Predictors of Mortality in Chronic Pulmonary Aspergillosis (CPA)
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1 Predictors of Mortality in Chronic
2 Pulmonary Aspergillosis (CPA)
3
4 David Lowes MB ChB 1,2*; Khaled Al-Shair PhD1*; Pippa J. Newton FRCP1,2; Julie
5 Morris MSc3; Chris Harris1, Riina Rautemaa-Richardson FRCPath1; and David W.
6 Denning FRCP1,2.
7 *Joint 1st authors
8 1. The National Aspergillosis Centre, University Hospital of South Manchester,
9 The University of Manchester, Manchester Academic Health Science Centre,
10 Manchester, UK
11 2. North West Lung Research Centre, University Hospital of South Manchester,
12 The University of Manchester, Manchester Academic Health Science Centre,
13 Manchester, UK
14 3. Department of Medical Statistics, University Hospital of South Manchester,
15 The University of Manchester, Manchester Academic Health Science Centre,
16 Manchester, UK
17 Corresponding author:
18 Professor David Denning FRCP FRCPath FMedSci
19 The National Aspergillosis Centre
20 University Hospital of South Manchester, the University of Manchester,
21 Manchester Academic Health Science Centre,
22 Manchester, UK
23 E-mail: [email protected]
1 1 Take Home: This paper describes the world’s largest experience of chronic pulmonary
2 aspergillosis and its outcome.
3
4 Total number of words of the manuscript: 3005 words, not including abstract,
5 tables, references and figure legends.
6 Abstract: 200 words.
7
8 Running head: Predictors of mortality in CPA
9
10
2 1 Abstract
2 Chronic pulmonary aspergillosis (CPA) is a chronic progressive infection that
3 destroys lung tissue in non-immunocompromised patients. Contemporary series
4 suggest 50 to 85% five year mortality, with few prognostic factors identified.
5 A cohort of 387 CPA patients referred to the UK’s National Aspergillosis Centre from
6 1992 to June 2012 was studied until June 2015. The impact of objective and
7 subjective variables including age, sex, previous pulmonary conditions, dyspnea
8 score, quality of life, serum albumin and CRP and radiological appearances were
9 assessed using Kaplan-Meier curves, Log-Rank tests and Cox proportional hazards
10 modeling. In samples of patients, retrospective review of likely onset of CPA to
11 referral and cause of death was also investigated.
12 Survival was 86%, 62% and 47% at one, five and 10 years. Increased mortality was
13 associated with non-tuberculous mycobacterial infection (NTM) (HR 2.07 (1.22-
14 3.52), p<0.001), and COPD (HR 1.57 (1.05-2.36), p=0.029) as well as higher age (HR
15 1.053 (1.03-1.07)/year increase, p<0.001), lower albumin (HR 0.92 (0.87 to 0.96)
16 /g/L), lower activity (HR 1.021 (1.01-1.03) /point increase in St. George’s Respiratory
17 Questionnaire Activity Domain, p<0.001) and having one and especially bilateral
18 aspergillomas (p <0.001).
19 Several factors impact on mortality of CPA, and can be evaluated as tools to assess
20 CPA prognosis.
21
22
23
3 1 Introduction
2 Chronic pulmonary aspergillosis (CPA) is an infectious disease that often
3 progressively destroys lung tissue. It occurs principally in immunocompetent
4 individuals with a previous or underlying pulmonary condition such as tuberculosis or
5 chronic obstructive pulmonary disease (COPD) (1). Awareness of this debilitating
6 and ultimately fatal infection is increasing, and it is provisionally estimated that there
7 are 3 million patients with CPA worldwide (2).
8 There are 3 major patterns of disease; simple aspergilloma, chronic cavitary
9 pulmonary aspergillosis (CCPA) and Aspergillus nodule (3). Simple aspergilloma is
10 defined as a single pulmonary cavity containing a fungal ball, and is often cured by
11 surgical resection (4-6). CCPA is characterized by cavity formation and progression
12 without overt tissue invasion and is associated with significant morbidity and
13 mortality in contrast to simple aspergilloma. However, other aspects of the impact of
14 CPA such as pleural involvement and bilateral aspergilloma on mortality risk needs
15 further investigation.
