Graft Versus Host Disease: Management Issues in the Intensive Care Unit

Abstract

Graft versus host disease (GVHD) in acute and chronic forms is a frequent post-transplant complication and seen in 50% of patients in acute and up to 70% cases in chronic GVHD setting. Patients with multiorgan involvement and those who are steroid refractory, frequently present with complications arising from this post-transplant complication. These GVHD patients are frequently managed in the Intensive care unit for treatment of air leaks, effusions, management of hypoxemia due to lung GVHD or infections. Close coordination between hematologists and Pulmonary medicine specialists is critical for timely management of these complications to improve patient outcomes.

Keywords

chronic GVHD intensive care unit BOS

Introduction

Allogenic hematopoietic cell transplantation (allo-HCT) is an established form of immunotherapy and is a curative treatment modality for both malignant (ie acute leukemia, aggressive lymphoma) and nonmalignant hematologic disorders (ie bone marrow failure syndromes, metabolic disorders, immunodeficiency syndromes and hemoglobinopathies).¹ In the United States, approximately 8000 allo-HCTs are done annually, and acute myeloid leukemia (AML) is the leading indication for HCT based on the most recent data from the Center for International Blood and Marrow Transplant Registry (CIBMTR; Figure 1). In patients undergoing HCT, the main causes of treatment failure beyond Day +100 are relapse of primary malignancy or non-relapse mortality (NRM) due to opportunistic infections or graft-versus-host disease (GVHD). Patients with lung GVHD and infectious complications resulting in sepsis frequently need ICU care and given underlying comorbid conditions and immunocompromised status, the mortality in this high-risk group remains high.² GVHD is a multisystem alloimmune-mediated disorder seen in the post-HCT setting in more than 50% of patients undergoing HCT. This post-HCT complication was previously defined temporally with acute GVHD (aGVHD) developing within the first 100 days, and chronic GVHD (cGVHD) defined as occurring after Day +100 post-HCT. With a better understanding of disease biology, this temporal definition has given way to a newer classification based on presenting clinical symptoms.³ In aGVHD, patients present with skin (manifested as maculopapular erythematous skin rash), gastrointestinal (with symptoms of nausea, vomiting or diarrhea) or hepatic (elevated bilirubin or transaminitis) involvement, with most patients having multiorgan involvement. Risk factors for developing aGVHD include use of peripheral blood stem cell (PBSC) grafts, HLA disparity, utilization of unrelated donors, myeloablative conditioning regimens, older age of donor or recipient and female donor to male recipient.³ Chronic GVHD manifests as a multisystem alloimmune disorder with an inflammatory component (oral ulcerations, scleritis, skin rash) or with fibrotic manifestations in the skin (scleroderma), lungs (bronchiolitis obliterans syndrome), or joints (decreased range of movement). Patients oftentimes also present with chronic dry mouth, dry eyes (sicca syndrome), nail dystrophy, dysphagia (due to esophageal stricture), weight loss and failure to thrive due to malabsorption resulting from exocrine pancreatic insufficiency.³ Patients with cGVHD frequently have multiple organ involvement. Occasionally, patients may have manifestations of both acute and chronic GVHD and are classified as having overlap syndrome.⁴ Based on data from the CIBMTR, the incidence of aGVHD is approximately 40–60% with current GVHD prophylaxis regimens comprising of a calcineurin inhibitor (cyclosporine or tacrolimus) and methotrexate.⁵ Chronic GVHD is the leading cause of non-relapse mortality (NRM) in patients who are long-term survivors after allo-HCT and is seen in up to 50–70% of transplant survivors.^6,7 Recent data suggests that the clinical outcomes (overall survival, NRM and relapse rates) of patients transplanted in a more recent era (2013-2017) are improved compared to an earlier era (2003-2007) due to improvements in donor selection, GVHD prophylaxis/treatments, and advancements in supportive care practices.⁸ The prevalence of cGVHD in United States is estimated to be approximately 14,000 cases, of which 40% patients have severe cGVHD and ≥ 4 organ involvement at the time of diagnosis.^9,10 The common risk factors associated with the development of cGVHD include the use of unrelated donor transplants, increasing recipient age, HLA disparity, female donor to male recipient, use of myeloablative conditioning and the use of PBSC as the graft source.¹¹ With improvements in supportive care practices and decline in incidence of relapse and NRM, the population at risk for developing cGVHD is now higher as more patients are long term survivors post HCT.¹² Additionally, older patients are now being considered eligible for allo-HCT due to the adoption of reduced-intensity conditioning regimens (RIC), this trend will result in more cases of cGVHD as older age is considered a risk factor for cGVHD.¹³ A recent CIBMTR analysis of 26,563 allo-HCT recipients over three time periods showed that in the most recent era from 2004–2007, the incidence of cGVHD at the 1-year mark was higher compared to earlier years.¹⁴ These trends suggest that there will be a continued increase in the number of patients who are long-term survivors of allo-HCT and require management of late complications including cGVHD. Not only does cGVHD contribute to an increase in mortality, but these patients also have a poor quality of life, psychosocial issues and increased resource utilization resulting in increased healthcare costs.^15,16 As the prevalence of long-term survivors post-HCT increases, it is anticipated that more patients with advanced cGVHD will require ICU management mainly for management of respiratory failure or sepsis.¹⁷

Figure 1.

Data from CIBMTR showing indications (left) and trends in utilization of allo-HCT over time.

The pathophysiology of cGVHD can be described as a multisystem fibro-inflammatory disorder, which involves epithelial tissues and the lymphohematopoietic system.¹⁸ Previously, cGVHD was classified as limited or extensive based on the severity and number of organs involved.¹⁹ The development of NIH consensus criteria in 2005 (updated in 2014) has streamlined the classification of cGVHD using a grading system to assess patient symptom presentation and a response criterion to evaluate progress on long-term follow-up.^20,21 In the NIH grading system, eight organs (skin, eyes, gastrointestinal tract, mouth, genital tract, lungs, liver, joints fascia) are scored for severity of GVHD manifestations based on the classification of mild to moderate or severe cGVHD symptoms, which is predictive of overall survival.²² The NIH classification allows comparison of patient outcomes across multiple centers and guides management and response assessment of patients on treatment.³ Most patients with cGVHD can be managed as outpatient with a combination of corticosteroids and novel second-line agents, but certain manifestations of GVHD require patients to be cared for in a more acute setting with escalation of care to the intensive care unit (ICU). Such conditions include: i) respiratory failure arising from severe lung GVHD requiring noninvasive or invasive ventilation ii) severe GI aGVHD causing hypotension due to GI bleed or electrolyte abnormalities and dehydration from fluid losses iii) atypical pulmonary infections (viral, bacterial or fungal) caused by prolonged exposure to immunosuppressive therapy causing respiratory distress and requiring diagnostic procedures as bronchoscopy and microbiologic evaluation of lavage fluid iv) air leak arising from severe BOS requiring placement of chest tubes and oxygen therapy.¹⁷ In this review, we will cover ICU management of common complications arising from GVHD post allo-HCT focusing mainly on the pulmonary system.

