Benoit Pilmis

Pulmonary manifestations in adult patients with chronic granulomatous disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by failure of superoxide production in phagocytic cells. The disease is characterised by recurrent infections and inflammatory events, frequently affecting the lungs. Improvement of life expectancy now allows most patients to reach adulthood. We aimed to describe the pattern of pulmonary manifestations occurring during adulthood in CGD patients. This was a retrospective study of the French national cohort of adult patients (≥16 years old) with CGD. Medical data were obtained for 67 adult patients. Pulmonary manifestations affected two-thirds of adult patients. Their incidence was significantly higher than in childhood (mean annual rate 0.22 versus 0.07, p=0.01). Infectious risk persisted despite anti-infectious prophylaxis. Invasive fungal infections were frequent (0.11 per year per patient) and asymptomatic in 37% of the cases. They often required lung biopsy for diagnosis (10 out of 30). Noninfectious respiratory events concerned 28% of adult patients, frequently associated with a concomitant fungal infection (40%). They were more frequent in patients with the X-linked form of CGD. Immune-modulator therapies were required in most cases (70%). Respiratory manifestations are major complications of CGD in adulthood. Noninfectious pulmonary manifestations are as deleterious as infectious pneumonia. A specific respiratory monitoring is necessary. Pulmonary involvement is a major concern in adult CGD patients, making specific respiratory monitoring necessary http://ow.ly/FjaRS

Alternatives to carbapenems for infections caused by ESBL-producing Enterobacteriaceae

Since 2006, extended-spectrum beta-lactamase (ESBL)-producing isolates have spread in France, as well as elsewhere [1–3]. As these isolates are often multidrug-resistant, carbapenems are regarded as a major antibacterial resource [1, 4–6]. Massive prescriptions of broad-spectrum antibiotics reduce the commensal flora [7], increase the emergence of carbapenemase-producing Enterobacteriaceae [8], and, finally, increase the occurrence of subsequent infections [3, 4]. As a consequence, carbapenems alternatives for ESBL infections treatment have been evaluated in several limited studies. Cephalosporins use for the treatment ESBL infections have been associated with higher mortality, even if the minimum inhibitory concentration (MIC) for Enterobacteriaceae remains within the susceptible range [9, 10]. Fluoroquinolone use is restricted by the frequently observed coresistance of ESBL strains [5]. Recently, based on pharmacokinetics and pharmacodynamics data, some authors have emphasized the use of cephamycins as a potential appropriate response. However, only few data describe the clinical utility of cephamycins in case of ESBL-producing Enterobacteriaceae infections. We thus performed a one-year retrospective observational study in order to evaluate the use of antimicrobial agents other than carbapenems for the management of bloodstream and/or urinary tract infections (UTIs) caused by ESBL Enterobacteriaceae at Necker-Enfants Malades, a tertiary university hospital in France. All patients, both children and adults, hospitalized in our institution in 2011 were eligible for the analysis if they fulfilled the following criteria: (1) clinically significant monomicrobial infection (UTI or bloodstream infection) demonstrated via the isolation of ESBL-producing Enterobacteriaceae in blood or urine; (2) treatment with any carbapenem or one of the available alternatives to carbapenems for ≥48 h. Three groups were designed and analyzed separately. All strains had an MIC≤8 m.5–4.5 mg/l) to cefoxitin. The first group of patients had only received carbapenems during the course of their infection (group 1). The second group represented patients initially treated by carbapenems and whose therapy was subsequently switched to any of the available alternatives (group 2). The remaining group included patients who never received any carbapenem for the treatment of their current infectious episode (group 3). Demographic, biological, and microbiological data were collected from all patients. The main outcome was clinical recurrence or microbiological relapse within 30 days after the end of antibacterial therapy. Relapse or recurrence was defined by the reappearance of a positive bacteriological sample (bloodstream or urinary sample) with (clinical relapse) or without (isolated microbiological relapse) clinical symptoms. Clinical evolution evaluated by physicians at day 7, decrease of inflammatory reaction [leukocytes count, C-reactive protein (CRP) serum levels], and time to bacteriological cure were also analyzed. Statistical analysis was performed using the Fisher or Kruskal–Wallis tests. A difference was regarded as significant at a level of 5 % (alpha risk). Fifty-three patients were identified with bloodstream and/ or UTI due to ESBL-producing Enterobacteriaceae. Group 1 included 31 patients (58 %), group 2 consisted of nine patients (nine carbapenem-treated cases then receiving cefoxitin), and, finally, group 3 included 13 patients (25 %) (receiving J.R. Zahar and O. Lortholary contributed equally to the work. B. Pilmis (*) : P. Parize :O. Lortholary Service des Maladies Infectieuses et Tropicales, Institut Imagine, APHP, Centre d’Infectiologie Necker-Pasteur, Université Paris-Descartes, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France e-mail: bpilmis@gmail.com

