Polymorphisms in tumor necrosis factor-α increase susceptibility to intra-abdominal Candida infection in high-risk surgical ICU patients*.

OBJECTIVES: To evaluate the influence of genetic polymorphisms on the susceptibility to Candida colonization and intra-abdominal candidiasis, a blood culture-negative life-threatening infection in high-risk surgical ICU patients. DESIGN: Prospective observational cohort study. SETTING: Surgical ICUs from two University hospitals of the Fungal Infection Network of Switzerland. PATIENTS: Eighty-nine patients at high risk for intra-abdominal candidiasis (68 with recurrent gastrointestinal perforation and 21 with acute necrotizing pancreatitis). MEASUREMENTS AND MAIN RESULTS: Eighteen single-nucleotide polymorphisms in 16 genes previously associated with development of fungal infections were analyzed from patient's DNA by using an Illumina Veracode genotyping platform. Candida colonization was defined by recovery of Candida species from at least one nonsterile site by twice weekly monitoring of cultures from oropharynx, stools, urine, skin, and/or respiratory tract. A corrected colonization index greater than or equal to 0.4 defined "heavy" colonization. Intra-abdominal candidiasis was defined by the presence of clinical symptoms and signs of peritonitis or intra-abdominal abscess and isolation of Candida species either in pure or mixed culture from intraoperatively collected abdominal samples. Single-nucleotide polymorphisms in three innate immune genes were associated with development of a Candida corrected colonization index greater than or equal to 0.4 (Toll-like receptor rs4986790, hazard ratio = 3.39; 95% CI, 1.45-7.93; p = 0.005) or occurrence of intra-abdominal candidiasis (tumor necrosis factor-α rs1800629, hazard ratio = 4.31; 95% CI, 1.85-10.1; p= 0.0007; ß-defensin 1 rs1800972, hazard ratio = 3.21; 95% CI, 1.36-7.59; p = 0.008). CONCLUSION: We report a strong association between the promoter rs1800629 single-nucleotide polymorphism in tumor necrosis factor-α and an increased susceptibility to intra-abdominal candidiasis in a homogenous prospective cohort of high-risk surgical ICU patients. This finding highlights the relevance of the tumor necrosis factor-α functional polymorphism in immune response to fungal pathogens. Immunogenetic profiling in patients at clinical high risk followed by targeted antifungal interventions may improve the prevention or preemptive management of this life-threatening infection.

ß-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis.

RATIONALE: Life-threatening intraabdominal candidiasis (IAC) occurs in 30 to 40% of high-risk surgical intensive care unit (ICU) patients. Although early IAC diagnosis is crucial, blood cultures are negative, and the role of Candida score/colonization indexes is not established. OBJECTIVES: The aim of this prospective Fungal Infection Network of Switzerland (FUNGINOS) cohort study was to assess accuracy of 1,3-ß-d-glucan (BG) antigenemia for diagnosis of IAC. METHODS: Four hundred thirty-four consecutive adults with abdominal surgery or acute pancreatitis and ICU stay 72 hours or longer were screened: 89 (20.5%) at high risk for IAC were studied (68 recurrent gastrointestinal tract perforation, 21 acute necrotizing pancreatitis). Diagnostic accuracy of serum BG (Fungitell), Candida score, and colonization indexes was compared. MEASUREMENTS AND MAIN RESULTS: Fifty-eight of 89 (65%) patients were colonized by Candida; 29 of 89 (33%) presented IAC (27 of 29 with negative blood cultures). Nine hundred twenty-one sera were analyzed (9/patient): median BG was 253 pg/ml (46-9,557) in IAC versus 99 pg/ml (8-440) in colonization (P < 0.01). Sensitivity and specificity of two consecutive BG measurements greater than or equal to 80 pg/ml were 65 and 78%, respectively. In recurrent gastrointestinal tract perforation it was 75 and 77% versus 90 and 38% (Candida score ≥ 3), 79 and 34% (colonization index ≥ 0.5), and 54 and 63% (corrected colonization index ≥ 0.4), respectively. BG positivity anticipated IAC diagnosis (5 d) and antifungal therapy (6 d). Severe sepsis/septic shock and death occurred in 10 of 11 (91%) and 4 of 11 (36%) patients with BG 400 pg/ml or more versus 5 of 18 (28%, P = 0.002) and 1 of 18 (6%, P = 0.05) with BG measurement less than 400 pg/ml. ß-Glucan decreased in IAC responding to therapy and increased in nonresponse. CONCLUSIONS: BG antigenemia is superior to Candida score and colonization indexes and anticipates diagnosis of blood culture-negative IAC. This proof-of-concept observation in strictly selected high-risk surgical ICU patients deserves investigation of BG-driven preemptive therapy.

