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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
New guidelines regarding the endocrine effects of long-term inhaled glucocorticoids in children (April 2016)
The Pediatric Endocrine Society Drugs and Therapeutics Committee released guidelines regarding adrenal insufficiency in children on long-term inhaled corticosteroids (ICS) . The guidelines recommend testing for adrenal insufficiency in children and adolescents who are taking long-term ICS (eg, >6 months) and have symptoms suggesting adrenal insufficiency (hypoglycemia, altered mental status, fatigue, weakness, anorexia, Cushingoid features, growth failure, or weight loss). The guidelines also suggest screening asymptomatic children and adolescents who are taking high-dose ICS. However, because of the rarity of clinically significant adrenal insufficiency, we prefer to follow an individualized determination of the need for screening, based on the presence of the following risk factors: >6 months' use of ICS at doses exceeding those considered "high," combined use of high-dose ICS and intranasal glucocorticoids or intermittent use of systemic glucocorticoids, and low body mass index (BMI) (eg, <15th percentile for age). The first step in screening for adrenal insufficiency is measurement of an 8 AM serum cortisol, followed by additional testing based on the result. (See "Major side effects of inhaled glucocorticoids", section on 'Children and adolescents'.)
A second monoclonal antibody against interleukin-5 approved for severe eosinophilic asthma (April 2016)
Reslizumab, a monoclonal antibody to interleukin (IL)-5, has been approved by the US Food and Drug Administration (FDA) for add-on maintenance therapy of severe asthma in patients who are age 18 or older and have an eosinophilic phenotype . It is similar to mepolizumab, which was approved in late 2015. In clinical trials of reslizumab, an eosinophilic phenotype was defined as a peripheral blood absolute eosinophil count ≥400/microL. Studies in patients with severe eosinophilic asthma have shown that reslizumab reduces the rate of exacerbations by approximately 50 percent compared with placebo [3,4]. Reslizumab is administered intravenously at four-week intervals. The US FDA has added a boxed warning because anaphylaxis occurred in 0.3 percent of treated patients. (See "Treatment of severe asthma in adolescents and adults", section on 'Reslizumab'.)
Safety of fluticasone-salmeterol combination therapy in asthma (March 2016)
In early studies, a small increase in asthma-related deaths associated with salmeterol led the US Food and Drug Administration to place a boxed warning on the use of salmeterol in asthma. While concerning, the number of events was small, and the magnitude of the risk was unclear. In addition, it could not be determined if the potential risk of salmeterol could be mitigated by combining it with an inhaled glucocorticoid. The safety of salmeterol in combination with fluticasone has been assessed in a multicenter trial, in which almost 12,000 adolescents and adults with persistent asthma were randomly assigned to take inhaled fluticasone or the combination of inhaled fluticasone-salmeterol (in a single inhaler) for 26 weeks . The rate of serious asthma-related adverse events was similar in the two groups, and no deaths occurred in either group. In addition, no difference was noted in the rate of asthma-related hospitalizations. Thus, for patients over age 12 who do not have a history of life-threatening asthma events, data are reassuring about the safety of fluticasone-salmeterol in a fixed-dose inhaler. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Potential risk mitigation'.)
New biologic therapy approved for severe eosinophilic asthma (November 2015, Modified March 2016)
Mepolizumab, a monoclonal antibody to interleukin (IL)-5, has been approved by the US Food and Drug Administration and is commercially available for add-on, maintenance treatment of severe asthma in patients who are age 12 or older, have frequent asthma exacerbations, and have an eosinophilic phenotype . One marker of an eosinophilic phenotype is an absolute eosinophil count in peripheral blood of ≥150/microL. Studies in patients with severe eosinophilic asthma have shown that mepolizumab reduces the rate of exacerbations  and enables a reduction in the oral glucocorticoid dose . Mepolizumab is administered subcutaneously at four-week intervals. Based on a small increase in herpes zoster in treated adults, we suggest that patients who meet criteria for the varicella-zoster vaccine be immunized at least four weeks prior to initiation of mepolizumab. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5 therapy'.)
Bronchoscopic therapies for severe emphysema (December 2015, Modified January 2016)
Two investigational devices, endobronchial valves and nitinol coils, can provide benefit by deflating areas of emphysematous lung that compromise function.
