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What's new in pulmonary and critical care medicine
Official reprint from UpToDate® ©2017 UpToDate®
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
What's new in pulmonary and critical care medicine
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2017. | This topic last updated: Jun 22, 2017.

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.


Tyrosine kinase inhibition and severe asthma (June 2017)

Mast cells are typically increased in asthmatic airways and are associated with greater bronchial hyperresponsiveness. The KIT tyrosine kinase inhibitor, imatinib, inhibits the major growth factor for mast cells, raising the possibility that imatinib may ameliorate severe asthma. In a proof-of-principle randomized trial, 62 adults with severe asthma were assigned to imatinib or placebo for six months [1]. Airway hyperresponsiveness, as determined by methacholine inhalation challenge, was decreased in the imatinib group, indicating a potential role for KIT-dependent processes and mast cells in severe asthma. Whether tyrosine kinase inhibition by imatinib or a related agent will prove to be a safe and effective treatment for severe asthma awaits further study. (See "Investigational agents for asthma", section on 'Tyrosine kinase inhibitors'.)

Maternal fish oil supplementation and asthma in offspring (February 2017)

Maternal supplementation with fish oil, which consists of two n-3 long chain polyunsaturated fatty acids (docosahexaenoic acid [DHA]) and eicosapentaenoic acid [EPA]), has been proposed to improve a variety of pregnancy outcomes. In a placebo-controlled randomized trial of third-trimester maternal supplementation with fish oil 2.4 grams daily (55 percent EPA and 37 percent DHA), supplementation resulted in a 7 percent reduction in the absolute risk of persistent wheeze or asthma in offspring followed to age three to five years [2]. Because of limitations in the design of this trial, UpToDate does not advise routine supplementation with this dose of fish oil, but continues to recommend that all pregnant women achieve DHA intake of at least 200 to 300 mg/day. (See "Fish consumption and docosahexaenoic acid (DHA) supplementation in pregnancy".)

Spirometry and asthma diagnosis (February 2017)

The importance of confirming reversible airflow limitation when making a diagnosis of asthma was illustrated in a study of 701 randomly selected adults who had a physician diagnosis of asthma in the previous five years [3]. Current asthma was excluded in 33 percent and, among these, less than half had previous testing to confirm airflow limitation. This observation suggests that a clinical diagnosis of asthma, if not supported by spirometry, may be incorrect and reinforces guideline recommendations that spirometry pre- and post-bronchodilator be obtained at the time of an initial diagnosis of asthma.

(See "Diagnosis of asthma in adolescents and adults", section on 'Diagnosis'.)


New ERS/ATS guidelines for the management of COPD exacerbations (April 2017)

The European Respiratory Society and American Thoracic Society (ERS/ATS) have published joint guidelines that address several issues in the management of chronic obstructive pulmonary disease (COPD) exacerbations. Among other recommendations, the guidelines suggest that the duration of oral glucocorticoids administered for exacerbations be ≤14 days, noting that the evidence for an exact number of days is weak [4]. UpToDate's suggestion of a 5 to 14 day course is consistent with this recommendation. (See "Management of exacerbations of chronic obstructive pulmonary disease", section on 'Systemic glucocorticoids'.)

Updated guidelines for chronic obstructive pulmonary disease (March 2017)

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published updated guidelines that focus on a combined assessment of an individual's symptoms and exacerbation history to guide therapy [5]. Symptoms are assessed using standardized instruments, such as the COPD Assessment Tool (CAT) or the modified Medical Research Council (mMRC) dyspnea scale. Future exacerbation risk is based on the number of exacerbations and hospitalizations for exacerbations in the previous 12 months. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging", section on 'GOLD system'.)


Time to treatment and mortality in sepsis (May 2017)

Timely administration of fluids and antibiotics is the cornerstone of therapy for patients with sepsis and septic shock. A recent database study of patients with sepsis reported increased mortality in association with the delayed administration of antibiotics (greater than three hours) but not with a longer time to completion of a fluid bolus (greater than six hours) [6]. This study further validates international guideline recommendations that antibiotics be administered within the first three hours, and preferably within the first hour after presentation in patients with sepsis and septic shock. We also continue to recommend infusion of intravenous fluids within the first three hours of presentation. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Initial resuscitative therapy'.)

