MAGNEsium Trial In Children (MAGNETIC): a randomised, placebo-controlled trial and economic evaluation of nebulised magnesium sulphate in acute severe asthma in children.


There are few data on the role of nebulised magnesium sulphate (MgSO4) in the management of acute asthma in children. Those studies that have been published are underpowered, and use different methods, interventions and comparisons. Thus, no firm conclusions can be drawn.
OBJECTIVES: Does the use of nebulised MgSO4, when given as an adjunct to standard therapy in acute severe asthma in children, result in a clinical improvement when compared with standard treatment alone?
DESIGN: Patients were randomised to receive three doses of MgSO4 or placebo, each combined with salbutamol and ipratropium bromide, for 1 hour. The Yung Asthma Severity Score (ASS) was measured at baseline, randomisation, and at 20, 40, 60 (T60), 120, 180 and 240 minutes after randomisation.
SETTING: Emergency departments and children`s assessment units at 30 hospitals in the UK. 
PARTICIPANTS: Children aged 2-15 years with acute severe asthma.
INTERVENTIONS: Patients were randomised to receive nebulised salbutamol 2.5 mg (ages 2-5 years) or 5 mg (ages >/= 6 years) and ipratropium bromide 0.25 mg mixed with either 2.5 ml of isotonic MgSO4 (250 mmol/l, tonicity 289 mOsm; 151 mg per dose) or 2.5 ml of isotonic saline on three occasions at approximately 20-minute intervals. MAIN OUTCOME MEASURES: The primary outcome measure was the ASS after 1 hour of treatment. Secondary measures included `stepping down` of treatment at 1 hour, number and frequency of additional salbutamol administrations, length of stay in hospital, requirement for intravenous bronchodilator treatment, and intubation and/or admission to a paediatric intensive care unit. Data on paediatric quality of life, time off school/nursery, health-care resource usage and time off work were collected 1 month after randomisation.
RESULTS: A total of 508 children were recruited into the study; 252 received MgSO4 and 256 received placebo along with the standard treatment. There were no differences in baseline characteristics. There was a small, but statistically significant difference in ASS at T60 in those children who received nebulised MgSO4 {0.25 [95% confidence interval (CI) 0.02 to 0.48]; p = 0.034} and this difference was sustained for up to 240 minutes [0.20 (95% CI 0.01 to 0.40), p = 0.042]. The clinical significance of this gain is uncertain. Assessing treatment-covariate interactions, there is evidence of a larger effect in those children with more severe asthma exacerbations ( p = 0.034) and those with a shorter duration of symptoms ( p = 0.049). There were no significant differences in the secondary outcomes measured. Adverse events (AEs) were reported in 19% of children in the magnesium group and 20% in the placebo group. There were no clinically significant serious AEs in either group. The results of the base-case economic analyses are accompanied by considerable uncertainty, but suggest that, from an NHS and Personal Social Services perspective, the addition of magnesium to standard treatment may be cost-effective compared with standard treatment only. The results of economic evaluation show that the probability of magnesium being cost-effective is over 60% at cost-effectiveness thresholds of pound1000 per unit decrement in ASS and pound20,000 per quality-adjusted life-year (QALY) gained, respectively; it is noted that for some parameter variations this probability is much lower, reflecting the labile nature of the cost-effectiveness ratio in light of the small differences in benefits and costs shown in the trial and the relation between the main outcome measure (ASS) and preference based measures of quality of life used in cost-utility analysis (European Quality of Life-5 Dimensions; EQ-5D).
CONCLUSIONS: This study supports the use of nebulised isotonic MgSO4 at the dose of 151 mg given three times in the first hour of treatment as an adjuvant to standard treatment when a child presents with an acute episode of severe asthma. No harm is done by adding magnesium to salbutamol and ipratropium bromide, and in some individuals it may be clinically helpful. The response is likely to be more marked in those children with more severe attacks and with a shorter duration of exacerbation. Although the study was not powered to demonstrate this fully, the data certainly support the hypotheses that nebulised magnesium has a greater clinical effect in children who have more severe exacerbation with shorter duration of symptoms.

