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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

Disclosures: Helen Hollingsworth, MD Nothing to disclose. April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)]. Geraldine Finlay, MD Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2015. | This topic last updated: May 21, 2015.

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.


Warning about use of non-prescription asthma treatments (April 2015)

The US Food and Drug Administration (FDA) released a consumer warning about the potential health risks of over-the-counter (OTC) homeopathic products for asthma [1]. The efficacy and safety of OTC products are not evaluated by the FDA. In addition, there is evidence that some non-prescription therapies, such as racemic epinephrine inhaler (sold as Asthmanefrin) and systemic ephedrine (sold as Bronkaid and Primatene tablets), are less effective than standard therapies for asthma and have a higher rate of side effects. Thus, OTC products are not recommended for the routine care of asthma, particularly acute asthma symptoms. These warnings are an important reminder for clinicians to ask their patients about use of OTC products. (See "Asthma in children younger than 12 years: Rescue treatment for acute symptoms", section on 'Nonstandard therapies' and "Alternative and experimental agents for the treatment of asthma", section on 'Risks associated with inhaled epinephrine' and "Alternative and experimental agents for the treatment of asthma", section on 'Homeopathic agents' and "Homeopathy", section on 'Specific diseases'.)

Safety of inhaled long-acting beta agonist/glucocorticoid for asthma during pregnancy (February 2015)

An important clinical question for pregnant women with asthma is whether using a combination long-acting beta-agonist (LABA) plus inhaled glucocorticoid confers an increased risk for adverse fetal outcomes, compared with monotherapy using a higher dose of the inhaled glucocorticoid. In a study of 1302 pregnant women with asthma, the risk for a major congenital malformation was not increased when a LABA plus low dose inhaled glucocorticoid was compared with a medium dose inhaled glucocorticoid, or when a LABA plus medium-dose inhaled glucocorticoid was compared with a high-dose inhaled glucocorticoid [2]. (See "Management of asthma during pregnancy", section on 'Long-acting beta-adrenergic agents'.)

Safety of omalizumab for asthma during pregnancy (February 2015)

The safety of omalizumab exposure during pregnancy in humans has not been formally evaluated, but outcomes from an omalizumab registry have been published [3]. There were 169 pregnancies with known outcomes: 156 live births (160 infants), 1 fetal death/stillborn, and 11 spontaneous abortions. The rate of preterm birth was 14 percent, and 11 percent of infants were small for gestational age. Congenital anomalies were present in 13 percent, and 4 percent had a major anomaly. While the sample size is small, these results are similar to findings from other studies of pregnant women with asthma. Further data are needed to more fully characterize outcomes of omalizumab use in pregnancy. (See "Management of asthma during pregnancy", section on 'Anti-immunoglobulin E'.)

Novel glucocorticoid receptor agonist for asthma (February 2015)

The investigational agent AZD5423 is a nonsteroidal compound that binds to the glucocorticoid receptor in a different manner from that of traditional glucocorticoids. It suppresses production of proinflammatory proteins (like traditional glucocorticoids), but with reduced adverse effects in animal models. An inhaled dry powder formulation of AZD5423 was assessed in a trial that randomly assigned 20 subjects with mild allergic asthma to pretreatment with AZD5423, budesonide, or placebo for seven days followed by allergen-bronchoprovocation [4]. AZD5423 attenuated the fall in forced expiratory volume in one second (FEV1) during the late phase asthmatic response compared with budesonide or placebo, but did not affect the early decrease in FEV1. AZD5423 also decreased allergen-induced sputum eosinophilia and allergen-induced airway hyperresponsiveness at 24 hours and was well-tolerated. Additional studies are needed to determine the safety and efficacy of AZD5423 compared with inhaled glucocorticoids. (See "Alternative and experimental agents for the treatment of asthma", section on 'Novel glucocorticoid receptor agonist'.)


