Figures
- Figure 1–
a) Comparison of survival curves (from rapid deterioration to death or last follow-up) between patients with acute exacerbation (AE) (—) and infection (---). b) Comparison of survival curves (from initial diagnosis to death or last follow-up) for patients with no rapid deterioration (RD) (—), AE (···), bilateral infection (----) and focal RD (– – –).
Tables
- Table 1– Incidence of acute exacerbation (AE) and rapid deterioration (RD)
Incidence# AE¶ RD 1-yr 58 (14.2) 97 (23.0) 2-yr 71 (18.8) 124 (31.2) 3-yr 75 (20.7) 134 (35.4) Data are presented as n (%). The cumulative incidences of AE, excluding patients first presented at the time of AE, are 11.6% (1-yr), 16.3% (2-yr) and 18.2% (3-yr). #: first event; ¶: 14 patients first presented at the time of AE.
- Table 2– Aetiologies of rapid deterioration (RD; first episode)
Aetiology Cases n (%)# Documented organisms¶ (n) Total RD 163 (35.4) Bilateral lesions 140 (30.4) AE 90 (19.5) Definite 57 (12.4) Suspected 33 (7.2) Infection 37 (8.0) Definite 21 (4.6) Bacterial 9 (2.0) Streptococcus pneumoniae (2)MRSA (1)Haemophilus influenzae (4)Legionella spp. (1)Klebsiella pneumoniae (1) Viral 7 (1.5) CMV (7; 2 mixed infections with RSV or Pneumocystis jiroveci)Influenza virus (1)RSV (1) Fungal 2 (0.4) Candida spp. (1)Aspergillus spp. (1) Parasitic 2 (0.4) Pneumocystis jiroveci (2) Mycobacterial 1 (0.2) Mycobacterium tuberculosis (1) Suspected+ 16 (3.5) Heart failure 5 (1.1) PTE 2 (0.4) AEP 1 (0.2) Uncertain§ 5 (1.1) Focal lesion 23 (5.0) Pneumothorax 9 (2.0) Infection 14 (3.0) Klebsiella pneumoniae (1)Klebsiella oxytoca (1)Streptococcus pneumoniae (1) AE: acute exacerbation; PTE: pulmonary thromboembolism; AEP: acute eosinophilic pneumonia; MRSA: methicillin-resistant Staphylococcus aureus; CMV: cytomegalovirus; RSV: respiratory syncytial virus. #: percentage of total subjects (n = 461); ¶: identified by culture, antigen test (for S. pneumoniae and Legionella), or direct fluorescence monoclonal antibody stain (for P. jiroveci); +: cases in which no organism was identified, but infection was clinically suspected due to symptoms such as grossly purulent sputum and rapid resolution of symptoms in response to antibiotics alone; §: cases in which no organism was identified, but the criteria for AE were not completely satisfied due to incomplete study.
- Table 3– Comparison of the baseline characteristics between patients with and without acute exacerbation (AE)
Characteristics Non-RD AE p-value Infection# p-value¶ Patients 298 90 37 Age yrs 63.4±8.1 64.3±8.9 ns 63.7±8.6 ns Males 228 (76.5) 69 (76.7) ns 30 (81.1) ns Smoking 0.107 ns Never smoked 76 (25.5) 31 (34.4) 10 (27.0) Smokers 222 (74.5) 59 (65.6) 27 (73.0) Smoking exposure pack-yrs 34.8±19.2 35.7±20.0 ns 34.0±16.2 ns PFT % pred+ FVC 77.6±17.0 72.0±15.7 0.005 75.5±18.5 ns DL,CO 66.4±19.0 62.2±19.3 ns 61.2±18.0 0.088 TLC 78.7±14.4 73.8±15.0 0.021 75.9±18.5 ns FEV1 88.5±18.0 86.0±18.3 ns 89.0±17.5 ns BAL %+ Macrophages 71.0±18.4 67.8±16.4 ns 66.9±16.1 ns Lymphocytes 15.7±12.4 15.7±11.2 ns 18.2±14.2 ns Neutrophils 9.4±14.1 11.3±13.7 ns 10.8±9.4 ns Eosinophils 3.2±4.6 3.2±4.4 ns 1.9±2.3 ns CRP mg·dL−1+ 0.5±0.7 0.4±0.3 ns 0.7±0.7 0.055 Steroid with/without cytotoxic agent§ 184 (61.7) 56 (62.2) ns 20 (54.1) ns Data are presented as n, mean±sd or n (%), unless otherwise stated. RD: rapid deterioration; PFT: pulmonary function test; % pred: % predicted; FVC: forced vital capacity; DL,CO: diffusing capacity of the lung for carbon monoxide; TLC: total lung capacity; FEV1: forced expiratory volume in 1 s; BAL: bronchoalveolar lavage; CRP: C-reactive protein; ns: nonsignificant. #: infection with bilateral lesions; ¶: No-RD versus infection; +: data from the patients who first presented with RD were excluded; §: within 30 days prior to RD.
