Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas.

BACKGROUND: Infections are well known complications of some targeted drugs used to treat solid organ cancer and hematological malignancies. Furthermore, Individual patient risk factors are associated with underlying pathologies, concomitant immunosuppressive treatment, prior treatment and use of anti-infective prophylaxis. Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. OBJECTIVES: In this narrative review, we present the current state of knowledge concerning the infectious complications occurring in patients treated with immune checkpoint inhibitors (ICIs), Bruton's tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors or CAR-T cell infusion. SOURCES: We searched for studies treating infectious complications of ICIs, BTK inhibitors, PI3K inhibitors, antiapoptotic protein BCL-2 inhibitors and CAR-T cell therapy. We included randomized, observational studies and case reports. CONTENT: Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Treatment of irAEs with corticosteroids and other immunosuppressive agents can lead to opportunistic infections. Bruton's tyrosine kinase (BTK) inhibitors are associated with higher rate of infections, including invasive fungal infections. IMPLICATIONS: Infections, particularly fungal ones, are common in patients treated with BTK inhibitors even though most of the complications occurring among patients treated by ICIs or CART-cells infusion are associated with the treatment of side effects related to the use of these new treatments. The diagnosis of these infectious complications can be difficult and may require extensive investigations.

Suction drainage fluid culture during septic orthopaedic surgery, a retrospective study.

We evaluated the usefulness of suction drainage fluid culture after septic orthopaedic surgery to predict early surgical reintervention. We conducted a retrospective observational study, at the Groupe Hospitalier Paris Saint-Joseph between 2014 and 2019. All the patients undergoing septic orthopaedic surgery, with perioperative samples and a postoperative suction drainage device, were enrolled. We compared the group with positive or negative postoperative drainage fluid cultures, respectively, on surgical outcome. We included 246 patients. The drainage fluid culture was positive in 42.3% of the cases. Early surgical reintervention concerned 14.6% of the cases (n = 36), including 61.1% of patients with positive drainage fluid culture (n = 22/36). The risk factors associated with positive drainage fluid cultures were the debridement of the infected site (without orthopaedic device removal), an infection located at the spine, perioperative positive cultures to Staphylococcus aureus. The complete change of the orthopaedic device, and coagulase-negative staphylococci on the preoperative samples, was associated with negative drainage fluid cultures. Positive drainage fluid culture was predictive of early surgical reintervention, and coagulase-negative staphylococci in the preoperative samples and knee infection were predictive of surgical success. Postoperative drainage fluid cultures were predictive of early surgical reintervention. Randomized multicentric studies should be further conducted.

Failure of multiplex meningitis/encephalitis (ME) NAT during cryptococcal meningitis in solid organ recipients.

Cryptococcal meningitis is a severe cause of central nervous system infections among immunocompromised solid organ transplant (SOT) patients. While new diagnostic methods as multiplex meningitis/encephalitis (ME) NAT (nucleic acid test) are increasingly used as a first-line tool in hospital practice, data in HIV-negative patients including SOT remain scarce. We report here false-negative results of multiplex NAT among SOT patients with proven cryptococcal meningitis.

Pseudomonas aeruginosa bloodstream infections in children: a 9-year retrospective study.

