Beyond survival: unraveling the dynamics of Ebola virus resurgence in Sub-Saharan Africa and the remarkable journey of survivors

1 Introduction

Ebola virus (EBOV) is a highly virulent pathogen in the Filoviridae family of negative-sense, single-stranded RNA viruses capable of inducing a severe haemorrhagic fever syndrome in humans and non-human primates (1, 2). The virus causes Ebola virus disease (EVD) and garnered worldwide attention due to the significant number of cases associated with the 2013-2016 outbreak, which marked one of the largest outbreaks of EVD in history (3, 4). Initially identified in 1976 during the first reported EVD epidemic in the Ebola River Valley in Yambuku, Zaire (now the Democratic Republic of the Congo), the virus has since caused sporadic human disease outbreaks in several African countries (5). Since its discovery, there have been at least 37 documented outbreaks of EVD in Africa, with the most recent outbreak being declared over in Uganda on January 11, 2023 (6).

Transmission of EVD to humans predominantly occurs through direct contact with infected humans or animals, such as fruit bats, apes, monkeys, and forest antelopes. The fruit bat is widely regarded as the likely natural host of EBOV, and the close interaction between local communities and these bats renders the local population susceptible to EVD (7–9). While EVD is characterized by fever, severe fatigue, headache, and hemorrhagic conditions leading to multiple organ dysfunction and death, it is noteworthy that some individuals survive despite the disease’s high mortality rate.

However, recent studies indicate that individuals who have overcome Ebola infection can experience relapses and initiate new outbreaks even several years after their initial infection (10, 11). This surprising revelation suggests that the virus can persist in specific bodily sites for extended periods, including the brain’s ventricular system, the eye’s aqueous humor, and the testes’ Sertoli cells in both human and non-human primate survivors of EBOV infection (12–16). Prolonged persistence can result in the virus resurfacing, causing severe and frequently fatal disease (12, 17, 18). Notably, the virus has been observed to enter a dormant state in a small subset of survivors who had previously tested negative, and in rare instances, it can reactivate to initiate new infections and transmissions years later (8, 13). This infrequent yet significant occurrence represents a novel paradigm, emphasizing the significance of understanding this rare transmission route that could contribute to the resurgence of Ebola outbreaks. While acknowledging its rarity, this discovery imparts vital insights into the potential mechanisms driving the resurgence of outbreaks.

Gaining a deeper understanding of the factors behind recent human outbreaks may provide enhanced strategies for their control. This review delves into the role of survivors in the resurgence of EBOV in Sub-Saharan Africa, as well as the factors that amplify the probability of the virus leading to disease recurrence within populations. Furthermore, the review thoroughly examines strategies for managing the ongoing health of survivors and effectively curbing the potential for the reemergence of new outbreaks in the future.

1.1 Epidemiology of Ebola virus

The first documented case of EBOV infection occurred in the Democratic Republic of the Congo (DRC) (19) during an outbreak of severe haemorrhagic fever. Concurrently, a similar outbreak occurred in Sudan (20). Subsequent investigations highlighted differences between the strains isolated from these two countries: Sudan ebolavirus (SUDV) in Sudan and Zaire ebolavirus (ZEBOV) in the DRC (21). Following the initial identification of the virus in 1976, sporadic outbreaks were documented in 1977 and 1979, preceding the occurrence of EVD outbreaks in various other countries.

Reston ebolavirus (RSTV) was discovered in 1989 and 1990, causing disease exclusively in non-human primates and guinea pigs (22, 23). During the same period, the Taï forest ebolavirus (TAFV) was isolated (24). The Bundibugyo ebolavirus (BDBV) first emerged in Uganda in 2007 (25) and again in 2012 (26), capable of inciting epidemics. In 2018, the Bombali virus (BOMV) was identified in Sierra Leone, although its potential to cause human disease remains uncertain (9), in contrast to the ZEBOV, which is the most virulent among all the strains (27).

