Post-Ebola Symptoms 7 Years After Infection: The Natural History of Long Ebola, 2022, Wohl et al

[Mij]

Long Ebola . . .

Abstract
Background
Lingering symptoms have been reported by survivors of Ebola virus disease (EVD). There are few data describing the persistence and severity of these symptoms over time.

Methods
Symptoms of headache, fatigue, joint pain, muscle pain, hearing loss, visual loss, numbness of hands or feet were longitudinally assessed among participants in the Liberian Ebola Survivors Cohort study. Generalized linear mixed effects models, adjusted for sex and age, were used to calculate the odds of reporting a symptom and it being rated as highly interfering with life.

Results
From June 2015 to June 2016, 326 survivors were enrolled a median of 389 days (range 51–614) from acute EVD. At baseline 75.2% reported at least 1 symptom; 85.8% were highly interfering with life. Over a median follow-up of 5.9 years, reporting of any symptom declined (odds ratio for each 90 days of follow-up = 0.96, 95% confidence interval [CI]: .95, .97; P < .0001) with all symptoms declining except for numbness of hands or feet. Rating of any symptom as highly interfering decreased over time. Among 311 with 5 years of follow-up, 52% (n = 161) reported a symptom and 29% (n = 47) of these as highly interfering with their lives.

Conclusions
Major post-EVD symptoms are common early during convalescence and decline over time along with severity. However, even 5 years after acute infection, a majority continue to have symptoms and, for many, these continue to greatly impact their lives. These findings call for investigations to identify the mechanisms of post-EVD sequelae and therapeutic interventions to benefit the thousands of effected EVD survivors.

https://academic.oup.com/cid/article-abstract/76/3/e835/6692535?redirectedFrom=fulltext

 

[Hutan]

Mostly from a North Carolina team, one Liberia-based researcher.

It's a shame there is a paywall. They appear to have a very high level of participant retention (311 out of 326) after 5 years.

I wonder if the authors are familiar with ME/CFS diagnostic criteria and the concept of PEM. It would be great to screen these people against the ME/CFS diagnostic criteria. I've sent a note to the corresponding author.

 

[SNT Gatchaman]

 

[SNT Gatchaman]

No mention of ME or PEM.

 

[Hutan]

Reply to my email to the corresponding author:

Thank you for your email, xxx. We agree that there may be parallels between Long Ebola, Long COVID, and ME/CFS.
We have found people who survive Ebola do not seem to have much in the way of heightened inflammation but there is some evidence for autoimmunity we are pursuing.
Will look at Dr. Nath’s work.
Thanks again

Unfortunately no comment on my mention of PEM. I'm not sure why the comment was made about heightened inflammation; possibly they believe that Long Covid is characterised by inflammatory cytokines?

 

[Mij]

From reading papers, it appears that post Ebola syndromes don't mention autonomic dysfunction or POTS.

Wouldn't that be an indicator that they don't experience PEM?

 

[rvallee]

Reply to my email to the corresponding author:


Unfortunately no comment on my mention of PEM. I'm not sure why the comment was made about heightened inflammation; possibly they believe that Long Covid is characterised by inflammatory cytokines?

My guess would be addressing the encephalomyelitis part.

 

[Mij]

This study was published in 2019

Long-term Complications of Ebola Virus Disease: Prevalence and Predictors of Major Symptoms and the Role of Inflammation; Sam Tozay, William A Fischer, II, David A Wohl, Kayla Kilpatrick, Fei Zou, Edwina Reeves, Korto Pewu, Jean DeMarco, Amy James Loftis, Katie King

https://academic.oup.com/cid/article/71/7/1749/5613876?login=false

Abstract
Background
Cohort studies have reported a high prevalence of musculoskeletal, neurologic, auditory, and visual complications among Ebola virus disease (EVD) survivors. However, little is known about the host- and disease-related predictors of these symptoms and their etiological mechanisms.

Methods
The presence and patterns of 8 cardinal symptoms that are most commonly reported following EVD survival were assessed in the 326 EVD survivors who participated in the ongoing longitudinal Liberian EVD Survivor Study. At quarterly study visits, symptoms that developed since acute EVD were recorded and blood was collected for biomarkers of inflammation and immune activation.

Results
At baseline (mean 408 days from acute EVD), 75.5% of survivors reported at least 1 new cardinal symptom since surviving EVD, which in 85.8% was rated as highly interfering with life. Two or more incident symptoms were reported by 61.0% of survivors, with pairings of joint pain, headache, or fatigue the most frequent. Women were significantly more likely than men to report headache, while older age was significantly associated with musculoskeletal and visual symptoms. In analyses adjusted for multiple comparisons, no statistically significant association was found between any symptom and 26 markers of inflammation and immune activation. Symptom frequency remained largely unchanged during study follow-up.

Conclusions
Post-EVD complications occur in a majority of survivors and remain present more than 4 years after acute infection. An association between markers of inflammation and immune activation and individual symptoms was not found, suggesting an alternative etiology for persistent post-EVD symptomatology.

