Modeling present and future climate risk of dengue outbreak, a case study in New Caledonia.

BACKGROUND: Dengue dynamics result from the complex interactions between the virus, the host and the vector, all being under the influence of the environment. Several studies explored the link between weather and dengue dynamics and some investigated the impact of climate change on these dynamics. Most attempted to predict incidence rate at a country scale or assess the environmental suitability at a global or regional scale. Here, we propose a new approach which consists in modeling the risk of dengue outbreak at a local scale according to climate conditions and study the evolution of this risk taking climate change into account. We apply this approach in New Caledonia, where high quality data are available. METHODS: We used a statistical estimation of the effective reproduction number (Rt) based on case counts to create a categorical target variable : epidemic week/non-epidemic week. A machine learning classifier has been trained using relevant climate indicators in order to estimate the probability for a week to be epidemic under current climate data and this probability was then estimated under climate change scenarios. RESULTS: Weekly probability of dengue outbreak was best predicted with the number of days when maximal temperature exceeded 30.8°C and the mean of daily precipitation over 80 and 60 days prior to the predicted week respectively. According to scenario RCP8.5, climate will allow dengue outbreak every year in New Caledonia if the epidemiological and entomological contexts remain the same. CONCLUSION: We identified locally relevant climatic factor driving dengue outbreaks in New Caledonia and assessed the inter-annual and seasonal risk of dengue outbreak under different climate change scenarios up to the year 2100. We introduced a new modeling approach to estimate the risk of dengue outbreak depending on climate conditions. This approach is easily reproducible in other countries provided that reliable epidemiological and climate data are available.

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.

Viral evolution sustains a dengue outbreak of enhanced severity.

Compared to the previous 2013-2014 outbreak, dengue 2016-2017 outbreak in New Caledonia was characterized by an increased number of severe forms associated with hepatic presentations. In this study, we assessed the virological factors associated with this enhanced severity. Whole-genome sequences were retrieved from dengue virus (DENV)-1 strains collected in 2013-2014 and from severe and non-severe patients in 2016-2017. Fitness, hepatic tropism and cytopathogenicity of DENV 2016-2017 strains were compared to those of 2013-2014 strains using replication kinetics in the human hepatic cell line HuH7. Whole-genome sequencing identified four amino acid substitutions specific to 2016-2017 strains and absent from 2013-2014 strains. Three of these mutations occurred in predicted T cell epitopes, among which one was also a B cell epitope. Strains retrieved from severe forms did not exhibit specific genetic features. DENV strains from 2016-2017 exhibited a trend towards reduced replicative fitness and cytopathogenicity in vitro compared to strains from 2013-2014. Overall, the 2016-2017 dengue outbreak in New Caledonia was associated with a viral genetic evolution which had limited impact on DENV hepatic tropism and cytopathogenicity. These mutations, however, may have modified DENV strains antigenicity, altering the anti-DENV immune response in some patients, in turn favoring the development of severe forms.Trial registration: ClinicalTrials.gov identifier: NCT04615364.

Flying Fox Hemolytic Fever, Description of a New Zoonosis Caused by Candidatus Mycoplasma haemohominis.

BACKGROUND: Hemotropic mycoplasmas, previously classified in the genus Eperythrozoon, have been reported as causing human infections in Brazil, China, Japan, and Spain. METHODS: In 2017, we detected DNA from Candidatus Mycoplasma haemohominis in the blood of a Melanesian patient from New Caledonia presenting with febrile splenomegaly, weight loss, life-threatening autoimmune hemolytic anemia, and hemophagocytosis. The full genome of the bacterium was sequenced from a blood isolate. Subsequently, we retrospectively (2011-2017) and prospectively (2018-2019) tested patients who had been hospitalized with a similar clinico-biological picture. In addition, as these patients had been in contact with frugivorous bats (authorized under conditions for hunting and eating in New Caledonia), we investigated the role of these animals and their biting flies by testing them for hemotropic mycoplasmas. RESULTS: There were 15 patients found to be infected by this hemotropic mycoplasma. Among them, 4 (27%) died following splenectomy performed either for spontaneous spleen rupture or to cure refractory autoimmune hemolytic anemia. The bacterium was cultivated from the patient's blood. The full genome of the Neocaledonian Candidatus M. haemohominis strain differed from that of a recently identified Japanese strain. Of 40 tested Pteropus bats, 40% were positive; 100% of collected bat flies Cyclopodia horsfieldi (Nycteribiidae, Diptera) were positive. Human, bat, and dipteran strains were highly similar. CONCLUSIONS: The bacterium being widely distributed in bats, Candidatus M. haemohominis, should be regarded as a potential cause of severe infections in humans.