All the six known EBOV species (SUDV, ZEBOV, RSTV, TAFV, BDBV and BOMV) share common features and gene order (28, 29). Their viral genomes, approximately 19 kb long, encode seven main proteins: nucleoprotein (NP), viral protein (VP) 24, VP30, VP35, VP40, the glycoprotein (GP), and the RNA-dependent RNA polymerase (L) (Figure 1) (30, 32). NP, a multifunctional protein, encapsulates the viral genome into the nucleocapsid (33, 34). VP40, one of the most abundantly expressed proteins, drives viral assembly and budding (35). L functions as an RNA-dependent RNA polymerase (RdRp) and, in association with VP30, forms the RdRp complex responsible for viral genome transcription and replication (36–38). VP24 and VP35 play roles in suppressing interferon signaling, aiding in evading the host’s immune response (39). GP, the sole protein found on the virion’s surface, is essential for binding to target cells, mediating membrane fusion, and facilitating the release of the viral genome. GP is responsible for pathogenic differences among ebolaviruses (30, 40).

Figure 1 Taxonomy and genome organization of Ebola virus. (A) Most species of the genus Ebolavirus are lethal to humans and non-human primates, with the exception of Bombali virus. *No human infections recorded. (B) Schematic representation of Ebola virus genome organization. All genes encode one protein each, except for GP, which produces three pre-proteins due to transcriptional editing (28, 30, 31). Created with BioRender.com.

EBOV genomes exhibit a remarkable level of similarity, characterized by identical genome organization and often identical sequences within the same strain (Figure 1) (27, 29). Comparative genomics analysis has shown approximately 97% similarity between the genomes of the 1976 DRC outbreak and the 2014 West Africa outbreak, indicating significant genetic sequence homogeneity within the EBOV species (29). Despite these similarities, there is considerable divergence in their sequences, particularly in the intergenic regions and specific areas of genes encoding the GP, NP, and L (25, 29). These genomic variations provide insights into the evolution and dynamics of EBOV, which are crucial for understanding the virus’s virulence and immune responses. Identifying specific regions within the genomes, such as epitope-binding sites, can aid in developing potential vaccine targets and therapeutic strategies.

In summary, the comparative genomics of EBOV species highlights the conservation of genetic organization and diversity within the EBOV genus. This knowledge contributes to our understanding of the virus’s origins, transmission, and potential strategies for combating the resurgence of EVD.

Since the year 2000, the prevalence of EVD outbreaks has firmly established EBOV as a prominent health concern within the African continent, particularly in central and western regions (41). As of 2023, a few cases of Ebola have been reported outside of Africa in countries including the United States, Italy, England, Russia, the Philippines, and Spain (42). These instances are attributed to human mobility, particularly air travel, which can facilitate the cross-border transmission of infectious diseases.

1.2 Viral persistence and reactivation in survivors

Since its initial appearance in 1976, the continuous emergence of various EBOV species across Sub-Saharan Africa has led to outbreaks of EVD spanning 13 African countries. Notably, significant resurgences have been witnessed in regions such as Sudan, Guinea, Uganda, and the DRC (Figure 2) (4, 41).

Figure 2 Ebola virus species outbreaks from 1976-2022. RC: Republic of the Congo; *Laboratory confirmed cases only; ^aWest African Epidemic in Guinea, Liberia and Sierra Leone. The figure was constructed based on information at the Centres for Disease Control and Prevention (CDC) (42). Created with BioRender.com.

Research focusing on survivors who triumphed over the virus across different epidemics throughout the continent has provided intriguing insights into the realm of EBOV RNA persistence, shedding light on its intricate dynamics. EBOV is believed to persist specifically in immune-privileged sites, including the eye, brain, and testes. This persistence is evident in various bodily fluids after recovery, with a comprehensive record, particularly in semen, breast milk, and aqueous humor (14, 15, 43–47). The detectability of EBOV RNA in skin swabs up to 23 days after viral clearance, despite concurrent negative cell culture results, indicates its enduring presence (48). A singular case even revealed the isolation of EBOV from a urine sample, a full 9 days following the cessation of viraemia (48). Strikingly, the virus’s tenacious persistence was confirmed in the aqueous humor of an eye from a survivor afflicted by severe acute EVD, complicated by sight-threatening uveitis and multisystem organ failure (14). During the 2014 Ebola outbreak in Sierra Leone, a nurse experienced meningitis 9 months after recovering from EVD, with subsequent detection of EBOV in her blood and cerebrospinal fluid (49). A similar study conducted on a pregnant woman in Guinea who survived EVD revealed the persistence of a high viral load in both the amniotic fluid and placenta (50). The cycle threshold (Ct) values for the viral load in the amniotic fluid were 22.2, while the placental swab recorded a value of 18.4. These findings strongly suggest that the virus can persist in these reproductive tissues even after the mother’s recovery from the infection (50, 51). This diversity of viral persistence across bodily fluids underscores the virus’s adaptability to distinct physiological niches, yet the selective preference for specific compartments remains an enigmatic puzzle.