P. aeruginosa bloodstream infection (BSI) is associated with high hospital mortality. Empirical combination therapy is commonly used, but its benefit remains debated. The purpose of this study was to describe in a paediatric population, demographical characteristics and outcome of children treated for P. aeruginosa BSI receiving either a combined or single antibacterial therapy. We performed a retrospective, single-centre, cohort study of hospitalized children with P. aeruginosa BSI from 2007 to 2015. A total of 118 bloodstream infections (BSI) were analysed (102 (86.4%) hospital-acquired, including 52 (44.1%) hospitalized in intensive care unit). In immunocompromised children, 52% of BSI episodes were recorded. Recent medical history revealed that 68% were hospitalized, 31% underwent surgery and 67% had a prior antibiotic therapy within the last 3 months. In-hospital mortality was similar for patients receiving single or combined anti-Pseudomonas therapy (p = 0.78). In multivariate analysis, independent risk factors for in-hospital mortality were neutropenia (OR = 6.23 [1.94-20.01], hospitalization in ICU (OR = 5.24 [2.04-13.49]) and urinary tract infection (OR = 4.40 [1.02-19.25]).Conclusion: P. aeruginosa BSI mainly occurred in immunocompromised children. Most infections were hospital-acquired and associated with high mortality. Combination therapy did not improve survival. What is Known: • P. aeruginosa bloodstream infection (BSI) is associated with high hospital mortality. Empirical combination therapy is commonly used but its benefit remains debated. What is New: • This is the largest cohort of Pseudomonas aeruginosa bacteraemia in children ever published. P. aeruginosa Bloodstream mainly occurred in immunocompromised children. Most infections were hospital-acquired and associated with high mortality. Combination therapy did not improve survival.

Listeria monocytogenes-associated endovascular infections: A study of 71 consecutive cases.

BACKGROUND: Listeria monocytogenes-associated endovascular infections are not well characterized. METHODS: Retrospective study of 71 culture-proven cases reported to the French National Reference Center for Listeria from 1993 to 2018. RESULTS: Seventy-one cases were identified: 42 with vascular aneurysms/prosthetic infections, 27 with endocarditis, 2 with both. Fifty-eight were men (82%); median age was 75 years [46-92]; 93% reported co-morbidities (66/71), including 50% with immunosuppressive conditions. Vascular infections consisted of infected aneurysms (68%) or prosthetic graft infections (32%); vascular rupture was reported in 25/42 (60%). Tissue samples grew L. monocytogenes in 98% (43/44) and blood cultures in 64% (27/42). Endocarditis cases involved prosthetic or native valves or intracardiac devices in respectively 62% (18/29), 28% (8/29) and 10% (3/29). Infected valves were aortic (62%, 16/26), mitral (31%, 8/26) or both (8%, 2/26); 38% patients required surgery; 45% displayed heart failure; 17% had concomitant neurolisteriosis. In-hospital mortality in vascular infections was 12% (5/42) and 41% (12/29) for Lm-associated endocarditis. CONCLUSIONS: Endovascular listeriosis is a rare but severe infection. It manifests as vascular infections and endocarditis, mostly in older patients with vascular or cardiac valve prosthetic devices and co-morbidities. Mortality in Lm-associated endocarditis is twice higher than with other pathogens, requiring prompt recognition and treatment.

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.

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

ᅟ: Helicobacter bilis is a commensal bacterium causing chronic hepatitis and colitis in mice. In humans, enterohepatic Helicobacter spp. are associated with chronic hepatobiliary diseases. PURPOSE: We aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis. METHODS: 16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis. RESULTS: Clinical 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. CONCLUSION: In conclusion, these data suggest a specific clinical and microbiological approach in patients with humoral deficiency in order to detect H. bilis hepatobiliary diseases.

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.

Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study.

