Notice of Special Interest (NOSI): Pulmonary Complications of Hematopoietic Stem Cell Transplantation (HCT)
Notice Number:

Key Dates

Release Date:

November 1, 2023

First Available Due Date:
February 05, 2024
Expiration Date:
January 08, 2027

Related Announcements

  • April 27, 2020 - Notice of Special Interest (NOSI): Pulmonary Complications of Hematopoietic Stem Cell Transplantation in Childhood. See Notice NOT-HL-20-761.
  • May 05, 2020 - Research Project Grant (Parent R01 Clinical Trial Required). See Notice PA-20-183.
  • May 05, 2020 - Research Project Grant (Parent R01 Clinical Trial Not Allowed). See Notice PA-20-185.

Issued by

National Heart, Lung, and Blood Institute (NHLBI)


the purpose of NOT-HL-23-116 is to further elucidate mechanisms underlying the life-threatening pulmonary complications that ensue after hematopoietic stem cell transplantation (HCT) in all age groups. This reissue of NOT-HL-20-761 expands the scope of the science to include children and adults, autologous transplant recipients, innovative technologies including device development, and mechanistic clinical trials in children and adults.

Approximately 20,000 hematopoietic stem cell transplants (HCT), of which about 2500 are in children, are currently performed annually in the USA. A number of conditions including sickle cell disease, aplastic anemia, recalcitrant malignancies and immunodeficiencies have been treated successfully with HCT. However, pulmonary complications are common in all age groups. They occur in 25-55% of all pediatric HCT recipients, with significant mortality (40%) and morbidity, representing the leading cause of death in children during the first year after HCT. Adults who receive HCT are frequently admitted to the intensive care unit (ICU) with respiratory insufficiency and/or the acute respiratory distress syndrome (ARDS), resulting in mortality (7-11%) and long-term pulmonary morbidity. The intensive care of these patients is fraught with challenges and disappointment. The use of immunosuppression during the transplant process is associated with respiratory muscle atrophy leading to increased ICU length of stay in patients with respiratory failure after HCT. The development of technology and devices in this field could help in early detection of respiratory failure and optimization of lung function after HCT. There is also a need for discovery of novel biomarkers that facilitate the diagnosis and respiratory care of patients post transplantation. Pulmonary complications from conditioning regimens for the increasing use of gene therapy and autologous transplantation beg elucidation. Pulmonary afflictions after HCT, such as peri-engraftment respiratory distress syndrome (PERDS), idiopathic and infectious pneumonia syndromes, diffuse alveolar hemorrhage (DAH), thrombotic microangiopathy (TMA), graft versus host disease (GVHD)/bronchiolitis obliterans, and interstitial lung disease progressing to pulmonary fibrosis are varied and complex. The co-occurrence of cardiovascular dysfunction, which could result from prior chemotherapy, fluid overload due to conditioning regimens, shock due to bacterial, viral, and fungal sepsis, and right heart dysfunction due to thrombotic microangiopathy and its associated pulmonary hypertension, among other causes, pose further unique challenges in recognition, diagnosis and treatment of these conditions. Immune-mediated vascular complications, specifically endothelial injury, and the associated inflammation, play an important role in progression of some of the life-threatening and pre-terminal lung diseases and require further study and development.

Assessment of pulmonary risk before and after HCT continues to be an important hurdle in the clinical setting. Early, accurate diagnosis of lung injury is key to optimizing treatment, mitigating pulmonary morbidity, and improving survival, yet is hampered by the lack of reliable monitoring techniques of lung function, especially in children. The development of a risk score based on pre-transplant pulmonary function, stem cell source, donor type, HLA-match, conditioning regimen intensity and composition, fecal microbiota diversity, day +7 GVHD biomarkers, and presence of comorbidities including prior infection history and pre-existing renal and cardiac impairment may help identify patients at risk for pulmonary complications after HCT and may inform decision-making on a patient’s potential to survive after HCT. Similarly, recent advances in deep exome and/or panel sequencing with enriched endothelial cells may elucidate some of the pulmonary endothelial mechanisms that play into unique HCT-related pulmonary complications such as TMA.

To continue to address this wide array of outstanding scientific questions involving post-HCT pulmonary complications across the lifespan, the NHLBI is interested in renewing its support for observational, mechanistic, and discovery-based research studies, mechanistic clinical trials, and novel medical device development that aim to elucidate mechanisms of acute airway, alveolar and vascular injury after HCT, and explore mechanism-based therapeutic strategies in this challenging field.

