A Multi-Season Randomised Controlled Trial of Advax-Adjuvanted Seasonal Influenza Vaccine in Participants with Chronic Disease or Older Age.

BACKGROUND: The aim of this study was to determine the safety and immunogenicity of trivalent inactivated influenza vaccine (TIV) alone or formulated with Advax™ delta inulin adjuvant in those of older age (> 60 years) or with chronic disease. METHODS: Over four consecutive years from 2008-2011, adult participants with chronic disease or over 60 years were recruited into a randomised controlled study to assess the safety, tolerability and immunogenicity of Advax-adjuvanted versus standard TIV. The per protocol (PP) population with at least one post-baseline measurement of influenza antibodies comprised 1297 participants: 447 in the TIV, and 850 in the Advax-adjuvanted TIV, groups. RESULTS: No safety issues were identified. Variables negatively affecting vaccine responses included obesity and diabetes mellitus. Advax adjuvant had a positive impact on anti-influenza IgM responses and on H3N2 and B strain seropositivity as assessed by hemagglutination inhibition. CONCLUSIONS: Advax-adjuvanted TIV was safe and well tolerated in individuals with chronic disease. There is an ongoing need for research into improved influenza vaccines for high-risk populations. Australia New Zealand Clinical Trial Registry: ACTRN 12608000364370.

Obstructive sleep apnoea and adherence to continuous positive airway therapy among Australian women.

BACKGROUND: Clinical characteristics of women with different obstructive sleep apnoea (OSA) severity and adherence to continuous positive airway pressure (CPAP) therapy have not been previously explored. AIMS: To assess OSA prevalence, predictors, clinical and polysomnographic (PSG) characteristics and adherence to CPAP therapy among adult Australian women in a retrospective study. METHODS: All female patients who underwent a diagnostic PSG between 2014 and 2015 were included. CPAP adherence was assessed during the study period between 2018 and 2019 using multiple regression models. RESULTS: Among a total of 591 women included in this study (Aboriginal, n = 86), OSA was diagnosed in 458/591 (78%) patients; mild, moderate and severe OSA was present in 44%, 27% and 29% respectively. Older age, higher BMI and hypertension predicted the presence and severity of OSA. The Epworth Sleepiness Scale (ESS) score was not significantly different with (8 (5, 12)) or without (10 (5, 13)) OSA. PSG showed the rapid eye movement (REM) sleep-associated apnoea-hypopnea index (AHI) was higher with all severity of OSA. Adherence to CPAP therapy was noted in 171 (57%) patients; 47% mild, 57% moderate and 63% with severe OSA respectively. Three multiple regression models (clinical, PSG parameters, OSA severity, combined (clinical and PSG)) showed the combined model had the strongest predictive value and demonstrated that higher ESS and more severe oxygen desaturation were associated with CPAP adherence irrespective of OSA severity. CONCLUSIONS: Older age, higher BMI and the presence of hypertension predicted the presence of OSA. The REM sleep-related AHI was higher. Adherence to CPAP was associated with symptomatic OSA and severe oxygen desaturation.

The effectiveness of small-bore intercostal catheters versus large-bore chest tubes in the management of pleural disease with the systematic review of literature.