Chronic Granulomatous Disease in Patients Reaching Adulthood: A Nationwide Study in France

Background Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points. Method Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry. Results Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood. Conclusions Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered.

Iatrogenic Cushing's Syndrome Induced by Posaconazole

ABSTRACT Iatrogenic Cushings syndrome is an undesirable outcome of glucocorticoids treatment. It can be increased by pharmacologic interactions. Glucocorticoid therapy, given in association with ritonavir, and some azole treatments are causes of iatrogenic Cushings syndrome. We present a patient with common-variable immunodeficiency who received 7 years of itraconazole therapy for bronchial colonization with Aspergillus in combination with inhaled fluticasone without any Cushingoid symptoms. After a switch to posaconazole, the patient developed Cushingoid symptoms.

Legionnaire’s Disease in Compromised Hosts

Legionnaires disease (LD) is mainly reported in apparently immunocompetent patients. Among them, risk factors include chronic lung disease and smoking. However, LD is also well reported among immunocompromised patients, particularly those treated with anti-tumor necrosis factor alpha therapy, patients with hematological malignancy, and transplant patients. This article discusses the available data on immunity against Legionella spp, epidemiology, clinical presentation, diagnosis, and treatment of LD in immunocompromised patients.

Could we predict airborne Aspergillus contamination during construction work

HighlightsAspergillus is a common airborne mold representing up to 40% of hospital and home fungal contamination.Building work activities, particularly demolition, are associated with fungal and Aspergillus airborne contamination.Climatic conditions influence airborne fungal contamination.High temperature and demolition are 2 factors associated with fungal air contamination.High temperature during a period of building work activities seems to be the only factor associated with Aspergillus airborne contamination. Background Aspergillus fumigatus is a major opportunistic pathogen causing nosocomial infection. Hospital outbreaks of invasive aspergillosis have been associated with demolition and building construction. This study was designed to examine the impact of meteorologic factors and different periods of work on outdoor fungal airborne concentrations. Methods The study was conducted at Necker Enfants Malades Hospital, a 650‐bed teaching care hospital recently involved in a large construction program, including renovation, construction, and demolition. During the work phases, prospective external air samplings were performed 3 times a week, and meteorologic parameters were collected every day. Results Two hundred and one samples were collected. Aspergillus spp were found in 80.1% of samples, with a median concentration of 16 colony forming units (CFU)/m3. A significant increase in the colony count of molds occurred after demolition. In the multivariate analysis, factors associated with overall fungi concentration were the type of work construction and temperature. Elevated Aspergillus spp concentrations (>20 CFU/m3) were associated with higher temperature. Conclusions Our findings underline the importance of environmental surveillance. According to our results we suggest that demolition work should be performed during the winter and fall seasons.

How Should We Treat Hospital-Acquired and Ventilator-Associated Pneumonia Caused by Extended-Spectrum β-Lactamase–Producing Enterobacteriaceae?

Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) due to extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-PE) represent a growing problem. Indeed, ESBL-PE is endemic in many countries, and 5 to 25% of intensive care unit (ICU) patients are ESBL-PE carrier on ICU admission. ESBL-PE HAP/VAP is associated with a higher mortality than HAP/VAP due to susceptible Enterobacteriaceae because the resistance profile decreases the adequacy rate of empiric therapy. ESBL-PE should be considered in the empirical treatment in case of the high burden of ESBL-PE in the unit, in the case of previous ESBL-PE colonization, when the HAP/VAP occurs late, and in patients with shock. A negative active systematic surveillance culture on rectal swab reduced the risk of ESBL-PE VAP to less than 1%. Rapid diagnostic tests are now able to confirm the presence of ESBL-PE in VAP within 24 hours; new molecular methods will provide results within few hours.Adequate treatment usually required carbapenems. The alternative β-lactams such as β-lactams/β-lactamases inhibitor combinations could be proposed as a step-down therapy according to the antibiotic susceptibility result. Optimization of pharmacokinetics requires high dosage and continuous or prolonged infusions for β-lactams. When the patient is stabilized, a therapy of duration 7 to 8 days is recommended.