Pathophysiology of GVHD

Our understanding regarding the biology of acute and chronic GVHD is derived mainly from mismatched mouse transplantation models that provides insights into the development and evaluation of GVHD and provides a model for testing new therapeutic agents before clinical use.¹⁸ These murine models show that the development of GVHD in recipient mice can be divided into three distinct phases. The early phase involves the activation of donor CD4 T-cells upon contact with antigen presenting cells (APCs: dendritic cells, monocytes, macrophages, and B cells). The donor T-cell activation by host antigens presented by APCs is initiated by tissue damage by conditioning regimen that releases damage associated molecular patterns (DAMPS: ATP, uric acid, IL-33) and pathogen associated molecular patterns (PAMPs: bacteria, viruses, fungi).²³ Epithelial damage from the conditioning regimen releases soluble inflammatory mediators (ATP, uric acid, interleukin-33, and Lipopolysaccharide) that activates APC to present host antigens to donor T-cells.²⁴ Endothelial damage due to intimal arteritis leads to reduced microvascular density, which predisposes to subsequent fibrotic manifestations of cGVHD. In the second (inflammatory) phase of cGVHD, alloreactive B- and T-cells primed by APCs proliferate and expand towards Type-1 (Th-1), Type-2 (Th-2), and Type-17 (Th-17) helper T-cells.^25,26 The inflammatory milieu is maintained by secretions of proinflammatory cytokines by CD4 positive T-cells which have previously escaped immune regulation. In the lymphoid follicles, these T-helper cells produce interleukin-21 leading to formation of germinal centers and expansion of B-cell clones.²⁷ Damage to the thymic epithelium from conditioning regimen and the reactive T-cells results in loss of regulatory T/B cells causing loss of peripheral tolerance.²⁸ In the final phase of GVHD, there is activation of fibroblasts by platelet-derived growth factor alpha and transforming growth factor beta secreted by macrophages resulting in production of collagen in the extracellular matrix resulting in sclerosis.²⁹ Unregulated immunoglobulin production by B-cells driven by B-cell activating factor results and pathogenic immunoglobulin deposition in organs contribute to organ damage and fibrosis.

Prevention of GVHD:

All patients undergoing HCT require GVHD prophylaxis prior to infusion of stem cell graft to prevent GVHD. The combination of calcineurin inhibitors (CNI) and methotrexate (MTX) 45 mg/m² is the current standard in patients undergoing allo-HCT in both reduced-intensity (RIC) or myeloablative (MAC) conditioning.³⁰ The incidence of aGVHD and cGVHD remains high with this prophylactic regimen (∼40-60%), and MTX use is associated with an increased incidence of mucositis (occasionally requiring intubation for airway protection) and delayed neutrophil engraftment. Hence, attempts have been made to add novel agents such as mycophenolate mofetil (MMF) or sirolimus in combination with CNI to improve clinical outcomes.^31,32 At our center, tacrolimus and sirolimus-based prophylaxis (T/S) is standard in both the RIC and MAC setting based on the promising results seen in Phase 2 studies with good disease control long term.^33,34 However, cGVHD rates remain high and attempts have been made to improve the composite outcome of 1-year GRFS (GVHD and relapse-free survival) with newer strategies.³⁵ Promising newer strategies to reduce cGVHD incidence include incorporation of post-transplant cyclophosphamide, antilymphocyte globulin, CTLA-4 antagonists, use of bone marrow graft, and ex-vivo graft engineering.^35–40 Novel GVHD prophylaxis strategies currently in clinical trials may influence natural history and lower the incidence of cGVHD in the future.

Treatment of GVHD

Corticosteroids remain the therapy of choice in both aGVHD and cGVHD.^41,42 In milder forms (Grade 1-2) of aGVHD, topical steroids may be used to successfully manage aGVHD. However, for more severe forms (Grade 3-4) of aGVHD, systemic corticosteroids such as methylprednisolone 1–2 mg/kg/day is recommended.⁴³ Patients who respond to frontline corticosteroids within 1–2 weeks typically have a good prognosis and, in many cases, steroids may gradually be tapered off after adequate clinical response is achieved. Serum biomarkers have been developed that are predictive of NRM and allows for better risk stratification, and patient counseling.⁴⁴ Clinical grading based on site and extent of organ involvement can also be used to classify patients as high versus low risk. Novel trials are in development that offer immunotherapy combination to high-risk patients.⁴⁵ Ruxolitinib, a JAK-STAT inhibitor, has been used successfully to control symptoms in patients who are deemed steroid-refractory. In a large randomized phase 3 study, ruxolitinib was associated with superior overall response rates (ORR 49% vs 25%) compared to best available therapy (BAT) resulting in its FDA approval in this setting.⁴⁶

Corticosteroids (prednisone 1 mg/kg/day or equivalent dose of alternative steroids) are also recommended as frontline therapy for patients with a new diagnosis of moderate to severe cGVHD.⁴² Patients with cGVHD are graded based on severity of organ involvement (score 0-3) in the NIH consensus criteria.²¹ Approximately, half of patients will respond to upfront therapy with steroids, but those who remain steroid-refractory (SR) or steroid-dependent (SD) require second and/or third-line therapies. Currently, there are three FDA approved drugs in this setting that inhibit alloreactive T-cells by inhibiting JAK-STAT (ruxolitinib), ROCK-2 (belumosudil) or BTK/ITK (ibrutinib) pathways with ORR of 60–75%.^47–49

Complications of GVHD Requiring ICU Care:

1. Pulmonary GVHD/Bronchiolitis Obliterans Syndrome (BOS)

Pulmonary cGVHD/BOS is a distinct form of cGVHD which is seen in less than 10% of patients undergoing allo-HCT, and is associated with disproportionately large mortality in HCT patients.⁵⁰ The 5-year OS is now improved to 40% in BOS patients due to improved understanding of its pathophysiology, availability of newer treatment options, and more awareness of screening pulmonary function tests (PFTs) which may allow for earlier diagnosis of BOS and intervention.⁵¹ BOS primarily results from immune cell-mediated damage to the small bronchioles leading to fibrotic occlusion and airway obstruction.⁵²

Diagnosis of BOS: This requires the following physiologic and radiographic criteria: i) New onset obstructive airway defect defined as an FEV₁< 75% of predicted ii) FEV₁:FVC ratio of < 0.70; or below 90% confidence iii) absence of infection; iv) evidence of airtrapping identified by an inspiratory/expiratory noted on high resolution CT scan or pulmonary function testing.residual volume (RV) > 120% or RV/total lung capacity exceeding the 90% confidence interval.^21,53 Newer guidelines do not require the presence of air trapping at diagnosis, as this is a late finding and lung biopsy is rarely required for diagnosis as non-invasive testing with PFTs, CT-imaging in an approproate clinical setting is sufficient to make a diagnosis of BOS.^50,53 Patients with extrapulmonary restriction due to scleroderma, myopathy (GVHD-induced or steroid myopathy), or polyneuritis may present with extrapulmonary restriction and occasionally make it difficult to distinguish from BOS.⁵⁴ Serial PFTs and the measurement of maximum inspiratory pressures (MIP) and expiratory pressure may help with the diagnosis of respiratory muscle weakness arising from muscle weakness (myositis, steroid-induced myopathy) or neuropathy. PFTs in patients with BOS shows a progressive decline in FEV1, FEV1/FVC ratio on spirometry and flattening of expiratory limb of flow volume loop (Figure 2).⁵⁵

Figure 2.

Pulmonary function testing showing reduction in FEV1 and FEV1/FVC rations in patients with BOS.

Differential diagnosis: Conditions that can present with progressive dyspnea post-HCT should be ruled out, which include: opportunistic lung infections, cryptogenic organizing pneumonia (COP), radiation fibrosis, idiopathic pneumonia syndrome (IPS) and exacerbation of underlying asthma or chronic obstructive pulmonary disease (COPD). Decline in FEV1 is seen in asthma, but this is reversible with bronchodilators, in contrast to BOS, wherein the decline in FEV1 is fixed. Patients with COP respond very well to the initiation of systemic corticosteroids, in contrast to BOS, where clinical responses are slow.⁵³ IPS is a pulmonary complication that can develop in up to 10% of patients in the first four months after allo-HCT. Diagnosis requires evidence of alveolar injury as noted by multifocal opacities on CT chest, hypoxemia manifested by increased alveolar arterial gradient or need for supplemental oxygen and absence of documented lower respiratory tract infection is negative bronchoscopy/BAL. Treatment is by using immunosupression with high-dose steroids and etanercept.⁵⁶ COPD also presents with a decline in FEV1, but patients typically have this condition prior to transplant. Prior to the diagnosis of BOS, pulmonary infections need to be ruled out using imaging and invasive tests such as bronchoscopy. Patients with clincial diagnosis of BOS should have serial PFTs from previous evaluations documenting slope of decline in FEV1. During acute decompensation and ICU transfer, PFTs have limited applicability and patients are too sick to perfom these tests and the findings may be altered by added conditions such as congestive heart failure (CHF), infection, and etc.

