Intussusception Among Young Children in Europe - CiteSeerX

SUPPLEMENT ARTICLE

Intussusception Among Young Children in Europe Hans-Iko Huppertz, Prof. Dr.,* Montse Soriano-Gabarro´, MD, MSc,† Emmanuel Grimprel, MD,‡ Elisabetta Franco, Prof,§ Zsofia Mezner, MD, PhD,储 Ulrich Desselberger, MD,¶ Yolba Smit, MD, MSc,# Judith Wolleswinkel-van den Bosch, PhD,# Beatrice De Vos, MD,† and Carlo Giaquinto, MD** Abstract: Intussusception, a potentially lethal condition with poorly understood etiology, is the most common cause of acute intestinal obstruction in children younger than 5 years old. In some cases, the condition has been associated with administration of the first licensed rotavirus vaccine, the reassortant rhesus-human tetravalent rotavirus vaccine (RRV-TV; RotaShield威). No such association has to date been reported from large phase III safety trials with new rotavirus vaccines. As 2 new, live-attenuated oral rotavirus vaccines are currently under review for approval by the European Union regulatory authorities, a review of the clinical, etiologic and epidemiologic aspects of intussusception in Europe is urgently needed. We conducted a review of Medline literature, published from 1995 onwards on intussusception in the World Health Organization’s European Region. The results are compared with data from previous reviews and other regions. The classic triad of intussusception symptoms (abdominal pain, abdominal mass, bloody stools) was present in 29–33% of patients according to the medical literature reviewed. Conservative treatment (barium, air or saline enema) was the rule (81% of cases), and few complications were observed during treatment. Treatment outcome was generally favorable, with recurrence occurring in ⬃1 in 10 patients, and only 1 death reported. Structural lead points were seen in 3% of patients; no other reliable data on the etiology of intussusception were found. The incidence of acute intussusception in young children in Europe, according to 6 heterogeneous hospital-based studies, ranged from 0.66 to 2.24 per 1000 children in inpatient departments and from 0.75 to 1.00 per 1000 children in emergency departments. Peak incidences were found in children 3–9 months of age. There are still gaps in our knowledge of intussusception with respect to its etiology and especially by which mechanisms RRV-TV might have caused it to occur. Data from regions outside Europe showed that rotavirus infection and disease are not associated

From *Prof.-Hess-Kinderklinik, Bremen, and Children’s Hospital, University of Go¨ttingen, Germany; †GlaxoSmithKline Biologicals, Rixensart, Belgium; ‡Hoˆpital d’Enfants Armand Trousseau, Paris, France; the §Department of Public Health, University Tor Vergata, Rome, Italy; the 㛳National Institute of Child Health, Budapest, Hungary; ¶Cambridge, United Kingdom; #Pallas Health Research and Consultancy, Rotterdam, the Netherlands; and the **Department of Pediatrics, University of Padova, Padova, Italy. Dr. Desselberger’s current address is the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy. Address for reprints: Prof. Dr. Hans-Iko Huppertz, Prof.-Hess-Kinderklinik, Sankt-Ju¨rgen-Strasse, 28177 Bremen, Germany. Fax 49 421-497-3311; E-mail [email protected]. Copyright © 2005 by Lippincott Williams & Wilkins ISSN: 0891-3668/06/2501-0022 DOI: 10.1097/01.inf.0000197713.32880.46

S22

with intussusception. As new rotavirus vaccines become available for use in Europe, postlicensure surveillance for intussusception is indicated and may be instrumental in further understanding the epidemiology of this condition and in further assessing the safety of future vaccines. Key Words: intussusception, epidemiology, Europe, rotavirus vaccine (Pediatr Infect Dis J 2006;25: S22–S29)

I

ntussusception is the most common cause of acute intestinal obstruction in infants, occurring when 1 portion of small bowel invaginates into a more distant portion of the bowel. Venous congestion and bowel wall edema can cause obstruction of the intestine, and infarction and perforation of the bowel wall can occur. If intussusception progresses and is not treated, it can eventually become fatal. Mortality caused by intussusception has become rare in developed countries through timely diagnosis and treatment with enema or surgery. In developing countries, patients might present with more serious illness, and mortality rates are higher because of limited access to health care.1 Intussusception has drawn additional attention from the pediatric medical community, because of its association with the first licensed rotavirus vaccine, the rhesus rotavirus (RRV), tetravalent (TV), human reassortant vaccine (RRV-TV; RotaShield威; Wyeth, Collegeville, PA) licensed in the United States. This risk led to withdrawal of the vaccine in 1999,2–4 but the underlying pathogenic mechanisms remain poorly understood.5 New rotavirus vaccines, different in terms of viral characteristics from RRV-TV, are likely to become available in the near future, and their benefits, safety, costs and other characteristics will influence decisions on their widespread introduction.6 There are 2 candidate vaccines, both of which are live attenuated vaccines for oral use. These vaccines are currently under review for approval by the European Union (EU) regulators.2 The first is a pentavalent, bovine-human reassortant rotavirus vaccine (RotaTeq威; Merck, Whitehouse Station, NJ), and the second, RIX4414 (Rotarix™; GlaxoSmithKline, Rixensart, Belgium), is a vaccine derived from a human strain only. Both vaccine candidates have been tested in extensive phase III safety trials (⬎60,000 infants per trial), and both have demonstrated favorable safety profiles, as well as high immunogenicity and efficacy.7–10 The data from these studies exclude any major immediate risk of intussusception attributable to the new vaccines (risk ⬍1 in 20,000), with long term safety surveillance also showing encouraging results.

