Epidemiology of lower respiratory tract infections and community-acquired respiratory viruses in patients with bronchiolitis obliterans syndrome after hematopoietic cell transplant: a retrospective cohort study

Abstract

Background

Bronchiolitis obliterans syndrome (BOS)—chronic graft-versus-host disease (cGVHD) affecting the lungs—is an uncommon complication of allogeneic hematopoietic cell transplant (HCT). The epidemiology and complications of lower respiratory tract infections (LRTIs) and community-acquired respiratory viruses (CARVs) in these patients are poorly understood.

Objectives

We aim to characterize the epidemiology of LRTIs in patients with BOS complicating HCT. We also aim to explore the association of LRTIs and CARV detection on lung function in BOS patients.

Study design

Adult patients with BOS at Stanford Health Care between January 2010 and December 2019 were included in this retrospective cohort study. LRTI diagnosis was based on combined clinical, microbiologic, and radiographic criteria, using consensus criteria where available.

Results

Fifty-five patients with BOS were included. BOS was diagnosed at a median of 19.2 (IQR 12.5–24.7) months after HCT, and patients were followed for a median of 29.3 (IQR 9.9–53.2) months from BOS diagnosis. Twenty-two (40%) patients died after BOS diagnosis; 17 patients died from complications of cGVHD (including respiratory failure and infection) and 5 died from relapsed disease. Thirty-four (61.8%) patients developed at least one LRTI. Viral LRTIs were most common, occurring in 29 (52.7%) patients, primarily due to rhinovirus. Bacterial LRTIs—excluding Nocardia and non-tuberculous mycobacteria (NTM)—were the second most common, occurring in 21 (38.2%) patients, mostly due to Pseudomonas aeruginosa. Fungal LRTIs, NTM, and nocardiosis occurred in 14 (25.5%), 10 (18.2%), and 4 (7.3%) patients, respectively. Median time to development of the first LRTI after BOS diagnosis was 15.3 (4.7–44.7) months. Twenty-six (76.5%) of the 34 patients who developed LRTIs had infections due to more than one type of organism—fungi, viruses, Nocardia, NTM, and other bacteria—over the observation period. Patients with at least one LRTI had significantly lower forced expiratory volume in one second percent predicted (FEV1%) (37% vs. 53%, p = 0.0096) and diffusing capacity of carbon monoxide (DLCO) (45.5% predicted vs. 69% predicted, p = 0.0001). Patients with at least one LRTI trended toward lower overall survival (OS) (p = 0.0899) and higher non-relapse mortality (NRM) (p = 0.2707). Patients with a CARV detected or LRTI diagnosed after BOS—compared to those without any CARV detected or LRTI diagnosed—were more likely to have a sustained drop in FEV1% from baseline of at least 10% (21 [61.8%] versus 7 [33.3%]) and a sustained drop in FEV1% of at least 30% (12 [36.4%] versus 2 [9.5%]).

Conclusions

LRTIs are common in BOS and associated with lower FEV1%, lower DLCO, and a trend toward decreased OS and higher NRM. Patients with LRTIs or CARVs (even absent lower respiratory tract involvement) were more likely to have substantial declines in FEV1% over time than those without. The array of organisms—including P. aeruginosa, mold, Nocardia, NTM, and CARVs—seen in BOS reflects the unique pathophysiology of this form of cGVHD, involving both systemic immunodeficiency and structural lung disease. These patterns of LRTIs and their outcomes can be used to guide clinical decisions and inform future research.

Introduction

Background

Bronchiolitis obliterans syndrome (BOS), chronic graft-versus-host disease (cGVHD) of the lungs after allogeneic hematopoietic cell transplantation (HCT), is characterized by a persistent obstructive ventilatory defect, small airways disease, and bronchiectasis.[1] BOS affects between 3% and 9% of patients after allogeneic HCT.[2–5] Though the lung is less often affected by cGVHD than other organs, patients with moderate or severe lung involvement at time of cGVHD diagnosis have a higher risk of non-relapse mortality (NRM) than those with mild or no lung involvement.[6] In one study describing two cohorts, the all-cause 6-month mortality associated with BOS was 41.3%; those surviving at 6 months had a 2-year overall survival (OS) of 76% or 72% depending on the cohort.[7] This largest and most detailed study to date on BOS, which followed 82 patients from two BOS cohorts, found heterogeneous but overall declining forced expiratory volume in one second (FEV₁) similar to the trend in patients with emphysematous chronic obstructive pulmonary disease.[7] Notably, this study only followed spirometric measurements for a maximum of 18 months after BOS diagnosis.

