Procalcitonin as a biomarker to guide treatments for patients with lower respiratory tract infections.

INTRODUCTION: Lower respiratory tract infections are amongst the main causes for hospital/intensive care unit admissions and antimicrobial prescriptions. In order to reduce antimicrobial pressure, antibiotic administration could be optimized through procalcitonin-based algorithms. AREAS COVERED: In this review, we discuss the performances of procalcitonin for the diagnosis and the management of community-acquired and ventilator-associated pneumonia. We provide up-to-date evidence and deliver clear messages regarding the purpose of procalcitonin to reduce unnecessary antimicrobial exposure. EXPERT OPINION: Antimicrobial pressure and resulting antimicrobial resistances are a major public health issue as well as a daily struggle in the management of patients with severe infectious diseases, especially in intensive care units where antibiotic exposure is high. Procalcitonin-guided antibiotic administration has proven its efficacy in reducing unnecessary antibiotic use in lower respiratory tract infections without excess in mortality, hospital length of stay or disease relapse. Procalcitonin-guided algorithms should be implemented in wards taking care of patients with severe infections. However, procalcitonin performances are different regarding the setting of the infection (community versus hospital-acquired infections) the antibiotic management (start or termination of antibiotic) as well as patient's condition (immunosuppressed or in shock) and we encourage the physicians to be aware of these limitations.

Infectious complications after intensive chemotherapy with CLAG-M versus 7+3 for AML and other high-grade myeloid neoplasms.

Contemporary data on infections after intensive chemotherapy for acute myeloid leukemia (AML) are scarce. Cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone ("CLAG-M") may result in higher remission rates than standard-dose cytarabine plus anthracycline ("7 + 3") but may result in more infections. We compared moderate to severe infections occurring up to 90 days after the first induction cycle for AML or other high-grade myeloid neoplasms in patients receiving CLAG-M for newly diagnosed (n = 196) or relapsed/refractory disease (n = 131) or 7 + 3 for newly diagnosed disease (n = 115). For newly diagnosed disease, microbiologically documented infections were more frequent after CLAG-M compared to 7 + 3 (adjusted rate ratio, 1.65 [95% CI, 1.06-2.58]; P = 0.03), with a cumulative incidence of 27.8% and 16.5% by day 90, respectively. Patients receiving CLAG-M for relapsed/refractory disease had the highest cumulative incidence of 50.7%. Bacterial bloodstream infections were the most frequent followed by respiratory tract infections. Among 29 patients (7%) who died, infection was a primary or contributing cause of death in 59%. These data indicate that infections continue to cause substantial morbidity in patients treated for AML, especially those treated for relapsed/refractory disease, and are more common with newer, more myelosuppressive regimens such as CLAG-M. Improved strategies for infection prevention are needed.

Synergistic effect of Mahaenggamseok-tang in the treatment of pediatric patients with lower respiratory tract infections: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Infants are often hospitalized because of lower respiratory tract infections, and overuse of antibiotics to treat such infections has led to severe problems. Herbal medicines may be more effective and safer than antibiotics. Mahaenggamseok-tang is a common herbal medicine in Asia, but the evidence for its effectiveness in lower respiratory tract infection treatment is insufficient. This review assesses the efficacy of Mahaenggamseok-tang in treating lower respiratory tract infections. METHODS: The study used Chinese, English, and Korean databases, as well as one Japanese database. All included studies were randomized controlled trials comparing Mahaenggamseok-tang with medication to treat lower respiratory tract infections. Studies using Mahaenggamseok-tang plus Western medicine were also included. Standardized mean difference (SMD), risk ratio (RR) with 95% confidence interval (CI), and risk of bias were analyzed using Review Manager 5.4 software. The GRADEpro website was used to assess the reviews. RESULTS: Seventeen randomized controlled trials with a total of 1993 participants were included in the meta-analysis. All studies compared the Mahaenggamseok-tang plus Western medicine group to the Western medicine only group. Meta-analysis showed that Mahaenggamseok-tang affected total effective rate (risk ratio: 1.20, 95% confidence interval [CI]: 1.10-1.31, P < .001), cough disappearance time (SMD: -1.62, 95% CI: -2.30 to -0.95, P < .001), fever disappearance time (SMD: -2.04, 95% CI: -2.87 to -1.21, P < .001), abnormal lung sound disappearance time (SMD: -1.68, 95% CI: -2.43 to -0.93, P < .001), Creactive protein (SMD: -3.18, 95% CI: -4.36 to -1.99, P < .001), procalcitonin (SMD: -5.04, 95% CI: -9.20 to -0.88, P < .05), tumor necrosis factor-α (SMD: -0.84, 95% CI: -1.46 to -0.23, P < .01), IgE (SMD: -2.69, 95% CI: -2.91 to -2.47, P < .001), and adverse events (risk ratio: 0.44, 95% CI: 0.29-0.68, P < .001), but not interleukin-6 (SMD: -1.59, 95% CI: -3.48 to 0.30, P>.05). DISCUSSION: Mahaenggamseok-tang plus Western medicine is more effective and safer than Western medicine alone for treating lower respiratory tract infections. However, the included randomized controlled trials were not randomized well; therefore, better randomized randomized controlled trials are needed to make significant recommendations.PROSPERO registration number: CRD42020165698.

