Review of Mathematical Modeling of the Inflammatory Response in Lung Infections and Injuries

The 21st Century Cures Act requires FDA to expand its use of real-world evidence (RWE) to support approval of previously approved drugs for new disease indications and post-marketing study requirements. To address this need in neonates, the FDA and the Critical Path Institute (C-Path) established the International Neonatal Consortium (INC) to advance regulatory science and expedite neonatal drug development. FDA recently provided funding for INC to generate RWE to support regulatory decision making in neonatal drug development. One study is focused on developing a validated definition of bronchopulmonary dysplasia (BPD) in neonates. BPD is difficult to diagnose with diverse disease trajectories and few viable treatment options. Despite intense research efforts, limited understanding of the underlying disease pathobiology and disease projection continues in the context of a computable phenotype. It will be important to determine if: 1) a large, multisource aggregation of real-world data (RWD) will allow identification of validated risk factors and surrogate endpoints for BPD, and 2) the inclusion of these simulations will identify risk factors and surrogate endpoints for studies to prevent or treat BPD and its related long-term complications. The overall goal is to develop qualified, fit-for-purpose disease progression models which facilitate credible trial simulations while quantitatively capturing mechanistic relationships relevant for disease progression and the development of future treatments. The extent to which neonatal RWD can inform these models is unknown and its appropriateness cannot be guaranteed. A component of this approach is the critical evaluation of the various RWD sources for context-of use (COU)-driven models. The present manuscript defines a landscape of the data including targeted literature searches and solicitation of neonatal RWD sources from international stakeholders; analysis plans to develop a family of models of BPD in neonates, leveraging previous clinical trial experience and real-world patient data is also described.

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“… Abstract representation of model including all interactions [modified from ( Cogo et al, 2007 ; Minucci et al, 2020 ). …”

Section: Resultsmentioning

confidence: 99%

Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data

et al. 2022

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“…Models for general lung injury not caused by infection have also been explored [32][33][34][35] as well as general inflammatory dynamics [4,36]. A review of mathematical models that focus generally on the immune response in the lungs has also been published [37]. Past models for MV and VILI have generally focused on airway mechanics to inform and optimize machine settings and assess stress [38][39][40][41][42][43][44][45][46], with some models incorporating fluid-structure interactions [44,47,48].…”

Section: Mathematical Backgroundmentioning

confidence: 99%

Age-dependent ventilator-induced lung injury: Mathematical modeling, experimental data, and statistical analysis

Hay

Grubb

Minucci

et al. 2023

Preprint

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A variety of pulmonary insults can result in the necessity for mechanical ventilation, which, when misused, used for prolonged periods of time, or associated with an excessive inflammatory response, can result in ventilator-induced lung injury. Older patients have been observed to have an increased risk for respiratory distress with ventilation and more recent studies suggest that this could be linked to disparities in the inflammatory response. To address this, we ventilated young (2-3 months) and old (20-25 months) mice for 2 hours using high pressure mechanical ventilation and extracted data for inflammatory cell ratios, namely macrophage phenotypes, and lung tissue integrity. A large difference in naive macrophages at baseline, alternatively-activated (M2) macrophages at baseline, and airspace enlargement after ventilation was observed in the old mice. The experimental data was used to fit a mathematical model for the inflammatory response to lung injury. Model variables include inflammatory markers and cells, namely neutrophils and macrophages, epithelial cells at varying states, and repair mediators. Parameter sampling was performed using an iterative sampling method and parameter sets were selected based on their ability to fit either the old or young macrophage phenotype percentages and epithelial variables at zero and two hours. Classification methods were performed to identify influential parameters separating the old and young parameter sets as well as user-defined health states. Parameters involved in repair and damage to epithelial cells and parameters regulating the pro-inflammatory response were shown to be important. Local sensitivity analysis preformed for the different epithelial cell variables produced similar results. A pseudo-intervention was also performed on the parameter sets. The results were most influential for the old parameter sets, specifically those with poorer lung health. These results indicate potential targets for therapeutic interventions prior to and during ventilation, particularly for old subjects.Author summaryA variety of inhaled pathogens and other pulmonary insults prompt the need for mechanical ventilation; a procedure that has become increasingly necessary following the 2019 coronavirus pandemic. A proportion of patients respond poorly to ventilation, some resulting in ventilator-induced lung injury. Observational data has shown increased instance of severe disease in older patients as well as differences in the inflammatory response to injury, although more research is needed to confirm this. We performed high-pressure ventilation on young (2-3 months) and old (20-25 months) mice and observed large disparities in inflammatory cell ratios at baseline and lung tissue integrity after ventilation. The experimental data was then used to fit a mathematical model of the inflammatory response to lung injury. We used a variety of analysis methods to identify important parameters separating the young and old parameter sets and user-defined health states of the resulting simulations. Parameters involved in damage and repair of epithelial cells in the lung as well as parameters controlling the pro-inflammatory response to injury were important in both classifying between old and young sets and determining predicted health after ventilation. These results indicate potential targets for therapeutic interventions prior to and during ventilation.

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“…Minuci et al presented the review of mathematical modelling of the inflammatory response in lungs infections and injuries. They emphasised that mathematical modelling is a great tool for understanding infectious diseases [ 24 ]. Huttinger et al, in 2017, developed a mechanistic mathematical model explaining the dynamic relationship between streptococcus pneumonia (Sp), immune cells and epithelial tissues for the better understanding of complex dynamically changing host–Sp interaction.…”

Section: Literature Surveymentioning

confidence: 99%

Modeling the transmission dynamics of delayed pneumonia-like diseases with a sensitivity of parameters

et al. 2021

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Pneumonia is a highly transmitted disease in children. According to the World Health Organization (WHO), the most affected regions include South Asia and sub-Saharan Africa. 15% deaths of children are due to pneumonia. In 2017, 0.88 million children were killed under the age of five years. An analysis of pneumonia disease is performed with the help of a delayed mathematical modelling technique. The epidemiological system contemplates subpopulations of susceptible, carriers, infected and recovered individuals, along with nonlinear interactions between the members of those subpopulations. The positivity and the boundedness of the ongoing problem for nonnegative initial data are thoroughly proved. The system possesses pneumonia-free and pneumonia existing equilibrium points, whose stability is studied rigorously. Moreover, the numerical simulations confirm the validity of these theoretical results.

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Review of Mathematical Modeling of the Inflammatory Response in Lung Infections and Injuries

Cited by 23 publications

References 204 publications

Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data

Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data

Age-dependent ventilator-induced lung injury: Mathematical modeling, experimental data, and statistical analysis

Modeling the transmission dynamics of delayed pneumonia-like diseases with a sensitivity of parameters

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