 

Bivalirudin Started during Emergency Transport for Primary PCI.


BACKGROUND

Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown.

METHODS

We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding.

RESULTS

Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients.

CONCLUSIONS

Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis.

Source: NEJM

 

Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest.


BACKGROUND

Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever.

METHODS

In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale.

RESULTS

In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar.

CONCLUSIONS

In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C.

Source: NEJM

 

Intrarenal Resistive Index after Renal Transplantation.


BACKGROUND

The intrarenal resistive index is routinely measured in many renaltransplantation centers for assessment of renal-allograft status, although the value of the resistive index remains unclear.

METHODS

In a single-center, prospective study involving 321 renal-allograft recipients, we measured the resistive index at baseline, at the time of protocol-specified renal-allograft biopsies (3, 12, and 24 months after transplantation), and at the time of biopsies performed because of graft dysfunction. A total of 1124 renal-allograft resistive-index measurements were included in the analysis. All patients were followed for at least 4.5 years after transplantation.

RESULTS

Allograft recipients with a resistive index of at least 0.80 had higher mortality than those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 5.20 [95% confidence interval {CI}, 2.14 to 12.64; P<0.001]; 3.46 [95% CI, 1.39 to 8.56; P=0.007]; and 4.12 [95% CI, 1.26 to 13.45; P=0.02], respectively). The need for dialysis did not differ significantly between patients with a resistive index of at least 0.80 and those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 1.95 [95% CI, 0.39 to 9.82; P=0.42]; 0.44 [95% CI, 0.05 to 3.72; P=0.45]; and 1.34 [95% CI, 0.20 to 8.82; P=0.76], respectively). At protocol-specified biopsy time points, the resistive index was not associated with renal-allograft histologic features. Older recipient age was the strongest determinant of a higher resistive index (P<0.001). At the time of biopsies performed because of graft dysfunction, antibody-mediated rejection or acute tubular necrosis, as compared with normal biopsy results, was associated with a higher resistive index (0.87±0.12 vs. 0.78±0.14 [P=0.05], and 0.86±0.09 vs. 0.78±0.14 [P=0.007], respectively).

CONCLUSIONS

The resistive index, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft.

 

Souirce: NEJM

 

 

CLOTBUST-Hands Free.


Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke

Background and Purpose—The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health–sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion.

Methods—All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days.

Results—Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5–29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%–64%) complete and 2 of 20 (10%; 95% confidence interval, 1%–32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%–82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%–49) patients had a modified Rankin scale of 0 to 1.

Conclusions—Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial.

Source: Stroke

Narrow-Spectrum Antibiotics Effective for Pediatric Pneumonia.


Narrow-spectrum antibiotics have similar efficacy and cost-effectiveness as broad-spectrum antibiotics in the treatment of pediatric community-acquired pneumonia (CAP), according to the findings of a retrospective study.

Derek J Williams, MD, MPH, from Vanderbilt University School of Medicine in Nashville, Tennessee, and colleagues published their findings online October 28 in Pediatrics.

“The 2011 Pediatric Infectious Diseases Society/Infectious Diseases Society of America…guideline for the management of children with [CAP] recommends narrow-spectrum antimicrobial therapy for most hospitalized children,” the authors write. “Nevertheless, few studies have directly compared the effectiveness of narrow-spectrum agents to the broader spectrum third-generation cephalosporins commonly used among hospitalized children with CAP.”

Therefore, the researchers used the Pediatric Health Information System database to assess the hospital length of stay (LOS) and associated healthcare costs of children aged 6 months to 18 years who were diagnosed with pneumonia between July 2005 and June 2011 and treated with either narrow-spectrum or broad-spectrum antibiotics. The authors excluded children with potentially severe pneumonia, those at risk for healthcare-associated infections, and those with mild disease requiring less than 2 days of hospitalization.

