Post-acute sequelae after Nipah virus infection: a systematic review

This systematic review reveals that Nipah virus infection survivors face a substantial long-term disease burden, with a pooled prevalence of 24% for residual neurological deficits and 10% for late-onset or relapsing symptoms, though these estimates are primarily derived from the Malaysia/Singapore outbreak and may not fully generalize to current South Asian strains.

The Gist

Imagine the Nipah virus as a fierce, unexpected storm that hits a village. Most people know the storm causes immediate damage: houses get flooded, roofs blow off, and people get sick right away. But this paper asks a different question: What happens to the village and its people long after the storm has passed?

The authors of this study went looking for "lingering damage"—symptoms that stick around months or years after the initial infection, or symptoms that suddenly appear later, like a surprise aftershock. They call these "post-acute sequelae," but you can think of them as the "ghosts of the storm."

Here is what they found, broken down simply:

1. The Search for the Ghosts

The researchers acted like detectives, scouring through old case files (scientific studies) from the 1990s and 2000s. They were looking for survivors of the Nipah virus who were still dealing with health issues long after they were supposed to be "cured."

They found 8 studies to look at. However, there was a catch: 7 of these studies were about the storm that hit Malaysia and Singapore in the late 90s. Only one study looked at survivors from Bangladesh. This is like trying to understand how a hurricane affects Florida by only looking at data from a hurricane that hit Texas. The paper warns that the results might not perfectly apply to the current outbreaks happening in South Asia today, because the "storm" (the virus strain) is slightly different there.

2. The Main Findings: Who is Still Hurting?

The study found that while many survivors recover completely, a significant number are still carrying the weight of the storm.

• The "Brain Fog" and Body Aches: About 24% of all survivors (including those who had mild cases) still had some lingering neurological problems, like trouble with movement, sensation, or thinking.
• The Heavy Hit: For those who had the severe form of the illness (encephalitis, which is swelling of the brain), the number jumps to 45%. It's like saying if you were hit by the worst part of the storm, nearly half of you are still dealing with broken windows and a shaky foundation years later.
• The "Tired" Survivors: One of the most common lingering issues was extreme fatigue. It was like the survivors' batteries were permanently drained. In one study, nearly half of the survivors were still exhausted, and this tiredness was significantly worse than in people who never got the virus.
• The "Surprise" Aftershocks: About 10% of survivors experienced a "late-onset" or "relapsing" attack. Imagine recovering from the storm, feeling fine for a while, and then suddenly, months later, the roof starts leaking again. These new neurological symptoms appeared after the person thought they were fully recovered.

3. The Comparison: Survivors vs. Neighbors

The researchers compared the virus survivors to their own neighbors (people who lived in the same houses but didn't get sick).

• The survivors were significantly more likely to have residual neurological deficits (lasting brain or nerve damage), fatigue, and daytime sleepiness.
• It's as if the neighbors were walking around normally, while the survivors were walking with a limp or carrying a heavy backpack they couldn't put down.

4. The Limitations: Why We Need to Be Careful

The authors are very honest about the flaws in their detective work:

• The Data is Old and Sparse: Most of the data comes from the 1998-1999 outbreak. We don't have much information on the newer outbreaks in Bangladesh and India.
• The "Ruler" was Wobbly: Different studies used different ways to measure "sickness." Some asked people how they felt (which is subjective), while others did physical exams. It's like trying to measure the height of a building using a ruler that stretches and shrinks.
• Small Numbers: The total number of people they studied is quite small. It's like trying to predict the weather for a whole continent based on the temperature in just one town.

The Bottom Line

The paper concludes that the Nipah virus doesn't just leave a scar; it can leave a long-term disability. For the survivors, the battle doesn't always end when the fever breaks. There is a "second wave" of health issues—brain fog, paralysis, and exhaustion—that can last for years.

The authors say we need to keep an eye on survivors for at least a year after they get sick, because the "aftershocks" can happen later. They also warn that we need better data from the current outbreaks in South Asia to know if the "ghosts" there are the same as the ones in Malaysia.

In short: The storm passes, but for a large chunk of survivors, the cleanup crew is still working years later, and sometimes, the storm hits them again unexpectedly.

Technical Summary

Technical Summary: Post-acute Sequelae after Nipah Virus Infection

Problem Statement
While the long-term disease burden of infectious diseases (exemplified by post-acute sequelae following SARS-CoV-2) is increasingly recognized, the prevalence, incidence, and characteristics of post-acute sequelae following Nipah virus (NiV) infection remain poorly documented. Nipah virus, a priority pathogen identified by the WHO, causes recurrent outbreaks in South Asia and has a high case fatality rate. Although acute clinical features such as encephalitis and respiratory disease are well-characterized, the fragmented evidence base regarding long-term health effects in survivors hinders accurate public health risk assessment and the parameterization of mathematical models for future outbreak responses. Furthermore, significant differences exist between the viral strains causing outbreaks in Malaysia/Singapore (NiV-M) and those in South Asia (NiV-B), yet data on sequelae is predominantly derived from the former.