Immunoassay for acetaminophen-induced liver injury (May 2017)

Establishing the diagnosis of acetaminophen (APAP) poisoning in patients who present greater than 24 hours to several days after ingestion, when a serum APAP level may no longer be detectable, can be difficult. However, a recent observational cohort study found excellent performance for a rapid immunoassay that measures serum APAP-protein adducts in identifying patients with APAP-induced acute liver injury (ALI) [7]. In this study, a point of care immunoassay (AcetaSTAT) had 100 percent sensitivity and 100 percent negative predictive value, compared with results of high performance liquid chromatography as a reference standard, for identifying patients with such injury. If these results are validated in future clinical trials, this assay may provide a rapid means to distinguish APAP-induced ALI from other causes, and to begin appropriate management quickly. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis", section on 'Evaluation following delayed presentation'.)

Routine prophylactic antibiotics do not improve clinically important outcomes in survivors of out-of-hospital cardiac arrest (April 2017)

Many survivors of out-of-hospital cardiac arrest (OHCA) go on to develop pneumonia, but the value of prophylactic antibiotics is unproven. In a single-center clinical trial involving 60 comatose OHCA patients without obvious evidence of tracheobronchial aspiration on admission, random assignment to prophylactic antibiotics versus clinically-driven antibiotic therapy reduced the number of positive broncho-alveolar lavage cultures on hospital day 3, but did not improve survival or other patient-important outcomes [8]. We do not suggest routine prophylactic treatment with antibiotics in these patients. (See "Post-cardiac arrest management in adults", section on 'Antibiotic therapy and prophylaxis'.)

2011 shortage of norepinephrine in the United States and septic shock outcome (April 2017)

The impact of a shortage of norepinephrine in the United States in 2011 on vasopressor agent selection was recently highlighted in a study of 28,000 patients with sepsis. When norepinephrine (first-line agent) was in short supply, phenylephrine was the most frequent alternative agent chosen, during which time mortality rates from septic shock also rose (36 to 40 percent) [9]. While there is little guidance for selecting a second-line vasopressor agent in patients with sepsis, phenylephrine should continue to be avoided, when feasible. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Vasopressors'.)

2016 sepsis guidelines (March 2017)

Updated sepsis guidelines were issued by the Surviving Sepsis Campaign/Society of Critical Care Medicine/European Society of Intensive Care Medicine [10]. Major differences, compared with the 2012 iteration, include: the administration of intravenous antibiotics within one hour of presentation, with emphasis on source control and antibiotic stewardship; infusion of crystalloid solution at a rate at 30 mL/kg/hour within three hours for early fluid resuscitation; and movement away from previously recommended early goal-directed therapy targets (eg, central venous pressure) to use of dynamic predictors of fluid responsiveness, when feasible. Norepinephrine remains the vasopressor of first choice. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Hemodynamic'.)

Target blood glucose levels in critically ill children (March 2017)

Optimal target blood glucose levels in critically ill children are unknown. In the HALF-Pint randomized trial of intensive insulin therapy (IIT), a lower target blood glucose level (80 to 110 mg/dL [4.4 to 6.1 mmol/L] did not reduce the number of intensive care unit-free days in critically ill children when compared with a higher target level (150 to 180 mg/dL [8.3 to 10 mmol/L]) [11]. Rates of hypoglycemia and health care-associated infections were increased for the lower target group, but there was no difference in mortality. These results are consistent with trials in adults and, as in adults, we recommend against treatment with IIT regimens that target blood glucose levels between 80 to 110 mg/dL [4.4 to 6.1 mmol/L] in critically ill children. (See "Glycemic control and intensive insulin therapy in critical illness", section on 'Children'.)

The effect of tracheal intubation on in-patients with sudden cardiac arrest (February 2017)

The appropriate role for tracheal intubation during sudden cardiac arrest (SCA) remains a source of debate. In a large multicenter cohort study comparing outcomes between intubated patients and a propensity-matched group of non-intubated patients, all of whom sustained SCA while admitted to the hospital, intubated patients had lower rates of return of spontaneous circulation, survival, and survival with good functional outcome [12]. This study provides additional evidence that tracheal intubation is best withheld until the return of spontaneous circulation following SCA, unless adequate ventilation cannot be maintained with bag-mask ventilation or a supraglottic airway. (See "Advanced cardiac life support (ACLS) in adults", section on 'Airway management while performing ACLS'.)

