Edited by: James Donald Fortenberry, Emory University, United States
Reviewed by: Timothy M. Maul, Nemours Children's Hospital, United States; Ravi R. Thiagarajan, Boston Children's Hospital and Harvard Medical School, United States
This article was submitted to Pediatric Critical Care, a section of the journal Frontiers in Pediatrics
†These authors have contributed equally to this work and share first authorship
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Diffuse alveolar hemorrhage (DAH) is a known pulmonary complication following hematopoietic cell transplant (HCT). It usually occurs within the first 30 days following HCT and is diagnosed clinically by a constellation of hypoxemic respiratory failure, diffuse pulmonary infiltrates on chest radiography and progressively bloody bronchoalveolar lavage return on bronchoscopy (
An 18-year old female with Diamond-Blackfan anemia underwent a 10/10 matched unrelated donor (MUD) HCT, following a conditioning regimen consisting of cyclophosphamide, busulfan, fludarabine, thiotepa, and rabbit anti-thymoglobulin. The initial post-transplant course was complicated by fungal sepsis with
On HCT day 60 (
Timeline of Events for Case 1. HCT, hematopoietic cell transplant; ICU, intensive care unit; ECMO, extracorporeal membrane oxygenation; CD, cluster of differentiation; G-CSF, granulocyte-colony stimulating factor.
Serial chest radiographs for Case 1 demonstrating the progression and subsequent improvement of diffuse bilateral interstitial and alveolar opacities.
By HCT day 76, she progressed to severe acute respiratory distress syndrome (ARDS) with a peak oxygenation index (OI) of 40. Given her acute deterioration, poor organ reserve, and high mortality risk, she was transferred to the regional pediatric ECMO program at Le Bonheur Children's Hospital and emergently cannulated onto Veno-Venous (VV) ECMO with placement of two-21 French Biomedicus (Medtronic, Minneapolis, MN, USA) cannulas in the right femoral and right internal jugular veins. She was adequately supported with initial flows of 2.16 liters per minute (LPM), ~40 ml/kg/min, and sweep gas flow of 3 LPM using the Maquet Rotaflow centrifugal pump and Quadrox-iD adult oxygenator (Maquet, Harlingen, Germany). She was anticoagulated on our institution's bleeding protocol with unfractionated heparin targeting an activated clotting time (ACT) of 180–200 s and transfused with packed red blood cells (PRBC) and platelets to keep hematocrit > 35% and platelet count > 75 × 109/L, respectively. She was treated with intravenous methylprednisolone 2 mg/kg/day for 7 days followed by a 6 week wean. She was successfully decannulated after 7 days of VV ECMO support. There was no recurrence of pulmonary hemorrhage on ECMO and she was transferred back to the referring institution 3 days after decannulation.
After decannulation, she had multiple pulmonary hemorrhage episodes treated with methylprednisolone, aminocaproic acid, and IP-rFVIIa. A lung biopsy on HCT day 90 was indicative of recent and remote alveolar hemorrhages. Due to her recurrent pulmonary hemorrhages and evolving practice for early tracheostomy placement at that time, her tracheostomy was delayed for more than 60 days following her initial respiratory failure. She was considered a higher risk for early tracheostomy due to secondary graft insufficiency. She received a CD34+ cell boost on HCT day 259. After extensive inpatient rehabilitation, she was liberated from her tracheostomy and is successfully surviving 4 years after HCT.
A 4-year-old male with metastatic neuroblastoma underwent his second tandem autologous HCT following a conditioning regimen of melphalan, etoposide, and carboplatin. His medical history was notable for acute kidney injury secondary to cisplatin with non-functioning right kidney on imaging. His transplant course was complicated by fever and severe mucositis and mild sinusoidal obstructive syndrome (SOS). On HCT day 4 (
Timeline of Events for Case 2. HCT, hematopoietic cell transplant; ICU, intensive care unit; ETT, endotracheal tube; BAL, bronchoalveolar lavage; ECMO, extracorporeal membrane oxygenation; CRRT, continuous renal replacement therapy; TA-TMA, transplant-associated thrombotic microangiopathy.
On HCT day 24, he had an acute hypoxemic event with copious bloody secretions in his ETT. Chest radiography showed increased pulmonary opacities (
Serial chest radiographs for Case 2 demonstrating the progression and subsequent improvement of diffuse bilateral interstitial and alveolar opacities
Following return of renal function, CRRT was discontinued. He underwent tracheostomy placement 11 days following ECMO decannulation to allow gradual weaning of mean airway pressure and facilitate rehabilitation. He was weaned off mechanical ventilation support, transferred to the general medical floor under the care of the oncology team for continued radiation and chemotherapy, and successfully discharged to outpatient care on HCT day 109. He remains well 6 months following hospital discharge.
We asked the families to share their thoughts and experiences through the course of their children's illness and hospital course. As expected, the families' found the process stressful but were ultimately relieved and grateful for the outcome.
“There are things I remember so vividly about my daughter's experience on ECMO, and things that I think my mind has chosen to forget out of self-protection. I remember listening through the glass doors in the ICU, [the intensivist] arguing for why my daughter should be [an ECMO candidate]. I remember watching the team wheel her out [for transfer to the ECMO referral center], and the look on their faces is what sticks with me the most. They were trying so hard to be brave for us, but everyone knew […] that she may not come back. I was simply in survival mode at that point. My daughter doesn't remember much about ECMO, which is a blessing considering how difficult the experience was, both clinically and emotionally. I am forever grateful to everyone that played a part in saving my daughter's life, and my sanity during such trying times.”
