Development of a bedside score to predict dengue severity.

BACKGROUND: In 2017, New Caledonia experienced an outbreak of severe dengue causing high hospital burden (4379 cases, 416 hospital admissions, 15 deaths). We decided to build a local operational model predictive of dengue severity, which was needed to ease the healthcare circuit. METHODS: We retrospectively analyzed clinical and biological parameters associated with severe dengue in the cohort of patients hospitalized at the Territorial Hospital between January and July 2017 with confirmed dengue, in order to elaborate a comprehensive patient's score. Patients were compared in univariate and multivariate analyses. Predictive models for severity were built using a descending step-wise method. RESULTS: Out of 383 included patients, 130 (34%) developed severe dengue and 13 (3.4%) died. Major risk factors identified in univariate analysis were: age, comorbidities, presence of at least one alert sign, platelets count < 30 × 109/L, prothrombin time < 60%, AST and/or ALT > 10 N, and previous dengue infection. Severity was not influenced by the infecting dengue serotype nor by previous Zika infection. Two models to predict dengue severity were built according to sex. Best models for females and males had respectively a median Area Under the Curve = 0.80 and 0.88, a sensitivity = 84.5 and 84.5%, a specificity = 78.6 and 95.5%, a positive predictive value = 63.3 and 92.9%, a negative predictive value = 92.8 and 91.3%. Models were secondarily validated on 130 patients hospitalized for dengue in 2018. CONCLUSION: We built robust and efficient models to calculate a bedside score able to predict dengue severity in our setting. We propose the spreadsheet for dengue severity score calculations to health practitioners facing dengue outbreaks of enhanced severity in order to improve patients' medical management and hospitalization flow.

Relationships Between Clinico-Epidemiological Patterns of Invasive Meningococcal Infections and Complement Deficiencies in French South Pacific Islands (New Caledonia).

PURPOSE: Invasive Meningococcal Disease (IMD) is three fold more common in New Caledonia (NC) than in metropolitan France and many IMD cases (35.7%) are due to Y and W135 serogroups. The purpose of our study was to identify IMD risk factors in NC. METHODS: A retrospective study of all IMD cases that occurred in NC between 2005 and 2011 was conducted. Socio-environmental, clinical and biological data were collected. A search for immune deficiency was proposed to all cases. IMD presentation and outcome were compared according to meningoccal serogroups and the complement deficiency status (C-deficiency). RESULTS: Sixty-six sporadic IMD cases (29 B serogroup, 20 Y or W135, 6 C, 1 A, 10 unknown) occurred in 64 patients often <24 years-old and of Melanesian origin. Five patients died (7.8%). No socio-environmental risk factors were identified. No asplenia, HIV infection or immunoglobulin deficiencies were found. Two patients had diabetes and 28 of 53 (52.8%) patients had C-deficiency including 20 (71.4%) cases of late complement component deficiency. Patients with C-deficiency were mainly Melanesian (92.8%) originating from the Loyalty Islands (62.1%). They were mostly infected with Y/W135 (42.9%) or B serogroups (32.1%). They often developed later and more severe disease than patients without C-deficiency (need for intensive cares in 60% versus 28.0% of cases, p = 0.01). CONCLUSIONS: A high prevalence of C-deficiency in the Melanesian population may explain epidemiological and clinical features of IMD in NC. Our results imply an adaptation of meningococcal vaccine strategies in NC.

Epidemiological and molecular features of dengue virus type-1 in New Caledonia, South Pacific, 2001-2013.

BACKGROUND: The epidemiology of dengue in the South Pacific has been characterized by transmission of a single dominant serotype for 3-5 years, with subsequent replacement by another serotype. From 2001 to 2008 only DENV-1 was reported in the Pacific. In 2008, DENV-4 emerged and quickly displaced DENV-1 in the Pacific, except in New Caledonia (NC) where DENV-1 and DENV-4 co-circulated in 2008-2009. During 2012-2013, another DENV-1 outbreak occurred in NC, the third DENV-1 outbreak in a decade. Given that dengue is a serotype-specific immunizing infection, the recurrent outbreaks of a single serotype within a 10-year period was unexpected. FINDINGS: This study aimed to inform this phenomenon by examining the phylogenetic characteristics of the DENV-1 viruses in NC and other Pacific islands between 2001 and 2013. As a result, we have demonstrated that NC experienced introductions of viruses from both the Pacific (genotype IV) and South-east Asia (genotype I). Moreover, whereas genotype IV and I were co-circulating at the beginning of 2012, we observed that from the second half of 2012, i.e. during the major DENV-1 outbreak, all analyzed viruses were genotype I suggesting that a genotype switch occurred. CONCLUSIONS: Repeated outbreaks of the same dengue serotype, as observed in NC, is uncommon in the Pacific islands. Why the earlier DENV-1 outbreaks did not induce sufficient herd immunity is unclear, and likely multifactorial, but the robust vector control program may have played a role by limiting transmission and thus maintaining a large susceptible pool in the population.