OBJECTIVE: The purpose of this study was to compare the effectiveness of small-bore intercostal catheters (SB ICCs; 10-14 Fr) to large-bore intercostal tubes (LB ICTs; >20 Fr) in the management of pleural diseases. METHODS: A total of 52 patients (42 males) with a mean age of 55 ± 23 years undergoing pleural intervention were included in the analysis. Twenty-five patients (48.1%) had pneumothorax and rest (51.9%) had pleural effusion. Half of the patients underwent SB ICC (mean age: 63 ± 20 years) and the remaining 26 underwent LB ICT (mean age: 47 ± 25 years). RESULTS: SB ICCs were predominantly used in patients with primary pleural effusion and LB ICTs in patients presenting with pneumothorax. Failures were in <20% of SB ICC patients (mainly from loculation) and in <30% with LB ICT patients (from persistent airleak) - difference that was not statistically significant. In both groups, no deaths or major complications directly related to the procedure were observed. However, the proportion that needed surgery was significantly different in two cohorts (18.5% OF SB ICC and 42.3% of LB ICT cohorts). The ICC dwell time was less in SB ICC (5 ± 4 days), compared to LB ICT (8 ± 6 days). SB ICCs were associated with less pain and seem to be tolerated better by the patients. CONCLUSIONS: In well-supervised tertiary hospital setting, SB ICCs are as effective as LB ICTs with better patient tolerance, reduced dwell time, and reduced likelihood for surgical intervention.

Management of acute COPD exacerbations in Australia: do we follow the guidelines?

OBJECTIVE: We aimed to assess adherence to the Australian national guideline (COPD-X) against audited practice, and to document the outcomes of patients hospitalised with an acute exacerbation of chronic obstructive pulmonary disease (COPD) at discharge and 28 days after. METHODS: A prospective clinical audit of COPD hospital admission from five tertiary care hospitals in five states of Australia was conducted. Post-discharge follow-up was conducted via telephone to assess for readmission and health status. RESULTS: There were 207 admissions for acute exacerbation (171 patients; mean 70.2 years old; 50.3% males). Readmission rates at 28 days were 25.4%, with one (0.6%) death during admission and eight (6.1%) post-discharge within 28 days. Concordance to the COPD-X guidance was variable; 22.7% performed spirometry, 81.1% had blood gases collected when forced expiratory volume in 1 s was <1 L, 99.5% had chest radiography performed, 95.1% were prescribed systemic corticosteroids and 95% were prescribed antibiotic therapy. There were 89.1% given oxygen therapy and 92.6% when arterial oxygen tension was <80 mmHg; 65.6% were given ventilatory assistance when pH was <7.35. Only 32.4% were referred to pulmonary rehabilitation but 76.8% had general practitioner follow-up arranged. CONCLUSION: When compared against clinical practice guidelines, we found important gaps in management of patients admitted with COPD throughout tertiary care centres in Australia. Strategies to improve guideline uptake are needed to optimise care.

Sleep apnoea among Australian Aboriginal and non-Aboriginal patients in the Northern Territory of Australia-a comparative study.

Australian Aboriginal and Torres Straight Islanders (ATSI) are noted to have a higher burden of chronic health conditions. However, there is a paucity of data on obstructive sleep apnoea (OSA) in this population. In this retrospective study, we evaluated the clinical and polysomnographic (PSG) characteristics of ATSI and non-ATSI adult patients who underwent diagnostic PSG between 2011 and 2015. There were a total of 3078 patients. Of the total, 403 (13%) were of ATSI origin. Among those of ATSI origin, 61% were male and 39% females, while among the non-ATSI cohort, 66% were males. The median age was 47.8 years in ATSI and 51.5 years in the non-ATSI cohort. In the combined cohort, body mass index was more than 30 kg/m2 (61%), hypertension (14.4%), diabetes (17.8%), and heart disease (23.3%). The ATSI patients had higher rates of class III obesity (27 vs. 15%), hypertension (26 vs. 14%), cardiac disease (34 vs. 23%), and diabetes (37 vs. 17%). Among all the study participants, the PSG confirmed 83.7% of the patients had an apnoea-hypopnea index (AHI) more than 5/h, mild (AHI 5-15/h) in 28.4%, moderate (AHI 15-30/h) in 22.3%, and severe (AHI > 30/h) in 33.0%. Among the ATSI patients, 46% had severe OSA. The median total AHI value was higher in the ATSI population (25, interquartile range [IQR]: 11-58) compared to the non-ATSI (17, IQR: 7-36), and in rural/remote population (19, IQR: 8-42) compared to urban (17, IQR: 7-37). This trend was similar for NREM (non-rapid eye movement)-AHI and REM (rapid eye movement)-AHI scores, although statistically significant difference was found only with ATSI status. In the combined cohort the probability of (OR = 1.62, 95% CI: 1.32-2.00, p < 0.001) of severe OSA was 62% higher in individual with hypertension, however, when stratified by ATSI status, the association was only significant in the non-ATSI population (OR = 1.53 95% CI: 1.21-1.94, p < 0.001). The odds of severe AHI was also significantly associated with heart disease (1.37; 95% CI: 1.14,1.63, p < 0.001), diabetes (1.74; 95% CI: 1.43,2.10; p < 0.001) and smoking (1.28; 95% CI: 1.09,1.50, p = 0.0023) in the overall study cohort. In both ATSI and non-ATSI patients, body mass index, neck circumference, sleep efficiency, wake after sleep onset, and respiratory arousal index were significantly higher and independently associated with severe AHI.

