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matic trials are needed in which the treatment assignment takes into account the major syndromes associated with shock (Fig. 1). High-quality trials are essential to inform patient management and guide policy. Improving child survival with the development of a simple management protocol will have benefits beyond the boundaries of any one illness. But to achieve large-scale success with a simple protocol, it will be vital to increase human resources and train and support the staff in small hospitals in developing countries.
From the Paediatric Department, College of Medicine, Blantyre, Malawi (E.M.M.); and the Centre for Geographic Medicine Research (Coast), Kenya Medical Research Unit, Kilifi, Kenya (K.M.).
1. Robertson MA, Molyneux EM. Description of cause of serious illness and outcome in patients identified using ETAT guidelines in urban Malawi. Arch Dis Child 2001;85:214-7. 2. Idem. Triage in the developing world can it be done? Arch Dis Child 2001;85:208-13. 3. Wills BA, Nguyen MD, Loan HT, et al. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 2005;353:877-89. 4. Tamburlini G, Di Mario S, Maggi RS, Vilarim JN, Gove S. Evalu-

ation of guidelines for emergency triage assessment and treatment in developing countries. Arch Dis Child 1999;81:478-82. 5. Carcillo JA, Fields AI. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002;30:1365-78. 6. Cochrane Injuries Group Albumin Reviews. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 1998;317:235-40. 7. The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56. 8. Skellett S, Mayer A, Durward A, Tibby SM, Murdoch IA. Chasing the base deficit: hyperchloraemic acidosis following 0.9% saline fluid resuscitation. Arch Dis Child 2000;83:514-6. 9. Fleming AF. HIV and blood transfusion in sub-Saharan Africa. Transfus Sci 1997;18:167-79. 10. Chameides L, Hazinskii MF, eds. Pediatric advanced life support 1997-1999. Dallas: American Heart Association, 1997. 11. Advanced Life Support Group. Advanced paediatric life support: the practical approach. 4th ed. London: Blackwell Publishing, 2004. 12. Maitland K, Pamba A, English M, et al. Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis 2005; 40:538-45. 13. Duke T, Molyneux EM. Intravenous fluids for seriously ill children: time to reconsider. Lancet 2003;362:1320-3.
Copyright 2005 Massachusetts Medical Society.

Hepatitis A The Price of Progress

Loriana Di Giammarino, M.D., and Jules L. Dienstag, M.D. Hepatitis A tends to be a self-limited disease without serious sequelae and with a low case fatality rate1; unlike hepatitis B and hepatitis C, hepatitis A is not a cause of chronic liver disease. On the other hand, approximately 1.4 million clinical cases of hepatitis A occur each year worldwide, and in the United States, hepatitis A is a common cause of acute hepatitis and one of the most frequently reported vaccine-preventable diseases,1 responsible for a substantial economic burden on society.2 A seemingly welcome observation has been the recent decline in the incidence of new cases reported yearly in the United States. From an average annual incidence of 28,000 cases (9 to 14 cases per 100,000 population) reported to the Centers for Disease Control and Prevention during the 1980s and 1990s, the incidence of reported cases has been declining during the past 10 years toward the lowest ever recorded 7600 cases annually (2.7 cases per 100,000 population) in 2003.3 The downside of the reduction in new infections with hepatitis A virus has been a declining prevalence of antibody to hepatitis A in the population and the emergence of an adult population with limited immunity to infection. This temporal trend parallels an important dichotomy in the clinical expression of hepatitis A infection that relates to geographic differences in the endemicity of infection. In communities with a high prevalence of hepatitis A, infections with this enteric agent are most likely to occur in children, in whom the disease tends to be asymptomatic or mildly symptomatic.1 With advances in environmental hygiene that are typical of developed countries, the frequency of enteric infections, such as that with hepatitis A, declines, and children are spared, but the level of natural immunity in the population declines, and adults remain susceptible.1 When adults are infected, however, the resulting illness tends to be more severe.4 Paradoxically, then, as hepatitis A becomes less common, the burden of new infections shifts from children to adults, and the frequency of clinically severe acute hepatitis A increases an unintended consequence of progress. In the United States, despite declining rates of infection, sporadic outbreaks of foodborne hepatitis A continue to occur, and with increasing regularity, foodborne outbreaks unrelated to an index food handler have attracted attention. In this issue of the Journal, Wheeler and colleagues5 describe an