 

[Mij]

The prevalence of Post-Ebola Syndrome hearing loss, Sierre Leone

Abstract
Background
Globally, hearing loss is the second leading cause of disability, affecting approximately 18.7% of the world’s population. However, the burden of hearing loss is unequally distributed, with the majority of affected individuals located in Asia or Sub-Saharan Africa. Following the 2014 West African Ebola Outbreak, disease survivors began to describe hearing loss as part of the constellation of symptoms known as Post-Ebola Syndrome. The goal of this study was to more fully characterize hearing loss among Ebola Virus Disease (EVD) survivors.

Methodology and principal findings
EVD survivors and their household contacts were recruited (n = 1,12) from Eastern Sierra Leone. Each individual completed a symptom questionnaire, physical exam, and a two-step audiometry process measuring both air and bone conduction thresholds. In comparison to contacts, EVD survivors were more likely to have complaints or abnormal findings affecting every organ system. A significantly greater percentage of EVD survivors were found to have hearing loss in comparison to contacts (23% vs. 9%, p < 0.001). Additionally, survivors were more likely to have bilateral hearing loss of a mixed etiology. Logistic regression revealed that the presence of any symptoms of middle or inner ear (p < 0.001), eye (p = 0.005), psychiatric (p = 0.019), and nervous system (p = 0.037) increased the odds of developing hearing loss.

Conclusions and significance
This study is the first to use an objective and standardized measurement to report hearing loss among EVD survivors in a clinically meaningful manner. In this study it was found that greater than 1/5th of EVD survivors develop hearing loss. The association between hearing impairment and symptoms affecting the eye and nervous system may indicate a similar mechanism of pathogenesis, which should be investigated further. Due to the quality of life and socioeconomic detriments associated with untreated hearing loss, a greater emphasis must be placed on understanding and mitigating hearing loss following survival to aid in economic recovery following infectious disease epidemics.

LINK

 

[Mij]

Fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease in Democratic Republic of the Congo: a case study, 2024, Daniel Mukadi-Bamuleka et al

Summary
Background
During the 2018–20 Ebola virus disease outbreak in the Democratic Republic of the Congo, thousands of patients received unprecedented vaccination, monoclonal antibody (mAb) therapy, or both, leading to a large number of survivors. We aimed to report the clinical, virological, viral genomic, and immunological features of two previously vaccinated and mAb-treated survivors of Ebola virus disease in the Democratic Republic of the Congo who developed second episodes of disease months after initial discharge, ultimately complicated by fatal meningoencephalitis associated with viral persistence.
Methods
In this case report study, we describe the presentation, management, and subsequent investigations of two patients who developed recrudescent Ebola virus disease and subsequent fatal meningoencephalitis. We obtained data from epidemiological databases, Ebola treatment units, survivor programme databases, laboratory datasets, and hospital records. Following national protocols established during the 2018–20 outbreak in the Democratic Republic of the Congo, blood, plasma, and cerebrospinal fluid (CSF) samples were collected during the first and second episodes of Ebola virus disease from both individuals and were analysed by molecular (quantitative RT-PCR and next-generation sequencing) and serological (IgG and IgM ELISA and Luminex assays) techniques.
Findings
The total time between the end of the first Ebola virus episode and the onset of the second episode was 342 days for patient 1 and 137 days for patient 2. In both patients, Ebola virus RNA was detected in blood and CSF samples during the second episode of disease. Complete genomes from CSF samples from this relapse episode showed phylogenetic relatedness to the genome sequenced from blood samples collected from the initial infection, confirming in-host persistence of Ebola virus. Serological analysis showed an antigen-specific humoral response with typical IgM and IgG kinetics in patient 1, but an absence of an endogenous adaptive immune response in patient 2.
Interpretation
We report the first two cases of fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease who had received vaccination and mAb-based treatment in the Democratic Republic of the Congo. Our findings highlight the importance of long-term monitoring of survivors, including continued clinical, virological, and immunological profiling, as well as the urgent need for novel therapeutic strategies to prevent and mitigate the individual and public health consequences of Ebola virus persistence.

 

[Ash]

Fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease in Democratic Republic of the Congo: a case study, 2024, Daniel Mukadi-Bamuleka et al

So sad.

 

[Mij]

Advancing mechanistic understanding of post-acute sequelae of Ebola virus disease

We read with great interest the Article published in The Lancet Microbe by Mosoka P Fallah and colleagues,1 which investigated inflammatory pathways in post-acute sequelae of Ebola virus disease (PASE) using data of the PREVAIL III cohort.

The study provided important insights regarding mechanisms underlying the heterogeneity of PASE through an innovative hierarchical design and multi-marker analysis. Although a unique subgroup analysis in the study1 revealed distinct biological pathways associated with PASE, several aspects warrant further consideration to enhance mechanistic understanding.