Chronic Obstructive Pulmonary Disease In Aboriginal Patients Of The Northern Territory Of Australia: A Landscape Perspective.

Background: The Aboriginal population of Australia has a higher burden of chronic health conditions than non-Aboriginal Australians. However, there is a paucity of data on clinical and demographic characteristics of chronic obstructive pulmonary disease (COPD) in this population. Method: In this retrospective study we evaluated the clinical, demographic and environmental influences in adult Aboriginal patients with COPD living in the regional and remote communities of the Northern Territory of Australia. Results: There were 380 patients (49%) with a diagnosis of COPD of the 767 patients referred to specialist respiratory outreach clinics. The mean age was 57 years (56% were female) and mean±SD BMI was 24.30±7.01 kg/m2. Smoking history was noted in 93% of the study cohort. The most common respiratory symptom was shortness of breath in 62%, and inhaled medications (salbutamol, tiotropium, salmeterol/fluticasone) were used by 79%, 44% and 58% of patients, respectively. Spirometry showed obstructive impairment (FEV1/FVC <0.7) in 79% (0.56±0.17), with mean FEV1 42% of predicted, and a bronchodilator response was present in 28.6%. Comorbid bronchiectasis was diagnosed in 49.8% along with COPD. The relationship between COPD and community demography showed a higher proportion of smokers and those with underlying bronchiectasis to have lower FEV1/FVC ratios. Communities with a higher proportion of asthma were younger and had higher smoking rates. Mortality increased with increasing number of exacerbations and hospital admissions. Conclusion: The Aboriginal population with COPD has a higher prevalence of smoking, moderate to severe airflow obstruction on spirometry and frequently co-diagnosed bronchiectasis with increased severity of ventilatory impairment.

New cost-effective pleural procedure training: manikin-based model to increase the confidence and competency in trainee medical officers.

PURPOSE OF THE STUDY: Pleural diseases are common in clinical practice. Doctors in training often encounter these patients and are expected to perform diagnostic and therapeutic pleural procedures with confidence and safely. However, pleural procedures can be associated with significant complications, especially when performed by less experienced. Structured training such as use of training manikin and procedural skills workshop may help trainee doctors to achieve competence. However, high costs involved in acquiring simulation technology or attending a workshop may be a hurdle. We hereby describe a training model using a simple manikin developed in our institution and provide an effective way to document skill acquisition and assessment among trainee medical officers. STUDY DESIGN: This was a prospective observational study. The need for training, competence and confidence of trainees in performing pleural procedures was assessed through an online survey. Trainees underwent structured simulation training through a simple manikin developed at our institute. Follow-up survey after the training was then performed to access confidence and competence in performing pleural procedures. RESULTS: Forty-seven trainees responded to an online survey and 91% of those expressed that they would like further training in pleural procedure skills. 81% and 85% of responders, respectively, indicated preferred method of training is either practising on manikin or performing the procedure under supervision. Follow-up survey showed improvement in the confidence and competence. CONCLUSION: Our pleural procedure training manikin model is a reliable, novel and cost-effective method for acquiring competences in pleural procedures.

Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial.

Does sertraline provide symptomatic relief for chronic breathlessness in people with advanced disease whose underlying cause(s) are optimally treated?223 participants with chronic breathlessness (modified Medical Research Council breathlessness scale ≥2) who had optimal treatment of underlying cause(s) were randomised 1:1 to sertraline 25-100 mg (titrated upwards over 9 days) or placebo for 4 weeks. The primary outcome was the proportion who had an improvement in intensity of current breathlessness >15% from baseline on a 100-mm visual analogue scale.The proportion of people responding to sertraline was similar to placebo for current breathlessness on days 26-28 (OR 1.00, 95% CI 0.71-1.40) and for other measures of breathlessness. Quality of life in the sertraline arm had a higher likelihood of improving than in the placebo arm over the 4 weeks (OR 0.21, 95% CI 0.01-0.41; p=0.044). No differences in performance status, anxiety and depression, or survival were observed. Adverse event rates were similar between arms.Sertraline does not appear to provide any benefit over placebo in the symptomatic relief of chronic breathlessness in this patient population.

Extended-Release Morphine for Chronic Breathlessness in Pulmonary Arterial Hypertension-A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

CONTEXT: Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH. OBJECTIVES: This randomized, placebo-controlled, double-blind, crossover study aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness. METHODS: Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness "right now"-morning and evening-measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291). RESULTS: Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness "right now" was higher on morphine compared with placebo both for morning [mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = -0.22 (-0.6 to 0.2)] and evening [(M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = -0.33 (-0.8 to 0.1)]. All secondary measures of breathlessness were higher with morphine as were nausea and constipation. CONCLUSION: This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms.

Panblok-H1+advax H1N1/2009pdm vaccine: Insights into rapid development of a delta inulin adjuvanted recombinant pandemic influenza vaccine.

Timely vaccine supply is critical during influenza pandemics but is impeded by current virus-based manufacturing methods. The 2009 H1N1/2009pdm 'swine flu' pandemic reinforced the need for innovation in pandemic vaccine design. We report on insights gained during rapid development of a pandemic vaccine based on recombinant haemagglutinin (rHA) formulated with Advax™ delta inulin adjuvant (Panblok-H1/Advax). Panblok-H1/Advax was designed and manufactured within 1 month of the pandemic declaration by WHO and successfully entered human clinical testing in under 3 months from first isolation and sequencing of the novel pandemic virus, requiring several major challenges to be overcome. Panblok-H1/Advax successfully induced neutralising antibodies against the pandemic strain, but also induced cross-neutralising antibodies in a subset of subjects against an H1N1 strain (A/Puerto Rico/8/34) derived from the 1918 Spanish flu, highlighting the possibility to use Advax to induce more broadly cross-protective antibody responses. Interestingly, the rHA from H1N1/2009pdm exhibited variants in the receptor binding domain that had a major impact on receptor binding and hemagglutination ability. We used an in silico structural modeling approach to better understand the unusual behavior of the novel hemagglutinin, thereby demonstrating the power of computational modeling approaches for rapid characterization of new pandemic viruses. While challenges remain in ensuring ultrafast vaccine access for the entire population in response to future pandemics, the adjuvanted recombinant Panblok-H1/Advax vaccine proved its utility during a real-life pandemic situation.

Study protocol: a phase III randomised, double-blind, parallel arm, stratified, block randomised, placebo-controlled trial investigating the clinical effect and cost-effectiveness of sertraline for the palliative relief of breathlessness in people with chronic breathlessness.