16 CPA is usually diagnosed by a combination of symptoms, characteristic radiological
17 appearances in a non-immunocompromised individual and detectable Aspergillus IgG
18 antibodies (7, 8). Patients present initially with nonspecific symptoms including
19 chronic cough, shortness of breath, weight loss, and haemoptysis (3). Progression
20 over months or years results in significant loss of functional capacity and decline in
21 quality of life (9). Functional capacity reduction and quality of life impairment
22 reliably predict mortality risk in chronic respiratory illnesses such as COPD (10, 11).
23 However, these key measures of health status have not been investigated in CPA with
24 respect to prognosis.
4 1 We found only nine studies with sample sizes of 11–194 subjects reporting divergent
2 data on the survival of CPA patients, with five year survival ranged from 17.5% to
3 85% (12-20), as summarized in (Table 1).
4 Using data from a cohort of 392 CPA patients, we present data on long-term survival
5 from a well-experienced single center with a consistent approach to antifungal
6 therapy. Using a wide range of objective and subjective measures, we also examine
7 factors associated with mortality risk in CPA.
8 Patients and methods
9 Study design
10 This retrospective study reviewed patients referred to UK’s National Aspergillosis
11 Centre for medical management of CPA from June 1st 1992 until June 1st 2012 where
12 18 were seen prior to 2000 (3). Survival data was collected in June 2015, resulting in
13 a minimum follow up of three years for surviving patients. The clinical records of all
14 patients were examined and the diagnosis of CPA confirmed using criteria modified
15 from Denning et al 2003 (3), and described in detail recently by Farid et al (5) and
16 consistent with the recently published European guideline on CPA (Denning, et al
17 2016) (21). Radiological and immunological examinations were used to identify
18 immunocompetent patients with a history of cavitary or nodular disease caused by
19 Aspergillus of at least 3 months duration (5, 22), more information on the inclusion
20 and exclusion criteria is provided in the e-supplements, together with the STROBE
21 criteria checklist and a figure showing the disposition of patients (Figure S1).
22
23 The variables were collected on these patients included gender, age at referral,
24 previous or current underlying pulmonary conditions, St. George’s Respiratory
5 1 Questionnaire (SGRQ) score, serum albumin and C reactive protein (CRP), sputum
2 culture positivity for Aspergillus spp. and antifungal susceptibility and radiological
3 appearances. The closest available CT scan to referral was reviewed, usually prior to
4 referral. The CT scan appearances were categorized by unilateral or bilateral disease,
5 presence of pleural involvement (thickening) or not, cavitary or nodular appearances
6 and presence and location of aspergillomas. The full medical records of a random
7 sample of 120 patients were manually reviewed to record the baseline Medical
8 Research Council (MRC) dyspnea score (initiated in late 2009) (n=78), baseline
9 weight (n=102) and body mass index (BMI) (n=88), all antifungal treatment
10 administered (n=108) and to determine the date of the probable onset of CPA.
11 Baseline was defined as within six months of referral for all variables with the
12 exception of MRC dyspnea score (within 12 months of referral). Causes of death were
13 available for 40 patients.
14
15 The MRC dyspnea scale is a well-validated tool (23, 24) that has been widely used in
16 respiratory field including CPA (9) . Quality of life (QoL) was assessed by the 76-
17 item SGRQ, which consists of three domains; symptoms, activity, and impact, and
18 total (25). The scores range from zero to 100 where a higher score indicates worse
19 quality of life (25, 26). Our recent work has extensively examined its validity and
20 reliability (27) and sensitivity to change with treatment in CPA (9).
21
22 Therapeutic approach
23 At the NAC patients were treated with oral triazole therapy where possible. First line
24 therapy is usually itraconazole, which was switched to voriconazole (from 1993) (28)
25 or posaconazole solution (7) (from 2007) in the event of intolerance, triazole
6 1 resistance or clinical failure. Therapeutic monitoring and dose adjustment of triazole
2 plasma concentrations was routine and frequent. In those unable to take oral therapy,
3 or with panazole resistance, intravenous liposomal amphotericin B (AmBisome,
4 3mg/Kg/d) or micafungin (150mg/d) were used, usually for 2-4 weeks but
5 occasionally for months as outpatients with homecare support. Surgical resection was
6 undertaken in a small proportion of patients for multiple reasons, as described
7 previously (5).
