Corticosteroids and Respiratory Tract Infection Risk in COPD

Abstract and Introduction

Abstract

Background: We aimed to assess the association between inhaled corticosteroids (ICSs) and the risk of upper respiratory tract infection (URTI) in patients with chronic obstructive pulmonary disease (COPD).

Methods: PubMed, Embase, Cochrane Library and Clinical Trials.gov were searched from inception to October 2019. Randomized controlled trials (RCTs) of any ICSs vs control for COPD with reporting of URTI as an adverse event were included. The study was registered with PROSPERO prospectively (#CRD42020153134).

Results: Seventeen RCTs (20,478 patients) were included. ICSs significantly increased the risk of URTI in COPD patients (RR, 1.13; 95% CI 1.03–1.24; P = 0.01; heterogeneity: I² = 7%). Futher subgroup analyses suggested that short-term use of ICSs increased the risk of URTI (RR, 1.29; 95% CI 1.06–1.56; P = 0.01; heterogeneity: I² = 14%) but not for long-term use (RR, 1.08; 95% CI 0.97–1.2; P = 0.14; heterogeneity: I² = 0%). Short-term use of high-dose fluticasone increased the risk of URTI (RR, 1.33; 95% CI 1.03–1.71; P = 0.03; heterogeneity: I² = 0%) but not for long-term use (RR, 1.12; 95% CI 0.97–1.29; P = 0.13; heterogeneity: I² = 50%). Medium-dose (RR, 0.97; 95% CI 0.71–1.32; P = 0.84; heterogeneity: I² = 0%) and low-dose (RR, 1.39; 95% CI 0.92–2.1; P = 0.12; heterogeneity: I² = 30%) fluticasone did not increase the risk of URTI regardless of duration. Neither mometasone (RR, 1.05; 95% CI 0.87–1.26; P = 0.61; heterogeneity: I² = 0%) nor budesonide (RR, 1.08; 95% CI 0.77–1.5; P = 0.67; heterogeneity: I² = 46%) increased the risk of URTI, regardless of dosage or duration.

Conclusions: Long-term use of ICSs does not increase the risk of URTI in patients with COPD. Short-term use of high-dose fluticasone increases the risk of URTI in patients with COPD, but not mometasone or budesonide.

Introduction

Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and disability worldwide.^[1–3] Exacerbation is the major reason for hospital admission of patients with COPD and related to a significantly worse survival outcome.^[4–6] Inhaled corticosteroids (ICSs) or combined with long-acting bronchodilators have been recommended to treat COPD patients with repeated exacerbations.^[1]

Although ICSs are generally considered to be relatively safe and well tolerated in patients, some adverse effects associated with ICSs have also been observed, such as the development of oropharyngeal candidiasis,^[6] adrenal suppression,^[7] diabetes,^[8] and pneumonia.^[9] However, the association between ICSs and risk of upper respiratory tract infection (URTI) remains unclear, though URTI is the most common respiratory infection and also an important cause of exacerbation of COPD.^[10] The large prospective study Toward a Revolution in COPD Health (TORCH) trial reported ICSs might increase the morbidity of URTI in COPD patients.^[11] Moreover, other randomized controlled trials (RCTs) reported different or even contrary outcomes, and most of these studies were inadequate to detect significant difference between ICSs treatment groups and control groups.^[12–17]

Whether ICSs increase the risk of URTI in COPD patients may depend on duration, dosage and type of ICSs. Lack of safety evidence may result in insufficient use or over use of ICSs. Therefore, we conducted this meta-analysis of RCTs to assess the association between ICSs use and the risk of URTI in patients with COPD. We also aimed to clarify the contributions of medication details for the association, including duration, dosage level and type of ICSs.