While short-term spirometric outcomes and survival have been described in BOS cohorts, no detailed data are available on infectious outcomes and their consequences.[7] Specifically, the epidemiology of lower respiratory tract infections (LRTIs) and consequences of LRTIs and community-acquired respiratory virus (CARV) detection in terms of FEV₁ decline in BOS patients have not been described.

Patients with cGVHD may have an increased incidence of LRTIs—due to Nocardia, invasive aspergillosis, and other opportunistic infections—because of exogenous immunosuppression and immunodeficiency associated with cGVHD. However, unlike patients with extensive extrapulmonary cGVHD, patients with BOS also have structural lung disease including bronchiectasis. For this reason, they may experience more frequent and different LRTIs than other patients with extensive cGVHD, including infections due to nontuberculous mycobacteria (NTM), Staphylococcus aureus, Pseudomonas aeruginosa, non-lactose-fermenting Gram-negative bacilli, and other organisms seen in patients with cystic fibrosis (CF) and non-CF bronchiectasis. Apart from clinically apparent LRTIs, patients with cGVHD can experience infection due to CARVs, which can be asymptomatic. CARVs may be associated with decreased FEV₁ and increased NRM after HCT, but the effect of CARVs in patients with known BOS has not been well characterized.[8]

In this study, we describe the epidemiology and impact of LRTIs in patients with BOS complicating HCT. We also explore the association of LRTIs and CARV detection on lung function in BOS patients.

Methods

Study design, setting, and participants

In this retrospective cohort study, we reviewed the medical records of patients at least 18 years of age at time of HCT who were diagnosed with or treated for BOS between January 2010 and December 2019 at Stanford Health Care. Infections and other clinical outcomes, including data from other healthcare systems available in the electronic medical record, were followed until transition to hospice or death, or until we were unable to evaluate patients due to transfer of care to another healthcare system. Patients were no longer followed after October 2020. This study was approved by the institutional review board at Stanford University.

BOS was diagnosed based on National Institutes of Health criteria, as previously described.[1] Pulmonary function tests (PFTs), including FEV₁ and diffusion capacity of carbon monoxide (DLCO) testing, were performed before HCT and based on clinician discretion after HCT (typically every 1–3 months after BOS diagnosis).

Diagnostic testing and treatment for suspected LRTIs or CARV detection was at the discretion of the treating clinicians, but frequently included chest computed tomography (CT) scans, nasopharyngeal swabs for polymerase chain reaction (PCR) testing, sputum collection, obtaining blood for non-invasive biomarkers of infection, and bronchoscopy.

All patients with BOS were treated by the same group of pulmonologists (J.L.H, Y.K.L, and H.S.). Patients initially diagnosed with BOS were typically started on montelukast and a combined inhaled corticosteroid (typically fluticasone propionate at a total daily dose of 1,000 mcg) and inhaled long-acting beta₂ agonist. Azithromycin was initially prescribed as part of the fluticasone, azithromycin, and montelukast regimen to treat BOS.[9] However, azithromycin was subsequently discontinued in 2017 based on the results of the ALLOZITHRO trial suggesting possible increase in disease relapse associated with azithromycin therapy.[10] Prednisone was typically started at a dose of 0.5 to 1 mg/kg/day depending on comorbidities and disease severity and tapered based on PFTs and other clinical factors. Additional inhaled corticosteroids (typically budesonide), inhaled short-acting beta₂ agonists, and inhaled muscarinic antagonists were added as clinically indicated. Corticosteroid-sparing therapies included tacrolimus, sirolimus, mycophenolate mofetil, ibrutinib, ruxolitinib, and extracorporeal photopheresis. Pirfenidone was used also used in the context of a phase I clinical trial for BOS.[11] Belumosudil was not commercially available at the time of this study. Our approach to infection prophylaxis is described in Table 1.