Dengue in New Caledonia: Knowledge and Gaps.

Arboviruses are viruses transmitted to humans by the bite of infected mosquito vectors. Over the last decade, arbovirus circulation has increasingly been detected in New Caledonia (NC), a French island territory located in the subtropical Pacific region. Reliable epidemiological, entomological, virological and climate data have been collected in NC over the last decade. Here, we describe these data and how they inform arboviruses' epidemiological profile. We pinpoint areas which remain to be investigated to fully understand the peculiar epidemiological profile of arbovirus circulation in NC. Further, we discuss the advantages of conducting studies on arboviruses dynamics in NC. Overall, we show that conclusions drawn from observations conducted in NC may inform epidemiological risk assessments elsewhere and may be vital to guide surveillance and response, both in New Caledonia and beyond.

Zika virus outbreak in New Caledonia and Guillain-Barré syndrome: a case-control study.

Zika virus (ZIKV) infection has been associated with neurologic disorders including Guillain-Barré syndrome (GBS). In New Caledonia during the ZIKV outbreak (2014-2015), case-control and retrospective studies have been performed to assess the link between ZIKV and GBS. Among the 15 cases included, 33% had evidence of a recent ZIKV infection compared to only 3.3% in the 30 controls involved. All patients were Melanesian, had facial diplegia and similar neurophysiological pattern consistent with acute inflammatory demyelinating polyneuropathy, and recovered well. Furthermore, during the peak of ZIKV transmission, we observed a number of GBS cases higher than the calculated upper limit, emphasizing the fact that ZIKV is now a major trigger of GBS.

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.

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.

Newly diagnosed rheumatic heart disease among indigenous populations in the Pacific.

OBJECTIVES: Rheumatic heart disease (RHD) remains the leading acquired heart disease in the young worldwide. We aimed at assessing outcomes and influencing factors in the contemporary era. METHODS: Hospital-based cohort in a high-income island nation where RHD remains endemic and the population is captive. All patients admitted with newly diagnosed RHD according to World Heart Federation echocardiographic criteria were enrolled (2005-2013). The incidence of major cardiovascular events (MACEs) including heart failure, peripheral embolism, stroke, heart valve intervention and cardiovascular death was calculated, and their determinants identified. RESULTS: Of the 396 patients, 43.9% were male with median age 18 years (IQR 10-40)). 127 (32.1%) patients presented with mild, 131 (33.1%) with moderate and 138 (34.8%) with severe heart valve disease. 205 (51.8%) had features of acute rheumatic fever. 106 (26.8%) presented with at least one MACE. Among the remaining 290 patients, after a median follow-up period of 4.08 (95% CI 1.84 to 6.84) years, 7 patients (2.4%) died and 62 (21.4%) had a first MACE. The annual incidence of first MACE and of heart failure were 59.05‰ (95% CI 44.35 to 73.75) and 29.06‰ (95% CI 19.29 to 38.82), respectively. The severity of RHD at diagnosis (moderate vs mild HR 3.39 (0.95 to 12.12); severe vs mild RHD HR 10.81 (3.11 to 37.62), p<0.001) and ongoing secondary prophylaxis at follow-up (HR 0.27 (0.12 to 0.63), p=0.01) were the two most influential factors associated with MACE. CONCLUSIONS: Newly diagnosed RHD is associated with poor outcomes, mainly in patients with moderate or severe valve disease and no secondary prophylaxis.

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.

Breast milk as a possible route of vertical transmission of dengue virus?

We report a case of vertical transmission of dengue infection. The virus was detected and quantified by reverse-transcription polymerase chain reaction in sequential blood samples from mother and child as well as in breast milk, but not in cord blood. This case poses questions about the risk of breastfeeding transmission of dengue virus.

Kinetic profiles and management of hepatitis B virus reactivation in patients with immune-mediated inflammatory diseases.