Narrow-spectrum therapy consisted of the exclusive use of penicillin or ampicillin, whereas broad-spectrum treatment was defined as the exclusive use of parenteral ceftriaxone or cefotaxime.

The median LOS for the entire study population (n = 15,564) was 3 days (interquartile range, 3 – 4 days), and LOS was not significantly different between the narrow-spectrum and broad-spectrum treatment groups (adjusted difference [aD], 0.12 days; P = .11), after adjustments for covariates including age, sex, and ethnicity.

Similarly, the investigators found no differences in the proportion of children requiring intensive care unit admission in the first 2 days of hospitalization (adjusted odds ratio [aOR], 0.85; 95% CI, 0.25 – 2.73) or hospital readmission within 14 days (aOR, 0.85; 95% CI, 0.45 – 1.63) were noted between the groups.

Narrow-spectrum treatment was also linked to a similar cost of hospitalization (aD, −$14.4; 95% CI, −$177.1 to $148.3) and cost per episode of illness (aD, −$18.6; 95% CI, −$194 to $156.9) as broad-spectrum therapy.

The researchers note that the limitations of the study were mostly related to its retrospective nature, including potential confounding by indication, the absence of etiologic and other clinical data, and a relative lack of objective outcome measures.

“Clinical outcomes and costs for children hospitalized with CAP are not different when empirical treatment is with narrow-spectrum compared with broad-spectrum therapy,” the authors write. “Programs promoting guideline implementation and targeting judicious antibiotic selection for CAP are needed to optimize management of childhood CAP in the United States.”

Vitamin D3 Supplements Do Not Lessen Cold, Influenza Risk.


Supplementation with vitamin D3 does not reduce the incidence or risk for upper respiratory tract infection (URTI) in adults, according to a new randomized controlled trial published onlineSeptember 6 and in the November 15 print issue of Clinical Infectious Diseases.

Judy R. Rees, MPH, PhD, from the Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, and colleagues enrolled 2259 participants (age, 45 – 75 years) who were also taking part in a colorectal adenoma chemoprevention trial. Participants were randomly assigned to receive 1000 IU/day of vitamin D3, 1200 mg elemental calcium/day, both, or placebo. All participants were in good health and had serum 25-hydroxyvitamin D levels of 2 ng/mL or higher.

Among the 759 participants who completed the study, the researchers found no significant decrease in the rate ratio (RR) of URTI episodes between the treatment groups (RR, 0.93; 95% confidence interval [CI], 0.79 – 1.09) or winter days of illness (RR, 1.13; 95% CI, 0.90 – 1.43). There was also no decrease noted in composite syndromes of influenza-like illness (ILI; RR, 0.95; 95% CI, 0.62 – 1.46) or colds (RR, 0.93; 95% CI, 0.78 – 1.10).

“Vitamin D supplementation conferred no significant protection against colds, ILI, or any URTI overall, nor among those with the lowest baseline serum 25(OH) vitamin D, although participants whose baseline concentration was <12 ng/mL were specifically excluded from our trial,” note Dr. Rees and colleagues.

Participants were recruited from 11 clinical centers, and the study was conducted November 2009 through March 2011. URTI was defined as either ILI (fever and 2 or more of the following: sore throat, cough, muscle aches, or headache) or a cold (absence of ILI, 2 or more of the following on a single day: runny nose, nasal congestion, sneezing, sore throat, cough, and swollen or tender neck glands).

Throughout the study period, researchers administered semiannual telephone surveys to 2228 participants and found no decrease in the odds ratio (OR) of ILI (OR, 1.14; 95% CI, 0.84 – 1.54) or colds (OR, 1.03; 95% CI, 0.87 – 1.23) among patients receiving vitamin D3 supplementation. Baseline vitamin D status, body mass index, adherence, or influenza vaccination also provided no significant benefit.