INTRODUCTION: Breathlessness remains a highly prevalent and distressing symptom for many patients with progressive life-limiting illnesses. Evidence-based interventions for chronic breathlessness are limited, and there is an ongoing need for high-quality research into developing management strategies for optimal palliation of this complex symptom. Previous studies have suggested that selective serotonin reuptake inhibitors such as sertraline may have a role in reducing breathlessness. This paper presents the protocol for a large, adequately powered randomised study evaluating the use of sertraline for chronic breathlessness in people with progressive life-limiting illnesses. METHODS AND ANALYSIS: A total of 240 participants with modified Medical Research Council Dyspnoea Scale breathlessness of level 2 or higher will be randomised to receive either sertraline or placebo for 28 days in this multisite, double-blind study. The dose will be titrated up every 3 days to a maximum of 100 mg daily. The primary outcome will be to compare the efficacy of sertraline with placebo in relieving the intensity of worst breathlessness as assessed by a 0-100 mm Visual Analogue Scale. A number of other outcome measures and descriptors of breathlessness as well as caregiver assessments will also be recorded to ensure adequate analysis of participant breathlessness and to allow an economic analysis to be performed. Participants will also be given the option of continuing blinded treatment until either study data collection is complete or net benefit ceases. Appropriate statistical analysis of primary and secondary outcomes will be used to describe the wealth of data obtained. ETHICS AND DISSEMINATION: Ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals and the key findings presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12610000464066.

Human Phase 1 trial of low-dose inactivated seasonal influenza vaccine formulated with Advax™ delta inulin adjuvant.

Influenza vaccines are usually non-adjuvanted but addition of adjuvant may improve immunogenicity and permit dose-sparing, critical for vaccine supply in the event of an influenza pandemic. The aim of this first-in-man study was to determine the effect of delta inulin adjuvant on the safety and immunogenicity of a reduced dose seasonal influenza vaccine. Healthy male and female adults aged 18-65years were recruited to participate in a randomized controlled study to compare the safety, tolerability and immunogenicity of a reduced-dose 2007 Southern Hemisphere trivalent inactivated influenza vaccine formulated with Advax™ delta inulin adjuvant (LTIV+Adj) when compared to a full-dose of the standard TIV vaccine which does not contain an adjuvant. LTIV+Adj provided equivalent immunogenicity to standard TIV vaccine as assessed by hemagglutination inhibition (HI) assays against each vaccine strain as well as against a number of heterosubtypic strains. HI responses were sustained at 3months post-immunisation in both groups. Antibody landscapes against a large panel of H3N2 influenza viruses showed distinct age effects whereby subjects over 40years old had a bimodal baseline HI distribution pattern, with the highest HI titers against the very oldest H3N2 isolates and with a second HI peak against influenza isolates from the last 5-10years. By contrast, subjects >40years had a unimodal baseline HI distribution with peak recognition of H3N2 isolates from approximately 20years ago. The reduced dose TIV vaccine containing Advax adjuvant was well tolerated and no safety issues were identified. Hence, delta inulin may be a useful adjuvant for use in seasonal or pandemic influenza vaccines. Australia New Zealand Clinical Trial Registry: ACTRN12607000599471.

Accidental Rivaroxaban Overdose in a Patient with Pulmonary Embolism: Some Lessons for Managing New Oral Anticoagulants.

Rivaroxaban is an orally active direct factor Xa inhibitor used to treat venous thromboembolism with approved starting dose of 15 mg twice-daily. We present a case of an accidental overdose in a patient with pulmonary thromboembolism, when the patient received two 150 mg doses of rivaroxaban, instead of 15 mg as prescribed, given 12 hours apart. This error was recognised ten minutes after the second dose, when 50 gm oral activated charcoal was given. Rivaroxaban was stopped and rivaroxaban concentrations, INR, and APTT were monitored. The overdose was uncomplicated and 15 mg twice-daily rivaroxaban was restarted on day two. Apparently unlikely and potentially hazardous dispensing errors do happen. Each oral anticoagulant has a different dosing schedule. In our patient, the prescription for 15 mg twice-daily rivaroxaban was misread as 150 mg twice-daily (a correct dose for dabigatran in atrial fibrillation). Such errors are preventable. Prompt administration of activated charcoal under monitoring of a specific rivaroxaban assay can greatly help management of unusual situations like this one.

