Features of cryptococcosis among 652 HIV-seronegative individuals in France: a cross-sectional observational study (2005-2020).

OBJECTIVES: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France. METHODS: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality. RESULTS: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). Solid-organ transplant patients were most likely to have disseminated infections and a positive serum cryptococcal antigen result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265; p 0.029). The crude 90-day case-fatality ratio was 27.2% (95% CI, 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26]; p < 0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7]; p 0.002), and malignancy (aOR: 2.4 [1.14-5.07]; p 0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71]; p 0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80]; p 0.006). DISCUSSION: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management.

Cryptococcus neoformans Infections Differ Among Human Immunodeficiency Virus (HIV)-Seropositive and HIV-Seronegative Individuals: Results From a Nationwide Surveillance Program in France.

Among 1107 cryptococcosis cases from the French surveillance network (2005-2020), the proportion of HIV-seronegative individuals has recently surpassed that of HIV-seropositive individuals. We observed marked differences in patient characteristics, disease presentations, cryptococcal antigen results, infecting species, and mortality according to HIV serostatus.

Favorable outcome without corticosteroids during post-artesunate delayed hemolysis with positive direct antiglobulin test in severe imported Plasmodium falciparum malaria, France.

OBJECTIVES: Positive direct antiglobulin tests (DATs) have been reported in cases of post-artesunate delayed hemolysis (PADH), but the causal role of auto-immune hemolysis remains unclear. We aimed to analyze a cohort of patients with PADH and DAT during severe malaria. METHODS: We describe PADH and DAT results in a 7-year multi-center retrospective cohort of patients receiving artesunate for severe imported malaria. RESULTS: Of 337 patients treated with artesunate, 46 (13.6%) had at least one DAT result within 30 days of treatment initiation, and 25/46 (54.3%) had at least one positive DAT. Among 40 patients with available data, 17 (42.5%) experienced PADH. Patient characteristics were similar for patients with a positive or negative DAT, and DAT positivity was not associated with PADH occurrence (P = 0.36). Among patients, 5/13 (38.5%) with a positive DAT after day 7 experienced PADH, compared to 10/13 (76.9%) of those with a negative DAT after day 7 (P = 0.11). Overall, 41% of patients required blood transfusions, and outcome was favorable without corticosteroids, even in cases of PADH. CONCLUSIONS: DAT does not appear to be a marker of PADH, but rather an indirect marker of an immune-mediated mechanism. DAT positivity should not lead to the administration of systemic corticosteroids during PADH.

Improving Diagnosis of Pulmonary Mucormycosis: Leads From a Contemporary National Study of 114 Cases.

BACKGROUND: Pulmonary mucormycosis (PM) is a life-threatening invasive mold infection. Diagnosis of mucormycosis is challenging and often delayed, resulting in higher mortality. RESEARCH QUESTION: Are the disease presentation of PM and contribution of diagnosis tools influenced by the patient's underlying condition? STUDY DESIGN AND METHODS: All PM cases from six French teaching hospitals between 2008 and 2019 were retrospectively reviewed. Cases were defined according to updated European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria with the addition of diabetes and trauma as host factors and positive serum or tissue PCR as mycologic evidence. Thoracic CT scans were reviewed centrally. RESULTS: A total of 114 cases of PM were recorded, including 40% with disseminated forms. Main underlying conditions were hematologic malignancy (49%), allogeneic hematopoietic stem cell transplantation (21%), and solid organ transplantation (17%). When disseminated, main dissemination sites were the liver (48%), spleen (48%), brain (44%), and kidneys (37%). Radiologic presentation included consolidation (58%), pleural effusion (52%), reversed halo sign (26%), halo sign (24%), vascular abnormalities (26%), and cavity (23%). Serum quantitative polymerase chain reaction (qPCR) was positive in 42 (79%) of 53 patients and BAL in 46 (50%) of 96 patients. Results of transthoracic lung biopsy were diagnostic in 8 (73%) of 11 patients with noncontributive BAL. Overall 90-day mortality was 59%. Patients with neutropenia more frequently displayed an angioinvasive presentation, including reversed halo sign and disseminated disease (P < .05). Serum qPCR was more contributive in patients with neutropenia (91% vs 62%; P = .02), and BAL was more contributive in patients without neutropenia (69% vs 41%; P = .02). Serum qPCR was more frequently positive in patients with a > 3 cm main lesion (91% vs 62%; P = .02). Overall, positive qPCR was associated with an early diagnosis (P = .03) and treatment onset (P = .01). INTERPRETATION: Neutropenia and radiologic findings influence disease presentation and contribution of diagnostic tools during PM. Serum qPCR is more contributive in patients with neutropenia and BAL examination in patients without neutropenia. Results of lung biopsies are highly contributive in cases of noncontributive BAL.