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outbreak of hepatitis A involving at least 601 patrons and workers at a single Pennsylvania restaurant, 124 of whom required hospitalization, including 4 with acute fulminant hepatitis and liver failure. Identical viral sequences obtained from 170 patients confirmed a common source of infection and linked the infections to isolates common in Mexico. Epidemiologic analysis exonerated restaurant employees as index cases but implicated green onions, which were used primarily to prepare not only the complimentary mild salsa but also other menu offerings and were imported from two farms in northern Mexico, where they probably had been cultivated with water contaminated with hepatitis A virus. The estimated attack rate was nearly 18 percent, and the 26 percent hospitalization rate among patients who were Pennsylvania residents and 0.7 percent frequency of liver failure were reflections of the increased severity of adult-acquired hepatitis A. As Wheeler and colleagues point out, there has been an increase in the frequency of hepatitis A outbreaks linked to imported fresh produce, such as green onions, lettuce, raspberries, and strawberries.6,7 Because of high-standard agricultural and manufacturing practices, food production in the United States is among the safest in the world. Unfortunately, the best local practices do not insulate us from the risk associated with importing food from countries with lower standards of environmental hygiene. In a global economy, developing countries compete successfully for our food dollars. Consequently, fruits and vegetables from Central America are just as likely as those grown locally to reach our dining-room tables and restaurants. Hence, the potential for importing contaminated produce and the spread of hepatitis A from areas where disease is endemic to nonendemic areas is another unintended consequence of progress and our modern global economy. Perhaps instead of questioning why foodborne outbreaks still occur, we should be asking why such outbreaks do not occur more often. Despite the decline in reported cases of hepatitis A in the United States in the past decade, the frequency of reported cases in Massachusetts quadrupled in 2004; five instances were reported of hepatitis A among food handlers who worked at local franchises of popular, national restaurant chains. Subsequently, reported cases increased among the homeless, users of injection drugs, and incarcerated persons. Although the trend subsided toward the end of the year, the upsurge in cases was never explained adequately.

Adding to the frustration in the control of hepatitis A is the observation that half of all reported cases occur in people with no identifiable risk factor for infection.2,3 The current policy for hepatitis A vaccination is targeted to groups who are at increased risk.1 Because half of all patients with hepatitis A are not in a high-risk category and because the frequency of foodborne disease is unpredictable, the Public Health Service should reassess its policy regarding hepatitis A vaccination. This suggestion is especially compelling, given the substantial public-health costs of responding to outbreaks, the costs of health care for acute hepatitis in adult populations, and the unconscionable persistence of sporadic deaths resulting from a vaccine-preventable disease. Just as targeted hepatitis B vaccination failed to reduce the burden of hepatitis B, targeted hepatitis A vaccination although it has had a measurable effect3,8 has not been successful in protecting our society from the risk of headline-grabbing, sporadic outbreaks and episodic increases in reported cases. Potentially, universal childhood vaccination against hepatitis A could eliminate the risk of new infections. Moreover, now that combination hepatitis A and hepatitis B vaccines are available and the infrastructure is in place to immunize children routinely against hepatitis B during well-child visits, a policy of universal hepatitis A vaccination in childhood would be facilitated. Certainly, the risk of hepatitis A remains relatively low, and the costs of universal vaccination are not inconsequential; however, several assessments indicate the cost-effectiveness of childhood hepatitis A vaccination to prevent infection in adolescents and adults.9-11 Berge et al.2 estimated that in 1997, the economic burden of symptomatic hepatitis A infection in adolescents and adults was $488.8 million. Moreover, direct medical costs and indirect productivity losses are only a minor proportion of health expenditures for the control of hepatitis A. During a 1992 foodborne outbreak of hepatitis A in Denver, direct medical costs amounted to only $46,064, whereas disease-control costs, including a mass program of immune-globulin administration, came to $689,314.12 If childhood immunization provides immunity that is sufficiently durable to prevent infection decades later (as is anticipated), universal vaccination could eliminate the specter of outbreaks of foodborne hepatitis A that have appeared periodically in the Journal for decades. An even more welcome report would be

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of the documented eradication of hepatitis A by vaccination.