In a pilot study involving 93 EVD survivors in Sierra Leone, EBOV RNA was identified in the semen of half of the participants at least once during the follow-up period. Remarkably, viral shedding persisted in 26% of the survivors, remaining evident even after 7-9 months (43).

In a related study, Thorson et al. reported the persistence of Ebola viral RNA in semen of male participants who survived EBOV infection in Sierra Leone (52). Post recovery examinations utilizing quantitative reverse transcription polymerase chain reaction (qRT-PCR) further revealed virus persistence in more than 20% of the survivors (>35 years) at 1 year.

Surprisingly, EBOV RNA persisted in the semen of 11 male survivors for more than two years, raising concerns about prolonged virus carriage and potential sexual transmission by asymptomatic survivors (53). While the exact mechanism behind EBOV RNA persistence in bodily fluids remains elusive, the need for further investigations into viability prevalence is evident.

Infectious virus has been detected in the semen of EVD survivors using Vero E6 cell culture models and qRT-PCR, bearing significant implications for personal and public health (15, 44). It’s worth noting that although the persistence of EBOV in a subset of survivors raises concerns about potential disease reactivation and viral transmission through bodily fluids, the proportion of survivors in whom this occurs is limited. Moreover, modern GeneXpert Ebola assays have effectively revealed prevalence and viability patterns in various fluids and whole blood samples (54, 55), dispelling cases where RNA detection might not necessarily indicate the presence of viable virus (56). These instances provide a fascinating glimpse into the nuanced landscape of EBOV persistence, highlighting its ability to inhabit distinct physiological niches. Understanding the potential events in ongoing outbreaks is crucial for designing effective prevention and control strategies to combat the ongoing threat of EBOV outbreaks.

While the persistence of the virus holds the potential to rekindle human-to-human infections, ultimately leading to the resurgence of Ebola outbreaks (Figure 3), the occurrence of such events remains rare (10, 58–60). In addition, the exact mechanisms and risk factors for such transmission are still being studied, and more research is needed to fully understand this process.

Figure 3 Factors that could potentially trigger current Ebola outbreaks. (A) Primary spillover event from animal reservoirs (bats and non-human primates) to humans, which occurs through bush meat hunting or direct contact with the fluids of infected animals. (B) Outbreak possibility linked to a small subset of survivors who may experience viral persistence in a population. The possibility of transmission is further amplified by viral reactivation and sexual contact. Dotted arrows indicate hypothetical factors that may occur (10, 18, 57). Created with BioRender.com.

For this reason, striking a delicate balance between acknowledging this documented phenomenon and avoiding unwarranted stigma towards survivors, given the exceedingly limited chance of transmission, is essential. The recognition of this rarity reinforce the importance of comprehensive research to fully comprehend its significance.

Noteworthy instances of possible sexual transmission of EBOV infection from male convalescent patients to female sexual partners have been reported (61–63), demonstrating Ebola as a potential sexually transmitted infection (STI). For example, it is reported that a survivor who continued to shed the virus in his semen for over 500 days after contracting EVD, transmitted the virus to his partner through sexual contact, subsequently triggering a reemergence in Guinea in 2016 (64). To further illustrate the role of survivors of Ebola in new outbreaks, genome sequencing analysis and epidemiological evidence provided by Keita et al. showed that the reactivation of a dormant infection in an asymptomatic person for almost 5 years triggered the 2021 Ebola outbreak in Guinea, West Africa (10). The duration of viral persistence following the conclusion of the 2013-2016 West African Ebola outbreak was astonishing, challenging the historical instances of clinically persistent EBOV infections reawakening.

A correlated study provided additional backing to the notion of infectious virus reawakening by tracing the origin of the 2021 EVD outbreak in the DRC to the reactivation of dormant EBOV infections stemming from the 2018-2020 outbreak (65). Further research by Dokubu et al. supports potential for persistent viral infection and transmission (59). Their investigation into an EVD cluster in Liberia revealed phylogenetic relatedness between Ebola virus genomes from the 2015 cluster and epidemiologically linked cases from the 2014–15 West African outbreak. This linkage strongly suggests the survival and transmission of the virus by an individual from a previous outbreak, highlighting the role of viral persistence in fueling recurrences.