8
9 Detailed description of consent and statistical analysis is provided in the e-
10 supplement.
11 Results
12 Three hundred and ninety two patients fulfilling criteria for CPA were referred to the
13 NAC during the study period, approximately 50% of the total referrals with
14 aspergillosis. Five patients were lost to follow up so 387 patients were studied. Of
15 these, over 95% were Caucasian (96.4%), 219 patients (56.6%) were male, the mean
16 (SD) age at referral was 59.4 ±13.0 years (range 18-86), and 166 patients had died
17 over the study period. The mean follow up of surviving patients was 5.65 years; the
18 time from referral to death in non-surviving patients (n=166) was 2.85 years. Figure 1
19 shows a survival curve from time of referral to the NAC. Overall, the one, five and
20 ten survival rates in our 387 patients were 86%, 62% and 47% (Table 1). The HR for
21 death for every ten year increase in age at referral was 1.69 (p < 0.001). Gender had
22 no impact on survival (Log rank p=0.067). There was no time trend for the first and
23 second 50% of patients referred (Fig S1).
24
7 1 Oral antifungal therapy had been initiated in 98% of 108 patients analyzed in detail.
2 Itraconazole was used first line in 77% of patients, voriconazole in 15.2% and
3 posaconazole in 7.6%. At least 1 month of oral itraconazole, voriconazole and
4 posaconazole was administered to 73.1%, 57.4% and 23.1% of patients respectively;
5 8.3% of patients did not receive at least one month of oral therapy. Of patients who
6 were initiated on itraconazole, 65% were switched to voriconazole, and 21% of these
7 were later escalated to posaconazole. Of those starting on voriconazole, 12.5% were
8 switched to posaconazole. Over 81% of patients attending the NAC for more than a
9 year had received at least 1 year of oral therapy. Of those who did not have 1 year of
10 therapy, 47% had received at least one course of intravenous voriconazole, liposomal
11 amphotericin B or micafungin. Sixteen patients had surgical resection of CPA
12 unresponsive lesions or for haemoptysis, and of these 6 (37.5%) relapsed, as reported
13 previously5.
14
15 Accurate data on underlying disease was available for 362 patients. The median
16 number of underlying pulmonary conditions was 2 (IQR 1-3, range 0-6). As shown in
17 table 2, COPD was the most common underlying disease (n=145 patients, followed
18 by pneumonia and TB (n=79 and 76 patients, respectively). Several co-existing
19 pulmonary illnesses were associated with increased mortality risk in CPA; however,
20 multivariable Cox regression analysis (including all underlying conditions and age)
21 showed that NTM infection (HR 2.212, p<0.001) and COPD (HR 1.580, p=0.006)
22 were associated with worse survival (Table 2).
23
8 1 Baseline SGRQ data were available for 327 patients. The activity domain was the
2 only significant predictor of survival by multivariate model including all domains; an
3 increase in 4 points had a HR of 1.13 (95% CI 1.09 to 1.18; p <0.001).
4
5 Baseline serum albumin (Figure S2) and CRP data (Figure S3) was available for 351
6 patients. Higher CRP was predictive of mortality in a univariate model (HR 1.03 (1.01
7 to 1.04); p<0.001 for a 5mg/L increase in CRP), but this significance was lost in a
8 multivariate analysis with albumin, which was related to an 11% decrease in mortality
9 risk per 1g/L increase (HR 0.89 (0.86 to 0.92); p<0.001).
10
11 Sputum from patients was sent to the NAC Mycology Reference Centre Manchester
12 laboratory for fungal culture, identification and susceptibility testing, usually on
13 multiple occasions for each patient. Positive cultures for Aspergillus spp. were
14 obtained in 48 patients; Aspergillus fumigatus in 43. Of these, twenty (47%) were
15 fully susceptible to all azoles tested (itraconazole, voriconazole and posaconazole).
16 Eight (19%) were pan-azole resistant and the remainder had reduced susceptibility to
17 at least one azole. Other Aspergillus spp. were isolated - one each of A. niger
18 complex, A. terreus, A. nidulans, A. glaucus (of uncertain significance) and one
19 unspeciated isolate. The 10-year survival of patients with isolates fully susceptible to
20 azoles was 68% in contrast to 46% in patients with an isolate with reduced
21 susceptibility to azoles (p=0.143 by Log Rank) (figure 2).
