PEDIATRICS Vol. 103 No. 5 May 1999, pp. 1057-1060

AMERICAN ACADEMY OF PEDIATRICS:
Measles Immunization in HIV-Infected Children

Committee on Infectious Diseases and Committee on Pediatric AIDS

	ABSTRACT

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Children infected with human immunodeficiency virus (HIV) have had high rates of mortality attributable to measles, but until recently, measles vaccine was assumed to be safe for these children. A single fatal case of pneumonia attributable to vaccine type-measles virus has been documented in a young adult with acquired immunodeficiency syndrome. Because a protective immune response often does not develop in severely immunocompromised HIV-infected patients after immunization and some risk of severe complications exists, HIV-infected children, adolescents, and young adults who are severely immunocompromised (based on age-specific CD4 lymphocyte enumeration) attributable to HIV infection should not receive measles vaccine. All other HIV-infected children, adolescents, and young adults who are not severely immunocompromised should receive measles-mumps-rubella vaccine.

	BACKGROUND

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Live attenuated measles virus vaccine has been recommended for children, adolescents, and young adults with known human immunodeficiency virus (HIV) infection to prevent morbidity and mortality attributable to measles.^1,2 The immunosuppressive effect of HIV predisposes to high mortality rates in HIV-infected children who develop measles. In developing nations, the mortality rate attributable to measles has been 50% for HIV-infected children.^1-3 From 1989 through 1991, 55 000 cases of measles occurred in the United States. New York City reported 19 deaths, 11 of which were known to be associated with HIV infection.² Measles-mumps-rubella (MMR) vaccine had been recommended for all HIV-infected children because it appeared to be safe without serious or unusual reactions.^4,5 MMR vaccine should be administered to children 12 to 15 months of age, and knowledge of HIV status is not a prerequisite for immunization.⁶

A single report of a 21-year-old college student who received a second dose of measles vaccine in September 1992 has provided the first indication of potential harmful consequences of measles vaccine in a severely immunocompromised HIV-infected person.⁵ This man had a CD4 cell count of 10/µL at the time of immunization, and Pneumocystis carinii pneumonia developed 1 to 2 months after he received the second dose of MMR vaccine. Approximately 1 year after vaccination, he was evaluated for progressive pulmonary disease. A transbronchial biopsy revealed multinucleated giant cells, and a measles virus was cultured that has been identified as vaccine-like by genomic sequencing. The patient died in December 1993, approximately 15 months after receipt of the vaccine. This patient had no identified measles rash, and progressive nodular disease was evident on the chest radiograph. Similar pulmonary disease associated with wild type and vaccine virus-induced disease has been reported in other immunocompromised patients.^7,8 Progressive pulmonary disease attributable to wild type measles infection has developed in HIV-infected persons.^9,10

Measles as the cause of the pneumonia in this HIV-infected patient was not appreciated until 11 to 12 months after administration of MMR vaccine. This long incubation period is unique; however, wild type measles virus may establish a persistent infection. This raises the possibility that other HIV-infected patients with pulmonary disease might not have been evaluated for the presence of measles virus, although no other cases of MMR-associated pulmonary complications have been reported after immunization in HIV-infected children.

	MEASLES IMMUNITY IN HIV-EXPOSED OR HIV-INFECTED INFANTS

HIV-infected women have lower concentrations of measles-specific antibodies and they transmit less measles antibody to their infants, resulting in susceptibility at a younger age than usual.¹¹

	ADMINISTRATION OF MMR TO HIV-INFECTED CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITHOUT SEVERE IMMUNOSUPPRESSION

Several studies have substantiated a suboptimal and unpredictable response to MMR vaccine in HIV-infected children.^12-14 Also, measles antibody titers decline more rapidly after immunization in HIV-infected children compared with uninfected children.^15,16 However, the administration of MMR vaccine to HIV-infected children, adolescents, and young adults without severe immunosuppression continues to be important, and administration of vaccine before deterioration of the immunologic status provides the best opportunity to induce protection. Immunization of HIV-infected infants at 9 to 11 months was associated with somewhat better antibody responses^17,18 than in children at 12 to 15 months in two small studies; this question of the optimal age of immunization is being addressed in a randomized study conducted by the AIDS Clinical Trial Group. Pending the results of this trial, HIV-infected children should be immunized as soon as they reach 12 months of age to induce an appropriate immune response. The second dose may be administered as soon as 30 days later in an attempt to induce early seroconversion. All persons in the household who are not HIV-infected and not otherwise immunocompromised should have immunity to measles. Immunity is defined as having been born before 1957, a history of physician-diagnosed measles, laboratory evidence of immunity, or age-appropriate immunization.