From the Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston.
1. Prevention of hepatitis A through active or passive immuniza-

6. Hutin YJF, Pool V, Cramer EH, et al. A multistate, foodborne out-

break of hepatitis A. N Engl J Med 1999;340:595-602.

7. Niu MT, Polish LB, Robertson BH, et al. Multistate outbreak of

tion: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1999;48(RR-12):1-37. 2. Berge JJ, Drennan DP, Jacobs RJ, et al. The cost of hepatitis A infections in American adolescents and adults in 1997. Hepatology 2000;31:469-73. 3. Hepatitis surveillance report no. 59. Atlanta: Centers for Disease Control and Prevention, September 2004. 4. Bell BP. Hepatitis A vaccine. Semin Pediatr Infect Dis 2002;13: 165-73. 5. Wheeler C, Vogt TM, Armstrong GL, et al. An outbreak of hepatitis A associated with green onions. N Engl J Med 2005;353:890-7.

hepatitis A associated with frozen strawberries. J Infect Dis 1992; 166:518-24. 8. Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United States in the era of vaccination. JAMA 2005;294:194-201. 9. Rosenthal P. Cost-effectiveness of hepatitis A vaccination in children, adolescents, and adults. Hepatology 2003;37:44-51. 10. Das A. An economic analysis of different strategies of immunization against hepatitis A virus in developed countries. Hepatology 1999;29:548-52. 11. Jacobs RJ, Greenberg DP, Koff RS, Saab S, Meyerhoff AS. Regional variation in the cost effectiveness of childhood hepatitis A immunization. Pediatr Infect Dis J 2003;22:904-14. 12. Dalton CB, Haddix A, Hoffman RE, Mast EE. The cost of a foodborne outbreak of hepatitis A in Denver, Colo. Arch Intern Med 1996;156:1013-6.
Copyright 2005 Massachusetts Medical Society.

Meconium Aspiration Syndrome More Than Intrapartum Meconium

Michael G. Ross, M.D., M.P.H. Meconium, the fecal material that accumulates in the fetal colon throughout gestation, is a term derived from the Greek mekoni, meaning poppy juice or opium. Beginning with Aristotles observation of the association between meconium staining of the amniotic fluid and a sleepy fetal state1 or neonatal depression, obstetricians have been concerned about fetal well-being in the presence of meconiumstained amniotic fluid. The passage of meconium normally occurs within the first 24 to 48 hours after birth. However, the passage of fetal meconium, resulting in meconiumstained amniotic fluid, occurs in approximately 12 percent of all deliveries. The meconium aspiration syndrome, associated with aspiration or perhaps diffusion of meconium into the fetal airways, occurs in 5 percent of these infants. Of infants in whom the meconium aspiration syndrome develops, more than 4 percent die,2 accounting for 2 percent of all perinatal deaths. The meconium aspiration syndrome is manifested by newborn respiratory compromise, with tachypnea, cyanosis, and reduced pulmonary compliance. Persistent pulmonary hypertension due to increased pulmonary vascular resistance may accompany the meconium aspiration syndrome; there is an increased prevalence of asthmatic symptoms and abnormal bronchial reactivity among survivors of the syndrome.3,4 When aspirated into fetal lungs, meconium particles mechanically obstruct the small airways. Meconium or the chemical pneumonitis it causes inhibits surfactant function, and inflammation of lung tissue contributes further to small-airway obstruction. Acute intrapulmonary meconium contamination induces a concentration-dependent pulmonary hypertensive response,5 with 15 to 20 percent of infants with the meconium aspiration syndrome demonstrating persistent pulmonary hypertension.6 However, evidence of a long-term process of muscularization of distal pulmonary arterioles in infants with the meconium aspiration syndrome who died suggests that factors other than meconium aspiration (e.g., chronic hypoxemia) may contribute to the pulmonary symptoms. Meconium may also stimulate the constriction and necrosis of umbilical vessels and the production of thrombi, although the clinical relevance of these effects is uncertain. The passage of meconium in utero occurs primarily in situations of advanced fetal maturity or fetal stress. Most infants who are delivered with meconium-stained amniotic fluid are 37 weeks of gestation or older; meconium rarely appears in amniotic fluid before 32 weeks of gestation. Fetal hypoxic stress may stimulate colonic activity, resulting in the passage of meconium, and also may stimulate fetal gasping movements that result in meconium aspiration. Amnioinfusion, the injection of fluid into the

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