22
23 We did not systematically collect bacterial culture data, primarily because it is likely
24 to be very incomplete. We have assembled information of the bacteria cultured from
25 our patients (29) and 19 of 364 patients attending our service (50% with CPA) grew
9 1 Pseudomona aeruginosa (5%), and slightly fewer all other rapidly growing bacteria.
2 No attempt was made to analyse any impact on survival of these bacterial infections.
3 CT scans were available for 320 patients. Pleural disease was seen in 250 (78.1%),
4 pulmonary cavities in 287 (89.7%) and aspergillomas in 224 (70%). Bilateral cavities
5 and aspergillomas were seen in 131 (40.9%) and 54 (41.6%) patient CT scans
6 respectively. The relationship of these different appearances to 2 year survival are
7 shown in Table 3. The presence of pleural disease was highly associated with a worse
8 2 year survival (p=0.001), as was cavitary disease (p=0.003). Bilateral disease was
9 associated with a worse outcome and having one or especially bilateral aspergillomas
10 was associated with worse survival (Figure 3). Thirty nine patients (12%) had
11 Aspergillus nodules on initial CT imaging, 13 of these were bilateral. Those with
12 Aspergillus nodules did not have significantly different survival to those with other
13 types of CPA (Log-Rank test p = 0.638).
14
15 A sub-sample of 120 patients was reviewed in further detail to collect baseline MRC
16 dyspnea score (n-78), baseline BMI (n= 88) and baseline weight (n=102). Those more
17 breathless with a higher baseline MRC score have shorter survival (p<0.001) as
18 demonstrated in figure 4. MRC scores 3 and 4 have been grouped for analysis due to
19 ambiguity in the questions used. A unit increase in baseline BMI has a HR of 0.89
20 (95% CI 0.81 to 0.97; p=0.010), that is a decrease in mortality risk of 11%. Weight at
21 baseline showed a 1kg increase in weight reduced risk of mortality by 4% (HR=0.96,
22 p=0.002). There was a reduction in mortality of 4% for every 1kg higher in weight.
23
24 Furthermore, multivariate analysis including age, gender, underlying pulmonary
25 conditions, location and presence of aspergillomas, serum albumin and CRP, and
10 1 SGRQ activity found that previous NTM (HR 2.07 (1.22 to 3.52); p = 0.007),
2 previous COPD (HR 1.57 (1.05 to 2.36); p = 0.029), age (HR 1.05 (1.03 to 1.07);
3 p<0.001), SGRQ activity score (HR 1.02 (1.01 to 1.03) per unit increase, p<0.001),
4 and albumin (HR 0.92 (0.87 to 0.96) per g/L, p<0.001), were independent predictors
5 of mortality.
6
7 The majority of patients cared for at the NAC who die do so at other centers, and
8 usually after months or years of ill health. Causes of death were available for 40
9 patients (see e-supplement). CPA was listed either in causal sequence to death or
10 contributing towards death in 27 (67.5%). Three patients (7.5%) died of conditions
11 unrelated to CPA. Ten patients (25%) are reported to have died of conditions such as
12 COPD or sarcoidosis, and it is likely that CPA was at least a contributory factor, but
13 was not recorded on the death certificate.
14 Discussion
15 We present a large retrospective cohort analysis of 387 CPA patients whose care was
16 delivered at our specialist center. We found that poor outcomes in CPA were
17 associated with several objective and subjective variables. NTM infections, prior
18 COPD, pleural involvement, bilateral cavitary disease or aspergillomas, low body
19 mass and low albumin are all associated with poor outcomes. Moreover, lower
20 activity score and higher dyspnea score identified patients with likely worse
21 prognosis. It is likely that azole resistance is associated with a worse outcome, but it
22 did not reach statistical significance.
23
11 1 The one, five and ten survival rates in our 387 patients of 86%, 62% and 47%
2 contrasts with other contemporary series from Japan (n=42) and Korea (n=43) of 63-
3 74%, 15-50% and 26% (14, 15). However, a recent Japanese study with 194 CPA
4 patients reported a closer figure to our finding with cumulative survival rate of 49%
5 and 34% at 5 and 10 years respectively (18). The underlying disease distribution and
6 baseline age in these series differed (Table 1) and mostly without sufficient detail to
7 comment on relative risks.