Rapidly progressive acute chest syndrome in sickle cell disease (February 2017)

Acute chest syndrome (ACS) in individuals with sickle cell disease (SCD) encompasses a variety of clinical presentations and severities. A distinct phenotype of ACS has been characterized, referred to as rapidly progressive ACS, in which respiratory failure occurs within 24 hours of initial respiratory symptoms [13]. In a cohort of 97 children and 76 adults with SCD and at least one prior ACS episode, rapidly progressive ACS occurred more commonly in adults than children (21 versus 2 percent). Adults with rapidly progressive ACS were more likely to have multiorgan failure compared with adults without this phenotype. The only laboratory predictor of rapidly progressive ACS was a decline in platelet count on presentation. (See "Evaluation of acute pain in sickle cell disease", section on 'Acute systemic illness, diffuse pain, or both'.)

The qSOFA prediction score and in-hospital mortality (January 2017)

Two recent studies have evaluated the quick sepsis-related organ failure assessment score (qSOFA) as a simple bedside tool to facilitate early identification of patients at risk of dying from sepsis [14,15]. In one study of patients presenting to the emergency department with suspected infection, the predictive validity of qSOFA for in-hospital mortality was similar to that of the full SOFA score [14]. In contrast, qSOFA was inferior to SOFA in a retrospective analysis of intensive care unit (ICU) patients with an infection-related diagnosis [15]. We believe that qSOFA is a valuable bedside tool in predicting death from sepsis outside the ICU. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Identification of early sepsis (qSOFA)'.)

Extubation during nighttime hours may be harmful (January 2017)

It is unclear whether patients who are mechanically ventilated can be safely extubated during nighttime hours. One recent retrospective study reported that, compared with patients extubated during daytime hours, patients who were extubated at nighttime (after 7:00 pm) had increased intensive care unit mortality [16]. These data support the typical practice of safe extubation during daytime hours, when personnel are usually more readily available for re-intubation. However, methodologic flaws (eg, incomplete capture of the circumstances surrounding extubation and analysis of older data) and incongruent results compared with earlier studies suggest that these findings should not prohibit clinicians from extubating select patients who are suitable for extubation at night (eg, terminal patients). (See "Extubation management", section on 'Timing of extubation'.)

Guidelines for weaning critically ill patients from mechanical ventilation (January 2017)

The American Thoracic Society and American College of Chest Physicians recently issued joint guidelines regarding weaning critically ill patients from mechanical ventilation [17-19]. Recommendations focus on the use of sedation, liberation, and early mobilization protocols in patients who were mechanically ventilated for more than 24 hours. Additional recommendations include the use of low-level inspiratory pressure support during spontaneous breathing trials, the application of noninvasive ventilation immediately following extubation in patients at high risk of extubation failure, and cuff leak testing and/or glucocorticoid administration in those at high risk of post-extubation stridor due to laryngeal edema. These guidelines are consistent with our current recommendations for weaning patients from mechanical ventilation. (See "Extubation management" and "Methods of weaning from mechanical ventilation" and "Weaning from mechanical ventilation: Readiness testing" and "Post-intensive care syndrome (PICS)", section on 'Prevention'.)


Screening interval for lung cancer (January 2017)

The optimal strategy for screening high-risk individuals for lung cancer is the subject of active study. In new results from the NELSON trial, in which almost 16,000 current or former smokers were randomly assigned to low-dose computed tomography (LDCT)-based screening versus observation only, extending the screening interval from 1 to 2.5 years reduced the proportion of cancers detected at an early stage [20]. These data support our approach to screen annually with LDCT when screening patients who are at high risk for lung cancer. (See "Screening for lung cancer", section on 'Other trials'.)


YEARS algorithm for the diagnosis of pulmonary embolism (June 2017)

Algorithms that integrate pretest probability (PTP) assessment using Wells criteria with a fixed cutoff level for D-dimer (<500 ng/mL) are typically used to target which patients with suspected pulmonary embolism (PE) should undergo computed tomography pulmonary angiography (CTPA). Compared with this typical approach, an alternative strategy using the YEARS items (clinical signs of deep venous thrombosis, hemoptysis, and PE as the most likely diagnosis) together with varying cutoff levels of D-dimer resulted in a 14 percent reduction in the number of CTPA scans performed, without increasing the risk of PE during a three-month follow-up [21]. While encouraging, this algorithm requires further validation before it is routinely used in practice. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'D-dimer'.)

