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.

Desenvolvimento do software para monitoração neural em hanseníase

No diagnóstico das lesões neurológicas periféricas é usualmente realizado o exame clínico que consta de mapeamento sensitivo, palpação de nervo e teste de força muscular associado a outros métodos como a avaliação analógica da dor. Todos esses exames podem ser graduados numericamente, constituindo assim um Escore Clínico (EC) para o monitoramento da função neural em estudos longitudinais e análises estatísticas. Atualmente os registros são manuais e anexados ao prontuário do paciente dificultando a organização e visualização em longo prazo da função neural.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.

This part of the EFISG guidelines focuses on non-neutropenic adult patients. Only a few of the numerous recommendations can be summarized in the abstract. Prophylactic usage of fluconazole is supported in patients with recent abdominal surgery and recurrent gastrointestinal perforations or anastomotic leakages. Candida isolation from respiratory secretions alone should never prompt treatment. For the targeted initial treatment of candidaemia, echinocandins are strongly recommended while liposomal amphotericin B and voriconazole are supported with moderate, and fluconazole with marginal strength. Treatment duration for candidaemia should be a minimum of 14 days after the end of candidaemia, which can be determined by one blood culture per day until negativity. Switching to oral treatment after 10 days of intravenous therapy has been safe in stable patients with susceptible Candida species. In candidaemia, removal of indwelling catheters is strongly recommended. If catheters cannot be removed, lipid-based amphotericin B or echinocandins should be preferred over azoles. Transoesophageal echocardiography and fundoscopy should be performed to detect organ involvement. Native valve endocarditis requires surgery within a week, while in prosthetic valve endocarditis, earlier surgery may be beneficial. The antifungal regimen of choice is liposomal amphotericin B +/- flucytosine. In ocular candidiasis, liposomal amphotericin B +/- flucytosine is recommended when the susceptibility of the isolate is unknown, and in susceptible isolates, fluconazole and voriconazole are alternatives. Amphotericin B deoxycholate is not recommended for any indication due to severe side effects.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT).

Fungal diseases still play a major role in morbidity and mortality in patients with haematological malignancies, including those undergoing haematopoietic stem cell transplantation. Although Aspergillus and other filamentous fungal diseases remain a major concern, Candida infections are still a major cause of mortality. This part of the ESCMID guidelines focuses on this patient population and reviews pertaining to prophylaxis, empirical/pre-emptive and targeted therapy of Candida diseases. Anti-Candida prophylaxis is only recommended for patients receiving allogeneic stem cell transplantation. The authors recognize that the recommendations would have most likely been different if the purpose would have been prevention of all fungal infections (e.g. aspergillosis). In targeted treatment of candidaemia, recommendations for treatment are available for all echinocandins, that is anidulafungin (AI), caspofungin (AI) and micafungin (AI), although a warning for resistance is expressed. Liposomal amphotericin B received a BI recommendation due to higher number of reported adverse events in the trials. Amphotericin B deoxycholate should not be used (DII); and fluconazole was rated CI because of a change in epidemiology in some areas in Europe. Removal of central venous catheters is recommended during candidaemia but if catheter retention is a clinical necessity, treatment with an echinocandin is an option (CII(t) ). In chronic disseminated candidiasis therapy, recommendations are liposomal amphotericin B for 8 weeks (AIII), fluconazole for >3 months or other azoles (BIII). Granulocyte transfusions are only an option in desperate cases of patients with Candida disease and neutropenia (CIII).

Upper and lower respiratory tract viral infections and acute graft rejection in lung transplant recipients.