BACKGROUND: Listeriosis is a severe foodborne infection and a notifiable disease in France. We did a nationwide prospective study to characterise its clinical features and prognostic factors. METHODS: MONALISA was a national prospective observational cohort study. We enrolled eligible cases declared to the National Reference Center for Listeria (all microbiologically proven) between Nov 3, 2009, and July 31, 2013, in the context of mandatory reporting. The outcomes were analysis of clinical features, characterisation of Listeria isolates, and determination of predictors of 3-month mortality or persisting impairment using logistic regression. A hierarchical clustering on principal components was also done for neurological and bacteraemic cases. The study is registered at ClinicalTrials.gov, number NCT01520597. FINDINGS: We enrolled 818 cases from 372 centres, including 107 maternal-neonatal infections, 427 cases of bacteraemia, and 252 cases of neurolisteriosis. Only five (5%) of 107 pregnant women had an uneventful outcome. 26 (24%) of 107 mothers experienced fetal loss, but never after 29 weeks of gestation or beyond 2 days of admission to hospital. Neurolisteriosis presented as meningoencephalitis in 212 (84%) of 252 patients; brainstem involvement was only reported in 42 (17%) of 252 patients. 3-month mortality was higher for bacteraemia than neurolisteriosis (hazard ratio [HR] 0·54 [95% CI 0·41-0·69], p<0·0001). For both bacteraemia and neurolisteriosis, the strongest mortality predictors were ongoing cancer (odds ratio [OR] 5·19 [95% CI 3·01-8·95], p<0·0001), multi-organ failure (OR 7·98 [4·32-14·72], p<0·0001), aggravation of any pre-existing organ dysfunction (OR 4·35 [2·79-6·81], p<0·0001), and monocytopenia (OR 3·70 [1·82-7·49], p=0·0003). Neurolisteriosis mortality was higher in blood-culture positive patients (OR 3·67 [1·60-8·40], p=0·002) or those receiving adjunctive dexamethasone (OR 4·58 [1·50-13·98], p=0·008). INTERPRETATION: The severity of listeriosis is higher than reported elsewhere. We found evidence of a significantly reduced survival in patients with neurolisteriosis treated with adjunctive dexamethasone, and also determined the time window for fetal losses. MONALISA provides important new data to improve management and predict outcome in listeriosis. FUNDING: Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

Legionnaire's Disease in Compromised Hosts.

Legionnaire's 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.

Biological markers in the diagnosis of tuberculous pleural effusion.

Tuberculosis is one of the main etiologies to evoke in the context of lymphocyte pleurisy. However, diagnosis is difficult and is based on mycobacteriology that is not enough sensitive and time-consuming, or on histology that requires invasive biopsy gesture. This literature review, carried out from Medline, summarizes the main meta-analyzes, reviews, and originator publications in English on biomarkers, classic and more innovative, studied for the diagnosis of tuberculous pleurisy. Among the immuno-biochemical markers, interferon-γ (IFN-γ), isoenzyme of adenosine deaminase 2 (ADA2) and total adenosine deaminase (ADA) seem the most relevant with respective sensitivities of 89% (87-91), 97.2% (95 to 98.7) and 92% (90-93) and specificities of 97% (96-98), 94.2% (91.8 to 96) and 90% (89-91). About molecular biology, PCR Xpert MTB/RIF has a sensitivity of 46.4% (26.3 to 67.8), which is much higher than the direct examination, while providing rapid diagnostic confirmation, with a specificity of 99.1% (95.2 to 99.8), and a resistance to rifampicin screening. The release assay of interferon-γ (IGRA) is less effective with a sensitivity of 75% (69-81) and a specificity of 82% (75-88) in blood and a sensitivity of 80% (74-86%) and a specificity of 72% (64-80) in pleural fluid. Other biomarkers (including several cytokines) might have an interest but are still under evaluation. These innovative methods, particularly the determination of ADA and the use of PCR Xpert MTB/RIF should find their place in the diagnostic algorithm of TB pleurisy.

A French National Survey on Clotting Disorders in Mastocytosis.

Mastocytosis 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 Willebrand's 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.

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.

[Mucormycosis: therapeutic news]. / Mucormycoses - Actualités thérapeutiques.

Mucormycosis is a life-threatening invasive fungal infection that arises among immunocompromised patients (haematological malignancies, solid organ transplantation, diabetes mellitus). The most frequent sites of infection are pulmonary, rhinocerebral, cutaneous and disseminated. Reversal of the underlying conditions is mandatory for controlling mucormycosis. Another cornerstone of mucormycosis treatment is prompt and aggressive surgery. It is achieved by extensive surgical debridement of necrotic tissues. Finally an antifungal therapy is needed. The first-line chemotherapy of mucormycosis includes high-dose liposomal amphotericin B (≥ 5 mg/kg/day). The duration of antifungal chemotherapy is not defined but guided by the resolution of all associated symptoms and findings (usually 6-8 weeks). Maintenance therapy/secondary prophylaxis by posaconazole has to be considered in persistently immuno compromised patients.