Associated risk factors of severe dengue in Reunion Island: A prospective cohort study

Mathys Carras; Olivier Maillard; Julien Cousty; Patrick Gérardin; Malik Boukerrou; Loïc Raffray; Patrick Mavingui; Patrice Poubeau; André Cabie; Antoine Bertolotti

doi:10.1371/journal.pntd.0011260

. 2023 Apr 17;17(4):e0011260. doi: 10.1371/journal.pntd.0011260

Associated risk factors of severe dengue in Reunion Island: A prospective cohort study

Mathys Carras ¹, Olivier Maillard ^2,^3,^*, Julien Cousty ¹, Patrick Gérardin ^2,³, Malik Boukerrou ⁴, Loïc Raffray ^5,⁶, Patrick Mavingui ⁶, Patrice Poubeau ⁷, André Cabie ^8,⁹, Antoine Bertolotti ^3,⁷

Editor: Mellisa Roskosky¹⁰

PMCID: PMC10138848 PMID: 37068115

Abstract

Background

Since 2018, a dengue epidemic has been raging annually in Reunion Island, which poses the major problem of its morbidity and mortality. However, there is no consensus in the literature on factors associated with severity of illness. The objective of this study was to identify the factors associated with the occurrence of severe dengue (SD) according to the criteria adopted in 2009 by the World Health Organization (WHO), during the 2019 epidemic.

Methodology/Principal findings

A total of 163 patients with RT-PCR-confirmed dengue were included in a multicenter prospective cohort study in Reunion Island between January and June 2019. Of these, 37 (23%) were classified as SD, which involves presentation dominated by at least one organ failure, and 126 (77%) classified as non-SD (of which 90 (71%) had warning signs). Confusion, dehydration, and relative hypovolemia were significantly associated with SD in bivariate analysis (p < 0.05). The factors associated with SD in multivariate analysis were a time from first symptom to hospital consultation over 2 days (OR: 2.46, CI: 1.42–4.27), a history of cardiovascular disease (OR: 2.75, 95%CI: 1.57–4.80) and being of Western European origin (OR: 17.60, CI: 4.15–74).

Conclusions/Significance

This study confirms that SD is a frequent cause of hospitalization during dengue epidemics in Reunion Island. It suggests that cardiovascular disease, Western European origin, and delay in diagnosis and management are risk factors associated with SD fever, and that restoration of blood volume and correction of dehydration must be performed early to be effective.

Trial registration

NCT01099852; clinicaltrials.gov

Author summary

Dengue fever is a viral disease transmitted by mosquitoes that threatens more than half of the world’s population. This re-emerging disease predominates in tropical areas such as Reunion Island, but is also expanding in formerly temperate regions. Some patients with dengue may have early signs (warning signs) of life-threatening complications (dengue hemorrhagic fever/shock syndrome) and require hospitalization, but only a minority of patients will progress to severe dengue. Identification of patients at risk is crucial to deliver optimal treatment without saturating intensive care units during epidemic periods. To this end, we followed 163 hospitalized patients with dengue during the 2019 epidemic in Reunion Island. Nearly a quarter of the patients had a severe form of the disease. The presence of cardiovascular disease, Western European origin, and delay in diagnostic and management were the main risk factors. This observation underlines the importance of an efficient detection of vulnerable populations and of an early management based on rehydration to prevent the occurrence of severe dengue in Reunion Island.

Introduction

Dengue is the most common mosquito-borne arbovirosis. In 2017, its incidence was estimated at more than 104 million people, of which 40,000 induced a death [1,2].

In 2019, in view of the re-emergence and rapid expansion of this arbovirosis, the World Health Organization (WHO) ranked dengue among the top ten global health threats [3]. Dengue is caused by four viral serotypes (DENV 1–4) with significant genotypic variability [4] and is characterized by a large clinical polymorphism with numerous signs of varying severity. In 2009, WHO proposed to distinguish between non-severe dengue, dengue with warning signs (WS) and severe dengue (SD), the latter being marked by major plasma leakage, severe bleeding and/or organ failure [5]. The case fatality can reach 20% in severe forms in the absence of early and appropriate medical management [6].

Reunion, a French island in the Indian Ocean with a population of 860,000, has been experiencing seasonal dengue epidemics since 2018. Nearly 70,978 confirmed cases, 2,672 hospitalizations, and 75 deaths have been reported up until May 2022 [7].

This re-emergence on the island has caused saturation of the healthcare system during epidemic peaks, necessitating a better estimation of each individual’s risk of developing SD. The performance of prognostic factors for SD varies according to the studies and the definitions of organ failure used when defining SD [8]. The objective of this multicenter prospective cohort study, conducted in the university hospitals of Reunion Island, was to identify the clinical factors associated with the development of SD in our context.