Rivaroxaban for treatment of superficial vein thrombosis (May 2017)

Short-term anticoagulation is recommended for treatment of superficial vein thrombosis (SVT) in patients at high risk for venous thromboembolism (VTE). The phase 3b SURPRISE trial randomly assigned over 400 patients with SVT to oral rivaroxaban (a direct factor Xa inhibitor) or subcutaneous fondaparinux and found that both groups had similar rates of symptomatic VTE, progression or recurrence of SVT, and all-cause mortality at 45 days [22]. There were no major bleeds in either group, but clinically relevant nonmajor bleeding occurred more often in the rivaroxaban group. Thus, rivaroxaban appears to be an effective anticoagulant for patients with SVT and may be a more convenient and less expensive option than subcutaneous therapy. (See "Phlebitis and thrombosis of the superficial lower extremity veins", section on 'Increased risk for thromboembolism'.)

Rivaroxaban versus aspirin for indefinite treatment of venous thromboembolism (April 2017)

The optimal antithrombotic agent for patients with venous thromboembolism (VTE) who have indications for indefinite therapy to reduce the risk of recurrent VTE is unclear. A randomized trial compared rivaroxaban (a direct factor Xa inhibitor) and aspirin for long-term treatment of patients who had completed a 6- to 12-month course of therapeutic anticoagulation [23]. Rivaroxaban, either at a treatment (20 mg daily) or a prophylactic (10 mg daily) dose, was superior to aspirin in preventing VTE recurrence for up to 12 months, without increasing the risk of major bleeding. While rates of recurrence were comparable between both doses of rivaroxaban, further studies are warranted before reduced intensity regimens can be recommended. For most patients with VTE requiring long-term treatment, we suggest full intensity anticoagulation rather than low intensity regimens or aspirin. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Factor Xa and direct thrombin inhibitors'.)

Anticoagulant thromboprophylaxis not warranted in nonmajor lower limb orthopedic surgery (January 2017)

Whether anticoagulation thromboprophylaxis is indicated for patients with lower leg immobilization from below knee casting or undergoing arthroscopy was evaluated in a randomized trial [24]. The rate of symptomatic venous thromboembolism (VTE) was low (<2 percent) and not affected by the administration of anticoagulant prophylaxis. Risk factors in addition to the surgery itself were present among the few patients who did develop thrombus. This trial supports the current recommendation that, for patients with lower leg immobilization due to below knee casting or arthroscopy who do not have additional risk factors for VTE, anticoagulant prophylaxis is not warranted. (See "Prevention of venous thromboembolic disease in surgical patients", section on 'Orthopedic surgery'.)


Guideline on obstructive sleep apnea diagnosis and treatment in commercial drivers (May 2017)

The American Academy of Sleep Medicine (AASM) has released consensus-based recommendations on screening, diagnosis, and management of obstructive sleep apnea (OSA) in commercial drivers [25]. The AASM recommends that drivers meeting any of the following high-risk criteria be referred to a sleep medicine specialist for clinical sleep evaluation and diagnostic testing:

Body mass index (BMI) ≥40 kg/m2

Fatigue or sleepiness during the duty period or involvement in a sleepiness-related crash or accident

BMI ≥33 kg/m2 and either hypertension requiring two or more medications to control or type 2 diabetes

The document also provides guidance on determining when to restrict driving certification based on OSA severity, symptoms, and adherence with positive airway pressure therapy. (See "Drowsy driving: Risks, evaluation, and management", section on 'Special considerations in commercial drivers'.)

Adaptive servoventilation in adults with central sleep apnea and heart failure (April 2017)

A previous randomized trial (SERVE-HF) found that adaptive servoventilation (ASV), a modified method of positive airway pressure ventilation, increased cardiovascular mortality in patients with central sleep apnea (CSA) due to symptomatic heart failure with reduced ejection fraction. In the CAT-HF trial, 126 hospitalized patients with heart failure and moderate-to-severe CSA were randomly assigned to ASV plus optimized medical therapy or medical therapy alone [26]. While the trial showed no difference between the groups in a combined endpoint (death, cardiovascular hospitalizations, and timed walk distance), the confidence intervals were wide and there was a suggestion of increased harm in the ASV group (HR 1.06, 95% CI 0.75-1.51). The trial was stopped early, in part due to results of SERVE-HF. Although this limits interpretation of the CAT-HF results, we continue to recommend against use of ASV in patients with CSA and heart failure with reduced ejection fraction. (See "Sleep-disordered breathing in heart failure", section on 'Adaptive servoventilation' and "Central sleep apnea: Treatment", section on 'Patients with ejection fraction ≤45 percent'.)