	HIV-INFECTED CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH SEVERE IMMUNOSUPPRESSION

Attenuated measles vaccine virus has caused fatal disease in one severely immunosuppressed HIV- infected patient. Because measles vaccine has been safely administered to >1000 HIV-infected children in the United States, we know that the risk of vaccine-induced virus disease is much less than that of wild type measles virus, but most of the children were not severely immunocompromised at the time of immunization. The antibody response to measles vaccine decreases as the level of immunosuppression increases.^13,17,18 In one study, measles antibody developed after vaccination in 71% (12/17) of children without severe immunosuppression, but antibody developed in only 17% (3/18) of those with severe immunosuppression.¹⁵ In another study, 90% of HIV-infected children with CD4 lymphocyte counts <200/µL did not respond to measles vaccine, and severe disease after exposure to measles developed in some HIV-infected children who had been immunized.¹³ Thus, measles vaccine should not be administered to severely immunosuppressed HIV-infected children, adolescents, and young adults because they do not respond well to measles vaccine and there is some risk of serious complications. Whether a given CD4⁺ T-cell level achieved in response to antiretroviral therapy provides an equivalent assessment of the degree of immune system function or has the same predictive value for risk of opportunistic infections as do CD4⁺ T-cell levels obtained in the absence of therapy is unknown.

Mumps and rubella vaccine viruses have not been recognized to cause serious complications in HIV-infected persons, but these and other live vaccines should be withheld from severely immunocompromised persons as they are unlikely to benefit and complications could occur.

	ASSESSMENT OF IMMUNOLOGIC STATUS OF HIV-INFECTED CHILDREN, ADOLESCENTS, AND YOUNG ADULTS

The HIV infection status of all infants born to HIV-infected women should be monitored.¹⁹ An HIV culture or a polymerase chain reaction are the preferred methods for diagnosing HIV infection among infants.^19,20 The CD4 counts and percentages should be measured to assess the HIV-infected child's immune status, risk for disease progression, and need for antiretroviral therapy.^20-22 Quality standards for the enumeration of CD4 lymphocytes in children, adolescents, and young adults infected with HIV have been established.^20,23 All HIV-infected children, adolescents, and young adults should have an initial CD4 lymphocyte count determined and repeated at least every 3 to 4 months if the initial count is >500/µL. If the initial count is between 200 and 500/µL) and the patient is asymptomatic, the assay should be repeated at intervals determined by the physician but no less frequently than every 3 to 4 months.^20,23

Severe Immunosuppression

The definition of severe immunosuppression is currently based on CD4⁺ T-lymphocyte enumeration stratified by age^24,25 (Table 1). Once a child has met the definition of severe immunosuppression, the child is always considered severely immunosuppressed.

Passive Immunization to Prevent Measles

Immunized HIV-infected children, adolescents, and young adults have contracted wild type measles and sustained severe disease. If exposed to measles, all HIV-infected infants, children, and adolescents, as well as children of unknown infectious status born to HIV-infected women, should receive 0.5 mL/kg (maximum dose, 15 mL) of immune globulin intramuscularly, regardless of their immunization status, because it is impossible to know in a timely fashion if the child has protective antibody. If the person exposed to measles is receiving intravenous immune globulin (IGIV) (400 mg/kg) and 3 weeks have elapsed since the last dose, the person should receive IG (0.5 mL/kg) or IGIV (400 mg/kg) as soon as possible. Because of the uncertainty regarding measles antibody concentrations in IGIV and the rapid metabolism of IGIV in HIV-infected children, some experts have chosen to administer an additional dose of IGIV if 2 or more weeks have elapsed since IGIV has been administered at the time of measles exposure.

	RECOMMENDATIONS

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1. Severely immunosuppressed HIV-infected infants, children, adolescents, and young adults should not receive measles virus-containing vaccines.
2. HIV-infected children, adolescents, and young adults without evidence of severe immunosuppression should receive MMR vaccine. The first dose should be administered at 12 months of age. The second dose may be given as soon as 28 days after the first dose. In the event of an outbreak in the community, vaccination with monovalent measles vaccine (or MMR) is recommended for infants as young as 6 months when exposure to natural measles is considered likely. Children vaccinated before the first birthday should be revaccinated with MMR at 12 months, and an additional dose may be given as soon as 28 days later.
3. All members of the household of an HIV-infected person should receive measles vaccine unless they are HIV-infected and severely immunosuppressed, were born before 1957, have had physician-diagnosed measles, have laboratory evidence of measles immunity, have had age-appropriate immunizations, or have a contraindication to measles vaccine.
4. If they are exposed to wild type measles, immune globulin prophylaxis should be administered to all HIV-infected children and adolescents and to children of unknown infection status born to HIV-infected women, regardless of the degree of immunosuppression or measles immunization status.

