Severe influenza pneumonitis in children with inherited TLR3 deficiency.

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-ß and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

Tropheryma whipplei endocarditis.

Tropheryma whipplei endocarditis differs from classic Whipple disease, which primarily affects the gastrointestinal system. We diagnosed 28 cases of T. whipplei endocarditis in Marseille, France, and compared them with cases reported in the literature. Specimens were analyzed mostly by molecular and histologic techniques. Duke criteria were ineffective for diagnosis before heart valve analysis. The disease occurred in men 40-80 years of age, of whom 21 (75%) had arthralgia (75%); 9 (32%) had valvular disease and 11 (39%) had fever. Clinical manifestations were predominantly cardiologic. Treatment with doxycycline and hydroxychloroquine for at least 12 months was successful. The cases we diagnosed differed from those reported from Germany, in which arthralgias were less common and previous valve lesions more common. A strong geographic specificity for this disease is found mainly in eastern-central France, Switzerland, and Germany. T. whipplei endocarditis is an emerging clinical entity observed in middle-aged and older men with arthralgia.

Rise of CC398 lineage of Staphylococcus aureus among Infective endocarditis isolates revealed by two consecutive population-based studies in France.

Staphylococcus aureus isolates from two prospective studies on infective endocarditis (IE) conducted in 1999 and 2008 and isolated from non-IE bacteremia collected in 2006 were spa-typed and their virulence factors were analyzed with a microarray. Both populations were genetically diverse, with no virulence factors or genotypes significantly more associated with the IE isolates compared with the non-IE isolates. The population structure of the IE isolates did not change much between 1999 and 2008, with the exception of the appearance of CC398 methicillin-susceptible Staphylococcus aureus (MSSA) isolates responsible for 5.6% of all cases in 2008. In 1999, this lineage was responsible for no cases. The increasing prevalence of S. aureus in IE is apparently not the result of a major change in staphylococcal population structure over time, with the exception of the emerging CC398 MSSA lineage.

Temporal trends in infective endocarditis in the context of prophylaxis guideline modifications: three successive population-based surveys.

OBJECTIVES: The goal of this study was to evaluate temporal trends in infective endocarditis (IE) incidence and clinical characteristics after 2002 French IE prophylaxis guideline modifications. BACKGROUND: There are limited data on changes in the epidemiology of IE since recent guidelines recommended restricting the indications of antibiotic prophylaxis of IE. METHODS: Three 1-year population-based surveys were conducted in 1991, 1999, and 2008 in 3 French regions totaling 11 million inhabitants age ≥20 years. We prospectively collected IE cases from all medical centers and analyzed age- and sex-standardized IE annual incidence trends. RESULTS: Overall, 993 expert-validated IE cases were analyzed (323 in 1991; 331 in 1999; and 339 in 2008). IE incidence remained stable over time (95% confidence intervals given in parentheses/brackets): 35 (31 to 39), 33 (30 to 37), and 32 (28 to 35) cases per million in 1991, 1999, and 2008, respectively. Oral streptococci IE incidence did not increase either in the whole patient population (8.1 [6.4 to 10.1], 6.3 [4.8 to 8.1], and 6.3 [4.9 to 8.0] in 1991, 1999, and 2008, respectively) or in patients with pre-existing native valve disease. The increased incidence of Staphylococcus aureus IE (5.2 [3.9 to 6.8], 6.8 [5.3 to 8.6], and 8.2 [6.6 to 10.2]) was not significant in the whole patient population (p = 0.228) but was significant in the subgroup of patients without previously known native valve disease (1.6 [0.9 to 2.7], 3.7 [2.6 to 5.1], and 4.1 [3.0 to 5.6]; p = 0.012). CONCLUSIONS: Scaling down antibiotic prophylaxis indications was not associated with an increased incidence of oral streptococcal IE. A focus on avoidance of S. aureus bacteremia in all patients, including those with no previously known valve disease, will be required to improve IE prevention.