Natural History and phenotypes in BOS: Pathological review of surgical lung biopsy specimens obtained from patients with BOS reveals obliterative bronchiolitis and fibrosis resulting in luminal narrowing and obliteration.⁵² Risk factors for the development of BOS include : busulfun-based conditioning, ABO-mismatch HCT, peripheral stem cell transplant, unrelated donor transplant, respiratory viral infections, older age at transplant, and poor baseline lung function.⁵² Patients with BOS may exhibit distinct clinical courses, including those with a slow decline in lung function versus those with a rapid decline in FEV1, defined as those who develop BOS within six months of HCT or demonstrate a decline in FEV₁ of 25% within three months of BOS diagnosis.⁵² Cheng et al described the natural history of lung function decline in 36 patients in the FAM cohort (fluticasone, azithromycin, montelukast) versus 46 patients who developed BOS post-HCT, but were not treated with FAM.⁵⁷ In both cohorts, the overall trajectory of FEV1 showed consistent decline in the preceding six months prior to BOS diagnosis, which continued post-diagnosis as well. Additional PFT parameters, such as FVC and FEF_25–75, also declined in BOS patients. Poor survival was associated with diagnosis of BOS within 1-year post-HCT, FEV1 < 44% or FVC <67% and use of myeloablative regimens for HCT. Similar findings were reported in a larger subset of 1461 patients who underwent HCT at an academic center, of which 95 patients (6%) eventually developed BOS.⁵⁸ In this study, patients with a rapid initial 25% decline in FEV1 within the first three months after diagnosis of BOS had significantly worse lung function and poorer OS compared to patients with a more gradual initial decline in lung function.

Another form of lung dysfunction called chronic lung allograft dysfunction (CLAD) is seen frequently (30%) after lung transplantation.⁵⁹ Two distinct CLAD phenotypes are described, which include obliterative bronchiolitis (OB) and restrictive allograft syndrome (RAS or rCLAD).⁶⁰ Similar to the clincial syndrome of BOS noted post-allo-HCT, OB is characterized by an obstructive pattern on PFTs and air trapping on CT scan. RAS/rCLAD is manifested by restrictive pattern on PFTs, pleuroparenchymal pulmonary infiltrates on CT scan and fibroelastosis on lung biopsy. Patients with RAS/rCLAD have a worse prognosis with median OS of 6–18 months compared to 3–5 months after diagnosis of OB. Presence of bronchiectasis in patients with OB/BOS is associated with adverse clinical outcomes due to more infectious complications and airway colonization with Pseudomonas aeruginosa in patients with bronchiectasis.⁵⁶ Similar association of bronchiectasis and poor OS in BOS post-HCT is lacking, but it is possible that post- allo-HCT development of bronchiectasis may be associated with gram-negative bacilli and atypical mycobacterial colonization in allo-HCT recepients.⁵⁷ Recognizing CLAD is important in patients who receive solid organ HCT pre- or post-allo-HCT.^61,62

Prevention and Treatment: A large randomized prospective study was conducted in 465 HCT patients to evaluate azithromycin prophylaxis in preventing BOS post-HCT by assigning patients to receive either azithromycin 250 mg 3 times a week or placebo for two years at the initiation of the conditioning regimen (ALLOZITHRO Trial) which was based on a prior successful Phase 2 study.⁶³ Unfortunately, this trial was negative and in fact was associated with increased mortality in patients randomized to the azithromycin group. Thus, the approach of azithromycin prophylaxis is currently not recommended in post-allo-HCT setting.⁶⁴

Treatment of patients who are diagnosed with BOS post-HCT requires initiation of systemic immunosuppression with systemic and inhaled medications . A Phase 2 open-label study showed that patients with BOS treated with the FAM (fluticasone, azithromycin and montelukast) therapy had lower incidence decline in FEV1 > 10%, and was associated with reduction in systemic steroids and improved patient reported outcomes.⁶⁵ Another randomized study in 32 patients with BOS received either placebo or budesonide (800 µg)/formoterol (24 µg).Symbicort Turbuhaler] treatment for six months. This study showed significant increase in FEV1 after one month in patients randomized to budesonide/formoterol versus placebo (260 mL vs 5 mL; p = 0.012) and the beneficial effects were preserved in patients who completed the six month study.⁶⁶ Thus systemic and inhaled steroids are the current standard of care in slowing decline in FEV1 in patients with advanced BOS. This approach is supplemented with approved medications in cGVHD, which include: extracorporeal photopheresis (ECP), rituximab, and etanercept.^53,67 Novel agents such as ruxolitinib and belumosudil are associated with ORR of 30% in patients with BOS and are frequently used for outpatient management.⁶⁸ Ruxolitinib has been used in the first-line setting in patients with newly-diagnosed BOS in a small case series, suggesting the upfront use of JAK inhibitaors may be disease modifying.⁶⁹ Other agents which are in clinical development that have shown promise in BOS include axatilimab and pirfenidone. Axatilamab is a monoclonal antibody that targets the CSF-1R receptor present on tissue macrophages secreting fibrogenic peptides. In the multicenter Phase 1/2 open-label study, the ORR was 30% in BOS patients with 50% patients achieving a complete response.⁷⁰ Antifibrotic medications including pirfenidone are being studied in clinical trials based on the clinical benefit seen in idiopathic pulmonary fibrosis (NCT03315741). Most of the therapies are slow acting and require 4–6 weeks before clinical benefit is noted. In case of acute flareups, pulsed dosing of corticosteroids is recommended to achieve symptom control in the acute ICU setting and to avoid intubation and mechanical ventilation.⁷¹ In a recent retrospective study, the impact of cGVHD on ICU outcomes in patients post-HCT was reported. In their analysis, half of the patients in ICU had some degree of BOS as a manifestation of cGVHD and worsening respiratory function was the most common cause of ICU admission.¹⁷ Thus, in patients with compromised lung function due to BOS, additional insults such as lower respiratory tract infections, sepsis, CHF, pulmonary hypertension or anemia may cause acute decompensation, and the management of these reversible causes may restore patients back to baseline respiratory status. To summarize, prophylactic strategies have been unsuccessful in preventing BOS in HCT recipients, therefore treating patients with established BOS requires a combination of systemic and inhaled steroids and the addition of novel agents is recommended with close monitoring of FEV1 and respiratory symptoms every 3–4 months.

