The demographics, predisposing factors, clinical features, and microbiological spectrum of IE have all evolved in recent decades. Our study showed that in contrast with Chinese IE patients from the earlier time period, the clinical features in those from the later-period reflected the effects of older age at onset and less IVDU, and included similar manifestations despite more splenomegaly, fewer pulmonary embolisms and less renal dysfunction, but more complications from ischemic stroke. Also, the incidence of Staphylococcus aureus represented in the increased BC-positive rate was significantly decreased in the later-period group. Echocardiography showed that this group had fewer vegetations on the right heart.
IE has a well-recognized and consistent male predominance, although some studies did show a gradually increasing rate in females. Among the 313 IE patients in this study, the male-female ratio remained 2.6:1 over the 19-year period. Patients in the later-period group were older than those from the early-period group (44.9 ± 15.4 vs 36.5 ± 15.2, P<0.001), which was roughly similar to that reported in neighboring regions [8, 13, 14], but far younger than in developed countries [5, 12, 15]. The upward tendency of onset age was mainly reflected in the increase of patients aged 41-60 (43.1% vs 23.7%, P = 0.001, 0R = 2.433) and the reduction of patients aged 21-40 (35.2% vs 56.7%, P<0.001, OR = 0.415), which was probably related to the proportion of IVDUs. Compared with middle-aged and elderly people, young adults are more likely to be exposed to drugs. The use of intravenous drugs has been declining year by year in our country after the government launched a series of policies against drug use. Our study supported this conclusion because the percentage of IE patients who had been drug users decreased in the later-period group (12.0% vs 25.8%, P = 0.002, OR = 0.394), which was possibly responsible for the upward trend of the average onset age. In addition, the decrease in rheumatic heart disease from 22.7% to 17.6% and the increase in degenerative heart disease from 4.1% to 9.3%, although not significant, may lead to an increase in patients’ age.
Bacterial infection, cardiac signs and vascular embolism events, usually presenting as fever, heart murmurs and emboli to the brain, lung, spleen or kidney, are the three major clinical features of IE patients. In our study, fever, heart murmurs and embolic complications at the time of diagnosis accounted for 83.7%, 83.7% and 26.2% of patients respectively, which was similar to the data of the ESC guidelines.
The occurrence of splenomegaly is mainly due to bacteremia, and long-term stimulation of circulating immune complexes, leading to the proliferation of reticuloendothelial cells. We found that splenomegaly was more frequent in the later-period group (26.4% vs 15.5%, P = 0.034, OR = 1.960). This phenomenon had not previously been seen in domestic and foreign reports, owing perhaps to the development of improvements in imaging technology.
Ischemic stroke is one of the most common central nervous events in IE patients, and occurred in 22% of the patients in our study, and was more common in the later-period group (27.3% vs 10.3%, P = 0.001, OR = 3.269). It has been reported that Staphylococcus aureus infection and vegetations on the mitral valve were risk factors for ischemic stroke [18, 19], but among the patients in this study, the later-period group showed a lower percentage of Staphylococcus aureus infection (20.0% vs 41.3%, P = 0.004, OR = 0.355) and a nonsignificant rise in patients with mitral vegetations (34.7% vs 30.9%). We speculate that a significantly older age at onset and a higher proportion of diabetics (10.6% vs 5.2%) may play a more important role in triggering ischemic stroke. Pulmonary embolism occurs when blood clots break off from vegetations on right-sided endocardium or valves. The decrease of pulmonary embolism in the later-period group (1.9% vs 7.2%, P = 0.040, OR = 0.243) could be explained by less numerous right-sided IE compared to the early-period group (16.2% vs 25.8%, P = 0.047, OR = 0.557).
The decrease in pulmonary embolism may be responsible for the lower number of patients admitted to the respiratory department initially in the later-period group (4.6% vs 14.4%, P = 0.003, OR = 0.288). Some studies revealed that chronic heart failure, Staphylococcus aureus infection, and coagulase-negative staphylococci were associated with a high risk of renal failure.
