Brown, JS

Hall, J

José, RJ

English

UCL Discovery

De novo bronchiectasis in haematologicalmalignancies: patient characteristics, riskfactors and survivalTo the Editor:Patients with haematological malignancies often develop secondary immunodeficiency and respiratoryinfections that could predispose towards bronchiectasis, and this is supported by case reports and aprevious small case series of 22 patients [1–4]. To improve understanding of this association we performeda retrospective review of patients with clinically significant bronchiectasis (defined as radiological evidenceof bronchiectasis plus chronic productive cough or recurrent respiratory tract infections requiringantibiotic therapy) and haematological malignancy attending our respiratory clinic at a UK teachinghospital between January 2014 and April 2018. Patients were investigated according to the British ThoracicSociety guideline [5]. Bronchiectasis onset was defined as the computed tomography (CT) scan dateshowing bronchiectasis closest to when the clinical diagnosis was confirmed. 18.7% of patients werefollowed up for 1 year, 54.7% for 5 years, 20% for 10 years and 6.7% for >10 years. Data were extractedfrom electronic patient records under National Health Service research ethics committee approval 18/SC/0592 and analysed using SPSS version 22 (IBM, Chicago, IL, USA). For comparison between categoricalvariables, the Chi-squared or Fisher’s exact tests were used as appropriate. Due to the nonparametricnature of the data, the Mann–Whitney test was used for the comparison of two continuous variables.Univariate analysis was used to identify factors associated with the number of lobes affected, IgGdeficiency and mortality, and significant variables were entered alongside clinically relevant variables into aforward stepwise binary logistic regression model.A total of 75 patients (median (interquartile range (IQR)) age 59 (27) years, 65.3% male) withhaematological malignancy and clinically significant bronchiectasis were identified. None of these patientshad CT scan evidence of bronchiectasis at the time of haematological malignancy diagnosis. The mostprevalent haematological malignancies were non-Hodgkin’s lymphoma (NHL) (29.3%), chroniclymphocytic leukaemia (CLL) (22.7%), acute myeloid leukaemia (AML) (16%) and Hodgkin’s lymphoma(HL) (13.3%). Of the probable causes of bronchiectasis, 45 patients (60%) had had haematopoetic stemcell transplantation (HSCT), of which 37 (82.2%) were allografts. 37 patients (50.7%) were IgG deficient(IgG <7 g·L−1, median (IQR) IgG for all patients 6.5 (6.5) g·L−1), and 20 patients (26.7%) had bothprevious HSCT and IgG deficiency (figure 1a). For the remaining 13 patients, the bronchiectasis wassuspected to be related to CLL (n=5), intrapulmonary lymphoma (n=2) or post-radiotherapy (n=1), andunknown in five. All patients with AML, acute lymphocytic leukaemia (ALL), or multiple myeloma (MM)had had HSCT, compared to 60% of HL, 55.5% of NHL and 16.7% for CLL patients. 21 out of 45 (46.6%)HSCT patients were diagnosed with pulmonary graft versus host disease (pGVHD) and these patientswere younger than those without pGVHD (age 57 (19) versus 66 (23) years), p=0.015). The median (IQR)time to development of bronchiectasis was 5 (7) years from diagnosis of haematological malignancy anddeveloped faster in patients post-HSCT (3 (20) years, 14 (31.1%) within 1 year) or treated with rituximab(4 (12) years, 14 (40%) within 1 year) compared to all patients (5 (7) years, 10 (13.3%) within 1 year).Most patients had cylindrical bronchiectasis (73 out of 75, 97.3%), with one having cystic bronchiectasisand another one varicose bronchiectasis. 40 patients (53.3%) had bronchiectasis affecting three or more@ERSpublicationsBronchiectasis occurs de novo in haematological malignancy and is associated with significantmortality and morbidity. Rituximab predisposes to IgG deficiency and survival time issignificantly associated with age, FEV1 % and stem cell transplantation. http://bit.ly/2KZwCZtCite this article as: José RJ, Hall J, Brown JS. De novo bronchiectasis in haematologicalmalignancies: patient characteristics, risk factors and survival. ERJ Open Res 2019; 5: 00166-2019[https://doi.org/10.1183/23120541.00166-2019].Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.https://doi.org/10.1183/23120541.00166-2019 ERJ Open Res 2019; 5: 00166-2019ORIGINAL RESEARCH LETTERlobes, and this was associated with HSCT (OR 4.00 (95% CI 1.50–10.66), p=0.006) and pGVHD (OR 5.73(95% CI 1.70–19.31), p=0.005). In a binary logistic regression model including age, haematologicalmalignancy, HSCT and pGVHD, only pGVHD maintained an association with three or more lobesaffected (OR 6.7 (95% CI 1.2–36.6), p=0.028).1.0HSCTNoYesg)0.80.60.40.20Cumulative hazardSurvival time days0 500 100015002000 250030001.0h)0.80.60.40.20Cumulative hazardSurvival time days0 500 100015002000 25003000Number of lobes<3≥31.0d)0.80.60.40.20Cumulative survivalSurvival time days0 1000 2000 3000 4000 50001.0e)0.80.60.40.20Cumulative hazardSurvival time days0 500 100015002000 25003000Age≤40 years41–65 years≥66 years1.0f)0.80.60.40.20Cumulative hazardSurvival time days0 500 100015002000 25003000FEV1 % pred≤40.040.1–80.0≥80.1a)1713OtherpGVHDn=21HSCTn=4510141110IgG deficiencyn=3725b)20151050Patients≤3 yearsALL AML CLL HL MM OtherNHLp=0.031>3 years25c)20151050PatientsIgG <7 g·L–1ALL AML CLL HL MM OtherNHLp=0.007IgG ≥7 g·L–1FIGURE 1 a) Potential aetiology of bronchiectasis in individuals with haematolgoical malignancy. b) Proportion of patients with onset of clinicallysignificant bronchiectasis within 3 years of haematological diagnosis according to haematological diagnosis (n=75). c) Proportion of patients withIgG deficiency according to haematological diagnosis (n=73). d) Kaplan–Meier survival analysis of patients with haematological malignancy fromthe time of bronchiectasis diagnosis (mean survival time of 3329 days (95% CI 2771–3888 days). Unadjusted hazard ratios (HRs) for e) age (age⩽40 years: HR 0.104 (95% CI 0.02–0.84), p=0.034; age 41–60 years: HR 0.90 (95% CI 0.35–2.24), p=0.804) and f) forced expiratory volume in 1 s(FEV1) (FEV1 <40% pred: HR 4.27 (95% CI 1.29–14.09), p=0.017; FEV1 41–80% pred: HR 2.12 (95% CI 0.71–6.34), p=0.180). Age-adjusted HRs for g)haematological diagnosis for haematopoietic stem cell transplant (HSCT) (HR 3.94 (95% CI 1.03–15.14), p=0.046) and h) number of lobes affected(HR 2.70 (95% CI 1.00–7.34), p=0.051). pGVHD: pulmonary graft versus host disease; ALL: acute lymphocytic leukaemia; AML: acute myeloidleukaemia; CLL: chronic lymphocytic leukaemia; HL: Hodgkin’s lymphoma; MM: multiple myeloma; NHL: non-Hodgkin’s lymphoma.https://doi.org/10.1183/23120541.00166-2019 2ORIGINAL RESEARCH LETTER | R.J. JOSÉ ET AL.12 (16%) patients were colonised with bacterial pathogens, including seven (9.3%) with Pseudomonasaeruginosa. Eight colonised patients had IgG deficiency (21.6%) versus three with normal IgG levels (8.3%)(p=0.113) and the odds ratio for bacterial colonisation in those with IgG deficiency was 4.28 (95% CI0.89–20.49) (p=0.069) after adjusting for rituximab treatment. 17 patients (22.7%) had a past medicalhistory of COPD or asthma. Smoking history was available for 73 patients (92.3%), with 62% neversmokers, 33% ex-smokers and 5% current smokers. Lung function values were available for 65 patients;mean±SD forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were similar to thatobtained by replacing missing values by multiple imputation (74.9±24.8% versus 75.4±24.9% pred and86.7±20.8% versus 87.7±21.6% pred, respectively). Airflow limitation (FEV1 <80% pred) was present in55% of patients, with patients with pGVHD having lower mean±SEM FEV1 and FVC (61.3±6.6% versus80.9±3.7% pred, p=0.003; and 77.8±5.3% versus 91.7±3.5% pred, p=0.018) and patients with bacterialcolonisation having lower mean±SEM FEV1 (56.4±8.3% versus 79.1±3.8% pred, p=0.012).IgG deficiency was associated with the type of haematological malignancy (p=0.007) and rituximabtreatment; AML and HL patients were less likely (5.7% versus 26.3% and 2.9% versus 22.5% respectively,p<0.05) (figure 1c) and patients treated with rituximab were more likely (70.3% versus 29.7%, p<0.001; OR6.15 (95% CI 2.23–16.95), p<0.001) to have IgG deficiency. 36 (48%) patients had rituximab treatment,including all patients with CLL, 72.7% with NHL, 30% with HL and 10% with MM.The mortality in the cohort was high at 26.7% (20 out of 75) with 1-, 5- and 10-year survival followingdiagnosis of bronchiectasis of 82%, 65% and 59% (figure 1d). Nonsurvivors had a median (IQR) survivalof 324 (951) days, with the majority of patients post-HSCT dying within 2 years of the bronchiectasisdiagnosis (76.9% versus 42.9% of the non-HSCT patients, p=0.0001). In a binary logistic regression modelincluding age, haematological diagnosis, HSCT, pGVHD, IgG deficiency, FEV1 % pred and number oflobes affected, only age (OR 1.14 (95% CI 1.03–1.27), p=0.016) and FEV1 (OR 