Preeminence of Staphylococcus aureus in infective endocarditis: a 1-year population-based survey.

BACKGROUND: Observational studies showed that the profile of infective endocarditis (IE) significantly changed over the past decades. However, most studies involved referral centers. We conducted a population-based study to control for this referral bias. The objective was to update the description of characteristics of IE in France and to compare the profile of community-acquired versus healthcare-associated IE. METHODS: A prospective population-based observational study conducted in all medical facilities from 7 French regions (32% of French individuals aged ≥18 years) identified 497 adults with Duke-Li-definite IE who were first admitted to the hospital in 2008. Main measures included age-standardized and sex-standardized incidence of IE and multivariate Cox regression analysis for risk factors of in-hospital death. RESULTS: The age-standardized and sex-standardized annual incidence of IE was 33.8 (95% confidence interval [CI], 30.8-36.9) cases per million inhabitants. The incidence was highest in men aged 75-79 years. A majority of patients had no previously known heart disease. Staphylococci were the most common causal agents, accounting for 36.2% of cases (Staphylococcus aureus, 26.6%; coagulase-negative staphylococci, 9.7%). Healthcare-associated IE represented 26.7% of all cases and exhibited a clinical pattern significantly different from that of community-acquired IE. S. aureus as the causal agent of IE was the most important factor associated with in-hospital death in community-acquired IE (hazard ratio [HR], 2.82 [95% CI, 1.72-4.61]) and the single factor in healthcare-associated IE (HR, 2.54 [95% CI, 1.33-4.85]). CONCLUSIONS: S. aureus became both the leading cause and the most important prognostic factor of IE, and healthcare-associated IE appeared as a major subgroup of the disease.

Cerebral phaeohyphomycosis caused by Rhinocladiella mackenziei in a woman native to Afghanistan.

Rhinocladiella mackenziei is a recognized cause of endemic cerebral phaeohyphomycosis in the Middle East area. Surgical resection of the abscesses and posaconazole treatment have improved the ominous prognosis of this disease. We describe the case of a native Afghan woman living in France who presented with brain abscesses due to R. mackenziei.

Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases.

BACKGROUND. Blood culture-negative endocarditis (BCNE) may account for up to 31% of all cases of endocarditis. METHODS. We used a prospective, multimodal strategy incorporating serological, molecular, and histopathological assays to investigate specimens from 819 patients suspected of having BCNE. RESULTS. Diagnosis of endocarditis was first ruled out for 60 patients. Among 759 patients with BCNE, a causative microorganism was identified in 62.7%, and a noninfective etiology in 2.5%. Blood was the most useful specimen, providing a diagnosis for 47.7% of patients by serological analysis (mainly Q fever and Bartonella infections). Broad-range polymerase chain reaction (PCR) of blood and Bartonella-specific Western blot methods diagnosed 7 additional cases. PCR of valvular biopsies identified 109 more etiologies, mostly streptococci, Tropheryma whipplei, Bartonella species, and fungi. Primer extension enrichment reaction and autoimmunohistochemistry identified a microorganism in 5 additional patients. No virus or Chlamydia species were detected. A noninfective cause of endocarditis, particularly neoplasic or autoimmune disease, was determined by histological analysis or by searching for antinuclear antibodies in 19 (2.5%) of the patients. Our diagnostic strategy proved useful and sensitive for BCNE workup. CONCLUSIONS. We highlight the major role of zoonotic agents and the underestimated role of noninfective diseases in BCNE. We propose serological analysis for Coxiella burnetii and Bartonella species, detection of antinuclear antibodies and rheumatoid factor as first-line tests, followed by specific PCR assays for T. whipplei, Bartonella species, and fungi in blood. Broad-spectrum 16S and 18S ribosomal RNA PCR may be performed on valvular biopsies, when available.

Clinical and microbiologic features of multivalvular endocarditis.