Molecular Characterization of Dengue Type 2 Outbreak in Pacific Islands Countries and Territories, 2017-2020.

Dengue virus (DENV) serotype-2 was detected in the South Pacific region in 2014 for the first time in 15 years. In 2016-2020, DENV-2 re-emerged in French Polynesia, Vanuatu, Wallis and Futuna, and New Caledonia, co-circulating with and later replacing DENV-1. In this context, epidemiological and molecular evolution data are paramount to decipher the diffusion route of this DENV-2 in the South Pacific region. In the current work, the E gene from 23 DENV-2 serum samples collected in Vanuatu, Fiji, Wallis and Futuna, and New Caledonia was sequenced. Both maximum likelihood and Bayesian phylogenetic analyses were performed. While all DENV-2 strains sequenced belong to the Cosmopolitan genotype, phylogenetic analysis suggests at least three different DENV-2 introductions in the South Pacific between 2017 and 2020. Strains retrieved in these Pacific Islands Countries and Territories (PICTs) in 2017-2020 are phylogenetically related, with strong phylogenetic links between strains retrieved from French PICTs. These phylogenetic data substantiate epidemiological data of the DENV-2 diffusion pattern between these countries.

Pre-participation cardiovascular evaluation in Pacific Island athletes.

BACKGROUND: Pre-participation cardiovascular evaluation (PPE) aims to detect cardiac disease with sudden cardiac death (SCD) risk. No study has focused on Pacific Island athletes. METHODS: A total of 2281 Pacific Island athletes were studied with (i) a questionnaire on family, personal history and symptoms, (ii) a physical examination and (iii) a 12-lead ECG. RESULTS: 85% presented a normal history and examination. A positive family history was 1.4-1.9 fold higher in Melanesians, Polynesians and Métis than in Caucasians, while a positive personal history, abnormal symptoms and abnormal examination was 1.3 fold higher in Melanesians and Métis than in others. Neither gender nor training level had a bearing on these results. Melanesians had higher T wave inversions (TWIs) in V2-V4 leads but had no CV abnormalities. Lateral or infero-lateral TWIs were found in 6 male and in 5 highly trained athletes and cardiomyopathies were diagnosed in 3/6 athletes. Overall, 3.9% athletes were found to have a CV abnormality and 0.8% had a risk of SCD. Polynesians and males were more at risk than the others while the level of training made no difference. In athletes at risk of SCD, the main detected CV diseases were cardiomyopathies, Wolff-Parkinson-White (WPW) and severe valve lesions of rheumatoid origin. CONCLUSIONS: PPE revealed that 3.9% presented CV abnormalities. A risk of SCD was found in 0.8% with cardiomyopathies, WPW, and severe valve lesions of rheumatoid origin. Melanesians, Polynesians and male of high level of training were more at risk than others.

Vertical Transmission of Dengue Virus in the Peripartum Period and Viral Kinetics in Newborns and Breast Milk: New Data.

SUMMARY: We investigated 10 mother-newborn pairs and found a 90% rate of dengue virus (DENV) transmission during the perinatal period. Here, we describe DENV kinetics in the sera of newborns before the onset of disease. Of the breast-milk samples analyzed, 75% tested positive for DENV. BACKGROUND: Dengue is the most common mosquito-borne viral disease in humans. With this study, we aimed to investigate the risk of vertical (DENV) transmission during the peripartum period and to describe its viral kinetics in serum and breast milk. METHODS: We carried out a prospective study during the 2012-2013 dengue epidemic in New Caledonia, its most severe on record. All mothers hospitalized at the Centre Hospitalier Territorial in Nouméa, New Caledonia, with symptoms of dengue infection between 7 days before and 2 days after delivery and/or whose infant was infected during breastfeeding were investigated. DENV was detected and quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in sera and breast milk (mothers), sera and gastric fluid (newborns), cord blood, and placentas. DENV kinetics and sequences in sera and breast milk were studied. Clinical presentation and biological evolution in mother-newborn pairs were analyzed. RESULTS: Ten mother-newborn pairs were investigated over an 11-month period. One premature birth, 3 hemorrhagic complications, and 1 maternal death occurred. Nine newborns were infected and symptomatic. One case of deep thrombocytopenia and 1 case of anoxic encephalopathy occurred. DENV was detected in breast milk samples from 9 (75%) of 12 infected breastfeeding mothers. Original DENV kinetics in sera and breast milk were described. CONCLUSIONS: The occurrence of vertical DENV transmission was high (90%) in viremic mothers at delivery, and these mothers and their infants were at major risk for obstetric and neonatal complications. The modes of viral transmission are difficult to clarify. The risk of DENV transmission through breast milk seems plausible. Close follow-up of mothers and prolonged surveillance of their newborns are required for minimizing complications. Complementary studies are needed to elaborate preventive recommendations.