Methods

Ethical approval

Ethical clearance was obtained by the French National Agency for the Safety of Medicines and Health Products (ANSM) (n°IDRCB 2010-A00282-37) and by the committee for the protection of individuals (CPP Sud-Ouest and Outre-Mer III, 06/30/2010). Written and signed informed consent of all subjects was obtained and data was anonymized. This cohort study was reported according to the STROBE (Strengthening the reporting of observational studies in epidemiology) guideline (S2 Table).

Study population

CARBO (Cohorte ARBOviroses) is a French multicentric prospective cohort study dedicated to the understanding of the acute stage of arboviral infections. It was proposed by the university hospital of Martinique and is registered on clinicaltrials.gov (NCT01099852). All patients suspected of dengue fever who were admitted to emergency departments of the University Hospital of Reunion from 1st of January to 30th of June 2019, were eligible. Patients were recruited if they had a positive blood sample for DENV by RT-PCR, and onset of symptoms ≤7 days (until 21 days for SD). They must have presented at least two symptoms among the following: fever (documented or declared), headache, rash, myalgia, arthralgia, abdominal pain or tenderness, bleedings and/or low platelets blood level below 150 G/l. Children younger than 6 years of age need to present fever (documented or declared by the family) with or without pain on an age-adapted visual analogue scale.

The Tropical Fever Core multiplex RT-PCR (Fast Track Diagnostics) was used for on-site diagnosis. It was a conventional two step real-time RT-PCR, which could detect dengue (without differentiation between serotypes), chikungunya and West Nile viruses, Leptospira spp., Rickettsia spp. and Salmonella spp., and Plasmodium spp., which are pathogens that could circulate in the South West Indian Ocean region.

Serology was not routinely performed, but when there was a strong suspicion of dengue fever and a negative RT-PCR result. It was not systematically double checked three weeks later during the epidemic, or in ambulatory care, so the link between the data could not be made with confidence. For this reason, only cases with positive RT-PCR results were included in the study. Dengue reinfection was not systematically documented in 2019 because Reunionese people were considered naïve to dengue at this time, and serum neutralization was rarely performed.

Data collection and follow-up

The primary outcome was the determinants associated with severity by comparing characteristics of SD patients with non-SD patients. SD was identified according to the WHO 2009 classification. However, the definitions of organ failure were those of the various learned societies concerned (S1 Table). Sociodemographic and clinical data were collected by a clinician at each physical exam of the patient via a standardized questionnaire at Day 0 (D0), D3, D5-7, D8-10, D21, D45, D90, D180. Ethnicity was identified by patient self-determination, and divided into six categories: existence of a parent or an ancestor from Sub-Saharan Africa, India, West Europe, South-east Asia; being Native American; or from other origin(s). Biological data were collected only in the acute phase from day 1 to day 10 of symptoms. All biological exams were carried out in the laboratories of the University Hospital of Reunion. All collected data were reported in a case report form and are detailed in Table 1.

Table 1. Demographic, clinical and biological data in severe dengue and non-severe dengue, in DENV positive patients.

Reunion Island 2019 (N = 163).