Overall, the enduring presence of the virus presents the potential to rejuvenate human-to-human infections, consequently culminating in the resurgence of Ebola outbreaks (Figure 3). In light of these transmission dynamics, it is imperative to conduct further research to gain more insight into this atypical transmission events in the current post-Ebola scenario.

1.3 EBOV versus host immune system

1.3.1 Waned immunity of survivors may enhance viral persistence and transmission dynamics

Recovery from EBOV infection triggers the development of both cell-mediated and humoral immune responses. Nonetheless, the strength of these responses may diminish over time (66, 67). In a study involving 115 Ebola survivors in Sierra Leone, IgG levels—the most prevalent antibody in blood serum and extracellular fluids—were closely monitored, revealing intriguing patterns (68). Over a 500-day post-infection period, a substantial drop in IgG levels was observed. However, a fascinating pattern emerged – a subgroup of survivors experienced a resurgence of IgG around 200–300 days after the initial infection. Unfortunately, this resurgence was short-lived, followed by another decline in antibody levels. These findings illuminate the complexities of post-recovery immune responses and hold significant implications.

Ruibal and colleagues also identified activated CD8⁺ and CD4⁺ T cells in blood samples from EVD survivors, distinguishing them from fatal cases where higher levels of T cell inhibitory molecules PD-1 and CTLA-4 were expressed on CD4⁺ and CD8⁺ T cells. The latter group was more susceptible to disease (69). This suggest that a robust virus-specific T cell response is needed to ensure recovery from the acute phase. However, in scenarios where the virus persists in immune-privileged sites like the brain, eyes, and testes even after recovery, T cells might undergo exhaustion, or their proliferation could be delayed and limited. This phenomenon could be attributed to a high viral load and uncontrolled viral replication (70).

In a longitudinal study of EVD survivors, conducted by Sobarzo et al., significant CD8⁺ T cell responses were not identified (71). The authors also noted a decline in neutralizing antibodies, providing evidence that survivors might initially exhibit activated adaptive immunity that gradually wanes over a period of at least a decade.

Moreover, weak CD8⁺ EBOV-specific T cell responses have been detected in survivors for up to 40 days after clearance of viraemia (72). In fact, certain immunodeficiency conditions, such as the loss of primed CD4⁺ T cells, have previously been linked to EBOV persistence (73). Evidence indicates that some survivors experience substantial lymphocyte loss, combined with disrupted interactions between dendritic cells and T cells (74, 75). The expression of apoptotic genes such as Fas, Fas Ligand (FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in EVD patients has been proposed to induce lymphocyte apoptosis, potentially contributing to lymphocyte depletion in survivors over time (76, 77).

Besides the ability of EBOV to evade immune surveillance and ensure persistence (78), it is important to consider the influence of concurrent infections, such as HIV, tuberculosis, and malaria, which are prevalent in Sub-Saharan Africa (79). These co-infections may contribute to EBOV persistence dynamics, affecting immune responses even after recovery from EVD (80). For example, some Ebola patients who are co-infected with HIV may have compromised immune systems, affecting their ability to control EBOV persistence (81). Moreover, malaria and tuberculosis can induce immune-modulating effects that potentially favor EBOV’s ability to persist in a weakened host immune system (82–85). As a result, these concurrent infections could contribute to the gradual waning of immune responses in EVD survivors over time, subsequently enhancing viral persistence dynamics and the potential for reactivation (84).

The concept of reactivation of the initial pathogen through concurrent infections is supported by various studies. When multiple intracellular pathogens infect the same host cell, they can disable cellular immune defenses and evade immune responses, leading to the reactivation of a latent first pathogen and accelerated T-cell exhaustion or suppression regarding a second pathogen (86–89). While there is no confirmed evidence indicating genuine latency of EBOV, the existence of concurrent infections may potentially foster an environment that hinders the immune system’s capacity to manage the persistence of pathogens, including EBOV (87, 90–92). Therefore, understanding the interactions between different pathogens and their impact on the immune system is crucial when studying viral persistence and the potential for reactivation.

Considering the uncertainty surrounding the specific antibody threshold required for achieving optimal protection and nurturing immunological memory, the decline in antibodies among certain Ebola survivors over time warrants attention (93).