Roflumilast reduces exacerbations in severe COPD (April 2015)

Roflumilast is an oral medication that is occasionally used in severe chronic obstructive pulmonary disease (COPD). In a multicenter trial, nearly 2000 patients with COPD, severe airflow obstruction, and at least two exacerbations in the prior year were randomly assigned to oral roflumilast or placebo for one year [5]. All patients used a combination inhaled glucocorticoid and long acting beta-agonist inhaler in addition to study medication. Tiotropium was also allowed. Moderate-to-severe COPD exacerbations were 14 percent lower among those taking roflumilast compared with those taking placebo. Severe exacerbations requiring hospital admission were decreased by 24 percent, although confidence intervals approached no effect. Roflumilast may help to reduce COPD exacerbations when added to other respiratory medications, although the effect appears to be modest. (See "Management of stable chronic obstructive pulmonary disease", section on 'PDE-4 inhibitors'.)


PTSD experienced by survivors of critical care (April 2015)

Patients who survive critical care in an intensive care unit (ICU) are known to experience significant rates of posttraumatic stress disorder (PTSD). Less has been known about risk factors for PTSD in these patients or their symptom course over time. A recent meta-analysis found that 24 percent of patients who received critical care experienced clinically important PTSD symptoms one to six months after ICU discharge [6]. Only a small drop in the prevalence, to 22 percent, was seen 7 to 12 months post-discharge. Risk factors for PTSD symptoms included benzodiazepine use during critical care, early memories of frightening ICU experiences, and pre-ICU psychopathology. Neither the severity of critical illness nor length of ICU stay was predictive. PTSD symptoms were associated with poorer quality of life. Among several interventions that aim to reduce PTSD symptoms in this population, keeping an ICU diary has shown the most robust evidence of efficacy. (See "Posttraumatic stress disorder: Epidemiology, pathophysiology, clinical manifestations, course, and diagnosis", section on 'ICU hospitalization'.)

Diagnostic criteria for hepatorenal syndrome (April 2015)

The International Club of Ascites has altered their diagnostic criteria for hepatorenal syndrome [7]. The new criteria recognize that, in such patients, acute kidney injury can sometimes be characterized by small absolute increases in serum creatinine. (See "Hepatorenal syndrome", section on 'Diagnosis'.)

Mortality is unchanged in severe sepsis with early goal-directed therapy (April 2015)

Early goal-directed therapy (EGDT) is the administration of intravenous fluids to patients with severe sepsis or septic shock within the first six hours of presentation using physiologic targets to guide fluid management. Although EGDT is widely accepted, the impact on mortality is unclear. In three multicenter randomized trials involving 1300 patients (ProCESS) [8], 1600 patients (ARISE) [9], and 2160 patients (ProMISe) [10], EGDT, compared with usual care, did not improve mortality at 60 days or 90 days. The early administration of fluids and antibiotics prior to randomization in these trials likely biased the results. However, they suggest that strict adherence to an aggressive EGDT protocol is not required in every patient with severe sepsis. (See "Evaluation and management of severe sepsis and septic shock in adults", section on 'Protocol-directed therapy'.)

Increased mortality with delayed treatment for spontaneous bacterial peritonitis (April 2015)

Patients with spontaneous bacterial peritonitis (SBP) who develop septic shock have high mortality rates, but early initiation of antimicrobial therapy may result in improved outcomes. In a retrospective study of patients with cirrhosis and SBP-associated septic shock, the risk of mortality nearly doubled (1.9-fold increase) with every hour delay in administering antimicrobial therapy [11]. In patients with suspected SBP-associated sepsis, ascitic fluid cultures should be obtained immediately and empiric antimicrobial therapy initiated to maximize the patient's chance of survival. (See "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis", section on 'Prognosis'.)