Variables	N	Non-severe dengue (%) n = 126	Severe dengue (%) n = 37	P-value
Demographic data
Male	70	49 (39)	21 (57)	0.055^a
Female	93	77 (61)	16 (43)
Mean age (years), mean [StD]	163	51.0 [20.7]	53.1[22.4]	0.596^d
<18 years		6 (5)	3 (8)	0.464^a
18–65 years		81 (64)	20 (54)
>65 years		39 (31)	14 (38)
BMI (kg/m2), mean [StD]	145	25.7 [5.0]	25.8 [6.0]	0.926^c
BMI>30		21 (17)	5 (14)	0.640^a
Ethnic group
Africa	163	4 (3)	0	0.575^b
India	163	18 (14)	3 (8)	0.412^b
Asia	163	9 (7)	4 (11)	0.494^b
Europe	163	1 (1)	6 (16)	0.001^b
America	163	1 (1)	0	1.000^b
Others	163	54 (43)	16 (43)	1.000^a
Healthcare circuit
Delay from symptom to c(days), mean [StD]	155	2.6 [2.3]	3.8 [3.2]	0.010^d
Hospitalization	163	91 (72)	32 (87)	0.063^a
Length of stay (days), mean [StD]	121	4.9 [2.6]	7.1 [4.5]	0.013^d
Intensive Care Unit		19 (15)	15 (41)	0.002^a
Medicine (Short/Medium stay unit)		80 (64)	28 (76)	0.235^a
Medical history and treatments	163
Hypertension		40 (32)	15 (41)	0.340^a
Diabetes		27 (21)	11 (30)	0.314^a
Dyslipidemia		10 (8)	6 (16)	0.204^b
Cardiovascular disease		53 (42)	23 (62)	0.031^a
Chronic kidney disease		14 (11)	0	0.041^b
Dialysis		4 (3)	0	0.575^b
Cirrhosis		0	0	-
Peptic ulcer		5 (4)	0	0.590^b
Preventive anticoagulant		1 (1)	1 (3)	0.406^b
Curative anticoagulant		8 (6)	2 (5)	1.000^b
Antiplatelet agent		15 (12)	5 (14)	0.781^b
Clinical signs in the acute phase
Temperature (°C), mean [StD]	144	36.6 [0.8]	36.6 [0.8]	0.690^d
Heart rate (bpm), mean [StD]	143	77 [21.0]	82 [18.0]	0.179^d
Mean blood pressure (mmHg), mean [StD]	147	87 [16.0]	83 [16.0]	0.203^c
Skin recoloration time >3 seconds	163	6 (5)	4 (11)	0.237^b
Oliguria	163	2 (2)	1 (3)	0.543^b
Coinfection	163	12 (10)	7 (19)	0.146^b
Thrombocytopenia <150 G/L		52 (41)	19 (51)	0.278^a
Faintness	163	17 (14)	10 (27)	0.063^a
Confusion	163	12 (10)	12 (32)	0.001^a
Warning signs	163
Warning signs (WS)		90 (71)	30 (81)	0.229^a
Number of WS, mean [StD]		1.1 [1.1]	1.5 [1.0]	0.090^d
Abdominal pain		55 (44)	14 (38)	0.528^a
Persistent vomiting		15 (12)	7 (19)	0.281^b
Clinical fluid accumulation		1 (1)	0	1.000^b
Mucosal bleed		35 (28)	14 (38)	0.248^a
Lethargy, restlessness		5 (4)	6 (16)	0.018^b
Liver enlargement > 2cm		2 (2)	1 (3)	0.541^b
High hematocrit with low platelet count		14 (11)	9 (24)	0.054^a
Severity
SOFA Score, mean [StD]	26	4.4 [2.1]	4.3 [3.0]	0.981^d
Shock	163	0	14 (38)	<0.001^b
Respiratory failure	163	0	6 (16)	<0.001^b
Severe bleeding	163	0	14 (38)	<0.001^b
Liver failure	163	0	6 (16)	<0.001^b
Kidney failure	163	0	9 (24)	<0.001^b
Heart failure	163	0	0	-
Neurologic failure	163	0	2 (5)	0.050^b
Disseminated intravascular coagulation	163	0	0	-
Death	163	0	1 (3)	0.050^b
Dehydration^†	163	73 (58)	30 (81)	0.009^a
Hypovolemia^‡	163	2 (2)	5 (14)	0.007^b
Biology
Dengue virus reinfection	163	8 (6)	1 (3)	0.685^b
Sodium (mmol/L), mean [StD]	136	136.8 [4.3]	136.1 [4.8]	0.454^d
Haemoglobin (g/dL), mean [StD]	138	14.1 [9.1]	13.7 [2.7]	0.763^d
Hematocrit (%), mean [StD]	138	38.9 [4.9]	39.9 [7.4]	0.497^d
Leukocyte (G/L), mean [StD]	138	5.6 [3.3]	6.6 [4.8]	0.222^d
Neutrophils (G/L), mean [StD]	133	4.1 [3.1]	4.8 [4.7]	0.337^d
Lymphocyte (G/L), mean [StD]	133	1.3 [4.1]	1.0 [0.7]	0.683^d
Platelets (G/L), mean [StD]	137	158 [81]	173 [153]	0.586^d
Prothrombin Time (%),mean [StD]	53	92 [22]	82 [33]	0.199^d
ACT ratio, mean [StD]	52	1.17 [0.22]	1.44 [0.83]	0.228^d
Fibrinogen (g/L), mean [StD]	47	3.9 [1.0]	4.0 [1.5]	0.677^d
Albumin (g/L), mean [StD]	8	44.0 [3.0]	44.5 [2.1]	0.848^d
Protein (g/L), mean [StD]	118	73.8 [6.7]	72.9 [8.5]	0.568^c
Creatinine (μmol/L), mean [StD]	135	108 [106]	97 [57]	0.550^d
Urea (mmol/L), mean [StD]	135	5.9 [4.0]	6.2 [6.0]	0.683^d
AST (UI/L), mean [StD]	131	73 [91]	368 [746]	0.036^d
ALT (UI/L), mean [StD]	131	50 [64]	265 [650]	0.076^d
Total bilirubin (μmol/L), mean [StD]	102	10.5 [13.7]	9.9 [9.2]	0.837^d
Conjugated bilirubin (μmol/L), mean [StD]	92	5.1 [10.9]	5.4 [7.9]	0.916^d
Lipase (UI/L), mean [StD]	97	51 [49]	43 [27]	0.435^d
C-Reactive Protein (mg/mL), mean [StD]	129	22 [38]	22 [25]	0.940^d
Lactate (mmol/L), mean [StD]	5	3.00	2.9 [1.4]	0.977^d
Troponin (ng/mL), mean [StD]	8	0.019 [0.040]	0.046 [0.051]	0.123^d
Brain Natriuretic Peptide (pg/mL), mean [StD]	5	512	4330 [2909]	0.297^d

