Gallbladder (GB) diseases are uncommon in children and adolescents. Cholecystitis during childhood and adolescence is a rare condition, and seldom considered in the evaluation of childhood abdominal pain (1). In comparison with adults, in whom only 2% to 17% of cases of cholecystitis are caused by nonbiliary stone diseases, 30% to 50% of pediatric cases of cholecystitis are acalculous (2,3). Acute acalculous cholecystitis (AAC) in children has been found to be associated with intercurrent infections, metabolic disorders, vascular problems, burn, trauma, and malignant diseases (3,4).
The exact etiology and pathogenesis of AAC remain unclear; however, AAC is frequently considered to be a complication of a severe systemic inflammation. Ternberg and Keating (5) analyzed 74 cases of AAC in children, 60% of which developed in association with a systemic infection. It is postulated that sepsis, shock, and trauma cause GB ischemia and biliary stasis, which may predispose to AAC (6,7). The causative agents of infectious disease–associated AAC varied in different backgrounds (5,8,9). It is critical that the infectious etiology of childhood AAC in tropical and subtropical areas where infectious diseases are dominant be understood.
Sonography and computed tomography are the diagnostic imaging modalities of choice for patients with AAC (10,11). Various sonographic criteria for the diagnosis of AAC have been published (10,12); however, whether the severity of sonographic findings correlated with clinical outcome has not been well established. Treatment of AAC, from nonoperative treatment to cholecystectomy, has been controversial (6,13–15). The outcomes of AAC vary from self-limitation to a surgical emergency with potentially fatal complications. Delayed diagnosis or misdiagnosis of AAC may cause increases in morbidity and mortality rates (16).
Considering the sporadic presentation of AAC, the etiologic pattern and clinical spectrum of this disease in children have not been well established. Furthermore, understanding the risk factors for developing serious complications should be the key strategy as progress is made in treating childhood AAC. We retrospectively reviewed the case records of all of the children treated in our institution to investigate the etiology, clinical presentation, and prognosis of this rare childhood disease.
PATIENTS AND METHODS
Study Design and Participants
From January 2000 to December 2009, the medical charts of all of the children younger than 18 years who were diagnosed as having AAC in a tertiary medical center were analyzed retrospectively. Patients with stones in the GB or biliary tract in sonographic examinations were excluded. The demographic characteristics, clinical presentations, etiologies, and laboratory findings were recorded. The treatment, presence of complications, and outcomes also were evaluated. We divided the patients into 2 groups based on survival or mortality.
Sonographic Examination, Diagnostic Criteria, and Scoring of AAC
Diagnosis was suspected clinically and confirmed by sonography. Sonographic examination of the GB and right upper quadrant was performed by an experienced gastroenterologist using real-time sonography (Toshiba/SSA-550A, Tokyo, Japan). All of the images were obtained with either a 3.5- or 9-MHz transducer. The examinations were performed with patients in the supine position after at least a 6-hour fast. The sonographic studies were retrospectively reviewed by 2 pediatric gastroenterologists to exclude controversial cases.
AAC was defined as a GB wall thickness of >3.5 mm and duration of symptoms for <1 month. The sonographic findings were scored, with 1 point each given for wall thickness >3.5 mm, GB distention to 2 cm or more transversely and to 6 cm or more longitudinally in diameter, sludge (echogenic materials not casting an acoustic shadow) in the GB, and pericholecystic fluid collection (13).
The differences between patients with survival and mortality were assessed by the χ2 or independent t test for nominal or continuous variables, respectively. The Mann-Whitney U test was used to analyze the statistical significance of nonparametric data of sonographic scores for the severity of AAC between the 2 groups. Multiple logistic regression analysis was used to evaluate the independent factor for mortality among the significant variables tested by χ2 or independent t test analysis. A value of P < 0.05 was considered to be significant.