Table 1:

Suggested approach to infection prophylaxis in patients with BOS

Intervention category	Intervention description	Indications	Notes
Fungal prophylaxis	First-line: Posaconazole delayed-release tablets Alternatives: Posaconazole oral suspension, voriconazole, isavuconazonium sulfate	Treatment with ≥ 0.5 mg/kg of prednisone/day (or equivalent) or ≥ 2 therapies for BOS (including extracorporeal photopheresis)	Posaconazole reduces risk of mold infections in this setting. [1] Other agents are less well studied or have disadvantages relative to posaconazole. [2] Posaconazole delayed-release tablets are better absorbed than oral suspension. Significant drug interactions exist.
Prophylaxis against PJP and pneumococcus	First-line: TMP-SMX Alternatives: Dapsone, atovaquone, or pentamidine inhalation (all combined with penicillin or amoxicillin)	On any systemic immunosuppression for BOS	TMP-SMX reduces risk of PJP and potentially pneumococcal disease. [2] Atovaquone, dapsone, and inhaled pentamidine have disadvantages including lack of activity against encapsulated organisms. If used instead of TMP-SMX, co-administer with penicillin or amoxicillin given functional asplenia in patients with BOS and other forms of chronic graft-versus-host-disease. [2]
Prophylaxis against HSV and VZV	Acyclovir, famciclovir, or valacyclovir	On any systemic immunosuppression for BOS	These agents reduce risk of HSV and VZV infections. [2]
Prophylaxis in setting of impaired humoral immunity	Consider intravenous immunoglobulin or subcutaneous immunoglobulin	Recurrent sinopulmonary infections with IgG < 400 mg/dL	Relatively little evidence supporting use. [2]
Preemptive monitoring for CMV	Consider periodic testing for CMV DNAemia	On any systemic immunosuppression for BOS	Approaches to monitoring and treating preemptively for CMV infection in this setting vary widely. [2]
Monitoring for respiratory infections	Sputum sent at least annually for routine and acid-fast stains and cultures in spontaneously expectorating patients	Bronchiectasis with ability to expectorate sputum	At least annual monitoring of sputum cultures in patients who spontaneously produce (expectorate) mucus is recommended in the setting of bronchiectasis to identify new infection with Pseudomonas aeruginosa (for which eradication therapy can be considered) or NTM. [3] Evaluation for NTM is particularly important before starting azithromycin to avoid development of macrolide resistance.
Airway clearance	Counsel patients on airway clearance techniques	Bronchiectasis with chronic productive cough or difficulty expectorating sputum	Airway clearance is an important aspect of bronchiectasis management. [3]
Other counseling	Other counseling on reducing risk of infections	All patients with BOS	Patients should be counseled about reducing risk of respiratory infections by avoiding crowds, avoiding sick contacts, and hand washing. Consider counseling patients to reduce exposure to mold (in buildings, dusty outdoor sites, and areas with plant and organic matter).
Immunizations	Provide seasonal influenza vaccine and other recommended vaccinations	All patients with BOS	Efficacy may be low in this population.

BOS = bronchiolitis obliterans syndrome; PJP = Pneumocystis jirovecii pneumonia; TMP-SMX = trimethoprim-sulfamethoxazole; HSV = herpes simplex virus; VZV = varicella zoster virus; IgG = immunoglobulin G; CMV = cytomegalovirus; NTM = non-tuberculous mycobacteria

^1.Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356(4): 335–47.

^2.National Comprehensive Cancer Network. Prevention and Treatment of Cancer-Related Infections Versions 2.2020. Available at: https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed 08/03/20.

^3.Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. The European respiratory journal 2017; 50(3).

Variables and data sources

Bacterial and viral LRTIs were defined by presence of combined radiographic, clinical, and microbiologic evidence of lower respiratory tract disease, adapted from National Healthcare Safety Network criteria.[12] Radiographic evidence required new or progressive infiltrates on plain film or CT of the chest. Clinical features of lower respiratory tract disease included systemic or pulmonary signs or symptoms such as fever, new onset purulent sputum, and hypoxemia, among others. Microbiologic evidence of infection included growth in blood cultures of organisms associated with pneumonia, detection by culture or molecular tests of organisms from lower respiratory tract specimens, and nasopharyngeal swabs with detection of select pathogens by culture or molecular methods, among others.

Probable or proven invasive fungal diseases (IFDs) and NTM LRTIs were defined based on consensus criteria.[13, 14] Consensus criteria were used to distinguish between recurrent versus persistent infection when an organism was recovered more than once, and to describe co-infections.[15] NTM infections were classified as new or recurrent if the patient met criteria for infection after culture conversion (based on at least three negative acid-fast bacillus [AFB] cultures). (See supplemental material for further details on definitions of LRTIs). LRTIs were scored and adjudicated by DE and EL.

