Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients

Abstract

A novel influenza A (H7N9) virus of avian origin emerged in eastern China in the spring of 2013. This virus causes severe disease in humans, including acute and often lethal respiratory failure. As of January 2014, 275 cases of H7N9-infected patients had been reported, highlighting the urgency of identifying biomarkers for predicting disease severity and fatal outcomes. Here, we show that plasma levels of angiotensin II, a major regulatory peptide of the renin-angiotensin system, are markedly elevated in H7N9 patients and are associated with disease progression. Moreover, the sustained high levels of angiotensin II in these patients are strongly correlated with mortality. The predictive value of angiotensin II is higher than that of C-reactive protein and some clinical parameters such as the PaO2/FiO2 ratio (partial pressure of arterial oxygen to the fraction of inspired oxygen). Our findings indicate that angiotensin II is a biomarker for lethality in flu infections.

Figure 1. Angiotensin II levels are increased in plasmas of H7N9-infected patients.

Among the study participants, 46 patients were infected with avian-origin H7N9 Influenza A virus (A-OIV H7N9) and 21 were infected with swine-origin H1N1 influenza A virus (S-OIV H1N1). In addition, six healthy volunteers, 46 CHD patients and 35 CHD patients with hypertension were recruited as controls. (a) Angiotensin II levels in plasma of healthy controls, CHD group, CHD with hypertension group, and during H7N9 or H1N1 infection. The number of infected individuals for each group was: day 0–7 group (H7N9: n=24; H1N1: n=10), day 8–14 group (H7N9: n=11; H1N1: n=7) and day 15 group (H7N9: n=11; H1N1: n=4). The horizontal lines represent the median value in each group. Detailed statistical information is shown in Supplementary Table 4. (b) Angiotensin II plasma levels at week 1 and week 2 in H7N9-infected patients hospitalized less than 28 days (n=11), hospitalized longer than 28 days (n=6) and deceased (n=5). The horizontal lines represent the mean value in each group. All experiments were in duplicate. Mann–Whiney U test and Wilcoxon matched-pair test were used in the statistics. *P<0.05, **P<0.01, ***P<0.001.

Figure 2. APACHE II scores are highly positively correlated with plasma angiotensin II levels in H7N9-infected patients.

APACHE II scores from 21 and 32 avian-origin H7N9 Influenza A virus (A-OIV H7N9)-infected patients were available for the first and second week’s correlation analysis, respectively. Spearman rank correlation analysis (ρ) and P value are provided in each graph.

Figure 3. Fatal outcome is linked to high plasma levels of angiotensin II in H7N9-infected patients.

Angiotensin II concentrations in plasma from the first and second week of illness caused by avian-origin H7N9 Influenza A virus (A-OIV H7N9) in different outcome groups. The number of patients and the time-period in which they died are as follows. Patients with plasma harvested during the first week of illness: patients hospitalized less than 28 days (n=12), death (n=5). Patients with plasma harvested during the second week of illness: patients hospitalized less than 28 days (n=16), death (n=8). The horizontal lines represent the median value in each group. Mann–Whiney U test was used in the statistics. *P<0.05.

Figure 4. Receiver operating characteristic (ROC) curve of plasma angiotensin II levels and other biomarkers during the second week of H7N9 infection.

ROC curve of the plasma angiotensin II levels, C-reactive protein (CRP), PaO₂/FiO₂ ratios, pneumonia severity index (PSI) scores and SMART-COP scores in the second week of avian-origin H7N9 Influenza A virus (A-OIV H7N9) infection are shown. Detailed information on the area under the ROC curve (AUC), the cut-off values, sensitivity, specificity, the positive predictive value (PPV), the negative predictive value (NPV), the positive likelihood ratio (PLR), the negative likelihood ratio (NLR) and Youden’s index are shown in Supplementary Tables 6–11.