2. Management of Respiratory Failure in Patients with cGVHD

When admitted to the ICU due to respiratory complications, patients with pulmonary GVHD/BOS invariably require augmented respiratory support due to poor baseline reserve . Studies have demonstrated that 15% of patients who undergo alloHCT and develop acute respiratory distress syndrome (ARDS) with or without BOS, have a high mortality rate of 50–70%.^72,73 A recent report reviewed the outcomes of 70 patients who needed ICU care post allo-HCT patients, the most comon cause for ICU transfer post HCT was sepsis (50%) followed by respiratory failure(20%) and neurologic symptoms (20%) and half of the patients required mechanical ventilator support. The 30 day mortality of allo-HCT patients admitted to ICU was 48% and 1 year OS 16%, indicating that few patients survive long term in this setting.⁷⁴ Etilogy of respiratory failure is infectious pneumonia in majority of cases which could be secondary to bacterial, viral or fungal pathogens . Non infectious causes of respiratory failure include engraftment syndrome (11%), IPS (7.5%), diffuse alvelolar hemorrhage(4%), BOS (8%) and COP 2%.⁷⁵ Prior to requiring mechanical ventilation, many patients in the ICU setting are provided with supplemental respiratory and oxygenation support via high flow oxygen or non-invasive postive pressure ventilation (NIPPV). Historically, early initiated NIPPV was thought to be associated with decreased rates of progression to needing invasive mechanical ventilation and improved survival.⁷⁶ Newer data is inconclusive on the benefit of NIPPV, results demonstrating possibe increased mortality.⁷⁷ Due to the difficulty in delivering uniformly controlled tidal volumes with NIPPV and generation of high-delivered tidal volumes by the patient, there is a higher rate of NIPPV failure.⁷⁸ It is hypothesized that high-delivered tidal volumes leads to lung injury and potentiates respiratory failure. Moreover, recent studies indicate an increased role of high-flow nasal oxygen. NIPPV has not been demonstrated to have survival benefit over high-flow nasal oxygen in immunocompromised patients, including those who were HCT recipients.^78,79

HCT patients, particulary those with pulmonary GVHD, who progress to needing invasive mechanical ventilation have high mortality.^72,80 Ventilator strategies for these patients mirror those of non-HCT patients, with particular emphasis placed on preventing ventilator-induced lung injury. In patients with severe pulmonary GVHD, a volume-limited mode of ventilation is favored given the presence of airflow limitation. Ventilator settings and mode selection should be tailored to each patient's unique clinical situation, but general goals of low tidal volume for lung protection, avoidance of over oxygenation, and appropriate use of positive end-expiratory pressure depending on the underlying etiology of the patient's respiratory failure should be prioritized.

Pediatric studies have shown poor outcomes for patients admitted to the ICU for acute respiratory failure post-HCT due to the multiple etiologies (BOS, DAH, engraftment syndrome, COP) and requiring mechanical ventilation. Survival in these patients is poor with high mortality rates ranging from 24–40%.⁸¹ Multivariate analysis showed that the requirment of renal replacement therapy, CMV viremia, and severe hypoxemia is associated with increased ICU mortality in pediatric patients with pulmonary complications. Studies looking at the outcomes of patients with post-HCT BOS in adults are lacking, however, outcomes of patients who are transferred to the ICU in the peri-transplant period shows similar high 90-day mortality of approximately 50% in single-center studies.⁷⁴ In these settings, it may be appropriate to have a discussion with patient and family regarding palliation and symptom control rather than mechanical ventilation given the poor data regarding long-term survival in intubated patients. A frank and compassionate discussion with family member(s) regarding prognosis and expectations for successful extubation and rehabilitation needs to be done at the time of transfer to the ICU. A discussion between the patient and care providers ahead of time and having an advanced directive ready before any clinical deterioration occurs may help prevent instituting care that may be eventually futile. Tools are now availabe to help guide such discussions with critically ill patients in the ICU.⁸²

3. Diagnosis of Lower Respiratory Tract Infections in Patients with cGVHD

The predominant cause of respriatory failure in patients with cGHVD requiring ICU admission is infection. Pulmonary infection has a considerable effect on mortality in alloHCT recipients. A prospective study investigating the epidemiology, etiology, and outcome of pneumonia in all alloHCT recipients (with and without cGVHD) demonstrated that the 1-year probability of survival was 82.7% without the presence of pneumonia and decreased to 47.4% among those who had at least one episode of pneumonia.⁸³ Bronchosopic evaluation for the cause of respiratory infection remains an investigative mainstay. However, there is a wide discrepancy in the published diagnostic yield of a bronchoalveolar lavage (BAL) ranging on average from 30–65% (Table 1). BAL yields a diagnosis in half of the cases when done in alloHCT recipients and adding transbronchial biopsy adds to additional information in < 10% cases, thus for most patients, a bronchioloalveolar lavage (BAL) may be sufficient for microbiologic diagnosis.⁸⁴ Diagnostic yield has been correlated with specific morphology of the pulmonary lesions seen on radiographic studies. Consolidative infiltrates and tree-in-bud infiltrates (see Figure 3) have higher associated BAL diagnostic yield when compared to reticular or nodular infiltrates.⁸⁵ Early BAL performed within four days of presenation of respiratory symptoms was associated with a 2.5-fold higher yield than those performed after four days of presentation. Moreover, diagnostic yield was 75% when performed within 24 h of clinical presentation.⁸⁶ We recommed testing for i) respiratory virus pathogens using commercially available rapid screening tests (eg BioFireRP2.1 PCR), which tests for common respiratory pathogens such as adenovirus, coronaviruses, SARS-CoV-2, human metapneumovirus, human rhinovirus/enterovirus, influenza A and B, parainfluenza viruses (1, 2, 3, and 4), respiratory syncytial virus, bordetella pertussis, bordetella parapertussis, chlamydophila pneumoniae, and mycoplasma pneumoniae ii) culture, gram stain, and cytology iii) HSV, CMV PCR, pneumocysticis jiroveci qPCR and DFA and MTB PCR iv) fungal pathogens including mucor PCR and aspergillus galactomannan antigen testing. Additional tests may be added to BAL fluid based on geographic location or specific exposures in consultation with infectious disease specialists. The addition of a traditional transbronchial biopsy (TBB) has not been associated with an improved diagnostic yield for infectious processes, but has demonstrated a role in identifying non-infectious pulmonary complications and impacting the initiation of corticosteroid therapy.^87,88 TBB also carries an increased procedural risk due to the potential of pneumothorax and the possibility of bleeding in this thrombocytopenic patient population. In the ICU setting, BAL had a diagnostic yield of 27% and resulted in management change in only 38% of patients who were immuncompromised, with a majority of the patients possessing an underlying hematologic malignancy or were post-HCT. Bronchoscopic intervention was also associated with worsening respiratory status in 11% of patients and associated with higher ICU and in-hospital mortality with rates approaching 50%.⁸⁹ Therefore, the pursuit of brochoscopy in ICU patients should be a considered decision with emphasis on identifying if and how it will impact treatment and management decisions.

Figure 3.

Consolidative peripheral opacities seen in HCT patient, these tend to have higher yield from BAL.

Table 1.

Major Studies Looking at Diagnostic Yield of Bronchoscopy Post HCT.