●The STELVIO trial included 68 patients with severe emphysema, favorable anatomy, and no evidence of collateral ventilation . Subjects were randomly assigned to receive bronchoscopic endobronchial valve (EBV) placement (average four per lobe) or standard medical care. After six months, the increases in lung function and exercise tolerance in the EBV group were greater than in the usual care group. However, serious adverse events occurred in the EBV group, including one death, six pneumothoraces, and the necessity for valve removal in seven patients, compared with five serious adverse events and no deaths in the control group.
●The REVOLENS trial included 100 patients with severe emphysema, of whom two-thirds had homogeneous emphysema, considered an unfavorable pattern for either surgery or endobronchial valve placement. Patients were randomly assigned to undergo endobronchial deployment of nitinol coils or usual care . The coil group had significant improvements in lung function and quality of life at 6 and 12 months. Pneumonia was the most frequent serious adverse event.
Taken together, these studies show that endobronchial valves or nitinol coils can improve lung function, exercise tolerance, and quality of life in carefully selected patients with severe emphysema who are willing to accept the associated risks. (See "Emerging therapies for COPD: Bronchoscopic treatment of emphysema", section on 'Endobronchial valves' and "Emerging therapies for COPD: Bronchoscopic treatment of emphysema", section on 'Coils'.)
Combination glycopyrrolate-indacaterol approved for use in COPD (December 2015)
A twice daily, dry powder inhaler containing glycopyrrolate-indacaterol (15.6 mcg-27.5 mcg) has been approved by the US Food and Drug Administration for the treatment of chronic obstructive pulmonary disease (COPD) . The United States preparation, which contains lower medication doses than the product approved in Europe and Japan (table 1), was examined in 2038 patients with moderate-to-severe COPD in parallel randomized trials . Significant benefits were noted in lung function, health-related quality of life, and dyspnea in the combination group compared with the individual components or placebo. (See "Management of stable chronic obstructive pulmonary disease", section on 'Combined therapy'.)
Simplified approach to acetylcysteine infusion for acetaminophen poisoning (April 2016)
The treatment of acetaminophen poisoning with acetylcysteine is sometimes complicated by nonallergic anaphylactic reactions (NAARs). The results of a large retrospective study, in addition to recent clinical experience, suggest that these reactions can be reduced by using a two-bag regimen instead of the traditional three-bag regimen described in the manufacturer’s package insert and most dosing references. In the study, NAARs occurred in 10 percent of the 389 patients treated with the standard regimen versus 4.3 percent of the 210 patients treated with a modified two-bag regimen . In both regimens, acetylcysteine was infused over 20 hours. While further study is needed to ensure the safety and effectiveness of this regimen, we believe this is a reasonable approach to treatment in adults and older adolescents with acetaminophen poisoning. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'Simplified 20 hour IV protocol'.)
Noninvasive ventilation for postoperative respiratory failure (April 2016)
Patient selection is critical for the success of noninvasive ventilation (NIV). The indications for NIV in medical patients with respiratory failure are well defined. However, the indications in patients with postoperative respiratory failure are less clear. The role of NIV was studied in a trial of nearly 300 spontaneously breathing patients who developed acute hypoxemic respiratory failure following abdominal surgery . Compared with patients treated with oxygen only, patients who received NIV had fewer reintubations, more ventilator-free days, and fewer healthcare-associated infections. The exclusion of patients requiring immediate reintubation and lower than expected rates of reintubation in general limits interpretation of this study. Although encouraging, these results do not support the routine administration of NIV for the treatment of respiratory failure in surgical patients. Clinicians should continue to individualize NIV and utilize it on a trial basis in this population. (See "Overview of the management of postoperative pulmonary complications", section on 'Postoperative respiratory failure'.)
High-flow oxygen following extubation (March 2016)
High-flow oxygen delivered via nasal cannula (HFNC) is being increasingly used in intensive care and high-dependency units since it can deliver high amounts of supplemental oxygen and a small amount of positive expiratory pressure. The efficacy of HFNC following extubation was studied in over 500 patients (mostly postoperative or neurologic) who had been mechanically ventilated for an average of only one to two days and considered at low risk of reintubation . Patients were randomly assigned to conventional low-flow oxygen or HFNC immediately following extubation. HFNC led to a reduction in the rate of reintubation and respiratory failure at 72 hours. These findings suggest that HFNC may be useful in patients who are at low risk for reintubation. However, the results may not apply to other patient populations, since critically ill medical patients and patients at high risk of reintubation were excluded from this study. (See "Extubation management", section on 'Oxygen'.)