The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006


Understanding naturally occurring intussusception is important in order to distinguish it from vaccine-associated disease, and epidemiologic data are necessary to establish the baseline risk of intussusception. To ensure the accuracy and comparability of epidemiologic data, standardized criteria for defining intussusception, such as the Brighton Collaboration Intussusception Working Group definition, should be used. This paper describes the clinical presentation, detection and management of intussusception in young children as well as the current knowledge on its etiology and the availability of epidemiologic data in Europe. We also outline the role of surveillance for intussusception in Europe.

MATERIALS AND METHODS Studies for this review were identified through Medline and Cochrane searches with the use of a broad search strategy with the MeSH heading “intussusception” (which includes spelling variations and synonyms like intestinal invagination) and each country name for all 52 countries belonging to the World Health Organization (WHO) European Region. Results were restricted to articles published from January 1995 to April 2005, written in English, French, German, Spanish, Portuguese, Italian or Dutch. We searched the websites of the WHO, the EU, UNICEF, the Global Alliance for Vaccines and Immunization, Centers for Disease Control and Prevention, Program for the Introduction and Adaptation of Contraceptive Technology and the European Agency for the Evaluation of Medicinal Products for relevant reports. Additionally in Medline we used the search string “intussusception NOT case report” from February 2001 to April 2005, as 1 French article, found in a WHO report, was not retrieved through the search string “intussusception AND France.”11 A review of references within the articles retrieved allowed the identification of additional studies. To compare our data with earlier findings or with data from other regions, we identified additional papers on intussusception from Medline and the various websites.

Intussusception in Europe

nous congestion and bowel wall edema can cause obstruction of the intestine, infarction and perforation of the bowel wall (Fig. 1). Conservative treatment consists of opaque enema (barium enema), radioscopy-guided pneumoenema (air enema) or ultrasound-guided hydrostatic enema (saline enema), the advantage of the latter being that no ionizing radiation is needed.16 Ultrasound-guided reduction is an option, but this requires some expertise. Therefore the diagnosis and reduction are still frequently done by radiography with air or barium enema.17,18 Perforation is a rare complication of conservative management.1 In cases in which conservative treatment is contraindicated and perforation has occurred, followed by shock or peritonitis, emergency surgery will be needed. Recurrence of intussusception after conservative treatment occurs in about 1 in every 10 patients, and no predictable risk factors of recurrence have been identified.19,20 Recurrence after surgical intervention is rare (0 – 4%).19,21 Surgery rates differ around the world; longer delay in seeking treatment and lower access to radiologic tools are responsible for higher surgery rates.1 The longer signs and symptoms are present, the less successful conservative treatment will be.11,22 Characteristics of the clinical signs and management of intussusception for Europe during the past 10 years are summarized in Table 1.11,12,16,19,23–36 One German study found that 6% of intussusceptions were largely asymptomatic, and these were detected only through abdominal ultrasound in cases of nonspecific abdominal pain.27 Spontaneous reposition of the invaginated segment was described in 82% of patients with a small bowel intussusception in this study;27 similar findings were observed during investigations by ultrasound in a patient in another study.26 Four studies de-

RESULTS Clinical Presentation, Detection and Management of Intussusception The classic triad of intussusception (abdominal pain, a palpable abdominal mass and red-currant-jelly stool) is present in only about one-third of patients.1 Children might present screaming and with irritability, lethargy, abdominal pain, vomiting, diarrhea or constipation, rectal bleeding or fresh blood in stool, fever, dehydration, shock, an intestinal prolapse or a palpable abdominal or rectal mass.1 Given that the signs and symptoms of intussusception are alarming in many cases, most parents will try to seek medical attention quickly; this is fortunate, because a delay in diagnosis and treatment can lead to significantly poorer outcome.1,12 Clinical diagnosis of intussusception by signs and symptoms alone has been shown to be incorrect in one-half of patients presenting at an emergency department.13 The diagnosis can be made reliably with ultrasound, and spontaneous reduction occurs in up to 10% of patients.14,15 Most cases require either conservative treatment or surgery: untreated, prolonged ve© 2005 Lippincott Williams & Wilkins

FIGURE 1. Ileocecal intussusception. Intraoperative aspect of partial resolution of the ileum (black horizontal arrowhead) coming out of the cecum (gray broad vertical arrowhead) situated in front with the appendix (black horizontal arrow). The reduced ileum shows serosal damage (ⴱ) and bleeding caused by venous congestion. Part of the ileum (white horizontal arrow) is just exiting from the cecum, the last part of the ileum remains in the colon ascendens, covered by cotton (black vertical arrowhead), and will be evacuated immediately. Courtesy of Dr. H. Gitter, Consultant, Pediatric Surgery, Klinikum Bremen-Mitte, Germany.

S23


Huppertz et al

TABLE 1. Characteristics of the Clinical Presentation, Detection and Management of Intussusception in Europe Characteristic Classical triad of symptoms of intussusception present Recurrences after conservative treatment Conservative treatment complicated by perforation Surgery performed (all cases) Resection performed (surgery cases)

Median Range (%) (%)

No. of Studies 224,36

31

29 –33

8

3–16

1111,16,23–30,32

0

0–6

1111,16,19,23–28,31,33

19 18

10 – 68 9 –54

1511,12,19,23–28,30 –35 1011,12,23–26,30,33–35

patients were operated on, compared with 54% of inpatients.42 Two Dutch tertiary care centers reported much higher surgery rates (49 and 68%) compared with the other European centers, possibly because of the large numbers of referrals of complicated cases from other centers, a risk factor for surgery described in other studies in Europe and the United States.11,12,34,39 A lack of experience with conservative treatment is another probable risk factor for surgery; one of the Dutch centers reported having no experience with ultrasound guided reduction, and only limited experience with pneumatic reduction.34