- Table 4– Risk factors for acute exacerbation compared to no episodes of rapid deterioration (RD) at the time of initial diagnosis
Parameters HR (95% CI) p-value Univariate Cox analysis Age 1.021 (0.997–1.047) 0.093 Male sex 0.921 (0.563–1.506) ns Smoking 0.629 (0.407–0.972) 0.037 PFT % pred FVC 0.975 (0.960–0.989) 0.001 DL,CO 0.981 (0.967–0.994) 0.005 TLC 0.970 (0.953–0.987) 0.001 BAL Macrophages 0.991 (0.975–1.008) ns Lymphocytes 1.001 (0.977–1.025) ns Neutrophils 1.010 (0.989–1.031) ns Eosinophils 0.994 (0.929–1.064) ns CRP 0.786 (0.380–1.622) ns Steroids with/without cytotoxic agents# 1.045 (0.682–1.602) ns Multivariate Cox analysis¶ Smokers 0.585 (0.342–1.001) 0.050 FVC % pred 0.979 (0.964–0.995) 0.011 HR: hazard ratio; PFT: pulmonary function test; FVC: forced vital capacity; % pred: % predicted; DL,CO: diffusing capacity of the lung for carbon monoxide; TLC: total lung capacity; BAL: bronchoalveolar lavage; CRP: C-reactive protein; ns: nonsignificant. #: within 30 days prior to RD; ¶: TLC % pred was excluded from the multivariate analysis due to the close correlation between FVC % pred and TLC % pred (r = 0.765; p<0.001).
- Table 5– Comparison of the clinical features of the patients with acute exacerbation (AE) and the bilateral infection at the time of rapid deterioration (RD)
Characteristics AE Infection p-value Patients 90 37 Age yrs 65.3±7.9 66.1±7.6 ns Males 69 (76.7) 30 (81.1) ns Disease duration months 16.5±24.5 29.5±34.7 0.014 Steroid with/without cytotoxic agent use# 56 (62.2) 20 (54.1) ns Duration¶ months 3.4±3.8 4.5±5.2 ns Last dose¶ mg 18.8±13.2 18.4±15.0 ns Duration of dyspnoea days 11.2±12.5 6.1±7.4 0.030 Initial symptoms Documented fever 18 (20.0) 19 (51.4) 0.001 Sputum production 63 (70.0) 31 (83.8) ns CRP mg·dL−1 8.3±6.8 14.7±9.8 <0.001 Pa,O2/FI,O2 253±83 228±91 ns BAL Total cells·mm−3 292±168 349±342 ns Lymphocytes % 19.7± 19.6 8.1±7.5 0.041 Neutrophils % 22.9±19.9 55.2±28.9 0.001 Data are presented as n, mean±sd or n (%), unless otherwise stated. CRP: C-reactive protein; Pa,O2: arterial oxygen tension; FI,O2: inspiratory oxygen fraction; BAL: bronchoalveolar lavage; ns: nonsignificant. #: within 30 days prior to RD; ¶: steroid (prednisolone) treatment.
- Table 6– Prognostic factors for in-hospital mortality of patients with acute exacerbation
Parameters OR (95% CI) p-value Univariate logistic analysis Age 1.022 (0.969–1.078) ns Male sex 1.455 (0.543–3.895) ns Disease duration 0.994 (0.977–1.011) ns Steroid with/without cytotoxic agent use# 0.828 (0.353–1.943) ns Duration¶ 1.142 (0.932–1.399) ns Last dose¶ 1.034 (0.990–1.081) ns Duration of dyspnoea 0.939 (0.902–0.978) 0.003 Documented fever 2.364 (0.799–6.989) ns Sputum production 1.705 (0.684–4.252) ns Pa,O2/FI,O2 0.989 (0.983–0.996) 0.001 CRP 1.087 (1.009–1.172) 0.029 BAL Total cells 0.998 (0.992–1.003) ns Lymphocytes 0.905 (0.826–0.992) 0.033 Neutrophils 1.055 (0.996–1.118) 0.070 Multivariate logistic analysis CRP 2.467 (1.030–5.911) 0.043 BAL lymphocytes 0.869 (0.737–1.024) 0.093 Pa,O2: arterial oxygen tension; FI,O2: inspiratory oxygen fraction; CRP: C-reactive protein; BAL: bronchoalveolar lavage; ns: nonsignificant. #: within 30 days prior to rapid deterioration; ¶: steroid treatment.