0.91 (95% CI 0.84–0.99,p=0.033) were associated with overall mortality. Univariate analysis demonstrated that survival wasimproved in patients ⩽40 years old and reduced in patients with FEV1 <40% pred (figure 1e and f) [6]. Ina Cox regression model including age, haematological malignancy, HSCT, pGVHD, bacterial colonisation,FEV1 % pred and number of lobes, only age (hazard ratio (HR) 1.07 (95% CI 1.03–1.12), p=0.001), FEV1% pred (HR 0.96 (95% CI 0.94–0.98), p<0.001) and number of lobes affected (HR 3.53 (95% CI1.27–9.81), p=0.016) were significantly associated with survival duration (figure 1g and h).This is the largest reported study of patients with bronchiectasis and haematological malignancy, andalthough retrospective, the data provide insight into the development of bronchiectasis in these patients.Our cohort had a male predominance, whereas non-CF bronchiectasis usually has a female predominance[7], probably reflecting that myeloid and lymphoid malignancies are more common in males [8].Bronchiectasis in this cohort seemed to develop due to different mechanisms, either acquired IgGdeficiency (mainly in patients with CLL or NHL) or allograft HSCT (47% of whom had pGVHDcompared to <10% in all allograft HSCT patients) [9], but with some rarer causes. There was a strongassociation of rituximab treatment with IgG deficiency, and we suggest that there should be a high indexof suspicion for bronchiectasis in patients with CLL and NHL who have received rituximab. Haematologypatients frequently have multiple CT scans, allowing the timing of bronchiectasis development to beidentified, and this showed the disease can develop surprisingly rapidly, frequently within a year inpatients with IgG deficiency or after HSCT. Overall mortality was high, largely related to the highproportion of HSCT patients who died within 2 years of the diagnosis of bronchiectasis. Whetherbronchiectasis increased mortality and was a cause of death in these patients or is just a marker for thosewith a poorer prognosis is not clear. Overall, our data suggest that patients with haematologicalmalignancy can rapidly develop bronchiectasis, especially those receiving rituximab or allograft HSCT, andthis disease may make a significant contribution to their morbidity and perhaps mortality.Ricardo J. José1,2, Jocelin Hall1,2 and Jeremy S. Brown1,21Centre for Inflammation and Tissue Repair, UCL Respiratory, London, UK. 2Dept of RespiratoryMedicine, University College London Hospital, London, UK.Correspondence: Ricardo J. José, Centre for Inflammation and Tissue Repair, UCL Respiratory, 5University Street, London, WC1E6JF, UK. E-mail: r.jose@ucl.ac.ukReceived: 01 July 2019 | Accepted: 19 Aug 2019Conflict of interest: None declared.https://doi.org/10.1183/23120541.00166-2019 3ORIGINAL RESEARCH LETTER | R.J. JOSÉ ET AL.References1 Morehead RS. Bronchiectasis in bone marrow transplantation. Thorax 1997; 52: 392–393.2 Sargent MA, Cairns RA, Murdoch MJ, et al. Obstructive lung disease in children after allogeneic bone marrowtransplantation: evaluation with high-resolution CT. AJR Am J Roentgenol 1995; 164: 693–696.3 Graham NJ, Müller NL, Miller RR, et al. Intrathoracic complications following allogeneic bone marrowtransplantation: CT findings. Radiology 1991; 181: 153–156.4 Chen LW, McShane PJ, Karkowsky W, et al. De novo development of bronchiectasis in patients with hematologicmalignancy. Chest 2017; 152: 683–685.5 Pasteur MC, Bilton D, Hill AT. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 2010; 65:Suppl. 1, i1–58.6 Williams KM. How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Blood2017; 129: 448–455.7 Finch S, Polverino E, Blasi F, et al. Sex differences in bronchiectasis patient characteristics: an analysis of theEMBARC cohort. Epidemiology 2018; 52: PA2282.8 Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from theHaematological Malignancy Research Network. Br J Cancer 2011; 105: 1684–1692.9 Jose RJ, Faiz SA, Dickey BF, et al. Non-infectious respiratory disease in non-HIV immunocompromised patients. BrJ Hosp Med (Lond) 2014; 75: 691–697.https://doi.org/10.1183/23120541.00166-2019 4ORIGINAL RESEARCH LETTER | R.J. JOSÉ ET AL.

De novo bronchiectasis in haematological malignancies: patient characteristics, risk factors and survival

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De novo bronchiectasis in haematological malignancies: patient characteristics, risk factors and survival

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