Effectiveness of third-generation cephalosporins or piperacillin compared with cefepime or carbapenems for severe infections caused by wild-type AmpC ß-lactamase-producing Enterobacterales: A multi-centre retrospective propensity-weighted study.

BACKGROUND: The optimal treatment regimen for infections caused by wild-type AmpC ß-lactamase-producing Enterobacterales remains controversial. This study compared the outcomes of bloodstream infections (BSI) and pneumonia according to the type of definitive antibiotic therapy: third-generation cephalosporin (3GC), piperacillin ± tazobactam, cefepime or carbapenem. METHODS: All cases of BSI and pneumonia caused by wild-type AmpC ß-lactamase-producing Enterobacterales over 2 years in eight university hospitals were reviewed. Patients who received definitive therapy consisting of either a 3GC (3GC group), piperacillin ± tazobactam (piperacillin group), or cefepime or a carbapenem (reference group) were included in this study. The primary endpoint was 30-day all-cause mortality. The secondary endpoint was treatment failure due to infection by emerging AmpC-overproducing strains. Propensity-score-based models were used to balance confounding factors between groups. RESULTS: In total, 575 patients were included in this study: 302 (52%) with pneumonia and 273 (48%) with BSI. Half (n=271, 47%) received cefepime or a carbapenem as definitive therapy, 120 (21%) received a 3GC, and 184 (32%) received piperacillin ± tazobactam. Compared with the reference group, 30-day mortality was similar in the 3GC [adjusted hazard ratio (aHR) 0.86, 95% confidence interval (CI) 0.57-1.31)] and piperacillin (aHR 1.20, 95% CI 0.86-1.66) groups. The likelihood of treatment failure was higher in the 3GC (aHR 6.81, 95% CI 3.76-12.4) and piperacillin (aHR 3.13, 95% CI 1.69-5.80) groups. The results were similar when stratifying the analysis on pneumonia or BSI. CONCLUSION: Treatment of included BSI or pneumonia caused by wild-type AmpC ß-lactamase-producing Enterobacterales with 3GC or piperacillin ± tazobactam was not associated with higher mortality, but was associated with increased risk of AmpC overproduction leading to treatment failure compared with cefepime or a carbapenem.

Impact of prior cryptococcal antigen screening on in-hospital mortality in cryptococcal meningitis or fungaemia among HIV-seropositive individuals in South Africa: a cross-sectional observational study.