No effect of blood storage duration on transfusion outcomes (April 2015)

Observational studies have come to differing conclusions regarding the effect of red blood cell (RBC) storage duration on transfusion outcomes. Two new randomized trials addressing this question now demonstrate that blood storage duration does not affect clinical outcomes. The Age of BLood Evaluation (ABLE) trial evaluated critically ill adults requiring an RBC transfusion, and the REd CEll Storage duration Study (RECESS) evaluated patients undergoing complex cardiac surgery [12,13]. Neither trial found a difference in primary outcome (90-day mortality or change in multi-organ dysfunction score [MODS], respectively), or in a variety of secondary outcomes or adverse events. These data, along with a previously published randomized trial in premature infants, provide strong evidence in support of current transfusion practice that does not take into account RBC storage duration. (See "Red blood cell transfusion in adults: Storage, specialized modifications, and infusion parameters", section on 'Clinical relevance of storage time'.)

Transfusion threshold for patients who have undergone cardiac surgery (March 2015)

For patients undergoing cardiac surgery, significant postoperative anemia is associated with worse outcomes. However, transfusion of red blood cells carries with it significant risks and burdens. In the TITRe2 trial, 2007 patients who underwent cardiac surgery were randomly assigned to a restrictive transfusion threshold (hemoglobin <7.5 g/dL) or a liberal threshold (<9 g/dL) [14]. There was no difference in the rate of the primary combined outcome of serious infection or an ischemic event. We suggest a transfusion threshold of 7.5 to 8 g/dL for these patients. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Blood transfusion'.)

Warfarin reversal for urgent surgery: four-factor prothrombin complex concentrate versus Fresh Frozen Plasma (February 2015)

Patients receiving warfarin will occasionally require an urgent or emergent procedure, necessitating rapid reversal of anticoagulation. Available options include prothrombin complex concentrates (PCCs) and Fresh Frozen Plasma (FFP). In a trial that randomly assigned 181 such patients to receive 4-factor PCC or FFP, those receiving the PCC had better hemostasis, without increased toxicity [15]. This finding supports the use of a 4-factor PCC in this setting. Because of potential toxicities from all rapid reversal products, PCCs should be reserved for individuals with bleeding or high risk of bleeding. These products work transiently and thus should be accompanied by vitamin K administration for more prolonged reversal. (See "Correcting excess anticoagulation after warfarin".)

Ketamine for intubation in patients with elevated intracranial pressure (February 2015)

The use of ketamine as an induction agent for rapid sequence intubation (RSI) in patients with head trauma has been debated because some observational studies suggest it elevates intracranial pressure (ICP). However, a systematic review of 10 trials involving 953 critically ill patients, all managed with intubation and mechanical ventilation, concluded that the use of intravenous ketamine did not adversely affect patient outcomes, including mortality [16]. Most studies included in the review had methodological limitations, but two randomized, double-blinded controlled trials comparing the effects of prolonged ketamine and sufentanil infusions in patients with traumatic brain injury found no differences in mean daily ICP and cerebral perfusion pressures. The findings of this systematic review support our view that ketamine is an appropriate induction agent for RSI in patients with suspected ICP elevation and normal blood pressure or hypotension. (See "Sedation or induction agents for rapid sequence intubation in adults", section on 'Elevated intracranial pressure'.)

Driving pressure in acute respiratory distress syndrome predicts survival (February 2015)

Limiting pressure and over distension of mechanically ventilated lung improves survival in patients with acute respiratory distress syndrome (ARDS). Lung protective ventilation strategies traditionally use low tidal volume (VT) and plateau pressure (pPlat) with or without high positive end expiratory pressure (PEEP) to achieve this goal. One retrospective statistical analysis of nine trials compared driving pressure (ΔP; ie, difference between pPlat and applied PEEP) with the standard variables, VT, pPlat, and PEEP to predict survival in  3562 patients mechanically ventilated for ARDS [17]. Among ventilator variables, ΔP was the best predictor of survival. Even in patients who were ventilated using a lung protective strategy, small increases in ΔP resulted in a 30 to 40 percent increase in mortality. However, because ΔP is largely determined by VT, pPlat, and PEEP, we suggest the continued use of these standard variables rather than ΔP to manage ventilator settings in patients with ARDS. Use of ΔP will need to be tested in a large randomized trial before it can be routinely used in this population. (See "Mechanical ventilation of adults in acute respiratory distress syndrome", section on 'Driving pressure'.)