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BMI: body mass index, WS: warning signs, HCT: hematocrit, SOFA: Sequential Organ Failure Assessment, DENV: dengue-virus, ACT: activated clotting time, AST: aspartate-amino-transferase, ALT: alanine-amino-transferase, StD: standard deviation

†Rehydration (oral or intravenous)

‡ Fluid resuscitation

P-values were calculated using

^a Chi-square test

^b Fisher exact test

^c Student t test

^d Wilcoxon Mann Whitney test

Data analyses

Quantitative variables were described with means and standard deviations while categorical variables were described as numbers and percentages.

A bivariate analysis was performed to compare clinical and laboratory features of DF patients according to severity of illness (defined by the WHO in 2009). Gaussian variables were compared using the Student’s t-test, while non parametric continuous variables were compared using the Wilcoxon Mann Whitney test. The normality of the distributions was checked by the Shapiro-Wilk test, and the homogeneity of variances by the Levene test. Categorical variables were compared using Chi-square test or the Fisher’s exact test, as appropriate.

A multivariate logistic regression was performed to identify factors associated with SD. Variables with a p-value <0.2 in bivariate analysis were entered into a multivariate model. In the case of collinearity, detected by using the variance inflation factor (VIF), the most relevant variable was retained in the model. A backward stepwise automated procedure was used to select factors associated with p-value <0.05 in the final model. Adjusted odds ratios (OR) and their 95% confidence intervals (95%CI) were derived from the regression coefficients. Data were analyzed using SPSS software (IBM SPSS 23.0, IBM Corp. Armonk, NY, USA). All tests were two-tailed and the significance level was set at 0.05.

Results

Characteristics of the study population

In total, of 172 eligible patients who consented to participate, 163 were included in the study (Fig 1). The average age was 52 years old, and there were more women (57%) than men. Indian origin was the most represented (13%). Cardiovascular comorbidities were the most reported medical background (46%), followed by hypertension (34%), diabetes mellitus (23%), and obesity (16%) (Table 1). The most common serotype identified in 2019 was DENV-2.

The incidence of clinical and biological signs and their chronology are detailed in Fig 2. The clinical signs most frequently recorded in the acute phase were fever (93%), asthenia (94%), anorexia (83%), headache (59%), musculoskeletal signs with myalgia (69%), arthralgia (59%) and spinal pain (50%). Thrombocytopenia was present in 44% of patients. The earliest clinical signs of dengue were, in chronological order: vomiting (median 2 days), lipothymia (median 2.5 days), fever (median 3 days), and diarrhea (median 3 days). The maximum duration of symptoms was 150 days for asthenia and 167 days for arthralgia (Fig 2).

Of the 163 patients included, 37 (23%) were classed as severe of whom 24 (65%) at the time of recruitment, 14 (38%) with shock, 14 (38%) with severe hemorrhage, 23 (62%) with severe organ failure dominated by kidney failure (n = 9) and 1 (3%) which resulted in death. Hospitalization was required in 91 (72%) non-severe cases versus 32 (87%) severe cases (p = 0.063). Coinfections were not associated with severity (p = 0.146) and out of 19 (12%) co-infected patients, 9 urinary tract infections, 5 bacteremias, 4 pulmonary infections, 3 gastroenteritis and 1 skin infection were reported. They were present at admission in 15 (79%) patients. In bivariate analysis, the main factors associated with SD were: Western European origin (p = 0.001), a history of cardiovascular disease (p = 0.031), confusion (p = 0.001), dehydration defined as the need for oral or intravenous rehydration (p = 0.009), relative hypovolemia defined as the need for at least one vascular filling (p = 0.007), an increase in aspartate-amino-transferase (ASAT) level (p = 0.036) and the delay from symptom to consultation (p = 0.010) (Table 1). The mean length of stay was longer in cases of SD than in cases of non-SD (p = 0.013).