Alveolar recruitment maneuvers in postoperative mechanically ventilated patients (April 2017)

Unlike patients with acute respiratory distress syndrome (ARDS) in whom the value of alveolar recruitment maneuvers is known to be beneficial, their role in postoperative patients without ARDS is unknown. One single center study of 320 patients who had undergone elective cardiac surgery and were mechanically ventilated for hypoxemia compared an intensive recruitment strategy with a moderate strategy [27]. An intensive strategy resulted in fewer pulmonary complications as well as decreased intensive care unit length of stay and mortality, without increasing the incidence of barotrauma. This study suggests that the benefit from recruitment maneuvers in postoperative patients without ARDS may be similar to the benefit in patients with ARDS, and further investigation is warranted. (See "Positive end-expiratory pressure (PEEP)", section on 'Postoperative patients'.)

Psychiatric comorbidities in patients with narcolepsy (March 2017)

Small studies have found an increased rate of depression in patients with narcolepsy, but the risk of other psychiatric comorbidities has not been well established. In a population-based case-control study that included 9312 adults with narcolepsy and more than 45,000 age- and gender-matched controls, a broad range of psychiatric disorders were more common in patients with narcolepsy; the most prevalent were depressive disorders and anxiety, which were three to four times more common than in controls [28]. Thus, recognition and treatment of psychiatric disorders is an important component of the care of patients with narcolepsy. (See "Clinical features and diagnosis of narcolepsy in adults", section on 'Other features'.)

AASM guideline on pharmacotherapy for chronic insomnia in adults (March 2017)

The American Academy of Sleep Medicine (AASM) has released a new clinical practice guideline on the pharmacologic treatment of chronic insomnia in adults [29]. The guideline reviews evidence of effectiveness for a variety of medications (including benzodiazepines, nonbenzodiazepine hypnotics, ramelteon, doxepin, and suvorexant) and notes limitations and potential biases to the evidence, leading to low confidence in the overall estimation of risk-to-benefit ratio. The potential short-term benefits of pharmacologic therapy need to be balanced with the risk of side effects and dependence with long-term use. We continue to prefer behavioral therapy, rather than pharmacotherapy, as an initial treatment approach in most patients. (See "Treatment of insomnia in adults", section on 'Choice of an agent'.)

US Preventive Services Task Force recommendations on screening for obstructive sleep apnea (January 2017)

The value of predictive tools (eg, questionnaires) as a way to screen for obstructive sleep apnea (OSA) was recently reviewed by The US Preventive Services Task Force. Among the 110 studies evaluated, there were no randomized trials comparing screening with no screening in asymptomatic individuals [30,31]. Although severe OSA could be predicted by some questionnaires, this was only in high-risk populations. The task force identified a need for randomized trials in asymptomatic individuals and concluded that there was insufficient evidence to make a recommendation on screening for OSA in the community. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Screening questionnaires'.)

Continuous positive airway pressure and sleep apnea outcomes (January 2017)

A meta-analysis of 35 randomized trials comparing continuous positive airway pressure (CPAP) with sham CPAP in patients with obstructive sleep apnea (OSA) found that CPAP reduced sleep-related apneas and hypopneas (ie, the apnea-hypopnea index) and improved daytime sleepiness, blood pressure (systolic and diastolic), and sleep-related quality of life [30]. There was no demonstrable mortality benefit for CPAP, although cohort studies have demonstrated an association between the apnea-hypopnea index and all-cause mortality. CPAP should be the mainstay of therapy for OSA. (See "Management of obstructive sleep apnea in adults", section on 'Efficacy'.)

Diagnosis of OSA using limited data from a sleep study (January 2017)

In patients with suspected obstructive sleep apnea (OSA), a recent randomized trial compared diagnostic and functional outcomes when sleep physicians were presented with only limited polysomnographic data (simulating data provided by in-home studies) or the complete polysomnographic data set [32]. There was no difference in the distribution of initial diagnoses or functional outcome with limited or full testing. However, testing that was limited to oxygen saturation and heart rate was associated with lower physician diagnostic confidence and less continuous positive airway pressure use. While this study supports in-home testing, the studies were not performed in the home, which was a major limitation. Further validation comparing in-home testing with the gold standard of polysomnography is needed. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Home sleep apnea testing'.)