Etiology of Intussusception scribed some patients with a spontaneous reduction on the operating table, presumably caused by the relaxing effect of anesthetic medication.24 –26,34 Spontaneously resolving intussusceptions have been described as occasional findings during abdominal imaging.26 Similarly, in a Canadian study, 58% of intussusceptions were incidental findings, mostly being small bowel intussusceptions that subsequently reduced spontaneously.4,37 Recurrence rates of a median of 8% after conservative treatment in Europe are comparable with rates found in other parts of the world.14,20 In France, 44% of intussusception cases were managed in outpatient departments (barium enema reduction with subsequent observation period of ⬍24 hours).11 One Spanish article mentioned that there is no need to keep patients hospitalized after successful reduction, but they did not mention what percentage of patients in their series was managed as outpatients.31 In England, 53% of consultants would transfer a child with confirmed intussusception to a tertiary care center before attempting reduction, and a further 23% would transfer the child after 1 failed conservative attempt.17 Observation policies differed between countries and settings, with a minimum observation period of 12–36 hours after conservative treatment.19,26,30 In France and Scotland, the mean hospital stay of patients treated by air enema was 2 and 2.5 days, respectively (in France, most patients were managed ambulatory).11,33 Patients requiring surgery had an average hospital stay of 6 days.33 The success rate of conservative treatment appears to differ significantly between radiologists, with the more experienced radiologists having higher success rates in the 1 study that investigated this aspect.26 Some studies found that the presence of free fluid, trapped fluid or small bowel obstruction on ultrasound investigation lowered the success rate of conservative management, whereas other studies found no such correlation.26,33,35 The median surgery rate found in Europe is similar to Canadian surgery rates of ⬃15%; in contrast, the rate in the United States is ⬃50%.14,38 – 40 Differences in study methodology and local clinical practice (including the availability of ultrasound equipment and physician expertise) seem to account for at least part of this difference. In addition, heterogeneity of study populations may be important; many U.S. studies did not include short stay patients.38,41 One U.S. study describing treatment in both emergency departments and inpatient settings found that 16% of emergency department

S24

Intussusception can result from pathologic lead points, like Meckel’s diverticulum, polyps, lymphomas, hematomas of the intestinal wall in Henoch-Scho¨nlein purpura or hemophilia, intestinal duplications, cysts or neurofibromas.6 After abdominal surgery, or in children with cystic fibrosis, intussusception is more common. In Europe, intussusception has been associated with structural lead points in 1–11% of cases (median, 3%).11,12,19,23–25,27–30,33,35,36 The exact etiology of intussusception remains unclear in most (60 –100%) of socalled idiopathic cases, where no structural lead points are found.1,22 Swelling of the lymphoid tissue of the intestine (the mesenteric lymph nodes and the Peyer’s patches) is thought to act as a lead point for intussusception after infection or inflammation.6 Dietary factors have also been hypothesized as an associated risk factor, with malnourished children having less prominent intestinal lymphoid tissue, less suitable to act as a lead point and being considered to have a lower risk of intussusception.6 However, in a mouse model, the Peyer’s patches did not appear to act as the anatomic lead point for intussusception.5 In Europe, enlarged mesenteric lymph nodes have been found in 19 –50% of patients undergoing surgery or investigation by ultrasound.11,28,29 Two small studies explored the biologic plausibility of occurrence of intussusception in relation to rotavirus disease. One prospective, nonmatched observational study found an increase in bowel wall thickness in 3 of 5 infants during their illness, with no difference in the mesenteric lymph node size or intestinal motility during illness and convalescence.43 The second study (a prospective, matched cohort study) found increased bowel wall thickness in rotavirus-infected children compared with noninfected children and mesenteric lymph node swelling during infection compared with convalescence.15 It has also been hypothesized that the introduction of new foods, including proteins, might induce intestinal lymphoid tissue swelling.6 In the United States, infants who developed intussusception after vaccination with RRV-TV were more likely to be formula-fed than breast-fed.44 To date, the evidence for an increased risk caused by dietary factors is derived from animal studies, circumstantial or conflicting.1,6 Few cases of intussusception occur during the first 3 months of life, and there is a decline after 1 year of age; an age-specific distribution is seen in many other childhood infectious diseases.1,38 Between 5 and 60% of cases have a history of recent gastroenteritis or respiratory tract infection.1 After the withdrawal of RRV-TV, research into a possible © 2005 Lippincott Williams & Wilkins



causative role of natural rotavirus infection in intussusception has intensified.5,6 U.S. epidemiologic data suggest that wildtype rotavirus is not a cause of intussusception.6,45,46 Whereas rotavirus infection has a distinct seasonal pattern, intussusception lacks distinct seasonal peaks.6,46 The age ranges of intussusception and rotavirus disease are distinct although overlapping, with rotavirus disease occurring slightly later than intussusception.38 In a prospective casecontrol study, conducted with the aim of determining which enteropathogens are associated with intussusception, associations were found primarily with adenovirus infections but not infections with rotavirus.47 Several studies have also investigated the possible association of oral polio vaccine with intussusception, as polio virus and rotavirus are both enteric viruses that replicate in the intestine, but today there appears to be enough evidence to reject a link between the oral polio vaccine and intussusception.5 Numerous factors that might play a role, such as agent and host characteristics, are currently being investigated, mostly in animal models. Bacterial endotoxins can cause intussusception in animals without histopathologic changes, suggesting that inflammatory mediators can alter intestinal motility.6 Rotavirus infections have been shown to increase the synthesis of prostaglandins and cytokines (interleukin-10, tumor necrosis factor-␣ and ␥-interferon).6,48

case-control study for a risk period ⬎3 weeks after vaccination showed a nonsignificant odds ratio of ⬍1, triggering discussion of study design and the exact magnitude of the association.38,52–55 Vaccination with RRV-TV is now considered to be responsible for an additional risk of intussusception of 1 in 10,000 to 1 in 32,000 vaccinees.4 Although an epidemiologic association between RRV-TV and intussusception has been established, the underlying mechanism is not clear. Three theories have emerged, offering possible explanations56: (1) the “unique strain” hypothesis, in which intussusception is associated only with the rhesus rotavirus strains used in RRV-TV, but not with other vaccines or wild-type strains; (2) the “bolus dose” hypothesis, which suggests a high viral titer inoculum is necessary; (3) the “viral replication” theory, in which wild-type rotaviruses are a rare but consistent cause of disease.5 Because of the considerable uncertainty regarding how RRV-TV can cause intussusception, the manufacturers of the new rotavirus vaccines have conducted large safety trials (⬎60,000 infants per double blind, placebo-controlled trial), in which pentavalent, bovine-human reassortant rotavirus vaccine and the RIX4414 vaccine showed no association with intussusception.9,10 This finding seems to support the unique strain hypothesis.

