CLINICAL REVIEW

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Follow the link from the online version of this article Diagnosis, management, and prevention to obtain certi ed continuing medical education credits of in children Umesh D Parashar,1 E Anthony S Nelson,2 Gagandeep Kang3

1 Rotavirus is the leading cause of severe childhood gastro­ National Center for Immunizations SOURCES AND SELECTION CRITERIA and Respiratory Diseases, Centers . Each year, rotavirus is responsible for about 25 We looked at recent conference proceedings and searched for Disease Control and Prevention, million clinic visits, two million hospital admissions, and Atlanta, GA 30333, USA PubMed, the Cochrane Database of Systematic Reviews, 2Department of Paediatrics, The 180 000-450 000 deaths in children under 5 years of age and Clinical Evidence online using the terms “rotavirus”, Chinese University of Hong Kong, globally.1‑3 Although rotavirus is prevalent world- “rotavirus gastroenteritis”, and “rotavirus vaccines”. We Hong Kong wide, most deaths from this infection occur in developing focused on systematic reviews, meta-analyses, and high 3 Division of Gastrointestinal countries (fig 1). Gastroenteritis caused by rotavirus can- quality randomised controlled trials published in English Sciences, Christian Medical College, within the past 10 years (2004-13). Vellore, India not be clinically distinguished from that caused by other Correspondence to: U D Parashar enteric pathogens; diagnosis requires testing of faecal [email protected] specimens with commercially available assays. However, How does rotavirus gastroenteritis present clinically? Cite this as: BMJ 2013;347:f7204 rotavirus is not routinely tested for in patients with gas- The clinical spectrum of rotavirus infection ranges from sub- doi: 10.1136/bmj.f7204 troenteritis because the results do not alter clinical man- clinical illness or mild watery diarrhoea of limited duration agement, which relies mainly on appropriate rehydration to frequent profuse diarrhoea with and that therapy. Orally administered live attenuated vaccines that can result in with shock, imbalance, mimic natural infection offer the best protection against and death. Rotavirus illness usually begins with onset rotavirus. Two licensed rotavirus vaccines have been avail- of fever and vomiting, followed one or two days later by fre- able since 2006 and have been implemented in many quent watery stools. About 30-40% of children may have a countries. We review approaches to diagnosis, manage- moderate fever (temperature >39°C). Vomiting usually lasts ment, and prevention of rotavirus gastroenteritis. for only one or two days and other gastrointestinal symptoms generally resolve in three to seven days. Although gastroenteritis is the chief manifestation of rotavirus infection, neurological features—including benign convulsions (usually afebrile but febrile in some cases), encephalitis or encephalopathy, and cerebellitis— have also been described.4 For example, a multicentre study from Canada reported that 7% of 1359 children admitted to hospital with laboratory confirmed rotavirus had seizures at presentation.5 A variety of other clinical conditions (such as sudden infant death syndrome, necrotising , intussusception, Kawasaki’s disease, and type 1 ) have been associated with rotavirus gastroenteritis, but a Deaths per   causal association has not been confirmed. A transient rise -  -  in serum transaminase concentrations is also often seen in - patients with rotavirus gastroenteritis. <  Who gets rotavirus disease? Fig 1 | World Health Organization estimates of rotavirus mortality (deaths/100 000 children under Rotavirus infects nearly all children in developed and devel- 5 years of age) by country in 2008. Reproduced, with permission, from Lancet Infectious Diseases2 oping countries by 3-5 years of age. Neonatal occur but are often asymptomatic or mild, possibly because SUMMARY POINTS of protection from maternal antibody. The incidence of clini- Rotavirus is the leading cause of severe gastroenteritis in children worldwide, accounting for cal illness peaks in children aged 4-23 months, who are also 35-40% of hospital admissions for gastroenteritis at greatest risk of severe disease that requires hospital admis- Each year, 180 000-450 000 children under 5 years die from rotavirus gastroenteritis, with sion. Although repeat infections are common (three or more more than 90% of deaths occurring in developing countries rotavirus infections occurred in about 42% of children by 