Risk factors associated with nausea and vomiting in children with cancer receiving chemotherapy.

INTRODUCTION: Despite treatment with antiemetic medications, nausea remains uncontrolled for many children receiving chemotherapy. One reason is that risk factors for nausea in children remain poorly explored. The purpose of this study was to identify risk factors for chemotherapy-induced nausea (CIN) in children. METHODS: Prospective, observational study including 101 children (median age 6.4 years, range 0.8-17.9) with cancer receiving moderately or highly emetogenic chemotherapy. Primary endpoints were complete control of acute and delayed CIN, defined as no nausea in the acute phase 0-24 h after chemotherapy and in the delayed phase starting after the acute phase and ending 5 days later. Multivariable analyses included age, sex, cancer type, susceptibility to motion sickness, chemotherapy duration, numbers of antiemetics, co-administration with opioids or tricyclic antidepressants, and previously uncontrolled nausea or vomiting. RESULTS: Acute CIN was associated with susceptibility to motion sickness (odds ratio [OR] 5.73, 95% confidence interval [CI] 1.36-33.7) and older age (OR 4.19, 95% CI 1.30-14.7), comparing age group 8-18 years with 0-3 years. Delayed CIN was associated with uncontrolled acute nausea or vomiting (OR 10.3, 95% CI 2.65-50.9), highly emetogenic chemotherapy (OR 8.26, 95% CI 1.17-76.8), and having a hematologic cancer type (OR 7.81, 95% CI 1.05-79.2). CONCLUSIONS: Susceptibility to motion sickness and age can influence the risk of acute CIN. More research is needed on how best to integrate risk information in preventive antiemetic strategies. Sufficient acute nausea and vomiting control are crucial to prevent delayed CIN.

Shift in bacterial etiology from the CAPNETZ cohort in patients with community-acquired pneumonia: data over more than a decade.

To determine the most relevant pathogens for CAP in Germany, patients with radiologically confirmed pulmonary infiltrates and at least one clinical sign of lung infection were prospectively recruited within the CAPNETZ cohort from 2004 until 2016. In 990 out of 4.672 patients (21%) receiving complete diagnostics the most prominent change of pathogens was a decrease of S. pneumoniae (58% in 2004 to 37.5% in 2016; p ≤ 0.001, ρ = - 0.148) and an increase of H. influenzae (12.2% to 20.8%; p = 0.001, ρ = 0.104).

Health consequences of androgenic anabolic steroid use.

BACKGROUND: The lifetime prevalence of androgenic anabolic steroid abuse is estimated to be around 6% for men, but there is limited knowledge about the side effects of these drugs. OBJECTIVE: To investigate mortality and morbidity amongst users of androgenic anabolic steroids (AAS). METHODS: In this retrospective matched cohort study, 545 male subjects tested positive for AAS in Danish fitness centres during the period 3 January 2006 to 1 March 2018. Subjects were matched with 5450 male controls. In addition, 644 men who were sanctioned because they refused to submit to a doping test and 6440 controls were included as a replication cohort. RESULTS: Mortality was three times higher amongst users of AAS than amongst nonuser controls (hazard ratio 3.0, 95% CI 1.3-7.0). The median annual number of hospital contacts was 0.81 in the cohort of AAS users and 0.36 in the control cohort (P < 0.0001). Acne, gynaecomastia and erectile dysfunction affected more than 10% of the androgenic anabolic steroid users, and the prevalence of these disorders was significantly higher than in the control group (P < 0.0001). The results could be replicated in a similar cohort. CONCLUSION: Androgenic anabolic steroid users have an increased risk of dying and significantly more hospital admissions than their nonuser peers. Side effects of AAS and their metabolites were highly prevalent. Given the high rate of androgenic anabolic steroid abuse, these side effects are of public health concern.

Higher chlorzoxazone clearance in obese children compared with nonobese peers.

AIMS: To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS: Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS: Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P < 0.0001. Diabetic biomarkers were significantly increased in obese children, while fasting blood glucose and Hba1c levels were nonsignificant between groups. Liver fat content was not associated with CLZ Cl. CONCLUSION: Oral clearance of CLZ was increased two-fold in obese children vs. nonobese children aged 11-18 years. This indicates an increased CYP2E1 activity of clinical importance, and dose adjustment should be considered for CLZ.