Left atrial appendage closure in very elderly patients in the French National Registry.

OBJECTIVE: Left atrial appendage closure (LAAC) is recommended to decrease the stroke risk in patients with atrial fibrillation and contraindications to anticoagulation. However, age-stratified data are scarce. The aim of this study was to provide information on the safety and efficacy of LAAC, with emphasis on the oldest patients. METHODS: A nationwide, prospective, multicentre, observational registry was established by 53 French cardiology centres in 2018-2021. The composite primary endpoint included ischaemic stroke, systemic embolism, and unexplained or cardiovascular death. Separate analyses were done in the groups <80 years and ≥80 years. RESULTS: Among the 1053 patients included, median age was 79.7 (73.6-84.3) years; 512 patients (48.6%) were aged ≥80 years. Procedure-related serious adverse events were non-significantly more common in octogenarians (7.0% vs 4.4% in patients aged <80 years, respectively; p=0.07). Despite a higher mean CHA2DS2-VASc score in octogenarians, the rate of thromboembolic events during the study was similar in both groups (3.0 vs 3.1/100 patient-years; p=0.85). By contrast, all-cause mortality was significantly higher in octogenarians (15.3 vs 10.1/100 patient-years, p<0.015), due to a higher rate of non-cardiovascular deaths (8.2 vs 4.9/100 patient-years, p=0.034). The rate of the primary endpoint was 8.1/100 patient-years overall with no statistically significant difference between age groups (9.4 and 7.0/100 patient-years; p=0.19). CONCLUSION: Despite a higher mean CHA2DS2-VASc score in octogenarians, the rate of thromboembolic events after LAAC in this age group was similar to that in patients aged <80 years. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03434015).

Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections.

BACKGROUND: Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes. METHODS: A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses. RESULTS: A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour(-1), and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300-400 mg twice-daily oral doses and 200-300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68%-78% for the oral regimen and 70%-87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19%-29% for the oral regimen and 18%-37% for the intravenous regimen. CONCLUSIONS: Higher oral than intravenous VRC doses, followed by individualized adjustments based on measured plasma concentrations, improve achievement of the therapeutic target that maximizes the probability of therapeutic response and minimizes the probability of neurotoxicity. These findings challenge dose recommendations for VRC.

Outbreak of Mycobacterium haemophilum infections after permanent makeup of the eyebrows.

We report a Mycobacterium haemophilum outbreak after permanent make-up of the eyebrows performed by the same freelance artist. Twelve patients presented an eyebrow lesion and cervical lymphadenitis. All were treated with antibiotics. Surgery was required in 10 cases. M. haemophilum DNA was identified in the make-up ink.

Multicenter, prospective clinical evaluation of respiratory samples from subjects at risk for Pneumocystis jirovecii infection by use of a commercial real-time PCR assay.

Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection. Microscopic diagnosis, including diagnosis using the Merifluor-Pneumocystis direct fluorescent antigen (MP-DFA) test, has limitations. Real-time PCR may assist in diagnosis, but no commercially validated real-time PCR assay has been available to date. MycAssay Pneumocystis is a commercial assay that targets the P. jirovecii mitochondrial large subunit (analytical detection limit, ≤ 3.5 copies/µl of sample). A multicenter trial recruited 110 subjects: 54 with transplants (40 with lung transplants), 32 with nonmalignant conditions, 13 with leukemia, and 11 with solid tumors; 9 were HIV positive. A total of 110 respiratory samples (92% of which were bronchoalveolar lavage [BAL] specimens) were analyzed by PCR. Performance was characterized relative to investigator-determined clinical diagnosis of PCP (including local diagnostic tests), and PCR results were compared with MP-DFA test results for 83 subjects. Thirteen of 14 subjects with PCP and 9/96 without PCP (including 5 undergoing BAL surveillance after lung transplantation) had positive PCR results; sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were 93%, 91%, 59%, and 99%, respectively. Fourteen of 83 subjects for whom PCR and MP-DFA test results were available had PCP; PCR sensitivity, specificity, PPV, and NPV were 93%, 90%, 65%, and 98%, respectively, and MP-DFA test sensitivity, specificity, PPV, and NPV were 93%, 100%, 100%, and 98%. Of the 9 PCR-positive subjects without PCP, 1 later developed PCP. The PCR diagnostic assay compares well with clinical diagnosis using nonmolecular methods. Additional positive results compared with the MP-DFA test may reflect low-level infection or colonization.

Natural variability of in vitro adherence to fibrinogen and fibronectin does not correlate with in vivo infectivity of Staphylococcus aureus.

Adherence to fibrinogen and fibronectin plays a crucial role in Staphylococcus aureus experimental endocarditis. Previous genetic studies have shown that infection and carriage isolates do not systematically differ in their virulence-related genes, including genes conferring adherence, such as clfA and fnbA. We set out to determine the range of adherence phenotypes in carriage isolates of S. aureus, to compare the adherence of these isolates to the adherence of infection isolates, and to determine the relationship between adherence and infectivity in a rat model of experimental endocarditis. A total of 133 healthy carriage isolates were screened for in vitro adherence to fibrinogen and fibronectin, and 30 isolates were randomly chosen for further investigation. These 30 isolates were compared to 30 infective endocarditis isolates and 30 blood culture isolates. The infectivities of the carriage isolates, which displayed either extremely low or high adherence to fibrinogen and fibronectin, were tested using a rat model of experimental endocarditis. The levels of adherence to both fibrinogen and fibronectin were very similar for isolates from healthy carriers and members of the two groups of infection isolates. All three groups of isolates showed a wide range of adherence to fibrinogen and fibronectin. Moreover, the carriage isolates that showed minimal adherence and the carriage isolates that showed strong adherence had the same infectivity in experimental endocarditis. Adherence was proven to be important for pathogenesis in experimental endocarditis, but even the least adherent carriage strains had the ability to induce infection. We discuss the roles of differential gene expression, human host factors, and gene redundancy in resolving this apparent paradox.

Interhuman transmission as a potential key parameter for geographical variation in the prevalence of Pneumocystis jirovecii dihydropteroate synthase mutations.

BACKGROUND: Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations are associated with failure of prophylaxis with sulfa drugs. This retrospective study sought to better understand the geographical variation in the prevalence of these mutations. METHODS: DHPS polymorphisms in 394 clinical specimens from immunosuppressed patients who received a diagnosis of P. jirovecii pneumonia and who were hospitalized in 3 European cities were examined using polymerase chain reaction (PCR) single-strand conformation polymorphism. Demographic and clinical characteristics were obtained from patients' medical charts. RESULTS: Of the 394 patients, 79 (20%) were infected with a P. jirovecii strain harboring one or both of the previously reported DHPS mutations. The prevalence of DHPS mutations was significantly higher in Lyon than in Switzerland (33.0% vs 7.5%; P < .001). The proportion of patients with no evidence of sulfa exposure who harbored a mutant P. jirovecii DHPS genotype was significantly higher in Lyon than in Switzerland (29.7% vs 3.0%; P < .001). During the study period in Lyon, in contrast to the Swiss hospitals, measures to prevent dissemination of P. jirovecii from patients with P. jirovecii pneumonia were generally not implemented, and most patients received suboptimal prophylaxis, the failure of which was strictly associated with mutated P. jirovecii. Thus, nosocomial interhuman transmission of mutated strains directly or indirectly from other individuals in whom selection of mutants occurred may explain the high proportion of mutations without sulfa exposure in Lyon. CONCLUSIONS: Interhuman transmission of P. jirovecii, rather than selection pressure by sulfa prophylaxis, may play a predominant role in the geographical variation in the prevalence in the P. jirovecii DHPS mutations.