8
9 Once CCPA is established, an aspergilloma may form. The stages of formation of a
10 fungal ball on CT scan were well illustrated by Roberts et al (1987) and a
11 radiologically visible aspergilloma represents an advanced stage of infection (30).
12 Therefore, it is not surprising that bilateral aspergillomas carry a worse prognosis than
13 either no aspergilloma or a unilateral aspergilloma (figure 2). Both the presence of
14 pleural disease (unilateral or bilateral) or cavitary disease (unilateral or especially
15 bilateral) also confer a poorer outcome. In contrast, nodules and intraluminal cavities,
16 without pleural involvement confer a better outcome. The reason for these
17 associations with earlier death is not apparent. However, in addition to co-existing
18 structural tissue damage, several inflammatory, immunological and genetic features
19 are associated with CPA development and progression. Increased C-reactive protein
20 has been associated with increased mortality risk in CPA (18). Low mannose binding
21 lectin is associated with worse breathlessness in CPA (31, 32), not risk of disease.
22
23 Previous infection by NTM was shown to be an independent predictor of mortality.
24 This may represent the level of underlying damage caused by the infection. Three
25 studies have also examined the relationship between NTM and CPA, showing that in
12 1 patients with NTM, CPA is an independent predictor of mortality (33, 34). Further,
2 Takeda et al have recently found the non-treatment of CPA in NTM co-infected
3 patients lead to a higher mortality, suggesting that the driver for death was the CPA,
4 not the NTM infection (19). Another group have shown there is a risk of developing
5 NTM in cavities caused by CPA (35).
6
7 Clinically, these findings underscore the prognostic importance of early referral to
8 specialist centers to establish diagnosis, commence treatment and prevent further lung
9 tissue destruction and life-threating manifestations such as hemoptysis. Indeed,
10 delayed or inadequate antifungal therapy is usually associated with progression
11 whereas sustained clinical response is usually associated with long term antifungal
12 therapy. Second, early referral can assist in timely identification of patients who
13 progress rapidly and may need immunotherapy (usually replacement gamma
14 interferon) or challenging surgery, prevention of antifungal resistance and alternative
15 antifungal options for those who cannot take or fail azole therapy. Third, given the
16 estimated 3 million patients with CPA worldwide (2), additional antifungal agents and
17 strategies to prevent lung fibrosis and/or destruction are necessary.
18
19 BMI is a functional marker of poor prognosis in CPA, and our finding confirms
20 results of previous smaller studies (15, 18). We observed that a unit increase in
21 baseline BMI was associated with an 11% decrease in mortality risk. Moreover, we
22 found low weight to be a useful indicator of poor prognosis as in other chronic
23 progressive respiratory illnesses e.g. COPD (36, 37), possibly attributable to chronic
24 systemic inflammation (38, 39). Elevated inflammatory biomarkers are associated
13 1 with poor prognosis in CPA (18), COPD (39) and lung fibrosis (40), and could be
2 directly involved in lung tissue destruction and body mass depletion (41) in CPA.
3
4 Older age was associated with poor outcomes in CPA and other respiratory illnesses
5 (18, 42). We also found albumin to be a useful prognostic marker which remained
6 statistically significant in multivariate analysis, as in other respiratory conditions (43).
7
8 Moreover, we found that breathlessness as measured by the MRC dyspnea score was
9 a predictive of poor outcome. This replicates our recent finding from longitudinal
10 analysis (quarterly over a year) where the MRC dyspnea score is an independent
11 prognostic factor (9); as also seen in COPD (44). MRC dyspnea scores have only
12 been collected in our center since late 2009, hence the shorter follow up time and yet
13 those few without breathlessness (MRC score of one) all survived to at least three
14 years compared to only 26% of those with an MRC score of five (figure 4). Although
15 the MRC dyspnea scale is an old and simple measure, it has considerable clinical
16 value in assessing respiratory diseases prognosis (9, 44).