Dexmedetomidine for agitation in ventilated patients (March 2016)
Dexmedetomidine, a centrally active alpha-2 agonist with anxiolytic, sedative, and analgesic effects but no deleterious effect on respiratory drive, is being increasingly used for treatment of agitation in mechanically ventilated patients. The randomized DahLIa trial evaluated use of dexmedetomidine in weaning patients with delirium from mechanical ventilation . In a mixed population of 71 intensive care unit (ICU) patients in whom agitated delirium was prohibiting extubation, dexmedetomidine plus standard sedation (mostly propofol) resulted in an increase in ventilator-free hours and reduced time to extubation, compared with placebo plus standard sedation. However, the trial was stopped early before the target enrollment needed for adequate power was reached. Although encouraging, these results are not definitive and further studies are needed prior to recommendations for the routine use of dexmedetomidine to facilitate extubation in patients with delirium. (See "Sedative-analgesic medications in critically ill adults: Properties, dosage regimens, and adverse effects", section on 'Dexmedetomidine'.)
New definitions of sepsis and septic shock (March 2016)
The 2016 guidelines from The Society of Critical Care Medicine and European Society of Intensive Care Medicine (SCCM/ESICM) propose a new definition for sepsis and septic shock [17-19]. Compared with older guidelines, a major change is the focus on using a multi-organ dysfunction score, the Sequential Organ Failure Assessment (SOFA) score, to help identify those at risk of dying from sepsis. Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, where life-threatening organ dysfunction is identified by an increase of ≥2 points in the SOFA score; patients who fulfill these criteria have a predicted mortality of ≥10 percent. Patients with septic shock are defined as a subset of patients with sepsis who have profound circulatory, cellular, and metabolic abnormalities (ie, patients who, despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure ≥65 mmHg and have a lactate >2 mmol/L [>18 mg/dL]); these patients have a predicted mortality of ≥40 percent. The systemic inflammatory response syndrome (SIRS) criteria are no longer included in the definition. While not diagnostic, these definitions should help clinicians identify patients who are at increased risk of dying from sepsis. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Sepsis' and "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related) Organ Failure Assessment (SOFA)'.)
Identification of early sepsis (March 2016)
The identification of early sepsis is critical for the prevention of sepsis-related death. A task force from the 2016 Society of Critical Care Medicine and European Society of Intensive Care Medicine (SCCM/ESICM) has described a new assessment score for patients outside the intensive care unit (ICU) as a way to facilitate the identification of patients potentially at risk of dying from sepsis [17-19]. The quick Sequential Organ Failure Assessment score (qSOFA) can be easily calculated at the bedside; it comprises only three components, each worth 1 point: respiratory rate ≥22/minute, altered mentation, and systolic blood pressure ≤100 mmHg. Although this tool does not detect early sepsis, a score ≥2 was associated with poor outcomes in patients with suspected infection, and may prompt the clinician to consider sepsis so that they can monitor and/or or investigate accordingly. While promising, qSOFA requires prospective validation before it can be routinely used to identify patients with early sepsis outside of the ICU. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Identification of early sepsis' and "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related) Organ Failure Assessment (SOFA)'.)
Nutrition guidelines in critically ill adults (March 2016)
Guidelines for nutritional support in critically ill adult patients were published by the Society of Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition . Compared with earlier versions of the guidelines, emphasis is placed upon appropriate assessment of nutritional status in all critically ill patients using indirect calorimetry or published equations, as well as the early (within 48 hours of admission) administration of trophic enteral nutrition (EN) in adequately nourished patients using high-protein formulations. Supplementation of EN with glutamine, omega-3 fish oils, or antioxidants is discouraged. Parenteral nutrition is reserved for those who are unable to be fed adequately enterally and can be delayed for up to 10 days in those who are adequately nourished. Further detailed recommendations are made for specialized populations of critically ill patients including those who are inadequately nourished, postoperative patients, patients who are obese, as well as patients with acute pancreatitis, renal failure, liver failure, and sepsis. Notably, these guidelines only considered studies that were published up until 2014, and the overall quality of the evidence was low. (See "Nutrition support in critically ill patients: An overview", section on 'Introduction'.)