Multiplex ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification in human plasma of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, anidulafungin, and caspofungin.

Therapeutic drug monitoring (TDM) may contribute to optimizing the efficacy and safety of antifungal therapy because of the large variability in drug pharmacokinetics. Rapid, sensitive, and selective laboratory methods are needed for efficient TDM. Quantification of several antifungals in a single analytical run may best fulfill these requirements. We therefore developed a multiplex ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method requiring 100 µl of plasma for simultaneous quantification within 7 min of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, caspofungin, and anidulafungin. Protein precipitation with acetonitrile was used in a single extraction procedure for eight analytes. After reverse-phase chromatographic separation, antifungals were quantified by electrospray ionization-triple-quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. Deuterated isotopic compounds of azole antifungals were used as internal standards. The method was validated based on FDA recommendations, including assessment of extraction yields, matrix effect variability (<9.2%), and analytical recovery (80.1 to 107%). The method is sensitive (lower limits of azole quantification, 0.01 to 0.1 µg/ml; those of echinocandin quantification, 0.06 to 0.1 µg/ml), accurate (intra- and interassay biases of -9.9 to +5% and -4.0 to +8.8%, respectively), and precise (intra- and interassay coefficients of variation of 1.2 to 11.1% and 1.2 to 8.9%, respectively) over clinical concentration ranges (upper limits of quantification, 5 to 50 µg/ml). Thus, we developed a simple, rapid, and robust multiplex UPLC-MS/MS assay for simultaneous quantification of plasma concentrations of six antifungals and two metabolites. This offers, by optimized and cost-effective lab resource utilization, an efficient tool for daily routine TDM aimed at maximizing the real-time efficacy and safety of different recommended single-drug antifungal regimens and combination salvage therapies, as well as a tool for clinical research.

Ultra-performance liquid chromatography mass spectrometry and sensitive bioassay methods for quantification of posaconazole plasma concentrations after oral dosing.

Posaconazole (POS) is a new antifungal agent for prevention and therapy of mycoses in immunocompromised patients. Variable POS pharmacokinetics after oral dosing may influence efficacy: a trough threshold of 0.5 µg/ml has been recently proposed. Measurement of POS plasma concentrations by complex chromatographic techniques may thus contribute to optimize prevention and management of life-threatening infections. No microbiological analytical method is available. The objective of this study was to develop and validate a new simplified ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method and a sensitive bioassay for quantification of POS over the clinical plasma concentration range. The UPLC-MS/MS equipment consisted of a triple quadrupole mass spectrometer, an electrospray ionization (ESI) source, and a C(18) analytical column. The Candida albicans POS-hypersusceptible mutant (MIC of 0.002 µg/ml) Δcdr1 Δcdr2 Δflu Δmdr1 Δcan constructed by targeted deletion of multidrug efflux transporters and calcineurin genes was used for the bioassay. POS was extracted from plasma by protein precipitation with acetonitrile-methanol (75%/25%, vol/vol). Reproducible standard curves were obtained over the range 0.014 to 12 (UPLC-MS/MS) and 0.028 to 12 µg/ml (bioassay). Intra- and interrun accuracy levels were 106% ± 2% and 103% ± 4% for UPLC-MS/MS and 102% ± 8% and 104% ± 1% for bioassay, respectively. The intra- and interrun coefficients of variation were 7% ± 4% and 7% ± 3% for UPLC-MS/MS and 5% ± 3% and 4% ± 2% for bioassay, respectively. An excellent correlation between POS plasma concentrations measured by UPLC-MS/MS and bioassay was found (concordance, 0.96). In 26 hemato-oncological patients receiving oral POS, 27/69 (39%) trough plasma concentrations were lower than 0.5 µg/ml. The UPLC-MS/MS method and sensitive bioassay offer alternative tools for accurate and precise quantification of the plasma concentrations in patients receiving oral posaconazole.