BACKGROUND: Lung transplant recipients are frequently exposed to respiratory viruses and are particularly at risk for severe complications. The aim of this study was to assess the association among the presence of a respiratory virus detected by molecular assays in bronchoalveolar lavage (BAL) fluid, respiratory symptoms, and acute rejection in adult lung transplant recipients. METHODS: Upper (nasopharyngeal swab) and lower (BAL) respiratory tract specimens from 77 lung transplant recipients enrolled in a cohort study and undergoing bronchoscopy with BAL and transbronchial biopsies were screened using 17 different polymerase chain reaction-based assays. RESULTS: BAL fluid and biopsy specimens from 343 bronchoscopic procedures performed in 77 patients were analyzed. We also compared paired nasopharyngeal and BAL fluid specimens collected in a subgroup of 283 cases. The overall viral positivity rate was 29.3% in the upper respiratory tract specimens and 17.2% in the BAL samples (P < .001). We observed a significant association between the presence of respiratory symptoms and positive viral detection in the lower respiratory tract (P = .012). Conversely, acute rejection was not associated with the presence of viral infection (odds ratio, 0.41; 95% confidence interval, 0.20-0.88). The recovery of lung function was significantly slower when acute rejection and viral infection were both present. CONCLUSIONS: A temporal relationship exists between acute respiratory symptoms and positive viral nucleic acid detection in BAL fluid from lung transplant recipients. We provide evidence suggesting that respiratory viruses are not associated with acute graft rejection during the acute phase of infection.

Disseminated Rhizopus microsporus infection cured by salvage allogeneic hematopoietic stem cell transplantation, antifungal combination therapy, and surgical resection.

Invasive Zygomycetes infection complicating prolonged neutropenia is associated with high mortality in the absence of immune recovery. We report a patient who developed disseminated zygomycosis due to Rhizopus microsporus during induction chemotherapy for acute myeloid leukemia. Rescue allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed as her only chance of cure of this infection and to treat refractory leukemia. Posaconazole combined with liposomal amphotericin B contained the zygomycosis during prolonged neutropenia due to allo-HSCT followed by intense immunosuppression for grade IV acute graft-versus-host disease. Surgical removal of all infected sites after immune recovery, with prolonged posaconazole treatment, ultimately cured the infection. New combination antifungal therapies might sufficiently control disseminated zygomycosis to allow allo-HSCT to be performed, assuring life-saving immune recovery. Surgery appears to be necessary for definite cure of these infections.

Invasive fusariosis with prolonged fungemia in a patient with acute lymphoblastic leukemia: case report and review of the literature.

Fusariumspp are rare but important opportunistic pathogens in immunocompromised patients. Disseminated fusarial infections occur mostly in patients with hematologic malignancies with myelosuppressive chemotherapy or in patients with severe immunodeficiency. Although more frequent than Aspergillus fungemia, Fusarium fungemia remains a rare event. We describe the case of a female patient with febrile neutropenia and persistent fungemia due to Fusarium solani, treated with posaconazole and liposomal amphotericin B. A review of the literature for Fusariumspp fungemia was carried out.

A randomized prospective study of cefepime plus metronidazole with imipenem-cilastatin in the treatment of intra-abdominal infections.

BACKGROUND: Presumptive antimicrobial therapy is an important aspect of the management of intra-abdominal infections. Together with surgery, antimicrobial combinations are still widely used to achieve the required spectrum of activity. The aim of this study was to evaluate the efficacy of parenteral cefepime + metronidazole vs imipenem-cilastatin for the treatment of intra-abdominal infections in adult patients. METHODS: Patients with a clinically confirmed diagnosis of intra-abdominal infection were randomized to one of two treatment regimens: cefepime 2 g iv/12 h plus metronidazole 500 mg/8 h or imipenem-cilastatin 500 mg iv/6 h. The primary measure of clinical response was the decline of pre-treatment signs and symptoms of infection. The duration of follow-up was 30 days. Treatment failure was defined as either a lack of improvement or a worsening of pre-treatment signs and symptoms of infection. Surgical management of the infection was determined by the surgeon-in-charge. RESULTS: Of the 122 intended-to-treat patients included in the study, 60 patients (33 men) were randomized to cefepime + metronidazole and 61 (27 men) to imipenem-cilastatin. Cefepime + metronidazole treatment was successful in 52 (87%) patients and imipenem-cilastatin in 44 (72%) patients (p = 0.004). Microbiological eradication was established in similar proportions in both groups (cefepime + metronidazole, 43; imipenem-cilastatin, 38). CONCLUSION: Further studies are warranted to confirm the better results with the cefepime + metronidazole regimen for the treatment of intra-abdominal infections.

Impact of positive legionella urinary antigen test on patient management and improvement of antibiotic use.

