The Damage–Response Framework as a Tool for the Physician-Scientist to Understand the Pathogenesis of Infectious Diseases

Pirofski, Liise Anne; Casadevall, Arturo

doi:10.1093/infdis/jiy083

Cited by 44 publications

(24 citation statements)

References 52 publications

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“…This approach thus involves understanding initially the integration of the host into the consequences of viral pathogenesis. This relationship has been well described for microbial pathogenesis in the Damage-Response Framework (DRF) in infectious diseases (10). The damaging host factors described in this microbial model, namely cytokine release (storm), chemical mediators signalling, oxygen radical production and immune complexes leading to aberrant inflammation are not specific and in fact apply equally to viruses such as influenza and the current COVID-19 disease.…”

Section: Treating the Hostmentioning

confidence: 93%

A pharmacological framework for integrating treating the host, drug repurposing and the damage response framework in COVID‐19

Martin

Head

2020

Brit J Clinical Pharma

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With any new disease a framework for the development of preventative or treatment therapeutics is key; the absence of such in COVID‐19 has enabled ineffective and potentially unsafe treatments to be taken up by governments and clinicians desperate to have options for patients. As we still have few therapies and nil vaccines yet available, the void of a clear framework for research and practice is increasingly clear. We describe a framework that has been used to prioritise therapeutic research in previous pandemics which could be used to progress clinical pharmacology and therapeutics research in COVID‐19. This is particularly relevant as discussion has already moved on from antiviral therapeutics to delineating the treatment of the host from treatment and elimination of the infective agent. Focussing on the host brings together three concepts: host treatment, the damage response framework and therapeutic repurposing. The integration of these three areas plays to the traditional strength of pharmaceuticals in providing a period of stabilization to permit time for the development of novel antiviral drugs and vaccines. In integrating approaches to repurposing, host treatment and damage response we identified three key properties that a potentially effective repurposed drug must possess by way of a framework. There must be homology, i.e., the same or similar relation with the pathogenesis of the disease, ideally targeted to the conserved pathophysiological outcomes of the viral attack; there must be a defined locus within the spectrum to prevention to severe disease and the framework must draw upon the historical dose and safety experience of the repurposed drug. To illustrate, we have mapped therapeutics that impact upon a key dysregulated pathway in COVID‐19 – the renin angiotensin system – using this approach. Collectively this type of analysis reveals the importance of existing data (repurposed information and administrative observational data) and the importance of the details of the known pathophysiological response to viruses in approaches to treating the host.

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Section: Treating the Hostmentioning

confidence: 93%

A pharmacological framework for integrating treating the host, drug repurposing and the damage response framework in COVID‐19

Martin

Head

2020

Brit J Clinical Pharma

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“…Once CoV-2 gains entry into the target cell, the host response is a major determinant of severity of the ensuing pathogenesis ( Fig. 1) [18]. The bronchial mucosa is lined by mucosal associated invariant T (MAIT) cells and γδ T cells [19].…”

Section: Covid-19 and The Immune Responsementioning

confidence: 99%

COVID-19 and Cancer: a Comprehensive Review

et al. 2020

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Purpose of Review The outbreak of the novel coronavirus disease 2019 has emerged to be the biggest global health threat worldwide, which has now infected over 1.7 million people and claimed more than 100,000 lives around the world. Under these unprecedented circumstances, there are no well-established guidelines for cancer patients. Recent Findings The risk for serious disease and death in COVID-19 cases increases with advancing age and presence of comorbid health conditions. Since the emergence of the first case in Wuhan, China, in December 2019, tremendous research efforts have been underway to understand the mechanisms of infectivity and transmissibility of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a fatal virus responsible for abysmal survival outcomes. To minimize the mortality rate, it becomes prudent to identify symptoms promptly and employ treatments appropriately. Even though no cure has been established, multiple clinical trials are underway to determine the most optimal strategy. Managing cancer patients under these circumstances is rather challenging, given their vulnerable status and the aggressive nature of their underlying disease. Summary In this comprehensive review, we discuss the impact of COVID-19 on health and the immune system of those affected, reviewing the latest treatment approaches and ongoing clinical trials. Additionally, we discuss challenges faced while treating cancer patients and propose potential approaches to manage this vulnerable population during this pandemic.

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“…The AIDS crisis challenged many infectious disease specialists to change their approach to studying contagious diseases. One distinctive approach was developed at Einstein Medical School in New York City by Casadevall and Pirofski [64]. In an effort to teach medical students to think differently about infectious diseases they developed what they called the Damage/Response Framework.…”

Section: The Defense: Novel Ways Of Assessing Periodontitis As An Infmentioning

confidence: 99%

Aggregatibacter, a Low Abundance Pathobiont That Influences Biogeography, Microbial Dysbiosis, and Host Defense Capabilities in Periodontitis: The History of a Bug, and Localization of Disease

2020

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Aggregatibacter actinomycetemcomitans, the focus of this review, was initially proposed as a microbe directly related to a phenotypically distinct form of periodontitis called localized juvenile periodontitis. At the time, it seemed as if specific microbes were implicated as the cause of distinct forms of disease. Over the years, much has changed. The sense that specific microbes relate to distinct forms of disease has been challenged, as has the sense that distinct forms of periodontitis exist. This review consists of two components. The first part is presented as a detective story where we attempt to determine what role, if any, Aggregatibacter plays as a participant in disease. The second part describes landscape ecology in the context of how the host environment shapes the framework of local microbial dysbiosis. We then conjecture as to how the local host response may limit the damage caused by pathobionts. We propose that the host may overcome the constant barrage of a dysbiotic microbiota by confining it to a local tooth site. We conclude speculating that the host response can confine local damage by restricting bacteremic translocation of members of the oral microbiota to distant organs thus constraining morbidity and mortality of the host.

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The Damage–Response Framework as a Tool for the Physician-Scientist to Understand the Pathogenesis of Infectious Diseases

Abstract: The Damage-Response Framework (DRF) is a facile tool for the physician-scientist as it can integrate clinical observation with microbiology and immunology and incorporates the role of the host into the outcome of microbial pathogenesis.

Cited by 44 publications

References 52 publications

A pharmacological framework for integrating treating the host, drug repurposing and the damage response framework in COVID‐19

A pharmacological framework for integrating treating the host, drug repurposing and the damage response framework in COVID‐19

COVID-19 and Cancer: a Comprehensive Review

Aggregatibacter, a Low Abundance Pathobiont That Influences Biogeography, Microbial Dysbiosis, and Host Defense Capabilities in Periodontitis: The History of a Bug, and Localization of Disease

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