Piperacillin–tazobactam as alternative to carbapenems for ICU patients

Several studies suggest that alternatives to carbapenems, and particulary beta-lactam/beta-lactamase inhibitor combinations, can be used for therapy of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE)-related infections in non-ICU patients. Little is known concerning ICU patients in whom achieving the desired plasmatic pharmacokinetic/pharmacodynamic (PK/PD) target may be difficult. Also, in vitro susceptibility to beta-lactamase inhibitors might not translate into clinical efficacy. We reviewed the recent clinical studies examining the use of BL/BLI as alternatives to carbapenems for therapy of bloodstream infection, PK/PD data and discuss potential ecological benefit from avoiding the use of carbapenems. With the lack of prospective randomized studies, treating ICU patients with ESBL-PE-related infections using piperacillin–tazobactam should be done with caution. Current data suggest that BL/BLI empirical use should be avoided for therapy of ESBL-PE-related infection. Also, definitive therapy should be reserved to patients in clinical stable condition, after microbial documentation and results of susceptibility tests. Optimization of administration and higher dosage should be used in order to reach pharmacological targets.

A French National Survey on Clotting Disorders in Mastocytosis.

AbstractMastocytosis is characterized by a clonal mast cell proliferation with organ infiltration and uncontrolled degranulation. Although not characteristic and poorly explained, some patients develop clotting abnormalities.We retrospectively identified patients with established diagnosis of mastocytosis and related clotting abnormalities (clinical and/or biological) using the national French Reference Centre for Mastocytosis database.From our cohort of 14 adult patients with clotting abnormalities (median age 46 years [range 26–75]), 4 had a presentation suggestive of a primary hemostasis disorder alone (by their symptoms and/or abnormal clotting tests [PFA, von Willebrands disease [vWD] screening]) and 10 had a laboratory impairment of secondary hemostasis. Among these, 7 had bleeds characteristic of a coagulation cascade disorder (severe/life-threatening in 5 and mild in 2 patients). Clotting abnormalities were of variable severity, typically related to intense crisis of degranulation, such as anaphylactic reactions, and/or to severe organ infiltration by mast cells. Importantly, classical hemostatic management with platelet transfusion, fresh frozen plasma, or vitamin K infusions was unsuccessful, as opposed to the use of agents inhibiting mast cell activity, particularly steroids. This illustrates the crucial role of mast cell mediators such as tryptase and heparin, which interfere both with primary (mainly via inhibition of von Willebrand factor) and secondary hemostasis. There was interestingly an unusually high number of aggressive mastocytosis (particularly mast cell leukemia) and increased mortality in the group with secondary hemostasis disorders (n = 5, 36% of the whole cohort).Mast cell degranulation and/or high tumoral burden induce both specific biologic antiaggregant and anticoagulant states with a wide clinical spectrum ranging from asymptomatic to life-threatening bleeds. Hemostatic control is achieved by mast cell inhibitors such as steroids.

Helicobacter bilis -Associated Suppurative Cholangitis in a Patient with X-Linked Agammaglobulinemia

AbstractᅟHelicobacter bilis is a commensal bacterium causing chronic hepatitis and colitis in mice. In humans, enterohepatic Helicobacter spp. are associated with chronic hepatobiliary diseases.PurposeWe aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis.Methods16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis.ResultsClinical outcome resulted in the normalization of clinical and biological parameters under antibiotic treatment by a combination of ceftriaxone, metronidazole, and doxycyclin followed by a 2-week treatment with moxifloxacin and a 2-month treatment with azithromycin.ConclusionIn conclusion, these data suggest a specific clinical and microbiological approach in patients with humoral deficiency in order to detect H. bilis hepatobiliary diseases.