Rota and Pneumococcus Vaccine Success Stories: Pediatric Emergency Practitioners Wonder “Where Have the Kids Gone?”

Abstract

Across US emergency departments (EDs) this past winter, there was the usual range of childhood illnesses: fever, falls, flu. But to the enormous relief of pediatric emergency practitioners, 2 sets of symptom complexes made an appearance much less often: the severe gastroenteritis caused by rotavirus infection, and the pneumonia, bacteremia and meningitis of invasive S. pneumoniae disease. The near disappearance of rotavirus gastroenteritis and invasive pneumococcal disease is a real-world demonstration of the efficacy of vaccine, in this case Prevnar and Rotateq. Neither vaccine is brand-new: Prevnar was released in the United States in 2000, and Rotateq in 2006. Yet this winter in particular, emergency physicians seemed to find the vaccines' impact particularly striking, noticing the cases they were no longer seeing and reflecting on the changes the vaccines have brought to their working lives. “Without question, Prevnar and the rotavirus vaccine have remarkably changed our practice,” said Stuart Bradin, DO, assistant professor of pediatrics and emergency medicine at the University of Michigan Health System, Ann Arbor, MI. “The workups we do now on patients are much less invasive, at least for a well-appearing child.” Marianne Gausche-Hill, MD, Director, Emergency Medical Services at Harbor-UCLA Medical Center, Los Angeles, CA, who practices in both the pediatric and the adult EDs, added: “We've all been asking ourselves, Where have the kids gone?” The declines in incidence are so noticeable because the impact of those diseases was so recently so dire. Before the introduction of Prevnar, a 7-serotype conjugate vaccine made by Wyeth Lederle Vaccines, invasive pneumococcal disease occurred in 24 out of every 100,000 US children younger than 5. In the first year the vaccine was released—a year in which demand was so strong that there was a shortage—bacteremia and meningitis caused by the targeted serotypes fell by 29% in children under 5. Among children younger than 2, it sank 69%.1Whitney C.G. Farley M.M. Hadler J. et al.Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine.N Engl J Med. 2003; 348: 1737-1746Crossref PubMed Scopus (1919) Google Scholar By 2004, the vaccine was also shown to reduce hospitalizations of young children by 39%2Grijalva C.G. Nuorti J.P. Arbogast P.G. et al.Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis.Lancet. 2007; 369: 1179-1186Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar and outpatient visits by 41%.3Zhou F. Kyaw M.H. Shefer A. et al.Health care utilization for pneumonia in young children after routine pneumococcal conjugate vaccine use in the United States.Arch Pediatr Adolesc Med. 2007; 161: 1162-1168Crossref PubMed Scopus (114) Google Scholar It cut pneumococcal otitis media by 34%4Eskola J. Kilpi T. Palmu A. et al.Efficacy of a pneumococcal conjugate vaccine against acute otitis media.N Engl J Med. 2001; 344: 403-409Crossref PubMed Scopus (1293) Google Scholar and significantly reduced nasal carriage of both drug-sensitive and antibiotic-resistant S. pneumo.5Dagan R. Givon-Lavi N. Zamir O. et al.Effect of a nonavalent conjugate vaccine on carriage of antibiotic-resistant Streptococcus pneumoniae in day-care centers.Pediatr Infect Dis J. 2003; 22: 532-540PubMed Google Scholar And it created herd immunity as well, preventing pneumococcal disease among unvaccinated younger children6Givon-Lavi N. Fraser D. Dagan R. Vaccination of day-care center attendees reduces carriage of Streptococcus pneumoniae among their younger siblings.Pediatr Infect Dis J. 2003; 22: 524-532PubMed Google Scholar and among adults.1Whitney C.G. Farley M.M. Hadler J. et al.Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine.N Engl J Med. 2003; 348: 1737-1746Crossref PubMed Scopus (1919) Google Scholar The need for a rotavirus vaccine was just as great: Before Rotateq's introduction, rotavirus caused few deaths in the US—between 20 and 60 in any year, according to the Centers for Disease Control and Prevention (CDC)—but enormous amounts of illness: from 55,000 to 70,000 hospitalizations, 272,000 ED visits and 410,000 outpatient or office visits.7Fischer T.K. Viboud C. Parashar U. et al.Hospitalizations and deaths from diarrhea and rotavirus among children <5 years of age in the United States, 1993-2003.J Infect Dis. 2007; 195: 1117-1125Crossref PubMed Scopus (145) Google Scholar, 8Glass R.I. Kilgore P.E. Holman R.C. et al.The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden.J Infect Dis. 1996; 174: S5-S11Crossref PubMed Google Scholar But the road to a vaccine was bumpy. A tetravalent rhesus reassortant vaccine called RotaShield, also made by Wyeth, was introduced in 1998 after trials demonstrated efficacy of up to 83% against all rotavirus gastroenteritis, and up to 95% against severe disease.9Heaton P.M. Ciarlet M. Vaccines: the pentavalent rotavirus vaccine: discovery to licensure and beyond.Clin Infect Dis.15. 