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What's new in pulmonary and critical care medicine
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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: Feb 2017. | This topic last updated: Mar 20, 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.

ASTHMA

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 [1]. 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 omega-3 long-chain polyunsaturated fatty acid supplementation during pregnancy", section on 'Atopic and allergic disease, asthma'.)

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 [2]. 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'.)

Chest pain in patients with aspirin-exacerbated respiratory disease (November 2016)

Aspirin-exacerbated respiratory disease (AERD) describes patients with asthma and chronic rhinosinusitis with nasal polyposis who experience acute nasal symptoms and asthmatic reactions following the ingestion of aspirin and other nonsteroidal antiinflammatory drugs. Retrosternal chest pain may be another less common clinical feature of this syndrome. In a retrospective review of 153 individuals with AERD, 10 patients had been evaluated for chest pain that was variably associated with peripheral blood eosinophilia and vasospasm on angiography [3]. The pain did not respond to angina treatments but did improve with glucocorticoids. Further study of this possible feature of AERD is needed. (See "Aspirin-exacerbated respiratory disease", section on 'Chest pain'.)

Investigational interleukin-5 receptor antibody for asthma (November 2016)

Two trials found that an investigational anti-interleukin (IL)-5 receptor antibody, benralizumab, reduced exacerbations in patients with moderate to severe asthma who had elevated peripheral blood eosinophil counts.

In the multicenter SIROCCO trial, about 1200 adolescent and adult patients with severe asthma and at least two exacerbations in the prior year despite high-dose inhaled glucocorticoids and a long-acting beta agonist were randomly assigned to subcutaneous benralizumab or placebo for 11 months [4]. Benralizumab reduced exacerbations by approximately 50 percent in patients with a high peripheral blood eosinophil count (≥300/microL).

In the CALIMA trial, approximately 1300 patients with moderate-to-severe asthma received benralizumab or placebo for 14 months [5]. Among those with high peripheral blood eosinophil counts, the annual exacerbation rate was decreased in the benralizumab groups by 28 to 36 percent, compared with placebo.

In both studies, effects were less consistent for patients with lower eosinophil counts. The subcutaneous drug was well tolerated and might be effective with dosing every eight weeks. Benralizumab is not commercially available. (See "Investigational agents for asthma", section on 'Anti-IL-5 therapy'.)

Safety of inhaled glucocorticoid-LABA combination therapy in asthma (September 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 long-acting beta agonists (LABAs) in asthma. While concerning, the number of events was small, and it could not be determined if the potential risk of salmeterol could be mitigated by combining LABAs with inhaled glucocorticoids. Three large randomized trials including 30,000 children and adults found no increase in asthma-related adverse events or deaths among patients who used combination inhalers with salmeterol or formoterol plus an inhaled glucocorticoid versus glucocorticoid monotherapy [6-8]. These studies support the safety of these fixed-dose combination inhalers in patients with moderate-to-severe asthma. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Potential risk mitigation'.)

COPD

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 [9]. 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'.)

Lack of benefit for long-term oxygen therapy for COPD with mild-to-moderate hypoxemia (November 2016)

While long-term oxygen has demonstrated benefit in severe hypoxemia due to chronic obstructive pulmonary disease (COPD), effectiveness in patients with mild-to-moderate hypoxemia has been unclear. The long-term oxygen treatment trial (LOTT) enrolled over 700 adults with COPD and mild-to-moderate hypoxemia, based on defined parameters of resting and post-walk test oxygen saturation [10]. Participants were randomized to supplemental oxygen (either continuous, with exercise or sleep, depending on hypoxemia pattern) or no supplemental oxygen. There were no differences in time to death or first hospitalization, COPD exacerbations, quality of life, or exercise capacity at one to six years. While supplemental oxygen does not appear to benefit most patients with mild-to-moderate hypoxemia, the possibility of benefit for individual patients is not excluded. (See "Management of stable chronic obstructive pulmonary disease", section on 'Oxygen'.)