When describing the experience, our patient's mother's first response was that of shock. It was difficult for her to recall specific emotions or thoughts during this distressing experience. She expressed appreciation for the support she received from the medical team. She was particularly grateful for the careful and thoughtful approach from team members when making difficult medical decisions. She recognized it was not one individual deciding her son's care but a collaborative expert medical team. One statement she felt was unhelpful but heard repeatedly was “things will get worse before they get better.” She knew it was valuable information but hearing it continually became exasperating. She understood that once her son was on ECMO the only thing worse would be losing him. She is extremely grateful that he is better and doing well-today.
DAH is a known pulmonary complication of HCT with a historically high mortality rate (
Once DAH is diagnosed, our standardized treatment protocol includes systemic glucocorticoids and nebulized TXA, with the addition of IP-rFVIIa if there is refractory hemorrhage. Initially, methylprednisolone is dosed at 2 mg/kg/day with an accelerated taper over 4–8 weeks, particularly if there is concern for disseminated viral infection. We strongly consider the use of pulse dose glucocorticoids, methylprednisolone 15–30 mg/kg/day or dexamethasone 4-5 mg/kg/day, for 2–3 days followed by a taper over 4–8 weeks to maximize the genomic and non-genomic anti-inflammatory effects of glucocorticoids (
DAH has been described in the setting of TA-TMA (
Idiopathic pneumonia syndrome (IPS) is another non-infectious pulmonary complication of HCT and shares many clinical features with DAH. It is characterized by elevated levels of specific cytokines, including tumor necrosis factor receptor-1 (TNFR1), a marker for tumor necrosis factor- alpha (TNF-α). IPS is treated with glucocorticoids and etanercept, a TNF-α binding protein (
In cases of recurrent bleeding, in addition to the above treatments, we consider early tracheostomy with the goals of maintaining a high mean airway pressure with mechanical ventilation for >4 weeks while endothelial healing occurs and allowing for early mobilization and rehabilitation.
The medical complexity of HCT care inherently raises the PICU mortality when compared to the general population (
Choosing which HCT patient has a reasonable chance of recovery with ECMO support is challenging. In collaboration with our regional pediatric ECMO program at Le Bonheur Children's Hospital, we have developed a liaison team to assess ECMO candidacy with the goals of arranging timely transfer for ECMO evaluation and early ECMO initiation to limit significant ventilator-induced lung injury. This ECMO liaison team was instrumental in the process of case discussion and patient advocacy for transfer and early initiation of extracorporeal therapy in the cases reported here. The liaison teams consist of intensivists at both institutions and garners input from oncologists, HCT physicians and other specialties as needed on a case by case basis. We also review the indications, risks, and benefits of ECMO with the patient's family to allow them to make an informed decision regarding transfer for ECMO evaluation during these initial discussions. We begin ECMO candidacy discussions early—ideally days before the patient requires transfer for ECMO evaluation. In general, the criteria for ECMO initiation is similar to that which is used for our general pediatric population, with a few considerations specific to oncologic and HCT patients. HCT patients represent a heterogenous population with various underlying diseases, conditioning regimens, cell sources and post HCT comorbidities. These patients must be individually evaluated for the potential of ECMO benefit. The ECMO liaison team is invaluable for teasing out the nuances of individual patient factors.
Our report is limited by an inherent selection bias for HCT ECMO survivors who had cessation of pulmonary hemorrhage prior to ECMO initiation since active bleeding not controlled with medical management is considered an institutional contraindication for ECMO at this time. As such, we do not include patients with DAH who were not considered ECMO candidates in this case series. A concern in the HCT population has been that while ECMO supports the lungs, it may worsen other organ dysfunction and increase infection risk. This concern has limited the use of ECMO in the HCT population. Our cases highlight that HCT and DAH should not absolutely preclude patients from ECMO candidacy. HCT patients should be evaluated within the context of their overall clinical picture.
ECMO support has historically been considered contraindicated in HCT patients given the complexity of their disease. Through the development of a multidisciplinary approach in treatment of DAH post-HCT, as well as an expert ECMO liaison team to evaluate ECMO candidacy, we successfully supported two patients with respiratory failure secondary to DAH refractory with ECMO. Over the last decade, there have been significant advances made in ECMO technology as well as the field of HCT, we argue that ECMO use should be considered in select HCT patients.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.
KF provided substantial contribution to the conception, literature search, and drafting of the manuscript. CH provided substantial contribution to the drafting and critical revisions of the manuscript. MM and SF obtained informed consent for publication of the second case, contributed to writing the family perspective, and provided critical revisions of the content. AA, AQ, AS, JM, RM, HS, and SS provided critical intellectual revisions of the manuscript content. SG provided substantial contribution to the conception, literature search, intellectual content, critical revision, approval of the final version of the manuscript, and agrees to be accountable for all aspects of the work related to accuracy and integrity. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We would like to thank Ashlea Anderson, NP for obtaining informed consent for publication and the family perspective for case 1. We would like to thank the ICU team at St. Jude Children's Research Hospital, the ICU team, ECMO coordinators and specialists at Le Bonheur Children's Hospital for their management and family support during ECMO.