CARVs were mostly detected by a respiratory pathogen multiplex PCR test including influenza A and B, respiratory syncytial virus (RSV), parainfluenza virus (PIV) 1–4, metapneumovirus, rhinovirus/enterovirus, adenovirus, and seasonal coronavirus. Occasionally, patients were tested on influenza-specific PCR platforms or multiplex tests including only influenza and RSV. CARVs were recorded from time of first PFT with BOS diagnosis.

PFTs were normalized as percent predicted FEV1 (FEV₁%) and DLCO (DLCO%) per accepted reference equations.[16] FEV₁% at the time of BOS diagnosis was used to define the patient’s baseline value.

Statistical methods

Statistical analyses were performed with SAS Studio version 3.8 (SAS Institute Inc., Cary, NC) and GraphPad Prism version 9.2 (GraphPad Software, San Diego, CA). Microsoft Excel 2019 (Microsoft Corporation, Redmond, WA) and InteractiVenn were also used to generate figures.[17]

Patient characteristics were reported as medians and interquartile ranges for continuous variables, and counts and percentages for categorical variables. To account for differences in patient follow-up times, LRTI density was also calculated as LRTIs per 100 patient-days of follow up.

Kaplan-Meier curves were used to estimate OS from date of BOS diagnosis; patients still alive by October 2020 were censored. (Survival outcomes were available for all patients in this cohort). Probability of NRM was estimated using a cumulative incidence curve, with disease relapse as a competing risk. Time to first infection after BOS diagnosis was estimated using a cumulative incidence function with death as a competing variable; patients were censored if they were transitioned to hospice or if infection outcomes were otherwise unavailable or by October 2020. (Time to infection was estimated for any infection, and separately for viruses, fungi, NTM, Nocardia, and other bacteria).

The Mann-Whitney U test was used to estimate differences in nadir FEV₁% and DLCO% between patients who did and did not have LRTIs. The Mann-Whitney U test was also used to estimate differences between patients who did and did not receive prophylaxis with mold active azoles according to nadir FEV₁%, nadir DLCO%, nadir absolute neutrophil count, and highest prednisone dose. Fisher’s exact test was used to compare immunosuppressive drug regimens between patients who received mold-active azoles and those who did not. All statistical hypothesis testing was exploratory in nature, intended to generate hypotheses for future research, and not corrected for multiple hypotheses testing.

Results

Participants, baseline characteristics, and clinical course

The study cohort consisted of 55 patients with established BOS; baseline demographic and clinical data are described in Table 2.

Table 2.

Baseline patient characteristics

Baseline patient characteristic	(n = 55)
Race, n (%)
White	41 (74.6)
Asian	6 (10.9)
Unknown	8 (14.6)
Hispanic/Latino, n (%)	7 (12.7)
Male, n (%)	28 (50.9)
Age at transplant (years), median (IQR)	54.5 (46.5–62.9)
Underlying disease, n (%)
Acute myeloid leukemia/myelodysplastic syndrome	25 (45.5)
Myeloproliferative neoplasm	13 (23.6)
Acute lymphoblastic leukemia/lymphoma	7 (12.7)
Non-Hodgkin lymphoma	5 (9.1)
Chronic lymphocytic leukemia/prolymphocytic leukemia	3 (5.5)
Cutaneous T cell lymphoma	2 (3.6)
Karnofsky performance status score, n (%)
≥ 90%	29 (52.7)
80–89%	19 (34.6)
< 80%	3 (5.5)
Unknown	4 (7.3)
Peripheral blood stem cell source, n (%)	52 (94.6)
Donor, n (%)
Matched related donor	31 (56.4)
Matched unrelated donor	15 (27.3)
Mismatched unrelated donor	7 (12.7)
Mismatched related donor	1 (1.8)
Haploidentical donor	1 (1.8)
Myeloablative conditioning, n (%)	28 (50.9)
Graft-versus-host disease prophylaxis, n (%)
Tacrolimus/methotrexate	26 (47.3)
Cyclosporine/mycophenolate mofetil	14 (25.5)
Other or unknown	15 (27.3)

BOS was diagnosed at a median of 19.2 (IQR 12.5–24.7) months after HCT, and patients were followed for a median of 29.3 (IQR 9.9–53.2) months from BOS diagnosis (Table 3). Sixteen (29.2%) patients had grades 2–4 acute GVHD (Table 3). Laboratory and spirometric values, intravenous immunoglobulin (IVIG) use, cGVHD therapies, and data on cytomegalovirus (CMV) viremia are described in Table 3.