The researchers acknowledge that self-selection of the 759 participants from the parent trial may have influenced results if participants dropped out early because of a lack of treatment effect. The study authors also note that self-reported adherence to study protocol and lack of laboratory conformation of URTI may also have affected the results.

Michael Gleeson, PhD, from the School of Sport, Exercise and Health Sciences, Loughborough University, Leucestershire, United Kingdom, told Medscape Medical News, “Although participant numbers were large, I suspect that this dose of vitamin D3 is insufficient to affect respiratory illness incidence in individuals who are not vitamin D deficient,” and that “an effect might be seen in a more illness-prone population such as athletes.” Dr. Gleeson was not affiliated with the study.

“The effects on URTI of supplementation in adults with vitamin D deficiency (<12 ng/mL) should be addressed in future trials,” conclude the study authors. Studies should also address at what dose of vitamin D3 affects “markers of immune function that are important in defense against respiratory infections,” added Dr. Gleeson.

Morbidity and mortality in children with obstructive sleep apnoea: a controlled national study.


Abstract

Background Little is known about the diagnostic patterns of obstructive sleep apnoea (OSA) in children. A study was undertaken to evaluate morbidity and mortality in childhood OSA.

Methods 2998 patients aged 0–19 years with a diagnosis of OSA were identified from the Danish National Patient Registry. For each patient we randomly selected four citizens matched for age, sex and socioeconomic status, thus providing 11 974 controls.

Results Patients with OSA had greater morbidity at least 3 years before their diagnosis. The most common contacts with the health system arose from infections (OR 1.19, 95% CI 1.01 to 1.40); endocrine, nutritional and metabolic diseases (OR 1.30, 95% CI 0.94 to 1.80); nervous conditions (OR 2.12, 95% CI 1.65 to 2.73); eye conditions (OR 1.43, 95% CI 1.07 to 1.90); ear, nose and throat (ENT) diseases (OR 1.61, 95% CI 1.33 to 1.94); respiratory system diseases (OR 1.78, 95% CI 1.60 to 1.98); gastrointestinal diseases (OR 1.34, 95% CI 1.09 to 1.66); skin conditions (OR 1.32, 95% CI 1.02 to 1.71); congenital malformations (OR 1.56, 95% CI 1.31 to 1.85); abnormal clinical or laboratory findings (OR 1.21, 95% CI 1.06 to 1.39); and other factors influencing health status (OR 1.29, 95% CI 1.16 to 1.43). After diagnosis, OSA was associated with incidences of endocrine, nutritional and metabolic diseases (OR 1.78, 95% CI 1.29 to 2.45), nervous conditions (OR 3.16, 95% CI 2.58 to 3.89), ENT diseases (OR 1.45, 95% CI 1.14 to 1.84), respiratory system diseases (OR 1.94, 95% CI 1.70 to 2.22), skin conditions (OR 1.42, 95% CI 1.06 to 1.89), musculoskeletal diseases (OR 1.29, 95% CI 1.01 to 1.64), congenital malformations (OR 1.83, 95% CI 1.51 to 2.22), abnormal clinical or laboratory findings (OR 1.16, 95% CI 1.06 to 1.27) and other factors influencing health status (OR 1.35, 95% CI 1.20 to 1.51). The 5-year death rate was 70 per 10 000 for patients and 11 per 10 000 for controls. The HR for cases compared with controls was 6.58 (95% CI 3.39 to 12.79; p<0.001).

Conclusions Children with OSA have significant morbidities several years before and after their diagnosis.

Source: Thorax

Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial.


Abstract

Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides.

Methods We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ).

Results The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci.

Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study.

 

Source: Thorax

Inhaled corticosteroids in COPD and the risk of serious pneumonia


Abstract

Background Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use.

Methods We formed a new-user cohort of patients with COPD treated during 1990–2005. Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia. A nested case–control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity.

Results The cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year). Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75). The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17). The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26).

Conclusions ICS use by patients with COPD increases the risk of serious pneumonia. The risk is particularly elevated and dose related with fluticasone. While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials.