2 Because nearly all children are affected by rotavirus by age 5 years, good and years of age in one follow-up study in a cohort of Mexican alone are inadequate for prevention children), symptoms are milder with each subsequent infec- Orally administered live attenuated vaccines offer the best protection against rotavirus; as of tion.6 7 Therefore, rotavirus infections are usually subclini- December 2013, national immunisation programmes of 51 countries include cal or mild in adults, but they can be severe, particularly in Such programmes have greatly reduced morbidity and mortality from gastroenteritis immunocompromised and older people.8 Rotavirus is also A low risk of intussusception has also been documented post-licensure in some countries, an important cause of nosocomial diarrhoea. but this risk is greatly exceeded by the health benefits of vaccination Case-control studies in industrialised countries have

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Fig 2 | Mechanisms of rotavirus pathogenesis. Most information on rotavirus pathogenesis is derived from small animal models. Infection leads to attachment of the rotavirus to enterocytes (1), uncoating of the (2), followed by transcription and translation of viral proteins (3). This leads to the formation of a viroplasm, from which double layered particles assemble (4) and acquire outer coat proteins to form triple layered mature particles, which are shed by a non-classic secretory pathway (5). The viral enterotoxin non-structural protein 4 (NSP4; red triangles) is also released with the mature virions. NSP4 induces the release of intracellular calcium (Ca2+) (6) from the endoplasmic reticulum (ER) and disrupts tight junctions (7), resulting in paracellular leakage of fluid and . NSP4 can act on crypt cells to induce chloride (Cl−) secretion directly (8) or through the enteric nervous system (ENS) (9), both of which draw water into the lumen. A decrease in brush border enzymes induced by infection (10) results in accumulation of sugars in the lumen and osmotic fluid loss. Destruction of intestinal cells later in infection results in loss of surface area and a malabsorptive diarrhoea (11)

11 bmj.com shown that lack of breast feeding, prematurity, and low birth months. In tropical countries, rotavirus occurs all year Previous articles in this weight are associated with increased risk of hospital admis- round, although incidence often increases during the cool 9 10 series sion for rotavirus gastroenteritis. Protracted rotavirus diar- dry months. ЖЖTick bite prevention rhoea with prolonged viral excretion and, in rare instances, How do cause diarrhoea? and tick removal systemic dissemination has been described in severely immu- nodeficient children, particularly those with severe T cell and Mechanisms of rotavirus pathogenesis have been studied in (BMJ 2013;347:f7123) combined T and B cell deficiencies. People who are immuno- animal models and humans. The infectious dose of rotavirus ЖЖPolymyalgia rheumatica 12 suppressed in preparation for bone marrow transplantation is estimated to be 100-1000 viral particles. Transmission (BMJ 2013;347:f6937) are also at risk for severe or even fatal rotavirus disease. of rotavirus occurs mainly through the faecal-oral route, and ЖЖDiagnosis and In all regions of the world, rotavirus is the leading cause of viral spread can occur through contaminated hands, envi- management of hospital admission for gastroenteritis. A systematic review of ronmental surfaces and objects, and occasionally food and hyperhidrosis 131 surveillance studies published from 2001 to 2011 found water. Rotavirus exclusively infects the mature differentiated (BMJ 2013;347:f6800) that rotavirus accounted for 33-49% of hospital admissions enterocytes found at the tips of the villi in the small intes- ЖЖThe diagnosis for gastroenteritis in countries in different geographical tine (fig 2). Attachment of rotavirus to its sialoglycoprotein and management of regions and with varying levels of child mortality.2 However, and integrin receptors is mediated mainly by viral protein erythrocytosis more than 90% of global deaths from rotavirus occur in low 4 (VP4), but neutralising antibodies directed against VP4 (BMJ 2013;347:f6667) income countries in sub-Saharan Africa and South Asia, or VP7 (or both) can prevent viral binding and penetration. ЖЖCentral venous mainly because of suboptimal access to healthcare, including Infection of the enterocyte leads to virus entry, uncoating of catheters basic hydration therapy. In