OBJECTIVES: We investigated whether patients with cryptococcal meningitis (CM) or fungaemia detected through South Africa's laboratory cryptococcal antigen (CrAg) screening programme had better outcomes than those presenting directly to the hospital. METHODS: We compared 14-day in-hospital case-fatality ratios of HIV-seropositive individuals with CD4 counts below 100 cells/µL and laboratory-confirmed CM/fungaemia from 2017-2021, with or without evidence of a positive blood CrAg test within 14 days prior to diagnosis. We evaluated whether the impact of prior CrAg screening on mortality varied according to the study period (pre-COVID-19: before March 2020 vs. COVID-19: after March 2020). RESULTS: Overall, 24.5% (830/3390) of patients had a prior positive CrAg test within 14 days of diagnosis. CrAg-screened patients were less likely to have an altered mental status at baseline than non-CrAg-screened patients (38.1% [296/776] vs. 42.6% [1010/2372], p = 0.03), and had a lower crude 14-day case-fatality ratio (24.7% [205/830] vs. 28.3% [724/2560]; OR, 0.83 [95% CI, 0.69-0.99]; p = 0.045). Previous CrAg screening was associated with a greater reduction in the crude 14-day mortality during the COVID-19 period (OR, 0.64 [0.47-0.87]; p = 0.005) compared with before (OR, 0.95 [0.76-1.19]; p = 0.68). After adjustment, previous CrAg screening within 14 days was associated with increased survival only during the COVID-19 period (adjusted OR, 0.70 [0.51-0.96]; p = 0.03). DISCUSSION: Previous CrAg screening was associated with a survival benefit in patients hospitalized with CM/fungaemia during the COVID-19 period, with fewer patients having an altered mental status at baseline, suggesting that these patients may have been diagnosed with cryptococcosis earlier.

Main human inborn errors of immunity leading to fungal infections.

BACKGROUND: The host's molecular and genetic features are essential in providing susceptibility to a broad spectrum of fungal infections; most of these do not cause disease in healthy individuals because of mutual benefits with opportunistic fungi besides the host's capacity to control the infections. In contrast, patients with primary immunodeficiency can develop mild superficial to life-threatening invasive infections. In the last years, thanks to next-generation sequencing, several inborn-error variants have been discovered in genes encoding protein acting against fungal infections, contributing to better defining the role of innate and adaptive immunity cooperation during infection resolution. Candida fungal infection that sometimes strikes healthy subjects is responsible for the chronic mucocutaneous candidiasis that is one of the principal clinical manifestations occurring in several rare primary immunodeficiencies associated with an inborn error of interleukin-17 (IL-17) immunity. OBJECTIVE: This review aimed to provide an overview of chronic mucocutaneous candidiasis-derived genetic defects, including IL17 deficiencies (IL17A, IL17F, IL17RA, IL17RC), STAT1 gain-of-function deficiency, STAT3 hyper-IgE syndrome, and CARD9 deficiency. SOURCES: We carried out detailed research work to identify interesting articles, commentaries, and reviews in the PubMed literature to ensure a correct and updated narrative review. CONTENT: We propose an in-depth description and an update of genetic and cellular mechanisms underlying fungal infections, focusing on the IL17-mediated response, a report of clinical manifestations, and a description of therapeutic options. IMPLICATIONS: This narrative review will help clinician to identify the correct management of patients based on molecular and cellular findings underlying pathogenic mechanisms of different inborn errors of immunity. Moreover, enabling clinicians to achieve the genetic diagnosis will be useful to offer genetic counselling intra- and inter-family and to ensure a personalised treatment of patients.

Invasive Rhinosinusitis Caused by Alternaria infectoria in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature.

Phaeohyphomycoses comprise a heterogeneous group of fungal infections caused by dematiaceous fungi and have primarily been reported in patients with underlying acquired immunodeficiencies, such as hematological malignancies or solid-organ transplants. Over the past decade, a growing number of patients with phaeohyphomycosis but otherwise healthy were reported with autosomal recessive (AR) CARD9 deficiency. We report a 28-year-old woman who presented with invasive rhinosinusitis caused by Alternaria infectoria. Following a candidate gene sequencing approach, we identified a biallelic loss-of-function mutation of CARD9, thereby further broadening the spectrum of invasive fungal diseases found in patients with inherited CARD9 deficiency. In addition, we reviewed 17 other cases of phaeohyphomycosis associated with AR CARD9 deficiency. Physicians should maintain a high degree of suspicion for inborn errors of immunity, namely CARD9 deficiency, when caring for previously healthy patients with phaeohyphomycosis, regardless of age at first presentation.

Dual beta-lactam treatment: Pros and cons.

