Review Global prevalence & risk factors of fatigue and post-infectious fatigue among patients with dengue: a systematic review & meta-analysis,2024,Hertanti

[Dolphin]

https://www.sciencedirect.com/science/article/pii/S2589537024006205

eClinicalMedicine
Volume 80, February 2025, 103041
Articles
Global prevalence and risk factors of fatigue and post-infectious fatigue among patients with dengue: a systematic review and meta-analysis

Nuzul Sri Hertanti, Trung V. Nguyen, Yeu-Hui Chuang,
Global prevalence and risk factors of fatigue and post-infectious fatigue among patients with dengue: a systematic review and meta-analysis,
eClinicalMedicine,
Volume 80,
2025,
103041,
ISSN 2589-5370,
https://doi.org/10.1016/j.eclinm.2024.103041.

a
School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan
b
Center for Tropical Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
c
Faculty of Nursing, College of Medicine and Pharmacy, Tra Vinh University, Tra Vinh City, Vietnam
d
Department of Nursing, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
e
Research Center in Nursing Clinical Practice, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Received 2 August 2024, Revised 13 December 2024, Accepted 17 December 2024, Available online 31 December 2024, Version of Record 31 December 2024.


https://doi.org/10.1016/j.eclinm.2024.103041
open access

Summary

Background
Fatigue during the acute phase of dengue infection can persist as post-infectious fatigue (PIF), potentially impacting quality of life. We aimed to determine the prevalence and risk factors of fatigue and PIF among dengue patients.

Methods
This systematic review and meta-analysis was registered in the PROSPERO (CRD42024543058). We searched PubMed, Ovid MEDLINE, Web of Science, Embase, and CINAHL from their inception to June 22, 2024. Observational studies reporting the prevalence of fatigue or PIF among dengue patients were included. We excluded case studies, review articles, conference abstracts, protocols, duplicate publications, and studies without full text. Quality assessment was performed using Hoy's risk of bias tool. Data were analyzed using R software version 4.3.3. A random-effects model pooled prevalence with 95% confidence intervals (CIs). Risk factors were identified using odd ratios (ORs) and 95% CIs or p values. Heterogeneity, moderator analysis, sensitivity analysis, and publication bias were also assessed.

Findings
From 715 identified studies, 40 were included for review. Of these, 37 studies were included in the meta-analysis for fatigue prevalence and nine studies for PIF prevalence, respectively involving 37,790 and 5045 dengue patients. The pooled prevalence of fatigue was 59.0% (95% CI 0.47–0.70), and that of PIF was 20.0% (95% CI 0.10–0.36), with significant heterogeneity but no significant moderators. Sensitivity analysis confirmed the robustness of this meta-analysis. Female sex (pooled OR = 1.65, 95% CI 1.27–2.14), dengue hemorrhagic fever (pooled OR = 1.80, 95% CI 1.02–3.16), and preexisting comorbidities (pooled OR = 2.14, 95% CI 1.36–3.38) were significant risk factors for PIF.

Interpretation
This meta-analysis highlights the high prevalence of fatigue and PIF among dengue patients, with several risk factors identified. Although the study has its limitations, these results can inform future studies to more standardized study designs, improved definitions, and systematic assessment methods for fatigue, PIF, and potential moderators. These are essential to better understand the mechanisms of fatigue in dengue patients and explore potential interventions.

Funding
None.

Keywords
Dengue
Fatigue
Meta-analysis
Post-infectious fatigue (PIF)
Prevalence
Risk factors
Systematic review

Research in context

Evidence before this study
Fatigue is a subjective feeling of tiredness that can range from mild to severe and impair daily functioning. Post-infectious fatigue (PIF), however, refers to persistent fatigue that lasts for weeks or months after the acute phase of an infection. PIF has been observed in infections such as Q fever, Epstein–Barr virus, Ebolavirus, SARS-CoV-2, and chikungunya, with prevalence ranging from 10% to 50%, depending on the infection. Although fatigue is recognized as a common symptom in dengue, its global prevalence and factors contributing to it in dengue patients have not been systematically studied.

Added value of this study
To the best of our knowledge, this is the first systematic review and meta-analysis to estimate the global prevalence and risk factors of fatigue and PIF following dengue. By including 40 studies across multiple countries, our study provides a comprehensive analysis of these symptoms. The findings emphasize the importance of recognizing fatigue, as almost 60% of dengue patients experience this symptom, and 20% suffer from PIF.

Implications of all the available evidence
The high prevalence of fatigue and PIF among dengue patients emphasizes the need for healthcare professionals to recognize and address fatigue during the acute phase of infection and monitor patients in the convalescent phase. Future research should focus on understanding the mechanisms behind fatigue and PIF in dengue patients and explore potential interventions to prevent the worsening of these conditions and improve patient outcomes.

 

[Hutan]

In the context of dengue, fatigue can persist into the convalescent phase after the acute phase has passed. While the majority of dengue patients recover from the acute phase with no complications, a minority can experience various post-acute symptoms, such as myalgia, weakness, headaches, and fatigue.23 Fatigue that persists beyond the acute phase can progress to PIF, lasting from 2 weeks to 6 months or longer, depending on the severity of the infection and the patient’s overall health.14,23–28 Unlike acute fatigue, PIF can result in decreased productivity, challenges in working, and dif- ficulties with daily activities.23,27 Dengue patients with persistent symptoms experienced a 45% reduction in work productivity and a 13% increase in the economic burden due to productivity loss.29

Some strategies that have been explored to manage post-viral fatigue in other infections include the use of Chinese medicine, supportive therapies, self- management, educational programs, nutritional sup- plements, and rehabilitation approaches.30–33 However, evidence for effective interventions to reduce fatigue following dengue infection remains limited, possibly due to the lack of a synthesis of its prevalence and contributing factors. Additionally, the assessment of fatigue in dengue patients is often inadequate, indi- cating that this symptom is underrecognized in clinical practice.26

In total, 40 included studies

Among the 37 studies included for fatigue preva- lence, 37,790 dengue patients were analyzed, with 48.3% of them being female and a mean age (SD) of 41.1 (18.5) years.

