Post-Ebolavirus disease syndrome: what do we know?

Abstract

As the current Zaire ebolavirus disease outbreak in West Africa fades, the health problems of the more than 16,500 survivors have come to light. A wide range of mental and physical symptoms may occur during the convalescence stage. Reported symptoms of “post-Ebolavirus disease syndrome” (PEVDS) include chronic joint and muscle pain, fatigue, anorexia, hearing loss, blurred vision, headache, sleep disturbances, low mood and short-term memory problems. PEVDS has been associated with a decrease in functionality and difficulties to return to work. Further studies are needed to fully categorize the clinical spectrum of PEVDS. Diagnostic criteria and surrogate markers for the early diagnosis of PEVDS, and implementation of specialized health services to treat and follow-up survivors are also needed.

Keywords:

• convalescence
• Ebolavirus disease
• fatigue
• post-Ebola syndrome
• uveitis

The ongoing West Africa Zaire ebolavirus disease (EVD) epidemic, the largest outbreak in the history of this disease, has caused substantial mortality and morbidity. There have been more than 27,740 cases since the outbreak started at the end of 2013, affecting mainly Guinea, Liberia and Sierra Leone [1]. Once the epidemic began to recede, the long-term consequences have come to light. Now, with at least 16,500 survivors, a post-Ebolavirus disease syndrome (PEVDS) has emerged requiring more specialized health care services.

The long-term effects of Ebolavirus infection are poorly understood and studies about PEVDS are scarce. EVD survivors have reported a variety of symptoms including impaired sight and hearing, headache, muscle and joint aches, fatigue, dizziness, abdominal pain and weight loss [2,3].

The current epidemic is caused by Zaire ebolavirus; however, similar symptoms were reported among survivors of Bundibugyo and Sudan ebolavirus species. In a recently published study, 49 Bundibugyo ebolavirus survivors were matched with 157 controls after the 2007 Uganda EVD outbreak. Blurred vision, retro-orbital pain, hearing loss, neurological symptoms, fatigue, sleep disorders, large joint arthralgias, low mood and memory loss were reported during the convalescence period [4]. Long-term sequel persisted for more than 2 years after EVD.

Fatigue & musculoskeletal pain

Fatigue, joint, muscle and chest pain are the common symptoms following EVD [5]. Low back and sacroiliac pain and bilateral enthesitis of Achilles tendon have also been reported during the convalescence period [6]. In the current outbreak, around 50% of survivors complained of fatigue. Severe fatigue made it difficult for them to take up their earlier professions, as many survivors were farmers, laborers and were involved in manual work [2].

A recent study analyzed 105 EVD survivors approximately 3.5 months post-discharge from a Guinea treatment unit [7]. Anorexia (100%), chest (31%), joint (87%) and back pain (46%), and myalgias (27%) were reported. The severity of arthralgias was significantly associated with low recovery and poor functional status.

A cohort of 29 convalescent patients from the 1995 Kikwit outbreak (Democratic Republic of Congo) and 152 household contacts were studied prospectively. EVD survivors reported severe fatigue, joint and abdominal pain, myalgia and anorexia more frequently than their household contacts during the first 6 months of follow-up. Arthralgias (79.3%) and myalgias (55.2%) were the most commonly reported symptoms among convalescents at 6- and 21-month follow-up [8]. The most frequently involved joints were (by order): knee, back, hip, fingers, wrists, neck, shoulders, ankles and elbows.

Ophthalmic symptoms

The incidence and pathogenesis of ocular complications during the convalescence period is unknown. In a recent survey of EVD survivors from Sierra Leone, around 40% reported eye problems [2]. Uveitis can develop during the convalescence stage in EVD survivors, and persistence of Zaire ebolavirus in ocular fluid was described [6]. In a study of 20 survivors from the 1995 Zaire ebolavirus outbreak, at least three suffered from uveitis that occurred between 40 and 72 days after EVD onset [9]. Ocular pain, photophobia, hyperlacrimation and loss of visual acuity were the common symptoms.

Severe unilateral panuveitis occurring during convalescence has been described in a patient who recovered from EVD. The aqueous humor tested positive for Ebolavirus RNA on quantitative reverse transcriptase polymerase chain reaction assay, and viable Zaire ebolavirus was isolated from viral culture in the aqueous humor 14 weeks after the onset of EVD and 9 weeks after viremia clearance [6].

Other symptoms

Prevalence of hearing loss is unknown in PEVDS. Sensorineural hearing loss may occur with other hemorrhagic fevers, and was reported in one-third of Lassa virus infections [10,11]. The risk of hearing loss was two-times higher for Bundibugyo ebolavirus survivors as compared to controls, and 50% reported moderate hearing loss [4]. In the Kikwit study, serial audiometric testing was performed on 28 convalescents. Approximately 40% could not hear at least one of four frequencies during the first 6 months of follow-up. Seven of the eight patients followed up at 21 months could not hear at least one frequency [8].

Headache is a common symptom during EVD and may persist for months during convalescence. Chronic headache picture needs further characterization as some patients may have throbbing migraine-like headaches. Other headaches could be neuropathic or referred pain. Retro-orbital pain was four-times higher for Bundibugyo ebolavirus survivors as compared to controls [4].