Study, year of publication	Study design (number of procedures)	Population	Diagnostic yield (%)	Major conclusions
Burger et al 2007⁹⁰	Retrospective (N = 21)	HCT	52%	BAL is not predictive of mortality. Respiratory failure occurred in 73% with positive BAL versus 30% with negative BAL (p = 0.09).
Patel et al 2005⁸⁴	Retrospective (N = 169)	HCT	51% alloHCT, 41% autoHCT	No change in therapy after positive BAL: 64% autoHCT and 50% alloHCT. TBB only provided additional specific information in <10% of cases. BAL with specific diagnosis, pathogen identified, or therapy change did not impact hospital mortality rate. BAL complications 9% of all HCT pts.
Dunagen et al 1997⁹¹	Retrospective (N = 305)	HCT	46%	Antibiotic changes after BAL in 41% of pts, 65% of pts when infectious organism found. Pathogen identified via BAL did not impact survival. Major complications from BAL 8%.
Shannon et al 2010⁸⁶	Retrospective (N = 598)	HCT	55%	Highest yield (75%) if within <24 h versus > 5 days. Mortality lower in pt with early BAL versus late BAL (6% vs 14%, p = 0.03). Antibiotic changes after BAL 51%. TBB in 11% of pts. Major complications from BAL 0.3%.
Hofmeister et al 2006⁹²	Retrospective (N = 91)	HCT	49%	Additional therapy changes after positive BAL (20%). Therapy changes or diagnostic BAL did not improve survival. BAL complications 7.6%.
O’Dwyer et al 2018⁸⁷	Retrospective (N = 130)	HCT	Transbronchial biopsy 47%	Positive TBB was not associated with change in overall therapy (OR 1.92, p = 0.15), but led to higher complications than BAL alone (14% vs 5%, p = 0.01)
Feinstein et al 2001⁹³	Retrospective (N = 76)	Allo-HCT	42.1%	Change in management (31.6%). TBB increased yield by 2.6%. BAL complications 3.9%.
Gruson et al 2000⁹⁴	Prospective (N = 93)	Hematologic malignancy/HCT neutropenic	49%	Therapy changed in 67% but did not impact mortality. BAL complications 17.2%.
Peikert et al 2005⁹⁵	Retrospective (N = 35)	Hematologic malignancy/HCT neutropenic	49%	Changes in management 51%. TBB did not significantly increase yield.
Katsumata et al 2019⁹⁶	Retrospective (N = 37)	Hematologic malignancy/HCT	29.7%	Positive BAL had better 30-day and 90-day outcomes versus negative BAL.
Kim et al 2015⁹⁷	Retrospective (N = 206)	Hematologic malignancy/HCT	65%	Changes in management 30.1% but did not impact survival outcomes. No major complications from BAL.
Bissigner et al 2005⁹⁸	Retrospective (N = 95)	Hematologic malignancy/HCT	73%	Described common pathogens recovered in BAL. CMV most common.
Brownback et al 2013⁸⁴	Retrospective (N = 133)	80% HCT or receiving chemo	52.6%	In patients with positive yield, diagnosis made with FOB with BAL occurred in 73.4% of cases. Complication rate was 7.3%.
Jahn et al 2024⁹⁸	Retrospective (N = 1311)	42% Hematologic malignancy/HCT	33%	Change in management 48.75% of hematologic cases. Cases requiring change had worse 30-day survival than those which no changes needed.
Azoulay et al 2008⁹⁹	Retrospective (N = 148)	Patients on chemotherapy, 45 s/o HCT	50.5%	Respiratory status deterioration seen in 48% patients post FO-BAL and did not impact survival. On multivariate analysis, mortality associated with remission status, allo-HCT, cause of respiratory failure and need for mechanical ventilator

In order to increase the diagnostic accuracy of bronchoscopy and BAL, cell free DNA analysis is currently being evaluated like the Karius test.¹⁰⁰ In a study of 257 patients, where standard testing was unable to make a microbial diagnosis in patients with pneumonia who underwent diagnostic bronchoscopy and BAL evaluation, the use of the Karius test increased the probability of microbial diagnosis by another 20%. More widespread adoption of DNA-based testing such as universal PCR may also increase diagnostic yield in patients where current tests are unable to determine etiology of infections.¹⁰¹

Recently, there has been advancement in the fields of bronchoscopy and interventional pulmonology with the introduction of robotic assisted bronchoscopy. These robotic systems allow for increased precison and targeting of peripheral pulmonary lesions and promote stability during biopsy.¹⁰² Currently, there are three FDA-approved robotic bronchoscpy systems. Primarily developed for peripheral biopsy of lesions suscpicious for solid organ malignancy, the advantages offered by robotic assisted bronchoscopy can be extrapolated to the HCT population in the diagnostic work-up of pulmonary lesions suspicious for infectious or inflammatory etiology. Biopsies performed with increased proximity to the target lesion can be hypothesized to have increased diagnostic yield when compared to traditional TBB. Morever, intraoperative confirmation of the biopsy tool being close to the lesion can be obtained with augmented fluoroscopy or Cone-Beam CT. In addition, BAL can be performed via robotic-assisted bronchoscopy allowing sampling from an optimized, locoregional position in close vicinity to the target lesion. It is theorized that this improved positioning could lead to an increased diagnostic yield. It is important to note that currently no retrospective or prospective studies have been performed investigating the use of robotic-assisted bronchoscopy in the HCT patient population for idenftification of infectious or inflammatory etiologies of pulmonary lesions. Likewise, there have been no studies to date studying whether robotic-assisted bronchoscpy is associated with increased diagnostic yield or therapeutic benefit when compared to traditional bronchoscopy with BAL and/or TBB. There are currently no guidelines regarding which point in a patient's work-up for pulmonary lesions robotic-assisted bronchoscopy should be used. It is also important to take into consideration bleeding risk and pneumothorax risk in the HCT population, given an increased incidence of thrombocytopenia and potentially lower pulmonary reserve, particularly in patients with pulmonary GVHD.

4. Management of Air Leak in Lung GVHD

A rare complication of late pulmonary cGVHD is spontaneous thoracic air leakage syndrome, which is the presence of extra-alveolar air including spontaneous pneumothorax, pneumomediastinum, pneumopericardium, and subcuteanous/interstitial emphysema.¹⁰³ The reported incidence of spontaneous thoracic air leakage syndrome is only 0.83%-2.3%.¹⁰⁴ Though these occurrences are likely secondary to archictecural distortion of the lung parenchyma, pleura and airways; they may also be secondary to the violation of these anatomical structures by invasive infectious organisms. Pneumothorax as result of cGVHD falls under the classifcation of spontaneous secondary pneumothorax (SSP) which is a pneumothorax due to underlying lung disease. SSP is associated with more challenging management and increased morbidity and mortality.¹⁰⁵ Air leak is unlikely to spontaneously resolve in patients with SSP and the symptoms related to pneumothorax are greater in this patient population due to their underlying lung disease. Patients with pulmonary GVHD should have their pneumothoraces managed according to standard guidelines established for all SSPs.

Initial management of a patient with SSP depends on their clinical symptoms and the radiographic size of the pneumothorax.^105,106 Small bore chest tube placement is advised, particulary in the setting of clinical symptoms and pneumothorax size >2 cm.¹⁰⁵ Smaller pneumothoraces, in the absence of clinical symptoms, can be monitored in the hospital setting with oxygen treatment, or if symptoms are present, can be considered for needle aspiration versus chest tube placement.^105,106 Those patients with increased respiratory compromise being considered for mechanical ventilation may benefit from larger size chest tube placement due to the concern for large airway leak due to positive airway pressure.¹⁰⁶ Figure 4 displays a patient presenting with a pneumothorax with improvement after the placement of a chest tube.

Figure 4.

Patient with lung GVHD presenting with dyspnea and Chest X ray showed right sided pneumothorax (left panel) that improved with placement pf chest tube and re-expansion of underlying lung (right panel).

Patients with SSP with a persistent air leak or inadequate lung re-expansion despite chest tube intervention should be considered for additional treatment including medical or surgical chemical pleurodesis or video assisted thoracoscopic surgery (VATS) with pleurectomy and pleural abrasion.^105,106 However, given these patients’ underlying respiratory insufficiency, they are occasionally not candidates for invasive interventions. Other techniques to treat persistent air leaks include autologous blood patch pleurodesis, sealants, and spigots/coils have been described.¹⁰⁷ Moreover, in the past few years, increasingly minimally invasive techniques to address persistent air leaks have been developed, including the use of bronchial valves.¹⁰⁸ These valves are placed bronchoscopically, and allow for unidirectional airflow preventing air entry during inspiration, but allowing expiratory airflow.¹⁰⁹ A large reterospective single-center study published their results on the efficacy of bronchial valves, with over 68% of patients having SSPs, demonstrated successful closure of persistent air leaks with chest tube removal in 80% of patients.¹⁰⁸ Other smaller retrospective studies have demonstrated resolution of persistent air leaks in almost 90% of patients.¹⁰⁷ Prospective studies are currently underway to further clarify use of bronchial valves in the treatment of persistent air leaks. There is currently no published experience of the use of bronchial valves in patients with pulmonary GVHD, but given their success in other causes of SSPs, they should be considered as a treatment strategy in patients with pulmonary GVHD with pneumothorax complicated by persistent air leaks. The majority of studies looking at the implications of endbronchial valve placement are related to bronchoscopic lung volume reduction. In several studies, a low infection risk has been identified and ranges from 1.7–3%. Though an immuncomprised patient with pulmonary GVHD is at higher risk of developing a pulmonary infection, the placement of broncial valves is temporary. The benefit of resolving a patient's persistent air leak despite other more conservative methods needs to be considered, especially if leading to prolonged ICU stay. In the presence of existing pulmonary infection, the placement of bronchial valves should be avoided.

