PIRO concept: Staging of sepsisS Rathour1, S Kumar1, V Hadda2, A Bhalla1, N Sharma1, S Varma1
1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pulmonary Medicine, All India Institute of Medical Sciences, New Delhi, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.166511
Source of Support: None, Conflict of Interest: None
Introduction: Sepsis is common presenting illness to the emergency services and one of the leading causes of hospital mortality. Researchers and clinicians have realized that the systemic inflammatory response syndrome concept for defining sepsis is less useful and lacks specificity. The predisposition, infection (or insult), response and organ dysfunction (PIRO) staging of sepsis similar to malignant diseases (TNM staging) might give better information. Materials and Methods: A prospective observational study was conducted in emergency medical services attached to medicine department of a tertiary care hospital in Northern India. Patients with age 18 years or more with proven sepsis were included in the first 24 hours of the diagnosis. Two hundred patients were recruited. Multivariate logistic regression analysis was done to assess the factors that predicted in-hospital mortality. Results: Two hundred patients with proven sepsis, admitted to the emergency medical services were analysed. Male preponderance was noted (M: F ratio = 1.6:1). Mean age of study cohort was 50.50 ± 16.30 years. Out of 200 patients, 116 (58%) had in-hospital mortality. In multivariate logistic regression analysis, the factors independently associated with in-hospital mortality for predisposition component of PIRO staging were age >70 years, chronic obstructive pulmonary disease, chronic liver disease, cancer and presence of foley's catheter; for infection/ insult were pneumonia, urinary tract infection and meningitis/encephalitis; for response variable were tachypnea (respiratory rate >20/minute) and bandemia (band >5%). Organ dysfunction variables associated with hospital mortality were systolic blood pressure <90mm Hg, prolonged activated partial thromboplastin time, raised serum creatinine, partial pressure of oxygen in arterial blood/ fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio <300, decreased urine output in first two hours of emergency presentation and Glasgow coma scale ≤9. Each of the components of PIRO had good predictive capability for in-hospital mortality but the total score was more accurate than the individual score and increasing PIRO score was associated with higher in-hospital mortality. The area under receiver operating characteristic curve for cumulative PIRO staging system as a predictor of in-hospital mortality was 0.94. Conclusion: This study finds PIRO staging as an important tool to stratify and prognosticate hospitalised patients with sepsis at a tertiary care center. The simplicity of score makes it more practical to be used in busy emergencies as it is based on four easily assessable components.
Keywords: Emergency services, infection, organ dysfunction, predisposition, response, sepsis
Sepsis is one of the leading causes of death worldwide. Its incidence is increasing though mortality attributed to it has decreased over the years at least in developed world. , A proper operational definition was coined for sepsis in 1991 to facilitate standardized enrolment into clinical trials.  However, with years of experience clinicians and researchers had realized that the systemic inflammatory response syndrome concept is less useful than originally thought and lacks specificity and clinical utility.  International Sepsis Definitions Conference in 2001 proposed a new sophisticated but more conceptual way of looking at sepsis syndrome: The predisposition, infection (or insult), response and organ dysfunction, also called as "PIRO" staging. 
Sepsis is a dynamic process involving humoral and cellular immune reactions leading to systemic inflammatory and anti-inflammatory responses, and coagulation abnormalities.  It should be realized that sepsis is manifestation of many different infective disease states. This heterogeneity makes risk stratification for short term prognostication and response to therapeutic interventions difficult in these patients. A few scoring systems like Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score (SAPS) have been proposed but none of them is specific for sepsis patients and most of these scoring systems have been more predictive for large populations than individual patients and are more predictive of organ dysfunction. ,, Moreover, with the recent understanding of the pathophysiology of sepsis, the limitations of these scoring systems have come into the picture. The PIRO staging system emphasizes on accurately describing the phenotype of a patient with sepsis similar to the tumour, nodes, metastasis (TNM) model in malignancies. 
Each individual behaves differently to the same illness/insult/injury and the response to therapy is also not similar. Equally important is that all infections are not similar and the prognosis differs based on infection site, type of organism, extent of infection and response of the patient to infection as well as therapy. Patients might have significantly different responses to treatment based on their PIRO scores. Therefore, characterization and classification of a patient's phenotype based on parameters of PIRO staging would be more useful for enrolment in to interventional studies and prognostication as well as for better understanding of the pathophysiology of sepsis.
There are few studies which have shown the clinical utility of the PIRO staging in different clinical setting, mostly in the ICU setting. ,,,,,,,, Sepsis is one of the leading causes of emergency visits in our hospital and we expect same situation in other hospitals in developing countries too. However, there is no study published from Indian subcontinent to address this important issue. Therefore we planned this study with the aim to develop a PIRO staging model for sepsis in the emergency setting.