2007; 45: 1618-1624Crossref PubMed Scopus (65) Google Scholar However, the vaccine was withdrawn the next year after 15 infants experienced intussusception and 8 required surgery.10Intussusception among recipients of rotavirus vaccine--United States, 1998-1999.MMWR Morb Mortal Wkly Rep. 1999; 48: 577-581PubMed Google Scholar It took 7 years before a substitute vaccine—Rotateq, a pentavalent human-bovine reassortant made by Merck—was introduced. Its introduction has also not been trouble-free: In March 2007, the CDC announced that 17 children had experienced intussusception within 21 days of vaccination, out of 3.6 million doses sold in its first year of release—a proportion that the agency said was not above usual background rates.11Postmarketing monitoring of intussusception after RotaTeq vaccination-United States, February 1, 2006-February 15, 2007.MMWR Morb Mortal Wkly Rep. 2007; 56: 218-222PubMed Google Scholar A second rotavirus vaccine, Rotarix, licensed in Mexico by GlaxoSmithKline and intended primarily for the developing world, came on the US market in late 2008.12Ward R.L. Bernstein D.I. Rotarix: a rotavirus vaccine for the world.Clin Infect Dis. 2009; 48: 222-228Crossref PubMed Scopus (76) Google Scholar Rotateq was deployed so recently that little nationwide surveillance has been published to assess its impact. (The CDC only published in December its first population-based surveillance of the last year before Rotateq began to be sold.13Payne D.C. Staat M.A. Edwards K.M. et al.Active, population-based surveillance for severe rotavirus gastroenteritis in children in the United States.Pediatrics. 2008; 122: 1235-1243Crossref PubMed Scopus (148) Google Scholar) But 2 partial, voluntary systems indicate an effect. The National Respiratory and Enteric Virus Surveillance System, comprised of laboratories that report positive test results for a variety of pathogens to the CDC, found that the 2007-2008 season began months later than any other rotavirus season back to 1991, and resulted in two-thirds fewer positives than in the previous 7 seasons. And the New Vaccine Surveillance Network, which conducts prospective surveillance in 3 US counties, found that the percentage of fecal specimens testing positive for rotavirus went from 51% in 2006 to 6% in 2008.14Cortese M.M. Parashar U.D. Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2009; 58: 1-25PubMed Google Scholar Internal data from Morristown Memorial Hospital and Goryeb's Children's Hospital in Morristown, NJ shows a slight but steady decline in gastrointestinal illness, though any obvious rotavirus reduction is muted by the data being all gastrointestinal illness among all ages. “My general gestalt is that there is a decrease of rota being seen in the emergency department,” said Christopher S. Amato, MD, a pediatric emergency medicine attending. The final phase of the Rotateq trials predicted 74% efficacy against all rotavirus gastroenteritis, and 98% against serious disease.15Vesikari T. Matson D.O. Dennehy P. et al.Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine.N Engl J Med. 2006; 354: 23-33Crossref PubMed Scopus (1566) Google Scholar The anecdotal experience of emergency physicians appears to be bearing that out. “We still see rotavirus infection, and we see other viruses that cause GI symptoms, but the severity of the disease and the degree of dehydration are not as high,” said Dr. Bradin of the University of Michigan. Charles Jennissen, MD, director of pediatric emergency medicine at the University of Iowa Children's Hospital, Iowa City, IA, agreed. “I think we are seeing fewer patients who need to be admitted with these kinds of illnesses,” he said. “Part of that might be that we are doing a better job of oral rehydration in the emergency department, or that we have other tools that can help, such as IV Zofran. But I do think the fewer patients who are significantly dehydrated enough that we have