[Epidemiology, Diagnosis and Treatment of Adult Patients with Nosocomial Pneumonia - Update 2017 - S3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy, the German Radiological Society and the Society for Virology]. / Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie ­ Update 2017.

Nosocomial pneumonia (HAP) is a frequent complication of hospital care. Most data are available on ventilator-associated pneumonia. However, infections on general wards are increasing. A central issue are infections with multidrug resistant (MDR) pathogens which are difficult to treat in the empirical setting potentially leading to inappropriate use of antimicrobial therapy.This guideline update was compiled by an interdisciplinary group on the basis of a systematic literature review. Recommendations are made according to GRADE giving guidance for the diagnosis and treatment of HAP on the basis of quality of evidence and benefit/risk ratio.This guideline has two parts. First an update on epidemiology, spectrum of pathogens and antimicrobials is provided. In the second part recommendations for the management of diagnosis and treatment are given. New recommendations with respect to imaging, diagnosis of nosocomial viral pneumonia and prolonged infusion of antibacterial drugs have been added. The statements to risk factors for infections with MDR pathogens and recommendations for monotherapy vs combination therapy have been actualised. The importance of structured deescalation concepts and limitation of treatment duration is emphasized.

Recommendations of the German Central Committee against Tuberculosis (DZK) and the German Respiratory Society (DGP) for the Diagnosis and Treatment of Non-tuberculous Mycobacterioses.

Non-tuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis-complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide, a rising prevalence and significance of non-tuberculous mycobacterioses is recognized. The present recommendations summarise current aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of non-tuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

[Management of Adult Community-acquired Pneumonia and Prevention - Update 2016]. / Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie und Prävention - Update 2016.

The present guideline provides a new and updated concept of treatment and prevention of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2009.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment as well as primary and secondary prevention.

Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

[Recommendations for diagnosis and treatment of nontuberculous mycobacterioses of the German Central Committee against tuberculosis and the German Respiratory Society]. / Empfehlungen zur Diagnostik und Therapie nichttuberkulöser Mykobakteriosen des Deutschen Zentralkomitees zur Bekämpfung der Tuberkulose (DZK) und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Nontuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide a rising prevalence and significance of nontuberculous mycobacterioses can be recognized. The present recommendations summarise actual aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of nontuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

Pulmonary haptoglobin and CD163 are functional immunoregulatory elements in the human lung.

BACKGROUND: The acute-phase protein haptoglobin (Hp) and its receptor CD163 serve as immunomodulators and possess anti-inflammatory besides antioxidant functions. OBJECTIVES: To further understand the role of the recently described pulmonary Hp (pHp) and its receptor CD163 in case of inflammation and infection, pHp and CD163 were investigated on mRNA and protein level to gain insight into the cellular events taking place upon stimulation with the inflammatory mediators LPS, Pam3, cytokine IL-6 and dexamethasone, and upon infection with respiratory pathogens (Haemophilus influenzae, Streptococcuspneumoniae and Chlamydia pneumoniae) by use of a human ex vivo tissue culture model and cell cultures of A549 and alveolar epithelial cells type II. In addition, pHp and CD163 expression in COPD and sarcoidosis was assessed. METHODS: We conducted experiments using 942 ex vivo cultured lung samples applying immunohistochemistry, immunocytochemistry, in situ hybridization, immunofluorescence, real-time PCR, RT-PCR, slot and Western immunoblot analyses with tissue lysates and culture supernatants as well as ELISA and cytometric bead array analyses. RESULTS: This study describes for the first time the expression, regulation and secretion of pHp and its receptor CD163 in the human lung. The release of soluble mediators from A549 cell line and human monocyte-derived macrophages was observed indicating that Hp differentially activates the release of soluble mediators and major chemoattractants. CONCLUSIONS: The findings indicate a native function of pHp and CD163 as functional pulmonary defense elements due to local expression, regulation and secretion during lung infection and as part of the inflammatory immune response of the respiratory system.

Urine and serum concentrations of inhaled and oral terbutaline.