Multivariate analysis identified an increased risk of SD in patients with a time from first symptom to consultation over 2 days (OR: 2.46, CI: 1.42–4.27), a history of cardiovascular disease (OR: 2.75, 95%CI: 1.57–4.80), being of Western European origin (OR: 17.60, CI: 4.15–74) (Table 2).

Table 2. Factors associated with severity of dengue in adults with positive RT-PCR at disease onset. Multivariate analysis using logistic regression. CARBO cohort study, Réunion Island 2019 (N = 163).

Variables	Adjusted Odds Ratio (95%CI)	P-value
Time elapsed between illness onset and presentation to hospital > 2 days	2.46 (1.42–4.27)	0.036
West European origin	17.60 (4.15–74)	0.011
Cardiovascular disease	2.75 (1.57–4.80)	0.021

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95%CI: 95% confidence interval

Discussion

The prevalence of SD was 23% in this study. The warning signs had a low discriminatory value as their proportion was similar between the two groups. There was a co-circulation of two serotypes, dominated by DENV-2 [9]. This result is similar to that of a study carried out in French Guyana which identified 16% of SD during an epidemic mixing the same two serotypes [10]. Serotype 2 is the most virulent strain according to the literature [11]. The co-circulation of several serotypes in Reunion Island raises the threat of more serious future epidemics linked to the ADE (antibody-dependent enhancement) phenomenon observed during secondary infections [12].

A history of cardiovascular disease was associated with SD according to a recent meta-analysis, which reported that hypertension and diabetes were predictive factors for SD [13]. These comorbidities lead to dysfunction of the capillary endothelium, with increased vascular permeability and the occurrence of hypovolemic shock responsible for SD. Moreover, the co-existence of these comorbidities also favors organ decompensation [14,15]. The population of Reunion Island is particularly exposed to cardiovascular risk factors, which are potentially linked to genetic factors [16–18].

Our work suggests that Western European origin is also a risk factor for progression to SD. These results are similar to those of a study conducted in the Cuban population. In that study, the authors suggested that polymorphism in genes associated with the immune response may be responsible for the increased susceptibility of European ethnicity to ADE [19]. Risk factors associated with SD, such as cardiovascular disease and Western European origin, raise concerns that the recent spread of dengue to these new areas may increase the incidence of SD and its lethality [20,21].

Dehydration defined as the need for oral or intravenous rehydration was associated with SD. Rehydration is the main treatment for dengue with warning signs to prevent progression to a severe form. It may cause confusion or lipothymia, which are two warning signs present in one third of SD cases in our study. These elements suggest that dehydration plays a predominant role in the critical phase, just as it can cause complications in other arboviroses [22–24]. A late consultation, which delays intravenous rehydration, could also explain the increased risk of SD.

Indeed, delay in diagnosis and management was also associated with SD. Severe bleedings were the only severity component to be significantly associated with a consultation time greater than 2 days after onset. Although the date of illness onset is declarative, this is consistent with the literature which reports that delay in diagnosis is associated with severity including severe bleedings, complications, and mortality of dengue [6,25–27].

No patient with chronic kidney disease presented with SD. The difficulty in applying the KDIGO definition could be the cause. Indeed, urine quantification was not routinely measured in conventional hospitalization, baseline creatinine was not always available, and isolated increase in blood creatinine was insufficient because of already high levels in patients with chronic kidney disease. We used Stage 3 of the KDIGO classification to define acute kidney failure. By choosing a severe and restrictive definition of kidney failure to target severe cases in an inpatient cohort, cases of moderate acute kidney failure were not selected. With a less restrictive definition, eighteen patients had acute kidney failure according to KDIGO Stage 2, including 3 patients with chronic kidney disease.

The strengths of this study were (i) the early inclusion and prospective follow-up of patients, (ii) systematic clinical examination by a clinical investigator at admission and up to day 10, and (iii) use of the definitions of each learned society to estimate organ failure. There were, however, limitations within this study: (i) it was a cohort not derived from a consecutive series, or randomly sampled among patients, (ii) the cohort represented 19% of patients who consulted the hospital with PCR-confirmed dengue in 2019 in Reunion Island according to epidemiological data [7] (these results were related to a time-consuming inclusion of patients in an epidemic context and a large number of patient refusals), (iii) the use of a uniform definition of SD for all age groups could lack reproducibility in the pediatric population, especially for the shock criterion and the biological variables of liver and kidney failure, and (iv) the viral serotype of dengue patients could not be identified in all patients during the epidemic. A serum library was established, which will allow for future studies.

This first prospective study conducted during a dengue epidemic in Reunion Island allowed us to describe the risk factors specific to the Reunionese population and the evolution of the disease among patients who attended the hospital. Our study highlights the poor performance of warning signs in predicting SD, as well as the variability of the criteria for admission to intensive care depending on the clinician. Besides a history of cardiovascular disease and Western European origin that were associated with SD in our setting, the time to diagnosis and management of dengue is crucial, and rehydration appears to play a central role in preventing progression to SD.

