A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease.

Chikungunya virus (CHIKV) is a re-emerging arbovirus responsible for a massive outbreak currently afflicting the Indian Ocean region and India. Infection from CHIKV typically induces a mild disease in humans, characterized by fever, myalgia, arthralgia, and rash. Cases of severe CHIKV infection involving the central nervous system (CNS) have recently been described in neonates as well as in adults with underlying conditions. The pathophysiology of CHIKV infection and the basis for disease severity are unknown. To address these critical issues, we have developed an animal model of CHIKV infection. We show here that whereas wild type (WT) adult mice are resistant to CHIKV infection, WT mouse neonates are susceptible and neonatal disease severity is age-dependent. Adult mice with a partially (IFN-alpha/betaR(+/-)) or totally (IFN-alpha/betaR(-/-)) abrogated type-I IFN pathway develop a mild or severe infection, respectively. In mice with a mild infection, after a burst of viral replication in the liver, CHIKV primarily targets muscle, joint, and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to other tissues including the CNS, where it specifically targets the choroid plexuses and the leptomeninges. Together, these data indicate that CHIKV-associated symptoms match viral tissue and cell tropisms, and demonstrate that the fibroblast is a predominant target cell of CHIKV. These data also identify the neonatal phase and inefficient type-I IFN signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates.

Multidisciplinary prospective study of mother-to-child chikungunya virus infections on the island of La Réunion.

BACKGROUND: An outbreak of chikungunya virus affected over one-third of the population of La Réunion Island between March 2005 and December 2006. In June 2005, we identified the first case of mother-to-child chikungunya virus transmission at the Groupe Hospitalier Sud-Réunion level-3 maternity department. The goal of this prospective study was to characterize the epidemiological, clinical, biological, and radiological features and outcomes of all the cases of vertically transmitted chikungunya infections recorded at our institution during this outbreak. METHODS AND FINDINGS: Over 22 mo, 7,504 women delivered 7,629 viable neonates; 678 (9.0%) of these parturient women were infected (positive RT-PCR or IgM serology) during antepartum, and 61 (0.8%) in pre- or intrapartum. With the exception of three early fetal deaths, vertical transmission was exclusively observed in near-term deliveries (median duration of gestation: 38 wk, range 35-40 wk) in the context of intrapartum viremia (19 cases of vertical transmission out of 39 women with intrapartum viremia, prevalence rate 0.25%, vertical transmission rate 48.7%). Cesarean section had no protective effect on transmission. All infected neonates were asymptomatic at birth, and median onset of neonatal disease was 4 d (range 3-7 d). Pain, prostration, and fever were present in 100% of cases and thrombocytopenia in 89%. Severe illness was observed in ten cases (52.6%) and mainly consisted of encephalopathy (n = 9; 90%). These nine children had pathologic MRI findings (brain swelling, n = 9; cerebral hemorrhages, n = 2), and four evolved towards persistent disabilities. CONCLUSIONS: Mother-to-child chikungunya virus transmission is frequent in the context of intrapartum maternal viremia, and often leads to severe neonatal infection. Chikungunya represents a substantial risk for neonates born to viremic parturients that should be taken into account by clinicians and public health authorities in the event of a chikungunya outbreak.

[Early maternal-fetal transmission of the Chikungunya virus]. / Transmission materno-foetale précoce du virus Chikungunya.

INTRODUCTION: Since the onset of the Chikungunya outbreak in Reunion Island, vertical maternal-fetal transmission of the virus has been observed in newborns, but no such transmission has been demonstrated early during pregnancy. We report here the first three cases of maternal-fetal transmission of the Chikungunya virus (CHIKV) before 16 weeks' gestational age. CASES: Maternal infections occurred at terms of 12 weeks and 4 days, 15 weeks and 5 days, and 15 weeks and were confirmed by positive findings for specific anti-CHIKV IgM. Fetal deaths were subsequently observed, and at that point, CHIKV RT-PCR was negative for all three maternal blood samples. Amniocentesis preceded rupture of membranes in all three cases. RT-PCR showed viral genome in the amniotic fluid of the three fetuses, in the placentas of two, and in the brains of two. Autopsy found no malformations, and all other bacterial and viral test results were negative. DISCUSSION: These findings demonstrate early maternal-fetal transmission of CHIKV, which is suspected to be directly linked to the fetal deaths. This vertical transmission, probably abortifacient, should be considered in the light of human and animal responses to other arboviruses.