We examined urine and serum concentrations after therapeutic use of single and repetitive doses of inhaled and supratherapeutic oral use of terbutaline. We compared the concentrations in 10 asthmatics and 10 healthy subjects in an open-label, cross-over study with 2 mg inhaled and 10 mg oral terbutaline on 2 study days. Further, 10 healthy subjects were administrated 1 mg inhaled terbutaline in 4 repetive doses with total 4 mg. Blood samples were collected at baseline and during 6 h after the first inhalations. Urine samples were collected at baseline and during 12 h after the first inhalations. Median (IQR) urine concentrations peaked in the period 0-4 h after inhalation with Cmax 472 (324) ng/mL in asthmatics and 661 (517) ng/mL in healthy subjects, and 4-8 h after oral use with Cmax 666 (877) ng/mL in asthmatic and 402 (663) ng/mL in healthy subjects. In conclusion we found no significant differences in urine and serum concentrations between asthmatic and healthy subjects. We compared urine and serum concentrations after therapeutic inhaled doses and supratherapeutic oral doses and observed significant statistical differences in both groups but found it impossible to distinguish between therapeutic and prohibited use based on doping tests with urine and blood samples.

[Tumor and pulmonary cysts - Lice, fleas or both?]. / Tumor und Zysten in der Lunge - Läuse, Flöhe oder beides?

The article reports on a 60-year-old female patient with insulin-dependent diabetes who presented with coughing, chest pains and low-grade fever. Auscultation revealed a vesicular breathing noise bilaterally and the laboratory results showed slightly increased infection parameters. The initial diagnostic work-up included chest x-ray and contrast-enhanced computed tomography (CT). The diagnostics resulted in a pulmonary adenocarcinoma with osseous and hepatic metastases. Furthermore, widespread bilateral pulmonary cystic lesions were observed. Regarding the wide spectrum of differential diagnoses and the clinical pattern, the findings have to be regarded as cystic metastases and not as primary cystic lung disease.

[Recommendations for therapy, chemoprevention and chemoprophylaxis of tuberculosis in adults and children. German Central Committee against Tuberculosis (DZK), German Respiratory Society (DGP)]. / Empfehlungen zur Therapie, Chemoprävention und Chemoprophylaxe der Tuberkulose im Erwachsenen- und Kindesalter. Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose (DZK), Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Several new international recommendations have been published since the German Central Committee against Tuberculosis (DZK) published its recommendations for drug treatment of tuberculosis (TB) in 2001 and for chemoprevention of latent tuberculosis infection (LTBI) in 2004. These international publications have been integrated in the present new recommendations which describe both the treatment of active TB and preventive treatment, pointing out specific adaptations for Germany. Separate sections deal with the current management of mono-, poly-, and multiresistance or drug intolerance, of TB in children, of different forms of extrapulmonary TB, of LTBI and of special situations such as HIV infection, renal or hepatic insufficiency, infection following BCG instillation in bladder cancer or in case of adverse drug reactions. The following aspects differ from the previous recommendations: A three-drug regimen for the so-called fully susceptible minimal TB is no longer recommended in adults. A dosage of 15 mg/kg body weight of ethambutol for adults is regarded as sufficient. Four secondline drugs (supplemented by pyrazinamide, where appropriate) are recommended for multidrug-resistant tuberculosis (MDR-TB). MDR-TB should be treated over a period of at least 20 months, with an injectable drug administered for a minimum of 8 months (initial phase). Ciprofloxacine and ofloxacine are no longer used to treat TB. It is also recommended to offer an HIV test to all TB patients to complement antiretroviral therapy, if necessary, and to adapt the antituberculous therapy accordingly.

[Epidemiology, diagnosis and treatment of adult patients with nosocomial pneumonia. S-3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy]. / Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie. S-3 Leitlinie der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin e.V., der Deutschen Gesellschaft für Infektiologie e.V., der Deutschen Gesellschaft für Hygiene und Mikrobiologie e.V., der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e.V. und der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V.

Nosocomial pneumonia (HAP) is a frequent complication of hospital care. Most data are available on ventilator-associated pneumonia. However infections on general wards are also increasing. A central issue are infections with multi drug resistant (MDR) pathogens which are difficult to treat particularly in the empirical setting potentially leading to inappropriate use of antimicrobial therapy. This guideline was compiled by an interdisciplinary group on the basis of a systematic literature review. Recommendations are made according to GRADE giving guidance for the diagnosis and therapy of HAP on the basis of quality of evidence and benefit/risk ratio. The guideline has two parts. First an update on epidemiology, spectrum of pathogens and antiinfectives is provided. In the second part recommendations for the management of diagnosis and treatment are given. Proper microbiologic work up is emphasized for knowledge of the local patterns of microbiology and drug susceptibility. Moreover this is the optimal basis for deescalation in the individual patient. The intensity of antimicrobial therapy is guided by the risk of infections with MDR. Structured deescalation concepts and strict limitation of treatment duration should lead to reduced selection pressure.