Rotavirus Vaccines

Incidence of Intussusception in Europe. The incidence of acute intussusception in children, according to hospital-based studies, ranged from 0.66 to 2.24 per 1000 children for inpatient departments and for emergency departments from 0.75 to 1.00 per 1000 children, with studies including different age groups (Table 2).11,24,36,57–59 In the Netherlands and Germany, the burden of intussusception on pediatric surgical departments was 1.2–1.4% of all inpatients (the age of the population was not specified).12,29 In Australia, New Zealand and the United States, the incidence of intussusception appears similar to recent European estimates, at 0.50 –2.30 cases per 1000 live births.1 Incidence data from other parts of the world are scarce. In China, the incidence was reported at 0.77 per 1000 live births; from Kuwait, the number was 0.50 per 1000 live births.1 South America is the exception, reporting lower incidences than all other continents, with 0.24 case per 1000 children younger than 1 year of age in Venezuela and 0.33 case per

RRV-TV was introduced in the United States in August 1998 and was subsequently recommended for all infants as part of their routine immunization schedule at 2, 4 and 6 months of age.49,50 In July 1999, the recommendation was temporarily suspended after 15 cases of intussusception in immunized infants had been reported; in October 1999, the vaccine was voluntarily withdrawn from the market by its manufacturer.3 During the 9-month period when the vaccine was used widely, ⬃1 million doses were given to ⬃0.5 million infants.51 Subsequent case-control, cohort studies and case-series analysis showed that the occurrence of intussusception peaked between 3 and 14 days after administration of the first vaccine dose, and the vaccine-attributable risk was estimated to be between 1 in 5000 and 1 in 10,000 vaccinees.40,44 However, studies that compared groups of children, without data on vaccination at the individual level, did not reveal evidence of increased intussusception rates, and a

Epidemiology of Intussusception in Europe

TABLE 2. Incidence of Intussusception Among Children in Europe: Studies Published During the Years 1995–2005 Country Denmark58 France11 Israel24 Norway57 United Kingdom59 United Kingdom36

Setting and Study Design Birth cohort, with the use of national hospital discharge data Emergency department, with the use of discharge data Chart review of hospital admissions Chart review, with the use of regional hospital discharge data English hospital discharge data Emergency department, with the use of hospital discharge data

© 2005 Lippincott Williams & Wilkins

Age Group (yr)

No. of Cases

Incidence/ 1000 Children/yr

1980 –2001

⬍5

1814

1.08

1993–1996

101

0.75

1986 –1995

Infants and children ⬍1

90

2.24

1983–1992

⬍14

142

1.40 –1.80

⬍1 ⬍1

833 100

0.66 1.00

Years of Observation

April 1993–March 1995 1983–1993

S25

Huppertz et al


1000 children younger than 2 years of age in Chile; no explanation is available for these lower findings.1,60 Earlier European studies (1940 –1988) reported somewhat higher incidence rates of 1.10 to 4.30 per 1000 live births.1 Whether the incidence has truly declined during the past decades, or whether differences in case detection, case definition or disease management underlie this declining trend, is not clear.5 In Denmark, the intussusception incidence rate fell by 55% between 1990 and 2001. This decline was greatest among children 3–5 months of age and could not be explained by differences in reporting, diagnosis or treatment practices.58 Large hospital discharge data sets from the United States have shown falling intussusception rates over time, sometimes caused by a logistic shift from inpatient to outpatient treatment, sometimes in parallel with a concomitant decline in diarrhea-associated hospitalizations.38,41 In other parts of the world, including Africa, Asia and Central America, both temporary increases and decreases in hospital admissions for intussusception have been observed; one hypothesis is that these changes might be the result of epidemics or environmental factors including dietary intake.1 Mortality from Intussusception. Mortality from intussusception has become rare in Europe.1 Only 1 death has been reported, in a series of 151 patients.31 Hospital-based data may underestimate the true death rate attributable to intussusception, if children die before reaching the hospital, or if autopsy is not frequently performed. One-third of intussusception deaths in England and Wales between 1984 and 1989 occurred at home.61 Autopsy data from Australia indicate that in 0.05% of all autopsies intussusception was the cause of death in children.62 U.S. data indicate that 2.3 deaths per 1,000,000 live births are caused by intussusception, based on a hospitalization rate of 18 –56 per 100,000 for the years 1994 –1996.41 In developing countries, in-hospital mortality from intussusception remains high (up to 54% in Africa); patients usually present later, and higher rates of surgical intervention are observed.1,12

Demographic and Seasonal Distribution of Intussusception in Europe In Europe, intussusception was rare in infants younger than 2 months of age and in children older than 1 year of age: 68 –92% of intussusception diagnoses were in children younger than 1 year of age.12,24,31,33,36,58 Peak incidences were found in children 3–9 months of age,12,24,58,59 which is in line with a global peak incidence at 4 –7 months of age.1 The mean age at diagnosis ranged from 6.8 to 14 months (median, 13 months), with studies including different age groups.19,24 –26,28,30,32,33,35,36 The age at diagnosis might be related to the site of intussusception. In Germany, many small bowel intussusceptions were found at a higher median age of 50 months, compared with ileocolic intussusceptions occurring at a median age of 11 months.27 In this study, 43% of all intussusceptions were located in the small bowel, an exceptional finding that may be attributable to the use of new, high resolution ultrasound techniques. Small bowel intussusceptions have been prominent as incidental findings in other series, with a high rate of spontaneous reduction.37