[Vertical maternal fetal transmission of the chikungunya virus. Ten cases among 84 pregnant women]. / Transmission verticale materno-foetale du virus chikungunya. Dix cas observés sur l'île de la Réunion chez 84 femmes enceintes.

INTRODUCTION: In March 2005, an epidemic of chikungunya virus began in the southern portion of Reunion Island (French overseas district in the Indian Ocean) and spread to the northern part of the island at the end of 2005. The Reunion-South Hospital Group observed the first cases of pregnant women infected with the virus in June 2005. We report here for the first time maternal-fetal transmission of this virus. CASES: From June 2005 through the end of January 2006, 84 pregnant women had acute chikungunya infections during pregnancy. In 88% of these cases (n=74)--all involving infections relatively distant from delivery--the newborns appeared asymptomatic. Conversely, 10 newborns had severe attacks (4 with meningoencephalitis and 3 with intravascular coagulations) after birth and required prolonged neonatal hospitalization (6 in the neonatal intensive care unit with intubation and assisted ventilation). No infants died, but there was one case of severe intracerebral hemorrhage after severe thrombocytopenia. These cases were confirmed by specific serology testing or PCR or both for mothers and newborns. We note that all severe cases involved women with viremia and fever in the intrapartum period.

A case of postoperative breast infection by Mycobacterium fortuitum associated with the hospital water supply.

This report describes the first known laboratory-confirmed case of Mycobacterium fortuitum breast infection related to the hospital water supply. The source of the M fortuitum infection was identified by repetitive extragenic palindromic sequence-based polymerase chain reaction genotyping. In addition, we discuss appropriate infection control measures to minimize patient exposure to waterborne pathogens, in particular, in the context of nontuberculous mycobacteria, which is difficult to eradicate from the water supply network.

Immature ovarian teratoma with hyponatremia and low antidiuretic hormone level.

BACKGROUND: Inappropriate antidiuretic hormone secretion syndrome is rare in patients with gynecologic tumors. CASE: A 22-year-old woman presented with inappropriate antidiuretic hormone secretion symptoms during the 2 months preceding the diagnosis of an immature ovarian teratoma. Vasopressin levels in serum and in the urine were very low. Restriction of water intake and surgical removal of the teratoma resulted in the definitive correction of the hyponatremia. This observation suggests that immature teratoma cells can produce a vasopressin-like factor, and the syndrome may be a sign of an ovarian malignancy. CONCLUSION: Pelvic organs should be examined when the more common causes of inappropriate antidiuretic hormone secretion syndrome have been ruled out.

Obstetric and neonatal outcomes in grand multiparity.

OBJECTIVE: To compare the incidence of antenatal and intrapartum complications and neonatal outcomes among grand multiparas with age-matched multiparas. METHODS: Six hundred twenty-one grand multiparas (para more than 4) women were prospectively compared with 621 age-matched multiparous (para 2-4) controls. RESULTS: Grand multiparity was associated with low socioeconomic status and education (odds ratio [OR]6.4; 95% confidence interval [CI] 4.5, 9.0), poorer prenatal care (OR 3.1; 95% CI 1.5, 6.1), smoking (OR 2.2; 95% CI 1.5, 3.2), and alcohol consumption (OR 9.0; 95% CI 2.1, 39.3). Grand multiparas had a higher body mass index (OR 1.5; 95% CI 1.2, 1.9) and rate of insulin-dependent gestational diabetes (OR 1.7; 95% CI 1.02, 3.1). They had more previous intrauterine (OR 4.2; 95% CI 1.5, 11.3) and perinatal deaths (OR 3.2; 95% CI 2.0, 5.0). They had fewer intrapartum complications (arrests of cervical dilatation [OR 0.19; 95% CI 0.06, 0.66], instrumental deliveries [OR 0.31; 95% CI 0.16, 0.59], and fever during labor [OR 0.47; 95% CI 0.26, 0.86]). Conditional logistic regression models found that grand multiparity was the most closely correlated factor to a previous history of fetal death (OR 4.3; 95% CI 1.6, 11.6), but it was not an independent predictor of insulin-dependent gestational diabetes mellitus (OR 1.3; 95% CI 0.75, 2.2). CONCLUSION: Grand multiparas, when compared with same-age multiparous controls, appear to have fewer intrapartum complications. However, they present several prenatal risk factors that require special antenatal care. LEVEL OF EVIDENCE: II-3