Asthma symptoms and respiratory infections in Malaysian students-associations with ethnicity and chemical exposure at home and school.

Little is known on respiratory effects of indoor chemicals in the tropics. We investigated associations between asthma and respiratory infections in Malaysian students and chemical exposure at home and at school. Moreover, we investigated differences in home environment between the three main ethnic groups in Malaysia (Malay, Chinese, Indian). Totally, 462 students from 8 junior high schools in Johor Bahru participated (96% participation rate). The students answered a questionnaire on health and home environment. Climate, carbon dioxide (CO2), volatile organic compounds (VOC), formaldehyde and nitrogen dioxide (NO2) were measured inside and outside the schools. Multilevel logistic regression was applied to study associations between exposure and health. Totally 4.8% were smokers, 10.3% had wheeze, 9.3% current asthma, and had 18.8% any respiratory infection in the past 3 months. Malay students had more dampness or mould (p < 0.001), more environmental tobacco smoke (ETS) (p < 0.001) and more cats (p < 0.001) at home as compared to Chinese or Indian students. Wheeze was associated with ethnicity (p = 0.02; lower in Indian), atopy (p = 0.002), current smoking (p = 0.02) and recent indoor painting at home (p = 0.03). Current asthma was associated with ethnicity (p = 0.001; lower in Chinese) and para-dichlorobenzene in classroom air (p = 0.008). Respiratory infections were related to atopy (p = 0.002), ethylbenzene (p = 0.02) and para-dichlorobenzene (p = 0.01) in classroom air. Para-dichlorobenzene is used in Asia against insects. In conclusion, chemical emissions from recent indoor painting at home can increase the risk of wheeze. In schools, para-dichlorobenzene can increase the risk of current asthma and respiratory infections while ethylbenzene can increase the risk of respiratory infections.

Association of immune checkpoint inhibitors with respiratory infections: A review.

Treatment with immune-checkpoint inhibitors (ICIs) has shown efficacy against a variety of cancer types. The use of anti PD-1, anti PD-L1, and anti CTLA-4 antibodies is rapidly expanding. The side effects of ICIs are very different from conventional cytocidal anticancer and molecular target drugs, and may extend to the digestive organs, respiratory organs, thyroid gland, pituitary gland, skin, and others. Although the details of these adverse events are becoming increasingly apparent, much is unknown regarding the effects and adverse events related to infections. This review focuses specifically on the impact of ICIs on respiratory infections. The impact of ICIs on pathogens varies depending on the significance of the role of T-cell immunity in the immune response to the specific pathogen, as well as the different modes of infection (i.e., acute or chronic), although the impact of ICIs on the clinical outcome of infections in humans has not yet been well studied. Enhanced clearance of many pathogens has been shown because immune checkpoint inhibition activates T cells. In contrast, reactivation of tuberculosis associated with ICI use has been reported, and therefore caution is warranted. In COVID-19 pneumonia, ICI administration may lead to exacerbation; however, it is also possible that ICI may be used for the treatment of COVID-19. It has also been shown that ICI has potential in the treatment of intractable filamentous fungal infections. Therefore, expanded clinical applications are expected.

Effects of indoor pollution on acute respiratory infections among under-five children in India: Evidence from a nationally representative population-based study.