For the nine studies analyzing the PIF prevalence, 5045 dengue patients were included, with 50.8% of them being female and a mean age (SD) of 29.5 (13.7) years.

 

[Hutan]

Fatigue - defined here as

a sense of tiredness or weakness that impacts the ability to perform usual activities,8 experienced during the acute phase of dengue, typically lasting 2–7 days.

Post-infection fatigue (PIF) - defined here as

fatigue that persisted beyond the acute phase of dengue,14 lasting from 2 weeks to 6 months or longer.23–28

Prevalence and risk factors

The pooled prevalence of fatigue was 59.0% (95% CI 0.47–0.70), with significant heterogeneity (Q = 32026.88, p < 0.0001, I2 = 99.90%)

The pooled prevalence of PIF was 20.0% (95% CI 0.10–0.36), and significant hetero- geneity was observed

Cross-sectional studies re- ported a higher prevalence of PIF (39.7%) compared to other study designs (18.2%), and studies with older participants tended to report a higher prevalence of PIF. However, due to the limited number of studies included in these moderator analyses, the results should be interpreted with caution.

See my previous post - the nine studies investigating the prevalence of post-infection fatigue had a low mean age (29.5 years)

DHF - Dengue hemorrhagic fever, so, a severe acute illness

Moreover, four studies provided data on risk factors for PIF (Table 2).14,25,26,41 Six risk factors (older age, female sex, post-discharge myalgia, post-discharge headaches, DHF, and preexisting comorbidities) were reported in more than one article, and thus the ORs were pooled. The remaining risk factors were only reported by single studies, so pooled OR could not be determined.

Dengue patients who were female (pooled OR = 1.65, 95% CI 1.27–2.14), had DHF (pooled OR = 1.80, 95% CI 1.02–3.16), or had preexisting comorbidities (pooled OR = 2.14, 95% CI 1.36–3.38) had higher odds of experiencing PIF compared to their counterparts

Much like Long Covid, it looks as though there are two things combined here - fatigue following a severe acute illness, and something along the lines of ME/CFS. Unfortunately the looseness of '2 weeks to 6 months or longer' time requirement doesn't help to separate out the two. It seems likely that increased age and co-morbidities would increase the risk of an acute severe illness.

The inclusion of 'post-discharge myalgia' and 'post-discharge headaches' as risk factors for what is essentially post-discharge fatigue is a slightly odd way to put it. Rather, they are likely to be part of the clinical picture of a post-dengue ME/CFS-type syndrome.

Being female appears to be a risk factor for PIF (pooled odds ratio 1.65).

 

[Hutan]

The incidence of fatigue during the acute illness is very variable, as is the incidence of PIF. Methods of assessment and timing of assessment undoubtedly affects the numbers a lot.

Figure 3
Forest plot of the global prevalence of post-infectious fatigue among dengue patients (n = 9).
Events is the number of PIF; Total is the total number of people with dengue; Proportion is the percentage of people in the study found to have PIF.
Most studies were prospective.

 

[Hutan]

Our findings identified female sex, DHF, and pre- existing comorbidities as significant risk factors for developing PIF among dengue patients. Previous studies did not explore the mechanisms behind these associations.14,26,28 However, the condition of PIF may be linked to the complex immune response between the virus and host,77 which is influenced by factors such as genetics, gender, dengue severity, comorbidities, and autoimmune responses.14,26,28,77 Females tend to have stronger immune responses than males, producing more antibodies and higher levels of immune cells like cluster of differentiation 4 (CD4) cells.78 In addition, estrogens stimulate B cell activation and antibody pro- duction, which can lead to a prolonged immune response and increase the likelihood of autoimmune reactions.78 These autoimmune reactions, where the immune system mistakenly attacks healthy cells, may contribute to persistent fatigue.77 However, this pro- posed mechanism requires further confirmation.

For DHF patients, the severity of dengue infection results in intense inflammation and plasma leakage, which can extend the recovery time and contribute to persistent symptoms such as fatigue.77 In addition, PIF was also more prevalent among dengue patients with preexisting comorbidities. This could be associated with complex immunological responses involving cytokines and in- teractions with the neuroendocrine, musculoskeletal, and immune systems.12,26 Patients with underlying dis- eases, such as diabetes, chronic renal disease, and heart disease, had higher relative odds of progressing to se- vere dengue,79 which can further delay recovery and worsen fatigue.

the methods used to measure fatigue varied across studies, with some using validated questionnaires and others relying on clinical symptoms reported by patients or observed by healthcare professionals. This lack of standardization made it difficult to compare results across studies and might not have accurately identified fatigue. Future research should aim to use standardized and validated tools to assess fatigue.

This systematic review and meta-analysis concluded that almost 60% of dengue patients experience fatigue, and one-fifth suffer from PIF.

Despite PIF potentially reducing productivity and extending the recovery period,23 there is insufficient evidence on its management in dengue pa- tients. Future research should explore interventions to alleviate fatigue in dengue patients.