Delta Inulin Adjuvant Enhances Plasmablast Generation, Expression of Activation-Induced Cytidine Deaminase and B-Cell Affinity Maturation in Human Subjects Receiving Seasonal Influenza Vaccine.

UNLABELLED: There is a major need for new adjuvants to improve the efficacy of seasonal and pandemic influenza vaccines. Advax is a novel polysaccharide adjuvant based on delta inulin that has been shown to enhance the immunogenicity of influenza vaccine in animal models and human clinical trials. To better understand the mechanism for this enhancement, we sought to assess its effect on the plasmablast response in human subjects. This pilot study utilised cryopreserved 7 day post-vaccination (7dpv) peripheral blood mononuclear cell samples obtained from a subset of 25 adult subjects from the FLU006-12 trial who had been immunized intramuscularly with a standard dose of 2012 trivalent inactivated influenza vaccine (TIV) alone (n=9 subjects) or combined with 5mg (n=8) or 10mg (n=8) of Advax adjuvant. Subjects receiving Advax adjuvant had increased 7dpv plasmablasts, which in turn exhibited a 2-3 fold higher rate of non-silent mutations in the B-cell receptor CDR3 region associated with higher expression of activation-induced cytidine deaminase (AID), the major enzyme controlling BCR affinity maturation. Together, these data suggest that Advax adjuvant enhances influenza immunity in immunized subjects via multiple mechanisms including increased plasmablast generation, AID expression and CDR3 mutagenesis resulting in enhanced BCR affinity maturation and increased production of high avidity antibody. How Advax adjuvant achieves these beneficial effects on plasmablasts remains the subject of ongoing investigation. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Register ACTRN12612000709842 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362709.

Pulmonary hypertension and right heart dysfunction in chronic lung disease.

Group 3 pulmonary hypertension (PH) is a common complication of chronic lung disease (CLD), including chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep-disordered breathing. Development of PH is associated with poor prognosis and may progress to right heart failure, however, in the majority of the patients with CLD, PH is mild to moderate and only a small number of patients develop severe PH. The pathophysiology of PH in CLD is multifactorial and includes hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, small vessel destruction, and fibrosis. The effects of PH on the right ventricle (RV) range between early RV remodeling, hypertrophy, dilatation, and eventual failure with associated increased mortality. The golden standard for diagnosis of PH is right heart catheterization, however, evidence of PH can be appreciated on clinical examination, serology, radiological imaging, and Doppler echocardiography. Treatment of PH in CLD focuses on management of the underlying lung disorder and hypoxia. There is, however, limited evidence to suggest that PH-specific vasodilators such as phosphodiesterase-type 5 inhibitors, endothelin receptor antagonists, and prostanoids may have a role in the treatment of patients with CLD and moderate-to-severe PH.

The COPD assessment test (CAT) assists prediction of COPD exacerbations in high-risk patients.

UNLABELLED: We evaluated the predictive value of the COPD assessment test (CAT™) for exacerbation in the following six months or time to first exacerbation among COPD patients with previous exacerbations. COPD outpatients with a history of exacerbation from 19 hospitals completed the CAT questionnaire and spirometry over six months. Exacerbation events were prospectively collected using a structured questionnaire. The baseline CAT score categorised into four groups (0-9, 10-19, 20-29, and 30-40) showed strong prediction for time to first exacerbation and modest prediction for any exacerbation or moderate-severe exacerbation (AUC 0.83, 0.64, and 0.63 respectively). In multivariate analyses, the categorised CAT score independently predicted all three outcomes (p = 0.001 or p < 0.001). Compared with the lowest CAT score category, the higher categories were associated with significantly shorter time to first exacerbation and higher exacerbation risks. The corresponding adjusted median time was >24, 14, 9, and 5 weeks and the adjusted RR was 1.00, 1.30, 1.37, and 1.50 in the category of 0-9, 10-19, 20-29, and 30-40 respectively. Exacerbation history (≥2 vs. 1 event in the past year) was related to time to first exacerbation (adjusted HR 1.35; p = 0.023) and any exacerbation during the study period (adjusted RR 1.15; p = 0.016). The results of this study support the use of the CAT as a simple tool to assist in the identification of patients at increased risk of exacerbations. This could facilitate timely and cost-effective implementation of preventive interventions, and improve health resource allocation. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01254032.