Undoubtedly, immunity plays a pivotal role in containing viral infections and preventing recrudescence. The immune system’s response to initial infection is typically robust, with antibodies and immune cells efficiently targeting the virus. Nevertheless, over time, this immune response might wane, potentially enabling shifts in the balance between the host and the virus (68, 94, 95). This weakening of the immune response creates an environment in which the virus, potentially persisting in bodily reservoirs, can reactivate and replicate (68, 73, 96). Consequently, this reactivation could result in the reappearance of symptoms observed in some survivors. The immune system’s once-robust capacity to suppress viral replication might become compromised, potentially facilitating the re-emergence of the virus within a population.

The intricate interplay between immunity, viral persistence, and reemergence underscores the multifaceted nature of Ebola virus outbreaks. In light of these complexities, vigilant monitoring of survivor health becomes imperative. Considering interventions such as administering supplementary vaccinations to invigorate the immune system holds promise in curbing the risk of viral relapse among survivors (97). By proactively supporting survivors’ immune responses, the potential for reseeding outbreaks can be effectively mitigated.

1.3.2 Persistent viral pathogenesis

The severity of the disease and its fatality in the context of EBOV infection can largely be attributed to the robust inflammatory response activated by the virus within the host. Generally, this interaction between EBOV and host cells amplifies the release of oxygen-free radicals and various cytokines and chemokines, including TNFα, IL-1, IL-6, IL-8, IL-15, IL-16, IFN-α, IFN-β, IFN-γ, IP-10, CCLs-2, -3, -4, CXCL-10, MCSF ultimately leading to severe illness and death (71, 98–101).

The persistence of cytokine activity may play a critical role in promoting long-term EBOV persistence by dampening T cell activation, creating a conducive environment for the establishment of a pool of infected cells within immune-privileged sites (102). This implies that, beyond the influence of cytokine activity, the specific cells within these immune-privileged sites could also contribute to the extended presence of the virus. In view of this, the hypothesis that certain cell types might act as reservoirs for the virus is currently being investigated, with particular attention on myeloid cells. Resident tissue macrophages and dendritic cells, both originating from the adult bone marrow, are vital components (103). The bone marrow’s susceptibility to infection during the acute phase is evident from the presence of viral inclusion bodies within its cells and substantial antigen deposition in its stroma. Given the continuous production of cells by the bone marrow throughout life, it becomes plausible that myeloid-dendritic progenitor (MDP) cells could also fall victim to the virus. MDP cells, in their regular lifecycle, enter the bloodstream and populate tissues, eventually differentiating into resident tissue macrophages and dendritic cells. If these cells succumb to infection, they could potentially serve as repositories for viral persistence within tissues, persisting for the cell’s natural lifespan, possibly lasting several weeks to months. This paradigm of myeloid cell involvement resonates with similar mechanisms observed in other infections such as HIV, Dengue, and Marburg virus persistence (104–106). Directing attention towards the myeloid cells holds the potential to address the prolonged EBOV reservoir that has been identified in certain survivors.

In addition, the biochemical strategy employed by EBOV to ensure viral persistence in infected cells is not yet fully understood. Nonetheless, it is hypothesized that specific inflammatory markers present in survivors’ blood samples could indicate ongoing viral persistence and inflammation (96). While some survivors of EBOV infection may display a milder inflammation profile and less pronounced cytokine and chemokine responses compared to fatal cases, the persistence of structural damage to the epithelial barrier and immune dysfunction could characterize a state akin to chronic EVD (96). This raises the critical need to investigate whether these survivors are progressing toward a chronic disease state. In this context, the study conducted by Shantha et al. holds significance as they examined EBOV survivors with uveitis who underwent cataract surgeries to explore viral persistence and chronic inflammation (107). Their research sheds light on how sustained low-level viral replication might contribute to recurring inflammation even after the virus has been cleared. The presence of recurrences in immune-privileged sites prompts inquiries into the dynamics of viral replication and the immune response in these specific contexts. The study’s observations offer compelling evidence that EBOV RNA is frequently detected in extracellular compartments during instances of disease recurrence, and the ability to culture the virus from tissue samples in these sites suggests ongoing replication. This observation aligns seamlessly with the concept that sustained low-level viral replication, coupled with an imbalanced immune response, could foster chronic inflammation and ultimately contribute to recurrence (107, 108).

Collectively, the inflammatory response may contribute to the residual levels of viral persistence in cellular reservoirs and potentially lead to disease recurrences among survivors (101). Further research is essential to delve into the intricate mechanisms behind EBOV persistence, as well as the impact of immune markers and inflammation. These investigations hold the potential to provide valuable insights into prolonged inflammation among EVD survivors.