This prospective observational study was conducted in emergency medical services attached to medicine department of a tertiary care hospital in Northern India over 10 month's period. Patients with age 18 years or more with proven sepsis were included in the first 24 hours of the diagnosis. Two hundred patients were recruited. Sepsis was defined based on diagnostic criteria given in the 2001 International Sepsis Definitions Conference.  Diagnosis of various infections was done according to the CDC criteria.  We included variables for development of PIRO staging defined in the 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference guideline document where mention of this staging system was made.  Importantly, logistics and feasibility regarding testing of many response and some organ dysfunction variables impacted the decision to include those variables in final model. The different variables which were considered for development of PIRO staging are given below:
The final outcome was in-hospital mortality. Various demographic, clinical examination data pertaining to patients were recorded in a predesigned instrument. Laboratory evaluation routinely done for all patients with sepsis at first contact with health system at emergency services was also recorded in proforma. All patients were followed up during entire hospital stay i.e., till discharge or death. All patients or their legally authorized representatives provided written informed consent. The study was approved by the institute ethics committee.
Data were expressed as percentages (%), mean ± SD, or median and 25% to 75% inter-quartile range (IQR), as appropriate. Patients were divided into hospital survivors and non-survivors. The dichotomous variables were created using clinically relevant thresholds. Continuous, normally distributed variables were compared with t-test, and for non-normally distributed, Mann-Whitney U-test was used. Categorical variables were compared by means of chi-square test. Any variable with a P value of 0.05 or less was eligible for inclusion in a logistic regression model for their corresponding individual component of the PIRO staging. Next, a stepwise logistic regression was performed to create a separate model for each component of PIRO (P, I, R, and O) to yield four final models of significant predictors of hospital mortality. Discrimination was assessed by using the area under the receiver operating characteristics curve (AUC). Finally a weighted integer score for each parameter of the PIRO score was calculated. The total PIRO score was obtained by addition of the individual P, I, R, and O integer scores. To create the weighted integer score for each parameter of the PIRO score, individual values were calculated by dividing the β-coefficient from the regression model for each independent predictor in each group by total β-coefficient and multiplying it by a multiplication factor. Multiplication factor was 5 if total beta coefficient of group was <5 and if >5 then multiplication factor was 10. Using the β-coefficient for each covariate, we created a weighted clinical decision rule by assigning a corresponding integer value for each covariate to yield the final PIRO Score. All the statistical tests performed were two tailed; P < 0.05 was considered statistically significant. Analysis was done using the statistical software " IBM SPSS version 21.0" (IBM Corp., Chicago, USA).
Two hundred adult (age ≥18 years) patients with proven sepsis, admitted to the emergency medical services were included within the first 24 hours of the diagnosis of sepsis. Male preponderance was noted (M:F ratio = 1.6:1). Mean age of study cohort was 50.50 ± 16.30 years. Out of 200 patients, 116 (58%) had in-hospital mortality. Details of demographic, clinical, microbiological and laboratory characteristics of study cohort have been further elaborated in [Table 1]a-e.
Various predisposing factors were noted and analysed. In univariate analysis, factors significantly associated with in-hospital mortality concerning P component were age >70 years, COPD, DM, CLD, cancer and presence of foley's catheter [Table 2]. In the multivariate logistic regression analysis predisposing factors independently associated with in-hospital mortality were age >70 years, COPD, CLD, cancer and presence of foley's catheter [Table 6].
Pneumonia, urinary tract infection and meningitis/encephalitis were the infections significantly associated with in-hospital mortality, concerning I component in univariate analysis [Table 3]. In the multivariate logistic regression analysis, same variables were associated with in-hospital mortality as found in initial univariate analysis [Table 6].
Response variables significantly associated with mortality in univariate and multivariate logistic regression analysis were respiratory rate >20/minute and band forms >5% [Table 4] and [Table 6].
Organ dysfunction variables significantly associated with mortality in univariate analysis were systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), prothrombin time (PT), activated partial thromboplastin time (APTT), serum creatinine, PaO 2 /FiO 2 ratio, urinary output in first two hours of emergency presentation, vasopressor use and GCS ≤9 [Table 5]. In multivariate analysis factors associated with in-hospital mortality were SBP <90 mm Hg, prolonged APTT (>35 sec), raised serum creatinine (>1.8 mg/dL), PaO 2 /FiO 2 <300, decreased urinary output in first two hours of emergency presentation (<30 ml) and GCS ≤9 [Table 6].
Using the β-coefficient for each covariate, we created a weighted clinical decision rule by assigning a corresponding integer value for each covariate to yield the final PIRO Score [Table 7]. Each of the components of PIRO had good predictive capability for in-hospital mortality but the total score was more accurate than the individual score. We grouped the patients into logical categories by PIRO score; an increasing PIRO score was associated with higher in-hospital mortality [Figure 1]. The area under the curve for cumulative PIRO score as a predictor of in-hospital mortality was 0.94 [Table 8].
This prospective observational study undertaken in patients with sepsis admitted to emergency medical services of a large tertiary care center identified a group of variables associated with each component of the PIRO staging system independently associated with hospital mortality.
