteroviruses
 * Human herpesvirus 6, 7 and other herpes viruses
 * Influenza viruses
 * Parovirus B19
 * Ross River virus
 * SARS-CoV, the coronavirus that causes SARS
 * Varicella zoster virus, which causes Chickenpox

ICD-10 title
Postviral fatigue syndrome is the official concept title of code G93.3 in the ICD-10, the medical classification list of the World Health Organization (WHO). "Benign myalgic encephalomyelitis" is inscribed as an inclusion, while "chronic fatigue syndrome" is listed only in the index. Since postviral fatigue syndrome is seldom used in scientific research and clinical practice, some argue it should be removed as a concept title. Mary Dimmock and Suzy Chapman for example propose to list PVFS in the upcoming ICD-11 as a synonym term under a new concept title "Myalgic encephalomyelitis". The proposal of the IACFS/ME, written by Lily Chu, however suggests to retain the term PVFS as a concept title and to simply elevate the terms "chronic fatigue syndrome" (CFS) and "myalgic encephalomyelitis" (ME) to concept titles at the same level, with each of the three terms given a unique code. Both proposals to the ICD-11 advocate to maintain the classification of these three terms in the neurological chapter.

Post-infectious Fatigue Syndrome
The Oxford criteria has a post-infectious fatigue syndrome (PIFS) as one of its definitions. The Argus Report article US NIH Report Calls for UK Definition of ME/CFS to be Scrapped states: "The NIH has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community."

Post-EBV ME/CFS
Several studies have performed an extensive follow-up on adolescents with infectious mononucleosis resulting from the Epstein-Barr virus (EBV). In general these studies have found that approximately 10% of the sample meets the diagnosis of ME/CFS after 6 months, though the percentage decreases as time moves on. Research has not been able to identify significant predictors of ME/CFS diagnosis except for the severity of the acute Epstein-Barr virus (EBV) infection.

More fatigue after EBV compared to other infections
White et al. showed the percentage of patients developing chronic fatigue syndrome to be significantly higher after an infection with EBV (9-47%) than after an upper respiratory tract infection (0-6%). Other research has shown that persistent fatigue is much more common after infectious mononucleosis than after other infectious diseases such as influenza or tonsillitis.

Independent of psychological factors
The study by White et al. demonstrated that EBV does not cause an increase in psychiatric disorder and that psychosocial factors were not predictors of persistent complaints. This indicated that the postviral fatigue syndrome is a distinct disease category. According to the authors, patients with the postviral fatigue syndrome reported more severe physical fatigue, especially after exertion, than patients with psychiatric disorders. A similiar conclusion was drawn by Buchwald et al., who followed up on 150 patients with infectious mononucleosis in the Seattle area. After six months, 12% of the patient sample said they still were not recovered. In agreement with White, the authors stated that they “do not believe that the postinfectious fatigue syndrome after infectious mononucleosis can be explained primarily by psychologic factors.”

Only severity of  the acute illness predicts ME/CFS
The most comprehensive study of postviral fatigue syndrome was organized and funded by the CDC in the 2000s. The study focused on Dubbo a remote township in Australia where it is easier to follow up on medical records; 253 patients with either an acute infection with Epstein-Barr virus (EBV), coxiella burnetti (the bacteria that causes Q-fever) or Ross River virus were studied. After six months, 11% of the patient sample met diagnostic criteria for chronic fatigue syndrome, with no significant differences in prevalence between the different infections. ME/CFS was predicted mostly by the severity of the acute infection, rather than by demographic, psychological or microbiological factors. There was no significant difference in cytokine expression or reactivation of herpesviruses (EBV, HHV-6, CMV) between the group that did or did not recover.

ME/CFS cases decrease over time
A study in the Chicago area showed that the percentage of patients meeting ME/CFS criteria after infectious mononucleosis decreases as time moves on. While 13% met ME/CFS criteria at the six-month time interval, this decreased to 7% at 12 months and only 4% at 24 months. The most important predictors of ME/CFS caseness were autonomic symptoms and days spent in bed since mono. This confirmed the main conclusion of the Dubbo studies, namely that the severity of the acute infection is the main predictor of ME/CFS. In the Chicago study however, cytokine expression indicated differences in Th17 function in patients with post-infectious ME/CFS.

Psychosocial factors determine persistent fatigue but not ME/CFS
Studies that looked at a broader definition of fatigue after an EBV infection have reached different conclusions. Candy et al. (2003) for example found that persistent fatigue six months after infectious mononucleosis was predicted by certain illness perceptions such as the belief that the illness would take more than one month to recover from and would have serious consequences. Moss-Morris et al. followed-up on 246 patients with glandular fever from New Zealand. After six months, 7.8% still reported severe fatigue. Depression, anxiety and perfectionism were associated with persistent complaints though perceived stress and limiting activity were not. A Norwegian study found that fatigue after acute EBV was predicted by variables related to symptoms and negative emotions instead of immune processes. These findings would later be disrupted, and patient attitudes beliefs are no longer considered influence outcomes. 

Books

 * 1992, Post-Viral Fatigue Syndrome, James Mowbray, Rachel Jenkins (Eds). ISBN 978-0471938798.
 * 1999, Living with Me: the Chronic, Post-viral Fatigue Syndrome, Charles Shepherd. ISBN 0091816793.

Articles and blogs

 * May 18, 2020, Paul Garner: Covid-19 and fatigue—a game of snakes and ladders - The BMJ
 * I got a virus, but I didn't die - Millions Missing campaign video about Graded exercise therapy

Learn more

 * Postviral fatigue syndrome - Lask and Dillon (1990)