Multi-organ post-acute sequelae of major respiratory and Aedes-borne arboviral diseases: a systematic review and meta-analysis

This systematic review and meta-analysis synthesizes evidence on multi-organ post-acute sequelae across major respiratory and Aedes-borne diseases, revealing that infant RSV infection significantly increases asthma risk and dengue fever elevates risks for various neurological, psychiatric, autoimmune, and cardiovascular conditions, while highlighting substantial heterogeneity in study designs that limits broader comparability.

The Gist

Imagine your body is a bustling city. When a virus like the flu or dengue fever attacks, it's like a sudden, violent storm hitting that city. We've all heard about the massive damage caused by the recent "Great Storm" (COVID-19), which left many citizens struggling with long-term repairs. But this new study asks a crucial question: Do other, older storms leave their own unique scars on the city long after the rain stops?

The researchers, acting like a team of global detectives, gathered 51 different reports from around the world to see what happens to people months or years after they recover from six specific viral storms: Flu, RSV (a common respiratory virus), Dengue, Chikungunya, Zika, and Yellow Fever.

Here is what they found, broken down into simple stories:

1. The "RSV Storm" and the Fragile Young City

The Finding: For babies and young children who survived a severe RSV infection, the city of their lungs seemed to stay damaged.
The Analogy: Think of RSV as a hurricane that hits a nursery. The study found that children who weathered this storm were nearly three times more likely to develop asthma later in life compared to those who didn't have the storm. It's as if the hurricane didn't just knock down a few trees; it weakened the very foundation of the nursery, making it prone to future leaks (asthma) for years.

2. The "Dengue Storm" and the Widespread Aftermath

The Finding: Dengue fever, often thought of as just a bad fever that passes, actually leaves a trail of long-term trouble across the entire body.
The Analogy: If the flu is a localized fire, Dengue is like a flood that seeps into the basement, the electrical system, and the mental health of the city. The study found that people who survived Dengue had higher risks of:

• Anxiety and Depression: The emotional landscape of the city remained cloudy.
• Dementia: The city's "memory banks" seemed more vulnerable.
• Autoimmune Issues: The city's security guards (immune system) started getting confused and attacking their own buildings.
• Heart Trouble: The city's power grid (cardiovascular system) showed signs of strain.
  Essentially, Dengue didn't just leave a scratch; it seemed to rewire the city's long-term operating system.

3. The "Flu Storm" vs. The "COVID Storm"

The Finding: This part is a bit tricky because the researchers compared Flu survivors to COVID survivors.
The Analogy: Imagine two cities hit by storms. One city (Flu) was compared to a city hit by a much more massive, destructive storm (COVID). The study found that the Flu city actually looked better than the COVID city in terms of long-term damage to the brain and heart.
The Catch: This doesn't mean the Flu is harmless. It just means that when compared to the massive devastation of COVID, the Flu's long-term scars looked smaller. It's like saying a broken arm is "better" than a crushed leg; the arm is still broken, but the comparison makes it look less severe. The study suggests we need to be careful not to think Flu is "safe" just because it's better than COVID.

4. The "Missing Storms" (Chikungunya, Zika, Yellow Fever)

The Finding: For these three viruses, the detectives couldn't find enough reliable reports to draw a clear picture.
The Analogy: It's like trying to map a forest fire in a remote area where no one has kept a logbook. We know the fires happened, and we know they caused pain (like joint pain for Chikungunya), but we don't have enough data to say exactly how big the long-term damage is. The study highlights that we need more research here, especially in the regions where these viruses are most common.

The Big Picture: Why the Detective Work Was Hard

The researchers admitted that comparing these "storms" was like trying to compare apples, oranges, and pineapples.

• Different Maps: Some studies looked at people for 3 months, others for 5 years.
• Different Rulers: Some measured damage by hospital records, others by patient complaints.
• Different Cities: The studies came from very different countries with different healthcare systems.

Because of this "messy data," the researchers couldn't combine every single study into one perfect number. They had to be very selective, only pooling data where the "rulers" and "maps" matched up.

The Bottom Line

This study tells us that viral infections are not just a "one-and-done" event.

• RSV in early childhood can set the stage for lifelong breathing issues.
• Dengue can leave a lingering shadow over the heart, mind, and immune system.
• Flu causes long-term issues, though perhaps less severe than the recent COVID pandemic.

The main message is that we need to stop treating these viruses as if they disappear the moment the fever breaks. They leave behind "ghosts" in the body that can haunt patients for years, and we need better, more consistent ways to track these long-term scars to help people heal fully.

Technical Summary

Technical Summary: Multi-organ post-acute sequelae of major respiratory and Aedes-borne arboviral diseases

Problem Statement
While post-acute sequelae of COVID-19 (PASC) are well-characterized, evidence regarding long-term complications following other major respiratory infections (Influenza, Respiratory Syncytial Virus [RSV]) and Aedes-borne arboviral diseases (Dengue, Chikungunya, Zika, Yellow Fever) remains fragmented. Existing literature suffers from significant heterogeneity in study design, population demographics, exposure definitions, outcome ascertainment, and follow-up durations. This lack of standardization limits the ability to compare disease burdens across pathogens and hinders causal inference regarding the long-term multisystem impact of these infections.