2 Post-Ebola virus syndrome

The emergence of post-Ebola virus syndrome (PES) among survivors further highlights the complex aftermath of Ebola virus infection. This syndrome has been observed in a small subset of individuals who have successfully recovered from the virus (109, 110). Despite overcoming the acute phase of the disease, some survivors may experience long-term health effects that encompass a range of symptoms and conditions. The underlying factors contributing to PES are multifaceted, with persistent virus reactivation in immune-privileged sites playing a pivotal role in the reappearance of infection during the convalescent phase (111–113).

PES manifests with a range of clinical symptoms, encompassing conditions like arthralgia, uveitis, arthritis, and psychological stress (109). The health implications faced by EVD survivors have undergone comprehensive evaluation, shedding light on various aspects of the syndrome.

Pediatric survivors in Sierra Leone showed higher prevalence of ophthalmic complications like uveitis and vernal keratoconjunctivitis (110). Similarly, Qureshi and colleagues observed anorexia (100%), chest pain (31%), joint pain (87%), back pain (46%), and myalgias (27%) among 105 EVD survivors who were discharged from treatment after approximately 3.5 months (114). Musculoskeletal issues, particularly arthralgia and myalgia, have been frequently reported among survivors, marking them as common features of PES (115–117).

Additionally, PES is associated with cognitive and psychological symptoms like headaches, insomnia, memory loss, hearing loss, depression, and anxiety (112, 114, 115, 118). These psychosocial factors significantly affect survivors, leading to stigma and hindrances in societal integration (119, 120).

Despite the prevalence of PES, research has indicated that certain chronic PES symptoms may improve with time. Evidence suggests that headache, sleeping disorder, anxiety, depression and fatigue decreased significantly from 0-3 months to 10-12 months among post-EVD participants in Liberia (121). A decline in chronic symptoms of PES with the exception of uveitis has also been reported by the PREVAIL III study, suggestive of the fact that survivors after surviving acute manifestations may still show symptoms of chronic clinical manifestations, and these manifestations may decrease with time (122). This implies that the clinical symptoms of PES may exhibit improvement as time progresses. In contrast, Tozay and colleagues later reported no reduction in the prevalence of post-EVD symptoms among survivors four years after infection (123). The influence of various methodologies, including the choice of symptom-detection questions, the duration of follow-up, and the use of medications by survivors (such as pain medication), might all contribute to the diverse outcomes observed. Although individual survivors may experience specific PES symptoms, the combination of both physical and psychological manifestations could potentially contribute to a more severe clinical presentation (124, 125).

Regarding skin disorders in Ebola survivors, reports have identified common skin symptoms, including alopecia, which affects more than 30% of Ebola survivors (126–128). However, these cutaneous manifestations could potentially stem from hematological compromises like prolonged anemia and leukopenia.

2.1 PES Systematic review

2.1.1 Methods

To comprehensively explore the manifestations of PES, we retrieved online data collected from Ebola survivors reporting symptom manifestations, primarily from endemic areas within the Sub-Saharan region, in order to identify commonly reported complications.

2.1.2 Data source and searches

We conducted electronic searches to identify publications reporting on PES among EVD survivors from January 1, 2015, to April 7, 2023. The research methodology followed a systematic approach adhering to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) standard (129). No restrictions were applied regarding study period or sample size. The complete search protocol is detailed in supplementary methods (Supplementary 1).

2.1.3 Study selection

Our systematic review excluded experimental research, reviews, editorials, letters to the editor, and case reports. Inclusion criteria were based on studies providing data on the prevalence of signs and symptoms among EVD survivors during the convalescent phase. Two authors (WA, TN-B) independently reviewed all relevant titles and abstracts, selecting articles for full-text review when inclusion criteria were met. Any discrepancies were resolved through consensus with a third author (PO). Articles that met the inclusion criteria were short-listed for the final systematic review.

2.1.4 Evidence of the study

The literature search yielded 762 articles, of which 49 underwent full review, and 38 were included in the final analysis (Figure 4 and Supplementary 2).

Figure 4 PRISMA flow diagram of the selection of studies included in the systematic review and meta-analysis of PES.