Randomized clinical trial of immunogenicity and safety of a recombinant H1N1/2009 pandemic influenza vaccine containing Advax™ polysaccharide adjuvant.

BACKGROUND: Timely vaccine supply is critical during influenza pandemics. A recombinant hemagglutinin (rHA)-based vaccine could overcome production hurdles of egg-based vaccines but has never previously been tested in a real-life pandemic setting. The primary aim was to determine the efficacy of a recombinant pandemic vaccine and whether its immunogenicity could be enhanced by a novel polysaccharide adjuvant (Advax™). METHODS: 281 adults aged 18-70 years were recruited in a randomized, subject and observer blinded, parallel-group study of rHA H1N1/2009 vaccine with or without adjuvant. Immunizations were at 0 and 3 weeks with rHA 3, 11 or 45 µg. Serology and safety was followed for 6 months. RESULTS: At baseline, only 9.1% of subjects (95% CI: 6.0-13.2) had seroprotective H1N1/2009 titers. Seroconversion rates varied by rHA dose, presence of adjuvant, subject age and number of immunizations. Eighty percent (95% CI: 52-96) of 18-49 year olds who received rHA 45 µg with adjuvant were seroprotected at week 3, representing a 11.1-fold increase in antibody titers from baseline. Advax™ adjuvant increased seroprotection rates by 1.9 times after the first, and 2.5 times after the second, immunization when compared to rHA alone. Seroprotection was sustained at 26 weeks and the vaccine was well tolerated with no safety issues. CONCLUSIONS: The study confirmed the ability to design, manufacture, and release a recombinant vaccine within a short time from the start of an actual influenza pandemic. Advax™ adjuvant significantly enhanced rHA immunogenicity.

Management of dyspnea in advanced pulmonary arterial hypertension.

PURPOSE OF REVIEW: Pulmonary hypertension leads to progressive increase in pulmonary vascular resistance, heart failure, and death. Pulmonary arterial hypertension (PAH) is a subset of pulmonary hypertension affecting small pulmonary arteries and not associated with underlying heart or lung disease. Dyspnea and exercise intolerance are hallmarks of PAH and are used to monitor disease progression. This review focuses on recent advances in the pathophysiology and treatment of dyspnea in PAH. RECENT FINDINGS: The etiological classification of pulmonary hypertension and World Health Organization functional class clinical classification, as used to guide management, have recently been revised. Dyspnea and PAH disease progression are best assessed by cardiopulmonary exercise testing and the six-minute walk test. Understanding of the molecular pathogenesis of PAH has led to new classes of treatments, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Prostanoids have the longest track record in treatment of PAH but a short half-life and cumbersome delivery systems limit their utility. More convenient endothelin receptor antagonists are becoming mainstream in PAH management. Phosphodiesterase-5 inhibitors improve exercise capacity and quality of life, although long-term outcome data are pending. Combination therapy with different medication classes appears promising for progressive disease. SUMMARY: Establishing the cause and clinical severity of pulmonary hypertension is critical for management. The pathophysiology of dyspnea in PAH is complex and related to pulmonary vascular resistance. Although disease-specific treatments are now available, a cure for PAH remains elusive and trials of combination treatments to improve symptoms and outcomes are ongoing.