Our results will be used in other large-scale studies during future dengue epidemics in Reunion Island, which will allow the identification of predictive factors in the evolution towards a more severe form of the disease, as well as the drafting of referral protocols to specialized services adapted to the profile of the patient.

Supporting information

S1 Table. Definitions of organ failure according to learned societies.

Legend: SBP: systolic blood pressure, DBP: diastolic blood pressure, SpO2: saturation pulse oxygen, ECG: electrocardiography, KDIGO: Kidney Disease Improving Global Outcomes, AST: aspartate-amino-transferase, ALT: alanine-amino-transferase

(DOCX)

Click here for additional data file.^{(21.3KB, docx)}

S2 Table. STROBE (Strengthening the reporting of observational studies in epidemiology) checklist for cohort studies.

(DOCX)

Click here for additional data file.^{(25.6KB, docx)}

Acknowledgments

We would like to thank Drs E. Antok, Q. Balacheff, E. Barange, J.P. Becquart, L. Brochet, R. Chane Teng, R. Crouzet, A.B. Da Silva Gomez, C. Daubard, A. Desvergez, D. Khemiri, K. Larsen, M. Lemeur, L. Raffray, M. Ruin, F. Tixier, N. Ebran, B. Fontaine, C. Hebert, D. Hirschinger, E. Huchot, E, Jarlet, H. Flodrops, M. Lafon, A. Laval, O. Lamouret, J. Lemant, J.C. Maiza, R. Manaquin, R. Perrin, A. Plantier, C. Schweizer, L. Thibault. We also would like to thank V. Grondin, J. Jean-Marie, I. Calmont, J. Ruiz, and our copy editor Jennifer Sanders. The protocol was prepared with the help of the INSERM Research and Action Targeting Emerging Infectious Disease (REACTing) network.

Data Availability

All relevant data are within the manuscript and its Supporting Information files. The data underlying the results presented in the study are available from the INSERM CIC 1410 (cic@chu-reunion.fr).

Funding Statement

AC was supported by a grant from the French Ministry of Health (PHRC, 2009, n° 29-01), https://solidarites-sante.gouv.fr/systeme-de-sante-et-medico-social/innovation-etrecherche/ l-innovation-et-la-recherche-clinique/appels-a-projets/article/les-projetsretenus, and a grant from the French network for Research and Action targeting emerging infectious diseases (REACTING), https://aviesan.fr/aviesan/accueil/toute-lactualite/ reacting-une-approche-multidisciplinaire-pour-relever-le-defi-des-crisesepidemiques PM was supported by a grant of the European Regional Development Fund (ERDF) through the RUNDENG project (No. 20202640-0022937), http://www.reunioneurope.org/UE_beneficiaire_aides2014.asp The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011260.r001

Decision Letter 0

Elvina Viennet, Mellisa Roskosky

9 Nov 2022

Dear Dr Maillard,

Thank you very much for submitting your manuscript "Associated risk factors of severe dengue in Reunion Island: A prospective cohort study" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

The manuscript is well written and covers an important topic that will be interesting to readers. As described in the detailed reviewer feedback, much more detail is needed in the methods section, including an in depth description of the univariate and multivariate analyses. Prior to resubmission the authors will need to review and respond to all reviewer comments. A more detailed description of analytical methods and results is expected as part of this revision.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Mellisa Roskosky, Ph.D

Academic Editor

PLOS Neglected Tropical Diseases

Elvina Viennet

Section Editor

PLOS Neglected Tropical Diseases

***********************

The manuscript is well written and covers an important topic that will be interesting to readers. As described in the detailed reviewer feedback, much more detail is needed in the methods section, including an in depth description of the univariate and multivariate analyses. Prior to acceptance the authors will need to review and respond to all reviewer comments. A more detailed description of analytical methods and results is expected as part of this revision.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: The objectives are clearly stated and hypothesis covered the factors included by the WHO classification. The design is adequate.

The population description requires more details for those who are not local to Reunion Island, the issue is what they cover in the classification of ethnic groups and how other groups are classified (maybe they include all in other?).

What is the definition of Indian and Asian ethnicities please specify (line 98 , page 10)

The sample size is adequate for most analysis.This number of cases for those younger than 18 is relatively small. This can limit the interpretation. The description of the statistical analysis seems correct but lacks some details specially in the clear flow in the use of specific tests

No concerns about ethical or regulatory requirements.