OBJECTIVE: Immunosuppressive therapy may trigger hepatitis B virus (HBV) reactivation for increased morbidity and mortality. We aimed to describe HBV reactivation in patients receiving treatment for immune-mediated inflammatory diseases (IMIDs) and to evaluate a predefined algorithm for its prevention. METHODS: Physicians submitted data for patients receiving treatment for IMIDs and exhibiting HBV reactivation, defined as an increase of >1 log10 IU/ml of HBV DNA levels or DNA reappearance. We systematically reviewed cases in the literature. RESULTS: The 35 physician-collected patients had rheumatoid arthritis (n = 14), connective tissue disease (n = 7), vasculitis (n = 5), and other diseases (n = 9). At baseline, 65.7% of patients were positive for hepatitis B surface antigen (HBsAg), 31.4% had a history of HBV infection, and 2.9% had occult HBV infection. Reactivation occurred a median of 35 weeks (range 2-397 weeks) after the start of corticosteroid and/or immunosuppressive therapy. In all, 88.6% of patients were clinically asymptomatic, but 25.7% had severe hepatitis; none had fulminant hepatitis. Management was antiviral therapy for 91.4%, with discontinuation or decrease of immunosuppressive therapy for 45.7%. In pooling these 35 cases and 103 patients from the literature, 73.9% of patients were clinically asymptomatic, 33.3% had severe hepatitis, and 12.3% died and/or had fulminant hepatitis. Reactivation occurred early with rituximab or cyclophosphamide therapy and in HBsAg-positive/HBV DNA-positive patients. Using the predefined algorithm, 78% of patients with reactivation would have received preemptive antiviral therapy. CONCLUSION: We provide new insights into HBV reactivation in patients receiving treatment for IMIDs. A predefined algorithm may be effective in reducing the risk of HBV reactivation in this population.

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.

Long-term impact of treated congenital toxoplasmosis on quality of life and visual performance.

BACKGROUND: Long-term evolution of congenital toxoplasmosis is not documented. We assessed the outcome of treated congenital toxoplasmosis in a cohort of adult individuals who had undergone ante- and postnatal treatment to provide information for pediatricians and parents on the evolution of the disease. METHODS: We conducted a questionnaire study on 126 adults with congenital toxoplasmosis (mean age: 22.2 years; age range: 18-31 years) monitored regularly until the time of inclusion. The main outcome measures were quality of life (Psychological General Well-Being Index) and visual function (VF14 questionnaire), and the outcomes were correlated with disease-specific factors. RESULTS: Of the 102 patients (80.9%) who were finally included in the study, 12 (11.8%) presented neurologic effects and 60 (58.8%) manifested ocular lesions; in the latter category, 13 individuals (12.7%) had reduced visual function. The overall global quality-of-life score (74.7 ± 14.2) was close to the expected normal range for the general population (73.7 ± 15.3). Overall, visual function was only slightly impaired (M = 97.3; 95% confidence interval, 95.8-98.8). Although disease-independent critical life circumstances were associated with a reduced Psychological General Well-Being Index, this index was not influenced by any of the clinical characteristics of congenital toxoplasmosis. Neurologic pathologies, reduced visual acuity, foveal location of the retinal lesion, and squinting contributed to decreased visual function at follow-up. CONCLUSIONS: Our data reveal that treated congenital toxoplasmosis has little effect on the quality of life and visual function of the affected individuals. These encouraging findings may help to alleviate the anxiety of affected individuals and their parents.

Mefloquine adverse effects with atypical facial lesions in an overweight patient.

BACKGROUND: The recommended dosage of mefloquine to treat Plasmodium falciparum infection is 25 mg/kg, with no recommendation for dosage exceeding 1500 mg. We describe an original case of adverse reaction to mefloquine in an overweight patient. METHOD: Case report. RESULTS: A 32-year-old woman weighing 139 kg presented with uncomplicated P. falciparum infection after returning from Cameroon. She received 3250 mg of mefloquine (i.e. 23 mg/kg) administered in four doses. On day 2, she developed neuropsychiatric disorders and facial lesions. Nasal mucocutaneous vesicles and bullae, depressive mood, mild thrombocytopenia and hepatic cytolysis were evidenced. Parasitemia was negative. Recovery was complete on day 17. High mefloquine serum levels were measured (8.030 mg/L on day 3, 6.880 mg/L on day 8, and 3.370 mg/L on day 17). CONCLUSIONS: The causal relationship between mefloquine and the occurrence of these adverse effects is probable. However, as no viral or bacteriological investigations were performed, the drug responsibility remains uncertain. Mefloquine-induced bullous and facial lesions reversible upon drug withdrawal have already been described. The associated neuropsychiatric symptoms were strongly suggestive of mefloquine adverse effects, as such events are more frequently observed in cases of overdosage. Our case emphasizes the difficulties of dosage adaptation in overweight patients.