Interactive web-based CBT for chronic insomnia (January 2017)

Cognitive behavioral therapy (CBT) is an effective treatment of chronic insomnia, but access to trained practitioners can be limited. In a randomized trial of 303 adults recruited via the internet, a six-week interactive web-based CBT program resulted in greater improvement in subjective sleep measures than internet patient education alone, and benefits were sustained at one year [33]. Thus, internet-based CBT programs may be an alternative to in-person delivery for motivated, technology-savvy individuals. (See "Treatment of insomnia in adults", section on 'Cognitive behavioral therapy'.)

Inadequate sleep and adverse cardiometabolic outcomes (December 2016)

The adverse health outcomes of inadequate sleep duration (<7 hours per night) and quality are increasingly recognized. A new scientific statement from the American Heart Association reviews data linking sleep restriction with adverse cardiometabolic outcomes and recommends that healthy sleep behavior be addressed in public health campaigns to promote ideal cardiac health, alongside blood pressure, cholesterol, diet, blood glucose, physical activity, weight, and smoking cessation [34]. (See "Insufficient sleep: Definition, epidemiology, and adverse outcomes", section on 'Cardiovascular morbidity'.)

Flumazenil in patients with refractory hypersomnolence (December 2016)

Preliminary data suggest that compounded preparations of flumazenil, a gamma-aminobutyric acid type A receptor antagonist, may benefit some patients with hypersomnolence of central origin. In a case series of 153 patients with refractory hypersomnolence due to idiopathic hypersomnia, obstructive sleep apnea, or other disorders, compounded sublingual or transdermal flumazenil was well tolerated and associated with sustained improvement in subjective sleepiness in 39 percent of patients [35]. These results suggest that controlled studies of flumazenil in this patient population are warranted. (See "Idiopathic hypersomnia", section on 'Pharmacotherapy'.)


High-dose influenza vaccine in older adults (March 2017)

For influenza vaccination of adults ≥65 years of age, we recommend the high-dose inactivated influenza vaccine, which has previously been shown to be more immunogenic and modestly more effective at preventing influenza infection than the standard-dose vaccine. In a study of United States Medicare beneficiaries ≥65 years of age, the high-dose vaccine was more effective than the standard-dose vaccine for preventing postinfluenza death during the 2012-2013 influenza season, a season when circulation of H3N2 influenza A (a strain associated with severe disease) was common [36]. In contrast, it was not more effective for preventing postinfluenza death during the following season, when H1N1 influenza A (a strain associated with mild disease) predominated. This difference was likely due to the difficulty in demonstrating benefit during a mild influenza season, when death is a rare outcome. The high-dose vaccine was associated with a reduced risk of hospitalization during both seasons. (See "Seasonal influenza vaccination in adults", section on 'High-dose vaccine'.)

High-dose IV zanamivir does not improve outcomes for severe influenza (February 2017)

There has been interest in determining whether doubling the dose of a neuraminidase inhibitor improves outcomes for severe influenza. Previous studies have not demonstrated a benefit to doubling the dose of oral oseltamivir. An intravenous (IV) formulation of zanamivir has been developed but remains investigational. In a trial, patients with severe influenza were randomly assigned to receive the standard dose of either oral oseltamivir (75 mg twice daily) or IV zanamivir (300 mg twice daily) or a double dose of IV zanamivir (600 mg twice daily) for 5 to 10 days [37]. The time to clinical response (a composite of vital sign stabilization and hospital discharge) was similar in all three groups. (See "Treatment of seasonal influenza in adults", section on 'Dosing'.)

Guidelines for the diagnosis of primary ciliary dyskinesia (February 2017)

Primary ciliary dyskinesia (PCD, also called the immotile cilia syndrome) is an inherited disease that presents, often in childhood, with recurrent respiratory infections and chronic rhinosinusitis. The European Respiratory Society has published new guidelines for the diagnosis of PCD [38]. For patients with clinical features suggestive of PCD, a combination of tests is usually needed to confirm or exclude the diagnosis, given that there is no “gold standard.” The most commonly used tests are nasal nitric oxide, high-speed videomicroscopy analysis, and transmission electron microscopy. Genotyping may be useful in a small number of selected patients. (See "Primary ciliary dyskinesia (immotile-cilia syndrome)", section on 'Diagnostic evaluation'.)