addition, compared with indus- the virus, transcription of nucleic acid, translation of viral (BMJ 2013;347:f6570) trialised countries, severe rotavirus gastroenteritis occurs at proteins, formation of viroplasms, and apical release of a younger age in developing countries (up to two thirds of all the virus and viral protein by a non-classic secretory path- ЖЖThe diagnosis and 13 management of gastric paediatric disease occurs in the first year of life) and coinfec- way. The progeny virus are produced after 10-12 hours tions with other enteric pathogens are more common. and released in large numbers into the intestinal lumen. cancer In temperate climates, rotavirus gastroenteritis shows Rotavirus can infect neighbouring cells, leading to contin- (BMJ 2013;347:f6367) prominent seasonality, occurring mainly during the autumn ued replication and shedding, which consists initially of a and winter, with little disease activity during summer high viral load. In children, the viral load decreases rapidly

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33 34 accumulation of undigested sugars in the intestinal lumen. Four point modified Gorelick score This increases the osmotic gradient, which in turn favours 1 point for each of the signs listed below: further fluid secretion. • Ill general appearance Rotavirus infection was previously thought to be lim- • Absent tears ited to the intestine, but several studies over the past dec- • Dry mucous membranes ade have shown that rotavirus causes short term viraemia • Capillary refill >2 s in immunocompetent infants as well as in experimentally ≤1 points: maintain hydration (<5% dehydration). infected animals.16 The clinical relevance of this systemic 2 points: needs oral rehydration (5-10% dehydration). spread of rotavirus remains unclear, but it may be linked to 3-4 points with normal vital signs: needs intravenous rehydration (>10% dehydration). the extraintestinal clinical manifestations associated with Abnormal vital signs (increased heart rate, decreased blood rotavirus infection. pressure, decreased level of consciousness, increased capillary refill time): needs resuscitation. How is rotavirus diagnosed? Rotavirus can be detected in stool specimens from children as diarrhoea resolves, but viral nucleic acid can be detected with gastroenteritis by several techniques, including electron at low levels for several weeks.14 microscopy, polyacrylamide gel electrophoresis, antigen The pathogenesis of rotavirus diarrhoea includes effects detection assays, reverse transcription polymerase chain on absorption and on secretion. Morphologically, rotavirus reaction (RT-PCR), and virus isolation. Diagnosis of rotavi- infection causes enterocyte death and desquamation, lead- rus was initially by electron microscopy, with and without ing to the loss of absorptive villous cells and the proliferation agglutination by immune sera. Large numbers of rotavirus of secretory crypt cells.15 may also result from particles (up to 1011/g faeces) are excreted during the acute a virus induced reduction in the expression of absorptive phase of infection, and children with severe diarrhoea seem enzymes, as well as paracellular leakage as a consequence to excrete a greater number of .17 Polyacrylamide gel of functional changes in tight junctions between enterocytes, electrophoresis detects rotavirus RNA extracted directly from which may be mediated by the viral non-structural protein stool specimens; the electrophoretic migration pattern of the 4 (NSP4). Biopsies show atrophy of the villi and mononu- 11 segments of the double stranded RNA genome permits clear cell infiltrates in the lamina propria. Increased chloride analysis of the relatedness of circulating strains.18 secretion and loss of consequent water and electrolyte are Children with gastroenteritis are not routinely tested for mediated by NSP4, which acts as a viral enterotoxin, activat- rotavirus because the results do not alter treatment. When ing cellular calcium channels and inducing secretory diar- testing is performed, antigen detection tests—including com- rhoea. Activation of the enteric nervous system (also thought mercially available enzyme linked immunosorbent assays to be dependent on NSP4) induces secretory diarrhoea and (ELISAs) and immunochromatographic assays—are widely increases intestinal motility.13 Villous brush border enzymes used. Most of these tests have high sensitivity and specificity such as sucrase and isomaltase also decrease, resulting in (90-95%).19 RT-PCR is widely used in research