S26

Globally the male-female ratio of intussusception cases is ⬃2:1.1 In Europe, the male-female ratio ranged from 1.2 in Spain to 2.4 in Israel.11,19,24 –30,32,33,35,36,58 Some studies showed an increasing male preponderance with age.24,34 In Israel, a significant difference (P ⬍ 0.05) in the incidence rate was found between Jewish children (2.36 per 1000 live born) and Arab children (0.92 per 1000 live born).24 Ethnic differences have also been observed in Malaysia, Trinidad and Tobago, Kuwait and the United States; differences in weaning practices or in nutritional status have been proposed as hypotheses for underlying mechanisms by the authors.1 In a single study in France, a significant seasonal peak of intussusception occurred in spring, when 37% of all intussusception cases presented, but seasonal variation in intussusception was not found in any other study.11

DISCUSSION Intussusception is a clinically severe and potentially lethal condition, although mortality has become rare in developed countries through timely diagnosis and treatment with enema or surgery. Intussusception after universal vaccination with the first rotavirus vaccine (RRV-TV) in the United States affected 1 in 10,000 to 1 in 32,000 vaccinees.4 This vaccine has been withdrawn from the market. However, rotavirus gastroenteritis causes substantial morbidity and mortality worldwide, and conventional prevention strategies developed for other causes of diarrheal diseases are not as effective in rotavirus disease.6 Therefore there was a need to develop new rotavirus vaccines with improved safety, and 2 different preparations are likely to become widely available in the near future.9,10,63,64 Currently there are many gaps in our knowledge of intussusception, particularly with respect to the etiology of the disease and the mechanisms by which rotavirus vaccination might cause it to occur. In addition, reliable data on the baseline incidence of intussusception in Europe are lacking (see Table 2). The available hospital inpatient incidence rates range from 0.66 to 2.24 per 1000 children and emergency department incidence rates range from 0.75 to 1.00 per 1000. Furthermore these data are heterogeneous with respect to age groups and study design. Most studies were retrospective, thus relying on passive case-finding, and none used a standardized case definition of intussusception. Surveillance of intussusception can provide the baseline information needed. Table 3 gives an overview of surveillance tools. Large linked databases (LLDB) are useful to study adverse events after vaccination, because they link data on vaccination status and confounding factors to the occurrence of clinically evident side effects, such as intussusception. In the United Kingdom, LLDB have been used to investigate the possible association between intussusception and the oral polio vaccine (no association was found).73 Research with LLDB has shown that medical record verification, based on a standardized case definition, is an absolute prerequisite for definitive assessment and analysis of moderate to strong vaccine-outcome associations.79 In studies on intussusception, 5– 40% of cases could not be validated through medical chart review.40,42,58,73 © 2005 Lippincott Williams & Wilkins



TABLE 3. Overview of Surveillance Tools in Europe and Their Availability for Determining Baseline Incidence Rates of Intussusception and Their Possible Association With Rotavirus Vaccination Surveillance Tool

Description and Advantages/Disadvantages

Availability

Reporting of adverse events after vaccination

EMEA, EUSAFEVAC and the Uppsala Monitoring Centre, which runs the adverse drug reactions database for the WHO. Prone to observer bias when used for postmarketing surveillance because reporting is more likely to occur with new pharmaceutic products in general; if there has been publicity about the adverse event; with severe adverse events and with events that occur shortly after vaccination.65– 67 In most countries: lack of full time staff and funding; lack of (standardized) definitions; lack of denominators; lack of formal analysis and inappropriate or nonexistent feedback.68

All EU member states report to EMEA. Most European countries report to Uppsala Monitoring Centre.68

Health care utilization databases such as hospital discharge data

Readily available data, cheap and quick to use. Case definition is not standardized. Interpretation is hampered by changes in coding, diagnosis or management of the disease.41,69 Potential confounders and vaccination status cannot be measured at the individual level.

All 25 EU countries have such databases, with differences in compulsory collection of data, classification used, all cases or samples used and proportion of cases reported.70

LLDB

Can link data on vaccination status and confounding factors to the occurrence of intussusception. Makes cohort studies a feasible and desirable epidemiologic method for detecting the adverse effects of vaccines, with the advantage that incidence rates and attributable risks can be estimated.40,71 Affected by shifts in the health care system, like privatization, which affects the completeness of data.72

In the U.K., LLDB have been used to actively survey postmarketing vaccine safety, based on patient records of hospital admissions and general practitioner visits, linked to vaccine status.73–75

Routine morbidity and mortality registrations

European health for all database (WHO), EUROSTAT (EU) Intussusception is not selected as a disease to monitor.70,76

Electronic health records

Promoted by the EU, including standardization of definitions used.77 May facilitate future morbidity surveillance.

No timeline for EU-wide implementation is foreseen.77

Surveillance set up for intussusception

Possibility to standardize case definition and use medical record verification

Used in Swiss hospitals from April 2003.78

EMEA, European Agency for the Evaluation of Medicinal Products; EUSAFEVAC, European Research Programme for Improved Vaccine Safety Surveillance; EUROSTAT, Statistical Office of the European Communities.