Table 3.

Post-transplant patient characteristics

Post-transplant patient characteristic	(n = 55)
Duration of follow-up (months), median (IQR)	29.3 (9.9–53.2)
Onset of BOS diagnosis after transplant (months), median (IQR)	19.2 (12.5–24.7)
Acute graft-versus-host-disease, n (%)
None or grade 1	37 (67.3)
Grades 2–4	16 (29.1)
Unknown	2 (3.6)
Cytomegalovirus viremia leading to treatment, n (%)	14 (25.5)
Treatment with mycophenolate mofetil, n (%)	19 (34.6)
Treatment with ibrutinib, n (%)	12 (21.8)
Treatment with ruxolitinib, n (%)	12 (21.8)
Treatment with cyclosporine, n (%)	5 (9.1)
Treatment with tacrolimus, n (%)	25 (45.5)
Treatment with sirolimus, n (%)	16 (29.1)
Treatment with extracorporeal photopheresis, n (%)	16 (29.1)
Treatment with intravenous immunoglobulin, n (%)	36 (65.5)
Highest prednisone dose (milligrams), median (IQR)	60 (40–70)
Nadir IgG level (mg/dL), median (IQR)	379 (271.5–524.5)
Nadir absolute neutrophil count (cell/μL), median (IQR)	3,200 (1,484–5,060)
Nadir FEV1 (percent predicted), median (IQR)	42 (31–53)
Nadir DLCO (percent predicted), median (IQR)	49 (42–72)
Disease status, n (%)
Relapse before BOS diagnosis	5 (9.1)
Relapse after BOS diagnosis	3 (5.5)
No relapse	47 (85.5)
Death	22 (40%)

Abbreviations: BOS = bronchiolitis obliterans syndrome; IgG = immunoglobulin G; FEV₁ = forced expiratory volume in one second; DLCO = diffusing capacity for carbon monoxide

Twenty-two (40%) patients died after BOS diagnosis; 17 patients died from complications of cGVHD (including respiratory failure and infection) and 5 died from relapsed disease. Five patients relapsed prior to BOS diagnosis, and three patients relapsed after BOS diagnosis (Table 3, Figure S1). The probability of survival at 6 months after BOS diagnosis was 96.2%, declining to 70.3% at 2 years and to 52.8% by 5 years after BOS diagnosis (Figure S2). NRM at 6 months was 3.8%, increasing to 20.2% by 2 years and 33.0% by 5 years (Figure S3).

Epidemiology of LRTIs

Thirty-four (61.8%) patients developed at least one LRTI (Table 4, Figures 1, S4). Twenty-eight (50.9%) patients developed recurrent LRTIs (Figure S4). Viral LRTIs were the most common, occurring in 29 (52.7%) patients, and were primarily due to rhinovirus, followed by CMV, PIV, RSV, and influenza virus (Table 4). Of the 9 patients with a LRTI due to CMV, 7 had concomitant CMV viremia as well during each of their 11 episodes of CMV LRTI. Bacterial LRTIs—excluding Nocardia and NTM—were the second most common, occurring in 21 (38.2%) patients (Table 4). Pseudomonas aeruginosa was the most commonly isolated bacterial organism, followed by Stenotrophomonas maltophilia (Table 4). Fungal LRTIs, NTM, and nocardiosis occurred less often and are described in Table 4. Infection density reflected similar patterns (Table S1).

Table 4.

Number of infectious episodes and patients with at least one infection due to organism