laboratories to detect the viral genome.20 It provides data on the VP7 and Table 1 | World Health Organization guidelines for assessing dehydration in children with acute VP4 genotypes that form the basis of binary classification (G gastroenteritis40 and P type, respectively) of rotavirus strains. A B C Condition* How is rotavirus gastroenteritis treated? Well, alert Restless, irritable Lethargic or unconscious The management of acute rotavirus gastroenteritis focuses Eyes† on the treatment and prevention of dehydration. In most Normal Sunken Sunken Thirst situations the clinician will not be aware at the start of Drinks normally, not thirsty Thirsty, drinks eagerly Drinks poorly, or not able to drink treatment whether the gastroenteritis is caused by rota- Skin pinch‡ virus or another pathogen. Initial assessment therefore Skin goes back quickly Skin goes back slowly Skin goes back very slowly focuses on determining the degree of dehydration because Decision this will be used to guide and monitor treatment. No signs of dehydration Some dehydration if there Severe dehydration if there are ≥2 signs in C are ≥2 signs in B Many evidence based reviews and clinical guidelines are *Being lethargic and sleepy are not the same. A lethargic child is not simply asleep: the child’s mental state is dull and the available on various aspects of the assessment and treat- child cannot be fully awakened; the child may appear to be drifting into unconsciousness. ment of acute gastroenteritis in young children.21‑36 How- †In some infants and children the eyes normally appear somewhat sunken. It is helpful to ask the mother if the child’s eyes are normal or more sunken than usual. ever, a recent systematic review of eight guidelines noted ‡The skin pinch is less useful in infants or children with marasmus or kwashiorkor, and in obese children. considerable variation in their quality, inconsistencies between the recommendations, lack of evidence for many Table 2 | Clinical dehydration scale32 recommendations, and lack of generalisability to gen- 37 Score* eral practice. These were suggested as possible reasons Characteristic 0 1 2 why adherence to such guidelines is poor in high income General appearance Normal Thirsty, restless, or sleepy; Drowsy, limp, and cold; may countries. For example, the authors noted that in general irritable when touched be comatose practice it was unclear “how” or to “whom” oral rehydra- Eyes Normal Slightly sunken Deeply sunken tion therapy should be given. They concluded that future Tongue Moist Sticky Dry studies, particularly in general practice, need to determine Tears Present Decreased Absent the value of clinical in assessing dehy- *Total score: 0=no dehydration; 1-4=some dehydration; 5-8=moderate/severe dehydration. dration, the optimal dose of oral rehydration solution for

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each grade of dehydration, and the validity of reasons why less vomiting, and no increased risk of hyponatraemia.28 In clinicians prescribe other drugs. In contrast, another recent 2002, WHO recommended the routine use of a solution with assessment of the quality of clinical practice guidelines for reduced osmolarity (sodium 75 mmol/L, 75 mmol/L, acute gastroenteritis, using the appraisal of guidelines for and total osmolarity 224 mmol/L) for non- diarrhoea. research and evaluation instrument, concluded that the To maintain hydration of children with “no signs of dehy- overall quality of these guidelines was fair.38 dration,” WHO recommends giving extra fluid or oral rehydra- tion solution after each loose stool. The suggested volume is How should dehydration be assessed? 50-100 mL (quarter to half a large cup) for children under Several scoring systems have been devised to assess 2 years of age and a 100-200 mL (half to one large cup) for dehydration.39 The World Health Organization scale is those above 2.40 For children with “some signs of dehydra- probably most widely used in the developing world (table tion,” WHO recommends correcting hydration over four hours 1),40 whereas the modified four point Gorelick score (box) with 75 mL/kg of solution.40 However, a review of eight inter- and clinical dehydration scale (table 2) have been used in national guidelines showed that recommendations on the developed world settings.32‑34 39 The clinical dehydration dose of oral rehydration solution were not evidence based scale has been reported to help predict a longer length of and were inconsistent, reflecting the use of expert opinion stay and the