In our analysis, we employed both relative and absolute frequencies to calculate the prevalence percentage of signs and symptoms among survivors of EVD within a given population. The results of our analysis are presented in Table 1, and a visual summary of the findings can be found in Figure 5. Our results offer an overview of the frequency at which various symptoms are commonly manifested by individuals who have survived Ebola, thus contributing to the limited body of literature detailing the symptoms experienced by EVD survivors.

Table 1 Common clinical symptoms among persons with post-Ebola virus syndrome (PES).

Figure 5 The common chronic clinical manifestations observed among some survivors of Ebola virus disease. The reactivation of persistent Ebola virus in body sites such as testes, ovaries, and placenta can contribute to the development of chronic symptoms in EVD survivors. Created with BioRender.com.

2.1.5 Results

The evidence derived from our systematic review indicates that complications among the thousands of EVD survivors are primarily characterized by a range of disorders that are parallel to those experienced during the acute phase of the disease. Consistent with findings from other studies, arthralgia, headache, and photophobia emerge as the most frequently reported long-term symptoms among survivors, with a prevalence exceeding 40% (4, 112, 114, 118, 121, 122, 127, 128, 130–135).

General symptoms that are frequently identified in survivors during the acute phase, including fever, fatigue, anorexia, and chest pain, have been extensively documented (118, 121, 122, 130, 131). Our research further discloses that these symptoms endure in more than 20% of survivors even during the convalescent phase.

The prevalence of these commonly reported manifestations offers valuable insights into the enduring influence of the EBOV on survivors, serving as a stark reminder of the imperative to sustain vigilant monitoring and support for them as they navigate substantial long-term health challenges. Moreover, this intricacy gains even more significance as it engenders challenges in distinguishing between new cases of Ebola in endemic regions and potential reinfections among survivors (57).

In light of this complexity, addressing the predicaments associated with distinguishing between novel cases and observed symptoms among EVD survivors in Ebola-endemic areas demands further investigation.

It is also evident from our studies that certain symptoms may be underrepresented or overlooked in a population: dysphagia, chest pain, gastritis, and rash. These symptoms might indeed be influenced by other infections, underlying health conditions, or various external factors. Regarding the range of potential causes for these symptoms and their nonspecific nature, it becomes essential to exercise caution when attributing them solely to the lingering symptoms of PES.

Unraveling whether the lingering symptoms of PES can serve as distinctive markers holds the potential to substantially enhance the identification and response to outbreaks (4). Therefore, careful clinical assessment and thorough differential diagnosis are imperative to accurately identify the source of these symptoms and determine appropriate treatment strategies.

Given the hypothesis that the pathogenesis of lingering clinical sequelae stems from systemic damage caused by the initial infection, along with sustained immune responses, autoimmune-like inflammation, and potential viral persistence in immune privilege sites, it is vital to focus on treatment strategies that target the inflammatory cascade and the immune system. This approach could provide a promising foundation for exploring novel therapies (150). However, it’s important to note that, at present, there is no approved drug specifically designed for treating PES in Ebola survivors. Yet researchers speculate that genetic factors may play a role in contributing to prolonged Ebola sequelae, as genes can significantly impact how the body responds to infections (151, 152). In particular, genetic variations in the immune system have been associated with Ebola virus pathogenesis days post-infection (151).

To address the complex issue of genetics in this context, the recently completed PREVAIL VI study (NCT03098862) in Liberia will undergo analysis to determine the safety and efficacy of interventions, including the evaluation of viral persistence in Ebola survivors (153). Additionally, a separate study suggests that cannabidiol (CBD) might offer mitigation for some of the post-Ebola sequelae arising from inflammation or autoimmune responses (150). CBD encompasses a range of pharmacological actions that hold promise in potentially offering therapeutic solutions for mental and somatic well-being of individuals grappling with the aftermath of post-Ebola sequelae (150, 154).

Furthermore, in an endeavor to reduce the number of survivors who may experience viral persistence, health workers could consider the administration of combined therapeutics such as ZMAb, IFN-α, IFN-β and other antiviral drugs during the acute stage of the disease to prevent persistence at immune privilege sites post-infection (155–157). This strategy holds promise in preventing viral persistence, as has been observed in non-human primates that survived EVD (12).

3 Conclusions and future directions

In spite of the small sample size and insufficient data from the aforementioned studies, the long-term complications faced by certain EVD survivors stemming from previous Ebola outbreaks cannot be ignored. While these complications have often been associated with potential viral persistence, there have been few instances highlighting their contribution to new epidemics, raising complex concerns that compound the existing stigma faced by survivors.

