Mulholland, E Kim

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Helen K. Maher

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AAOHN Journal

Measles in the United States: 2006

LSHTM Research Online

Mulholland, EK (2006) Measles in the United States, 2006. The NewEngland journal of medicine, 355 (5). pp. 440-3. ISSN 0028-4793Downloaded from: http://researchonline.lshtm.ac.uk/11668/Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: Copyright the publishersPERSPECTIVEn engl j med 355;5 www.nejm.org august 3, 2006440suggest that the FDA alone con-trols access to experimental drugs, but major barriers to access lie beyond the agency’s jurisdiction. Manufacturers, for instance, wor-ry about liability, and physicians may not seek such drugs for fear of the FDA paperwork. In addi-tion, Medicare, Medicaid, and pri-vate insurers generally will not pay for experimental drugs.Pharmaceutical-industry repre-sentatives also express other res-ervations. “One of the biggest limitations is manufacturing ca-pacity,” says Scott Lassman of the Pharmaceutical Research and Manufacturers of America. “Es-pecially in very early phases, the company may still be working out how to manufacture the product.” Although the bill proposes al-lowing companies to charge for tier 1 drugs, says Lassman, they certainly couldn’t charge full price. More important, “the whole pur-pose of large clinical trials is to fully evaluate benefits and risks,” argues Frank Rockhold, an exec-utive at GlaxoSmithKline, “and short-changing that is not in pa-tients’ best interests.”Nonetheless, the recent actions have apparently stimulated efforts to broaden access to experimen-tal drugs within the current sys-tem, especially in light of in-creased demand from patients. “We’ve seen a significant increase in the treatment INDs that are requested,” says Scott Gottlieb, the FDA’s deputy commissioner for medical and scientific affairs. “The agency has generally been aggressive in granting those,” usually acting within 24 to 48 hours on physicians’ IND requests and encouraging companies to establish broader treatment IND programs if there is considerable demand for a drug. According to Gottlieb, the agency is working to clarify the process of requesting access to experimental drugs, in part by providing standardized application forms and an inter-face on the FDA’s Web site.This spring, the National Co-alition for Cancer Survivorship and the American Society for Clinical Oncology petitioned the FDA to issue guidance to the phar-maceutical industry on standards for expanded-access programs; they suggested criteria for decid-ing when such programs are ap-propriate, ways to ensure equi-tability, and approaches to data collection and informed consent. Gottlieb says that the FDA has created a task force to respond to the petition and is clarifying its rules regarding what companies may charge. The FDA is permitted to approve compassionate use only for diseases in which evidence suggests that a given medication may have efficacy. However, the agency hopes to persuade com-panies to sponsor “simple, large, nonrandomized, open-access tri-als” for certain drugs that are in phase 3 trials, or possibly late in phase 2 trials, to make them avail-able to more patients while pro-viding additional data. “We think that you can have an approval pro-cess that is rigorous . . . even though you have parallel mecha-nisms to allow broader access to a drug that has shown activity and promise,” Gottlieb says.An interview with Mr. William Schultz, a partner at the law firm Zuckerman Spaeder and a former deputy commissioner for policy at the FDA, can be heard at www.nejm.org.Dr. Okie is a contributing editor of the Journal.Society for Clinical Trials Board of Direc-tors. The Society for Clinical Trials opposes US legislation to permit marketing of un-proven medical therapies for seriously ill pa-tients. Clin Trials 2006;3:154-7.1.access before approval — a right to take experimental drugs?Measles in the United States, 2006E. Kim Mulholland, M.D.Related article, page 447 The control and virtual elimi-nation of measles in the Unit-ed States is a public health success that has provided a model for immunization programs in other parts of the developed world. Be-fore measles vaccination was in-troduced in the United States in the mid-1960s, more than half a million cases of measles were re-ported each year. Once a vaccine was developed, public health of-ficials set out to use it to control the disease, envisioning eventual global eradication. By the mid-1970s, fewer than 50,000 cases were being reported annually in the United States, but a severe out-break in Los Angeles in 1977 re-minded authorities how tenuous the control of measles was. Com-pulsory immunization of school-children followed — the first in a series of steps that led to the interruption of the transmission of measles in the United States. The most effective of these steps was probably the introduction of a second dose of measles vaccine in 1989, again in response to a The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on February 14, 2014. For personal use only. No other uses without permission.  