AIM: To assess the incidence of legionella infection over a 27 month period at a large university hospital. MATERIAL AND METHODS: The present retrospective cohort study enrolled patients with legionellosis, defined as those presenting a positive urinary antigen for legionella together with a medical history, clinical findings, and radiological findings consistent with pneumonia. These patients were evaluated to determine the relation between their test results and changes in treatment modalities. A control group of patients with pneumonia but a negative urinary antigen test for legionella were also analysed. RESULTS: Twenty seven of 792 assessed patients tested positive for legionella. In 22 of these patients, legionella active antibiotics were administered empirically. In seven patients, the test results prompted a legionella specific treatment, whereas in 12 cases, non-specific antibiotics were stopped within 24 hours. Overall, treatment was altered in more than half of the patients as a result of the test results. CONCLUSIONS: The urinary antigen may have a direct impact on clinical management of pulmonary legionellosis. However, patient comorbidities and individual clinical judgment are still important for determining the best treatment to be given in each individual case.

Caspofungin--a new therapeutic option for oropharyngeal candidiasis.

Patients with AIDS are often severely immunocompromised. These patients commonly develop opportunistic infections such as oropharyngeal candidiasis whose treatment may prove to be difficult. Caspofungin belongs to a new class of antifungal agents that have a different mode of action to azoles and polyenes. This new agent is the first inhibitor of fungal glucan synthesis to receive approval for the treatment of mucosal and invasive candidiasis and invasive aspergillosis. Caspofungin is well-tolerated and represents a substantial improvement over existing therapeutic options for patients prone to azole-resistant candida infection or who cannot tolerate amphotericin B.

Caspofungin in the treatment of oropharyngeal candidiasis.

A patient with AIDS developed oropharyngeal candidiasis. Candida albicans and C. glabrata were isolated from the patient and found to be resistant to fluconazole and itraconazole in vitro. Voriconazole therapy was initiated, but discontinued when the C. albicans strain isolated from the patient was found to be resistant to it. The patient failed to respond to subsequent therapy with a combination of amphotericin B and 5-flucytosine. Therapy with caspofungin was then initiated (70 mg loading dose, followed by 50 mg/day). The patient responded favourably to caspofungin, with complete resolution of signs and symptoms.

Arterial mycotic aneurysm rupture following kidney-pancreatic transplantation with exocrine pancreatic drainage into the bladder: an unusual observation.

In this case report, we describe two patients who received a kidney-pancreatic transplant through technique of exocrine pancreatic drainage into the bladder, and who subsequently developed arterial mycotic aneurysms at the site of the arterial anastomosis of the homograft.

Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients.

OBJECTIVE: Phase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DESIGN: Multicenter, double-blind, phase III, placebo-controlled, randomized study. SETTING: A total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PATIENTS: A total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. INTERVENTION: After randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17-96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor alpha concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. CONCLUSION: Lenercept had no significant effect on mortality in the study population.

Ecstasy ingestion and fulminant hepatic failure: liver transplantation to be considered as a last therapeutic option.

Severe adverse effects due to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are reported with increasing frequency in the medical literature. The signs of acute toxicity most often seen are fulminant hyperthermia, hyperexcitatory states, acute renal failure and hyponatraemia. In 1992, hepatotoxicity was also described with unexplained jaundice and hepatomegaly after ingestion of MDMA. We report a case of severe toxic hepatitis following ingestion of MDMA with fulminant hepatic failure which required auxiliary liver transplantation. The diagnosis was necrotic toxic hepatitis following ecstasy ingestion. The outcome was successful, and the patient was discharged from ICU 20 d after surgery. Hepatotoxic effects of MDMA seem infrequent, but may be lethal; liver transplantation is the ultimate therapeutic option in some cases.

Unusual association: Streptococcus bovis tricuspid endocarditis with atrial-septal aneurysm and patent foramen ovale.

Streptococcus bovis endocarditis is a frequent cause of streptococcal endocarditis and is associated with colonic tumours. The tricuspid valve is very rarely affected and its involvement is a complication which can lead to a less favourable outcome. We report the seventh case of tricuspid valve endocarditis due to S. bovis, and the first, to our knowledge, to be associated with an atrial-septal aneurysm and a patent foramen ovale. The underlying medical conditions and predisposing factors for development of tricuspid valve endocarditis are described and interesting new echocardiographic data are presented. The current guidelines on antibiotic therapy for S. bovis tricuspid valve endocarditis are reviewed.

p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group.