Discussion

Using a large population-based cohort of over 160 000 patients with COPD followed for up to 18 years, we found that ICS use is associated with a significant 69% increase in the risk of serious pneumonia, requiring hospitalisation or fatal. This risk was particularly increased with fluticasone, with a doubling of the rate, and dose dependent with doses of 1000 μg of fluticasone per day associated with a 122% increase. The risk with budesonide was comparatively much lower with an increase of 17% and no dose–response effect. These elevated risks disappeared within a few months of stopping the use of ICS.

Systemic corticosteroids have been associated with increased risks of pneumonia in patients with rheumatoid arthritis.26 ,27 In these patients, a dose–response increase in the risk of pneumonia was seen with doses of prednisone as low as ≤5 mg/day (RR 1.4; 95% CI 1.1 to 1.6),26 and as low as 7.5 mg or less (RR 2.3; 95% CI 1.2 to 4.4).27 It is then not unexpected that high doses of ICS have similar effects on the incidence of pneumonia, as 1000 μg of inhaled fluticasone is estimated to be equivalent to 10 mg per day of prednisone with systemic effects evaluated by suppression of serum cortisol.7

Our findings confirm the observations of several randomised trials of varying durations and doses. The 2-year INSPIRE and 3-year TORCH trials both studied high doses of fluticasone (1000 μg per day) and found HRs of pneumonia of 1.94 (95% CI 1.19 to 3.17) and 1.64 (95% CI 1.33 to 2.02), respectively,3 ,4 ,13 ,14 A 1-year trial of fluticasone 1000 μg/day found a higher increase in the risk (RR 3.1; 95% CI 1.3 to 7.3; our calculation),15 which is consistent with our findings of a somewhat higher early risk. Our results confirm the subgroup analyses of the meta-analysis, suggesting that the risk is particularly elevated with high doses and start at short durations of use.12 With respect to the effect of dose, the two trials that evaluated a lower dose of fluticasone (500 μg per day) for 1 year also found a close to twofold higher incidence of pneumonia at 1 year with fluticasone.16–18This is also consistent with the dose–response curve from our study, which shows an increase in risk with lower doses and a RR of 1.6 at 500 μg/day of fluticasone.

The findings for budesonide confirm the pooled analysis of several trials of budesonide that found no increased risk of pneumonia over 1 year (RR 1.05; 95% CI 0·81 to 1·37),19 and a meta-analysis that suggests a lower risk with budesonide compared with fluticasone.20 Our finding of a more moderate 17% increase in the rate of serious pneumonia is concordant with these trial data. Moreover, the risk of pneumonia did not increase with the dose of budesonide. Nevertheless, a concern remains with budesonide as a recent 1-year trial in COPD found increases in pneumonia adverse events with daily doses of 640 μg (RR 2.3; 95% CI 1.2 to 4.7) and 320 μg (RR 1.7; 95% CI 0.8 to 3.6), equivalent to 400 μg and 200 μg of fluticasone, respectively.28 Since the fluticasone–salmeterol combination was approved and therefore promoted for COPD during the time period under study while the budesonide–formoterol combination was not, it remains possible that those receiving the budesonide combination were more likely to have asthma rather than COPD and be at lower risk of pneumonia compared with subjects receiving the fluticasone–salmeterol combination. Furthermore, since a higher dose formulation was only available for the fluticasone–salmeterol combination, patients with more severe disease may have been more likely to have received a combination therapy containing fluticasone rather than budesonide. Therefore, data on this question from countries where budesonide has a greater market share would be a valuable addition to this evidence.

