Actinomycosis after allogeneic hematopoietic stem cell transplantation despite penicillin prophylaxis.

Actinomycosis is a rare chronic and multifaceted disease caused by Actinomyces species frequently mimicking malignancy or other chronic granulomatous lung diseases. We report 4 original presentations of actinomycosis arising under supposed penicillin prophylaxis in allogeneic stem cell transplantation recipients.

Combined medico-surgical strategy for invasive sino-orbito-cerebral breakthrough fungal infection with Hormographiella aspergillata in an acute leukaemia patient.

Hormographiella aspergillata is a rare causative agent of invasive filamentous breakthrough infection, mostly arising after echinocandin exposure. We report a neutropenic patient who developed a severe sino-orbito-cerebral H. aspergillata infection while receiving empirical caspofungin, successfully controlled by an aggressive strategy associating surgical debridement and combined high-dose regimen of antifungal drugs.

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients.

The mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (T(regs)) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4(+) T cell count (> or < 500/mm(3)). Clinical and virological data (including very low-level viraemia) were collected. In parallel, immunophenotyping of CD4(+) lymphocytes, including T(reg) subsets, and CD8(+) T cells was performed. Percentages of activated CD4(+) T cells, T(regs), effector T(regs) and terminal effector T(regs) were found to be significantly elevated in iIR. Neither the percentage of activated CD8(+) T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4(+) T cell count and percentage of T(regs) were the only two parameters associated independently with iIR [odds ratio (OR) = 2·339, P = 0·001, and OR = 0·803, P = 0·041]. We present here the largest study investigating simultaneously the immune response to long-term HAART, activation of CD4(+) and CD8(+) T cells, T(reg) percentages and very low-level viraemia. Causative interactions between T(regs) and CD4(+) T cells should now be explored prospectively in a large patients cohort.

Real-life use of delamanid: results from the European post-authorisation safety study.

BACKGROUND: A post-authorisation safety study (PASS) on delamanid (DLM) was conducted as part of a post-approval commitment to the European Medicines Agency. The aim of this study was to evaluate the use of DLM in a real-life setting, its safety, and treatment outcomes in patients with multidrug-resistant TB (MDR-TB). METHODS: This was a prospective, multicentric, non-interventional study conducted in the European Union. MDR-TB Regimen selection and patient monitoring were conducted in accordance with existing medical practices. Data on the use of DLM, related adverse events, and treatment outcomes were collected for up to 30 months after the first DLM dose. Descriptive summary statistics were used for continuous and categorical variables. RESULTS: Out of 86 patients, one had extrapulmonary TB. Two-thirds of the patients were treated with DLM for more than 24 weeks. The most frequent adverse drug reaction to DLM was QT interval prolongation. Resistance to DLM was detected in one patient during treatment. The treatment success rate was 77%. CONCLUSION: No new safety concerns were revealed, including in patients treated with DLM for more than 24 weeks. QT interval prolongations were well managed and did not lead to any clinically significant cardiac effects. The treatment outcomes were in line with the WHO target for Europe.

CONTEXTE: Une étude de sécurité post-autorisation (PASS) sur le délamanide (DLM) a été menée dans le cadre d'un engagement post-approbation auprès de l'Agence européenne des médicaments. L'objectif de cette étude était d'évaluer l'utilisation du DLM dans un contexte réel, son innocuité et les résultats du traitement chez les patients atteints de TB multirésistante (MDR-TB). MÉTHODES: Il s'agissait d'une étude prospective, multicentrique et non interventionnelle menée dans l'Union européenne. La sélection du schéma thérapeutique de la MDR-TB et le suivi des patients ont été effectués conformément aux pratiques médicales existantes. Les données sur l'utilisation du DLM, les effets indésirables connexes et les résultats du traitement ont été recueillies jusqu'à 30 mois après la première dose de DLM. Des statistiques sommaires descriptives ont été utilisées pour les variables continues et catégorielles. RÉSULTATS: Sur 86 patients, un avait une TB extrapulmonaire. Les deux tiers des patients ont été traités avec du DLM pendant plus de 24 semaines. L'effet indésirable le plus fréquent du DLM était l'allongement de l'intervalle QT. Une résistance au DLM a été détectée chez un patient pendant le traitement. Le taux de réussite du traitement était de 77%. CONCLUSION: Aucun nouveau problème de sécurité n'a été révélé, y compris chez les patients traités par le DLM pendant plus de 24 semaines. Les allongements de l'intervalle QT ont été bien gérés et n'ont pas entraîné d'effets cardiaques cliniquement significatifs. Les résultats du traitement étaient conformes à l'objectif de l'OMS pour l'Europe.