The battle against microscopic pathogens has always baffled the scientific community. Nowadays, multidrug-resistant microorganisms lead to high in-hospital mortality, increased hospital stays, and high health-related costs. Treating infections due to these high-resistance pathogens with a low number of antibiotic molecules creates the need for new strategies. Although some already think of a "postantibiotic era" with bacteriophages as the main futuristic weapon in antibacterial armament, others rethink the usage of the already existent drugs. Dual beta-lactam therapy has been used for quite some time as an empirical therapy for some severe infections such as endocarditis or meningitis. However, studies regarding the use of a beta-lactam combination stopped being made a long time ago, and it seems the scientific community has no interest in evaluating this as a treatment option. Could this strategy be applied to treat infections due to multidrug-resistant bacteria? Could this be the answer while waiting for the "postantibiotic era"? What kind of pathogens could we fight using dual beta-lactams? What are the downsides of this strategy? These are some of the questions the authors try to answer in this review. In addition, we try to convince our peers to turn once more into researching beta-lactam combinations and exploring its potential benefits.

Prevalence of Antimicrobial Resistance and Infectious Diseases in a Hospitalised Migrant Population in Paris, France, a Retrospective Study.

Objectives: The aim of this study was to estimate the prevalence of anti-microbial resistance (AMR) carriage and its risk factors in hospitalized migrants. Additionally, the prevalence of infectious diseases was evaluated, as well as symptoms of psychological trauma. Methods: We conducted a retrospective monocentric cross-sectional study including all migrant patients recently arrived and hospitalised over a one-year period. Results: Among 101 patients, seventy-nine percent originated from Sub-Saharan Africa. The overall AMR carriage rate was 20.7% [95% CI: 12.4; 28.9%]. We isolated 5/92 methicillin-resistant Staphylococcus aureus strains (5.4%) and 15/92 extended-spectrum beta-lactamase-producing Enterobacteriaceae (16.4%). AMR carriage was associated with older age, region of origin and length of migration. Rates of HIV, HBV, and HCV infection were 39.6%, 32.7%, and 5%, reflecting sampling bias linked to reasons for hospitalization. Eleven percent had serological evidence of treponemasis and 7.8% had Chlamydia trachomatis infection. Symptoms of depression or post-traumatic stress disorder were observed for more than half the patients. Conclusion: It appears essential to offer a systematic and comprehensive post-arrival screening of AMR carriage, infectious diseases and psychological trauma to subjects who experienced migration.

Simple and accurate quantitative analysis of cefiderocol and ceftobiprole in human plasma using liquid chromatography-isotope dilution tandem mass spectrometry: interest for their therapeutic drug monitoring and pharmacokinetic studies.

OBJECTIVES: Cefiderocol and ceftobiprole are new generation cephalosporin antibiotics that exhibit high inter-individual plasma concentration variability that potentially impact their efficacy or toxicity. The aim of this study was to develop and validate a selective, simple, and fast UPLC-MS/MS method for simultaneous quantification of cefiderocol and ceftobiprole in human plasma to enable their therapeutic drug monitoring (TDM) and support PK and PK/PD studies, in particular in critically ill patients. METHODS: After a simple and fast single-step protein precipitation, cefiderocol and ceftobiprole were separated on a Waters Acquity UPLC BEH C18 column by linear gradient elution; with subsequent detection by Shimadzu MS 8060 triple quadrupole tandem mass spectrometer in a positive ionization mode. RESULTS: Analysis time was 5 min per run. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect (ME), extraction recovery (ER), limit of quantification, dilution integrity, and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-200 mg/L for cefiderocol and 0.5-100 mg/L for ceftobiprole with a linear regression coefficient above 0.995 for both. CONCLUSIONS: A simple, fast, and selective liquid chroma-tography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of cefiderocol and ceftobiprole. This new method was successfully applied to the measurement of plasma concentration of cefiderocol and ceftobiprole in critically ill patients and showed good performance for their therapeutic monitoring and optimizing antibiotic therapy.

Cryptococcus gattii in Patients with Lymphoid Neoplasms: An Illustration of Evolutive Host-Fungus Interactions.