OBJECTIVE: Acute respiratory infections (ARI) are the leading causes of neonatal and child mortality. Despite several national efforts to reduce the incidence of mortality among children, India is one of the largest contributors to under-five mortality in the world. In this study, we examined the effects of indoor pollution on ARI among under-five children in India. METHODS: A cross-sectional study was carried using nationally representative data from the 2015-2016 National Family Health Survey (NFHS-4). This study is based on 247,743 living children under the age of five years. Bivariate and multivariate analyses were performed to assess the impact of indoor air pollution on children's ARI. RESULTS: Almost two-thirds of households (65.2%) used biomass fuels for cooking, 54.9% of households had a separate kitchen, and 47.2% of households had a smoker. About 2.7% of children suffered from ARI in the past two weeks preceding the survey. The use of biomass fuels (OR [odds ratio]: 1.10, 95% CI: 1.01-1.20), households having no separate kitchen (OR: 1.22, 95% CI: 1.14-1.30), and smoking behavior of household members (OR: 1.06, 95% CI: 1.00-1.12) were associated with greater risk of ARI among under-five children even after adjusting for age of child, sex of child, birth order, maternal age, maternal education, caste, religion, wealth quintile, any HH members suffer from tuberculosis (TB), and household crowding. Furthermore, the results revealed that the combined effects of biomass fuels and households without separate kitchen increased the likelihood of children's ARI by 36% (Adjusted OR: 1.35, 95% CI: 1.21-1.51). CONCLUSION: The findings of this study suggest policy interventions to reduce the exposure of indoor air pollution, particularly among the impoverished groups. The government should ensure cleaner fuels for cooking, such as LPG and electricity, to minimize the risk of respiratory diseases among children.

Pulmonary infections in patients with myelodysplastic syndromes receiving frontline azacytidine treatment.

Pulmonary infections (PIs) are a major complication of patients with myelodysplastic syndromes (MDS). We retrospectively evaluated 234 MDS patients treated with azacytidine (AZA). The total number of AZA cycles was 2886 (median 8 cycles per patient). There were 111 episodes of PI (3.8% of AZA cycles) in 81 patients (34.6%). PIs were considered of fungal origin in 27 cases (24.3%), associated to bacteremia in 11 cases (9.9%), to influenza infection in two cases (1.8%) and of unknown origin in the remaining 71 cases (64.0%). Forty-five PI episodes were documented in cycles 1 to 4 of AZA (5.1% of 875 cycles) and the remaining 66 episodes beyond the fourth cycle (3.2% of 2011 cycles) (P = .017). Overall, a fungal PI was documented in 13/875 (1.5%) cycles 1 to 4 and in 13/2011 (0.6%) cycles beyond the fourth cycle (P = .001). A baseline chronic pulmonary disease was significantly associated to a higher risk of severe PIs. In the survival analysis, cases of PI in patients who progressed to acute leukemia (PAL) were excluded, in view of the predominant influence of PAL on the outcome of the patients. A PI unrelated to PAL documented during the first 4 AZA cycles was an independent factor predicting lower survival (OR, 2.13; 95% CI, 1.37-3.33; P = .001). In conclusion, PIs are common in MDS patients receiving AZA, in particular during the first cycles of treatment and are associated with an unfavorable outcome. The results of our study raise the issue of the need of a tailored infection prevention strategy.

Impact of parental smoking on influenza and others respiratory infections in children.

BACKGROUND: The predisposition of cigarette smokers for the development of respiratory infections, including influenza, have been well documented. As well, those exposed to side stream smoke are prone to viral and bacterial infections of the respiratory tract. AIM: The study aimed to evaluate whether the prevalence of smoking parents is higher among children with respiratory tract infections, including influenza, in comparison to the general population. MATERIAL AND METHODS: Observational, cohort study. The authors surveyed a cohort of patients and their families, hospitalized in the Paediatric University Hospital in Warsaw during 2018 influenza season. Patients were diagnosed with influenza (using PCR) or other respiratory tract infections. A questionnaire on smoking habits was performed. RESULTS: Overall, 72 patients were included in the study, median age 2 years and 9 months (IQR: 1.4 - 7.2), influenza was diagnosed in 43% (n= 31) of patients. The percentage of regularly smoking parents in the whole cohort amounted to 33.3% (44 of 132) and was statistically significantly higher (p < 0.05) than in the general population (22.7%), whereas in the subgroup with influenza and non-influenza infections it reached 32.2% and 34.2%, respectively. CONCLUSIONS: The prevalence of smoking parents of children with acute respiratory tract infections is higher than in the general population: exposing children to tobacco smoke is one of the risk factors for acquiring influenza and others respiratory tract infections. Quitting smoking can decrease the risk of infectious diseases.

Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 years' follow-up.

OBJECTIVE: Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions. METHODS: Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed. RESULTS: 2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time. CONCLUSION: The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling.

National and sub-national exposure to ambient fine particulate matter (PM2.5) and its attributable burden of disease in Iran from 1990 to 2016.

Ambient particulate matter is a public health concern. We aimed (1) to estimate national and provincial long-term exposure of Iranians to ambient particulate matter (PM) < 2.5 µm (PM2.5) from 1990 to 2016, and (2) to estimate the national and provincial burden of disease attributable to PM2.5 in Iran. We used all available ground measurements of PM < 10 µm (PM10) (used to estimate PM2.5) from 91 monitoring stations. We estimated the annual mean exposure to PM2.5 for all Iranian population from 1990 to 2016 through a multi-stage modeling process. By applying comparative risk assessment methodology and using life table for years of life lost (YLL), we estimated the mortality and YLL attributable to PM2.5 for five outcomes. The predicted provincial annual mean PM2.5 concentrations range was between 21.7 µg/m3 (UI: 19.03-24.9) and 35.4 µg/m3 (UI: 31.4-39.4) from 1990 to 2016. We estimated in 2016, about 41,000 deaths (95% uncertainty interval [UI] 35634, 47014) and about 3,000,000 YLL (95% UI: 2632101, 3389342) attributable to the long-term exposure to PM2.5 in Iran. Ischemic heart disease was the leading cause of mortality by 31,363 deaths (95% UI: 27520, 35258), followed by stroke (7012 (5999, 8062) deaths), lower respiratory infection (1210 (912, 1519) deaths), chronic obstructive pulmonary disease (1019 (715, 1328) deaths), and lung cancer (668 (489, 848) deaths). In 2016, about 43% of all PM2.5 related mortality in Iran was, respectively, in the following provinces: Tehran (12.6%), Isfahan (9.3%), Khorasan Razavi (8.0%), Fars (6.5%), and Khozestan (6.4%). In summary, we found that the majority of Iranians were exposed to the levels of ambient particulate matter exceeding the WHO guidelines from 1990 to 2016. Further, we found that there was an increasing trend of total mortality attributed to PM2.5 in Iran from 1990 to 2016 where the slope was higher in western provinces.

Unique Effect of Aspirin Therapy on Biomarkers in Aspirin-exacerbated Respiratory Disease. A Prospective Trial.

Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease.Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease.Methods: Forty-two subjects with aspirin-exacerbated respiratory disease underwent an aspirin desensitization and were placed on high-dose aspirin (1,300 mg daily). Fifteen aspirin-tolerant subjects with asthma were also placed on high-dose aspirin. Biologic specimens and clinical parameters were collected at baseline and after 8 weeks on aspirin. Urinary eicosanoids, plasma tryptase and cytokine levels, platelet-leukocyte aggregates, and granulocyte transcripts were assessed.Measurements and Main Results: Eight weeks of high-dose aspirin decreased nasal symptoms and urinary prostaglandin E metabolite (P < 0.05) and increased urinary leukotriene E4 (P < 0.01) levels in subjects with aspirin-exacerbated respiratory disease, but not in those with aspirin-tolerant asthma. Urinary prostaglandin D2 and thromboxane metabolites decreased in both groups. Only in subjects with aspirin-exacerbated respiratory disease, exhaled nitric oxide (P < 0.05), plasma tryptase (P < 0.01), and blood eosinophil (P < 0.01) and basophil (P < 0.01) counts increased and plasma tryptase correlated with eosinophil counts (Pearson r = 0.514; P < 0.01) on aspirin. After correction for eosinophil counts, aspirin-induced changes in blood granulocyte transcripts did not differ between groups. Aspirin had no effect on platelet-leukocyte aggregates, platelet activation markers, or plasma cytokines in either group.Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.

Burden of respiratory disease attributable to secondhand smoke exposure at home in children in Spain (2015).