Underdosing of direct oral anticoagulants (February 2017)

The oral direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban (collectively called direct oral anticoagulants [DOACs]) have been available for several years. A real-world study of over 1500 patients with venous thromboembolism (VTE) who were treated with a DOAC found that dosing differed from the recommended product dosing in 20 to 50 percent of cases, depending on the agent [39]. These deviations (mostly underdosing) correlated with an increased frequency of VTE recurrence. Clinicians should familiarize themselves with prescribing information to avoid adverse outcomes. (See "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects", section on 'Clinician familiarity with dosing'.)

Role of person-to-person transmission in extensively drug-resistant tuberculosis (XDR-TB) (January 2017)

It has been postulated that extensively drug-resistant tuberculosis (XDR-TB) is acquired mainly as the result of inadequate treatment. However, in a study of 400 South African patients with XDR-TB, 69 percent had not received prior treatment for multidrug-resistant TB, and genotypic analysis demonstrated that over 80 percent of isolates belonged to one of several defined phylogenetic clusters, suggesting person-to-person transmission in the majority of cases [40]. These findings imply that focus on interrupting transmission (both community-based and health care facility-based) is paramount to limiting spread of complex drug-resistant TB strains. (See "Epidemiology of extensively drug-resistant tuberculosis", section on 'South Africa'.)

Diaphragmatic pacing harmful in patients with amyotrophic lateral sclerosis (January 2017)

Pacing the diaphragm in patients with amyotrophic lateral sclerosis (ALS) is controversial. A recent randomized trial of patients with early respiratory impairment from ALS reported that, compared with sham pacing, diaphragmatic pacing resulted in increased mortality and did not delay time to noninvasive ventilation [41]. We continue to prefer to avoid diaphragmatic pacing in this population until future trials demonstrate a clear benefit. (See "Pacing the diaphragm: Patient selection, evaluation, implantation, and complications", section on 'Amyotrophic lateral sclerosis'.)

Guidelines on diagnosis of tuberculosis (January 2017)

Guidelines from the American Thoracic Society, Infectious Diseases Society of America, and the Centers for Disease Control and Prevention on the diagnosis of tuberculosis in adults and children were published in December 2016 [42]. They state that an interferon-gamma release assay (IGRA) is generally preferred for diagnosis of latent tuberculosis infection (LTBI) in individuals five years or older who have low-to-intermediate risk of progression to active disease (table 1), although the tuberculin skin test (TST) is an acceptable alternative if IGRA is not available or too costly. For those who have high risk of progression to active disease, either IGRA or TST is acceptable, but many guideline panel members noted using the alternative test if the initial one was negative and considering a positive result from either test to indicate LTBI. The evaluation of suspected tuberculosis disease should include three sputum specimens for acid-fast bacilli (AFB) smear and culture and one or more specimens for nucleic acid amplification (NAA) testing. (See "Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults" and "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults" and "Latent tuberculosis infection in children" and "Tuberculosis disease in children".)

FDA warning removed from varenicline for smoking cessation (December 2016)

In 2009, the US Food and Drug Administration (FDA) required varenicline packaging to include a boxed warning about potential neuropsychiatric side effects, but this warning has been removed in 2016 [43], based on results of a randomized trial that found no difference in adverse neuropsychiatric events comparing varenicline with nicotine patch or placebo in patients with or without a coexisting psychiatric disorder [44]. As with any medication, we advise that patients should be told to contact their clinician if they or their family notice any unusual behavior or mood symptoms as well as any new or worsening symptoms of cardiovascular disease. (See "Pharmacotherapy for smoking cessation in adults", section on 'Safety'.)

Ibrutinib and Pneumocystis pneumonia (December 2016)

The Bruton tyrosine kinase inhibitor ibrutinib has not clearly been associated with an increased risk of opportunistic infections, but cases have been reported. In a series of 96 patients receiving ibrutinib as the sole agent for chronic lymphocytic leukemia (CLL), five were reported to have Pneumocystis pneumonia [45]. All of the infections were grade ≤2 and resolved with oral trimethoprim-sulfamethoxazole. A limitation is that the diagnoses were made by polymerase chain reaction (PCR) of bronchoalveolar lavage fluid, which could represent a false positive in the setting of colonization with Pneumocystis. Nevertheless, clinicians should have a high index of suspicion for Pneumocystis pneumonia in patients receiving ibrutinib, and the diagnosis should be sought in those with compatible signs and symptoms. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Ibrutinib' and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Ibrutinib and idelalisib'.)

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