5. Management of Pleuro-Pericardial Effusions

Another cause of significant respiratory morbidity in patients with pulmonary GVHD is the development of pleural and pericardial effusions. Depending on the size and laterality of the pleural effusions, they can cause significant respiratory failure leading to ICU admission. In a recent reterospective study in patients who had undergone HCT, 9.9% of patients developed a pleural effusion where prior studies have described an incidence of pleural effusion as high as 16%.¹¹⁰ Etiology of pleural effusion in HCT varies, and also depends on duration of time that has elapsed since undergoing HCT. Though volume overload and infection are predominant causes of pleural effusions throughout a patient's transplant course, the presence of pleural effusion due to GVHD and malignancy increases 100 days status post-HCT.¹¹¹ Pleural effusion secondary to cGVHD is related to pleural involvement with serositis. The majority of these patients usually have significant cGVHD, often with multiorgan involvement, prior to the development of a pleural effusion. Figure 5 illustrates a patient with cGVHD presenting with a signficiant pleural effusion. Often, the onset of pleural effusion coincides with development of a pericardial effusion and ascites as well.¹¹¹

Figure 5.

Patient with cGVHD presenting with moderately large left pleural effusion.

To determine the etiology and provide symptomatic relief, a thoracentesis should be promptly performed when safe to do so after managing any presenting thrombocytopenia or coagulopathy. Determination of whether the pleural fluid is a transudate or exudate should be made, most often by Light's criteria.¹¹² Further pleural fluid analysis should also include cell count and differential, microbiology cultures and cytology. Other correlating laboratory and radiographic studies should also be performed based on the patient's clinical scenario and suspected cause of pleural effusion to help clarify an etiology. Depending on the etiology and re-accumulation rate, placement of an indwelling pleural catheter(s) can be considered. Though not well described in the literature, medical or surgical thoracoscopy can be considered for diagnostic purposes if a thoracentesis does not yield a diagnosis. Similarly, pleurodesis could also be considered in select cases for refractory pleural effusion.

Similar to pleural effusions, pericardial effusions are a rare, but potentially life-threatening complication of HCT. Patients identified with pericardial effusion usually require prompt ICU management, especially in the setting of cardiac tamponade physiology. GVHD can lead to pericardial serositis in HCT patients, with a recent reterospective review by Azoulay et al describing the incidence to be 3.1% in the HCT population.¹¹³ Depending on the patient's hemodynamic stabilty and the presence of cardiac tamponade, prompt treatment with pericardiocentesis or pericardial window should be undertaken. Often, when a percardiocetensis is performed, a pericardial drain is placed to help prevent re-accumulation. When the pericardial effusion is suspected to be secondary to cGVHD, immunosuppressive treatment should also be started.¹¹³

Conclusion

Graft-versus-host disease remains a very common problem post allo-HCT. Approximately 40% patients develop acute and 50–70% of the patients will develop cGVHD post allo-HCT. Patients who fail frontline treatment with corticosteroids present with multiorgan involvement and require many lines of treatment for disease control. Corticosteroids still remain the first line therapy for both aGVHD and cGVHD. Patients failing corticosteroids can now consider recent FDA approved therapies available for the management of cGVHD. Availability of approved therapies and the improvement in supportive care practices has improved overall survival and quality of life in patients with cGVHD post-HCT. Patient with GVHD frequently require co-management with pulmonary medicine for i) diagnosis of lower respiratory tract infections ii) management of lung GVHD/BOS iii) management of complications arising from cGVHD including respiratory failure(due to infections,IPS,DAH, septic shock) and need for mechanical ventilation, management of air leaks and pleuropericardial effusions. Timely referral to the appropriate specialists is crucial in the symptom management and overall improvement in survival outcomes for GVHD in ICU patients.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Amandeep Salhotra

References

Kanate

Majhail

Savani

, et al. Indications for hematopoietic cell transplantation and immune effector cell therapy: Guidelines from the American society for transplantation and cellular therapy. Biol Blood Marrow Transplant. 2020;26(7):1247-1256.

Heybati

Ochal

Hogan

, et al. Temporal trends in critical care utilization and outcomes in allogeneic hematopoietic stem cell transplant recipients. Ann Hematol. 2024;103(3):957-967.

Lee

. Classification systems for chronic graft-versus-host disease. Blood. 2017;129(1):30-37.

Schoemans

Lee

Ferrara

, et al. EBMT−NIH−CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transplant. 2018;53(11):1401-1415.

Greinix

Eikema

Koster

, et al. Incidence of acute graft-versus-host disease and survival after allogeneic hematopoietic cell transplantation over time: A study from the transplant complications and chronic malignancies working party of the EBMT. Blood. 2018;132(Supplement 1):2120-2120.

Pidala

Kurland

Chai

, et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: Report on baseline data from the Chronic GVHD Consortium. Blood. 2011;117(17):4651-4657.

Hamilton

. Updates in chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2021;2021(1):648-654.

McDonald

Sandmaier

Mielcarek

, et al. Survival, nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: Comparing 2003–2007 versus 2013–2017 cohorts. Ann Intern Med. 2020;172(4):229-239.

Lee

Nguyen

Onstad

, et al. Success of immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24(3):555-562.

10.

Saillard

Crocchiolo

Furst

, et al. National Institutes of Health classification for chronic graft-versus-host disease predicts outcome of allo-hematopoietic stem cell transplant after fludarabine-busulfan-antithymocyte globulin conditioning regimen. Leuk Lymphoma. 2014;55(5):1106-1112.

11.

Atkinson

Horowitz

Gale

, et al. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood. 1990;75(12):2459-2464.

12.

Gooley

Chien

Pergam

, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091-2101.

13.

D'Souza

Fretham

Lee

, et al. Current use of and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2020;26(8):e177-e182.

14.

Arai

Arora

Wang

, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: A report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21(2):266-274.

15.

Lee

Kim

, et al. Quality of life associated with acute and chronic graft-versus-host disease. Bone Marrow Transplant. 2006;38(4):305-310.

16.

Lal

Anderson

, et al. Healthcare resource utilization and costs among patients with steroid-resistant chronic graft-versus-host disease in the United States: A retrospective claims database analysis. Curr Med Res Opin. 2021;37(5):755-759.

17.

Lueck

Tzalavras

Wohlfarth

, et al. Impact of chronic graft-versus-host-disease on intensive care outcome in allogeneic hematopoietic stem cell recipients. Bone Marrow Transplant. 2023;58(3):303-310.

18.

Zeiser

Blazar

. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565-2579.

19.

Sullivan

Shulman

Storb

, et al. Chronic graft-versus-host disease in 52 patients: Adverse natural course and successful treatment with combination immunosuppression. Blood. 1981;57(2):267-276.

20.

Filipovich

Weisdorf

Pavletic

, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-956.

21.

Jagasia

Greinix

Arora

, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1.

22.

Pidala

Kim

Anasetti

, et al. The global severity of chronic graft-versus-host disease, determined by National Institutes of Health consensus criteria, is associated with overall survival and non-relapse mortality. Haematologica. 2011;96(11):1678-1684.

23.