Novel UL23 and UL30 substitutions in HSV1 and HSV2 viruses related to polymorphism or drug resistance.

Data on herpes simplex virus (HSV) polymorphism as well as acyclovir (ACV) and foscarnet (FOS) resistance mutations are not exhaustive and may hinder accurate diagnosis by next-generation sequencing (NGS). Here, we report novel UL23 and UL30 substitutions for HSV1 and HSV2 identified in immunocompromised patients treated for hematological malignancies during the last 6 years of HSV resistance surveillance at the University Hospital of Lyon. For HSV1, 35 novel UL23 substitutions and 52 novel UL30 substitutions were identified. For HSV2, 2 novel UL23 substitutions and 12 novel UL30 substitutions were identified. These results allow to complete the database of HSV1 and HSV2 substitutions, related either to polymorphism or to ACV and FOS resistance.

Contribution of amoebic coculture to recovery of Legionella isolates from respiratory samples: prospective analysis over a period of 32 months.

We evaluated the contribution of amoebic coculture to the recovery of Legionella spp. from 379 respiratory samples. The sensitivity of axenic culture was 42.1%. The combination of axenic culture with amoebic coculture increased the Legionella isolation rate to 47.1%. Amoebic coculture was particularly efficient in isolating Legionella spp. from respiratory samples contaminated with oropharyngeal flora.

What progress has been made in treatment of immunocompromised COVID-19 patients?

While immunocompromised patients are at very high risk of developing severe COVID 19, few of them have been enrolled in studies aimed at evaluating treatments. In the early stages of research on this disease, glucocorticoid therapy became the standard of care for patients requiring oxygen supplementation. It has been demonstrated that the neutralizing monoclonal antibody combination of Casirivimab and Imdevimab reduced (by 28 days) mortality in COVID-19 patients admitted to hospital who were seronegative at baseline, but not in those who were seropositive. There is still a need to determine the place of available various antivirals (Molnupiravir or Nirmatrelvir plus Ritonavir) and passive immunotherapies (Sotrovimab…) as well as convalescent plasma therapy in immunocompromised settings.

Cerebral aspergillosis in the era of new antifungals: The CEREALS national cohort study Nationwide CEREbral Aspergillosis Lesional study (CEREALS).

BACKGROUND: Cerebral aspergillosis (CA) is a life-threatening disease for which diagnosis and management remain challenging. Detailed analyses from large cohorts are lacking. METHODS: We included 119 cases of proven (n = 54) or probable (n = 65) CA diagnosed between 2006 and 2018 at 20 French hospitals. Data were collected at baseline and during follow-up. Cerebral imaging was reviewed centrally by two neuroradiologists. RESULTS: The most frequent underlying conditions were hematological malignancy (40%) and solid organ transplantation (29%). Galactomannan was detected in the serum of 64% of patients. In 75% of cases, at least one of galactomannan, Aspergillus PCR, and ß-d-glucan was positive in the cerebrospinal fluid. Six-week mortality was 45%. Two distinct patterns of disease were identified according to presumed route of dissemination. Presumed haematogenous dissemination (n = 88) was associated with a higher frequency of impaired consciousness (64%), shorter time to diagnosis, the presence of multiple abscesses (70%), microangiopathy (52%), detection of serum galactomannan (69%) and Aspergillus PCR (68%), and higher six-week mortality (54%). By contrast, contiguous dissemination from the paranasal sinuses (n = 31) was associated with a higher frequency of cranial nerve palsy (65%), evidence of meningitis on cerebral imaging (83%), macrovascular lesions (61%), delayed diagnosis, and lower six-week mortality (30%). In multivariate analysis and in a risk prediction model, haematogenous dissemination, hematological malignancy and the detection of serum galactomannan were associated with higher six-week mortality. CONCLUSION: Distinguishing between hematogenous and contiguous dissemination patterns appears to be critical in the workup for CA, as they are associated with significant differences in clinical presentation and outcome.

[Functional immunoassays in the setting of infectious risk and immunosuppressive therapy of non-HIV immunocompromised patients]. / Place des tests immunitaires fonctionnels dans la prise en charge du risque infectieux et de la gestion des thérapies immunosuppressives chez les patients immunodéprimés non-VIH.