Methodology
This study conducted a systematic review following PRISMA guidelines and registered with PROSPERO (CRD42024616198).

• Search Strategy: A systematic search of PubMed and Web of Science was performed for studies published up to November 17, 2025, using keywords related to Nipah virus and long-term outcomes (e.g., sequelae, chronic, relapsing, residual).
• Inclusion Criteria: Primary data reporting on post-acute sequelae in NiV survivors. Sequelae were defined as symptoms persisting ≥3 months, new late-onset symptoms, or relapsing symptoms after remission. Studies on functional outcomes alone, case reports, and non-English articles were excluded.
• Data Analysis: Eight articles were included. Data extraction covered study design, population, diagnosis methods, and prevalence/incidence of 34 potential neurological, psychiatric, and non-specific sequelae.
• Statistical Approach: Random-effects meta-analysis was used for outcomes reported in at least two studies. Subgroup analyses were conducted for (a) total NiV survivors, (b) survivors of acute NiV encephalitis, and (c) survivors of late-onset or relapsed encephalitis. Risk of bias was assessed using Joanna Briggs Institute (JBI) tools.

Key Contributions and Results
The review synthesized evidence from 8 studies (7 from the 1998–1999 Malaysia/Singapore outbreak, 1 from Bangladesh), encompassing a total of 34 distinct post-acute symptoms.

• Prevalence of Residual Neurological Deficits:

  • Among total NiV survivors, the pooled prevalence of residual neurological deficits was 24% (95% CI 9–49).
  • Among the subset of NiV encephalitis survivors, the prevalence was significantly higher at 45% (95% CI 11–85).
  • In a single study of survivors with relapsed/late-onset encephalitis, the prevalence was 61% (95% CI 36–83).
  • All reported cases of residual neurological deficits in total survivor cohorts occurred among patients who had experienced acute encephalitis.

• Specific Symptoms:

  • Of 34 reported symptoms, 71% were neurological (mostly motor/sensory dysfunction).
  • Fatigue was the most prevalent symptom among total survivors (48% in meta-analysis of two studies), while cognitive impairment was most prevalent among encephalitis survivors (46%).
  • In the single controlled study (Siva et al.), residual neurological deficits, fatigue, and daytime somnolence were significantly more prevalent in survivors compared to household controls 10 years post-infection.

• Late-onset and Relapsing Symptoms:

  • Approximately 10% (95% CI 4–20) of survivors experienced late-onset or relapsing neurological symptoms after initial recovery.
  • These episodes typically occurred within one year of the acute infection, though rare cases of delayed onset up to 11 years have been reported in literature.
  • Late-onset encephalitis occurred in patients with prior asymptomatic, non-encephalitic, and encephalitic acute infections.

• Duration and Recovery:

  • Symptoms persisted from 6 months up to 10 years post-infection.
  • Fatigue showed a strong time-dependent decline (from 68% at 6 months to 14% at 2 years), whereas significant neurological deficits remained stable in prevalence over a 10-year period.
  • Functional impairment was generally described as mild, though a subset required caregiver assistance.

Significance and Limitations
The paper concludes that Nipah virus infection imposes a substantial long-term disease burden, characterized by persistent neurological deficits and fatigue, particularly in survivors of acute encephalitis. These findings suggest that mathematical modeling studies for NiV must account for long-term disability and the risk of relapsing neurological symptoms to accurately estimate public health risks and health economic impacts.

However, the authors emphasize several critical limitations:

1. Generalizability: The estimates are primarily based on the NiV-M strain (Malaysia/Singapore) and may not apply to the NiV-B strain causing current outbreaks in Bangladesh and India, which presents with different clinical features (e.g., more respiratory involvement).
2. Data Scarcity: The evidence base is small (8 studies) and heavily reliant on uncontrolled cohorts. Only one study included a control group.
3. Methodological Heterogeneity: Variations in outcome assessment (often subjective), follow-up durations, and definitions of "survivors" (ranging from strictly encephalitic to seropositive asymptomatic cases) introduce uncertainty and potential bias.
4. Population Bias: The included populations for "total survivors" were heterogeneous, with the proportion of encephalitis cases varying widely (31–81%) across studies.

The authors assert that while their estimates provide the first comprehensive assessment of NiV post-acute sequelae, they should be interpreted with caution due to the high uncertainty and the lack of data regarding the South Asian viral strain.