Adjunctive glucocorticoids for hospitalized patients with community-acquired pneumonia (January 2015)

There has been interest in using glucocorticoids as adjunctive therapy to antibiotics in hospitalized patients with community-acquired pneumonia (CAP) in an attempt to reduce the inflammatory response, which is likely to contribute to the morbidity of the disease. There are conflicting data on this approach, but the largest randomized trial suggests a modest benefit. In the trial, which included 785 hospitalized adults with CAP, prednisone 50 mg daily for seven days shortened the time to clinical stability by approximately one day compared with placebo, without an increase in complications [18]. In another randomized trial that included 120 patients in Spain with severe CAP and a high inflammatory response, there was less treatment failure among patients who received methylprednisolone 0.5 mg/kg every 12 hours for five days than in those who received placebo, but no difference in the rate of in-hospital mortality [19]. Pending the results of a larger trial evaluating mortality rates in severe CAP, we do not favor the routine use of adjunctive glucocorticoids in adults with CAP. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Glucocorticoids'.)


Novel variants in telomerase pathway associated with familial interstitial pneumonia (March 2015)

Several genes that maintain chromosome telomeres have been associated with idiopathic pulmonary fibrosis (IPF). In a study of 25 kindreds of familial interstitial pneumonia (FIP), the familial form of IPF, nine rare loss-of-function variants were identified in the gene that encodes the regulator of telomere elongation helicase 1 (RTEL1), which helps regulate telomere replication and stability [20]. The rare variants identified in this study segregate with FIP in genetic studies and are associated with very short telomeres in peripheral blood mononuclear cells. In 163 additional FIP kindreds, heterozygous variants of RTEL1 were found in eight families (approximately 5 percent). These observations further support the role of genes affecting telomeres in FIP. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)


Inferior vena cava filter as adjunct to anticoagulation does not improve outcomes (May 2015)

In patients with significant pulmonary embolism (PE), it is unknown whether the routine insertion of an inferior vena cava (IVC) filter as an adjunct to anticoagulation provides additional protection against recurrent PE. In an open-label randomized trial (PREPIC2), 399 patients with "severe" PE (included patients with a diagnosis of PE plus at least one of the following: age >75 years, active cancer, signs of right ventricle dysfunction, chronic respiratory insufficiency, or other high-risk characters) received either standard anticoagulation alone or anticoagulation plus a retrievable IVC filter [21]. Adjunctive therapy with an IVC filter did not alter the rate of PE recurrence, deep vein thrombosis recurrence, or mortality at three or six months. This study suggests that the routine insertion of an IVC filter in patients with severe PE is not warranted. The main indication for filter insertion should continue to be a contraindication to anticoagulation, and any additional indications should be considered on a case-by-case basis. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Inferior vena cava filter'.)

Two distinct phenotypes in patients with idiopathic pulmonary artery hypertension (January 2015)

Vasoconstriction and luminal obstruction from plexiform lesions are both thought to play a role in the pathogenesis of idiopathic pulmonary artery hypertension (IPAH). A minority of patients responds to pulmonary vasodilators (responders), suggesting vasoconstriction may be more important in the pathogenesis of the disease in these patients compared with non-responders. Functional capillary surface area (FCSA) is a measurement of the amount of available pulmonary flow (ie, pulmonary reserve) that can be recruited during vasodilatation for improved gas exchange and hemodynamics. In an observational study of 14 patients with IPAH, FSCA response to a vasodilator challenge was compared between responders and non responders. Responders had a higher FCSA which increased during vasodilator testing, supporting the hypothesis that vasoconstriction, rather than luminal obstruction, was the dominant pathogenetic process in this population [22]. Further exploration of this theory with larger numbers of patients is warranted. (See "Pathogenesis of pulmonary hypertension", section on 'Pathophysiology'.)