Longitudinal health outcome and wellbeing of mother-infant pairs after adolescent pregnancy in Reunion Island, Indian Ocean.

OBJECTIVE: To evaluate longitudinal care needs and health service access among mother-infant pairs after adolescent pregnancy. METHODS: In a case-control study, data were analyzed from primiparous adolescent and adult mother-infant pairs who delivered at Reunion Island University Hospital, France, between January 2004 and December 2006, and were followed-up from maternity discharge until December 2011. Infant outcomes were hospitalization during the first 2 years of life, hospital access for "non-medical" reasons, and neuropsychiatric care. Maternal outcomes were number of pregnancies and childbirths, rapid repeat pregnancy (RRP) rate, pregnancy morbidities, and use of health services. RESULTS: Data from 476 cases and 476 controls were analyzed. Adolescent and control offspring did not differ in the measured outcomes. Adolescent and control mothers had, respectively, 2.4 ± 1.3 and 1.9 ± 1.1 pregnancies; 1.9 ± 0.8 and 1.6 ± 0.7 childbirths; and RRP rates of 7.6% and 2.7% (all P<0.001). Adolescents had less pregnancy-related pathologies at the index pregnancy and more frequently had natural deliveries (P<0.05). Younger mothers exhibited higher rates (19.7% versus 6.9%, P=0.001) of care for psychosocial reasons (suicide attempt, acute alcohol or drug intoxication, road accident, psychiatric problems, physical abuse). CONCLUSION: Concerns arise from the long-term psychosocial risk among adolescent mothers.

Obstetric and neonatal outcomes of adolescent primiparous singleton pregnancies: a cohort study in the South of Reunion Island, Indian Ocean.

OBJECTIVES: To describe the maternal and neonatal outcomes of a large cohort of adolescent pregnancies in a tertiary care hospital at Reunion Island. METHODS: Retrospective study of all primiparous singleton pregnancies over 10.5 years. Adolescent (<18 years) were compared to 18-29 years pregnancies. The maternal outcomes were obstetric illness, labor complications, and way of delivery. Neonatal outcomes were preterm birth, low birth weight (LBW), small for gestational age, birth asphyxia, need for mechanical ventilation, and mortality. RESULTS: We analyzed 1839 adolescent pregnancies and 11,445 controls. Adolescents had worse prenatal care than older mothers, (4.4 vs. 1.4%; p < 0.0001), higher rates of smoking and alcohol assumption (13 vs. 11% and 0.7 vs. 0.4%, both p < 0.05). They showed less pregnancy-related illness and labor complications and higher rates of normal vaginal delivery (80 vs. 69%; p < 0.0001), without increased risk of episiotomy or postpartum hemorrhage. Offspring mortality, preterm birth, and LBW were higher in adolescent pregnancies (3.3 vs. 2.2%; p = 0.001, 14 vs. 12%; p = 0.0008; 17 vs. 14%; p = 0.002). CONCLUSIONS: In this population, adolescents had an obstetrical outcome better than controls, but their offspring short-term outcomes were unfavorable. Furthers studies are needed to better elucidate the link between adolescent pregnancy and impaired neonatal outcome.

Low clinical burden of 2009 pandemic influenza A (H1N1) infection during pregnancy on the island of La Réunion.

