Inhaled Corticosteroids and the Risk of Pneumonia Tobias

Inhaled Corticosteroids and the Risk of Pneumonia Tobias Welte Department of Respiratory Medicine

ICS in COPD – A Risk Factor for CAP? Rate of pneumonia in ICS Studies 1 Calverley P. NEJM 2007; 356: 775 -89; 2 Kardos P. AJRCCM 2007; 175: 144 -49; 3 Wedzicha JA; AJRCCM 2008; 177: 19 -26 TORCH 1 3 -year Follow-Up Placebo Salmeterol or Tiotropium Fluticason Seretide (SAL/FLU) 12. 3% 13. 3% 18. 3%* 19. 6%* VIVACE 2 44 week Follow. Up 7 (=1. 5%) 23 (=5. 7%) INSPIRE 3 2 -year Follow-Up 24 (=4%) 50 (=8%)§ *p< 0. 001 vs. Placebo; § Hazard Ratio for time to reported pneumonia 1. 94 (p=0. 008) Welte – ICS and pneumonia 11. 10. 2014

Steroid Use in COPD - A Risk Factor for CAP? Ernst P. AJRCCM 2007; 176: 162 -66 • • • 175, 906 patients with COPD, 23, 942 hospitalized for pneumonia (1. 9 per 100 per year) Matched to 95, 768 control subjects. The adjusted RR of hospitalization for pneumonia associated with current use of ICS was 1. 70 (95% CI), 1. 63– 1. 77) and 1. 53 (95% CI, 1. 30– 1. 80) for pneumonia hospitalization followed by death within 30 days. The RR of hospitalization – • greatest with the highest doses of ICS equivalent to fluticasone at 1, 000 µg/day or more (RR, 2. 25; 95% CI, 2. 07– 2. 44). All-cause mortality was similar for patients hospitalized for pneumonia, whether or not they had received ICS (7. 4 and 8. 2%, respectively) Welte – ICS and pneumonia 11. 10. 2014

Steroid Use in COPD - A Risk Factor for CAP? Suissa S. Thorax 2013; 68: 1029 -36 • • New-user cohort of patients with COPD treated during 1990– 2005. A nested case–control analysis was used to estimate the ratio (RR) of serious pneumonia associated with current ICS use – • • adjusted for age, sex, respiratory disease severity and comorbidity. 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) Use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1. 69) The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months The rate of serious pneumonia was higher with fluticasone (RR 2. 01), increasing with the daily dose, but was much lower with budesonide (RR 1. 17) Welte – ICS and pneumonia 11. 10. 2014 Fluticasone Budesonid

Steroid Use in COPD - A Risk Factor for CAP? Suissa S. Thorax 2013; 68: 1029 -36 Welte – ICS and pneumonia 11. 10. 2014

Budesonide and the Risk of Pneumonia in COPD – a Meta-Analysis D SIn et al. , Lancet 374: 712 -719, 2009 Risk of pneumonia as SAE Welte – ICS and pneumonia 11. 10. 2014

BMJ 2013; 346: f 3306 Welte – ICS and pneumonia 11. 10. 2014 44

Cumulative number of pneumonia events and admissions to hospital because of pneumonia per patient over nine years after index date Janson C. et al. BMJ 2013; 346: f 3306 Welte – ICS and pneumonia 11. 10. 2014 44

Pneumonie related Mortality Janson C. et al. BMJ 2013; 346: f 3306 Welte – ICS and pneumonia 11. 10. 2014 44

Steroid Use in COPD - A Risk Factor for CAP? Eurich DT. CID 2013; 57: 1138 -44 • • Clinical and 5 -year follow-up data were collected on all adults aged ≥ 65 years with pneumonia over a period of 2 years. Nested case-control design matched on age, sex, and COPD – Cases • – Controls • • • free of pneumonia 653 recurrent pneumonia cases were matched with 6244 controls – – • patients with recurrent pneumonia ≥ 30 days after initial episode Mean age was 79 years 3577 (52%) male 2652 (38%) had COPD 2294 (33%) ever used ICS 123 of 870 (14%) current ICS users had recurrent pneumonia compared to 395 of 4603 (9%) never-users (adjusted odds ratio, 1. 90; P <. 001; number need to harm = 20) no association between past use of ICS and pneumonia: 9% of past users versus 9% never-users (P =. 36). Welte – ICS and pneumonia 11. 10. 2014

Eurich DT. CID 2013; 57: 1138 -44 Welte – ICS and pneumonia 11. 10. 2014

Steroid Use in COPD - A Risk Factor for CAP? Mc. Keever T. Chest 2013; 144: 1788 -94 • • Primary care data from The Health Improvement Network in the UK People with asthma with pneumonia or lower respiratory tract infection Age- and sex-matched control subjects. The highest strength of ICS ( >1, 000 µg) had a 2. 04 increased risk of pneumonia or LTRI compared with no prescription for ICS within the previous 90 days Welte – ICS and pneumonia 11. 10. 2014

ICS – Risk for Tuberculosis • • Case control study in Korea using the national health care data base 853 439 Pts prescribed ICS for the first time (2007 bis 2010) Pts with a first diagnosis of TB after starting ICS were included Data were adjusted for age, gender, Asthma-/COPD Diagnosis and time since start of ICS 4139 TB were diagnosed and compared with 20 583 controls ICS increased the likelihood for Tb (adjusted OR 1. 20) significantly The assoziation was dose dependend (p <0. 001) Welte – ICS and pneumonia 11. 10. 2014 Chang-Hoon L. et al. Thorax 2013; 68: 1105– 1113.

ICS – Risk for NTM CAndréjak C. et al. Thorax 2013; 68: 256– 62. • Case-control study in adults in Denmark with microbiologically confirmed NTM pulmonary disease between 1997 and 2008 • 10 matched population controls per case. • Chronic respiratory disease was associated with a 16. 5 -fold increased risk of NTM pulmonary disease • Adjusted OR for NTM disease was 15. 7 for COPD, 7. 8 for asthma, 9. 8 for pneumoconiosis, 187. 5 (95% for bronchiectasis, and 178. 3 for tuberculosis history • ORs were 29. 1 for patients with COPD on current ICS therapy and 7. 6 for patients with COPD who had never received ICS therapy • ORs increased according to • ICS dose from 28. 1 for low-dose intake to 47. 5 for high-dose intake (more than 800 μg/day) • OR was higher for fluticasone than for budesonide Welte – ICS and pneumonia 11. 10. 2014

ICS and Pneumonia Pleural Effusion Sellares J. et al. AJRCCM 2013: 1241 -48. • • Single center cohort study in Spain in 3, 612 CAP patients 633 Pts (17%) were treated with ICS before CAP was diagnosed (COPD 54%; Asthma, 13%) Incidence of a parapneumonic pleural effusion lower in ICS patiens compared to non ICS patients (5% vs. 12%; P < 0. 001). ICS pretreatment was associated with higher glucose and p. H and lower protein and LDH concentraitions in the pleural effusion Welte – ICS and pneumonia 11. 10. 2014

ICS and Pneumonia Pleural Effusion Sellares J. et al. AJRCCM 2013: 1241 -48. Welte – ICS and pneumonia 11. 10. 2014 45

Welte – ICS and pneumonia 11. 10. 2014