need for intravenous fluid rehydration.32 It and differences in how guidelines categorised dehydration.37 is generally accepted that conventional clinical signs of The authors concluded that the optimal regimen was unclear. dehydration are valid and reliable when used collectively It is important that breast feeding should continue through- but individually they lack sensitivity and specificity.41 The out the rehydration and maintenance phases of treatment.40 Vesikari and Clark scores are used in rotavirus vaccine effi- Feeding should be restarted as soon as possible because cacy trials for assessing the severity of gastroenteritis but this will reduce the duration and severity of diarrhoea, and are not designed to guide clinical management according there is no evidence that early refeeding increases the risk of to the degree of dehydration.35 unscheduled intravenous fluid use, episodes of vomiting, or development of persistent diarrhoea.22 Although -free Oral and intravenous rehydration therapy feeds may reduce the duration of diarrhoea in children with Oral and intravenous rehydration is the mainstay of treat- mild to severe dehydration compared with feeds containing ment for rotavirus and other causes of acute gastroenteritis. lactose, there is no evidence that lactose containing feeds are is the preferred treatment of mild to harmful for most children with acute gastroenteritis.42 moderate dehydration in children with acute diarrhoea.27 29 41 Randomised controlled trials—including some that spe- For every 25 children (95% confidence interval 14 to 100) cifically assessed efficacy against rotavirus gastroenteri- treated one will not respond and will require intravenous tis—have shown that other treatments such as , rehydration.27 Expert consensus recommends that children , , nitazoxanide, and some biological com- who are very ill, lethargic, drinking poorly, or have shock or pounds are effective in the management of acute gastroenteri- near shock are initially treated intravenously. Oral rehydration tis.21 23 24 40‑ 45 However, recommendations for the use of these therapy should not be given to children with intestinal treatments vary considerably between different developmen- until bowel sounds are audible, or in the presence of glucose tal regions and different countries, and further discussion of malabsorption.29 their use is beyond the scope of this article. For more than two decades, WHO recommended the stand- ard glucose based oral rehydration solution (90 mmol/L How can rotavirus gastroenteritis be prevented? sodium, 111 mmol/L glucose, and a total osmolarity 311 Because rotavirus infects nearly all children in both indus- mmol/L).28 However, subsequent studies have shown that trialised and developing countries early in life, good hygiene when compared with the standard WHO solution, reduced and sanitation alone are considered inadequate for preven- osmolarity oral rehydration solution is associated with tion. Observational studies have shown that breast feeding fewer unscheduled intravenous fluid infusions (odds ratio confers protection from rotavirus gastroenteritis, although 0.59, 0.45 to 0.79), lower stool volume after randomisation, one case-control study indicated that it may only postpone

Table 3 | Features of Rotarix and RotaTeq rotavirus vaccines Feature Rotarix RotaTeq Composition Single human rotavirus strain (P1A[8], G1) Five human G/P reassortants with bovine rotavirus strain WC3 (P7[5], G6): G1 × WC3; G2 × WC3; G3 × WC3; G3 × WC3; P1A[8] × WC3 Number of doses needed 2 oral doses 3 oral doses Schedule* Dose 1: minimum 6 weeks of age; dose 2: ≥4 weeks later; complete by 24 Dose 1: 6-12 weeks of age; doses 2 and 3: 4-10 weeks of age week intervals; complete by 32 weeks of age Dose Each dose (1-1.5 mL) contains at least 106 median cell culture infectious Each dose (2 mL) contains at least 2.0-2.8×106 doses infectious units per reassortant Shelf life 36 months 24 months Storage 2-8°C, protected from light 2-8°C, protected from light Contraindications History of hypersensitivity to the vaccine or any component of the vaccine; History of hypersensitivity to the vaccine or any history of uncorrected congenital malformation of the component of the vaccine; history of severe that would predispose to intussusception; history of severe combined combined immunodeficiency disease; history of immunodeficiency disease; history of intussusception intussusception *Ages for vaccine doses vary according to the recommendations of individual countries and vaccination schedules.