Table 1. Characteristics of the 17 RCTs included in the meta-analysis of ICSs and risk of URTI
Study	Duration (months)	Mean Age (years)	FEV1 (%predicted)	Male (%)	Interventions	NO. of URTI/Total
Mahler et al. [13]	5.5	63.5	40.8	66.0	T:FP 500 μg bid or FSC (S 50 μg/FP 500 μg) bid	T:84/342
C: Placebo or S 50 μg bid	C: 56/349
Hanania et al. [22]	5.5	63.8	41.8	63.2	T:FP 250 μg bid or FSC (S 50 μg/FP 250 μg) bid	T:40/361
C: Placebo or S 50 μg bid	C: 42/362
Calverley et al. [11]	36	65.0	44.0	75.5	T:FP 500 μg bid or FSC (S 50 μg/FP 500 μg) bid	T:309/3098
C: Placebo or S 50 μg bid	C: 277/3086
Zheng et al. [23]	5.5	66.2	47.0	89.2	T:FSC (S 50 μg/FP 500 μg) bid	T:32/297
C: Placebo	C: 14/148
Ferguson et al. [24]	12	65.0	32.8	55.0	T:FP 250 μg bid	T:31/394
C: S 50 μg bid	C: 31/388
Calverley et al. [25]	12	65.1	NR	68.3	T: MF 800 μg qd or MF 400 μg bid	T:164/616
C: Placebo	C: 71/295
Anzueto et al. [26]	12	65.4	34	54.0	T:FSC (S 50 μg/FP 500 μg) bid	T:41/394
C: Placebo	C: 30/403
Calverley et al. [27]	11	63.6	42.2	80.7	T:BDP/FM 200/12 μg bid or BUD/FM 400/12 μg bid	T:3/479
C: FM 12 μg bid	C: 5/239
Tashkin et al. [30]	6	59.8	NR	77.5	T: MF/FM 200/10 μg bid or MF/FM 400/10 μg bid or MF 400 μg bid	T:19/634
C: Placebo or FM 10 μg bid	C:13/421
Tashkin et al. [16]	12	59.7	39.1	76.0	T: MF/FM 200/10 μg bid or MF/FM 400/10 μg bid or MF 400 μg bid	T:58/1351
C: Placebo or FM 10 μg bid	C: 39/900
Doherty et al. [29]	6	59.6	38.6	75.2	T: MF/FM 200/10 μg bid or MF/FM 400/10 μg bid or MF 400 μg bid	T:39/717
C: Placebo or FM 10 μg bid	C: 26/479
Sharafkhaneh et al. [12]	12	63.0	37.7	62.0	T:BUD/FM 320/9 μg bid or BUD/FM 160/9 μg bid	T:90/815
C: FM 9 μg bid	C: 39/403
Boscia et al. [28]	1	57.9	49.8	46.3	T:FF/VI 50/25 μg qd or FF/VI 100/25 μg qd or FF/VI 200/25 μg qd	T:2/98
C: Placebo	C: 1/51
Vogelmeier et al. [15]	6	63.3	60.3	70.9	T: FSC (S 50 μg/FP 500 μg) bid	T:2/264
C: QVA149 110/50 μg qd	C: 7/258
Kerwin et al. [14]	5.5	62.5	48.3	66.6	T:FF/VI 50/25 μg qd or FF/VI 100/25 μg qd or FF 100 μg qd	T:50/618
C: Placebo or VI 25 μg qd	C: 19/412
Martinez et al. [17]	5.5	61.5	47.9	72.3	T:FF/VI 100/25 μg qd or FF/VI 200/25 μg qd or FF 100 μg qd or FF 200 μg qd	T:23/816
C: Placebo or VI 25 μg qd	C: 14/408
Huang et al. [31]	2.8	64.1	NR	86.4	T: BUD/FM 320/9 μg bid, I 40 μg qid and T 100 mg bid	T:4/293
C:I 40 μg qid and Th 100 mg bid	C: 2/289

Table 1. Characteristics of the 17 RCTs included in the meta-analysis of ICSs and risk of URTI

Study

Duration (months)

Mean Age (years)

FEV1 (%predicted)

Male (%)

Interventions

NO. of URTI/Total

Mahler et al. [13]

5.5

63.5

40.8

66.0

T:FP 500 μg bid or FSC (S 50 μg/FP 500 μg) bid

T:84/342

C: Placebo or S 50 μg bid

C: 56/349

Hanania et al. [22]