to admit them is due to the fact of the vaccine.” Several physicians said Prevnar's impact has been more dramatic, which may be due to its longer time on the market or to its prevention of more severe disease. “If we have a well-appearing febrile child who has had 3 doses (of Prevar) by 6 months of age, we don't do the blood work that we did before,” Dr. Bradin said. He noted that there are some exceptions to that rule, but, by and large, he said, the rate of bacteremia has fallen so low that on culture, positives are more likely to be false positives caused by contaminants, a view borne out by a 2006 paper in Pediatric Emergency Care.16Sard B. Bailey M.C. Vinci R. An analysis of pediatric blood cultures in the postpneumococcal conjugate vaccine era in a community hospital emergency department.Pediatr Emerg Care. 2006; 22: 295-300Crossref PubMed Scopus (56) Google Scholar The benefits of such sharp changes in incidence include not only reduced burden of disease but reduced health care utilization and cost; one 2007 study found that, thanks to Prevnar, annual hospitalization and ambulatory expenditures for children younger than 2 years shrank 45% between 1999 and 2004, from $688.2 million to $376.7 million.3Zhou F. Kyaw M.H. Shefer A. et al.Health care utilization for pneumonia in young children after routine pneumococcal conjugate vaccine use in the United States.Arch Pediatr Adolesc Med. 2007; 161: 1162-1168Crossref PubMed Scopus (114) Google Scholar There are more subtle effects as well, some as simple as reducing the stress on a child and his parents because less blood work means fewer needle sticks during an ED stay. But those effects may be fragile: Several studies have found post-Prevnar increases in pneumococcal meningitis caused by serotypes that are not covered by or cross-reactive with the vaccine. The most recent study, which drew on the CDC's eight-state Active Bacterial Core Surveillance system, found that meningitis caused by strains not covered by the vaccine increased by 61% between 1998-99 and 2004-2005, primarily in children younger than 2. The authors, from 11 health departments and medical schools as well as the CDC, were careful to say that the increase was small relative to the overall decline in meningitis: an increase of 2.10 cases per 100,000 versus an overall decline of 7.61 cases per 100,000. But they cautioned that rates of meningitis caused by non-covered serotypes are a concern and should be watched for.17Hsu H.E. Shutt K.A. Moore M.R. et al.Effect of pneumococcal conjugate vaccine on pneumococcal meningitis.N Engl J Med. 2009; 360: 244-256Crossref PubMed Scopus (391) Google Scholar Both vaccines' benefits may also be subject to disruption if uptake is reduced by public opinion turning against vaccines, or by the periodic shortages that bedevil vaccine manufacturing. That was demonstrated as recently as January, when 5 children in Minnesota contracted invasive Hemophilus influenzae type b disease, and one died. All 5 cases occurred during a vaccine recall and nationwide shortage that began in December 2007. Three of the 5 children had received no vaccine at all because their parents or guardians had refused it; one had received two doses but not the recommended booster dose.18Invasive Haemophilus influenzae Type B disease in five young children--Minnesota, 2008.MMWR Morb Mortal Wkly Rep. 2009; 58: 58-60PubMed Google Scholar Physicians who have been in the specialty long enough to have experienced the introduction of Hib vaccine in the mid 1980s, with its extraordinary suppression of bacterial meningitis, and the subsequent introduction of Prevnar, caution that success brings its own risks as well. The lower the incidence of a disease, the less likely younger physicians are to experience it in their training— and thus the more careful medicine must be to make sure certain procedures are still taught. Dr. Gausche-Hill, who entered practice before the Hib program began, offered an example. “I have done so many lumbar punctures, at least 1,000, and now I will go months without doing one at all,” she said. “I saw a 4-year-old the other day: headache, fever, vomiting. I asked the residents, ‘Does the child have meningeal signs?’ They said no. I asked them, ‘Have you ever seen a child with meningitis?’ And they said no. So I went in, and checked, and the child had a stiff neck, and we tapped him, and he had meningitis. But the residents, to that point in their training, had never seen a case before.”