Detection and outcomes in acute respiratory distress syndrome (March 2016)
Little is known about the global incidence of acute respiratory distress syndrome (ARDS) in adults and whether best practices are adhered to when treating patients with ARDS in the intensive care unit (ICU). In a multicenter, international, prospective, cohort study of nearly 30,000 ICU patients, ARDS was responsible for 10 percent of admissions and for 23 of patients who were mechanically ventilated . Despite published definitions of ARDS and known benefits of low tidal volume ventilation (6 to 8 mL/kg ideal body weight; the standard of care), clinicians demonstrated poor recognition of the disorder, particularly when it was mild, and less than two-thirds of patients received the recommended tidal volume. Mortality remained high, ranging from 35 (mild ARDS) to 46 (severe ARDS) percent. Thus, clinicians appear to under-recognize and use suboptimal ventilatory strategies in patients with ARDS, a disease that continues to be associated with a high disease burden in the ICU and significant mortality. (See "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults", section on 'Epidemiology'.)
FDA approval of sugammadex for reversal of neuromuscular blockade (January 2016)
Neuromuscular blockade due to rocuronium (or vecuronium) can be rapidly reversed with sugammadex, a novel chelating agent. Several trials have demonstrated that, compared with neostigmine, administration of sugammadex at the end of surgery results in faster complete reversal of neuromuscular blockade due to rocuronium or vecuronium, with shorter time to discharge from the operating room. Use of rocuronium with sugammadex reversal may be especially useful for potentially difficult or rapid sequence intubations, since sugammadex also results in a faster recovery of neuromuscular function compared with spontaneous recovery after succinylcholine administration. Sugammadex has been available in many countries for several years and was approved by the US Food and Drug Administration (FDA) in December 2015 . (See "Induction of general anesthesia", section on 'Sugammadex' and "Management of the difficult airway for general anesthesia" and "Overview of complications occurring in the post-anesthesia care unit" and "Neuromuscular blocking agents (NMBA) for rapid sequence intubation in adults".)
Venous thromboembolism risk with central versus peripheral insertion of central venous catheters (January 2016)
There is accumulating evidence that peripherally-inserted central venous catheters (PICCs) are associated with a greater risk for upper extremity deep vein thrombosis (UEDVT) compared with centrally-inserted central venous catheters (CICCs). The Medical Inpatients and Thrombosis (MITH) Study evaluated catheter use in 299 venous thromboembolism cases compared with controls without venous thromboembolism at a single institution . Central catheter use was associated with a 14-fold increased risk for UEDVT, without a significantly increased risk for pulmonary embolism. PICCs were associated with a higher cumulative risk compared with CICCs (8.1 versus 4.8 per 1000 admissions). Given the higher risk for UEDVT with PICCs, we generally avoid them in patients for whom maintaining vascular patency and integrity for long-term vascular access options (eg, future hemodialysis access) is essential. (See "Catheter-related upper extremity venous thrombosis", section on 'Peripheral versus central insertion' and "Overview of central venous access".)
Reversal agent for factor Xa inhibitors (November 2015)
Lack of reversal agents for the direct oral anticoagulants has been a concern. Andexanet alfa is a recombinant protein designed to reverse factor Xa inhibitors by binding to the drugs and sequestering them away from endogenous factor Xa. In a randomized trial in healthy volunteers, an andexanet bolus reduced anti-factor Xa activity by 94 percent and 92 percent for volunteers taking apixaban or rivaroxaban, respectively, compared with reductions of 21 and 18 percent for a placebo bolus . A study evaluating andexanet efficacy in patients with factor Xa inhibitor-associated bleeding is ongoing. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Antidotes under development'.)
INTERSTITIAL LUNG DISEASE
Everolimus for pulmonary lymphangioleiomyomatosis (October 2015)
The mechanistic target of rapamycin (mTOR) inhibitor, sirolimus, is approved for the treatment of moderate-to-severe pulmonary lymphangioleiomyomatosis (LAM), but not all patients are able to tolerate it. The effect of everolimus, another mTOR inhibitor, was assessed in a 26-week, multicenter, open-label study of 24 women with pulmonary LAM . The forced expiratory volume in one second (FEV1) and the six-minute walk distance both improved from baseline, while the forced vital capacity (FVC) remained stable. Adverse effects were similar to sirolimus, most commonly, stomatitis and mouth ulcers, but also peripheral edema, pneumonia, cardiac failure, and Pneumocystis jirovecii infection. Everolimus appears to have benefits that are comparable to sirolimus and may expand treatment options for pulmonary LAM. (See "Pulmonary lymphangioleiomyomatosis", section on 'Everolimus'.)