Acute renal insufficiency was lower in the later-period group (6.0% vs 15.5%, P = 0.007, OR = 0.350), which may be benefitting from the reduction in Staphylococcus aureus infection and the downward trend in cardiac insufficiency (56.5% vs 61.9%) in recent years.
Blood culture-negative infective endocarditis is associated with inappropriate antibiotic treatment, faulty culture techniques, atypical pathogens that are difficult to culture or identify such as Mycoplasma, Legionella, and Bartonella, and fungal endocarditis. In this study, up to 40.5% of patients were blood-culture negative, which was far higher than that reported in western countries [4, 5]. 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, 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 (37.5% vs 52.6%, P = 0.012, OR = 0.541); still, there is room for improvement and research efforts need to be continued.
Gram-positive cocci were the predominant species among causative pathogens, accounting for 89.0% of all detected microorganisms, far ahead of the number of cases caused by Gram-negative bacilli (6.1%) and fungi (3.3%). Streptococcus (42.0%) and Staphylococcus aureus (25.4%) remain the most common pathogens. The incidence of Staphylococcus aureus decreased strikingly in the later-period group (20.0% vs 41.3%, P = 0.004, OR = 0.355), while the echocardiography results showed a lower proportion of tricuspid valve vegetations in the later-period group. This may be linked to the significantly lower proportion of IVDU since it is generally known that IVDU-related IE is more likely to involve Staphylococcus aureus and infection of the tricuspid valve[16, 23]. Therefore, as mentioned above, the reduced proportion of IVDU in recent years may indirectly contribute to the downward trend of Staphylococcus aureus infection and right-sided IE. By comparison, the increase of other gram-positive cocci (27.2% vs 13.0%, P=0.048, OR=2.517) might be attributed to the relatively uprising of other predisposing factors besides IVDU.
The vegetations visible by echocardiography are the hallmark lesions of IE. However, negative echocardiography results (absence of vegetations) were also seen to increase significantly in the later-period group (15.3%vs 6.2%, P = 0.024, OR = 2.735). It is well-known that a negative echocardiographic examination does not rule out IE, and the sensitivity of TTE for the diagnosis of vegetations is about 75%. 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. IE Patients in the later-period group had a higher proportion of degenerative valvular heart disease (9.3% vs 4.1%), which manifested as high-density calcification on echocardiograms and was hard to distinguish from vegetations, resulting in false negative results. In addition, the overuse of antibiotics may shrink the vegetations, making them difficult to identify by echocardiography.
A systematic review of twenty-one regional literatures in the world revealed that the average fatality rate of IE is 21.1% ± 10.4%, while the mortality rate of our study was 11.2%, approaching the lower limit. The results did not represent a high cure rate of IE because only the in-hospital mortality rate was calculated in our study without follow-up data. Some patients may have died after discharge. As a retrospective study, the time span was too large and the survival data of this part of the population was missing. Even with the novel diagnostic and therapeutic strategies available now, the in-hospital mortality did not strikingly differ between the two time periods, which means minimizing the in-hospital mortality of IE is still a long-term undertaking.
What we can't ignore is that 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. Therefore, how to promote the medical capability for treating critically ill patients with IE is a question that deservers further study. This study focused on a single-center in a general teaching hospital without long-term follow-up. Most patients came from southern China, thus findings in this study may not be applicable to all populations. However, IE is an uncommon disease and few studies have been conducted in China. Our observations reflected a dynamic change of IE over a period of eighteen consecutive years with a relatively large sample size. The geographic variations observed in our study will be of important value to clinicians attempting to diagnose IE in our region.
In conclusion, patients with IE in recent years were relatively older and had a lower history of IVDU, which was probably responsible for fewer presentations of pulmonary embolism and renal failure, a lower positive rate of Staphylococcus aureus infection and fewer right heart vegetations. However, a greater incidence of ischemic stroke was observed possibly due to older age and unidentified factors. However, the in-hospital mortality rate was about the same for the two periods, which is an issue that deserves follow-up study.