Copyright © 2006 Massachusetts Medical Society. All rights reserved. n engl j med 355;5 www.nejm.org august 3, 2006PERSPECTIVE441large outbreak of disease. At a meeting in March 2000, leaders in the field concluded that “measles is no longer endemic in the U.S.”1Six years later, an article in this issue of the Journal (pages 447–455) describes a 2005 measles outbreak in Indiana. Begun when a 17-year-old girl who was incubating mea-sles returned to Indiana from Ro-mania, the outbreak ultimately involved at least 34 persons, 1 of whom had life-threatening illness. With U.S. vaccination coverage at record levels, how could one im-ported case of measles lead to such an outbreak? This example illustrates the highly infectious nature of measles and the vulner-ability of vaccinated communities in a world in which the virus con-tinues to circulate.Measles is an acute infectious disease that can affect persons of all ages but is most severe in young infants and adults. Person-to-per-son transmission occurs through direct contact or droplet spread, and there is some evidence that severity is related to in-fective dose, so that those who acquire the disease from close household contacts have the most severe disease.2 Infected persons can infect others during the prodromal period before the char-acteristic rash appears, creating ample opportu-nity for people who are incubating the disease to travel from a country where the virus is circu-lating, such as Romania or India (the latter being the probable origin of an outbreak in Boston in the spring and early sum-mer of 2006), and bring the virus with them.In any population, there are persons who are immune to measles, thanks to natural in-fection or immunization; per-sons who are susceptible to the disease; and persons with incom-plete immunity who may be sus-ceptible to mild disease. In places where measles virus circulates freely, persons with immunity ap-pear to have their immunity boost-ed by intermittent exposure to the wild virus3; those who are suscep-tible, meanwhile, will inevitably acquire the disease unless they are immunized. After the disease has swept through a community, very few persons will remain suscep-tible. With time, however, new persons who are susceptible — who either have not been vacci-nated or did not acquire protective immunity from the vaccine they did receive — will be introduced into the community. Their num-bers will gradually increase until there are enough such persons to sustain an epidemic — hence the unstable measles epidemiol-ogy found in partially vaccinated communities (see graph).In countries such as the Unit-ed States, where transmission of the wild virus has been interrupt-ed, the rate of increase in the num-ber of persons who are suscepti-ble to the disease will depend on the success of the immunization program. For control to be sus-tained, a two-dose vaccination strategy with very high coverage is needed.At the time of the 2005 out-break, the level of vaccination cov-erage in Indiana was 98 percent for the second dose delivered to school-age children. In such a set-ting, it can be expected that the number of vaccinated persons who do not acquire protective immu-nity will be small, so the primary group of persons who are suscep-tible to the disease will consist of those who are unvaccinated. An important subgroup will be chil-dren who are too young to be vac-cinated. These infants become susceptible when maternal im-munity wears off, and they remain susceptible until they are immu-nized.There is evidence that mater-nal immunity is declining in some countries because, without the boosting effect of circulating wild virus, mothers must rely on im-munity from their own vaccina-tions (which were usually deliv-ered in the second year of life). As a result, infants become sus-ceptible to measles earlier in the first year of life, thereby increas-ing the number of susceptible per-sons present in a community at any given time. The susceptibil-ity of young infants is of partic-ular concern, since they are more likely than older children to have severe disease if they become in-fected.measles in the united states, 2006Infants too young to be vaccinatedUnvaccinated personsTimeNo. SusceptibleFluctuation in the Number of Persons Susceptible to Measles in a Community Where Measles Virus Is Circulating.In general, only a small fraction of the community will be suscep-tible at the time of an outbreak. The horizontal double-pointed arrows represent periods between outbreaks of measles, which vary according to levels of vaccine coverage and other factors. The downward-pointing arrows represent outbreaks of measles.The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on February 14, 2014. For personal use only. No other uses without permission.  