17
18 Lower ‘activity domain’ score of the SGRQ was a stronger predictor of mortality in a
19 model consisting of all the SGRQ outputs. Prior studies showed that the SGRQ
20 activity domain correlated better than the total SGRQ score with key respiratory
21 measurements such as FEV1, PaO2 and exercise capacity (shuttle distance) (45). This
22 finding is not surprising since the SGRQ is a respiratory-specific and sensitive tool in
23 identifying patients at risk of mortality (11) and detects response to anti-fungal
24 treatment (9). Regular physical activity associates with reduced hospital readmission
14 1 and mortality risk as in COPD (10) and promoting physical activity is a promising
2 step in lowering re-hospitalization (46), which needs addressing in CPA patients.
3
4 The NAC sees patients from all over the UK, with higher referral rates from the
5 northwest of England and more complex patients referred from longer distances. Both
6 short term and long term health benefits with antifungal therapy (either improvement
7 or prevention of progression of disease) are obvious for some patients (7-9).
8 Unfortunately, antifungal therapy is often curtailed by numerous adverse events (9,
9 47). Triazole antifungal resistance is also a relatively frequent problem (48-50),
10 interrupting azole therapy, probably with a worse outcome in CPA as seen here.
11 Intermittent or occasionally long term intravenous liposomal amphotericin B or
12 micafungin provide some short term benefits for some patients unable to take oral
13 therapy or with pan-azole resistance.
14
15 Although we presented key prognostic factors that would assist in identifying patients
16 at risk of poor prognosis, our study has limitations. We could not achieve a full
17 dataset for all our patients, a common limitation in retrospective analysis. Substantial
18 effort was made to collect reliable data, and develop the largest dataset so far on this
19 currently incurable destructive lung disease. Second, azole resistance may be
20 correlated with poor outcomes, and this may need analyses of a bigger sample size.
21 Finally, we do not have sufficient data on causes of death in our CPA cohort, with
22 death certificates being incomplete and often inaccurate. However, this analysis has
23 underscored the importance of careful recording of mortality causes in CPA.
24
15 1 In conclusion, half of our CPA patients had died by their 5th anniversary of referral.
2 Several pulmonary and extra-pulmonary factors associated with high mortality risk
3 are identified; NTM infection, COPD, pleural involvement, cavitary disease, presence
4 of an aspergilloma, shortness of breath, low physical activity, and low body mass.
5 Early diagnosis, referral and improved treatments are required.
6
7 Authors contribution:
8 DL participated in the study design and data collection and analysis, and manuscript
9 writing, drafting and reviewing. KA participated in data analysis, manuscript writing,
10 drafting, editing and reviewing. PN participated in data analysis and manuscript
11 reviewing. JM participated in the data analysis and manuscript reviewing. CH
12 participated in data collection and analysis, and manuscript reviewing. RR
13 participated in the data analysis and manuscript writing, reviewing and editing. DWD
14 participated in the study design, data analysis, and manuscript writing, editing and
15 reviewing. All authors read and approved the manuscript.
16
17 Acknowledgement
18 We are indebted to Dr Edmund Jessop and the National Specialized Commissioning
19 team in the National Health Service for their consistent support of the National
20 Aspergillosis Centre. The multiple contributions to care by the physicians, nurses,
21 physiotherapists and the Mycology Reference Centre Manchester (MRCM) staff are
22 all gratefully acknowledged. The commissioning of the NAC would not have been
23 possible without long term support to The Aspergillus Website and the MRCM from
24 the Fungal Infection Trust.