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AREAS FOR FUTURE RESEARCH TIPS FOR NON-SPECIALISTS Exploring the role of rotavirus in extraintestinal clinical syndromes (such as neurological All children are infected with rotavirus in the first 3-5 years manifestations, necrotising enterocolitis) of life, regardless of hygiene and sanitation conditions Investigating the value of clinical signs and symptoms in assessing dehydration, Vaccines are therefore the most effective way to prevent particularly in general practice rotavirus diarrhoea Defining the optimal dose of oral rehydration solution for each grade of dehydration, so that Treatment of rotavirus diarrhoea relies on hydration consistent recommendations can be made therapy Identifying treatments (including antiviral agents) with clinical efficacy against rotavirus Rotavirus vaccines have performed well in countries gastroenteritis where they are used routinely; in some settings, they have Community based action research and sociocultural research on knowledge, attitudes, conferred additional benefits to unvaccinated children and perceptions, cultural practices, and health seeking behaviours with regard to rotavirus adults through herd protection infection Although rotavirus vaccines work less well in developing Understanding the benefit-risk profile of routine rotavirus vaccination in a diverse range of countries, the potential to prevent severe disease and geographical and socioeconomic settings deaths is greater because of the high disease burden in Investigating the effectiveness and impact of rotavirus vaccination in low income settings these settings Identifying interventions (such as additional vaccine doses or alternative schedules, The documented health benefits of rotavirus vaccines far supplementation with micronutrients) or alternative approaches (such as parenteral outweigh the small risk of intussusception that has been vaccines) that might improve the performance of rotavirus vaccines in low income settings seen in some settings

the occurrence of rotavirus gastroenteritis to the post-weaning pital admissions for gastroenteritis in children under 5 years period.46 within two years of vaccine introduction.53 Unexpectedly, Follow-up of birth cohorts indicates that, although children rotavirus vaccination of young infants has also resulted in can be infected with rotavirus four to five times in the first two decreases in rotavirus disease in children who missed vacci- years of life, the incidence of severe rotavirus gastroenteritis nation, older children, and even adults who were not eligible is reduced with each repeat infection.6 7 Therefore, orally for vaccination.54 This phenomenon, known as herd protec- administered, live, attenuated rotavirus vaccines have been tion, is probably related to reduced transmission of rotavirus developed to mimic the effect of natural infection and prevent in the community as a result of vaccination. Reductions in severe rotavirus disease. nosocomial rotavirus infections have also been seen since the A rhesus-human reassortant rotavirus vaccine (Rotashield, introduction of the vaccine.55 Lastly, ecological studies from Wyeth) was licensed in the US in 1998 after showing high Mexico and Brazil have shown a 35% and 22% decline in efficacy against severe rotavirus gastroenteritis in randomised childhood deaths from diarrhoea, respectively, since the intro- clinical trials.47 Rotashield was recommended for routine duction of the vaccine,56 57 and these reductions have been immunisation of US infants the same year but was abruptly sustained for four years in Mexico. These findings are particu- withdrawn a year later because post-licensure observational larly noteworthy because vaccine efficacy against death from studies found that it was associated with a severe adverse diarrhoea was not evaluated in pre-licensure trials. event, intussusception.48 49 Intussusception is a form of bowel Post-licensure observational studies in several countries, obstruction that often requires surgery and is associated with including the US, Australia, Mexico, and Brazil, have also high fatality if not treated. It was estimated that vaccination identified a low risk of intussusception with both rotavirus of 10 000 infants with Rotashield resulted in one excess case vaccines.58‑65 The evidence of risk for the two vaccines is of intussusception. difficult to compare