Zhao

Young

Chen

, et al. Alloimmune response results in expansion of autoreactive donor CD4+ T cells in transplants that can mediate chronic graft-versus-host disease. J Immunol. 2011;186(2):856-868.

24.

Wilhelm

Ganesan

Müller

, et al. Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat Med. 2010;16(12):1434-1438.

25.

Allen

Tata

Fore

, et al. Increased BCR responsiveness in B cells from patients with chronic GVHD. Blood. 2014;123(13):2108-2115.

26.

Young

Chen

, et al. Donor B cells in transplants augment clonal expansion and survival of pathogenic CD4+ T cells that mediate autoimmune-like chronic graft-versus-host disease. J Immunol. 2012;189(1):222-233.

27.

Srinivasan

Flynn

Price

, et al. Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood. 2012;119(6):1570-1580.

28.

Sakoda

Hashimoto

Asakura

, et al. Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood. 2007;109(4):1756-1764.

29.

Forcade

Paz

Flynn

, et al. An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition. JCI insight. 2017;2(12):1–15.

30.

Storb

Deeg

Whitehead

, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314(12):729-735.

31.

Cutler

Logan

Nakamura

, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014;124(8):1372-1377.

32.

Perkins

Field

Kim

, et al. A randomized phase II trial comparing tacrolimus and mycophenolate mofetil to tacrolimus and methotrexate for acute graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2010;16(7):937-947.

33.

Rodriguez

Nakamura

Palmer

, et al. A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. Blood. 2010;115(5):1098-1105.

34.

Salhotra

Hui

Yang

, et al. Long-Term outcomes of patients with acute myelogenous leukemia treated with myeloablative fractionated total body irradiation TBI-based conditioning with a tacrolimus- and sirolimus-based graft-versus-host disease prophylaxis regimen: 6-year follow-up from a single center. Biol Blood Marrow Transplant. 2020;26(2):292-299.

35.

Kröger

Solano

Wolschke

, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374(1):43-53.

36.

Bleakley

Heimfeld

Loeb

, et al. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015;125(7):2677-2689.

37.

Pierini

Ruggeri

Carotti

, et al. Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia. Blood Adv. 2021;5(5):1199-1208.

38.

Meyer

Laport

Xie

, et al. Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients. JCI Insight. 2019;4(10):2338–2348.

39.

Bolaños-Meade

Hamadani

, et al. Post-Transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N Engl J Med. 2023;388(25):2338-2348.

40.

Watkins

Qayed

McCracken

, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021;39(17):1865-1877.

41.

McDonald

. How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver. Blood. 2016;127(12):1544-1550.

42.

Flowers

MED

Martin

. How we treat chronic graft-versus-host disease. Blood. 2015;125(4):606-615.

43.

Mielcarek

Furlong

Storer

, et al. Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: A randomized controlled trial. Haematologica. 2015;100(6):842-848.

44.

Major-Monfried

Renteria

Pawarode

, et al. MAGIC Biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood. 2018;131(25):2846-2855.

45.

MacMillan

Robin

Harris

, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761-767.

46.

Zeiser

von Bubnoff

Butler

, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810.

47.

Cutler

Lee

Arai

, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: The ROCKstar study. Blood. 2021;138(22):2278-2289.

48.

Miklos

Cutler

Arora

, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243-2250.

49.

Zeiser

Polverelli

Ram

, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238.

50.

Williams

. Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. Jama. 2009;302(3):306-314.

51.

Ditschkowski

Elmaagacli

Koldehoff

, et al.

Bronchiolitis obliterans after allogeneic hematopoietic SCT: Further insight–new perspectives?

Bone Marrow Transplant. 2013;48(9):1224-1229.

52.

Astashchanka

Ryan

Lin

, et al. Pulmonary Complications in Hematopoietic Stem Cell Transplant Recipients-A Clinician Primer. J Clin Med. 2021;10(15):1–20.

53.

Williams

. How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Blood. 2017;129(4):448-455.

54.

Chien

Duncan

Williams

, et al. Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(1 Suppl):S106-S114.

55.

Hansen

Sun

Wasserman

. Spirometric criteria for airway obstruction: Use percentage of FEV1/FVC ratio below the fifth percentile, not < 70%. Chest. 2007;131(2):349-355.

56.

Tizon

Frey

Heitjan

, et al. High-dose corticosteroids with or without etanercept for the treatment of idiopathic pneumonia syndrome after allo-SCT. Bone Marrow Transplant. 2012;47(10):1332-1337.

57.

Cheng

Storer

Chien

, et al. Lung function trajectory in bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplant. Ann Am Thorac Soc. 2016;13(11):1932-1939.

58.

Kwok

Liang

B-M

Lui

, et al. Rapid versus gradual lung function decline in bronchiolitis obliterans syndrome after haematopoietic stem cell transplantation is associated with survival outcome. Respirology. 2019;24(5):459-466.

59.

de Jong

Dodd

Coxson

, et al. Bronchiolitis obliterans following lung transplantation: Early detection using computed tomographic scanning. Thorax. 2006;61(9):799-804.

60.

Verleden

Vos

Vanaudenaerde

, et al. Chronic lung allograft dysfunction phenotypes and treatment. J Thorac Dis. 2017;9(8):2650-2659.

61.

Brockmann

Broering

Raza

, et al. Solid organ transplantation following allogeneic haematopoietic cell transplantation: Experience from a referral organ transplantation center and systematic review of literature. Bone Marrow Transplant. 2019;54(2):190-203.

62.

Glanville

Benden

Bergeron

, et al. Bronchiolitis obliterans syndrome after lung or haematopoietic stem cell transplantation: current management and future directions. ERJ Open Res. 2022;8(3):1–16.

63.

Ruttens

Verleden

Vandermeulen

, et al. Prophylactic azithromycin therapy after lung transplantation: Post hoc analysis of a randomized controlled trial. Am J Transplant. 2016;16(1):254-261.

64.

Bergeron

Chevret

Granata

, et al. Effect of azithromycin on airflow decline–free survival after allogeneic hematopoietic stem cell transplant: The ALLOZITHRO randomized clinical trial. JAMA. 2017;318(6):557-566.

65.

Williams

Cheng

G-S

Pusic

, et al. Fluticasone, azithromycin, and montelukast treatment for new-onset bronchiolitis obliterans syndrome after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(4):710-716.

66.

Bergeron

Chevret

Chagnon

, et al. Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2015;191(11):1242-1249.

67.

Yanik

Mineishi

Levine

, et al. Soluble tumor necrosis factor receptor: Enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18(7):1044-1054.

68.

Salhotra

Sandhu

O’Hearn

, et al. A critical review of belumosudil in adult and pediatric patients with chronic graft-versus-host disease. Expert Rev Clin Immunol. 2023;19(3):241-251.

69.

Zhang

Zhao

Shen

, et al. Ruxolitinib as an effective and steroid-sparing first-line treatment in newly diagnosed BOS patients after hematopoietic stem cell transplantation. Front Pharmacol. 2022;13(13):916472.

70.

Kitko

Arora

DeFilipp

, et al. Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: Results of a phase I/II study. J Clin Oncol. 2023;41(10):1864-1875.

71.

Akpek

Lee

Anders

, et al. A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2001;7(9):495-502.

72.

Allareddy

Roy

Rampa

, et al. Outcomes of stem cell transplant patients with acute respiratory failure requiring mechanical ventilation in the United States. Bone Marrow Transplant. 2014;49(10):1278-1286.

73.

Yadav

Nolan

Bohman

, et al. Epidemiology of acute respiratory distress syndrome following hematopoietic stem cell transplantation. Crit Care Med. 2016;44(6):1082-1090.

74.

Garcia Borrega

Heger

J-M

Koehler

, et al. Allogeneic stem cell transplant recipients admitted to the intensive care unit during the peri-transplant period have unfavorable outcomes-results of a retrospective analysis from a German university hospital. Ann Hematol. 2022;101(2):389-395.