5.5

63.8

41.8

63.2

T:FP 250 μg bid or FSC (S 50 μg/FP 250 μg) bid

T:40/361

C: Placebo or S 50 μg bid

C: 42/362

Calverley et al. [11]

65.0

44.0

75.5

T:FP 500 μg bid or FSC (S 50 μg/FP 500 μg) bid

T:309/3098

C: Placebo or S 50 μg bid

C: 277/3086

Zheng et al. [23]

5.5

66.2

47.0

89.2

T:FSC (S 50 μg/FP 500 μg) bid

T:32/297

C: Placebo

C: 14/148

Ferguson et al. [24]

65.0

32.8

55.0

T:FP 250 μg bid

T:31/394

C: S 50 μg bid

C: 31/388

Calverley et al. [25]

65.1

68.3

T: MF 800 μg qd or MF 400 μg bid

T:164/616

C: Placebo

C: 71/295

Anzueto et al. [26]

65.4

54.0

T:FSC (S 50 μg/FP 500 μg) bid

T:41/394

C: Placebo

C: 30/403

Calverley et al. [27]

63.6

42.2

80.7

T:BDP/FM 200/12 μg bid or BUD/FM 400/12 μg bid

T:3/479

C: FM 12 μg bid

C: 5/239

Tashkin et al. [30]

59.8

77.5

T: MF/FM 200/10 μg bid or MF/FM 400/10 μg bid or MF 400 μg bid

T:19/634

C: Placebo or FM 10 μg bid

C:13/421

Tashkin et al. [16]

59.7

39.1

76.0

T: MF/FM 200/10 μg bid or MF/FM 400/10 μg bid or MF 400 μg bid

T:58/1351

C: Placebo or FM 10 μg bid

C: 39/900

Doherty et al. [29]

59.6

38.6

75.2

T: MF/FM 200/10 μg bid or MF/FM 400/10 μg bid or MF 400 μg bid

T:39/717

C: Placebo or FM 10 μg bid

C: 26/479

Sharafkhaneh et al. [12]

63.0

37.7

62.0

T:BUD/FM 320/9 μg bid or BUD/FM 160/9 μg bid

T:90/815

C: FM 9 μg bid

C: 39/403

Boscia et al. [28]

57.9

49.8

46.3

T:FF/VI 50/25 μg qd or FF/VI 100/25 μg qd or FF/VI 200/25 μg qd

T:2/98

C: Placebo

C: 1/51

Vogelmeier et al. [15]

63.3

60.3

70.9

T: FSC (S 50 μg/FP 500 μg) bid

T:2/264

C: QVA149 110/50 μg qd

C: 7/258

Kerwin et al. [14]

5.5

62.5

48.3

66.6

T:FF/VI 50/25 μg qd or FF/VI 100/25 μg qd or FF 100 μg qd

T:50/618

C: Placebo or VI 25 μg qd

C: 19/412

Martinez et al. [17]

5.5

61.5

47.9

72.3

T:FF/VI 100/25 μg qd or FF/VI 200/25 μg qd or FF 100 μg qd or FF 200 μg qd

T:23/816

C: Placebo or VI 25 μg qd

C: 14/408

Huang et al. [31]

2.8

64.1

86.4

T: BUD/FM 320/9 μg bid, I 40 μg qid and T 100 mg bid

T:4/293

C:I 40 μg qid and Th 100 mg bid

C: 2/289

Association Between Inhaled Corticosteroids and Upper Respiratory Tract Infection in Patients With Chronic Obstructive Pulmonary Disease

A Meta-Analysis of Randomized Controlled Trials

Abstract and Introduction

Abstract

Introduction

Association Between Inhaled Corticosteroids and Upper Respiratory Tract Infection in Patients With Chronic Obstructive Pulmonary Disease

A Meta-Analysis of Randomized Controlled Trials

Abstract and Introduction

Abstract

Introduction

Tables

References

Authors and Disclosures

Authors and Disclosures

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