Demographic Data and Characteristics of Patients With AAC
A total of 109 children were diagnosed as having AAC. The prevalence of childhood AAC based on sonographic examinations was 0.8% during the study period. The demographic data, clinical manifestations, and laboratory findings are shown in Table 1. There were 59 boys and 50 girls. Ages ranged from 4 days to 18 years, with a median of 4.9 years. The 4-day-old patient was a newborn girl diagnosed as having congenital complex heart disease with congestive heart failure and septic shock. The most common clinical presentations were fever (88%), hepatomegaly (72%), jaundice (49%), and abdominal pain (40%). Twenty-five percent of patients had septic shock on admission. Laboratory investigations showed 25% leukocytosis (white blood cell count >15,000/mm3), 36% leukopenia (white blood cell count <4000/mm3), 46% anemia (hemoglobin <10 g/dL), 65% thrombocytopenia (platelet count <1.5 × 105/mm3), 82% elevated aspartate aminotransferase (>40 U/L), 72% elevated alanine aminotransferase (>55 U/L), 45% hypoalbuminemia (albumin <2.5 g/dL), and 13% hypofibrinogenemia (fibrinogen <150 mg/dL).
Predisposing Etiologies of AAC
Table 2 illustrates the clinical conditions related to AAC in our patients. Eighty-one (74%) of 109 patients had infectious diseases. Among them, the common associated diseases were septic shock (33%), infectious mononucleosis (25%), and virus-associated hemophagocytic syndrome (22%). Results of blood cultures for bacteria and fungi of patients with AAC were positive in 15 (14%) patients. Streptococcus pneumoniae and Pseudomonas aeruginosa were the most frequently isolated organisms in blood (Table 3). Other associated viruses consisted of hepatitis A virus, dengue virus, and cytomegalovirus. Furthermore, 10% of infections were caused by noninfectious systemic illnesses, including systemic lupus erythematosus and Wilson disease. In addition, 10 (9%) subjects had malignant diseases, especially hematologic malignancy (acute lymphoblastic leukemia and non-Hodgkin lymphoma). In patients with malignant diseases, 5 of them were undergoing chemotherapy when they had AAC.
Sonographic Findings and Scoring
Table 4 showed the sonographic findings in patients with AAC. Besides GB wall thickening, other common diagnostic criteria were GB distension (34%), sludge in GB (15%), and pericholecystic fluid (14%) in sonographic examinations. The combination of at least 2 sonographic criteria was noted in 46% of patients (36 subjects with 2 points, 10 with 3 points, and 4 with 4 points).
Outcomes of Patients
All of our patients were treated nonoperatively with nasogastric suction, intravenous fluids, or antibiotics. Sixteen (15%) patients died of sepsis, shock, or multiple organ failure. The mortality rates were 17%, 0%, and 20% in patients with infectious diseases, systemic illnesses, and malignant diseases, respectively. There was no significant difference in the outcome among the different etiologies (P = 0.31). The underlying conditions in these patients were septic shock in 11, virus-associated hemophagocytic syndrome in 2, malignancy-associated hemophagocytic syndrome in 1, acute lymphoblastic leukemia in 1, and cytomegalovirus infection in 1. The mean period from diagnosis of AAC to mortality was 14.6 days in these patients (range 4–42 days).
Risk Factors Correlated to Mortality in Children With AAC
The differences of demographic, clinical, and laboratory characteristics between the 2 groups with survival and mortality are assessed in Table 1 and Table 4. Children with mortality related to AAC had a significantly higher rate of septic shock (P < 0.001), anemia (P = 0.01), thrombocytopenia (P = 0.04), and hypofibrinogenemia (P = 0.002) than those with survival. There were no significant differences between the 2 groups in terms of age, sex, white blood cell counts, and values of liver biochemistry, bilirubin, alkaline phosphatase, lactate dehydrogenase, albumin, and C-reactive protein. In sonographic examinations, the patients with fatal outcomes had a higher rate of presence of pericholecystic fluid (P = 0.04) and a higher sonographic score (P = 0.04) than the survivors. Using multiple logistic regression analysis, the presence of septic shock (P = 0.004) and hypofibrinogenemia (P = 0.014) were 2 independent risk factors to determine the poor outcomes in children with AAC.
AAC is usually complicated by serious medical illnesses (3,4). The prevalence of this disease in children is uncertain because we lack large serial reports. The age distribution of our cases varied, with a median of 4.9 years, which was younger than that (7.8–9.0 years) in previous articles (13,17). Although boys were predominant in the previous reports, the sex ratio in our study was equal (6,13,17).