This study aimed to estimate the number of incident cases and hospital admissions attributable to secondhand smoke (SHS) exposure at home for asthma, otitis media (OM), and lower respiratory infections (LRI) in children in Spain. The burden of respiratory disease caused by SHS exposure was estimated in terms of incident cases and hospitalized cases for asthma, OM, and LRI. Estimates were calculated using the population attributable fraction. The age-specific (0-1 year, 0-4 years, 5-11 years, and 0-11 years) prevalence of SHS exposure in children was estimated through a telephone survey performed in a representative sample of Spanish households with children in 2016. The risk estimates for all diseases were selected from international meta-analyses. The number of hospitalized cases was obtained for each disease from the Hospital Minimum Data Set provided by the Ministry of Health of Spain. Incident cases were obtained from the Global Health Data Exchange. In 2015, SHS exposure caused an estimated total of 136,403 incident cases of the following respiratory diseases: 9058 (8.5%) cases of asthma, 120,248 (8.5%) of OM, and 7097 (13.5%) of LRI in children aged 0-14 years old in Spain. Likewise, SHS exposure caused a total of 3028 hospitalized cases, with 379 (8.5%) for asthma and 167 (8.5%) for OM in children 0-11 years old, and 2482 (11.6%) for LRI in children <2 years old. The high burden of respiratory disease attributed to SHS exposure supports the need to improve protection of children against SHS exposure by extending smoke-free regulations to homes and cars.

Ambient fine particulate matter inhibits innate airway antimicrobial activity in preschool children in e-waste areas.

Ambient fine particulate matter (PM2.5) is a risk factor for respiratory diseases. Previous studies suggest that PM2.5 exposure may down-regulate airway antimicrobial proteins and peptides (AMPs), thereby accelerating airway pathogen infection. However, epidemiological research is scarce. Hence, we estimated the associations between individual PM2.5 chronic daily intake (CDI) and the levels of the airway AMP salivary agglutinin (SAG), as well as peripheral leukocyte counts and pro-inflammatory cytokines, of preschool children in Guiyu (an e-waste area) and Haojiang (a reference area located 31.6 km to the east of Guiyu). We recruited 581 preschool children from Guiyu and Haojiang, of which 222 were included in this study for a matching design (Guiyu: n = 110 vs. Haojiang: n = 112). Air PM2.5 pollution data was collected to calculate individual PM2.5 CDI. The mean concentration of PM2.5 in Guiyu was higher than in Haojiang, resulting in a higher individual PM2.5 CDI. Concomitantly, saliva SAG levels were lower in Guiyu children (5.05 ng/mL) than in Haojiang children (8.68 ng/mL), and were negatively correlated with CDI. Additionally, peripheral counts of white blood cells, and the concentrations of interleukin-8 and tumor necrosis factor-alpha, in Guiyu children were greater than in Haojiang children, and were positively associated with CDI. Similar results were found for neutrophils and monocytes. To our knowledge, this is the first study on the relationship between PM2.5 exposure and innate airway antimicrobial activity in children, in an e-waste area, showing that PM2.5 pollution may weaken airway antimicrobial activity by down-regulation of saliva SAG levels, which might accelerate airway pathogen infection in children.

Toxicity studies of 1020 Long Multiwalled Carbon Nanotubes (L-MWNT-1020) administered by inhalation to Sprague Dawley (Hsd:Sprague Dawley SD) rats and B6C3F1/N mice.

Multiwalled carbon nanotubes (MWCNTs) are highly ordered hexagonal lattices of carbon atoms arranged into cylinders by hydrogen bonding, dipolar forces, hydrophilic or hydrophobic interactions, gravity, and other forces. MWCNTs are synthesized by applying energy to a carbon source, which produces individual or groups of carbon atoms that reassemble into tubes. One of the primary uses of MWCNTs is in nanotube-reinforced polymer composite materials that take advantage of their low-density and high load-bearing capacity. Nanoscale materials were nominated by the Rice University Center for Biological and Environmental Nanotechnology to the National Toxicology Program for toxicologic testing. Because long-term inhalation toxicity and carcinogenicity studies were being conducted on a relatively short, rigid MWCNT, a representative long and thin MWCNT was selected for these studies. Following an evaluation of 24 different long, thin MWCNTs, the 1020 Long Multiwalled Carbon Nanotube (L-MWNT-1020) (Sun Innovations, Fremont, CA) was selected for study based on availability, high purity (97%), and the low amount of residual nickel catalyst (0.52% by weight). The average L-MWNT-1020 nanotube length was 2,600 nm and the average width was 15.3 nm. Because nickel was shown to be tightly bound to L-MWNT-1020, tissue nickel content was measured to determine lung burden. (Abstract Abridged).