First, the selected 25-marker panel, although derived from literature on HIV and COVID-19, inadequately captures Ebola-specific immune dysregulation patterns. Additionally, the acute-phase immunological correlates of disease severity, particularly markers indicative of T-cell over-activation or exhaustion, warrant inclusion in the panel because of their established prognostic value in the progression of Ebola virus disease.2

Two studies3,4 on post-acute sequelae of SARS-CoV-2 infection (also known as long COVID) reported persistently elevated levels of soluble co-inhibitory receptors such as TIM-3 and PD-1 in long-term sequelae, reflecting T-cell exhaustion patterns observed in both acute SARS-CoV-2 infection and Ebola virus disease. Even though the dynamics of soluble PD-1 and CTLA-4 remain uncharacterised in PASE, the mechanistic relevance of the markers to viral persistence and chronic inflammation necessitates systematic evaluation. Expanding the biomarker panel to include soluble immune checkpoints would facilitate a comprehensive mapping of immune dysregulation in the pathogenesis of PASE.

Second, the exclusion of female survivors from the viral shedding subgroup analyses in the study1 overlooks potential sex-specific immunological differences. Although no relevant reports have addressed sex-based differences in the incidence of PASE, accumulating evidence on long COVID suggests a female predisposition to post-acute sequelae, with notable sex-based variations in clinical manifestations (eg, fatigue and headache) and immune regulation.5,6 Male-specific analyses of semen viral shedding are valuable; however, they limit a comprehensive evaluation of sex as a biological variable in PASE pathogenesis. Future studies should prioritise sex-based analyses using alternative viral shedding measures to elucidate the complex relationship between inflammatory markers and PASE.

In conclusion, Fallah and colleagues provide compelling evidence of the heterogeneity in inflammatory pathways in PASE, demonstrating that different profiles of inflammatory markers reflect distinct biological mechanisms that drive post-acute sequelae. Future investigations should incorporate Ebola-specific soluble immune checkpoints and implement sex-based analyses to achieve a comprehensive understanding of the immune landscape of PASE.

 

[Mij]

This is the article they're referring to:

Associations of inflammatory markers with post-acute clinical findings among survivors of Ebola virus disease with and without viral RNA shedding in the semen in Liberia: a nested case-control study

Summary
Background
A high proportion of survivors of Ebola virus disease (EVD) have post-acute sequelae of EVD (PASE), but the relationship between inflammation and PASE pathogenesis is poorly understood. This study tests the hypothesis that inflammation is associated with PASE among survivors with and without viral RNA shedding in the semen.
Methods
This was a case–control study nested in a longitudinal cohort that recruited confirmed survivors of EVD and their uninfected contacts from the 2013–16 EVD epidemic in Liberia, starting on June 1, 2015. We included participants aged at least 18 years with clinical data and plasma available at cohort baseline for analysis. A semen donation substudy tested male survivors for Ebola virus RNA shedding in the semen. A sex-stratified and survivor-stratified random sample of cases (survivors) and controls (contacts) was obtained to select stored baseline plasma samples for cytokine testing of markers of inflammation, immune regulation, and antiviral responses. Serostatus of cases and controls was confirmed by Filovirus Animal Nonclinical Group assay. We identified inflammatory markers (adjusted p≤0·05) elevated in cases compared with controls and then used these biomarkers in analyses comparing survivors with and without pre-specified PASE-associated clinical findings (self-reported symptoms and abnormal examination findings). Survivors with viral RNA shedding in the semen formed subgroup analyses.
Findings
Our analysis cohort consisted of 1044 participants (594 survivors of EVD and 450 uninfected contacts); 515 (49·3%) were female and 529 (50·7%) were male. The subcohort of 243 male survivors with data on viral shedding included 81 (33%) participants with viral shedding in semen. Median time from acute EVD to baseline was 317 days (IQR 271–366). Survivors of EVD showed a pattern of elevated inflammatory markers indicative of macrophage (MCP-1, IL-1β, and M-CSF) and angiogenic factor activation (VEGF-A) compared with controls (adjusted p<0·05). In survivors with viral shedding in the semen compared with controls, VEGF-A was the only inflammatory marker that was significantly higher (adjusted p<0·001). After restricting the analysis to survivors, each inflammatory marker had a specific pattern of clinical findings. Higher levels of IL-1β were associated with higher odds of urinary frequency (p=0·002), musculoskeletal abnormalities (p=0·003), and abdominal abnormalities (p=0·03). By contrast, higher levels of MCP-1 were associated with lower odds of the same clinical findings. M-CSF was the only inflammatory marker associated with lower odds of joint pain (p=0·04). Higher levels of VEGF-A were associated with higher odds of abnormal chest findings in the overall survivor group (p=0·02) and in the subgroup with viral shedding in the semen (p=0·02).
Interpretation
We found evidence of distinct biological pathways for PASE. Although viral RNA shedding in the semen could be associated with angiogenic activation, it did not explain many of the PASE symptoms and exam findings associated with the elevated macrophage markers, suggesting the pathobiology of some clinical manifestations might be autoimmunity, immune dysregulation, or another biological mechanism. These findings could inform shared biological pathways with other infection-associated chronic conditions, including post-acute sequelae of SARS-CoV-2 infection.