IE is a fatal disease with diversity of clinical manifestations and risk factors, continuing to be associated with high mortality despite of novel diagnostic and therapeutic strategies[1]. The demographics, predisposing factors, clinical features, and microbiological spectrum of IE have evolved in recent decades. Relative studies remain scarce in China, and are usually of small sample. Our study was aimed to better understand the regional characteristics and the changing profile of IE over 18 years in our hospital, and to evaluate independent factors that influence the outcome of IE. To our knowledge, this is the largest study on IE performed in our region over 18 years.
Clinical features
Many studies detected an increase in cases of IVDU-related IE, a trend that has been documented in Australia[15], America[16-18] and Sweden[19]. Conversely, in our study, the proportion of IVDU-related IE declined by half in later-period group as the Chinese government had been stepping up efforts to crack down drug cartels[20], which might play an important reason for the changing profile of IE for 18 years in our region. IE patients in developed countries[8, 21-24] were markedly older than developing regions[10, 24-26]. The mean age of IE patients in the International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS), the largest cohort study of IE worldwide, was 57.9 years old[6], far older than ours (42.3 years old). As the young are more likely to be exposed to drugs compared to the middle-age and the old[17, 27], the downward trend of intravenous drugs abusing may be responsible for upward tendency of onset age in the later-period group. It is generally known that IVDU-related IE is more likely to be Staphylococcus aureus-related, and usually more frequently occur on tricuspid valve[27, 28]. With the significantly lower proportion of IVDUs, Staphylococcus aureus cultured from blood and vegetations on tricuspid valve decreased strikingly in the later-period group. Meanwhile, the decrease of patients with pulmonary embolism in the later-period group could be explained by less numerous right-sided IE. Besides, the lower occurrence of renal insufficiency in the later-period group might benefit from the reduction in Staphylococcus aureus, which was perceived as a risk factors for acute renal failure in some study[29].
Beyond the IVDU-related IE, there were still some other points below worth mentioning.
IE patients of the later-period group developed less ischemic stroke. Previous studies reported that Staphylococcus aureus infection and vegetations on the mitral valve were risk factors for ischemic stroke[30, 31], but among the patients in this study, the later-period group showed a lower percentage of Staphylococcus aureus infection and a nonsignificant rise in patients with mitral vegetations. We speculate that an older age at onset and a higher proportion of diabetics may play a more important role in triggering ischemic stroke.
The ICE-PCS reported that 87.1% of cases had echocardiographic evidence of vegetation[6], similar to our data. The negative echocardiography results(absence of vegetations) is still a stumbling block to diagnosis, which increased significantly in the later-period group. The most frequent explanations for a negative echocardiogram are very small vegetations, non-oscillating and/or atypically located vegetations, or severe, pre-existing lesions from rheumatic heart disease or degenerative heart disease in heart valves[32]. For suspected cases or cases with negative TTE, especially when a prosthetic heart valve or an intracardiac device is present, the appliance of TOE is strongly recommended[11, 32]. However, we observed that TOE was rarely applied to above cases in our study, which exactly need an improvement.
Up to 41.8% of patients were blood-culture negative in our study, which was similar to other region of China(from 31.4% to 51%)[10, 26, 33]. According to the available literature, the incidence of BCNE has been reported to be 7% in North America[6], 5.2-24% in Europe[9, 24, 34, 35], 20% in Japan[36], 20% in South America[6], 31-69% in South Asia[24, 37, 38]. Therefore we could draw a conclusion that BCNE occurs more frequently in developing countries. BCNE is associated with inappropriate antibiotic treatment, faulty culture techniques, atypical pathogens that are difficult to culture or identify[39]. Among these factors, the misuse and overuse of antibiotics remained a problem, especially for patients with long-term fever. Atypical pathogens can be identified by serological analysis and polymerase chain reaction (PCR) assays of blood and pathological specimens[40], which is difficult to realize in clinical practice due to economic and subjective factors. With the development of improved microbial culture techniques, increased medical expertise, and more accurate specifications for the diagnostic and treatment processes, the negative blood-culture rate achieved a remarkable decline in the later-period group. Still, there is room for improvement and research efforts need to be continued.
A systematic review of 21 regional literatures in the world revealed that the average fatality rate of IE is 21.1% ± 10.4%[2], and the ICE-PCS pointed out the in-hospital mortality was 18% worldwide by average[6]. The in-hospital mortality of our study was 11.2%, nearly approaching to the lower limit and quite similar to another research conducted in East China (10.9%). Moreover, it is noteworthy that even with the novel diagnostic and therapeutic strategies available now, the in-hospital mortality did not strikingly differ between the two groups, which means minimizing the in-hospital mortality of IE is still a long-term undertaking.
Risk factors for in-hospital mortality
To explore the independent risk factors for in-hospital mortality, we performed a forward stepwise logistic regression analysis model. The results indicated that IVDUs, prosthetic valve endocarditis[6, 41], hemorrhagic stroke, acute congestive heart failure[26, 42-44], renal insufficiency[42], left-sided endocarditis and early surgical treatment[6, 44-46] were the independent determinants of in-hospital mortality. Among these factors, prosthetic valve endocarditis had the highest odds ratio. Many of them are also confirmed by previous researches. Some factors, such as age, embolism (or Ischemic stroke), health-related endocarditis. were finally ruled out from forward stepwise method logistic regression analysis model, probably due to the multicollinearity with other variables. In other studies, increasing age, health care-associated IE, Staphylococcus aureus related IE, coagulase-negative staphylococcal infection, paravalvular complications and diabetes mellitus[6, 8, 47, 48] are also important factors contributing to the in-hospital mortality. These discrepancies may due to differences in samples and study design.
Early surgery has been proved to be associated with a significantly lower in-hospital mortality rate as compared to medical therapy[49, 50] Mortality of patients who underwent surgery was one sixth of that of patients who did not have the surgery. In our study, up to 59.7% of our patients underwent surgery during hospitalization, which is similar to other regions like Brazil (52.4-55.0%)[43], Spain (57.0%) and France (31.0-71.0%)[34], but relatively higher compared to Japan (17.0%)[8] and North America (45.0%). The ICE-PCSS showed that 46% of patients worldwide underwent early surgery[46]. In our studies, nearly 51.1% of cases were admitted to early surgery, which turned to be the only protective factor for prognosis of IE in our multivariate model. We believe that good standard of care in our hospital, and relatively younger age were a major reason for patients to make aggressive decision of surgical treatment.
The difference of in-hospital mortality between IVDU-related IE and none-IVDU-related IE was reported to be of no significance in previous studies[18, 51, 52], inconsistent with our conclusion. We speculated that the higher Staphylococcus aureus septicemia and repeated infection brought by intravenous drugs busing might contribute to the higher in-hospital mortality. We strongly proposed to conduct more further studies so as to verify our conclusions.
limitation
This study focused on a single-center in a general teaching hospital without long-term follow-up. Most patients came from south China, thus findings in this study may not be applicable to all populations. Besides, referral bias should be taken into consideration when describing the clinical spectrum and outcome of IE, as patients with more complications such as stroke, heart failure and new valvular regurgitation and surgery indications, who are more likely to be gravely ill patients, are more likely to choose a tertiary hospital[53]. So our conclusions may not apply to small hospital. However, our observations reflected a dynamic change of IE in our center over a period of eighteen consecutive years with a relatively large sample size, while relative study remains scarce in China. The geographic variations observed in our study will be of important value to profile the clinical feature of China and offer the reference for clinical decisions in our region.