A Novel Human T-lymphotropic Virus Type 1c Molecular Variant in an Indigenous Individual from New Caledonia, Melanesia.

BACKGROUND: Human T-Lymphotropic Virus type 1 (HTLV-1) is endemic among people of Melanesian descent in Papua New Guinea, Solomon Islands and Vanuatu, and in Indigenous populations from Central Australia. Molecular studies revealed that these Australo-Melanesian strains constitute the highly divergent HTLV-1c subtype. New Caledonia is a French overseas territory located in the Southwest Pacific Ocean. HTLV-1 situation is poorly documented in New Caledonia and the molecular epidemiology of HTLV-1 infection remains unknown. OBJECTIVES: Studying 500 older adults Melanesian natives from New Caledonia, we aim to evaluate the HTLV-1 seroprevalence and to molecularly characterize HTLV-1 proviral strains. STUDY DESIGN: Plasma from 262 men and 238 females (age range: 60-96 years old, mean age: 70.5) were screened for anti-HTLV-1 antibodies by particle agglutination (PA) and indirect immunofluorescence assay (IFA). Serological confirmation was obtained using Western blot assay. DNAs were extracted from peripheral blood buffy coat of HTLV-1 seropositive individuals, and subjected to four series of PCR (LTR-gag; pro-pol; pol-env and tax-LTR). Primers were designed from highly common conserved regions of the major HTLV-1 subtypes to characterize the entire HTLV-1 proviral genome. RESULTS: Among 500 samples, 3 were PA and IFA positive. The overall seroprevalence was 0.6%. The DNA sample from 1 New Caledonian woman (NCP201) was found positive by PCR and the complete HTLV-1 proviral genome (9,033-bp) was obtained. The full-length HTLV-1 genomic sequence from a native woman from Vanuatu (EM5), obtained in the frame of our previous studies, was also characterized. Both sequences belonged to the HTLV-1c Australo-Melanesian subtype. The NCP201 strain exhibited 0.3% nucleotide divergence with the EM5 strain from Vanuatu. Furthermore, divergence reached 1.1% to 2.9% with the Solomon and Australian sequences respectively. Phylogenetic analyses on a 522-bp-long fragment of the gp21-env gene showed the existence of two major clades. The first is composed of strains from Papua New Guinea; the second includes strains from all neighboring archipelagos (Solomon, Vanuatu, New Caledonia), and Australia. Interestingly, this second clade itself is divided into two sub-clades: strains from Australia on one hand, and strains from Solomon Islands, Vanuatu and New Caledonia on the other hand. CONCLUSIONS: The HTLV-1 seroprevalence (0.6%) in the studied adult population from New Caledonia appears to be low. This seroprevalence is quite similar to the situation observed in Vanuatu and Solomon Islands. However it is very different to the one encountered in Central Australia. Taken together, these results demonstrated that Australo-Melanesia is endemic for HTLV-1 infection with a high diversity of HTLV-1c strains and a clear geographic clustering according to the island of origin of HTLV-1 infected persons.

Filariasis serosurvey, New Caledonia, South Pacific, 2013.

BACKGROUND: Lymphatic filariasis (LF) is a major public health problem in the Pacific. As the global prevalence of infection was not known in New Caledonia (NC), a serosurvey study was conducted by determining the prevalence of circulating filarial antigens, as recommended by the World Health Organization. FINDINGS: A cross sectional study on a 2 degree stratified sample was carried out from June to November 2013. Inclusion criteria were: individuals aged 2 to 80 y/o, who had been hospitalized or sought medical care for a non-infectious cause and who had been living in NC for more than 6 months. LF antigenic detection was performed using the immunocromatographic BinaxNOW filariasis card test (ICT). Among the 1,035 individuals tested, 7 were antigenic. The overall LF antigenic prevalence was 0.62% (CI 95% [0.60-0.63]). All patients were unrelated to each other; none of them presented clinical symptoms of LF. Four of the 7 ICT positive patients reported having travelled to LF endemic areas, 2 patients had never traveled outside NC and the last one had only traveled in non-endemic areas. For the 7 ICT positive patients, the research of microfilariae in blood smears and filarial DNA by PCR was negative. CONCLUSION: The prevalence of filarial antigenemia in NC is less than 1%, the threshold that defines the filarial endemic areas for WHO. Nevertheless, as two patients who had never travelled outside NC and one who had only travelled to non-endemic areas were antigenic, we cannot conclude that NC is totally free of LF.