25
16 1
2
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21 1 43. Komiya K, Oka H, Ohama M, Uchida M, Miyajima H, Iwashita T, et al. 2 Evaluation of prognostic differences in elderly patients with pneumonia treated 3 by between pulmonologists and non-pulmonologists: a propensity score 4 analysis. Clin Respir J. 2016;10(4):462-8. 5 44. Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 6 5-year survival than airway obstruction in patients with COPD. Chest. 7 2002;121(5):1434-40. 8 45. Wilson CB, Jones PW, Oleary CJ, Cole PJ, Wilson R. Validation of the St. 9 George's Respiratory Questionnaire in bronchiectasis. Am J Respir Crit Care Med. 10 1997;156(2):536-41. 11 46. Nguyen HQ, Chu L, Amy Liu IL, Lee JS, Suh D, Korotzer B, et al. 12 Associations between physical activity and 30-day readmission risk in chronic 13 obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11(5):695-705. 14 47. Baxter CG, Marshall A, Roberts M, Felton TW, Denning DW. Peripheral 15 neuropathy in patients on long-term triazole antifungal therapy. J Antimicrob 16 Chemother. 2011;66(9):2136-9. 17 48. Bowyer P, Moore CB, Rautemaa R, Denning DW, Richardson MD. Azole 18 antifungal resistance today: focus on Aspergillus. Current Infectious Disease 19 Reports. 2011;13(6):485-91. 20 49. Denning DW, Park S, Lass-Florl C, Fraczek MG, Kirwan M, Gore R, et al. 21 High-frequency triazole resistance found In nonculturable Aspergillus fumigatus 22 from lungs of patients with chronic fungal disease. Clin Infect Dis. 23 2011;52(9):1123-9. 24 50. Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, 25 et al. Frequency and evolution of azole resistance in Aspergillus fumigatus 26 associated with treatment failure. Emerg Infect Dis. 2009;15(7):1068-76. 27
22 1 Table 1. Studies reporting survival of CPA
Survival Duration of observation period Study Year Country n Sub-category 1 year 40 Surgical management 90% The mean follow-up period was 8.7 years and 85% Jewkes et al. 1983 UK of patients were followed for five years or until (12) 36 Conservative Management 90% death. 12 Prior TB 80% Review of medical notes from 1975 to 1985. Tomlinson Follow-up period ranged from 2-11 years where and Sahn 1987 USA 13 Prior sarcoidosis 58% the majority were followed for > 4 years from the (13) aspergilloma diagnosis. Medical records for patients between 1995 and 2007 were reviewed. Nam et al. 2010 S. Korea 43 Prior TB/NTM 93% 65% The median follow-up period from disease (14) diagnosis to either death or closing date was 15 months (IQR 2.5– 32 months) for all patients. Medical record for patients between 2001 and Ohba et al. 2012 Japan 42 Prior TB 50%, COPD 14%, NTM 36% 70% 2009 were reviewed. (15) The observation period was 28.7 ± 26.6 months. Jhun et al. Medical records of patients between January 2008 2013 S. Korea 70 Prior TB 81%, COPD 50%, NTM 46% 93% (16) and January 2011 were reviewed. Medical records of patients between 1997 and Nakamoto et Prior TB 30%, emphysema 20%, ILD 17%, 2011 were reviewed. 2013 Japan 194 al. (17) NTM 15%, others 18% The patients were followed over a median follow- up time of 2.6 years. Aspergillus notifications of 1614 patients were Camara et al. 64% (1-3 2015 France 11 Prior TB 18%, COPD 18%, NTM 18% assessed from 2000 to 2011, and 11 patients had (18) years) CCPA, and 11 simple aspergilloma patients. 41 Medical records of patients between 2008 and (28 2013 were reviewed where many of the patients Takeda et al. CPA with other underlying diseases but 2016 Japan with 83% were followed for up to 6 years from diagnosis (19) not NTM (32) CCPA date. )