Organism	Infections N	Infection linked to death within 2 weeks	Patients with at least one infection due to organism (n = 55)
Bacteria, n (%)			21 (38.2)
Pseudomonas aeruginosa	35	3	16
Stenotrophomonas maltophilia	9	2	4
Klebsiella pneumoniae	3		2
Corynebacterium striatum	3		2
Staphylococcus aureus1	3		2
Streptococcus mitis	1		1
Escherichia coli	1	1	1
Streptococcus pneumoniae	1		1
Serratia marcescens	1		1
Abiotrophia	1		1
Nontuberculous mycobacteria, n (%)			10 (18.2)
Mycobacterium avium complex	7		7
Mycobacterium abscessus complex	4		4
Mycobacterium fortuitum complex	1		1
Nocardia, n (%)			4 (7.3)
Nocardia nova	2	1	2
Nocardia transvalensis	1		1
Nocardia abscessus complex	1		1
Fungi, n (%)			14 (25.5)
Aspergillus fumigatus complex	10		7
Aspergillus2	6		5
Rhizopus	3		3
Aspergillus terreus	2		1
Aspergillus niger complex	2		2
Scedosporium apiospermum (Pseudallescheria boydii)	2	1	2
Aspergillus ustus	1		1
Scedosporium prolificans	1	1	1
Rhizomucor	1		1
Pneumocystis jirovecii	1	1	1
Virus, n (%)			29 (52.7)
Rhinovirus/Enterovirus	45	2	18
Cytomegalovirus	16		9
Parainfluenza virus	13		9
Respiratory syncytial virus	12		9
Influenza virus	9	2	8
Coronavirus, seasonal	8		4
Metapneumovirus	5		5
Adenovirus	1		1
Total/any organism type	212	9	34 (61.8)

¹All were susceptible to methicillin

²Not identified to species level, for example diagnosis made based on Aspergillus galactomannan or PCR testing

Figure 1.

Swimmer plots highlighting individual patient events including LRTIs, survival, and follow-up duration. Individual patients are represented on the y-axis, sorted by duration of follow-up. LRTIs due to bacteria, including NTM and Nocardia, are indicated with a red diamond. Viral LRTIs and fungal LRTIs are indicated with a blue square and yellow circle, respectively. Death or transition to comfort care or hospice—after which infectious outcomes are no longer available—is indicated with a black triangle. Abbreviations: LRTI = lower respiratory tract infection, NTM = non-tuberculous mycobacteria, BOS = bronchiolitis obliterans syndrome.

Twenty-six (76.5%) of the 34 patients who developed LRTIs had infections due to more than one type of organism—fungi, viruses, Nocardia, NTM, and other bacteria—over the observation period (Figure 2a). LRTIs often occurred together, with multiple categories of organisms—fungi, viruses, Nocardia, NTM, and other bacteria—isolated concurrently or within a short period (Figure 2b).

Figure 2.

Co-occurrence of different infectious etiologies of LRTIs. (a) Distribution of patients according to development of LRTI due to various microbial etiologies over the observation period, and (b) Distribution of infectious episodes by microbial etiology. Abbreviations: LRTI = lower respiratory tract infection, NTM = non-tuberculous mycobacteria.

Median time to development of the first LRTI after BOS diagnosis was 15.3 (95% confidence interval [CI] 4.7–44.7) months (Figure 3). Viral LRTIs generally occurred first, at a median time of 43.7 (95% CI 8.7–68.7) months from BOS diagnosis (Figure S5). Median time to development of the first bacterial (excluding Nocardia and NTM) LRTI was 70.7 (95% CI 27.7-not estimable) months (Figure S6). By three years after BOS diagnosis, the probability of developing a LRTI due to NTM, Nocardia, and fungi was 17.1%, 9.1%, and 25.7% respectively (Figures S7–S9).

Figure 3.

Time to development of first LRTI (after BOS diagnosis) due to any etiology. Abbreviations: LRTI = lower respiratory tract infection, BOS = bronchiolitis obliterans syndrome.

Outcomes related to development of LRTI

Patients with at least one LRTI had a significantly lower nadir FEV₁% than patients without any LRTIs (37% [IQR 30.0–46.0] versus 53% [IQR 34.5–61.0]; p = 0.0096) (Figure S10a). Nadir DLCO% was similarly lower in patients who had any LRTIs compared to those who did not: 45.5% (IQR 36.0–57.0) versus 69% (IQR 55.0–86.0) (p = 0.0001) (Figure S10b).

Patients with at least one LRTI had decreased OS; however, this was not statistically significant (p = 0.0899) (Figure 4a). Two-year OS was 82.5% for those with no LRTIs and 64.3% for those with at least one LRTI. Median OS of the 34 patients with at least one LRTI was 33.3 (95% CI 25.0-not estimable) months. Similarly, patients with at least one LRTI had increased NRM, though the difference was not statistically significant (p = 0.2707) (Figure 4b). Two-year NRM was 12.2% for those with no LRTs and 23.9% for patients with at least one LRTI.

Figure 4.

Survival outcomes (after BOS diagnosis) according to development of any LRTI, including (a) OS and (b) NRM. Abbreviations: BOS = bronchiolitis obliterans syndrome, LRTI = lower respiratory tract infections, OS = overall survival, NRM = non-relapse mortality.