The Brighton Collaboration Intussusception Working Group has developed a case definition for intussusception and guidelines for data collection that can be used in study settings with varying availability of resources.80,81 According to the Brighton case definition, intussusception is confirmed by any of the following findings: the demonstration of intussusception at surgery or at autopsy; the roentgenographic demonstration of intussusception by either gas or liquid enema; the demonstration by ultrasound of an intraabdominal mass with specific features that is proved to be reduced by hydrostatic enema on postreduction ultrasound.80 As the accuracy and reliability of ultrasound have not been validated across a wide range of settings, the finding of an intussusception through ultrasound alone is not considered a definite case.80,81 Preliminary data from the intussusception surveillance program in Switzerland show that 81% of reported cases are confirmed by applying the Brighton case definition.82 © 2005 Lippincott Williams & Wilkins

Intussusception after vaccination with RRV-TV was a shocking lesson for the medical community. Unexpected, rare side effects can be detected only by carefully conducted, large prelicensure trials or by postlicensure surveillance. Postlicensure surveillance systems will alert the public, the authorities and the manufacturer at an early stage. Regulatory authorities have a crucial role: if they act too early, they could irreparably damage a valuable intervention; if they act too late, unnecessary further complications may occur. Therefore surveillance tools are needed that can provide sound epidemiologic data to establish baseline incidence rates of intussusception and monitor the incidence after the introduction of new rotavirus vaccines. These tools are currently lacking in most European countries: LLDB can be used to fill this gap. As new rotavirus vaccines are likely to become widely available in Europe, there will be a need for effective surveillance of intussusception in countries where those vaccines

S27


Huppertz et al

will be introduced into the routine childhood immunization schedule. REFERENCES 1. World Health Organization, Initiative for Vaccine Research Department of vaccines and Biologicals. Acute intussusception in infants and children. Incidence, clinical presentation and management: a global perspective. WHO/V&B/02.19. 2002. 2. Glass RI, Bresee JS, Parashar UD, Jiang B, Gentsch J. The future of rotavirus vaccines: a major setback leads to new opportunities. Lancet. 2004;363:1547–1550. 3. Withdrawal of rotavirus vaccine recommendation. MMWR. 1999;48: 1007. 4. Bines JE. Rotavirus vaccines and intussusception risk. Curr Opin Gastroenterol. 2005;21:20 –25. 5. Peter G, Myers MG. Intussusception, rotavirus, and oral vaccines: summary of a workshop. Pediatrics. 2002;110:e67. 6. Kombo LA, Gerber MA, Pickering LK, Atreya CD, Breiman RF. Intussusception, infection, and immunization: summary of a workshop on rotavirus. Pediatrics. 2001;108:e37. 7. Velazquez FR, Abate H, Costa Clemens SA, et al. The human monovalent G1P关8兴 rotavirus vaccine, Rotarix™ is highly efficacious and provides cross-protection against G1 and non-G1 serotypes. In: 23rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Valencia, Spain: European Society for Paediatric Infectious Diseases; 2005. 8. Vesikari T, Matson D, Dennehy P, et al. Protection against rotavirus gastroenteritis of multiple serotypes by a pentavalent (human-bovine) reassortant rotavirus vaccine (PRV). In: 23rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Valencia, Spain: European Society for Paediatric Infectious Diseases; 2005. 9. Vesikari T, O’Ryan M, Abate H, et al. Overcoming the safety hurdle: the rotavirus vaccine RIX4414 is not associated with intussusception. In: 23rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Valencia, Spain: European Society for Paediatric Infectious Diseases; 2005. 10. Vesikari T, Matson D, Van Damme P, et al. Incidence of intussusception with the pentavalent (human-bovine) reassortant rotavirus vaccine (PRV) is similar to placebo. In: 23rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Valencia, Spain: European Society for Paediatric Infectious Diseases; 2005. 11. Le Masne A, Lortat-Jacob S, Sayegh N, Sannier N, Brunelle F, Cheron G. Intussusception in infants and children: feasibility of ambulatory management. Eur J Pediatr. 1999;158:707–710. 12. van Heek NT, Aronson DC, Halimun EM, Soewarno R, Molenaar JC, Vos A. Intussusception in a tropical country: comparison among patient populations in Jakarta, Jogyakarta, and Amsterdam. J Pediatr Gastroenterol Nutr. 1999;29:402– 405. 13. Beasley SW, Auldist AW, Stokes KB. The diagnostically difficult intussusception: its characteristics and consequences. Pediatr Surg Int. 1988;3:135–138. 14. Ein SH, Alton D, Palder SB, Shandling B, Stringer D. Intussusception in the 1990s: has 25 years made a difference? Pediatr Surg Int. 1997;12: 374 –376. 15. Robinson CG, Hernanz-Schulman M, Zhu Y, Griffin MR, Gruber W, Edwards KM. Evaluation of anatomic changes in young children with natural rotavirus infection: is intussusception biologically plausible? J Infect Dis. 2004;189:1382–1387. 16. Tellado MG, Liras J, Mendez R, et al. 关Ultrasound-guided hydrostatic reduction for the treatment of idiopathic intestinal invagination兴. Cir Pediatr. 2003;16:166 –168. 17. Calder FR, Tan S, Kitteringham L, Dykes EH. Patterns of management of intussusception outside tertiary centers. J Pediatr Surg. 2001;36:312– 315. 18. Britton I, Wilkinson AG. Survey of intussusception reduction in England, Scotland and Wales: how and why we could do better. Clin Radiol. 2001;56:865– 866. 19. Champoux AN, Del Beccaro MA, Nazar-Stewart V. Recurrent intussusception: risks and features. Arch Pediatr Adolesc Med. 1994;148:474 – 478.