Controlled effectiveness trial of fluticasone furoate-vilanterol in COPD (November 2016)

One concern about randomized trials of chronic obstructive pulmonary disease (COPD) therapies is that their strict selection criteria exclude higher-risk patients and potentially miss adverse effects that could occur in routine clinical practice. A multicenter controlled effectiveness trial recruited almost 3000 patients with COPD who had had one or more exacerbations in the prior three years and assigned them to fluticasone furoate-vilanterol (100 mcg-25 mcg) once daily or usual care for one year [11]. The fluticasone furoate-vilanterol group experienced approximately 8 percent fewer exacerbations. The trial did not demonstrate a significant difference in the incidence of pneumonia between the groups. (See "Management of stable chronic obstructive pulmonary disease", section on 'Efficacy'.)

CRITICAL CARE

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]) [12]. 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 [13]. 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 [14]. 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 [15,16]. 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 [15]. In contrast, qSOFA was inferior to SOFA in a retrospective analysis of intensive care unit (ICU) patients with an infection-related diagnosis [16]. 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 [17]. 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 [18-20]. 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'.)

High-flow oxygen for the prevention of postextubation respiratory failure (October 2016)

Results from trials that compare high-flow oxygen delivered via nasal cannula (HFNC) and noninvasive ventilation (NIV) for the prevention of postextubation respiratory failure have been conflicting. In a recent multicenter trial of patients at high risk of reintubation following extubation, rates of reintubation, the primary outcome, were similar for NIV and HFNC, and there was no difference in rates of mortality, sepsis, or multiorgan failure [21]. For patients considered at high risk of reintubation, this study supports the use of a trial of HFNC as an alternative to NIV for those at high risk of reintubation. However, given conflicting earlier findings, additional trials are needed to determine strict selection criteria before routinely recommending HFNC for the prevention of postextubation respiratory failure. (See "Extubation management", section on 'High flow oxygen versus noninvasive ventilation'.)

Corticosteroids not beneficial in severe sepsis without shock (October 2016)

The administration of corticosteroids to patients with sepsis is generally reserved for those with septic shock. A recent randomized trial of nearly 400 adults examined the efficacy of corticosteroids in patients with severe sepsis who did not have shock [22]. Compared with placebo, an infusion of hydrocortisone (200 mg daily for five days followed by tapering until day 11) had no effect on mortality or progression to shock. This trial supports our current recommendation that corticosteroids not be routinely administered to septic patients without shock. (See "Glucocorticoid therapy in septic shock", section on 'HYPRESS'.)

Oxygenation goals in critically ill patients (October 2016)

The optimal level of oxygenation in mechanically ventilated patients is unknown. A recent randomized trial reported that, compared with a conventional approach to oxygenation (partial arterial pressure of oxygen [PaO2] up to 150 mmHg or peripheral arterial oxygen saturation [SpO2] 97 to 100 percent), a conservative approach (PaO2 70 to 100 mmHg or SpO2 94 to 98 percent) resulted in lower mortality and fewer episodes of shock, liver failure, and bacteremia [23]. However, these preliminary results should be confirmed by a larger multicenter trial before a conservative approach to oxygenation should be routinely adopted for mechanically ventilated patients. (See "Overview of mechanical ventilation", section on 'Fraction of inspired oxygen'.)

INTERSTITIAL LUNG DISEASE

Mycophenolate mofetil for scleroderma lung disease (October 2016)

Cyclophosphamide has been the suggested treatment for moderate-to-severe interstitial lung disease complicating systemic sclerosis (SSc-ILD) but has well-known toxicity. A recent randomized trial compared mycophenolate mofetil (MMF) with oral cyclophosphamide in 142 patients with SSc-ILD, exertional dyspnea, and features of progressive disease [24]. Pulmonary function and dyspnea improved in both groups, without a significant difference between groups. MMF was better tolerated than cyclophosphamide based on a longer time to patient withdrawal and lower incidence of leukopenia and thrombocytopenia. We now suggest initiating treatment for symptomatic progressive SSc-ILD with mycophenolate, rather than cyclophosphamide, due to comparable efficacy, better safety profile, and the option for longer-term therapy. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Choice of an agent'.)