Antimicrobial prophylaxis

Only one patient in this cohort never received prophylaxis against PJP—either trimethoprim/sulfamethoxazole (TMP-SMX), atovaquone, dapsone, or inhaled pentamidine—during the observation period.

Forty-four (80%) patients received a mold-active azole at some point during the observation period; these drugs were started for primary prophylaxis, secondary prophylaxis, targeted or empiric treatment, or some other indication or combination of indications. Differences in patients who did and did not receive azole antifungals are described in Table S2.

The one patient who developed PJP was not receiving Pneumocystis-active prophylaxis at the time of the infection. The one case of pneumococcal pneumonia in this cohort occurred in a patient on PJP prophylaxis with dapsone. Two patients who developed Nocardia infection were on atovaquone at the time of diagnosis; the other two were receiving TMP-SMX. Of 21 Aspergillus LRTIs, 20 (95%) occurred in patients receiving a mold-active agent at the time of disease onset: 10 were receiving posaconazole, 6 voriconazole, and 4 isavuconazonium sulfate.

Association between CARV detection and LRTI diagnosis and FEV₁%

All except one patient had at least two PFTs performed from the onset of BOS. The duration of spirometric follow-up varied, though 12 patients had spirometric data recorded for at least 4 years after BOS diagnosis with a maximum spirometric follow-up of 8.9 years after BOS diagnosis. Patients with a CARV detected or LRTI diagnosed after BOS—compared to those without any CARV detected or LRTI diagnosed—were more likely to have a sustained drop in FEV₁% from baseline of at least 10% (21 [61.8%] versus 7 [33.3%]) and a sustained drop in FEV₁% of at least 30% (12 [36.4%] versus 2 [9.5%]). (Figures S11–S12).

Discussion

In this study, we describe the epidemiology and impact of LRTIs and CARV detection in a cohort of patients with BOS complicating HCT. Overall, LRTIs were common with 61.8% of patients having had at least one LRTI, confirmed by microbiologic, clinical, and radiographic criteria. Infections were often recurrent: of patients who developed LRTIs, 82.4% developed recurrent LRTIs. While 7 patients only had viral LRTIs and 1 patient only a NTM LRTI during the observation period, most patients with LRTIs had infections associated with multiple types of pathogens—viruses, fungi, NTM, Nocardia, and other bacteria. In fact, patients often had LRTIs with multiple types of organisms simultaneously.

The array of respiratory pathogens affecting BOS patients in this cohort include those well-described in patients with extrapulmonary cGVHD, including CARVs, Aspergillus, and CMV.[18, 19] However, others, such as pulmonary NTM, are not commonly described infections after HCT.[20] In fact, the preponderance of LRTIs caused by P. aeruginosa and pulmonary NTM more closely resembles the pattern of infections in patients with CF and non-CF bronchiectasis.[21] The confluence of systemic immunodeficiency associated with extensive cGVHD and its treatments and structural lung disease associated with bronchiectasis likely explains this unique pattern of LRTIs seen in patients with BOS.

Very few patients in our cohort died within the first 6 months of BOS diagnosis relative to the higher early mortality described in cohorts by Cheng and others; we cannot directly compare two-year OS since Cheng and colleagues described two-year OS conditional on surviving to 6 months after BOS diagnosis.[7] Our study adds longer-term survival data and spirometric outcomes up to nearly 9 years after BOS diagnosis. Moreover, unlike the study by Cheng and others, we provide information on association of FEV₁ trends with infections.[7] While Sheshadri and colleagues found that patients with cGVHD were more likely to experience pulmonary impairment after a CARV infection, they did not specifically evaluate patients with BOS.[8] Patients with BOS who had LRTIs or CARVs detected (even without overt clinical or radiographic evidence of lower respiratory tract involvement) were more likely to have substantial declines in FEV₁% over time than those without, though significant variability existed among patients. Patients with LRTIs also had significantly lower nadir FEV₁% and DLCO% and a trend toward decreased OS and increased NRM.