S28

20. Daneman A, Alton DJ, Lobo E, Gravett J, Kim P, Ein SH. Patterns of recurrence of intussusception in children: a 17-year review. Pediatr Radiol. 1998;28:913–919. 21. Stringer MD, Pablot SM, Brereton RJ. Paediatric intussusception. Br J Surg. 1992;79:867– 876. 22. Gorenstein A, Raucher A, Serour F, Witzling M, Katz R. Intussusception in children: reduction with repeated, delayed air enema. Radiology. 1998;206:721–724. 23. Vetter R, Tzschoppe A. 关Experiences with ultrasonographic control of hydrostatic reduction of childhood intussusception兴. Zentralbl Kinderchir. 2001;10:49 –53. 24. Eshel G, Barr J, Heyman E, et al. Intussusception: a 9-year survey (1986 –1995). J Pediatr Gastroenterol Nutr. 1997;24:253–256. 25. Gonzalez-Spinola J, Del PG, Tejedor D, Blanco A. Intussusception: the accuracy of ultrasound-guided saline enema and the usefulness of a delayed attempt at reduction. J Pediatr Surg. 1999;34:1016 –1020. 26. Crystal P, Hertzanu Y, Farber B, Shabshin N, Barki Y. Sonographically guided hydrostatic reduction of intussusception in children. J Clin Ultrasound. 2002;30:343–348. 27. Siaplaouras J, Moritz JD, Gortner L, Alzen G. 关Small bowel intussusception in childhood兴. Klin Padiatr. 2003;215:53–56. 28. Rohrschneider WK, Troger J. Hydrostatic reduction of intussusception under US guidance. Pediatr Radiol. 1995;25:530 –534. 29. Staatz G, Alzen G, Heimann G. 关Intestinal infection, the most frequent cause of invagination in childhood: results of a 10-year clinical study兴. Klin Padiatr. 1998;210:61– 64. 30. Estevao-Costa J, Correia-Pinto J, Campos M, Mariz C, Carvalho JL. 关Intestinal invagination in children: reduction with pneumo-enema兴. Acta Med Port. 2001;14:381–384. 31. Rubi I, Vera R, Rubi SC, et al. Air reduction of intussusception. Eur J Pediatr Surg. 2002;12:387–390. 32. Hilal A, MacMahon P, Cosgrove JF. Outcome of acute intussusception in a regional paediatric centre. Ir Med J. 2002;95:58 –59. 33. Britton I, Wilkinson AG. Ultrasound features of intussusception predicting outcome of air enema. Pediatr Radiol. 1999;29:705–710. 34. Van der Laan M, Bax NM, Van der Zee DC, Ure BM. The role of laparoscopy in the management of childhood intussusception. Surg Endosc. 2001;15:373–376. 35. del-Pozo G, Gonzalez-Spinola J, Gomez-Anson B, et al. Intussusception: trapped peritoneal fluid detected with US: relationship to reducibility and ischemia. Radiology. 1996;201:379 –383. 36. Macdonald IA, Beattie TF. Intussusception presenting to a paediatric accident and emergency department. J Accid Emerg Med. 1995;12:182–186. 37. Kornecki A, Daneman A, Navarro O, Connolly B, Manson D, Alton DJ. Spontaneous reduction of intussusception: clinical spectrum, management and outcome. Pediatr Radiol. 2000;30:58 – 63. 38. Chang HG, Smith PF, Ackelsberg J, Morse DL, Glass RI. Intussusception, rotavirus diarrhea, and rotavirus vaccine use among children in New York state. Pediatrics. 2001;108:54 – 60. 39. Bratton SL, Haberkern CM, Waldhausen JH, Sawin RS, Allison JW. Intussusception: hospital size and risk of surgery. Pediatrics. 2001;107: 299 –303. 40. Kramarz P, France EK, DeStefano F, et al. Population-based study of rotavirus vaccination and intussusception. Pediatr Infect Dis J. 2001;20: 410 – 416. 41. Parashar UD, Holman RC, Cummings KC, et al. Trends in intussusception-associated hospitalizations and deaths among US infants. Pediatrics. 2000;106:1413–1421. 42. Staat MA, Roberts NE, Bernstein DI. Epidemiology and clinical features of intussusception in children 4 months of age in Hamilton County, Ohio. Pediatr Res. 2000;49:242A. Abstract. 43. Bass D, Cordoba E, Dekker C, Schuind A, Cassady C. Intestinal imaging of children with acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr. 2004;39:270 –274. 44. Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med. 2001;344:564 –572. 45. Chang EJ, Zangwill KM, Lee H, Ward JI. Lack of association between rotavirus infection and intussusception: implications for use of attenuated rotavirus vaccines. Pediatr Infect Dis J. 2002;21:97–102. 46. Rennels MB, Parashar UD, Holman RC, Le CT, Chang HG, Glass RI. Lack of an apparent association between intussusception and wild or vaccine rotavirus infection. Pediatr Infect Dis J. 1998;17:924 –925.