False-negative PCR result due to gene polymorphism: the example of Neisseria meningitidis.

Early treatment of meningococcal meningitis is mandatory but may negate the cerebrospinal fluid culture. Etiological diagnosis then mainly relies on PCR. Here, we report a case of false-negative results for real-time PCR for a Neisseria meningitidis serogroup B isolate with a polymorphism in the ctrA gene.

Matrix-assisted laser desorption ionization-time of flight mass spectrometry for direct bacterial identification from positive blood culture pellets.

An ammonium chloride erythrocyte-lysing procedure was used to prepare a bacterial pellet from positive blood cultures for direct matrix-assisted laser desorption-ionization time of flight (MALDI-TOF) mass spectrometry analysis. Identification was obtained for 78.7% of the pellets tested. Moreover, 99% of the MALDI-TOF identifications were congruent at the species level when considering valid scores. This fast and accurate method is promising.

Molecular detection and identification of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation.

The present study was performed to assess the interlaboratory reproducibility of the molecular detection and identification of species of Zygomycetes from formalin-fixed paraffin-embedded kidney and brain tissues obtained from experimentally infected mice. Animals were infected with one of five species (Rhizopus oryzae, Rhizopus microsporus, Lichtheimia corymbifera, Rhizomucor pusillus, and Mucor circinelloides). Samples with 1, 10, or 30 slide cuts of the tissues were prepared from each paraffin block, the sample identities were blinded for analysis, and the samples were mailed to each of seven laboratories for the assessment of sensitivity. A protocol describing the extraction method and the PCR amplification procedure was provided. The internal transcribed spacer 1 (ITS1) region was amplified by PCR with the fungal universal primers ITS1 and ITS2 and sequenced. As negative results were obtained for 93% of the tissue specimens infected by M. circinelloides, the data for this species were excluded from the analysis. Positive PCR results were obtained for 93% (52/56), 89% (50/56), and 27% (15/56) of the samples with 30, 10, and 1 slide cuts, respectively. There were minor differences, depending on the organ tissue, fungal species, and laboratory. Correct species identification was possible for 100% (30 cuts), 98% (10 cuts), and 93% (1 cut) of the cases. With the protocol used in the present study, the interlaboratory reproducibility of ITS sequencing for the identification of major Zygomycetes species from formalin-fixed paraffin-embedded tissues can reach 100%, when enough material is available.

New nonculture-based methods for the diagnosis of invasive candidiasis.

PURPOSE OF REVIEW: Invasive candidiasis is a severe infectious complication occurring mostly in onco-hematologic and surgical patients. Its conventional diagnosis is insensitive and often late, leading to a delayed treatment and a high mortality. The purpose of this article is to review recent contributions in the nonconventional diagnostic approaches of invasive candidiasis, both for the detection of the epidose and the characterization of the etiologic agent. RECENT FINDINGS: Antigen-based tests to detect invasive candidiasis comprise a specific test, mannan, as well as a nonspecific test, beta-D-glucan. Both have a moderate sensitivity and a high specificity, and cannot be recommended alone as a negative screening tool or a positive syndrome driven diagnostic tool. Molecular-based tests still have not reached the stage of rapid, easy to use, standardized tests ideally complementing blood culture at the time of blood sampling. New tests (fluorescence in-situ hybridization or mass spectrometry) significantly reduce the delay of identification of Candida at the species level in positive blood cultures, and should have a positive impact on earlier appropriate antifungal therapy and possibly on outcome. SUMMARY: Both antigen-based and molecular tests appear as promising new tools to complement and accelerate the conventional diagnosis of invasive candidiasis with an expected significant impact on earlier and more focused treatment and on prognosis.