Tacrolimus decreases proteinuria in patients with refractory IgA nephropathy.

In clinical practice, some IgA nephropathy (IgAN) patients show resistance to or are unable to achieve complete remission using steroids and/or immunosuppressants. The current study aimed to assess the efficacy and safety of tacrolimus in the treatment of cases of refractory IgAN.In this retrospective observational study, 34 primary IgAN patients with refractory proteinuria received tacrolimus for at least 12 months. Complete remission, partial remission, and other clinical data were measured at 1, 3, 6, and 12 months after the initiation of treatment.After 12 months, complete remission was achieved in 20 (58.8%) patients and partial remission in 5 (14.7%) patients, yielding a total response rate of 73.5%. The mean time for response to tacrolimus for those who achieved complete remission and partial remission was 7.0 ±â€Š4.7 weeks. Serum creatinine (Scr), uric acid, estimated glomerular filtration rate, alanine aminotransferase, aspartate transaminase, white blood cell count, blood pressure, blood glucose, total cholesterol, and total triglyceride were stable over time. Three patients demonstrated a loss of eGFR >15 mL/min·1.73 m from baseline. Three cases of upper respiratory infection and 2 cases of urinary tract infection were observed during the study. Patients who achieved complete remission had better renal function and lower baseline proteinuria than partial remission and nonresponder patients. Crescent formation in biopsy specimens was seen more often in nonresponder patients.Tacrolimus was safe and effective at lowering proteinuria in refractory IgAN patients. Lower baseline proteinuria and better renal function were associated with a higher probability of complete remission, while crescent formation was associated with a worse prognosis.

Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study.

Objectives: To assess long-term efficacy, safety and tolerability of secukinumab up to 104 weeks in patients with active PsA. Methods: Patients with PsA (n = 397) were randomized to s.c. secukinumab 300, 150 or 75 mg or placebo at baseline, weeks 1, 2, 3 and 4 and every 4 weeks thereafter. Placebo-treated patients were re-randomized to receive secukinumab 300 or 150 mg s.c. from week 16 (placebo non-responders) or week 24 (placebo responders). Exploratory endpoints at week 104 included 20, 50 and 70% improvement in ACR criteria (ACR20, 50, 70); 75 and 90% improvement in the Psoriasis Area Severity Index, 28-joint DAS with CRP, presence of dactylitis and enthesitis and other patient-reported outcomes. For binary variables, missing values were imputed; continuous variables were analysed by a mixed-effects model for repeated measures. Results: A total of 86/100 (86%), 76/100 (76%) and 65/99 (66%) patients in the secukinumab 300, 150 and 75 mg groups, respectively, completed 104 weeks. At week 104, ACR20 response rates after multiple imputation in the 300, 150 and 75 mg groups were 69.4, 64.4 and 50.3%, respectively. Sustained clinical improvements were observed through week 104 with secukinumab across other clinically important domains of PsA. Responses were sustained through week 104 regardless of prior anti-TNF-α use. Over the entire treatment period the incidence, type and severity of adverse events were consistent with those reported previously. Conclusion: Secukinumab provided sustained improvements in signs and symptoms and multiple clinical domains in patients of active PsA through 2 years of therapy. Secukinumab was well tolerated, with a safety profile consistent with that reported previously. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT01752634.

The association between environmental tobacco smoke exposure and childhood respiratory disease: a review.

INTRODUCTION: Childhood respiratory illness is a major cause of morbidity and mortality particularly in low and middle-income countries. Environmental tobacco smoke (ETS) exposure is a recognised risk factor for both acute and chronic respiratory illness. Areas covered: The aim of this paper was to review the epidemiology of ETS exposure and impact on respiratory health in children. We conducted a search of 3 electronic databases of publications on ETS and childhood respiratory illness from 1990-2015. Key findings were that up to 70% of children are exposed to ETS globally, but under-reporting may mask the true prevalence. Maternal smoking and ETS exposure influence infant lung development and are associated with childhood upper and lower respiratory tract infection, wheezing or asthma. Further, exposure to ETS is associated with more severe respiratory disease. ETS exposure reduces lung function early in life, establishing an increased lifelong risk of poor lung health. Expert commentary: Urgent and effective strategies are needed to decrease ETS exposure in young children to improve child and long-term lung health in adults especially in low and middle income countries where ETS exposure is increasing.

Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2).

BACKGROUND: Randomized, controlled trials demonstrated efficacy and safety of apremilast for moderate-to-severe plaque psoriasis and psoriatic arthritis. OBJECTIVE: Assess long-term safety of oral apremilast in psoriasis patients. METHODS: Safety findings are reported for 0 to ≥156 weeks from the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2. RESULTS: The 0 to ≥156-week apremilast-exposure period included 1184 patients treated twice daily with apremilast 30 mg (1902.2 patient-years). During 0 to ≤52 weeks, the adverse events (AEs) that occurred in ≥5% of patients included diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. From 0 to ≥156 weeks, no new AEs (affecting ≥5% of the population) were reported. AEs, serious AEs, and study drug discontinuations caused by AEs did not increase with long-term exposure. During the 0 to ≥156-week period, the rates of major cardiac events (exposure-adjusted incidence rate [EAIR] 0.5/100 patient-years), malignancies (EAIR 1.2/100 patient-years), depression (EAIR 1.8/100 patient-years), or suicide attempts (EAIR 0.1/100 patient-years) did not increase in comparison with the rates found during the 0 to ≤52-week period. No serious opportunistic infections, reactivation of tuberculosis, or clinically meaningful effects on laboratory measurements were reported. LIMITATIONS: This study had a high dropout rate (21% of patients ongoing >156 weeks); most were unrelated to safety concerns. CONCLUSIONS: Apremilast demonstrated an acceptable safety profile and was generally well tolerated for ≥156 weeks.

Infection-related complications during treatment for childhood acute lymphoblastic leukemia.

Background: Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking. Patients and methods: We evaluated infection-related complications that were grade ≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period. Results: Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n = 389), followed by ear (n = 151), bloodstream (n = 147), and gastrointestinal tract (n = 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n = 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P = 0.002) during induction and febrile neutropenia and documented infection (both P < 0.001) during later continuation. White race was associated with documented infection (P = 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P < 0.001) and documented infections (P = 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P < 0.001). Conclusions: The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.

Safety of Alirocumab (A PCSK9 Monoclonal Antibody) from 14 Randomized Trials.

Previous individual trials of alirocumab (a PCSK9 monoclonal antibody) showed significant low-density lipoprotein cholesterol reductions with overall treatment-emergent adverse event (TEAE) rates comparable with controls. This analysis evaluated safety data from 14 trials (4 phase 2 and 10 phase 3, 8 to 104 weeks; n = 5,234), in 2 pools according to control (placebo/ezetimibe). Overall, 3,340 patients received alirocumab (4,029 patient-years' exposure), 1,276 received placebo, and 618 received ezetimibe. Incidence of deaths, serious TEAEs, discontinuations because of TEAEs, and overall TEAEs were similar between alirocumab and control groups. Alirocumab was associated with a higher incidence of local injection site reactions (7.4% vs 5.3% with placebo; 3.1% vs 2.3% with ezetimibe), pruritus (1.3% vs 0.4% placebo; 0.9% vs 0.5% ezetimibe), and upper respiratory tract infection signs and symptoms (2.1% vs 1.1% placebo; 1.3% vs 0.8% ezetimibe). Incidence of musculoskeletal, neurologic, neurocognitive, ophthalmologic, hepatic events, and TEAEs related to diabetes/diabetes complications was similar between alirocumab and control groups. In a prespecified analysis of phase 3 studies, adjudicated major adverse cardiovascular events (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, and unstable angina requiring hospitalization) occurred in 1.8% alirocumab versus 2.6% placebo patients (hazard ratio 0.69, 95% confidence interval 0.43 to 1.11) and 2.8% alirocumab versus 1.5% ezetimibe patients (hazard ratio 1.4, 95% confidence interval 0.65 to 3.02). In conclusion, pooled safety data from 14 trials demonstrate that alirocumab is generally well tolerated with a favorable safety profile.