- Table 7– Treatment during acute exacerbation (AE) and in-hospital outcome of patients with AE according to treatment
Treatment regimen Cases Survival p-value Steroid pulse# 13 (14.4) 7 (53.8) 0.933 Steroid pulse# plus cytotoxic agent¶ 8 (8.9) 4 (50.0) High-dose steroid+ 46 (51.1) 19 (41.3) High-dose steroid+ plus cytotoxic agent¶ 14 (15.6) 11 (78.6) Low-dose steroid§ 6 (6.7) 3 (50.0) Low-dose steroid§ plus cytotoxic agent¶ 1 (1.1) 1 (100.0) No treatment 2 (2.2) 0 Total 90 (100) 45 (50) Data are presented as n (%) unless otherwise stated. #: steroid pulse was ≥500 mg·day−1 methylprednisolone for 3 days, followed by high-dose steroid; ¶: cytotoxic agents were azathioprine, cyclosporine or cyclophosphamide; +: high-dose steroid was ≥0.5 mg·kg−1·day−1 prednisolone; §: low-dose steroid was ≤0.5 mg·kg−1·day−1 prednisolone.
- Table 8– Prognostic factors for the overall survival from the initial diagnosis of idiopathic pulmonary fibrosis
Parameters HR (95% CI) p-value Univariate Cox analysis Age 1.016 (1.001–1.031) 0.032 Male sex 0.910 (0.685–1.209) NS Smoking 0.737 (0.568–0.956) 0.021 PFT % pred FVC 0.976 (0.968–0.984) <0.001 DL,CO 0.978 (0.971–0.986) <0.001 TLC 0.975 (0.965–0.984) <0.001 BAL Macrophages 1.003 (0.993–1.014) NS Lymphocytes 0.998 (0.985–1.012) NS Neutrophils 0.996 (0.980–1.012) NS Eosinophils 0.979 (0.941–1.018) NS CRP 1.073 (0.808–1.423) NS Steroid with/without cytotoxic agent 1.529 (1.177–1.986) 0.001 Occurrence of AE# 2.770 (2.132–3.599) <0.001 Multivariate Cox analysis¶ Age 1.017 (1.001–1.033) 0.032 PFT % pred FVC 0.987 (0.977–0.997) 0.009 DL,CO 0.985 (0.976–0.994) 0.001 Steroid with/without cytotoxic agent 1.552 (1.113–2.164) 0.010 Occurrence of AE 2.592 (1.888–3.560) <0.001 HR: hazard ratio; PFT: pulmonary function test; % pred: % predicted; FVC: forced vital capacity; DL,CO: carbon monoxide diffusing capacity of the lung; TLC: total lung capacity; BAL: bronchoalveolar lavage; CRP: C-reactive protein; AE: acute exacerbation; NS: not significant. #: overall occurrence during follow up; ¶: TLC % pred was excluded from the multivariate analysis due to the close correlation between FVC and TLC % pred (r = 0.765; p<0.001).
Supplementary tables
Files in this Data Supplement:
- Supplementary tables -
Table E1. Diagnostic criteria for acute exacerbation by Collard et al.
Table E2. Investigation protocol for the patients with suspected acute exacerbation (AE) of IPF
Table E3. Immunosuppressive therapy before rapid deterioration in patients with opportunistic infection
Table E4. Discriminating factors for acute exacerbation compared to infection at the time of rapid deterioration
Table E5. Immediate outcomes of rapid deterioration from the onset of rapid deterioration
Table E6. Comparison of clinical features between survivors and non-survivors of acute exacerbation
Table E7. Impact of rapid deterioration: comparison of the overall survival after the initial diagnosis between patients with and without rapid deterioration
Table E8. Multiple episodes of rapid deterioration
Table E9. Etiologies of multiple episodes of rapid deterioration
- Supplementary tables -