The holistic approach of the human immune system is based on the study of its components collectively driving a functional response to an immunogenic stimulus. To appreciate a specific immune dysfunction, a condition is mimicked ex vivo and the immune response induced is assessed. The application field of such assays are broad and expanding, from the diagnosis of primary and secondary immunodeficiencies, immunotherapy for cancer to the management of patients at-risk for infections and vaccination. These assays are immune monitoring tools that may contribute to a personalised and precision medicine. The purpose of this review is to describe immune functional assays available in the setting of non-HIV acquired immune deficiency. First, we will address the use of theses assays in the diagnosis of opportunistic infections such as viral reactivation. Secondly, we will report the usefulness of these assays to assess vaccine efficacy and to manage immunosuppressive therapies.

Cerebral empyema and abscesses due to Cutibacterium acnes.

INTRODUCTION: Cutibacterium acnes is a commensal bacterium of the skin, frequently reported in prosthetic shoulder or spinal implant infections, but rarely in cranial and intracranial infections. METHODS: We retrospectively reviewed patients with intracranial samples positive to Cutibacterium acnes managed in the neurosurgical units of our hospital of Lyon, France, between 2008-2016. RESULTS: We included 29 patients, of whom 23 had empyema (with or without abscess), 17 had cranial osteomyelitis, and six only had abscess. Prior neurosurgery was reported in 28 patients, and the remaining patient had four spontaneous abscesses. Twelve patients had polymicrobial infections, including methicillin-susceptible Staphylococcus in 11 cases. The clinical diagnosis was difficult because of indolent and delayed symptoms: a CT scan or MRI was required. Thirteen patients (52%) had material at the infection site. All patients with bone flap implant or bones from biological banks had a bone flap-associated infection. Drainage was surgically performed in 25 cases or by CT scan-guided aspiration in four cases. All patients received an adapted antibiotic therapy (from three weeks to six months). The outcome was favorable in 28 patients. Three patients relapsed during the antibiotic therapy, requiring further surgery. CONCLUSION: Cutibacterium acnes can be responsible for postoperative empyema and cerebral abscesses, with particular indolent forms, which make their diagnosis difficult. They are often polymicrobial and associated with bone flap osteomyelitis. Their outcome is favorable after drainage and adapted antibiotic therapy.

Efficacy of a long-term antibiotic treatment in patients with a chronic Tick Associated Poly-organic Syndrome (TAPOS).

SETTINGS: Despite a now codified antibiotic treatment for Lyme disease, a significant proportion of patients treated according to recommendations complain of persistent signs and symptoms. The pathophysiological mechanisms which underlie this syndrome of post-treatment chronic systemic illness remain unclear. For some physicians post-treatment symptoms indicate a persistent infection requiring prolonged antibiotic therapy. For others, there is no benefit from antimicrobial therapy. The difficulty of assessment encountered in studies is significant because many symptoms are subjective. We think that the term "chronic Lyme disease" is not appropriate and should be replaced by chronic "tick associated poly-organic syndrome" (TAPOS). OBJECTIVE: This open-label prospective study was made on a group of 100 patients having followed a medical treatment for a chronic TAPOS and to evaluate their evolution under prolonged antibiotic treatment. RESULTS: The medical management was found to be effective for symptoms, especially for patients with a high probability of chronic TAPOS (NEJM score). Patients with post tick-bite symptoms, which often worsens their quality of life, deserve particular attention. CONCLUSION: This study had methodological limitations but could help in terms of feasibility, choice of inclusion criteria, and design of follow-up for a future randomized, double blind study to test for an optimal management of TAPOS.

A practical approach to tuberculosis diagnosis and treatment in liver transplant recipients in a low-prevalence area.

Solid organ transplant candidates/recipients are at risk of mycobacterial infections. Although guidelines on the management of latent tuberculosis infection and active tuberculosis are available for solid organ transplant recipients, limited guidance focuses on end-stage liver disease or liver transplant recipients who require management in a referral center. Therapeutic challenges arise from direct antituberculosis drug-related hepatotoxicity, and substantial metabolic interactions between immunosuppressive and antituberculosis drugs. Another issue is the optimal timing of therapy with regards to the time of transplantation. This review focuses on the importance of tuberculosis screening with immunological tests, challenges in the diagnosis, management, and treatment of latent tuberculosis infection and active tuberculosis, as well as risk assessment for active tuberculosis in the critical peri-liver transplantation period. We detail therapeutic adjustments required for the management of antituberculosis drugs in latent tuberculosis infection and active tuberculosis, particularly when concomitantly using rifampicin and immunosuppressive drugs.