FDA approval for alectinib in crizotinib-resistant ALK-positive NSCLC (December 2015)
Alectinib was recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) who have progressed on or are intolerant of crizotinib. This approval was based on the results of two single-arm phase II studies in patients with crizotinib-resistant ALK-positive, locally advanced or metastatic NSCLC that suggested a 50 percent response rate to alectinib [26,27]. Among patients with brain metastases, the majority of whom had received prior radiation therapy, the objective central nervous system (CNS) response rate was 57 percent in one study and 75 percent in the other, and the median duration of CNS response was 10 and 11 months, respectively. These data support the use of alectinib in patients with crizotinib refractory ALK-positive NSCLC and demonstrate its efficacy for managing both systemic and brain metastases. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Alectinib'.)
Zika virus and tissue/gamete donation (March 2016)
Zika virus has been detected in a number of tissues and body fluids. To avoid possible transmission of Zika virus infection, the US Food and Drug Administration (FDA) has issued donor deferral recommendations for hematopoietic stem cells, tissues, and donor sperm or eggs; the recommendations do not apply to solid organs . Living donors with Zika virus infection or relevant epidemiologic exposure (residence in or travel to an area where mosquito-borne transmission of Zika virus infection has been reported, or unprotected sexual contact with a person who meets these criteria) should be considered ineligible for donation for six months. Deceased donors with Zika virus infection in the preceding six months should also be considered ineligible. The deferral period recommended by the FDA for blood donors with risk factors for Zika virus infection remains at four weeks. (See "Zika virus infection: An overview", section on 'Blood/tissue donation'.)
Small versus large chest tubes for malignant effusion pleurodesis (January 2016)
The optimal diameter chest tube for malignant effusion pleurodesis is uncertain. Smaller diameter tubes are assumed to be more comfortable, but larger diameter tubes may provide better drainage. Nonrandomized studies suggest there is no difference. A multicenter trial compared pleurodesis failure rates and pain scores among 100 patients treated using either a small (12 Fr) or large (24 Fr) chest tube . At three months of follow-up, pleurodesis failure rates were not statistically different for smaller versus larger tubes (30 versus 24 percent). Pain scores were slightly lower for patients receiving smaller chest tubes. The small sample size for the tube diameter comparison may have limited the ability to detect a difference in pleurodesis failure rates, if one existed. Until a larger trial is available, we continue to use a smaller bore catheter (8 to 18 Fr) chest tube placed under imaging guidance for initial malignant effusion pleurodesis. (See "Placement and management of thoracostomy tubes", section on 'Malignant effusion' and "Management of malignant pleural effusions", section on 'Chest tube size'.)
PULMONARY VASCULAR DISEASE
Updated guidelines for the treatment of venous thromboembolism (March 2016)
The American College of Chest Physicians (ACCP) has published new guidelines on antithrombotic therapy for venous thromboembolic (VTE) disease that include guidance on choice of anticoagulant, indications for extended anticoagulation, and indications for thrombolytic therapy in patients with acute pulmonary embolism (PE) . In addition to a preference for direct oral anticoagulants for the treatment of VTE, the ACCP suggests extending anticoagulation beyond three months (ie, no scheduled stop date) in patients with unprovoked VTE or active cancer. For most patients with small subsegmental pulmonary embolism (SSPE), anticoagulation is suggested; however, clinical surveillance with lower extremity Doppler ultrasound may be appropriate for select patients with a low burden of SSPE who have no evidence of thrombus elsewhere and in whom the risk of recurrence is low. The guidelines suggest administration of systemic thrombolytic therapy, rather than catheter-directed thrombolysis (CDT), for patients with hemodynamically-significant PE; CDT may be appropriate for those who fail systemic thrombolysis or who are at high risk of bleeding. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Indications' and "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent' and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Patients likely to benefit' and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Patients with subsegmental PE'.)
Agent selection for anticoagulation in venous thromboembolism (March 2016)
Guidelines for the treatment of acute venous thromboembolism (VTE) were issued by The American College of Chest Physicians (ACCP) . Compared with earlier versions of the guidelines, the direct oral anticoagulants (DOACs) apixaban, edoxaban, rivaroxaban, or dabigatran are now the preferred agents for long-term anticoagulation in patients who are not pregnant and do not have active cancer or severe renal insufficiency. This preference was based upon randomized trials that consistently reported similar efficacy, a lower bleeding risk, and improved convenience when compared with warfarin. We agree with this preference for DOACs in patients with acute VTE, understanding that choosing among anticoagulants frequently depends upon availability and cost as well as patient comorbidities and preferences. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent'.)