Negative D-dimer does not predict recurrence risk in unprovoked VTE (January 2015)

Indefinite anticoagulation is preferred in patients with a first episode of unprovoked venous thromboembolism (VTE). The D-dimer assay has been proposed as a test to identify patients in whom anticoagulant therapy may be safely discontinued. However, a prospective study that measured the VTE recurrence rate in 319 patients with a first episode of unprovoked VTE who had two consecutive negative D-dimer levels does not support this indication for d-dimer testing [23]. The first level was drawn following completion of a standard course of anticoagulant therapy and the second after one month off anticoagulation. The two year recurrence rate was 7 percent per patient-year, with higher rates reported in men (10 percent per patient year) compared with women (5 percent per patient year). These rates are sufficiently high that they support the current recommendation of indefinite anticoagulation in this population; D-dimer measurements do not appear to be useful in identifying candidates for more limited treatment. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Elevated D-dimer'.)

Novel anticoagulant strategies with potentially lower bleeding risk (December 2014)

Anticoagulants reduce the risk of thromboembolism, but this benefit is balanced by an increased risk of bleeding. Two new strategies for anticoagulation are in development that may carry a lower risk of bleeding compared with currently available agents. The first uses an antisense oligonucleotide to reduce production of coagulation factor XI (FXI-ASO). In patients undergoing knee replacement, treatment with FXI-ASO was associated with a 3 percent risk of venous thromboembolism, compared with approximately 30 percent with low molecular weight heparin, without increasing bleeding [24]. However, the duration of anticoagulation was long and injection site reactions were common. The second strategy targets polyphosphate, a pro-thrombotic substance released from activated platelets or microbes [25]. In preclinical models, polyphosphate inhibitors have shown reduced arterial thrombosis without increased bleeding. Additional studies are awaited to determine the role of these new strategies in clinical practice. (See "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Anticoagulants in development'.)


Herbal products for treatment of insomnia (March 2015)

A variety of herbal products are purported to be useful for insomnia. There is little evidence from randomized controlled trials about the efficacy of many herbals, however, and for those that have been well studied (eg, valerian), there is little evidence of benefit. A meta-analysis of 14 randomized trials in over 1600 patients found no significant difference between any herbal medicine and placebo on any clinical insomnia outcome measure [26]. The majority of the trials (11 out of 14) studied valerian; chamomile, kava, and wuling were studied in one trial each. Unlike other herbals in the study, valerian was associated with a greater number of adverse events per person compared with placebo. (See "Treatment of insomnia", section on 'Over-the-counter'.)

Risk factors for neurodegeneration in REM sleep behavior disorder (March 2015)

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia in which individuals act out their dreams due to loss of REM sleep paralysis. RBD has been increasingly recognized as a prodromal symptom of alpha-synuclein neurodegeneration (eg, Parkinson disease, dementia with Lewy bodies, and multiple system atrophy). In a 10-year prospective cohort study of 89 patients with idiopathic RBD, the rate of conversion to one of these disorders was 30 percent at 3 years and 66 percent at 7.5 years [27]. The strongest risk factors for conversion were subtle motor dysfunction, abnormal color vision, olfactory dysfunction, and nonuse of antidepressants. These characteristics may prove useful for identifying candidates for novel, early-intervention neuroprotective trials in Parkinson disease and related disorders. (See "Rapid eye movement sleep behavior disorder", section on 'Prognosis and counseling'.)