Reviewer #3: There is a need to revamp method section. It is not clear on the type of study design and measure used to assess difference between severe and non-severe dengue. Study population is not clearly defined and sample size was not reported.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: The results seem according to the analysis plan however there are some issues with the interpretation of the multivariate analysis, the ORs and CI for the variable Age provide the idea of a protective effect in general, but affirming that population under 18 years is at high risk requires to show the analysis of the different age groups and ORs and CI greater than 1 (maybe they just need to do it more explicit in the manuscript). The multivariate analysis table should be in the main text just like the descriptive statistics

Reviewer #3: The main finding in placed in the supplementary file. It has to be relocated in the main content.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: Most of the conclusions are well supported by the data but identifying the age as risk factor requires at least to make explicit the work done with that variable and explaining how univariate analysis contributed/not contributed to reach the final model

Limitations are well described. I found a limited discussion of the contribution of this findings to the understanding of severe dengue and the most recent classification issued by WHO.

Public health relevance is addressed.

Reviewer #3: Conclusion is presented according to the finding of the study

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: Provide more information about the breakdown of the population in ethnic groups, and clarify the process of identification of Age (and the category < 18 yrs as risk factor, State with clarity if the data support the serotype 2 as responsible for the described epidemic.

I think this modifications/additions qualify as minor revision

Reviewer #3: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: In this cohort study, authors recruited confirmed dengue patients within 7 days of symptom onset and clinical and biological data was collected at various times post recruitment. Bivariate and multivariate analysis was performed to identify risk factors that are associated with developing severe dengue.

This may be the first study from Reunion Island but risk factors associated with severe dengue are extensively studied in the literature.

Please clarify in the text what symptom/s were used for patient recruitment.

What percentage of patients met the case definition of severe dengue at the time of recruitment?

Confusion is a subjective factor and therefore cannot be used for prediction. Authors seem to indicate in the abstract and conclusion that identified factors can predict who will develop severe dengue disease but in realty these are risk factors that are associated with severity and may or may not accurately predict severity of a disease. For example, diabetes, hypertension and various other factors correlated with severe dengue in various other dengue studies but did not associate in this cohort.

Line 108 authors meant p values of < 0.02 or 0.2? Age was not significantly associated in the bivariate analysis and so why was it included in the multivariate analysis?

Viral titers or ns1 levels will be important to report in this dataset.

Please describe which co-infections were reported.

Dengue reinfection- how it’s determined and whether it was homologous or heterologous reinfection? Please describe in the text.

Multivariate- what set of independent variables were used in multivariate analysis? Full table should be reported in the supplemental file.

For some factors such as age less than 18years and Western European the sample size is too small to make any meaningful determination.

Reviewer #2: My general impression is that this study was well designed and conducted considering the clinical setting and the unpredictable flow of cases in an epidemic, however the manuscript needs to be expanded to explain the process of handling the variables in the multivariate analysis compared with the univariate analysis

Reviewer #3: This study warrants major revision with special focus on method section

--------------------

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Figure Files:

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Attachment

Submitted filename: Review Comments_Nov2022.docx

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PLoS Negl Trop Dis. 2023 Apr 17;17(4):e0011260. doi: 10.1371/journal.pntd.0011260.r002

Author response to Decision Letter 0

15 Jan 2023

Attachment

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Click here for additional data file.^{(119.5KB, docx)}

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011260.r003

Decision Letter 1

Elvina Viennet, Mellisa Roskosky

16 Feb 2023

Dear Dr Maillard,

Thank you very much for submitting your manuscript "Associated risk factors of severe dengue in Reunion Island: A prospective cohort study" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

This version of the manuscript is much improved. There are a few minor revisions that will need to be addressed prior to publication. These revisions include adding some additional detail in the methods section that were provided in your response to reviewers of your original submission and expanding on your conclusions related to between disease onset and hospital presentation. Please see reviewer comments for additional details.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Mellisa Roskosky, Ph.D

Academic Editor

PLOS Neglected Tropical Diseases

Elvina Viennet

Section Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: The objectives are clearly stated, and the study design in general is adequate to pursue the mentioned objectives. The description of the population is much clear than before and it contain the elements to test the hypothesis. The sample size goes according to the possibilities to gather a prospective cohort. Statistical analysis is fine and consistent to previous studies, and they support the conclusion. They followed a conventional method to reach their conclusion.

I don't find ethical or regulatory issues to be solved.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: Analysis was done according to the plan stated by the authors, results are completely presented, Tables reflect the analysis work done by the authors and they convey well the results they obtained. My only concern is how the presentation of results provide enough basis to discuss a richer discussion.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: The conclusions are supported by the data but they don't expand on the implication of one of the severe dengue predictors:

Time elapsed between illness onset and presentation to hospital. The authors should elaborate what is the practical meaning of that: failure in the early detection of cases, lack of information in the population. The other element to hypothesize is how the cardiovacular co-morbidities interact with that delay.