Copyright © 2006 Massachusetts Medical Society. All rights reserved. PERSPECTIVEn engl j med 355;5 www.nejm.org august 3, 2006442Furthermore, a generation of young adults with waning, vac-cine-derived immunity may be-come susceptible to some extent to wild measles infection, al-though the role of such “second-ary vaccine failures” in measles epidemiology is unclear. The lon-ger a community goes without circulating measles virus, the more vigilant public health officials must be to maintain immunity levels in the community.The Indiana outbreak was strik-ing for a number of reasons. All but two of the cases occurred in unvaccinated hosts, indicating that it was the failure to vaccinate rather than vaccine failure that caused the problem. Five hundred people were reportedly present at the church gathering where the initial U.S. transmission occurred. Church officials estimated that 10 percent of them were unvac-cinated, but it is unclear how they knew this or how accurate their estimate was. It seems unlikely that the person with the index case of measles could have direct-ly infected 32 percent of all sus-ceptible persons at the meeting, and I would suggest that the number of unvaccinated persons there may have been higher. But even 10 percent is a high propor-tion in a state with 98 percent coverage for the second dose of measles vaccine, despite the fluc-tuations in coverage that may have occurred during the lifetimes of those who became infected, most of whom were younger than 20 years old. Community-based data such as levels of vaccine coverage repre-sent averages for a district, state, or country; although homogene-ity may seem to be implied, it never exists. Moreover, objection to immunization tends to occur in clusters, sometimes affecting whole communities. Thus, even with excellent coverage, there re-main subgroups in which condi-tions suitable to an outbreak may persist. Large gatherings of these groups provide an ideal setting for transmission, and if a person who is incubating the disease attends such a gathering, an outbreak is inevitable.Of the two vaccinated persons who acquired measles in Indiana, one was 34 years old and had been vaccinated only once in infancy. We cannot tell whether this case represents a primary vaccine fail-ure (a failure of the vaccine to in-duce immunity) or a secondary vaccine failure (the result of wan-ing immunity). The severity of the case suggests the former, since secondary vaccine failures tend to produce mild disease.4 In addi-tion, a 16-year-old student acquired measles despite having received two doses of measles vaccine dur-ing early childhood.In the United States, measles vaccine is delivered in combina-tion with mumps and rubella vaccines. Although the two-dose strategy ensures that a high pro-portion of vaccinees will be im-mune to measles (seroconversion after two doses of vaccine is es-timated to be 98 percent), the con-version rate is lower for mumps (approximately 88 percent). Thus, the proportion of persons in a U.S. community who are suscep-tible to mumps is greater than the proportion who are suscep-tible to measles, and outbreaks, when they occur, will be larger. More than 50,000 cases of mumps have been identified in the United Kingdom during the past few years, and more than 2500 cases have already been identified in a U.S. outbreak this year.5 About half the persons af-fected in the U.S. outbreak had been vaccinated, and most were young adults. Although mumps is a less severe disease than measles, it does cause substantial illness, including parotitis, orchitis, and aseptic meningitis. These out-breaks demonstrate the potential for rapid dissemination of respi-ratory pathogens, facilitated by air travel and crowded conditions.Despite the vision of the pub-lic health officials of the 1960s, global eradication of measles re-mains a long way off. In the mean-time, countries must strive to im-munize as high a proportion of children as possible, using a sec-ond dose to minimize the risk of primary vaccine failure and im-prove coverage. Better understand-ing of the epidemiology of measles in vaccinated communities will permit the optimization of vac-cination strategies. The importa-tion of virus can be minimized by ensuring that travelers to and from regions where the viruses are en-demic provide evidence of immu-nization. Yet as long as measles continues to circulate in other parts of the world, cases will con-tinue to be imported. And as long as some groups within a given measles in the united states, 2006Measles Rash.The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on February 14, 2014. For personal use only. No other uses without permission.  