Estimation of pulmonary artery pressure by echocardiography (February 2016)
The accuracy of echocardiographic estimation of pulmonary artery systolic pressure has been questioned. While some studies have reported that echocardiographic estimates and right heart catheterization results correlate strongly, other studies have found only weak correlations. Suboptimal echocardiogram quality is a likely cause of these discrepant results. In a retrospective study of 307 echocardiograms in patients with advanced lung disease or pulmonary arterial hypertension, only 61 percent of studies were deemed sufficient for estimation of pulmonary artery pressure . For interpretable studies, identification of pulmonary hypertension by expert readers was excellent (area under the curve 0.97). We suggest adherence to specific quality metrics for acquisition and interpretation of echocardiograms to optimize pulmonary artery pressure estimation, with confirmation of pressures by invasive right heart catheterization as clinically indicated. (See "Echocardiographic assessment of the right heart", section on 'Estimation of pulmonary artery systolic pressure'.)
Oral prostacyclin receptor agonist in pulmonary arterial hypertension (January 2016)
Prostanoids are highly effective agents for group 1 pulmonary arterial hypertension (PAH), but have only been available in parenteral formulations and are typically reserved for those with the most severe disease (World Health Organization [WHO] class IV). Less severe PAH (WHO class II or III) is usually treated with oral non-prostanoid pulmonary vasodilators. Selexipag is a selective prostacyclin receptor agonist, with actions similar to prostanoids, which is now available in an oral formulation and was evaluated in a randomized trial in 1156 patients with group 1 PAH, WHO class II or III . Selexipag was associated with a significant benefit compared with placebo, which was largely driven by a reduction in hospitalizations and disease progression, rather than by improved survival. Adverse effects were mostly mild and consistent with the known side effects of prostanoids, including headache, diarrhea, nausea, and jaw pain. We consider selexipag as a useful alternative to other oral agents for the treatment of patients with group 1 PAH, WHO class II or III. Parenteral prostanoids should remain the mainstay of therapy for WHO class IV disease. (See "Treatment of pulmonary hypertension in adults", section on 'Selexipag'.)
Warfarin associated with worse survival in systemic sclerosis-associated pulmonary arterial hypertension (December 2015)
Early studies suggested a possible mortality benefit for anticoagulation with warfarin in patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). However, a post-hoc analysis of a PAH registry study reported a trend towards worse survival in patients with SSc-PAH who received anticoagulant therapy compared with those not receiving anticoagulant therapy . A subsequent analysis of a separate registry of PAH patients also reported an increased mortality in the same population, even after adjustment for confounders including disease severity . Based on findings of these studies, we suggest that anticoagulant therapy not be administered to patients with systemic sclerosis-associated PAH. (See "Treatment of pulmonary hypertension in adults", section on 'Anticoagulation'.)
Racial and ethnic disparities in sleep duration and quality (February 2016)
Survey-based studies have consistently found that black Americans and other racial and ethnic minorities report higher rates of insufficient sleep and poor sleep quality compared with white Americans. These disparities were confirmed in a recent population-based study in which nearly 500 individuals completed seven nights of wrist actigraphy monitoring . Black Americans had significantly shorter mean sleep duration compared with white Americans (6.7 versus 7.5 hours), independent of age, gender, education, work status, and medical comorbidities. Multiple indicators of sleep quality were also worse in blacks and other racial and ethnic minorities. Further studies are needed to better understand the causes of these disparities, as short sleep duration has been associated with a wide range of adverse health outcomes, including cardiovascular morbidity and all-cause mortality. (See "Sleep insufficiency: Definition, consequences, and management", section on 'Epidemiology'.)
Respiratory effects of suvorexant in patients with obstructive sleep apnea (February 2016)
Limited available data suggest that suvorexant, an orexin receptor antagonist recently approved for treatment of insomnia, has the potential to worsen respiration during sleep in vulnerable patients. In a sleep laboratory study in which 26 adults with mild to moderate obstructive sleep apnea (OSA) were given 40 mg of suvorexant or placebo for four consecutive nights, the apnea-hypopnea index (AHI) increased by a mean of 2.7 events per hour after multiple doses of suvorexant . The AHI rose by 5 or more in eight patients (range 5 to 20), an increase that is generally considered to be clinically significant. These data suggest that suvorexant, like other sedatives, should be used cautiously in patients with OSA and other sleep-related breathing disorders. (See "Treatment of insomnia", section on 'Adverse effects of orexin antagonists'.)
