Ken M. Kunisaki

Influenza in Immunosuppressed Populations: A Review of Infection Frequency, Morbidity, Mortality, and Vaccine Responses

Patients that are immunosuppressed might be at risk of serious influenza-associated complications. As a result, multiple guidelines recommend influenza vaccination for patients infected with HIV, who have received solid-organ transplants, who have received haemopoietic stem-cell transplants, and patients on haemodialysis. However, immunosuppression might also limit vaccine responses. To better inform policy, we reviewed the published work relevant to incidence, outcomes, and prevention of influenza infection in these patients, and in patients being treated chemotherapy and with systemic corticosteroids. Available data suggest that most immunosuppressed populations are indeed at higher risk of influenza-associated complications, have a general trend toward impaired humoral vaccine responses (although these data are mixed), and can be safely vaccinated--although longitudinal data are largely lacking. Randomised clinical trial data were limited to one study of HIV-infected patients with high vaccine efficacy. Better trial data would inform vaccination recommendations on the basis of efficacy and cost in these at-risk populations.

Vitamin D Status and Longitudinal Lung Function Decline in the Lung Health Study

Low blood vitamin D levels have been postulated to be a risk factor for worse lung function, based largely on cross-sectional data. We sought to use longitudinal data to test the hypothesis that baseline plasma 25-hydroxyvitamin D (25(OH)D) is lower in subjects with more rapid lung function decline, compared to those with slow lung function decline. We conducted a nested, matched case–control study in the Lung Health Study 3 cohort. Cases and controls were continuous smokers with rapid and slow lung function decline, respectively, over ∼6 yrs of follow-up. We compared baseline 25(OH)D levels between cases and controls, matching date of phlebotomy and clinical centre. Among 196 subjects, despite rapid and slow decliners experiencing strikingly and significantly different rates of decline of forced expiratory volume in 1 s (-152 versus -0.3 mL·yr−1; p<0.001), there was no significant difference in baseline 25(OH)D levels (25.0 versus 25.9 ng·mL−1; p = 0.54). There was a high prevalence of vitamin D insufficiency (35%) and deficiency (31%); only 4% had a normal 25(OH)D level in the winter. Although vitamin D insufficiency and deficiency are common among continuous smokers with established mild-to-moderate chronic obstructive pulmonary disease, baseline 25(OH)D levels are not predictive of subsequent lung function decline.

Vitamin D Levels and Risk of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study

RATIONALE Low blood levels of 25-hydroxyvitamin D (25[OH]D) have been associated with a higher risk of respiratory infections in general populations and higher risk of exacerbations of lung disease in people with asthma. We hypothesized that low blood levels of 25(OH)D in patients with chronic obstructive pulmonary disease (COPD) would be associated with an increased risk of acute exacerbations of COPD (AECOPD). OBJECTIVES To determine if baseline 25(OH)D levels relate to subsequent AECOPD in a cohort of patients at high risk for AECOPD. METHODS Plasma 25(OH)D was measured at baseline in 973 participants on entry to a 1-year study designed to determine if daily azithromycin decreased the incidence of AECOPD. Relationships between baseline 25(OH)D and AECOPD over 1 year were analyzed with time to first AECOPD as the primary outcome and exacerbation rate as the secondary outcome. MEASUREMENTS AND MAIN RESULTS In this largely white (85%) sample of North American patients with severe COPD (mean FEV(1) 1.12L; 40% of predicted), mean 25(OH)D was 25.7 ± 12.8 ng/ml. A total of 33.1% of participants were vitamin D insufficient (≥20 ng/ml but <30 ng/ml); 32% were vitamin D deficient (<20 ng/ml); and 8.4% had severe vitamin D deficiency (<10 ng/ml). Baseline 25(OH)D levels had no relationship to time to first AECOPD or AECOPD rates. CONCLUSIONS In patients with severe COPD, baseline 25(OH)D levels are not predictive of subsequent AECOPD. Clinical trial registered with www.clinicaltrials.gov (NCT00119860).

Exhaled nitric oxide, systemic inflammation, and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease: A prospective study

Background: A subset of patients with chronic obstructive pulmonary disease (COPD) may respond more favorably to inhaled corticosteroids (ICS), but no simple method is currently utilized to predict the presence or absence of ICS responses in patients with COPD. We evaluated the ability of exhaled nitric oxide (FENO) and serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], and interleukin-8 [IL-8]) to independently predict spirometric responses to ICS in patients with COPD. Methods: Among 60 ex-smokers with severe COPD (mean FEV1 1.07 L, 36% of predicted), we conducted a single-arm, open-label study. Participants spent four weeks free of any ICS, followed by four weeks of ICS use (fluticasone propionate 500 mcg twice daily). FENO, CRP, IL-6, IL-8, and pre-bronchodilator spirometry were measured immediately before and after the four weeks of ICS use. Results: Baseline FENO, CRP, IL-6, and IL-8 showed no correlations to FEV1 responses to ICS. ICS responders (increase in FEV1 ≥ 200 mL after four weeks of ICS) did have significantly higher baseline FENO levels compared with non-responders (46.5 parts per billion [ppb] vs. 25 ppb, p = 0.028). The receiver operating characteristic curve for FENO to discriminate responders from non-responders had an area under curve of 0.72. Baseline serum inflammatory markers did not differ between responders and non-responders. Conclusion: In ex-smokers with severe COPD, a measure of local pulmonary inflammation, FENO, may be more closely associated with FEV1 responses to four weeks of ICS than are standard markers of systemic inflammation, serum CRP, IL-6, and IL-8