The clinical presentations and laboratory data of childhood AAC were related to the underlying diseases and were nonspecific. Hence, the clinical diagnosis of AAC was difficult. Most of our patients had fever. Other common manifestations were hepatomegaly (72%) and jaundice (49%). With regard to laboratory data, abnormal liver function test (72%), thrombocytopenia (65%), anemia (46%), and hypoalbuminemia (45%) were frequent findings. In our opinion, AAC should be considered in every patient who is critically ill and who has clinical findings of sepsis.
Similar to other reports, AAC in our series was most commonly associated with infectious diseases (74%) and systemic medical illnesses (10%) (5–7). Bacteremia, fungemia, and systemic viral infections have been reported to be associated with childhood AAC (5,8,9). In contrast to previous reports, in which infection caused by Gram-negative bacilli was most prevalent, S pneumoniae was the most common bacterial pathogen isolated in our series. The pneumococcal conjugated vaccine (PCV7) has been available in Taiwan only since 2006, hence most children studied had not been vaccinated. It is possible that with vaccination, the number of children with AAC caused by S pneumoniae may be lower in the future. AAC occurring in the course of primary Epstein-Barr virus infection in childhood was uncommon (8), but in our series, Epstein-Barr virus was the most frequent pathogen to cause infectious diseases in AAC, including infectious mononucleosis and hemophagocytic syndrome. Therefore, not only septicemia but also viremia impairs hepatocytes’ transport of bile acid, which subsequently causes clinical presentations of AAC (18). Few cases of childhood AAC associated with noninfectious diseases, such as systemic lupus erythematosus, Wilson disease, and Kawasaki disease, were present in our patients, as in earlier reviews (19,20). Of note, 10 (9%) subjects of our patients with AAC were related to malignant diseases. Despite various etiologies of AAC identified in previous reports, AAC associated with malignant diseases was rare (3,4).
Sonography was the main diagnostic modality for patients with AAC (10,11). The sensitivity of sonography for this condition ranges from 80% to 100%, and specificity ranges from 60% to 100% (21,22). In the present study, we defined the diagnostic criteria of AAC as GB wall thickening >3.5 mm based on the exclusive finding of patients who underwent laparotomy in previous studies (6,13,17). Other sonographic findings, including distended GB, sludge, and pericholecystic fluid for the diagnosis of AAC, have been reported (10,12). By scoring these sonographic findings with 1 point each, the severity scores of sonographic findings ranged from 1 to 4. We found that the patients who died had a higher mean score than those who survived (P = 0.04). In particular, the presence of pericholecystic fluid was greatly correlated with death (P = 0.04). Therefore, the sonographic scoring system could be a useful tool to predict the prognosis of childhood AAC.
Therapeutic management strategies for AAC range from medical treatment to cholecystostomy or cholecystectomy (6,13–15). In our series, all of the patients were treated medically. Sixteen patients died of sepsis, shock, or multiple organ failure, with a high mortality rate of 15%; however, no patient was found to have definite morbidity of the GB, such as perforation, gangrene, or empyema. In cases of AAC that are secondary to infection, management with appropriate intravenous antibiotics has been shown to be adequate (15). Otherwise, Tsakayannis et al (6) believed that nonoperative management of AAC may be appropriate for only selected critically ill children who had an underlying disorder. A strategy for managing AAC based on daily sonographic examination was reported in 2002 (13).
The outcome of AAC varies from self-limitation to a surgical emergency with potentially fatal complications (6,13,14). To our knowledge, risk factors to predict mortality in childhood AAC have never been reported. Therefore, in the present study, we attempted to identify the risk factors associated with consequent fatalities. The results revealed that the patients with septic shock, anemia, thrombocytopenia, hypofibrinogenemia, the presence of pericholecystic fluid, and higher sonographic scores were correlated with a poor outcome. Moreover, multiple logistic analysis further confirmed that 2 independent factors to predict mortality in childhood AAC were the presence of septic shock and hypofibrinogenemia. The main limitation of the present study was a small case number in the mortality group. This may make the sonographic predictors, the presence of pericholecystic fluid and higher sonographic scores, not significantly different between survival and mortality groups in the multiple logistic analysis.
In summary, childhood AAC is secondary to a variety of etiologies, especially during the course of infectious disease. A low value of hemoglobin, platelet count, and fibrinogen; the presence of pericholecystic fluid; high sonographic scores; and septic shock are risk factors of mortality in childhood AAC.
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