OBJECTIVE: To evaluate the safety and efficacy of p55 tumor necrosis factor receptor fusion protein, a recombinant chimeric protein of human p55 (type I) tumor necrosis factor receptor (CD120a) extracellular domain and IgG1 sequences (referred to as p55-IgG), in the treatment of patients with severe sepsis or septic shock. DESIGN: Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. SETTING: Forty-four community and university-affiliated hospitals in the United States and Europe. PATIENTS: There were 498 patients enrolled in this clinical trial. INTERVENTION: Patients prospectively stratified within each site into refractory shock or severe sepsis groups were randomized to receive a single infusion of p55-IgG, 0.083 mg/kg, 0.042 mg/kg, or 0.008 mg/kg, or placebo. Patients received standard aggressive medical/surgical care during the 28-day postinfusion period. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: The distribution of variables describing demographics, organ system dysfunction or failure, infecting microorganisms, predicted mortality, plasma interleukin 6 levels, and plasma tumor necrosis factor alpha (TNF-alpha) levels were similar among patients in the p55-IgG and placebo treatment arms. A planned interim analysis was performed after 201 patients were enrolled. Because a statistically nonsignificant trend toward increased mortality was present in patients who had received 0.008 mg/kg, this treatment arm was discontinued, and the study continued with 3 arms. Among all infused patients, there was a statistically nonsignificant trend toward reduced 28-day all-cause mortality in those who received p55-IgG compared with placebo-treated patients (5% reduction, 0.042 mg/kg vs placebo; 15% reduction, 0.083 mg/kg vs placebo; P=.30). However, in patients with severe sepsis and early septic shock (n=247), therapy with p55-IgG, 0.083 mg/kg, was associated with a 36% reduction in 28-day all-cause mortality compared with placebo (P=.07): 20 (23%) of 87 patients died among those treated with p55-IgG, 0.083 mg/kg; 30 (37%) of 82 among those treated with p55-IgG, 0.042 mg/kg; and 28 (36%) of 78 in the placebo group. A prospectively planned logistic regression analysis to assess treatment effect on 28-day all-cause mortality by means of predicted mortality and serum interleukin 6 levels as continuous covariates demonstrated a significant improvement in outcome for the patients with severe sepsis treated with p55-IgG, 0.083 mg/kg, compared with placebo (P=.01). Serious adverse events, including death and the development of new organ system dysfunction, were reported in 65% of patients infused with placebo, with no increased frequency (56%) present in the 2 p55-IgG treatment arms. There were no reports of immediate hypersensitivity reactions caused by p55-IgG. CONCLUSIONS: In this dose-finding study, there was no decrease in mortality between placebo and p55-IgG in all infused patients. In the prospectively defined population of patients with severe sepsis who received p55-IgG, 0.083 mg/kg, there was a trend toward reduced mortality at day 28 that became significant when predicted mortality and plasma interleukin 6 levels were included in a logistic regression analysis.

ARDS caused by herpes simplex virus pneumonia in a patient with Crohn's disease: a case report.

Pneumonia caused by herpes simplex virus type 1 (HSV1) is rare and occurs in severely immunosuppressed patients. HSV1 can be detected in bronchoalveolar lavage (BAL) from patients presenting with respiratory failure, but its direct effect on disease is difficult to prove. We demonstrate the causative role of HSV1 in the case of a 44-year-old male with Crohn's disease who presented to the intensive care unit with the acute respiratory distress syndrome after surgery. BAL cells were cultured and immunofluorescence confirmed the presence of HSV1 during the first weeks of illness. Increased IgG titers confirmed the diagnosis of a recurrent HSV1 infection. A lung biposy specimen showed fibroproliferation without pathogens. Immunosuppressive therapy had been stopped and acyclovir was introduced at this time. The diagnostic difficulties in this patient underline the importance of early recognition of viral infection as a potential cause of severe pneumonia in severely ill, immunocompromised patients.