directly because the study populations Two other live oral rotavirus vaccines—a pentavalent and designs differed. In general, the overall risk is one to bovine-human reassortant vaccine (RotaTeq, Merck) and a five excess cases of intussusception per 100 000 vaccinated monovalent human vaccine (Rotarix, GSK Biologicals)—were infants. Considering the substantial and well documented in advanced stages of clinical testing when Rotashield was health benefits of vaccination against this low intussuscep- withdrawn (table 3). RotaTeq and Rotarix were each tested in tion risk, policy makers in countries with documented risk, randomised clinical trials of 60 000-70 000 infants to assess as well as global health authorities such as WHO, strongly the risk of intussusception before licensure.50 51 No increase support rotavirus vaccination of infants. in risk was found during the 42 and 30 days post-vaccina- Live oral vaccines against many diseases, such as , tion after the three doses of RotaTeq or two doses of Rotarix, typhoid, and cholera, have performed less well in develop- respectively. The vaccines showed 85-98% efficacy against ing countries than in industrialised ones. The reasons for severe rotavirus gastroenteritis in these trials conducted in this variability are not completely understood. Potential the Americas and Europe, with good protection against dis- explanations include interference in vaccine uptake by ease caused by rotavirus strains not included in the vaccines greater levels of maternal antibody or concurrent enteric (heterotypic ). These findings supported vaccine infections in developing countries, as well as reduced licensure and recommendations for use by policy groups in immune response in infants because of comorbidities or the US and Europe and by WHO.52 , including micronutrient deficiencies.66 As of December 2013, 51 countries include rotavirus Because of these concerns, randomised efficacy trials of vaccines in their national immunisation programmes. A both RotaTeq and Rotarix were conducted in developing systematic review of ecological studies from eight countries countries in Africa and Asia.67‑69 These trials showed mod- reported a 49-89% decline in laboratory confirmed rotavirus est vaccine efficacy (50-64%) against severe rotavirus gas- hospital admissions and 17-55% reduction in all cause hos- troenteritis. Despite this reduced efficacy, the public health

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ADDITIONAL EDUCATIONAL RESOURCES As rotavirus vaccines are introduced into immunisation programmes of low income countries globally, it will be Resources for healthcare professionals important to assess the real world impact of vaccination Centers for Disease Control and Prevention. Prevention of rotavirus gastroenteritis among infants to gain a better understanding of vaccine effectiveness and children—recommendations of the Advisory Committee on Immunization Practices (ACIP). and safety in a range of settings. Although both of the MMWR 2009;58(RR02):1-25. licensed rotavirus vaccines have shown good protection www.cdc.gov/mmwr/preview/mmwrhtml/rr5802a1.htm (free access) against a range of circulating rotavirus strains, including WHO. WHO position paper on rotavirus vaccines. Wkly Epidemiol Rec 2013;88:49-64. ` strains with either or both G and P types not contained in www.who.int/wer/2013/wer8805.pdf (free access) the vaccine, further monitoring of the long term impact Soares-Weiser K, MacLehose H, Bergman H, Ben-Aharon I, Nagpal S, Goldberg E, et al. of vaccination on strain ecology is vital. Also, given the Vaccines for preventing rotavirus diarrhoea: vaccines in use. Cochrane Database Syst Rev moderate efficacy of rotavirus vaccines in low income 2012;11:CD008521 (subscription required) countries, interventions to improve vaccine performance PATH (http://sites.path.org/rotavirusvaccine/rotavirus-advocacy-and-communications-toolkit/) (such as additional vaccine doses or different vaccination —Free rotavirus disease and vaccine resources schedules) should be considered and evaluated. Finally, to PATH (http://sites.path.org/rotavirusvaccine/current-issue-of-rotaflash-jpg/) sustain global implementation of vaccination, an adequate —Breaking news and updates on rotavirus vaccines supply of affordable rotavirus vaccines must be assured. Resources for patients and parents It is therefore encouraging that several manufacturers