Socio-economic and Climate Factors Associated with Dengue Fever Spatial Heterogeneity: A Worked Example in New Caledonia.

BACKGROUND/OBJECTIVES: Understanding the factors underlying the spatio-temporal distribution of infectious diseases provides useful information regarding their prevention and control. Dengue fever spatio-temporal patterns result from complex interactions between the virus, the host, and the vector. These interactions can be influenced by environmental conditions. Our objectives were to analyse dengue fever spatial distribution over New Caledonia during epidemic years, to identify some of the main underlying factors, and to predict the spatial evolution of dengue fever under changing climatic conditions, at the 2100 horizon. METHODS: We used principal component analysis and support vector machines to analyse and model the influence of climate and socio-economic variables on the mean spatial distribution of 24,272 dengue cases reported from 1995 to 2012 in thirty-three communes of New Caledonia. We then modelled and estimated the future evolution of dengue incidence rates using a regional downscaling of future climate projections. RESULTS: The spatial distribution of dengue fever cases is highly heterogeneous. The variables most associated with this observed heterogeneity are the mean temperature, the mean number of people per premise, and the mean percentage of unemployed people, a variable highly correlated with people's way of life. Rainfall does not seem to play an important role in the spatial distribution of dengue cases during epidemics. By the end of the 21st century, if temperature increases by approximately 3 °C, mean incidence rates during epidemics could double. CONCLUSION: In New Caledonia, a subtropical insular environment, both temperature and socio-economic conditions are influencing the spatial spread of dengue fever. Extension of this study to other countries worldwide should improve the knowledge about climate influence on dengue burden and about the complex interplay between different factors. This study presents a methodology that can be used as a step by step guide to model dengue spatial heterogeneity in other countries.

El Niño Southern Oscillation and leptospirosis outbreaks in New Caledonia.

Leptospirosis is an important cause of seasonal outbreaks in New Caledonia and the tropics. Using time series derived from high-quality laboratory-based surveillance from 2000-2012, we evaluated whether climatic factors, including El Niño Southern Oscillation (ENSO) and meteorological conditions allow for the prediction of leptospirosis outbreaks in New Caledonia. We found that La Niña periods are associated with high rainfall, and both of these factors were in turn, temporally associated with outbreaks of leptospirosis. The sea surface temperature in El Niño Box 4 allowed forecasting of leptospirosis outbreaks four months into the future, a time lag allowing public health authorities to increase preparedness. To our knowledge, our observations in New Caledonia are the first demonstration that ENSO has a strong association with leptospirosis. This association should be tested in other regions in the South Pacific, Asia or Latin America where ENSO may drive climate variability and the risk for leptospirosis outbreaks.

Seasonal influenza vaccine policies, recommendations and use in the World Health Organization's Western Pacific Region.

OBJECTIVE: Vaccination is the most effective way to prevent seasonal influenza and its severe outcomes. The objective of our study was to synthesize information on seasonal influenza vaccination policies, recommendations and practices in place in 2011 for all countries and areas in the Western Pacific Region of the World Health Organization (WHO). METHODS: Data were collected via a questionnaire on seasonal influenza vaccination policies, recommendations and practices in place in 2011. RESULTS: Thirty-six of the 37 countries and areas (97%) responded to the survey. Eighteen (50%) reported having established seasonal influenza vaccination policies, an additional seven (19%) reported having recommendations for risk groups for seasonal influenza vaccination only and 11 (30%) reported having no policies or recommendations in place. Of the 25 countries and areas with policies or recommendations, health-care workers and the elderly were most frequently recommended for vaccination; 24 (96%) countries and areas recommended vaccinating these groups, followed by pregnant women (19 [76%]), people with chronic illness (18 [72%]) and children (15 [60%]). Twenty-six (72%) countries and areas reported having seasonal influenza vaccines available through public funding, private market purchase or both. Most of these countries and areas purchased only enough vaccine to cover 25% or less of their populations. DISCUSSION: In light of the new WHO position paper on influenza vaccines published in 2012 and the increasing availability of country-specific data, countries and areas should consider reviewing or developing their seasonal influenza vaccination policies to reduce morbidity and mortality associated with annual epidemics and as part of ongoing efforts for pandemic preparedness.

