| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 106 === Background Heterotaxy syndrome is a kind of developmental defect. During fetal stage, normally, the thoracic and visceral organs including the lungs, tracheobronchi, heart, and visceral organs developed asymmetrically. However, in heteotaxy syndrome patients, internal organs developed in pairs as mirror images, instead of having the unique right and left asymmetry characteristics. It can be further divided into right atrial isomerism (RAI) and left atrial isomerism (LAI). In RAI, complex congenital heart disease (CHD) is very common, and spleen is always non-developed or mal-developed. They are also called asplenism. By contrary, the patients of LAI are also called polysplenism. The prevalence of RAI is significantly higher in Asian population, and it is a featured disease in Taiwan.
Patients with heterotaxy syndrome often associated with abnormal splenic function. Spleen is an important immune organ, and patients receiving splenectomy are susceptible to infection, including lethal overwhelming postsplenectomy infection. Therefore, the suspectibility to severe infection in these heterotaxy syndrome patients may be similar to postsplenectomy patients. Because of the frequent association with concomitant complex CHD, whether the increasing risk of infection is related to hyposplenism or repeated admission is unknown.
Immunological function of spleen is still difficult to evaluate nowadays. Traditionally, Howell-Jolly body count was suggested as a marker of hyposplenism. Neither is the sensitivity optimal nor is the count objective, which limits its clinical use. IgM memory B cell represents the potential counterpart of B lymphocyte in the marginal zone of the spleen, and has good correlation with splenic function. However, its clinical use is still uncertain.Patients with impaired splenic function is susceptible to encapsulated bacteria, such as pneumococcus. Pneumococcal vaccine, since its introduction, has changed the disease pattern and incidence of invasive pneumococcal disease, not only in general population but also in high risk patients. However, its protective function in heterotaxy patients is still unknown.
Thesis First, through the largest cohort in the world, we define the epidemiology data and risks of severe bacterial infection (SBI) in these heterotaxy patients.
Second, we delineate the clinical implication of I IgM memory B cell in predicting the high risk group of SBI in heterotaxy syndrome.
Third, we exam the efficacy of pneumococcal vaccine in these heterotaxy patients. We also investigate the pneumococcal vaccination status in these patients.
Methods and Results In epidemiology study, we enroll consecutive 95 patients with heterotaxy syndrome and 142 patients with other complex CHDs born between 2001 and 2011 in our hospital. SBI was defined as sepsis with positive culture results or infection with abscess formation at sterile sites. With 1026 person-years follow-up, the 5-year survival rate was 52% and 65.7% in heterotaxy and complex CHD groups, respectively (p=0.239). Community acquired SBI (CASBI) occurred only in heterotaxy syndrome (13 episodes in 10 patients) with 2 and 5 years cumulative SBI rate of 9.6% and 14.5%, respectively. The overall mortality rate of those with community acquired SBI was 31%. Pneumococcus and Citrobacter freundii were the most common pathogens. Nosocomial SBI occurred in 33.3% of all patients. The rates and the pathogens of nosocomial SBI were similar between heterotaxy and complex CHD groups. The results implied that heterotaxy syndrome patients are at high risk for community acquired SBI and also have high mortality rate.
Second, we enrolled 46 heterotaxy syndrome patients, aged > 1 year, and followed during the period 2010-2012 in our hospital. We analyzed IgM+IgD+memory B cell percentages. Patients with simple CHD and complex CHD served as controls. The mean IgM memory B cell were the lowest in the heterotaxy syndrome group, compared with those in complex CHD and simple CHD groups. In the heterotaxy syndrome group, 41.3% had low IgM memory B cell percentages (<1% of B cells). Seven had a history of community-acquired bacterial infection and 85.7% of these had low IgM memory B cell percentages, which was the only significant factor related to community-acquired bacterial infection. (p=0.028).
Third, we analyzed the pneumococcal vaccination status for all patients with heterotaxy and complex CHD in our institution between 2010 and 2015. The geometric mean concentrations (GMCs) of serotypes 6B, 14, 19F, and 23F did not differ significantly between patients with heterotaxy and those with complex CHD. The GMCs were also not affected by impaired splenic function. Most patients had GMCs higher than 0.35 μg/mL (protection level) 4-5 years after either PPV or PCV injection. In some patients, the durability of PPV and PCV decreased with time, highlighting the importance of booster doses. In addition, 21.4% of 42 patients with heterotaxy did not receive any dose of pneumococcal vaccine, and none of 42 patients completely adhered to the vaccine guidelines.
Conclusion From epidemiology study, we found the CASBI was significantly higher in heterotaxy syndrome than other complex CHD patients, with high mortality rate. We also found IgM memory B cell percentage by flow cytometery analysis was the best predictive marker of community-acquired BI. The pneumococcal vaccine efficacy was acceptable in the heterotaxy syndrome, even in patients with impaired splenic function. However, the adherence to the vaccination guideline is still unsatisfactory.
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