There is good evidence supporting the effect of ICS on human pulmonary host defence, acting through several biological pathways, such as an inhibitory action on macrophage functions, a decrease in cytokine production and nitric oxide expression, which may lead to a failure to control infection.29 ,30 Although there have been no studies directly comparing the effects of fluticasone and budesonide on host defence, differences are likely related to their contrasting pharmacokinetic and pharmacodynamic properties. Fluticasone is known to be more potent (ie, greater effect on intracellular steroid receptors), more lipophilic and has a longer half life than budesonide.29Accordingly, fluticasone has a better penetration at the site of action and a more prolonged effect. It is therefore not surprising that a greater risk of oropharyngeal side effects is found with fluticasone compared with budesonide.31 While high potency and lipophilicity can be positive features allowing a lower dose to exert the desired effect, these characteristics may adversely affect drug safety. Indeed, a more prolonged corticosteroid effect in the lungs and greater pulmonary retention will facilitate the local immunosuppressive action.32 ,33 Budesonide enters the lungs with a lower lipophilicity, dissolves more quickly into pulmonary fluids, leading to a reduced local effect because of a more rapid cleavage and passage into the systemic circulation.30

This study has strengths and some limitations. The size of the population-based cohort of over 160 000 patients observed over 18 years permitted the identification of over 20 000 cases of serious pneumonia, allowing precise estimates of the risk associated with the different ICS at several doses. In this study, we defined serious pneumonia as a hospitalisation with a primary diagnosis of pneumonia or death from pneumonia, but did not have proof that the diagnosis was based on radiographic findings as these are not recorded in the RAMQ databases. However, it is most likely that as a primary inpatient diagnosis, it was in fact supported by a radiographic finding. To address confounding by COPD severity, we adjusted for the number of prescriptions for respiratory medications other than ICS, and for exacerbations as measured by prescriptions for oral corticosteroids, antibiotics, as well as prior hospitalisations for pneumonia and COPD exacerbation. Yet, residual confounding arising from unmeasured covariates can still be present. Of most concern is the possibility that budesonide may have been preferentially prescribed to patients with a lower risk of pneumonia, such as those with asthma or less severe COPD. In this specific study, however, our main results, adjusted for differences in severity, are consistent with those of several randomised trials which are inherently free of confounding, albeit less powerful with smaller study populations. Exposure to ICS was measured from dispensed prescriptions so that one must assume that the drugs were actually taken. However, not taking these medications would actually tend to underestimate the true risk increase. The definition of COPD used to identify the patients in our cohort was not based on a physician diagnosis of COPD or objective criteria for the diagnosis of COPD, but rather on including only subjects who started using respiratory medications at the age of 55 years or later and excluding subjects with a prior asthma hospitalisation or who used asthma-specific medications such as nedocromil, ketotifen, cromolyn or antileukotrienes. Nevertheless, our definition likely captured some patients with asthma. One can expect that this would reduce the estimate of risk of ICS since ICS do not appear to increase the risk of pneumonia in patients with asthma.34 Our sensitivity analysis within subjects previously hospitalised for COPD found practically the same differences in estimates of risk for fluticasone and budesonide.

The dose–response effect with fluticasone that we found on the incidence of serious pneumonia, sustained over a long time, is important in the risk–benefit balance for patients with COPD. While ICS are clearly effective for the treatment of asthma, their effectiveness in treating COPD is still controversial.1 ,2 The fact that ICS are now commonly combined in a single device with a long-acting bronchodilator, the latter recommended earlier in COPD, has resulted in ICS now being used by over 70% of patients with COPD.2 Moreover, these combined medications most often contain high doses of ICS, as high as 1000 μg of fluticasone per day.3 ,4 Consequently, the widespread use of ICS at higher doses in patients with COPD, along with the elevated incidence of pneumonia in this age group and their uncertain effectiveness, impact on the risk–benefit profile of ICS in COPD.

In conclusion, high and low doses of fluticasone in patients with COPD are associated with an important increase in the risk of serious pneumonia, while the risk with budesonide is comparatively low, even at high doses, though it needs further examination in light of recent data and the possibility that patients receiving budesonide are inherently at lower risk of pneumonia than those prescribed fluticasone. Further investigations into why the two popular ICS fluticasone and budesonide have such different effects on the risk of pneumonia are warranted.

Source: BMJ Thorax.