Quorum-sensing activity and related virulence factor expression in clinically pathogenic isolates of Pseudomonas aeruginosa.

Respiratory isolates of Pseudomonas aeruginosa were collected from 58 critically-ill patients with ventilator-associated pneumonia. Expression of elastase and pyocyanin was assessed semi-quantitatively, while quorum-sensing activity was assessed by quantifying the levels of the autoinducers N-3-oxododecanoyl-L-homoserine lactone (C12-HSL) and N-butanoyl-L-homoserine lactone (C4-HSL). Correlations were sought between quorum-sensing activity and the expression of these two virulence factors, and all results were compared to those obtained with the laboratory reference strains PA103, a strain defective in quorum-sensing, and PAO1, a functional quorum-sensing strain. More than two-thirds of clinically pathogenic isolates had increased levels of elastase and/or pyocyanin, and high quorum-sensing activity, as assessed by autoinducer levels. However, a strong correlation between quorum-sensing activity and virulence factor production was revealed only for elastase and not for pyocyanin (C12-HSL/elastase, r = 0.7, p 2 x 10(-9); C4-HSL/elastase, r = 0.7, p 2 x 10(-9)). These data suggest that the pathogenicity of P. aeruginosa isolates from critically-ill patients with ventilator-associated pneumonia is caused, at least in part, by an increase in elastase production regulated by quorum-sensing, while increased pyocyanin production in these isolates may be regulated predominantly by mechanisms other than quorum-sensing.

[Results of a prospective standardized study of 30 patients with chronic neurological and cognitive disorders after tick bites]. / Enquête étiologique standardisée sur une cohorte de 30 patients atteints de troubles neurologiques et cognitifs chroniques après piqûre de tiques results of a prospective standardized study of 30 patients with chronic neurological and cognitive disorders after tick bites.

OBJECTIVE: Patients with chronic neurological disorders and cognitive impairment after tick bites are difficult to manage despite standard antibiotic therapy for Lyme disease. We wanted to correctly assess the disorders. METHODS: Thirty patients were hospitalized for a standardized evaluation of their disorders: clinical examination, biological and serological studies, cerebral MRI, CSF study, neurophysiological exams, and neuropsychological evaluation of cognitive functions. RESULTS: Clinical and biological results were non informative. We observed significant CSF abnormalities (64%), MRI Flair pictures (41%), neurophysiological exams (47%), and cognitive evaluation (100%). CONCLUSIONS: A large and standardized evaluation should be made for each patient to improve the management and probably the treatment of these complex chronic symptoms observed after tick bites.

Outpatient parenteral antibiotic therapy: Evaluation of practices and limits of use in rural areas in France.

OBJECTIVES: To evaluate outpatient parenteral antibiotic therapy (OPAT) practices in a French rural area. MATERIAL AND METHODS: Descriptive study assessing knowledge, practices, and limitations of OPAT use among hospital practitioners (HP), family physicians (FP), and private nurses (PN). RESULTS: OPAT (mainly ceftriaxone and penicillins) was used by 69.6%, 73.3%, and 97.7% of the 23 HPs, 45 FPs, and 46 PNs mostly for respiratory or urinary tract infections, bacteremia, and/or multidrug-resistant bacterial infections. Overall, 65.2% of HPs and 37.8% of FPs were in contact with an infectious disease specialist. Knowledge of OPAT benefits and risks was lower for FPs than HPs. The main obstacles were the patient's geographic isolation (HPs), the availability of a venous catheter, the lack of training (FPs), and the expected OPAT-associated overwork (PNs). CONCLUSION: OPAT practice is weak in rural areas. Declared obstacles constitute fields of improvement for its essential expansion.

Chronic disseminated candidiasis and acute leukemia: Impact on survival and hematopoietic stem cell transplantation agenda.

OBJECTIVES: To study the management of chronic disseminated candidiasis (CDC) in patients presenting with acute leukemia. PATIENTS AND METHODS: Single-center retrospective study of acute leukemia patients (2006-2015) to investigate three aspects of CDC: its impact on the time interval between diagnosis and hematopoietic stem cell transplantation, when required (non-parametric Wilcoxon-Mann-Whitney test); its impact on overall survival (Cox proportional hazard regression model); antifungal therapeutic strategies implemented. RESULTS: A total of 639 patients presenting with acute leukemia were included; 144 were transplanted and 29 developed CDC. CDC did not significantly increase the time interval between diagnosis and transplantation, nor did it impact the overall survival of recipients. An improved overall survival was observed in non-transplanted acute leukemia patients presenting with CDC. CONCLUSION: CDC should not postpone transplantation if antifungal treatment is optimized.