LUNG CANCER

Ceritinib in ALK-positive non-small cell lung cancer (January 2017)

For patients with anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC), inhibition of ALK is the preferred frontline approach. A randomized trial compared ceritinib, an ALK inhibitor, with pemetrexed and a platinum agent in such patients and found improved progression-free survival (17 versus 8 months) and, for those with brain metastasis, a higher intracranial objective response rate (73 versus 27 percent) [25]. Although we use ceritinib only for patients with ALK-positive NSCLC who are intolerant of or who have progressed on the ALK inhibitor crizotinib, these data support further study of ceritinib in the frontline setting. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Ceritinib'.)

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 [26]. 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'.)

PULMONARY VASCULAR DISEASE

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 [27]. 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'.)

Syncope and pulmonary embolus (October 2016)

While pulmonary embolus (PE) has generally been considered to be a relatively rare cause of syncope, a recent study reported a 17 percent prevalence of PE among patients admitted to hospital with syncope, and a 25 percent prevalence among those without an alternative etiology for syncope [28]. Two-thirds of patients with syncope secondary to PE had thrombus located in the mainstem or lobar arteries, suggesting that syncope may indicate a high burden of thrombus. The study underscores the importance of syncope as a presenting manifestation of clinically significant PE among patients with syncope who are admitted to the hospital. The prevalence of diagnosed PE was lower (4 percent) when looking at all patients seen in the emergency department with syncope, although the total number of these patients who were assessed for PE was not reported. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'History and examination'.)

SLEEP MEDICINE

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 [29]. 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 [30]. 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 [31,32]. 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 [31]. 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 [33]. 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 [34]. 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 [35]. (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 [36]. These results suggest that controlled studies of flumazenil in this patient population are warranted. (See "Idiopathic hypersomnia", section on 'Pharmacotherapy'.)

OTHER PULMONARY MEDICINE

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: 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'.)

E-cigarette use and respiratory symptoms in adolescents (November 2016)

Use of e-cigarettes has been rising among adolescents in the United States, and the long-term health consequences of e-cigarette use are unknown. A survey of 11th and 12th grade students in California found an association between self-reported chronic bronchitic symptoms (chronic cough, phlegm, bronchitis in the past year) and current or past e-cigarette use that remained after adjustment for confounders such as cigarette smoking or secondhand smoke exposure; risk of respiratory symptoms increased with frequency of current use of e-cigarettes [46]. (See "E-cigarettes", section on 'Adverse health effects'.)

New guideline recommendations on treatment of drug-susceptible tuberculosis in HIV-infected patients (September 2016)

For patients with tuberculosis (TB) and newly diagnosed HIV infection, a number of trials have established the benefits of initiating antiretroviral therapy (ART) soon after initiating TB therapy. New guidelines on the treatment of drug-susceptible tuberculosis (TB), developed jointly by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America, also recommend initiating ART during TB treatment (within the first two weeks if the CD4 cell count <50 cells/microL and within 8 to 12 weeks if the CD4 cell count >50 cells/microL), rather than waiting until after TB therapy is completed [47]. However, HIV-infected patients with TB involvement of the central nervous system (CNS) are an exception; for these patients, the guidelines recommend against initiating ART in the first eight weeks of antituberculous therapy (even for patients with CD4 cell counts <50 cells/microL), since development of immune reconstitution inflammatory syndrome in patients with CNS TB may cause severe or fatal neurological complications. (See "Treatment of pulmonary tuberculosis in HIV-infected adults", section on 'Timing of ART in the treatment-naive patient' and "Central nervous system tuberculosis".)

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