Urine concentrations of repetitive doses of inhaled salbutamol.

We examined blood and urine concentrations of repetitive doses of inhaled salbutamol in relation to the existing cut-off value used in routine doping control. We compared the concentrations in asthmatics with regular use of beta2-agonists prior to study and healthy controls with no previous use of beta2-agonists. We enrolled 10 asthmatics and 10 controls in an open-label study in which subjects inhaled repetitive doses of 400 microgram salbutamol every second hour (total 1600 microgram), which is the permitted daily dose by the World Anti-Doping Agency (WADA). Blood samples were collected at baseline, 30 min, 1, 2, 3, 4, and 6 h after the first inhalations. Urine samples were collected at baseline, 0-4 h, 4-8 h, and 8-12 h after the first inhalations. Median urine concentrations peaked in the period 4-8 h after the first inhalations in the asthmatics and between 8-12 h in controls and the median ranged from 268 to 611 ng×mL (-1). No samples exceeded the WADA threshold value of 1000 ng×mL (-1) when corrected for the urine specific gravity. When not corrected one sample exceeded the cut-off value with urine concentration of 1082 ng×mL (-1). In conclusion we found no differences in blood and urine concentrations between asthmatic and healthy subjects. We found high variability in urine concentrations between subjects in both groups. The variability between subjects was still present after the samples were corrected for urine specific gravity.

[Community-acquired pneumonia]. / Ambulant erworbene Pneumonie.

Community-acquired pneumonia (CAP) is the most common form of severe infectious disease in developed countries. The mortality is particularly high in elderly patients. For risk stratification simple clinical scores such as the CRB-65 (confusion, respiratory rate, blood pressure, age over 65 years) are recommended. The spectrum of pathogens is characterized by Pneumococcus and Haemophilus influenzae as well as atypical and viral pathogens. Resistance plays a subordinate role in Germany. In addition to the clinical symptoms an X-ray examination is also helpful to confirm the diagnosis and biomarkers can also be useful. Microbiological investigations are not necessary in practice. Particularly in cases of uncharacteristic clinical symptoms and therapy failure there are many differential diagnoses which can be hidden behind the clinical diagnosis of pneumonia. The calculated treatment of CAP should correspond to the current recommendations in national guidelines. The options for prevention by general measures and vaccinations should be applied consistently.

Challenges in conducting paediatric trials with off-patent drugs.

INTRODUCTION: For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge. AIM: This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement. DISCUSSION: Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug. CONCLUSION: Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life.

[Diagnosis of infections in pneumology]. / Infektionsdiagnostik in der Pneumologie.

Lower respiratory tract infections rank among the leading causes of morbidity and mortality worldwide. In clinical practice, especially in the care of severely ill patients, discrimination between tracheobronchial colonisation with potentially pathogenic microorganisms and infection is a common diagnostic challenge. While prompt antibiotic treatment is needed in critically ill patients with pneumonia, an inadequate use of antibiotics is the major cause for the emergence of drug-resistant microorganisms. The first part of this review provided a detailed overview of the currently available methods for the diagnosis of pulmonary infectious diseases. In the present second part of the manuscript, we focus upon methods and criteria for the differentiation between lower respiratory tract bacterial colonisation and lower respiratory tract infections, highlighting important pathogens.

[Diagnosis of infections in pneumology]. / Infektionsdiagnostik in der Pneumologie.

Lower respiratory tract infections play an important role in the ambulatory and hospital health-care sectors. State-of-the-art diagnoses of lower respiratory tract infections and methods to differentiate bacterial lower respiratory tract infections from colonisation have been described in the first two parts of this review series. The present article summarises current diagnostic methods and treatment indications for viral and fungal respiratory infections. These recommendations may guide clinicians in their decision to prescribe or withhold antibiotic therapies in daily clinical practice.