The manifestations of PES, primarily reported by certain survivors, may lack the robustness required to definitively establish a direct causal link between these symptoms and the Ebola infection. This is due to the possibility that such symptoms could potentially arise as a consequence of other endemic diseases prevalent in the Sub-Saharan region, such as malaria and Dengue. The similarity in clinical symptoms among various diseases complicates the attribution of symptoms solely to Ebola infection. On account of this, a comprehensive differential diagnosis approach is essential, considering multiple contributing factors to these symptoms among Ebola survivors.

Prioritizing the well-being of survivors is crucial to curtailing cases of EVD relapse, especially within Western and Central Africa, where a significant number of survivors are recorded (120). Achieving this demands a multifaceted approach including long-term follow-up care, pharmaceutical interventions to manage chronic conditions and comorbidities, addressing social stigma, providing mental health support, education, employment opportunities, and implementing rehabilitation programs to minimize the impact on survivors’ health and quality of life.

While viral persistence and reactivation in Ebola survivors may not be the primary driver of current outbreaks due to their rarity, the potential for these occurrences to spark flare-ups and re-ignition highlights the need for further investigation. In this regard, the World Health Organization’s recommendations on semen testing programs and advocating safe sex practices using condoms for at least 12 months among male survivors—potential virus shedders—require strong emphasis (16, 98). Although, instances of viral persistence beyond 12 months have been reported (46, 53, 64), and resource limitations might delay testing in certain endemic regions. Strategically identifying candidates for continued testing, using determinants like age, severity of acute EVD, elevated serum IgG3 levels, and the HLA-C*03:04 allele, is essential in extending testing and counseling beyond established follow-up periods (52, 158).

An essential area for research is the impact of pre-existing immunity from related viruses on post-EVD outcomes (159, 160). While such immunity could potentially bolster viral control, it may also have negative consequences, such as antibody-dependent enhancement (ADE) and original antigenic sin (OAS), potentially exacerbating inflammation and tissue damage—aggravating chronic PES symptoms (161–163). Investigating the impact of pre-existing immunity on the immune response and clinical outcomes in EVD survivors is crucial. This understanding is essential for comprehending the immunological mechanisms underlying PES and evaluating innovative modalities, including immunomodulation and antiviral strategies (164). These approaches aim to alleviate the PES burden and enhance survivor well-being.

In light of the evolving COVID-19 pandemic, re-emerging cases of EVD and other high-threat diseases, a unified approach to managing outbreaks and tackling associated stigma is essential (119, 120, 165). The collaborative synergy between researchers, healthcare practitioners, and policymakers is indispensable in infectious disease management. Investing in building local surge capacities, including rapid response teams and epidemic intelligence, is critical to address the re-emergence of Ebolaviruses (166). Besides, international partnerships play a pivotal role in sharing information, resources, diagnostics, and therapeutics for ongoing EVD survivorship and treatment research in the Sub-Saharan region (167). These endeavors collectively combat EVD and emerging infectious diseases, minimizing their impact and enhancing global public health preparedness against future outbreaks.

Looking forward, the establishment of a comprehensive database containing hematological, immunological, and virological data proves invaluable in identifying common patterns associated with viral persistence and the clinical presentation of PES (168–173). Additionally, the creation of a biobank with DNA samples from patients experiencing viral persistence and PES is essential for genomic studies and the identification of biomarkers linked to these conditions (18, 64, 174). These proposed initiatives would undoubtedly advance our understanding of EVD survivor health and potentially lead to more effective interventions and treatment strategies in the future. As the global community remains vigilant in addressing infectious diseases, these collaborative efforts are crucial in mitigating their impact and enhancing global public health resilience.

Author contributions

EAF and TN-B contributed to the conception of this study. EAF wrote the first draft of the manuscript. PO, WA and TN-B organized databases for the systematic studies and metaanalysis. WA performed the statistical analysis. All authors contributed to the article and approved the submitted version.

Funding

The authors declare that financial support was received for the publication of this article. Open access funding for this paper was provided by the Universität Konstanz.

Acknowledgments

We would like to express our deepest gratitude to Dr. Karla Martinez-Cruz at the Universität Konstanz, for her guidance, comments and suggestions in reviewing this paper. We are also thankful to Svenja Hehn for her comments and contributions to the graphical enhancements of the figures.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fviro.2023.1227314/full#supplementary-material

References