Novel agent for refractory cough in adults (May 2015)

Increased sensitivity of P2X3 receptors on airway sensory nerve fibers may contribute to refractory cough. In a randomized, cross-over trial of 24 subjects with refractory cough, an investigational P2X3 antagonist (AF-219) decreased cough counts during the two-week study blocks by 75 percent compared with placebo [28]. However, taste disturbance was noted in all patients taking AF-219 and caused six subjects to withdraw from the study; nausea was also common (38 percent). These results support a role for P2X3 receptor hypersensitivity in refractory cough, but further study is needed to determine safety, efficacy, and tolerability in a larger number of patients. (See "Treatment of subacute and chronic cough in adults", section on 'Future directions'.)

Pneumococcal conjugate vaccine in adults ≥65 years of age (September 2014, MODIFIED March 2015)

The CAPiTA trial, which is the largest trial to assess the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar 13) in adults, compared PCV13 to placebo in approximately 85,000 immunocompetent adults ≥65 years of age in the Netherlands who had not received a pneumococcal vaccine previously [29]. The trial demonstrated 46 percent efficacy of PCV13 against vaccine-type pneumococcal pneumonia, 45 percent efficacy against vaccine-type nonbacteremic pneumococcal pneumonia, and 75 percent efficacy against vaccine-type invasive pneumococcal disease. Efficacy persisted for the duration of the trial (mean follow-up four years). However, some concern has been raised that since this trial began before PCV13 was used routinely in infants in the Netherlands, it might not answer the question of whether its use in adults is efficacious in countries that routinely vaccinate infants. (See "Pneumococcal vaccination in adults", section on 'Efficacy'.)

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for many years in the United States for all adults ≥65 years of age. In September 2014, the United States Advisory Committee on Immunization Practices (ACIP) began also recommending PCV13 for all adults ≥65 years of age [30]. The ACIP revision was prompted by results from the CAPiTA trial. Current recommendations for individuals ≥65 years of age who have not previously received either PCV13 or PPSV23 are to administer PCV13 followed 6 to 12 months later by PPSV23 (algorithm 1). In patients who have already received PPSV23, at least one year should elapse before they are given PCV13. (See "Pneumococcal vaccination in adults", section on 'Indications'.)

Approval of the direct factor Xa inhibitor edoxaban (January 2015)

The US Food and Drug Administration has approved the oral direct factor Xa inhibitor edoxaban (Savaysa; Lixiana in Japan) for the prevention of stroke in nonvalvular atrial fibrillation and the treatment of venous thromboembolism, based upon earlier randomized trials demonstrating non-inferiority to warfarin [31-33]. Dosing is once daily at a fixed dose without monitoring. There are Boxed Warnings regarding avoidance of edoxaban in patients with atrial fibrillation who have a creatinine clearance >95 mL/minute, spinal/epidural hematoma in patients undergoing neuraxial procedures, and ischemic events following premature discontinuation. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization" and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)" and "Anticoagulation in acute pulmonary embolism" and "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Edoxaban'.)

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  1. Over-the-Counter Asthma Products Labeled as Homeopathic: FDA Statement - Consumer Warning About Potential Health Risks.
  2. Eltonsy S, Forget A, Beauchesne MF, Blais L. Risk of congenital malformations for asthmatic pregnant women using a long-acting β₂-agonist and inhaled corticosteroid combination versus higher-dose inhaled corticosteroid monotherapy. J Allergy Clin Immunol 2015; 135:123.
  3. Namazy J, Cabana MD, Scheuerle AE, et al. The Xolair Pregnancy Registry (EXPECT): the safety of omalizumab use during pregnancy. J Allergy Clin Immunol 2015; 135:407.
  4. Gauvreau GM, Boulet LP, Leigh R, et al. A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses. Am J Respir Crit Care Med 2015; 191:161.
  5. Martinez FJ, Calverley PM, Goehring UM, et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015; 385:857.
  6. Parker AM, Sricharoenchai T, Raparla S, et al. Posttraumatic stress disorder in critical illness survivors: a metaanalysis. Crit Care Med 2015; 43:1121.
  7. Angeli P, Ginès P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol 2015; 62:968.
  8. ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683.
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  28. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 2015; 385:1198.
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  30. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014; 63:822.
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