Investigators are encouraged to submit applications under the investigator-initiated R01 mechanism in basic science, translational studies, and mechanistic clinical trials focused on pulmonary complications after allogeneic and autologous HCT in all age groups. The inclusion of studies with solely adult participants are accepted under this NOSI. Science aimed at developing clinical consortia in children and/or adults to facilitate pulmonary risk assessment, address the complications secondary to conditioning regimens employed in gene therapy and autologous transplantation, evaluate responses to specific treatments, and address pulmonary phenotyping/follow-up after HCT may be proposed.  Proposals that address the development of innovative technologies and devices, and testing newer, non-invasive biomarkers of assessing lung injury may be submitted under this notice. Additional resources for proposals for development of pediatric devices are available at the recently-announced design phase of a public-private partnership through the Foundation for the National Institutes of Health (FNIH), to support the development, evaluation, regulatory approval and commercialization of medical devices that meet needs of children. Proposals for prospective clinical studies, observational, or mechanistic clinical trials as part of PA-20-183 Research Project Grant (Parent R01 Clinical Trial Required) will be accepted and awarded for up to 5 years. This NOSI aims to address many gaps of critical clinical importance in this field to improve outcomes in this vulnerable population.

Research Areas that could be addressed in response to this NOSI could include, but are not limited to, the following:

  • Prospective observational and mechanistic studies before and after HCT, deeply phenotyped for pulmonary function
  • Diversity, equity, inclusion, and accessibility to pulmonary evaluation before and pulmonary monitoring after HCT
  • Development and refinement of age-specific definitions of pulmonary conditions associated with HCT 
  • Development of an algorithm for age-appropriate pulmonary risk prior to, and for a year after HCT, and the employment of emerging advances in machine learning, artificial intelligence, natural language processing, and bioinformatics to achieve this goal 
  • Identification of candidate genes and putative functional variants associated with risk of specific pulmonary complications post-HCT 
  • Identification of effective cytokine panels and novel methods, such as use of cell-free DNA, to assess risk for pulmonary complications at multiple points in the transplant process 
  • Development of novel, standardized pulmonary function testing in young children (6 months to 3 years)
  • Refinement of novel imaging techniques to predict risk and trajectory of pulmonary conditions pre- and post-HCT 
  • Characterization and identification of factors contributing to resilience to pulmonary complications after HCT 
  • Device-related research to optimize neuro-electrical stimulation of the diaphragm 
  • Validation of inhalation devices used in small children for delivery of antibiotics 
  • Optimizing anticoagulant regimes in HCT patients on extra-corporeal membrane oxygenation (ECMO)
  • Improving mechanistic understanding of post-HCT complications; e.g.,
    • Endothelial and related signaling mechanisms in lung injury after HCT 
    • Animal models to study pulmonary manifestations post HCT 
    • The role of the microbiome in elucidating infectious versus non-infectious mechanisms of pneumonias after HCT
    • The role of cardiac dysfunction and pulmonary hypertension and their impact on pulmonary function post-HCT
  • Standardization of multidisciplinary clinical care approaches; e.g.,
    • Clinical criteria and monitoring standards for pulmonary function tests (PFTs) to define and diagnose early bronchiolitis obliterans syndrome (BOS) after HCT
    • Identification of criteria to optimize the use of ECMO in children
    • Definition of patient-centered outcomes; e.g., the timing/role/use of palliative care in pediatric HCT recipients
    • Mechanistic clinical trials evaluating why certain pre-transplant evaluation criteria or conditioning regimens mitigate pulmonary risk 

Application and Submission Information

This notice applies to due dates on or after February 5, 2024 and subsequent receipt dates through January 7, 2027. This NOSI expires on January 8, 2027. Applications submitted on or after January 8, 2027 will not be accepted.

Submit applications for this initiative using one of the following notices of funding opportunities (NOFOs) or any reissues of these announcements through the expiration date of this notice.

  • PA-20-183 Research Project Grant (Parent R01 Clinical Trial Required)
  • PA-20-185 Research Project Grant (Parent R01 Clinical Trial Not Allowed)

NOTE: The NHLBI will only accept applications to PA-20-183 - Research Project Grant (Parent R01 Clinical Trial Required) that propose mechanistic studies which meet the NIH's definition of a clinical trial and that have the primary goal of understanding how an intervention works per guidance in NOT-HL-19-690.  Applicants are strongly encouraged to consult the contact(s) listed below prior to submission to confirm that the proposed clinical trial application meets these requirements.

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-HL-23-116” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Aruna Natarajan, MD, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Division of Lung Diseases
Telephone: 301-827-0180

Siddharth Shenoy, PhD 
National Heart, Lung, and Blood Institute (NHLBI)
Division of Lung Diseases (Device Development)
Telephone: 301-827-4751

Nancy L. DiFronzo, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Division of Blood Diseases and Resources
Telephone: 301-827-8267

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Laurel Kennedy, M.A.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301 827 4777