23 29 2 year survival Poor prognostic feature of CPA (multivariate) was Chan et al. Hong CPA Prior TB in 69 and 81%; COPD in 41% 72.4% and higher leukocyte count at admission. 2016 (20) Kong 31 and 32% (CPA and PA). 77.4% (CPA vs PA PA) Patients were followed from 1992 to June 2012 (a Lowes et al. 2016 UK 387 Prior TB 21%; COPD 40%, NTM 10% 86% minimum follow up of three years for surviving patients) 1 2 UK = United Kingdom; USA = United States of America; TB = tuberculosis; NTM = non-tuberculous mycobacterial disease. PA = simple aspergilloma 3 4
24 1 Table 2. Underlying pulmonary diseases and their effect on survival of 387 CPA 2 patients, not including those with simple aspergilloma. Cox Proportional Hazards Kaplan-Meier analysis Model including all
Underlying underlying conditions and Pulmonary N (%) age Condition Two year survival % ± Std. Log Rank Adjusted Hazard p value Error Test p value ratio (95% CI)
With 82.9% ± 4.3 TB 76 (21.0%) 0.199 NS Without 78.3% ± 2.5 With 62.2% ± 8.0 NTM 37 (10.2%) <0.001 2.212 (1.43 – 3.42) <0.001 Without 80.9% ± 2.2 With 73.1% ± 3.7 COPD 145 (40.1%) <0.001 1.580 (1.14 – 2.19) 0.006 Without 82.9% ± 2.6 With 91.8% ± 3.2 Asthma 73 (20.2%) 0.014 NS Without 75.8% ± 2.5 With 95.5% ± 3.1 ABPA 44 (12.2%) 0.053 NS Without 76.7% ± 2.4 With 72.2% ± 5.0 Pneumonia 79 (21.8%) 0.075 NS Without 80.9% ± 2.3 With 88.5% ± 4.4 Pneumothorax 52 (14.4%) 0.011 NS Without 77.24% ± 2.4 With 81.8% ± 5.2 Bronchiectasis 55 (15.2%) 0.446 NS Without 78.5% ± 2.3 With 86.4% ± 7.3 Sarcoidosis 22 (6.1%) 0.576 NS Without 78.5% ± 2.2 Inflammatory With 76.5% ± 7.3 34 (9.4%) 0.960 NS Arthritis Without 79.3% ± 2.2 With 87.5% ± 4.4 Thoracic surgery* 56 (15.4%) 0.036 NS Without 77.5% ± 2.4 Lung Cancer With 77.3% ± 8.9 22 (5.7%) 0.081 NS survivor Without 79.1% ± 2.2 With 64.0% ± 9.6 Other 25 (6.9%) 0.502 NS Without 80.1% ± 2.2 3 4
5 * Twenty five patients had pleural surgery, 23 resection and seven had other procedures. NS; 6 not significant. Additionally, some conditions had a prevalence too small to justify statistical 7 analysis; these were childhood pneumonia (n = 11), asbestos-related pleural disease (n = 9), 8 and prior sub-acute invasive aspergillosis (n = 9).
25 1 Table 3. Radiological feature on thoracic CT scan and their association with survival
2 (n=320).
Kaplan Meier Analysis / Log Rank test 2 year Comparison Unilateral Parameter n (%) survival ± Nil compared to of all 3 compared Std. Error unilateral/bilateral categories to bilateral 70 90.0% ± Nil (21.9%) 3.6 Pleural 70 75.7% ± Unilateral p = 0.003 p = 0.001 disease (21.9%) 5.1 p = 0.851 180 77.2% ± Bilateral (56.3%) 3.1 Nil (nodular 33 90.9% ± / pleural (10.3%) 5.0 Cavitary disease p = 0.001 p = 0.003 disease only) 156 83.3% ± Unilateral (48.8%) 3.0 p = 0.018 131 72.5% ± Bilateral (40.9%) 3.9 96 86.5% ± Nil (30.0%) 3.5 170 80.6% ± Aspergilloma Unilateral p = 0.001 p = 0.024 (53.1%) 3.0 p = 0.005 54 64.8% ± Bilateral (16.9%) 6.5 3
4
26 1 Figure legends
2 Figure 1. Censored survival curve of patients from the first time they are seen at the
3 National Aspergillosis Centre (NAC). N = 387. 1, 5 and 10 year survival 86%, 62%
4 and 47% respectively.
5
6 Figure 2. Survival for the 43 patients with a positive culture that was susceptibility
7 tested (P=0.143). 1,5 and 10 year survival for fully susceptible patients 75%, 68% and
8 68% respectively; and 87%, 46% and 46% for those with resistance or intermediate
9 susceptibility
10
11 Figure 3, Survival stratified by presence of one or more aspergillomas (n=340). p =
12 0.001. 1,5 and 10 year survival for those with no aspergilloma 88%, 71% and 66%
13 respectively; 88%, 63% and 49% for those with unilateral aspergilloma; and 79%,
14 49% and 18% for those with bilateral aspergillomas.
15
16 Figure 4. Severity of breathlessness and outcome as determined by the MRC dyspnea
17 score in a subset of patients (n = 78; p <0.001). 1 and 5 year survival for those with an
18 MRC score of 1 100% and 89% respectively; 96 and 79% for those with a score of 2;
19 91% and 47% for those with a score of 3 or 4; and 46% and 21% for those with a
20 score of 5.
21
22
27