Methodology
The authors conducted a systematic review and meta-analysis following MOOSE and PRISMA guidelines, prospectively registered with PROSPERO.

• Search Strategy: Five databases (PubMed, Embase, CINAHL, Scopus, Web of Science) and Global Health were searched from inception to August 25, 2025. Forward citation searching was employed to identify additional studies.
• Eligibility: The review included non-randomized observational studies (cohort, case-control, surveillance) assessing post-acute neurological, psychiatric, gastrointestinal, cardiovascular, respiratory, renal, musculoskeletal, autoimmune, or endocrine outcomes following confirmed infection with Influenza, RSV-ARI, Dengue, Chikungunya, Zika, or Yellow Fever. Studies required appropriate comparator groups (uninfected or infected with other viruses) and excluded case reports, modeling studies, and self-reported symptom-only outcomes without clinical diagnosis.
• Risk of Bias: The Risk Of Bias In Non-randomized Studies of Exposure (ROBINS-E) tool was used to assess bias across seven domains, including confounding, exposure measurement, and outcome assessment.
• Meta-analysis: Random-effects models with restricted maximum likelihood estimation were used to pool effect estimates (HRs, IRRs, ORs, RRs) when at least three comparable studies were available. Heterogeneity was assessed using $\tau^2$, $I^2$, and $H^2$. Prediction intervals were calculated to account for between-study variance.

Key Contributions and Results
The review synthesized data from 51 studies, predominantly retrospective cohorts from high-income regions. Meta-analyses were feasible for RSV-ARI, Influenza, and Dengue fever, while data for Chikungunya, Zika, and Yellow Fever were insufficient for pooling.

1. RSV-ARI:

   • All included studies focused on pediatric populations infected during infancy.
   • Result: Symptomatic RSV-ARI in infancy is associated with a significantly higher pooled odds of physician-diagnosed asthma compared to uninfected controls (OR: 2.93, 95% CI: 2.12–4.06).
   • Heterogeneity was substantial (prediction interval: 0.97–8.84), but the direction of association was consistent.

2. Influenza:

   • Studies primarily used COVID-19 patients as comparators.
   • Result: Compared to COVID-19, Influenza was associated with a lower risk of neurological outcomes (HR: 0.82, 95% CI: 0.76–0.89) and composite post-acute sequelae (RR: 0.88, 95% CI: 0.82–0.95).
   • Other organ-specific outcomes were not statistically significant. The authors note these findings likely underestimate the absolute burden of post-influenza sequelae, as the comparator group (COVID-19) may have higher baseline risks due to more severe disease or intensive surveillance.

3. Dengue Fever:

   • Studies spanned all age groups and used non-dengue individuals as controls.
   • Result: Prior Dengue infection is associated with increased risks of:
     • Cardiovascular outcomes: HR: 1.51 (1.27–1.80)
     • Autoimmune outcomes: RR: 1.39 (1.17–1.67)
     • Dementia: HR: 1.61 (1.10–2.35)
     • Anxiety: HR: 1.34 (1.01–1.78)
     • Psychiatric outcomes (composite): HR: 1.17 (1.07–1.28)
     • Any post-acute sequelae: HR: 1.19 (1.13–1.25)

4. Chikungunya, Zika, and Yellow Fever:

   • No eligible effect estimates were available for Yellow Fever.
   • Chikungunya and Zika studies were limited to descriptive surveillance or prospective cohorts reporting incidence only (e.g., arthralgia, neurological outcomes), preventing meta-analysis.

Significance and Interpretation
The paper establishes that post-acute sequelae are a measurable component of the disease burden for RSV-ARI and Dengue fever, extending beyond the acute phase of infection.

• RSV: The strong association with asthma supports the hypothesis that early-life RSV infection may induce persistent immune dysregulation or airway remodeling.
• Dengue: The findings challenge the traditional view of Dengue as solely an acute febrile illness, suggesting it confers long-term risks across multiple organ systems, potentially driven by mechanisms such as NS1-mediated glycocalyx disruption, blood-brain barrier compromise, and innate immune reprogramming.
• Methodological Gaps: The review highlights that current evidence is limited by heterogeneity in study design and a lack of standardized definitions for post-acute periods and outcomes. The reliance on COVID-19 as a comparator for Influenza studies complicates the interpretation of absolute risks.
• Future Directions: The authors call for standardized study designs, particularly well-designed population-based cohort studies with uninfected control groups, standardized follow-up windows, and validated outcome measurements. They emphasize the need for greater representation from low- and middle-income countries, where Aedes-borne diseases are most prevalent, to accurately characterize the global burden of these infections.