Divergent KSHV/HHV-8 subtype D strains in New Caledonia and Solomon Islands, Melanesia.

BACKGROUND: KSHV/HHV-8 is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma and most multicentric Castleman's disease cases. KSHV exhibits a high genetic variability comprising five genotypes (A-E). Few data are yet available concerning the situation of KSHV, its genetic variability and the associated diseases in Melanesia. OBJECTIVES: We performed a study on 626 natives Melanesians from New Caledonia and Vanikoro Island to evaluate KSHV seroprevalence and characterize molecularly the viral strains. STUDY DESIGN: Plasma from 343 males and 283 females (age range: 15-86 years, mean age: 60) were tested for KSHV latent antibodies by an immunofluorescence assay (IFA) using BC-3 cells. DNAs extracted from peripheral blood buffy-coat of KSHV seropositive individuals were amplified to obtain a 737-bp fragment of the ORF-K1 gene. Phylogenetic analyses were then performed. RESULTS: Among 626 samples, 148 were IFA positive (dilution≥1:80). The overall seroprevalence was 23.6% (25.2% in New Caledonia, 17.5% in Vanikoro). Fifteen (8 men and 7 women, mean age 69 years) out of 148 DNA samples were found PCR positive. All ORF-K1 sequences belonged to KSHV genotype D. A geographic clustering according to the island of origin of KSHV infected persons was clearly observed with sequences from New Caledonia clustering with most Vanuatu strains. CONCLUSIONS: New Caledonia and Vanikoro are endemic for KSHV with a high diversity of genotype D variants. These strains were probably introduced into New Caledonia during multiple waves of migrations of Melanesian and Polynesian individuals that have colonized this archipelago.

Climate-based models for understanding and forecasting dengue epidemics.

BACKGROUND: Dengue dynamics are driven by complex interactions between human-hosts, mosquito-vectors and viruses that are influenced by environmental and climatic factors. The objectives of this study were to analyze and model the relationships between climate, Aedes aegypti vectors and dengue outbreaks in Noumea (New Caledonia), and to provide an early warning system. METHODOLOGY/PRINCIPAL FINDINGS: Epidemiological and meteorological data were analyzed from 1971 to 2010 in Noumea. Entomological surveillance indices were available from March 2000 to December 2009. During epidemic years, the distribution of dengue cases was highly seasonal. The epidemic peak (March-April) lagged the warmest temperature by 1-2 months and was in phase with maximum precipitations, relative humidity and entomological indices. Significant inter-annual correlations were observed between the risk of outbreak and summertime temperature, precipitations or relative humidity but not ENSO. Climate-based multivariate non-linear models were developed to estimate the yearly risk of dengue outbreak in Noumea. The best explicative meteorological variables were the number of days with maximal temperature exceeding 32°C during January-February-March and the number of days with maximal relative humidity exceeding 95% during January. The best predictive variables were the maximal temperature in December and maximal relative humidity during October-November-December of the previous year. For a probability of dengue outbreak above 65% in leave-one-out cross validation, the explicative model predicted 94% of the epidemic years and 79% of the non epidemic years, and the predictive model 79% and 65%, respectively. CONCLUSIONS/SIGNIFICANCE: The epidemic dynamics of dengue in Noumea were essentially driven by climate during the last forty years. Specific conditions based on maximal temperature and relative humidity thresholds were determinant in outbreaks occurrence. Their persistence was also crucial. An operational model that will enable health authorities to anticipate the outbreak risk was successfully developed. Similar models may be developed to improve dengue management in other countries.

Influenza A(H1N1)2009 in the French Pacific territories: assessment of the epidemic wave during the austral winter.

The three French territories in the Pacific (New Caledonia [NC], French Polynesia [FP] and Wallis and Futuna [WF]) have been affected by an outbreak of influenza A(H1N1)2009 during the austral winter of 2009. This wave of influenza-like illness was characterized by a short duration (approximately 8 weeks) and high attack rates: 16-18% in NC and FP, 28% in Wallis and 38% in Futuna. The number of infected patients requiring hospitalization in critical care services and the number of deaths were, respectively, 21 and 10 in NC and 13 and 7 in FP (none in WF). Diabetes, cardiac and pulmonary diseases, obesity in adults, neuromuscular diseases in children, and Oceanic origin were frequently observed among severe cases and deaths. A significant proportion of the population remains susceptible to A(H1N1)2009, making the occurrence of a second wave likely. A state of preparedness and control efforts must be implemented, based on preventive measures (immunization), as well as combined clinical and virological surveillance and health organization.