Why START? Reflections that led to the conduct of this large long-term strategic HIV trial

This monograph describes a cohort of 4685 HIV-positive persons, most of whom were recently infected, who volunteered to dedicate several years to being participants in a research study that addresses the question of when antiretroviral therapy (ART) should be initiated. Should it be started early after HIV infection occurs, or should it be deferred until the infection has started to impair immune function but before the risk of AIDS increases? There has been consensus based on robust data for many years that ART should be initiated following the development of AIDS. Also, within the past 6 to 7 years, data from randomized trials [1–3] and observational studies [4–7] emerged that supported the initiation of ART when the CD4 cell count declined to < 350 cells/μL among asymptomatic individuals. It has been hotly debated whether the clinical benefits of initiating ART at a CD4 cell count > 500 cells/ μL, compared with deferring ART until the CD4 cell count decreases to 350 cells/μL, as is being tested in the Strategic Timing of AntiRetroviral Treatment (START) study, outweigh the risks [8–10]. The debate is lively because the data available are not optimal. The fact that 4685 persons from 215 clinics in 35 countries volunteered to be randomized in START reflects the considerable uncertainty that many individuals with HIV infection and investigators around the world have about the answer to the question being addressed by START.

Acute exacerbations and lung function loss in smokers with and without chronic obstructive pulmonary disease

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown. Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow‐up. Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5‐year follow‐up period, we collected self‐reported acute respiratory event data at 6‐month intervals. We used linear mixed models to fit FEV1 decline based on reported exacerbations or acute respiratory events. Measurements and Main Results: In subjects with COPD, exacerbations were associated with excess FEV1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2‐44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23‐151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV1 decline. Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Supplemental vitamin D and physical performance in COPD: a pilot randomized trial

Background Low 25-hydroxyvitamin D (25[OH]D) levels, commonly observed in chronic obstructive pulmonary disease (COPD), are associated with muscle weakness in elderly populations, and vitamin D supplementation appears to improve muscle strength and decrease falls in older individuals. We tested the effect of vitamin D supplementation on physical performance in patients with COPD. Methods Patients were randomized to daily cholecalciferol (2000 IU) or placebo for 6 weeks. The primary outcome was the 6-week change in Short Physical Performance Battery (SPPB) score. Secondary outcomes included changes in the St George’s Respiratory Questionnaire (SGRQ) score, and serum 25(OH)D. Results Thirty-six participants (mean age 68 years, all Caucasian males, mean forced expiratory volume in one second 33% of predicted) completed the study. Despite an increase in 25(OH)D levels in the intervention arm to a mean of 32.6 ng/mL (versus 22.1 ng/mL in the placebo arm), there was no difference in improvements in either SPPB scores (0.3 point difference; 95% confidence interval −0.8 to 1.5; P = 0.56) or SGRQ scores (2.3 point difference; 95% confidence interval −2.3 to 6.9; P = 0.32). Conclusion Among patients with severe COPD, 2000 IU of daily vitamin D for 6 weeks increased 25(OH)D to a level widely considered as normal. However, compared with placebo, short-term vitamin D supplementation had no discernible effect on a simple measure of physical performance.

Pulmonary function in an international sample of HIV-positive, treatment-naïve adults with CD4 counts > 500 cells/μL: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial

The aim of the study was to describe the prevalence and correlates of chronic obstructive pulmonary disease (COPD) in a multicentre international cohort of persons living with HIV (PLWH).

Antibiotic prophylaxis for chronic obstructive pulmonary disease: resurrecting an old idea.

50% reduction in the occurrence of recurrent wheeze even after controlling for potential confounding variables (16). One can also speculate that RVs were likely to be responsible for many wheezing events in infants in that study who were not protected by the use of the RSV monoclonal antibody. Prospective trials with antiviral strategies, including potential new vaccines targeting RSV and RV in selected populations at risk, should give us better understanding of the role of viral infections in early life in the causation of childhood asthma.

Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease in the Elderly

Chronic obstructive pulmonary disease (COPD) is a debilitating disease with rising worldwide prevalence. Exacerbations of COPD cause significant morbidity and become more common with advancing age. Healthcare providers caring for elderly patients should therefore be familiar with effective treatments for exacerbations of COPD. An extensive body of literature has identified several effective drug therapies for exacerbations. These drugs include inhaled bronchodilators, systemic corticosteroids and antibacterials. The two main classes of inhaled bronchodilators are β-adrenoceptor agonists and anticholinergics. These drugs optimise lung function during exacerbations, with neither class demonstrating clear superiority over the other. Systemic corticosteroids are effective when used either for inpatient or outpatient treatment of exacerbations. They hasten recovery from exacerbations and reduce relapse rates. Antibacterials decrease morbidity from exacerbations and may decrease mortality in the more severe exacerbations. Other effective therapies for the treatment of acute exacerbations of COPD include oxygen and non-invasive ventilation. Oxygen can be safely administered in acute exacerbations associated with hypoxaemia, with titration of oxygen delivery to a goal oxygen saturation of 90%. Non-invasive ventilation reduces the morbidity and mortality associated with acute exacerbations complicated by hypercapnic respiratory failure. Strategies to prevent COPD exacerbations include smoking cessation, long-acting inhaled β-adrenoceptor agonists, inhaled long-acting anticholinergics, inhaled corticosteroids and vaccination. Mucolytic agents, pulmonary rehabilitation, and case management programmes may also reduce exacerbation risk, but the current evidence supporting these interventions is weaker.