There is an enormous heterogeneity in the patients with sepsis presenting to emergency medical services of a large tertiary care center. Importantly, severity of illness is due to combination of the type and intensity of the initial insult, impacting on a patient with comorbidities and individual genetic backgrounds. The combination of these factors may result in variable degree and type of organ dysfunction. This calls for development of uniform risk assessment score for patients with sepsis which could incorporate factors like demographic profile, co-morbidities, type and intensity of infection; and lastly pattern and degree of organ involvement. It has been suggested that staging of sepsis similar to cancer staging (TNM staging) might give better information to assess risk and predict outcome in these patients, help in enrolment of patients into clinical studies and might also help in assessing the likely patient response to specific therapeutic interventions. The PIRO concept of classification scheme for sepsis includes predisposing condition, nature and the extent of insult, the nature and magnitude of host response, pattern and the degree of organ dysfunction. Recently this concept has been validated in studies done in western countries and it could successfully predict the risk of mortality in patients with sepsis. This proposed staging system is unique in that it considers multiple different known independent predictors of outcome. This prospective derivation study is possibly one of the first few studies done in Indian subcontinent. It confirmed findings from previous studies concerning predisposing factors, procedures, type of infections and; type and severity of organ dysfunction associated with increased risk of mortality in patients with sepsis. Rello et al. created a severity assessment score based on the PIRO concept in patients with severe community-acquired pneumonia in a historical cohort of 529 patients from the CAPUCI study. They compared the performance of the PIRO score with the APACHE II score and 2007 American Thoracic Society/Infectious Disease Society of America criteria as a prognostic index. It performed better to identify patients with higher risk of 28-day mortality.  Lisboa et al. derived a PIRO score for 441 ICU patients with ventilator associated pneumonia. It performed better than APACHE II score.  These studies though, were restricted to a specific cohort of patients admitted in ICUs. Our study developed a clinical staging system in patients presenting in emergency medical services with features of sepsis with various types of infective disease conditions and wide range of disease severity, widening its application to the broad range of infected patients. Howell et al. did secondary analysis of three prospectively collected, observational cohorts of patients with clinically suspected infection admitted to the hospital from the emergency department to derive a sepsis staging system based on the PIRO concept that risk stratifies patients. Validation of the staging system was undertaken in independent internal and external cohorts. There was a stepwise increase in mortality with increasing PIRO score. They however included patients with suspected infection and did not procure subsequent information from their hospital course. Considering the low mortality rate, there is high possibility that patients without sepsis might have been included in this study.  Our study included patients with proven sepsis only, thus minimizing selection bias. Studies undertaken by Rubulotta and Moreno et al. on the other hand were based on secondary analysis of cohorts with different primary objectives. , In another prospective, multicenter observational study from Portugal by Granja et al., included biomarkers as well in the response category and took a dynamic view of the patient's daily clinical course to formulate the score and finally concluded that this novel approach to PIRO concept and overall score can be a better predictor of mortality for patients with community-acquired sepsis admitted to ICUs. 
In study by Howell et al. in patients admitted to emergency services AUC of PIRO in predicting in-hospital mortality was 0.90 in the derivation cohort, 0.86 in the internal validation cohort, and 0.83 in the external validation cohort.  Nguyen et al. compared the performance of PIRO score with APACHE II and MEDS scores in patients admitted into the emergency department with sepsis with hospital mortality as primary outcome. The discrimination power of PIRO (AUC = 0.71) was better than MEDS but similar to APACHE II score.  Chen et al. carried a prospective observational study in emergency department involving 680 patients with sepsis to assess the performance of PIRO in predicting multiple organ dysfunction, intensive care unit admission, and 28-day mortality. The AUC of PIRO in predicting 28 day mortality was 0.90.  In our study, AUC for cumulative PIRO staging system as a predictor of hospital mortality was 0.94, higher as compared to previous studies with similar patient population i.e. from emergency area with sepsis. In another study by Cardoso et al., patients with infections (n = 1035) admitted in various wards of a large tertiary care hospital over a period of one year were analysed. The combined PIRO model as a predictor for mortality had an AUC of 0.85 in the derivation cohort and 0.84 in the validation cohort. 
The other merits of our study are the simplicity of score making it more practical to be used in busy emergencies as it is based on four easily assessable components. This staging system can be used for risk stratification in patients with sepsis. It represents a highly effective and easy to perform tool applicable for categorization and prognostication in emergency medical services patients.
Our study also has certain limitations. The sample size was small. This staging system needs validation in larger set of patients. As this was a prospective observational study, bias associated with these studies e.g. ascertainment bias, informational bias cannot be excluded. Our model did not include information on variables reflecting genetic polymorphism known to place patients at increased risk of severe infection and adverse outcomes. We included limited variables in R component. Various biomarkers of response such as CRP, procalcitonin, inflammatory cytokines and coagulation protein should be included in future studies to more accurately characterize this component. Many of these biomarkers are not routinely available to clinicians and researchers especially those from developing world at present. Sepsis is a dynamic process, therefore sequential changes in biomarkers and patterns of variation in organ dysfunction during hospital stay might be more important than single values at the time of emergency presentation.
In conclusion, this prospective observational study finds PIRO staging as an important tool to stratify and prognosticate hospitalised patients with sepsis at a tertiary care center. The simplicity of score makes it more practical to be used in busy emergencies as it is based on four easily assessable components.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]