in Centers for Disease Control and Prevention at (www.cdc.gov/rotavirus/index.html) emerging markets, including India, China, Indonesia, and —Basic information on the symptoms, treatment, and prevention of rotavirus gastroenteritis Brazil, are developing candidate rotavirus vaccines that may be available within the next five years. benefits of vaccination in terms of number of severe rota- Contributors: UDP searched the literature and is guarantor. UDP, EASN, and GK virus gastroenteritis episodes prevented per 100 infants each wrote different sections of the manuscript and revised the entire draft of was greater in developing than in industrialised countries. the manuscript. This is because of the substantially greater rate of severe Competing interests: UDP and GK—none. EASN has participated in vaccine and disease surveillance studies funded by GlaxoSmithKline and Pfizer. rotavirus gastroenteritis in developing countries. These Provenance and peer review: Commissioned; externally peer reviewed. considerations led WHO to issue a global recommenda- The findings and conclusions in this report are those of the authors and do tion for vaccination in 2009 and have prompted several not necessarily represent the views of the Centers for Disease Control and low income countries to include rotavirus vaccination in Prevention (CDC). their immunisation programmes. References are in the version on bmj.com.

ANSWERS TO ENDGAMES, p 38 For long answers go to the Education channel on bmj.com ANATOMY CASE REPORT QUIZ A patient with hypertrophic cardiomyopathy undergoing non-cardiac surgery Longitudinal 1 Hypertrophic cardiomyopathy is an autosomal dominant genetic disorder characterised by left ventricular hypertrophy, impaired diastolic filling, and abnormalities of the mitral valve. These features can cause dynamic obstruction of the ultrasound left ventricular outflow tract, diastolic dysfunction, myocardial ischaemia, and an increased risk of supraventricular and through the ventricular tachyarrhythmias. testicle 2 Most people with hypertrophic cardiomyopathy are asymptomatic, although symptoms may develop at any age. A: Epididymis Symptoms include exertional chest pain; dyspnoea as a result of heart failure, which may be progressive; palpitations or stroke from arrhythmia; syncope; and sudden death owing to arrhythmias and obstruction of the left ventricular outflow B: Mediastinum tract. Because obstruction of the left ventricular outflow tract is dynamic, symptoms can be exacerbated during exercise testis or surgery, which may increase cardiovascular stress or reduce preload or afterload. C: Tunica 3 Features such as personal or family history of sudden cardiac death, history of ventricular fibrillation or sustained albuginea ventricular tachycardia, recent unexplained syncope, non-sustained ventricular tachycardia, massive maximal left D: Testicular ventricular hypertrophy, and abnormal blood pressure response to exercise convey a greater risk of sudden cardiac parenchyma death. Because our patient first presented with symptoms of left ventricular hypertrophy in her 70s and has no relevant E: Scrotal wall personal or family history, she is probably at low risk of sudden cardiac death or rapidly progressive disease. 4 The condition is associated with an increased incidence of congestive heart failure, myocardial ischaemia, hypotension, STATISTICAL and atrial and ventricular arrhythmias after non-cardiac surgery. This is probably as a result of worsened left ventricular QUESTION outflow tract obstruction, diastolic dysfunction, cardiac ischaemia, and risk of arrhythmias. Exacerbating intraoperative and postoperative factors include increased sympathetic discharge during intubation and surgery, as well as reduced Snowball preload and afterload from preoperative fluid restriction, fluid and blood loss during surgery, and the effects of sampling anaesthetic and analgesic agents. Statement c is 5 Intraoperative and postoperative care should aim to minimise excessive catecholamine discharge, which is common true, whereas a during anxiety, intubation, and pain. Preload and afterload should be maintained by minimising both fluid losses and and b are false. vasodilation through careful choice of anaesthetic and analgesic technique. Close monitoring and minimisation of ventilator pressures are also important.

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