Dengue 1 diversity and microevolution, French Polynesia 2001-2006: connection with epidemiology and clinics.

BACKGROUND: Dengue fever (DF) is an emerging infectious disease in the tropics and subtropics. Determinants of DF epidemiology and factors involved in severe cases-dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS)-remain imperfectly characterized. Since 2000, serotype 1 (DENV-1) has predominated in the South Pacific. The aim of this study was (i) to determine the origin and (ii) to study the evolutionary relationships of DENV-1 viruses that have circulated in French Polynesia (FP) from the severe 2001 outbreak to the recent 2006 epidemic, and (iii) to analyse the viral intra-host genetic diversity according to clinical presentation. METHODOLOGY/PRINCIPAL FINDINGS: Sequences of 181 envelope gene and 12 complete polyproteins of DENV-1 viruses obtained from human sera in FP during the 2001-2006 period were generated. Phylogenetic analysis showed that all DENV-1 FP strains belonged to genotype IV-"South Pacific" and derived from a single introduction event from South-East Asia followed by a 6-year in situ evolution. Although the ratio of nonsynonymous/synonymous substitutions per site indicated strong negative selection, a mutation in the envelope glycoprotein (S222T) appeared in 2002 and was subsequently fixed. It was noted that genetic diversification was very significant during the 2002-2005 period of endemic DENV-1 circulation. For nine DF sera and eight DHF/DSS sera, approximately 40 clones/serum of partial envelope gene were sequenced. Importantly, analysis revealed that the intra-host genetic diversity was significantly lower in severe cases than in classical DF. CONCLUSIONS/SIGNIFICANCE: First, this study showed that DENV-1 epidemiology in FP was different from that described in other South-Pacific islands, characterized by a long sustained viral circulation and the absence of new viral introduction over a 6-year period. Second, a significant part of DENV-1 evolution was observed during the endemic period characterized by the rapid fixation of S222T in the envelope protein that may reflect genetic drift or adaptation to the mosquito vector. Third, for the first time, it is suggested that clinical outcome may be correlated with intra-host genetic diversity.

Influence of age at disease onset in the outcome of paediatric systemic lupus erythematosus.

OBJECTIVES: The aim of this study was to investigate the influence of age at disease onset in the outcome of paediatric SLE (pSLE). METHODS: Fifty-six patients with pSLE, divided into three groups (pre-pubertal, peripubertal and post-pubertal onset), were studied. The SDI (SLICC/ACR Damage Index for SLE), patients' characteristics, disease manifestations and treatments were compared using Fisher's exact test and Kruskal-Wallis test. Kaplan-Meier curves were constructed to compare the risk of damage occurrence. RESULTS: The risk of damage (SDI >or=1) significantly decreased when age at disease onset increased (89% in pre-pubertal pSLE, 57% in peripubertal pSLE and 38% in post-pubertal pSLE). This excess of risk was found in all disease duration intervals studied (1-3, 3-5, 5-8, 8-10, >10 years) and at the end of follow-up. Kaplan-Meier curves indicated a higher and earlier risk of damage in younger patients. Young children showed higher frequency of autoimmune family history. The frequency of neuropsychiatric disorders and damages decreased with age at disease onset (P < 0.05). Cumulative duration of high-dose prednisone (> 0.5 mg/kg/day) and number of immunosuppressive drugs used that seem to contribute to damage significantly increased when age at disease onset decreased. CONCLUSIONS: The risk of damage is inversely correlated with age at disease onset in pSLE. The poorer outcome observed in younger children may be explained by a more severe disease expression, may be a higher infectious susceptibility, and a more aggressive therapy, particularly within the first 6 months of disease course.