Copyright © 2006 Massachusetts Medical Society. All rights reserved. n engl j med 355;5 www.nejm.org august 3, 2006PERSPECTIVE443community respond to spurious claims about the risks of the vac-cine by refusing to vaccinate their infants, further outbreaks will oc-cur even in industrialized coun-tries.Dr. Mulholland is a professor in the Infec-tious Disease Epidemiology Unit of the Lon-don School of Hygiene and Tropical Medi-cine, London.Katz SL, Hinman AR. Summary and con-clusions: measles elimination meeting, 16-17 March 2000. J Infect Dis 2004;189:Suppl 1:S43-S47.Garenne M, Aaby P. Pattern of exposure and measles mortality in Senegal. J Infect Dis 1990;161:1088-94.Whittle HC, Aaby P, Samb B, Jensen H, Bennett J, Simondon F. Effect of subclinical 1.2.3.infection on maintaining immunity against measles in vaccinated children in West Afri-ca. Lancet 1999;353:98-102.Edmonson MB, Addiss DG, McPherson JT, Berg JL, Circo SR, Davis JP. Mild measles and secondary vaccine failure during a sus-tained outbreak in a highly vaccinated popu-lation. JAMA 1990;263:2467-71.Update: multistate outbreak of mumps — United States, January 1–May 2, 2006. MMWR Morb Mortal Wkly Rep 2006;55:559-63.4.5.measles in the united states, 2006No Refuge for the AilingRanjana Srivastava, F.R.A.C.P.The still, oppressive heat of the afternoon seems to magnify the queue of waiting patients. A young woman separates herself from the crowd.“Excuse me, Doctor, how long will you be?”I answer with a f licker of an-noyance, “I am not sure, but I will see you.”An hour later, it is her turn. She looks far too well, I silently judge. The well worried. She springs from her seat at the sound of her name but moves away from me toward the stairs. There, she utters a rapid command in a for-eign tongue before turning apol-ogetically toward me. Before I can greet her, a scarf-clad head comes into view. It belongs to an elderly woman physically supported by aides on each side. The aides stop on the landing, then wordlessly and cautiously lift her up to carry her into the only chair in my of-fice. Her features are wizened, her frame more shrunken than the six decades indicated on her chart would predict. Her eyes are dull, opaque, her face a repository of apprehension, anxiety, perhaps worse. She periodically glances at her daughter, but mostly she keeps her face averted as we settle into the consultation. The daughter speaks for her.“I am sorry if I was rude, Doc-tor. My mother has breast cancer, and she was waiting downstairs for a long time. We can’t afford to see anyone. We need your help.”I am caught unaware.This is a refugee clinic, run out of a makeshift health care facil-ity as bare as any in the Third World. Volunteer physicians bring their own equipment and, often, spare drug samples. Limited num-bers of doctors and meager do-nations mean that we can barely treat hypertension, eczema, and headache; we are rarely able to provide refugees with anything remotely resembling the standard of care.“We don’t do cancer,” I want to say, keen to end the conversa-tion right there.“Doctor, my mother has no one. We can’t pay the specialists. The emergency room bills us if it doesn’t turn us away. They said you would help.” Her tone com-bines pleading with frustration and accusation. The mother winc-es with pain. The daughter solici-tously measures out some mor-phine. As the patient swallows it with a wry face, the daughter murmurs, “This is the last mor-phine. We have to wait now un-til . . .”“Until . . . ?”“Until my husband’s disability pension arrives.”She brusquely runs her hand across the involuntary tears that have started. Her mother’s hand surreptitiously reaches out to com-fort her. In that moment, the enor-mity and heartache of the situa-tion descend on me, and Mrs. Habib becomes my patient.Having lost all the male mem-bers of her family through war, Mrs. Habib arrived from Afghan-istan to live with her only daugh-ter, an Australian resident. Here, her application for refugee status was denied on grounds of insuf-ficient evidence, thus denying her access to any form of government support, including food, shelter, employment, and health care. While the decision is appealed on humanitarian grounds, a process that can take years, the restric-tions continue. Reliance on the family’s small earnings worked until she developed cancer. A pub-lic hospital provided her with a free mastectomy but no follow-up. Now she is riddled with painful bony metastases. I read letters The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on February 14, 2014. For personal use only. No other uses without permission.  Copyright © 2006 Massachusetts Medical Society. All rights reserved. 

Measles in the United States, 2006.

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Measles in the United States, 2006.

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