The PIRO (predisposition, insult, response, organ dysfunction) model: toward a staging system for acute illness

Abstract

Multimodal therapy for diseases like cancer has only become practicable following the development of staging systems like the TNM (tumor, nodes, metastases) system. Staging enables the identification of subgroups of patients with a disease who not only have a differing prognosis, but who are also more likely to benefit from a specific therapeutic modality. Critically ill patients represent a highly heterogeneous population for whom multiple therapeutic options are potentially available, each carrying not only the potential for differential benefit, but also the potential for differential harm. The PIRO system (predisposition, insult, response, organ dysfunction) is a template proposal for a staging system for acute illness that incorporates assessment of pre-morbid baseline susceptibility (predisposition), the specific disorder responsible for acute illness (insult), the response of the host to that insult, and the resulting degree of organ dysfunction. However the creation of a valid, robust, and clinically useful system presents significant challenges arising from the complexity of the disease state, the lack of a clear phenotype, the confounding influence of the effects of therapy and of cultural and socio-economic factors, and the relatively low profile of acute illness with clinicians and the general public. This review summarizes the rationale for such a model of illness stratification and the results of preliminary cohort studies testing the concept. It further proposes two strategies for building a staging system, recognizing that this will be a demanding undertaking that will require decades of work.

Keywords: clinical trials; critical illness; epidemiology; sepsis; staging; stratification.

Figure 1. Studies of the neutralization of tumor necrosis factor in a variety of pre-clinical models reveal that the consequences are model-dependent. Survival is improved in models of systemic challenge with endotoxin, E. coli, or S. aureus, unaffected in cecal ligation and puncture (CLP) models, and reduced when the challenge organism is S. pneumoniae, Candida, Listeria, or M. tuberculosis. Adapted from reference .

Figure 2. The impact of baseline interleukin-6 levels on survival following neutralization of tumor necrosis factor in a randomized controlled trial of 2634 patients with sepsis; survival curves were modestly separated at the cutoff level of 1000 pg/ml used in the trial, but diverged further at higher levels of IL-6.