Our study is limited in part by inherent difficulties in diagnosis of LRTIs. We likely missed LRTIs for which microbiologic evidence was not available, as patients are often treated for LRTIs empirically with no specific microbial etiology identified. While we may have captured more LRTIs with less stringent diagnostic criteria, this approach would have reduced specificity and may have led to inclusion of non-infectious processes. On the other hand, even with our relatively rigorous diagnostic criteria, we may have included non-infectious episodes. For example, aspiration pneumonitis or organizing pneumonia would be adjudicated as a LRTI by our criteria if bacteria or mold were identified, though whether there is a causal relationship in these cases is generally unknowable. In other cases, patients may have a LRTI caused by one organism, however attributed to multiple organisms based on our diagnostic criteria. For example, a patient with lung nodules with both Aspergillus and Nocardia cultured from sputum would have been diagnosed with two LRTIs, though only one of these organisms may have been responsible for the patient’s clinical and radiographic findings. Nonetheless, our approach reflects the best balance between sensitivity and specificity that could be reasonably obtained.

In addition, while our approach was exploratory in nature, we found statistically significant relationships between development of LRTIs and impairment in pulmonary function. Our relatively small sample size—expected for a relatively rare disease—precluded formal hypothesis testing. This single-center design also limits generalizability of our findings, but as an academic tertiary care center, our geographic catchment area is wide and we often co-manage patients with providers across California and surrounding states. Moreover our patients’ baseline characteristics were similar to nationally reported trends.[22] The retrospective nature of this study necessarily resulted in heterogeneity in diagnosis and monitoring, for example in PFT intervals. Finally, due to the sometimes-daily adjustment of immunosuppressive drugs and doses, and fluctuations of laboratory values and PFTs over time, describing and analyzing relationships between these constantly changing variables was difficult. Therefore, accurately discerning effects of neutropenia, hypogammaglobulinemia (and immunoglobulin replacement with IVIG), CMV viremia, and treatment with various immunosuppressive drugs on infectious, spirometric, and other patient outcomes was not possible. Future prospective studies, especially interventional studies randomizing patients to particular therapies, are needed to understand these relationships and guide clinical decisions on use of IVIG and choosing immunosuppressive drugs for patients at risk of infections.

Understanding these patterns of LRTIs and CARV detection can help clinicians decide on monitoring, prophylaxis, treatment, and patient counseling. For example, the high incidence of pulmonary NTM in patients with BOS (relative to other patients with cGVHD) argues for regular screening of spontaneously expectorating patients with AFB cultures, as is recommended in the setting of CF and non-CF bronchiectasis.[23, 24] This screening is particularly important when azithromycin is used to treat BOS, as azithromycin monotherapy risks macrolide-resistance in patients with unrecognized NTM infections.[9, 25] The frequency of recurrent infections, particularly with P. aeruginosa, has also led us to prescribe inhaled tobramycin to prevent bronchiectasis exacerbations.[24] The high incidence of invasive fungal LRTIs warrants close monitoring and a low threshold to obtain CT scans in patients with possible infections. That PJP and pneumococcal pneumonia occurred in patients not on effective prophylaxis at the time of these infections reinforces the risk of these preventable infections. Our approach to infection prevention in BOS patients is described in Table 1. In the longer term, more data are needed, particularly from clinical trials, on these and other interventions, for example whether attempts at eradication of P. aeruginosa upon initial isolation from culture improves patient outcomes.

In conclusion, we present the first study to our knowledge describing LRTIs in patients with BOS complicating HCT and their outcomes. We demonstrate that LRTIs are common and often recurrent. The array of organisms—including P. aeruginosa, mold, Nocardia, NTM, and CARVs—seen in BOS reflects the unique pathophysiology of this form of cGVHD, involving both systemic immunodeficiency and structural lung disease. Patients with BOS who had LRTIs had lower nadir FEV₁% and DLCO% with trends toward decreased OS and increased NRM, and patients with LRTIs or detection of CARVs were more likely to have sustained FEV₁% declines over time. These patterns of LRTIs and their outcomes can be used to guide clinical decisions and inform future research.

Highlights:

• Fifty-five patients with bronchiolitis obliterans syndrome (BOS) were followed for infectious complications and changes in lung function.

• More than half of BOS patients developed at least one lower respiratory tract infection (LRTI); infections were often recurrent.

• Viral LRTIs predominated, followed by bacterial LRTIs (especially due to Pseudomonas aeruginosa). Non-tuberculous mycobacteria (NTM) were unexpectedly common.

• BOS patients with LRTIs had inferior lung function compared to those without and trended toward decreased overall survival.

• Patients with BOS should be monitored closely for LRTIs including those due to NTM.