Online versus face-to-face cognitive behavioral therapy for insomnia (February 2016)
Telephone or online delivery of cognitive behavioral therapy for insomnia (CBT-I) has been proposed as an alternative to face-to-face delivery, which could help overcome some of the access barriers to traditional therapy. In a trial comparing face-to-face and guided online CBT-I with a wait-list control in 90 patients with insomnia, both delivery methods performed better than the wait-list control, but face-to-face CBT-I was associated with larger treatment effects and better depression and anxiety outcomes than online delivery . These results, along with those of other small trials, suggest that online CBT-I may be an alternative to traditional CBT-I in patients with limited access to in-person therapy, particularly those without comorbid mood disorders. (See "Treatment of insomnia", section on 'Cognitive behavioral therapy'.)
Mandibular advancement devices lower blood pressure in sleep apnea (December 2015)
Improved blood pressure control is a benefit associated with continuous positive airway pressure (CPAP) treatment in patients with obstructive sleep apnea (OSA) and hypertension. However, it is unclear whether therapeutic modalities other than CPAP result in the same benefit. One meta-analysis of 51 studies of patients with hypertension and OSA reported that compared with patients on placebo or not receiving therapy, mandibular advancement devices (MADs) were associated with a significant reduction in systolic and diastolic blood pressure . The level of reduction was similar to that reported in patients treated with CPAP. While this study does not alter the indications for either therapy, it suggests that patients with OSA who are treated with MADs may derive similar positive effects on blood pressure control as those treated with CPAP. (See "Obstructive sleep apnea and cardiovascular disease", section on 'Impact of treatment'.)
OTHER PULMONARY MEDICINE
New ACCP guidelines for the treatment of unexplained chronic cough (March 2016)
The American College of Chest Physicians has published new guidelines for the treatment of unexplained chronic cough (defined as cough >8 weeks' duration that is unexplained after systematic investigation and treatment) . The guidelines newly include a suggestion for a therapeutic trial of gabapentin (a central inhibitor of neurotransmitter release). Due to the known adverse effects of gabapentin (eg, somnolence, weakness, diarrhea, and nausea), the initial dose should be 300 mg daily, which can be gradually increased as tolerated to a maximum dose of 900 mg twice daily. (See "Treatment of subacute and chronic cough in adults", section on 'Gabapentin and pregabalin'.)
Treatment of unexplained chronic cough with pregabalin (March 2016)
Like gabapentin, pregabalin is thought to act centrally to inhibit neurotransmitter release. Evidence for its use in chronic cough comes from a randomized trial in which 40 adults with chronic refractory cough were assigned to take pregabalin daily or placebo combined with speech pathology treatment for 14 weeks . Baseline cough frequency was 24 coughs/hour in both groups; spirometry was normal. Both groups experienced a reduction in cough severity and cough frequency, and improvements in cough-related quality of life (QOL). The pregabalin group experienced greater improvement in cough severity and QOL. Adverse effects in the pregabalin group included dizziness in 45 percent and cognitive changes in 30 percent, although these did not lead to discontinuation of the study drug. Four weeks after withdrawal of study medication, there was no deterioration in symptom control. To minimize sedation and dizziness, pregabalin is initiated at a low dose and gradually increased as tolerated over a week. Of note, the American College of Chest Physicians (ACCP) guidelines do not include pregabalin because this study was published after the guidelines were prepared. (See "Treatment of subacute and chronic cough in adults", section on 'Gabapentin and pregabalin'.)
Nontuberculous mycobacteria in patients with cystic fibrosis (February 2016)
Nontuberculous mycobacteria (NTM) are in the sputum of up to 20 percent of patients with cystic fibrosis (CF), and some of these patients develop progressive NTM pulmonary disease (NTM-PD). New guidelines provide recommendations for the screening, diagnosis, and management of NTM in CF patients . Annual screening of sputum is recommended for all expectorating patients. Patients with persistently positive results or symptoms suggesting NTM-PD should have a full evaluation including high-resolution computed tomography (HRCT) and sometimes bronchoscopy to determine if they meet criteria for NTM pulmonary disease (table 2). For any patient on chronic azithromycin therapy suspected of NTM infection, azithromycin should be stopped temporarily pending further diagnostic evaluation, to reduce the risk of inducing resistance because of monotherapy. (See "Cystic fibrosis: Antibiotic therapy for lung disease", section on 'Nontuberculous mycobacteria'.)