BACKGROUND: Pregnant women have been identified as a group at risk, both for respiratory complications than for the admissions to the Intensive Care Unit (ICU) during the 2009 H1N1 influenza pandemic (pdm). The purpose of this prospective register-based cohort-study was to characterize the clinical virulence of the pdm (H1N1/09)v during pregnancy in La Réunion. METHODS/PRINCIPAL FINDINGS: Over a twelve-week pdm wave (13 July to 3 October 2009), 294 pregnant women presented with an influenza-like illness (ILI) to one of the three maternity departments of the South Reunion area, Indian Ocean. Out of these, 278 were checked by RT-PCR for influenza viruses (157 positive and 121 negative, of whom, 141 with pdm flu and 132 with ILIs of non pdm origin, 5 untyped). The median body temperature was higher in women experiencing pdm flu than in those with non pdm ILI (38.9 degrees C versus 38.3 degrees C, P<0.0001), without evidence linked to circulating viremia. Oseltamivir was given for 86% of pdm flu cases in a median time inferior than 48 hrs (range 0-7 days). The hospitalization rate for pdm flu was of 60% and not associated with underlying conditions. Six viral pneumonia and fourteen asthma attacks were observed among 84 hospitalized pdm flu cases, of whom, only one led to the ICU for an acute lung injury. No maternal death occurred during the pdm wave. None adverse pregnancy outcome was associated with pdm flu. No congenital birth defect, nor early-onset neonatal influenza infection was attributable to pdm flu exposure. CONCLUSIONS/SIGNIFICANCE: This report mitigates substantially the presumed severity of pandemic H1N1/09 influenza infection during pregnancy. The reasons for which the clinical burden of H1N1/09 influenza virus may differ worldwide raise questions about a differential local viral-strain effect and public health preparedness, notably in timely access to special care and antiviral treatments.

Development of a sensitive real-time reverse transcriptase PCR assay with an internal control to detect and quantify chikungunya virus.

BACKGROUND: The chikungunya virus (CHIKV; Alphavirus, Togaviridae) has emerged in the south Western Indian Ocean since early 2005. A major outbreak of CHIKV infection occurred in Réunion Island, where the virus is transmitted by Aedes albopictus mosquitoes. Facing an outbreak of unprecedented magnitude, we developed a rapid, sensitive, and reliable assay for the detection and quantification of CHIKV in plasma samples. METHODS: A dual-color TaqMan 1-step reverse transcriptase PCR assay was developed in a LightCycler 2.0 system. A coextracted and coamplified chimerical RNA sequence was used as an internal control (IC) to eliminate false-negative results. The CHIKV-specific and IC probes were labeled with 6-carboxyfluorescein (530 nm) and the wide span dye DYXL (705 nm), respectively, eliminating the need for color compensation. A synthetic RNA was used as an external calibrator for CHIKV absolute quantification. RESULTS: The detection limit was 350 copies/mL (3 copies/capillary). A further improvement to approximately 40 copies/mL was obtained by use of a larger volume of plasma. The assay specificity was confirmed in vitro and in silico. CHIKV in 343 patients was present at viral loads >10(8) copies/mL, mainly in newborns and seniors >60 years old. Long viremic phases of up to 12 days were seen in 6 patients. CONCLUSIONS: The assay is rapid, CHIKV-specific, and highly sensitive, and it includes an IC. It proved useful to detect and quantify CHIKV during the Réunion Island epidemic. The assay might be applicable to other CHIKV epidemics, especially in the Indian subcontinent, where an extensive outbreak is ongoing.

Case report: a prenatal case of Jarcho-Levin syndrome diagnosed during the first trimester of pregnancy.

The Jarcho-Levin syndrome is a specific form of spondylocostal/spondylothoracic dysostosis. There have been various classifications of this syndrome. We present the case of a severe prenatal Jarcho-Levin syndrome, diagnosed by ultrasound examination during the first trimester of pregnancy in a family with no previous medical history of an affected child. X-ray exploration, high-resolution spiral computed tomography and autopsy confirmed the diagnosis.