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

[Ventilator-associated pneumonia and chronic obstructive pulmonary disease]. / Pneumonies acquises sous ventilation mécanique invasive et bronchopneumopathie chronique obstructive.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common pulmonary and systemic inflammatory disease. Patients with COPD frequently require mechanical ventilation for acute exacerbations. BACKGROUND: The incidence of ventilator-associated pneumonia (VAP) in COPD patients varies from 6 to 33%. Tracheo-bronchial colonisation, local and systemic immuno-supression and frequent antibiotic treatment are factors predisposing to VAP in these patients. Gram negative bacilli are commonly isolated in COPD patients with VAP. Pseudomonas aeruginosa reported to be the most common. The diagnosis of VAP can be difficult in patients with COPD because of the low sensitivity of the portable chest radiograph. VAP is associated with higher mortality rates, longer duration of mechanical ventilation and ITU stay in patients with COPD. Initial antibiotic treatment should be based on recent guidelines and should take account of frequent prior hospitalisation and antibiotic treatment which are well known risk factors for multidrug resistant bacteria. Preventative measures recommended for the general population should be applied to COPD patients. In the absence of contraindications the use of non-invasive ventilation is recommended to reduce the risk of VAP. VIEWPOINT AND CONCLUSION: Future studies should better determine the incidence of VAP in COPD, improve the diagnostic approach and determine the effects of treating malnutrition, chronic tracheobronchial colonisation and limiting antibiotic and corticosteroid treatment on the incidence of VAP.

[Vaccination against influenza: results of a study on vaccination coverage among health care workers in the Croix-Rousse Hospital (Hospitals of Lyon)]. / Vaccination contre la grippe: résultats d'une enquête sur la couverture vaccinale du personnel hospitalier à l'hôpital de la Croix-Rousse (hôpitaux de Lyon).

INTRODUCTION: The aim of this study was to evaluate the vaccinal status among Croix-Rousse Hospital workers, attitude towards this vaccination, and the information delivered in order to promote this vaccination. METHODS: Questionnaires were delivered by electronic mailing. RESULTS: Six hundred (and) twenty-nine questionnaires were analyzed (26.7% of hospital workers); 30.7% of responders were vaccinated against influenza, 89.2% of responders were aware of influenza and vaccine. Vaccine coverage was lower in younger workers, non health-care workers, non physician health-care workers, and surgeons who responded. Motivation and reserve varied according to the status, position, and age, with some discrepancies. CONCLUSION: These results suggest implementing a better targeted vaccination campaign, according to the various categories of personnel.

[Acute invasive pulmonary aspergillosis in chronic lung disease--a review]. / Aspergillose pulmonaire aiguë invasive et pathologies pulmonaires chroniques.

INTRODUCTION: Apart from malignancies and solid organ transplant, chronic lung disease, in particular chronic obstructive pulmonary disease (COPD), is a third important predisposing factor for acute invasive pulmonary aspergillosis. STATE OF THE ART: COPD is present in 2% of patients dying from invasive aspergillosis. This opportunistic infection occurs because of an immunodeficiency linked both to altered local immunity and to systemic factors such as long term steroid treatment and malnutrition. In patients whose sputum and/or endotracheal aspirate specimens contain hyphal forms of filamentous Aspergillus, half will have a clinically significant aspergillus infection. Diagnostic tests include serum galactomannan antigen test, serum antibody titre, thoracic CT scan and bronchoalveolar lavage (BAL). The identification of fungal hyphae in BAL fluid by microscopy and/or on culture is critical for a positive diagnosis. The mortality rate for acute invasive pulmonary aspergillosis in chronic lung diseases reaches almost 100%. Antifungal monotherapy is still recommended as a first line treatment. Combined treatment can be used in refractory aspergillosis as a salvage therapy. The question of maintaining, decreasing or interrupting steroid treatment must be considered. PERSPECTIVES: Prospective studies are needed to evaluate a standardised diagnostic strategy such as exists for patients with haematological disease. Whether this will improve prognosis remains to be seen. CONCLUSION: Acute invasive pulmonary aspergillosis complicating chronic lung disease is not rare. Improved diagnosis procedures and recent therapeutic advances may have a positive impact on patient prognosis.