Notice of Special Interest: Research to Advance the Understanding and Management of the Multiple Organ Dysfunction Syndrome in Children (R01, R21)
Notice Number:

Key Dates

Release Date:

April 2, 2021

First Available Due Date:
June 05, 2021
Expiration Date:
May 08, 2023

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-183 - Research Project Grant (Parent R01 Clinical Trial Required)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-20-194 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)

Issued by

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)


The purpose of this Notice of Scientific Interest (NOSI) is to continue a program of research to advance the understanding, prevention and treatment of pediatric multiple organ dysfunction syndrome (MODS). MODS is a clinical condition commonly encountered in the pediatric intensive care unit that is associated with significant morbidity and mortality. It is characterized by the failure or dysfunction of a consistent group of body organs or organ systems. It is triggered by a wide range of disease processes and clinical insults, most notably sepsis and trauma, and is frequently associated with uncontrolled inflammation. Despite its high prevalence and unfavorable outcomes, this clinical entity remains poorly understood. First described over 40 years ago, it still can only be described as a “syndrome,” a constellation of symptoms, rather than as a specific pathologic entity with a distinguishable cause. The current lack of understanding underscores the need for more basic, exploratory and longitudinal research. Applications may include any appropriate study design ranging from basic science and animal models through prospective randomized controlled trials. It is hoped that as a result of research solicited through this NOSI, outcomes will improve both in terms of the prevention and treatment of MODS in children. Applicants planning to submit an application in response to this NOSI are strongly encouraged to contact the NICHD scientific/programmatic contact(s) listed on this NOSI in advance of the application due date.

Topics of Interest

Topics to be addressed by this NOSI include any areas where knowledge gaps exist and research needs remain in the understanding and management of pediatric MODS. To address these needs, a wide range of science must be conducted ranging from basic science molecular and genomic studies up to large scale, longitudinal epidemiology projects and clinical trials. Studies that assess specific etiologies associated with MODS including, but not limited to, sepsis, trauma, acute respiratory distress syndrome, inborn errors of metabolism, burns, cancer, transplantation and congenital heart disease are encouraged. Applications in response to this NOSI should address one or more of the following five priority areas:

Epidemiology and Outcomes

  • Studies directed at developing and validating new definitions of the syndrome that are evidence-based and expanded to include contemporary data such as biomarker levels.
  • Studies designed to secure large scale epidemiology data needed to most completely understand the precipitants of the syndrome, assess the magnitude of the problem and establish the long-term outcomes beyond simply hospital survival.

Detection and Monitoring of MODS

  • Studies aimed at the re-assessment of clinical criteria for diagnosing and monitoring the progression of MODS given advancements in monitoring capabilities over time.
  • Studies designed to identify associations between biomarker levels and MODS; identified relationships must be further validated in prospective, multicenter study, and performed in a manner to be clinically relevant.
  • Studies attempting to identify unique endotypes and phenotypes that may exist among those given the global diagnosis of MODS.
  • Studies that test novel techniques and technologies used in the diagnosis and monitoring of MODS which may include, but are not limited to, the following:
  • Mechanistic, mathematical modeling
  • Redox monitoring
  • Assessment of heart and respiratory rate variation
  • Continuous, real-time assessment of biomarker levels
  • Non-invasive monitoring of biomarkers through sweat and other mechanisms


  • Studies directed at elucidating the complex, inter-related pathophysiologic processes associated with this condition.
  • Studies aimed at identifying mechanisms common to all MODS patients as well as those developed to characterize pathophysiologic features unique to specific phenotypes.
  • Basic science studies designed to identify the most rudimentary cause of the syndrome at a molecular, cellular and genomic level that can then be advanced into translational and clinical projects.
  • Studies focused on specific pathophysiologic processes that include, but are not limited to, any of the following:
  • The role of damage-associated molecular pattern molecules (DAMPs) and pathogen-associated molecular pattern molecules (PAMPs)
  • Hyperinflammatory syndromes
  • Thrombocytopenia-associated multiple organ failure
  • Mitochondrial dysfunction
  • Immunoparalysis
  • Endothelial and epithelial injury
  • Alterations in redox potentials
  • Gastrointestinal perturbations
  • Alterations in the microbiome

Specific Triggering Etiologies

  • Studies focused on the assessment of MODS within specific disease categories (e.g. MODS among children with sepsis, cancer, acute respiratory distress syndrome, congenital heart disease, inborn errors of metabolism, etc.).
  • Studies designed to compare MODS across different disease categories identifying key similarities and differences in terms of pathophysiology, epidemiology, and outcomes.
  • Studies directed at the assessment and occurrence of MODS in children who have experienced external injury such as trauma and burn victims.
  • Studies aimed at minimizing the occurrence of MODS associated with therapeutic interventions such as blood transfusions, medications, and organ and stem cell transplantation.

Promising Therapies

  • Exploratory studies to assess novel therapeutic interventions in the treatment of MODS. Studies of the use of anti-cytokine antibodies, anti-toxin therapies, and anti-oxidant interventions represent but a few potential examples.
  • Large scale, multicenter, prospective clinical studies to assess the true value of therapies found to be effective in case series and small, uncontrolled trials.
  • Comparative effectiveness studies designed to identify the most effective therapies across centers including optimal supportive care.
  • Studies designed to assess and identify differences in responsiveness to therapies among all pediatric MODS patients.

This Notice replaces NOT-HD-20-019.

Application and Submission Information

This notice applies to due dates on or after June 5, 2021 and subsequent receipt dates through May 08, 2023. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-183 - Research Project Grant (Parent R01 Clinical Trial Required)
  • PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
  • PA-20-194 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)

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

  • For funding consideration, applicants must include “NOT-HD-21-024” (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 funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Tessie October, MD, MPH
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-6757

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