Low mood, anxiety, coping problems and cognitive symptoms affecting attention, and concentration and short-term memory problems have been reported in a quarter of survivors. The conjunction of physical and psychological symptoms may induce a more severe clinical picture [12].

Pathogenesis

Pathogenesis may be multifactorial in origin and is poorly understood. PEVDS could be related to direct effect of Ebolavirus, persistence of the virus and treatment effect [3]. Alternative pathogenic explanations have arisen, including the use of chlorine heavy disinfection. Chronic fatigue syndrome may occur following Lyme, Epstein–Barr and dengue infections, among others. Filovirus, like dengue viruses, may cause fatigue through a variety of pathogenic mechanisms including encephalomyelitis and neuromuscular immune-mediated syndromes (Guillain–Barré syndrome) [13]. The incidence of these neurological conditions during EVD convalescence is unknown.

Immune dysregulation and persistent elevation of proinflammatory cytokines have been described in other post-viral syndromes. Symmetric polyarthropathy has been associated with parvovirus and hepatitis C infections [14]. Chronic joint pain is common after chikungunya infection and occurs in at least 10% of patients [15]. Joint pain and arthropathy could result from either Ebola viral replication or immune complex deposition in the joint tissue. Another potential mechanism includes development of cross-reactive antibodies to host proteins. Zaire ebolavirus antibody titers were higher in EVD survivors who reported joint pain as compared to those without arthralgias [8]. Those who had joint and muscle pain during convalescence also suffered from similar symptoms during acute EVD. Disseminated intravascular coagulation and elevated D-dimers have been detected in the acute stage of infection, and could also play a role in the pathogenesis of late osteoarticular lesions [7].

Severe panuveitis may be caused by a direct cytopathic effect due to active replication of Ebolavirus persisting in an immune-privileged organ. A high burden of viable Zaire ebolavirus was detected when ocular symptoms appeared in patients [6]. Ophthalmic involvement can occur following other viral infections. Uveitis and retinitis have been described in Rift Valley fever [16]. Marburg virus has been associated with uveitis, orchitis and hepatitis [17], and has been isolated and cultured from aqueous humor in a patient who suffered from acute anterior uveitis 3 months after infection [18].

EVD survivors may harbor the virus in other immunologically privileged sites like joint cartilage, gonads or central nervous system for a period of time after convalescence [6]. Zaire ebolavirus RNA has been detected in semen up to 101 days after symptom onset, and the virus has also been isolated from semen as long as 82 days after symptom onset [8]. Unprotected vaginal intercourse with a survivor may have sexually transmitted Zaire ebolavirus in Liberia [19]. Sexual transmission was also reported from a convalescent patient in the 1967 Marburg virus infection [20].

Future directions

The question of whether different Ebolavirus species can cause different long-term sequelae remains to be resolved. A higher rate of hemorrhagic manifestations, arthralgias, myalgias and anorexia during the 1995 EVD outbreak was noted, as compared to the current West Africa epidemic.

Epidemiological research is needed to fully characterize the entire PEVDS clinical spectrum. Small sample size, study design and selection criteria may have inadvertently introduced effect modifiers or confounding variables when evaluating the prevalence and severity of PEVDS. There is an urgent need to gather clinical data about the long-term consequences of EVD. In particular, nervous, ocular, hearing, muscle and joints systems should be evaluated. The effect on cardiovascular function, blood pressure, sleep, skin and liver needs further characterization. The long-term consequences on cognitive and neurological function among children who survived the infection are unknown [21]. The effect on reproductive health is also unknown, although some surviving women reported stopped menstrual periods. Other questions such as how long the sequelae will take to resolve and whether there are sequelae that may develop later need to be answered.

Strategies should be implemented to recognize and treat these symptoms early. Diagnostic criteria for PEVDS should be developed, and sensitivity and specificity analyzed. There is a need for research on surrogate markers during the acute EVD stage to predict the risk of PEVDS. Seizures and melena developed during the acute stage were associated with increased risk of dysphagia and joint stiffness in the Uganda 2007 outbreak [4]. Persistent immune activation is a plausible pathogenic hypothesis; further studies are needed to confirm if EVD antibody levels could be greater among patients suffering from PEVDS. The effect of specific antiviral treatments during acute EVD on PEVDS incidence and severity is also unknown.

EVD survivors should be evaluated at the earliest for any symptoms associated with PEVDS, and symptomatic treatment offered. Multidisciplinary healthcare services must be implemented for EVD survivors. Ophthalmic, rheumatologic, neurological and neuropsychological services are needed. The lack of specialized services in poor countries may be another challenge for their limited health structure.

The impact on mental health is underestimated, and the consequences of the recent outbreak on families, villages and social network have to be carefully studied. Social workers and anthropologists should evaluate the degree of community isolation and exclusion that Ebola survivors may suffer. PEVDS, poverty, fear of Ebolavirus and stigma should be analyzed in the context of a multidisciplinary assessment.

In summary, there is a dual need for both clinical research and clinical care in PEVDS. The latter should be emphasized and the former should not impede the efforts taken to care for the many survivors who are suffering.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.