Multivalvular endocarditis accounts for 15% of all endocarditis. The mechanisms of spread of the infection differs whether endocarditis is only left-sided (involving both the mitral and aortic valves) or bilateral. In left-sided bivalvular endocarditis, it is often a secondary mitral lesion following a primary aortic endocarditis. Multivalvular endocarditis often results in severe and extensive cardiac lesions, well described at echocardiography and frequently responsible for severe heart failure. Patients often need surgery, which consists of radical debridement of all the infected tissue with reconstruction using different types of prostheses; therefore, the surgery may be very complex. The goal should be an early diagnosis of endocarditis to avoid spread of the infection to more than one valve, to improve the prognosis for those patients.

Diabetes mellitus and infective endocarditis: the insulin factor in patient morbidity and mortality.

AIMS: To analyse the characteristics of infective endocarditis (IE) in patients with diabetes mellitus (DM), and to evaluate the prognostic significance of DM according to insulin use. METHODS AND RESULTS: A total of 559 patients with definite IE including 75 patients (13%) with DM (insulin use n = 22; oral antidiabetic n = 53) were evaluated. Comparison of insulin-DM, oral-DM, and non-DM patients showed an older age (66 +/- 13, 66 +/- 10, 58 +/- 17, respectively; P = 0.004) in DM patients, and more frequent IE on prosthetic valves (32, 11, and 15%, respectively; P = 0.068) in insulin-DM patients. Oral streptococci (0, 8, and 18%, respectively; P = 0.016) were less frequently the causative organism than staphylococci (64, 26, and 29%, respectively; P = 0.002) in insulin-DM patients. Vegetations, dehiscence, abscess, and regurgitation rates did not differ among the three groups, nor did cardiac surgery rates (32, 47, and 48%, respectively; P = 0.334), but in-hospital mortality was higher in insulin-DM patients (50, 19, and 15%; P < 0.001). In multivariable analysis, independently of other determinants of death (age, IE location, Staphylococcus aureus, history of heart failure, immunosuppression, creatinine serum), insulin-DM was a predictor of death (OR, 4.69; 95% CI, 1.77-12.44), whereas oral-DM was not. CONCLUSION: IE prognosis in insulin-DM patients is poor due to the coexistence of host and pathogen factors. Insulin-DM patients with IE may require specific management.

Molecular diagnosis of infective endocarditis by PCR amplification and direct sequencing of DNA from valve tissue.

We used broad-range eubacterial PCR amplification followed by direct sequencing to identify microbial pathogens in heart valve material from 29 patients with histologically confirmed infective endocarditis and 23 patients free of infective endocarditis. Microorganisms cultured by conventional techniques matched those identified by PCR in 21 cases. PCR alone identified the causative agent in three cases (Streptococcus bovis, Staphylococcus cohnii, and Coxiella burnetii), allowing better patient management. PCR corrected the initial bacteriological diagnosis in three cases (Streptococcus bovis, Streptococcus mutans, and Bartonella henselae). Among the 29 cases of histologically confirmed infective endocarditis, PCR findings were positive in 27 cases and were consistent with the bacterial morphology seen at Gram staining (26 cases) or with the results obtained by immunohistologic analysis with an anti-C. burnetii monoclonal antibody (one case). In two other cases of histologically confirmed infective endocarditis, PCR remained negative in a blood culture-negative case for which no bacteria were seen at histological analysis and in one case with visualization of cocci and blood cultures positive for Enterococcus faecalis. Ten clinical diagnoses of possible infective endocarditis were ruled out by histopathological analysis of the valves and subsequently by PCR. PCR was negative in 13 of the 14 patients in whom infective endocarditis was rejected on clinical grounds; the other patient was found to have Coxiella burnetii infective endocarditis on the basis of PCR and histopathological analysis and was subsequently included in the group of 29 definite cases. In total, PCR contributed to the diagnosis and management of infective endocarditis in 6 of 29 (20%) cases.