MAPT (Mono Antiplatelet Therapy) as Regular Regimen After COBRA PzF™ NanoCoated Coronary Stent (NCS) Implantation.

AIMS: To report procedural and 1-year outcomes following COBRA PzF NCS implantation in a routine daily setting with high bleeding risk (HBR) patients treated with clopidogrel as mono antiplatelet therapy (MAPT). METHODS: This is a prospective, consecutive, observational study in HBR patients who underwent PCI with COBRA PzF NCS and treated with clopidogrel alone at discharge. The primary endpoint was definite stent thrombosis at one month. The secondary endpoint was MACE (Cardiac Death, myocardial infarction (MI), target lesion revascularization (TLR)) at 12 months. RESULTS: From October 2015 to December 2018, 77 patients with 120 lesions were enrolled and treated. Mean age was 78.7 ±â€¯8.89 years, 58.5% men and 18.2% had ACS. Patients included had a minimum of 2.0 inclusion LEADERS FREE criteria. Angiographic success was achieved in all cases. The primary endpoint occurred in 0%, no stent thrombosis was occurred. MACE at 12-months (available for 52 patients) was 3.8% including cardiac death 0%, MI 0% and TLR 3.8%. No severe bleeding events (BARC3-5) or stroke or late stent thrombosis were noted. CONCLUSION: Clopidogrel as MAPT after COBRA PzF NCS implantation in HBR patients is feasible and an attractive option. One-year follow-up was associated with excellent clinical outcomes and should be confirmed with large randomised study. CONDENSED ABSTRACT: This is prospective registry of high bleeding risk patients treated with the COBRA PzF NCS and MAPT at discharge. The primary end point demonstrated no stent thrombosis. The rate of major cardiac adverse events (a composite of cardiovascular death, myocardial infarction and target lesion revascularisation) at 1 year was 3.8%. No severe bleeding events, stroke or late stent thrombosis were noted. One-year follow-up was associated with good clinical outcomes and compared favorably with current devices.

Etiology of community-acquired pneumonia in hospitalized children based on WHO clinical guidelines.

Community-acquired pneumonia (CAP) is a major cause of death in developing countries and of morbidity in developed countries. The objective of the study was to define the causative agents among children hospitalized for CAP defined by WHO guidelines and to correlate etiology with clinical severity and surrogate markers. Investigations included an extensive etiological workup. A potential causative agent was detected in 86% of the 99 enrolled patients, with evidence of bacterial (53%), viral (67%), and mixed (33%) infections. Streptococcus pneumoniae was accounted for in 46% of CAP. Dehydration was the only clinical sign associated with bacterial pneumonia. CRP and PCT were significantly higher in bacterial infections. Increasing the number of diagnostic tests identifies potential causes of CAP in up to 86% of children, indicating a high prevalence of viruses and frequent co-infections. The high proportion of pneumococcal infections re-emphasizes the importance of pneumococcal immunization.

[Doctor, I have a lymph node]. / Docteur, j'ai un ganglion.

To investigate a recently developed lymphadenopathy can be simple or complex. The medical history, presence or not of symptoms, the general physical examination, and the localization and characteristics of the adenopathy, most often lead to a diagnosis and therapy when indicated. Among young adults, the etiology is either infectious or reactive, rarely tumoral, as opposed to elderly persons. The most important step is to look at signs of severity (or non banality) such as an increased size, hard consistency, supra-clavicular location, an immunocompromised host, a history of Tb exposition. If present, these signs will trigger a biopsy with cyto- or histopathological examination mostly to rule out a malignant tumor. This article reviews the practical steps of an investigation of an isolated adenopathy in an adult patient.

Femoral Versus Nonfemoral Peripheral Access for Transcatheter Aortic Valve Replacement.

