In this large population-based study, we used a nationally representative database and calculated the incidence of HUS in China for the first time. The incidence rate of HUS was 0.66 cases per 100,000 person-years, with a peak incidence in children younger than 1 year old (5.08 cases per 100,000 person-years). The season with the highest incidence of HUS was autumn (0.9 cases per 100,000 person-years). The total cost associated with HUS was 456.86 thousand US dollars per year, with an average of 2.15 thousand US dollars per patient per year.
The incidence of HUS is likely to be related to the incidence of STEC infections, as these infections are the most common cause of HUS and are usually epidemic. The epidemiologic features of HUS have been thoroughly studied in many countries. A wide range of incidences of HUS have been reported, depending on the diagnostic criteria and populations studied. The incidence of HUS was 0.66 cases per 100,000 person-years in China, which is lower than the 2.1 cases per 100,000 person-years reported in in the United Kingdom and 2.7 cases per 100,000 person-years in the United States.(11) However, the annual incidence of HUS has been reported to be 0.07 cases per 100,000 person-years in Australia and 0.28 cases per 100,000 person-years in Iran,(20) which are lower than our results. These differences may be caused by the following factors. First, our estimation of the incidence of HUS was extrapolated from the Urban Medical Insurance databases. Some studies have shown that urban residents may have a lower prevalence of STEC-HUS than rural residents. Cows, which are a reservoir of STEC, are much rarer in urban areas. In addition, because of better sanitary conditions in urban areas, the risk of gastroenteric infections with STEC is also reduced.(5) North American seroepidemiological surveys have shown higher frequencies of antibodies against the O157 lipopolysaccharide among residents of rural areas than among those of urban areas.(21) Second, HUS is a rare disease. Many physicians may have difficulty diagnosing of HUS. Some hospitals in developing countries may lack the laboratories and facilities required for an accurate diagnosis.(22) These factors may have caused the incidence of HUS in China to be underestimated. Third, the influence of ethnic factors is still unclear. In different study populations, there may also be differences in the genetic propensity to develop HUS.(5, 23)
In our study, the incidence was slightly higher in males than in females, but the difference was not significant. aHUS can be triggered by cancer and hypertension.(24, 25) Both the crude incidence rate of cancer and the prevalence of hypertension in China are higher among men than women(26, 27), which may be the reason the incidence of HUS is higher in men than in women. However, many previous studies reported a higher incidence of HUS in women. The reasons for the higher incidence in female patients are unknown, but it may be partially attributable to the increased risk of HUS after E. coli O157:H7 gastroenteritis in females(28-30)and some cases of aHUS have been found to be associated with pregnancy.(31) However, the proportions of HUS cases that were STEC-HUS and pregnancy-associated aHUS in our study were unknown. More research in the future is needed on specific triggers in female and male Chinese patients.
The incidence rate was highest in children <1 year of age, with an annual incidence rate of 5.08 cases per 100,000 person-years. However, many previous reports from Europe and North America showed the age group younger than 5 years was the most frequently affected, and the age-specific incidence of HUS is similar to that of STEC.(32-34)The incidence rate of HUS in Chinese children younger than 5 years old (0.38 cases per 100,000 person-years) was lower than those in the United States and Western Europe (1.57 to 3 cases per 100,000 person-years),(9, 32)but similar to the incidence of 0.49 cases per 100,000 person-years in Australia. This may be due to the low proportion of patients with STEC-HUS in our study. First, there are some different habits and customs in exposure to STEC; for example, Chinese people prefer fully cooked meat and boiled water. Second, the STEC infection rate is lower in urban areas than in rural areas.(5) At last, the peak season of HUS in our study was not summer, which is usually the season during which there is a high incidence of STEC infection. Therefore, we speculate that STEC may not be the main cause of HUS in China's urban population.
The peak incidence of HUS in our study was in autumn (0.9 cases per 100,000 person-years) and winter (0.7 cases per 100,000 person-years), which is different from other reports(35-37). In previous studies, HUS was most commonly triggered by STEC. The peak incidence of HUS was in summer, which is the peak incidence of STEC infections occurred. This significant seasonal difference suggests that STEC may not be the main cause of HUS in China, at least in the urban population. There are many risk factors for developing STEC-HUS that differ between China and Europe or the Americas, including eating habits, the local environment, meteorological conditions, and the population genetic background.(38) In China, we prefer fully cooked meat. Moreover, aHUS cases are relatively more common in adults. Most of the patients in our study were over the age of 18 years, accounting for approximately 98.1% of the total number, which was much higher than the proportion of adults with HUS reported elsewhere.(39) Furthermore, the lower pneumonia and influenza vaccination rates(40, 41) and high population density in China may lead to a relatively higher incidence of HUS associated with respiratory infections in autumn and winter. However, these speculations need investigation in the future.
The total cost incurred by HUS patients over our study period in the 16 provinces was 456.86 thousand US dollars per year, and the total expenses associated with the first hospitalization was 1,105.41 thousand US dollars. The average hospitalization cost for each HUS patient was 1.75 thousand US dollars, which is significantly higher than the national average hospitalization cost of 1.30 thousand US dollars per patient during the same period.(42) The total cost for each patient per year was 2.15 thousand US dollars per patient per year, which was also apparently higher than the national average medical care cost of urban residents (250 US dollars per patient).(42)The treatment of HUS includes supportive treatment, antibiotics, plasma infusion, plasma exchange, renal replacement therapy (CRRT or dialysis), and treatment for neurologic involvement. Most of these patients have to pay these high medical expenses. For example, the expense of single plasma exchange or CRRT session is approximately 1.50 thousand US dollars in China, and some patients may need to receive multiple treatments before recovery. In addition, eculizumab has been successfully used in patients with HUS in many countries but is still not available in China. This drug is expensive (for example the treatment of a child with a body weight of 30 kg would cost 350,000 US dollars per year), which imposes a significant economic burden.(32) Medical costs due to HUS may increase significantly after the introduction of eculizumab to the Chinese market in the near future. Finally, it is worth noting that some reports have highlighted that there has been an increase in morbidity due to HUS.(11) In this new situation, the prevalence of HUS becomes an important indicator for healthcare planning.
China's basic medical insurance system can cover approximately 95% of the population, and the combined basic population structure was close to the distribution in the Chinese 2010 census population data. However, the use of a medical insurance database still results in certain limitations. First, our data were extracted from urban populations. However, as STEC infection is more common in rural areas, we may have underestimated the annual incidence of STEC-HUS in China. Second, HUS is a rare disease, and many physicians in developing countries may not have enough clinical experience with this disease. The incidence rates of HUS in hospitals lacking diagnostic capabilities are probably underestimated. Third, newborns may not be insured for various reasons, but the insurance policy in China allows newborns to be covered by medical insurance for the first 90 days after birth. Moreover, the triggers for HUS in our patients were also not available. The current recommended diagnostic tests for HUS (such as Shiga toxin assay, Complement Factor H level, membrane cofactor protein expression, ect.) are not feasible for many hospitals of China. To develop better preventive measures and treatment,