47. Velazquez FR, Luna G, Cedillo R, Torres J, Munoz O. Natural rotavirus infection is not associated to intussusception in Mexican children. Pediatr Infect Dis J. 2004;23(suppl):S173–S178. 48. Azim T, Ahmad SM, Sefat-E-Khuda, et al. Immune response of children who develop persistent diarrhea following rotavirus infection. Clin Diagn Lab Immin. 1999;6:690 – 695. 49. American Academy of Pediatrics. Prevention of rotavirus disease: guidelines for use of rotavirus vaccine. Pediatrics. 1998;102:1483–1491. 50. Centers for Disease Control and Prevention. Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1999;48(RR-2):1–20. 51. Smith PJ, Schwartz B, Mokdad A, Bloch AB, McCauley M, Murphy TV. The first oral rotavirus vaccine, 1998 –1999: estimates of uptake from the National Immunization Survey. Public Health Rep. 2003;118:134 –143. 52. Simonsen L, Morens D, Elixhauser A, Gerber M, Van RM, Blackwelder W. Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception. Lancet. 2001;358:1224 –1229. 53. Hall AJ. Ecological studies and debate on rotavirus vaccine and intussusception. Lancet. 2001;358:1197–1198. 54. Murphy BR, Morens DM, Simonsen L, Chanock RM, La M Jr, Kapikian AZ. Reappraisal of the association of intussusception with the licensed live rotavirus vaccine challenges initial conclusions. J Infect Dis. 2003; 187:1301–1308. 55. Murphy TV, Smith PJ, Gargiullo PM, Schwartz B. The first rotavirus vaccine and intussusception: epidemiological studies and policy decisions. J Infect Dis. 2003;187:1309 –1313. 56. Offit PA, Clark HF, Ward RL. Current state of development of human rotavirus vaccines. In: Desselberger U, Gray J, eds. Viral Gastroenteritis. Amsterdam, the Netherlands: Elsevier Science; 2003:345–356. 57. Eikeset K, Markestad T. 关Intestinal invagination in children in the county of Hordaland 1983–92兴. Tidsskr Nor Laegeforen. 1998;118: 4197– 4199. 58. Fischer TK, Bihrmann K, Perch M, et al. Intussusception in early childhood: a cohort study of 1.7 million children. Pediatrics. 2004;114: 782–5. 59. Gay N, Ramsay M, Waight P. Rotavirus vaccination and intussusception. Lancet. 1999;354:956. 60. Lucero Y, Valenzuela MT, O’Ryan M. 关Clinical and epidemiological profile of intestinal intussusception among infants of Metropolitan Santiago兴. Rev Med Chil. 2004;132:565–572. 61. Stringer MD, Pledger G, Drake DP. Childhood deaths from intussusception in England and Wales, 1984 –9. BMJ. 1992;304:737–739. 62. Byard RW, Simpson A. Sudden death and intussusception in infancy and childhood: autopsy considerations. Med Sci Law. 2001;41:41– 45. 63. Steele AD, Tumbo J, Armah G, et al. Concomitant administration of a live-attenuated oral rotavirus vaccine (RIX4414) with poliovirus vaccines in African infants. In: 23rd Annual meeting of the European Society for Paediatric Infectious Diseases (ESPID). Valencia, Spain: European Society for Paediatric Infectious Diseases; 2005. 64. O’Ryan M, Abate H, Linhares AC, et al. A novel rotavirus vaccine RIX4414 RotarixRTM is not associated with intussusception (IS). In: 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, October 30 –November 2, 2004, Washington, DC, 2004. Washington, DC: American Society for Microbiology; 2004. 65. Haber P, Chen RT, Zanardi LR, Mootrey GT, English R, Braun MM. An analysis of rotavirus vaccine reports to the vaccine adverse event


66. 67.

68. 69. 70. 71. 72. 73.

74. 75. 76.

77. 78.

79. 80. 81.

82.


reporting system: more than intussusception alone? Pediatrics. 2004; 113:e353– e359. Rosenthal S, Chen R. The reporting sensitivities of two passive surveillance systems for vaccine adverse events. Am J Public Health. 1995;85: 1706 –1709. Verstraeten T, Baughman AL, Cadwell B, Zanardi L, Haber P, Chen RT. Enhancing vaccine safety surveillance: a capture-recapture analysis of intussusception after rotavirus vaccination. Am J Epidemiol. 2001;154: 1006 –1012. Lankinen KS, Pastila S, Kilpi T, Nohynek H, Makela PH, Olin P. Vaccinovigilance in Europe: need for timeliness, standardization and resources. Bull World Health Organ. 2004;82:828 – 835. Campbell SE, Campbell MK, Grimshaw JM, Walker AE. A systematic review of discharge coding accuracy. J Public Health Med. 2001;23: 205–211. Eurostat. Explanatory notes of the collection public health from the domain health and safety. Luxembourg: Unit E3, Health, Education and Culture; 2003. Schneeweiss S, Avorn J. A review of uses of health care utilization databases for epidemiologic research on therapeutics. J Clin Epidemiol. 2005;58:323–337. Chen RT, DeStefano F, Davis RL, et al. The Vaccine Safety Datalink: immunization research in health maintenance organizations in the USA. Bull World Health Organ. 2000;78:186 –194. Andrews N, Miller E, Waight P, et al. Does oral polio vaccine cause intussusception in infants? Evidence from a sequence of three selfcontrolled cases series studies in the United Kingdom. Eur J Epidemiol. 2001;17:701–706. Farrington P, Pugh S, Colville A, et al. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet. 1995;345:567–569. Miller E, Andrews N, Grant A, Stowe J, Taylor B. No evidence of an association between MMR vaccine and gait disturbance. Arch Dis Child. 2005;90:292–296. World Health Organization Regional Office for Europe. European health for all databases. 关World Health Organization Regional Office for Europe web site兴. 2005. Available at: http://www.euro.who.int/hfadb. Accessed May 4, 2005. Commission of the European Communities. e-Health—making healthcare better for European citizens: an action plan for a European e-Health Area. COM(2004)356final. 2004. Swiss Paediatric Surveillance Unit. Evaluation of intussusception in children in Switzerland. 关Bundesamt fu¨r Gesundheit web site兴. 2005. Available at: http://www.bag.admin.ch/infekt/publ/wissenschaft/d/invag. pdf. Accessed May 20, 2005. Mullooly J, Drew L, DeStefano F, et al. Quality assessments of HMO diagnosis databases used to monitor childhood vaccine safety. Methods Infect Med. 2004;43:163–170. Bines JE, Ivanoff B, Justice F, Mulholland K. Clinical case definition for the diagnosis of acute intussusception. J Pediatr Gastroenterol Nutr. 2004;39:511–518. Bines JE, Kohl KS, Forster J, et al. Acute intussusception in infants and children as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation. Vaccine. 2004; 22:569 –574. Heininger U, Schaad UB. 关Invagination兴. Bull Bundesamt Gesundh. 2004;37:615.

S29