BACKGROUND: Femoral access is the gold standard for transcatheter aortic valve replacement (TAVR). Guidelines recommend reconsidering surgery when this access is not feasible. However, alternative peripheral accesses exist, although they have not been accurately compared with femoral access. OBJECTIVES: This study compared nonfemoral peripheral (n-FP) TAVR with femoral TAVR. METHODS: Using the data from the national prospective French registry (FRANCE TAVI [French Transcatheter Aortic Valve Implantation]), this study compared the characteristics and outcomes of TAVR procedures according to whether they were performed through a femoral or a n-FP access, using a pre-specified propensity score-based matching between groups. Subanalysis during 2 study periods (2013 to 2015 and 2016 to 2017) and among low/intermediate-low and intermediate-high/high volume centers were performed. RESULTS: Among 21,611 patients, 19,995 (92.5%) underwent femoral TAVR and 1,616 (7.5%) underwent n-FP TAVR (transcarotid, n = 914 or trans-subclavian, n = 702). Patients in the n-FP access group had more severe disease (mean logistic EuroSCORE 19.95 vs. 16.95; p < 0.001), with a higher rate of peripheral vascular disease, known coronary artery disease, chronic pulmonary disease, and renal failure. After matching, there was no difference in the rate of post-procedural death and complications according to access site, except for a 2-fold lower rate of major vascular complications (odds ratio: 0.45; 95% confidence interval: 0.21 to 0.93; p = 0.032) and unplanned vascular repairs (odds ratio: 0.41; 95% confidence interval: 0.29 to 0.59; p < 0.001) in those who underwent n-FP access. The comparison of outcomes provided similar results during the second study period and in intermediate-high/high volume centers. CONCLUSIONS: n-FP TAVR is associated with similar outcomes compared with femoral peripheral TAVR, except for a 2-fold lower rate of major vascular complications and unplanned vascular repairs. n-FP TAVR may be favored over surgery in patients who are deemed ineligible for femoral TAVR and may be a safe alternative when femoral access risk is considered too high.

Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.

BACKGROUND: Voriconazole is the therapy of choice for aspergillosis and a new treatment option for candidiasis. Liver disease, age, genetic polymorphism of the cytochrome CYP2C19, and comedications influence voriconazole metabolism. Large variations in voriconazole pharmacokinetics may be associated with decreased efficacy or with toxicity. METHODS: This study was conducted to assess the utility of measuring voriconazole blood levels with individualized dose adjustments. RESULTS: A total of 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A large variability in voriconazole trough blood levels was observed, ranging from 5.5 mg/L (a level possibly associated with toxicity) in 31% of cases. Lack of response to therapy was more frequent in patients with voriconazole levels 1 mg/L (15 [12%] of 39 patients; P=.02). Blood levels >1 mg/L were reached after increasing the voriconazole dosage, with complete resolution of infection in all 6 cases. Among 16 patients with voriconazole trough blood levels >5.5 mg/L, 5 patients (31%) presented with an encephalopathy, including 4 patients who were treated intravenously with a median voriconazole dosage of 8 mg/kg per day, whereas none of the patients with levels

Candida arteritis in patients who have not received organ transplants: case report and review of the literature.

Fungal arteritis is a rare entity, associated with significant morbidity and mortality, that typically involves graft arteries in solid organ transplant recipients. Here, we report the first case of Candida carotid arteritis and review 22 other cases of Candida arteritis reported since 1966 in patients who have not received transplants. Most patients had serious underlying conditions. All cases were anatomically characterized by pseudoaneurysm formation. Patients presented with fever (n=7), local pain (n=13), and an expanding pulsatile mass (n=4), with subsequent rupture and hemorrhage (n=7). Evidence of Candida colonization or infection was present in 15 patients before arteritis occurred. Treatment typically included a combined surgical and antifungal approach. The outcome was favorable in 11 patients, but follow-up was limited. A high index of suspicion, early diagnosis, and prompt antifungal and surgical treatment seem crucial to efforts to avoid life-threatening arterial rupture and hemorrhage.