Recent outbreaks of Cryptococcus gattii (CG) infections in North America have sparked renewed interest in the pathogenic potential of CG, and have underscored notable differences with Cryptococcus neoformans in terms of geographic distribution, pathogen virulence, and host susceptibility. While cases of CG are increasingly reported in patients with a wide variety of underlying conditions, only very few have been reported in patients with lymphoid neoplasms. Herein, we report a case of autochthonous CG meningitis in a patient receiving ibrutinib for chronic lymphocytic leukemia in France, and review available data on the clinical epidemiology of CG infections in patients with lymphoid neoplasms. We also summarise recent data on the host responses to CG infection, as well as the potential management pitfalls associated with its treatment in the haematological setting. The clinical epidemiology, clinical presentation, and course of disease during infections caused by CG involve complex interactions between environmental exposure to CG, infecting genotype, pathogen virulence factors, host susceptibility, and host immune responses. Future treatment guidelines should address the challenges associated with the management of antifungal treatments in the onco-haematological setting and the potential drug-drug interactions.

Current Spectrum of Infections in Patients with X-Linked Agammaglobulinemia.

Outcome of patients with X-linked agammaglobulinemia (XLA) has improved with the widespread use of immunoglobulin replacement therapy (IgRT). There are few data on the spectrum of infections experienced by patients undergoing IgRT. We carried out a retrospective cross-sectional analysis of the records of XLA patients seen at Necker-Enfants Malades Hospital, Paris. For each infection, we evaluated infection site, microbial etiology, antibiotic prophylaxis, immunosuppressive treatment, IgRT route, and last known IgG trough level. Sixty patients were included, who cumulated a follow-up of 1470 patient-years. We recorded 188 infections, including 97 after initiation of IgRT. The rate of infection was highest before IgRT (0.66 vs. 0.06 per person-year (ppy), p < 0.001) and was higher after the age of 16 compared to before (0.14 vs. 0.05 ppy, p = 0.048). It was similar for patients receiving intravenous or subcutaneous Ig (0.09 vs 0.05 ppy, p = 0.54). The lungs and gastrointestinal tract accounted for 71% of infection sites. Forty-six (47%) infections occurred in patients receiving antibiotic prophylaxis. Sixteen (16.5%) infections occurred in patients receiving immunosuppressive therapy, which more frequently occurred after age 16 (35% vs. 2.4%, p < 0.001). The median IgG trough level prior to all infections was 8.4 g/L. Almost half (44.3%) of infections occurred with prior IgG trough levels > 8 g/L, and 16/97 (16.7%) in patients with trough levels > 10 g/L. Infection remains a significant issue in patients with XLA undergoing IgRT despite adequate IgG trough levels. Chronic inflammatory manifestations of X-linked agammaglobulinemia and immunosuppressive therapies may be significant drivers of infection during adulthood.

Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19.

BACKGROUND: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients. METHODS: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2. RESULTS: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs). CONCLUSION: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.

The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study.

PURPOSE: Little is known about the neuronal substrates of neuropsychiatric symptoms associated with COVID-19 and their evolution during the course of the disease. We aimed at describing the longitudinal brain metabolic pattern in COVID-19-related encephalopathy using 18F-FDG-PET/CT. METHODS: Seven patients with variable clinical presentations of COVID-19-related encephalopathy were explored thrice with brain 18F-FDG-PET/CT, once in the acute phase, 1 month later and 6 months after COVID-19 onset. PET images were analysed with voxel-wise and regions-of-interest approaches in comparison with 32 healthy controls. RESULTS: Patients' neurological manifestations during acute encephalopathy were heterogeneous. However, all of them presented with predominant cognitive and behavioural frontal disorders. SARS-CoV-2 RT-PCR in the CSF was negative for all patients. MRI revealed no specific abnormalities for most of the subjects. All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities. CONCLUSION: The implication of this widespread network could be the neural substrate of clinical features observed in patients with COVID-19, such as frontal lobe syndrome, emotional disturbances and deregulation of respiratory failure perception. This study suggests that this network remains mildly to severely impaired 6 months after disease onset.