75.

Finan

Pastores

. Acute respiratory failure after hematopoietic stem cell transplantation. In: Esquinas

Pravinkumar

Soubani

, eds. Mechanical Ventilation in Critically Ill Cancer Patients: Rationale and Practical Approach. Springer International Publishing; 2018:347-354.

76.

Hilbert

Gruson

Vargas

, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001;344(7):481-487.

77.

Neuschwander

Lemiale

Darmon

, et al. Noninvasive ventilation during acute respiratory distress syndrome in patients with cancer: Trends in use and outcome. J Crit Care. 2017;38(4):295-299.

78.

Carteaux

Millán-Guilarte

De Prost

, et al. Failure of noninvasive ventilation for De Novo acute hypoxemic respiratory failure: Role of tidal volume. Crit Care Med. 2016;44(2):282-290.

79.

Lemiale

Resche-Rigon

Mokart

, et al. Acute respiratory failure in patients with hematological malignancies: Outcomes according to initial ventilation strategy. A groupe de recherche respiratoire en reanimation onco-hematologique (Grrr-OH) study. Ann Intensive Care. 2015;5(1):28.

80.

Gilbert

Vasu

Baram

. Use of mechanical ventilation and renal replacement therapy in critically ill hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2013;19(2):321-324.

81.

Elbahlawan

Srinivasan

Morrison

. A critical care and transplantation-based approach to acute respiratory failure after hematopoietic stem cell transplantation in children. Biol Blood Marrow Transplant. 2016;22(4):617-626.

82.

Chatterjee

Roberts

Ahluwalia

, et al. Integrating narrative goals of care in the medical intensive care unit: Impact on educational and clinical outcomes. ATS Sch. 2022;3(3):449-459.

83.

Aguilar-Guisado

Jiménez-Jambrina

Espigado

, et al. Pneumonia in allogeneic stem cell transplantation recipients: A multicenter prospective study. Clin Transplant. 2011;25(6):E629-E638.

84.

Patel

Lee

Kim

, et al. The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients. Chest. 2005;127(4):1388-1396.

85.

Brownback

Simpson

. Association of bronchoalveolar lavage yield with chest computed tomography findings and symptoms in immunocompromised patients. Ann Thorac Med. 2013;8(3):153-159.

86.

Shannon

Andersson

Lei

, et al. Utility of early versus late fiberoptic bronchoscopy in the evaluation of new pulmonary infiltrates following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010;45(4):647-655.

87.

O'Dwyer

Duvall

Xia

, et al. Transbronchial biopsy in the management of pulmonary complications of hematopoietic stem cell transplantation. Bone Marrow Transplant. 2018;53(2):193-198.

88.

Chellapandian

Lehrnbecher

Phillips

, et al. Bronchoalveolar lavage and lung biopsy in patients with cancer and hematopoietic stem-cell transplantation recipients: A systematic review and meta-analysis. J Clin Oncol. 2015;33(5):501-509.

89.

Bauer

Chevret

Yadav

, et al. Diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy. Eur Respir J. 2019;54(1):1–11.

90.

Burger

. Utility of positive bronchoalveolar lavage in predicting respiratory failure after hematopoietic stem cell transplantation: A retrospective analysis. Transplant Proc. 2007;39(5):1623-1625.

91.

Dunagan

Baker

Haponik

, et al. Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest. 1997;111(1):135-141.

92.

Hofmeister

Czerlanis

Forsythe

, et al. Retrospective utility of bronchoscopy after hematopoietic stem cell transplant. Bone Marrow Transplant. 2006;38(10):693-698.

93.

Feinstein

Mokhtari

Ferreiro

, et al. Fiberoptic bronchoscopy in allogeneic bone marrow transplantation: Findings in the era of serum cytomegalovirus antigen surveillance. Chest. 2001;120(4):1094-1100.

94.

Gruson

Hilbert

Valentino

, et al. Utility of fiberoptic bronchoscopy in neutropenic patients admitted to the intensive care unit with pulmonary infiltrates. Crit Care Med. 2000;28(7):2224-2230.

95.

Peikert

Rana

Edell

. Safety, diagnostic yield, and therapeutic implications of flexible bronchoscopy in patients with febrile neutropenia and pulmonary infiltrates. Mayo Clin Proc. 2005;80(11):1414-1420.

96.

Katsumata

Terada

Abe

, et al. An analysis of the clinical benefit of 37 bronchoalveolar lavage procedures in patients with hematologic disease and pulmonary complications. Intern Med. 2019;58(8):1073-1080.

97.

Kim

Rhee

Kang

, et al. Diagnostic value of bronchoscopy in patients with hematologic malignancy and pulmonary infiltrates. Ann Hematol. 2015;94(1):153-159.

98.

Bissinger

Einsele

Hamprecht

, et al. Infectious pulmonary complications after stem cell transplantation or chemotherapy: Diagnostic yield of bronchoalveolar lavage. Diagn Microbiol Infect Dis. 2005;52(4):275-280.

99.

Azoulay

Mokart

Rabbat

, et al. Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: Prospective multicenter data. Crit Care Med. 2008;36(1):100-107.

100.

Bergin

Chemaly

Duttagupta

, et al. 544. PICKUP: Pneumonia in the immunocompromised - use of the karius test for detection of undiagnosed pathogens. Open Forum Infect Dis. 2022;9(Supplement_2):153–159.

101.

Kubiak

Morgan

Kirmaier

, et al. Universal PCR for bacteria, mycobacteria, and fungi: A 10-year retrospective review of clinical indications and patient outcomes. J Clin Microbiol. 2023;61(1):2023.08.02.23293145.

102.

Agrawal

Hogarth

Murgu

. Robotic bronchoscopy for pulmonary lesions: A review of existing technologies and clinical data. J Thorac Dis. 2020;12(6):3279-3286.

103.

Vogel

Brodoefel

Bethge

, et al. Spontaneous thoracic air-leakage syndrome in patients following allogeneic hematopoietic stem cell transplantation: Causes, CT-follow up and patient outcome. Eur J Radiol. 2006;60(3):392-397.

104.

Haider

Durairajan

Soubani

. Noninfectious pulmonary complications of haematopoietic stem cell transplantation. Eur Respir Rev. 2020;29(156):1–8.

105.

MacDuff

Arnold

Harvey

. Management of spontaneous pneumothorax: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65(Suppl 2):ii18-ii31.

106.

Baumann

Strange

Heffner

, et al. Management of spontaneous pneumothorax: An American College of Chest Physicians Delphi consensus statement. Chest. 2001;119(2):590-602.

107.

Dugan

Laxmanan

Murgu

, et al. Management of persistent air leaks. Chest. 2017;152(2):417-423.

108.

Bermea

Miller

Wilson

, et al.

One-Way endobronchial valves as management for persistent air leaks: A preview of what's to come?

Am J Respir Crit Care Med. 2019;200(10):1318-1320.

109.

Fiorelli

D’Andrilli

Cascone

, et al. Unidirectional endobronchial valves for management of persistent air-leaks: Results of a multicenter study. J Thorac Dis. 2018;10(11):6158-6167.

110.

Noble

. The pulmonary complications of bone marrow transplantation in adults. West J Med. 1989;150(4):443-449.

111.

Modi

Jang

Kim

, et al. Incidence, etiology, and outcome of pleural effusions in allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2016;91(9):E341-E347.

112.

Light

. Pleural effusions: The diagnostic separation of transudates and exudates. Ann Intern Med. 1972;77(4):507-513.

113.

Azoulay

Schellongowski

Darmon

, et al. The Intensive Care Medicine research agenda on critically ill oncology and hematology patients. Intensive Care Med. 2017;43(9):1366-1382.