IDSA guidelines on the management of candidiasis (January 2016)
The Infectious Diseases Society of America released updated guidelines for the management of patients with candidiasis . A substantial change compared with previous versions is the preference for echinocandins (anidulafungin, caspofungin, micafungin) as first-line therapy for candidemia and invasive candidiasis. As an example, for both nonneutropenic and neutropenic patients with candidemia, an echinocandin is the preferred choice for initial therapy (table 3). This change is due to an increase in fluconazole-resistant Candida infections, the favorable safety profile of the echinocandins, and accumulating efficacy data and clinical experience to support the echinocandins. Important exceptions include Candida central nervous system, eye, and urinary tract infections, for which other antifungals are preferred. (See "Treatment of candidemia and invasive candidiasis in adults", section on 'Nonneutropenic patients'.)
Adjuvanted influenza vaccine approved for elderly adults in the United States (November 2015)
There has been interest in using adjuvants in influenza vaccines in elderly individuals, who have reduced immune responses to influenza vaccines; adjuvants are substances that amplify the immune response to an antigen. In November 2015, an adjuvanted trivalent inactivated influenza vaccine (Fluad) was approved for use in individuals ≥65 years of age in the United States . It is the first adjuvanted seasonal influenza vaccine to be approved in the United States, but it has been approved already in >35 other countries. The vaccine is formulated with the adjuvant MF59, an oil-in-water emulsion of squalene oil. Studies have shown that the MF59-adjuvanted vaccine has comparable  or higher immunogenicity compared with unadjuvanted vaccines [44-46]. Until further data are available, we continue to suggest the non-adjuvanted high-dose inactivated vaccine for individuals ≥65 years of age. (See "Seasonal influenza vaccination in adults", section on 'Adjuvanted vaccine' and "Seasonal influenza vaccination in adults", section on 'Vaccine formulations'.)
Statins and influenza vaccine immunogenicity and effectiveness (November 2015)
Statins are used commonly in older adults with hyperlipidemia and are known to have immunomodulatory effects, which could affect vaccine responses. In an observational study conducted in the context of a randomized trial that evaluated influenza vaccines in individuals >65 years of age, hemagglutination inhibition (HAI) geometric mean titers to various influenza strains were substantially lower in those receiving chronic statin therapy than in those not receiving it . In addition, in the adjusted analysis of a large retrospective cohort study, statin use was associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness . The observed associations between statin use and vaccine effectiveness could be due to confounding, as patients receiving statins are likely to be at differing baseline risk of influenza from those not receiving statins. Although these studies raise the possibility that older patients receiving statins are less likely to be protected by the influenza vaccine, such individuals should still receive statins, when indicated, as well as an influenza vaccine annually. (See "Seasonal influenza vaccination in adults", section on 'Efficacy'.)
Updated guidelines for the diagnosis and management of primary immunodeficiency (November 2015)
A revised “Practice parameter for the diagnosis and management of primary immunodeficiency,” developed by the three national allergy and immunology societies in the United States, has been published to aid allergy/immunology specialists and other practitioners in the recognition, diagnosis, and general management of these disorders . Highlights include screening and advanced laboratory tests for the different components of immune function, characteristic clinical manifestations and laboratory findings for a number of disorders, internet resources, antibiotic prophylaxis, and indications for hematopoietic cell transplantation or gene therapy. There are now more than 200 genetically distinct disorders of immune function that are classified using the system devised by the World Health Organization (WHO) and International Union of Immunological Societies (IUIS). Consultation with an immunology specialist with experience in diagnosing and managing primary immunodeficiencies is recommended. Our approach is consistent with that outlined in this practice parameter. (See "Approach to the child with recurrent infections" and "Laboratory evaluation of the immune system" and "Medical management of immunodeficiency".)
Influenza vaccination and influenza-associated pneumonia (October 2015)
Many studies have demonstrated that influenza vaccination decreases the incidence of laboratory-confirmed influenza infection, but few have evaluated the effect on the serious complications of influenza. Recent data suggest that vaccination is associated with a reduced risk of influenza pneumonia. In a case-control study of adult and pediatric patients hospitalized for community-acquired pneumonia (CAP), those with laboratory-confirmed influenza-associated pneumonia had lower odds of having received an influenza vaccine during the same influenza season compared with those with CAP not associated with influenza . The estimated vaccine effectiveness for preventing influenza-associated pneumonia was 57 percent. (See "Seasonal influenza vaccination in adults", section on 'Trivalent inactivated vaccines' and "Seasonal influenza in children: Prevention with vaccines", section on 'Indications'.)
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