In general terms the limitations were mentioned . The authors provide the implications of their findings to understand the local characteristics of Severe dengue and how they are consistent to the general epidemiology of dengue.

Even when they approach from a clinical perspective they touch well the Public Health implications.

--------------------

Editorial and Data Presentation Modifications?

Reviewer #1: (No Response)

Reviewer #2: My suggestion is to discuss the predictors and their potential interactions (based on other international references). Once they do that the paper is good to accept. I think this paper qualify for Minor revision.

--------------------

Summary and General Comments

Reviewer #1: [Comment: Please describe which co-infections were reported.

Response: Of 19 (12%) co-infected patients, 9 urinary tract infections, 5 bacteriemia, 5 4 pulmonary infections, 3 gastroenteritis and 1 cutaneous infection, were reported. Fifteen (79%) were diagnosed at admission. Five patients had complications related to their coinfection. As coinfections were not associated with severity, no more information was added in the manuscript.]

Comment: Please add above response information to the method section since related data is presented in table-1.

[Comment: Dengue reinfection- how it’s determined and whether it was homologous or heterologous reinfection? Please describe in the text.

Response: Dengue reinfection was not systematically documented in 2019 because Reunionese people were considered naïve to dengue at this time, and serum neutralization was not routinely done.]

Comment: Please add in the method section that DENV re-infection was determined based on the presence of DENV reactive IgG at the time of enrollment using Dengue Duo kit or howsoever authors determined it, if differently.

Reviewer #2: The manuscript was improved and the suggestions were addressed by the authors. No additonal comments

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Eduardo Fernandez C.

Figure Files:

Data Requirements:

Reproducibility:

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

PLoS Negl Trop Dis. 2023 Apr 17;17(4):e0011260. doi: 10.1371/journal.pntd.0011260.r004

Author response to Decision Letter 1

13 Mar 2023

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(62.1KB, docx)}

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011260.r005

Decision Letter 2

Elvina Viennet, Mellisa Roskosky

21 Mar 2023

Dear Dr Maillard,

We are pleased to inform you that your manuscript 'Associated risk factors of severe dengue in Reunion Island: A prospective cohort study' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Mellisa Roskosky, Ph.D

Academic Editor

PLOS Neglected Tropical Diseases

Elvina Viennet

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

Thank you for this thorough and thoughtful revision and response to comments.

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011260.r006

Acceptance letter

Elvina Viennet, Mellisa Roskosky

12 Apr 2023

Dear Dr Maillard,

We are delighted to inform you that your manuscript, "Associated risk factors of severe dengue in Reunion Island: A prospective cohort study," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Definitions of organ failure according to learned societies.

(DOCX)

Click here for additional data file.^{(21.3KB, docx)}

S2 Table. STROBE (Strengthening the reporting of observational studies in epidemiology) checklist for cohort studies.

(DOCX)

Click here for additional data file.^{(25.6KB, docx)}

Attachment

Submitted filename: Review Comments_Nov2022.docx

Click here for additional data file.^{(14.3KB, docx)}

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(119.5KB, docx)}

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(62.1KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files. The data underlying the results presented in the study are available from the INSERM CIC 1410 (cic@chu-reunion.fr).

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PERMALINK

Associated risk factors of severe dengue in Reunion Island: A prospective cohort study

Mathys Carras

Olivier Maillard

Julien Cousty

Patrick Gérardin

Malik Boukerrou

Loïc Raffray

Patrick Mavingui

Patrice Poubeau

André Cabie

Antoine Bertolotti

Roles

Abstract

Background

Methodology/Principal findings

Conclusions/Significance

Trial registration

Author summary

Introduction

Methods

Ethical approval

Study population

Data collection and follow-up

Table 1. Demographic, clinical and biological data in severe dengue and non-severe dengue, in DENV positive patients.

Data analyses

Results

Characteristics of the study population

Fig 1. Study population, CARBO cohort study, Reunion Island 2019.

Fig 2. Incidence and timing (time to illness onset and duration) of dengue manifestations, in patients with positive Dengue virus RT-PCR. CARBO cohort, Reunion Island 2019.

Table 2. Factors associated with severity of dengue in adults with positive RT-PCR at disease onset. Multivariate analysis using logistic regression. CARBO cohort study, Réunion Island 2019 (N = 163).

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Elvina Viennet

Mellisa Roskosky

Roles

Author response to Decision Letter 0

Decision Letter 1

Elvina Viennet

Mellisa Roskosky

Roles

Author response to Decision Letter 1

Decision Letter 2

Elvina Viennet

Mellisa Roskosky

Roles

Acceptance letter

Elvina Viennet

Mellisa Roskosky

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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