COMMITTEE ON INFECTIOUS DISEASES, 1998-1999
Neal A. Halsey, MD, Chairperson
Jon S. Abramson, MD
P. Joan Chesney, MD
Margaret C. Fisher, MD
Michael A. Gerber, MD
S. Michael Marcy, MD
Dennis L. Murray, MD
Gary D. Overturf, MD
Charles G. Prober, MD
Leonard B. Weiner, MD
Richard J. Whitley, MD
Ram Yogev, MD

EX-OFFICIO
Carol J. Baker, MD
Georges Peter, MD
Larry K. Pickering, MD

LIAISON REPRESENTATIVES
Robert Breiman, MD
  National Vaccine Program Office
M. Carolyn Hardegree, MD
  Food and Drug Administration
Anthony Hirsch, MD
  AAP Council on Pediatric Practice
Richard F. Jacobs, MD
  American Thoracic Society
Noni E. MacDonald, MD
  Canadian Paediatric Society
Walter A. Orenstein, MD
  Centers for Disease Control and Prevention
N. Regina Rabinovich, MD
  National Institutes of Allergy and Infectious Diseases
Ben Schwartz, MD
  Centers for Disease Control and Prevention

COMMITTEE ON PEDIATRIC AIDS, 1998-1999
Catherine Wilfert, MD, Chairperson
Jane Ellen Aronson, MD
Donna T. Beck, MD
Alan R. Fleischman, MD
Mark W. Kline, MD
Lynne M. Mofenson, MD
Gwendolyn B. Scott, MD
Diane W. Wara, MD
Patricia N. Whitley-Williams, MD

LIAISON REPRESENTATIVE
Mary Lou Lindegren, MD
  Centers for Disease Control and Prevention

	FOOTNOTES

The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

	ABBREVIATIONS

HIV, human immunodeficiency virus; MMR, measles-mumps-rubella (vaccine); IGIV, intravenous immune globulin.

	REFERENCES

Top Abstract Background Recommendation References

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4. Friedman S Measles in New York City. JAMA. 1991; 266:1220
5. Centers for Disease Control and Prevention Measles pneumonitis following measles-mumps-rubella vaccination of a patient with HIV infection: 1993. MMWR Morb Mortal Wkly Rep. 1996; 45:603-606 [Medline]
6. American Academy of Pediatrics. Measles. In: Peter G, ed. 1997 Red Book. Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997:348-350
7. Enders JF, McCarthy K, Mitus A, Cheatham WJ Isolation of measles virus at autopsy in cases of giant-cell pneumonia without rash. N Engl J Med. 1959; 261:875-881
8. Mitus A, Holloway A, Evans AE, Enders JF Attenuated measles vaccine in children with acute leukemia. Am J Dis Child. 1962; 103:413-418
9. Nadel S, McGann K, Hodinka RL, Rutstein R, Chatten J Measles giant cell pneumonia in a child with human immunodeficiency virus Infection. Pediatr Infect Dis J. 1991; 10:542-544 [Medline]
10. Markowitz LE, Chandler FW, Roldan EO, Fatal measles pneumonia without rash in a child with AIDS. J Infect Dis. 1988; 158:480-483 [Medline]
11. Embree JE, Datta P, Stackiw W, Increased risk of early measles in infants with human immunodeficiency virus type 1-seropositive mothers. J Infect Dis. 1992; 165:262-267 [Medline]
12. Krasinski K, Borkowsky W Measles and measles immunity in children infected with human immunodeficiency virus. JAMA. 1989; 261:2512-2516 [Abstract/Free Full Text]
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14. Brena AE, Cooper ER, Cabral HJ, Pelton SI Antibody response to measles and rubella vaccine by children with HIV infection. J Acquir Immune Defic Syndr. 1993; 6:1125-1129
15. Walter EB, Katz SL, Bellini WJ Measles immunity in HIV-infected children. Pediatr AIDS HIV Infect. 1994; 5:300-304 [Medline]
16. Al-Attar I, Reisman J, Muehlmann M, McIntosh K Decline of measles antibody titers after immunization in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1995; 14:149-151 [Medline]
17. Arpadi SM, Markowitz LE, Baughman AL, Measles antibody in vaccinated human immunodeficiency virus type 1-infected children. Pediatrics. 1996; 97:653-657 [Abstract/Free Full Text]
18. Rudy BJ, Rutstein RM, Pinto-Martin J Responses to measles immunization in children infected with human immunodeficiency virus. J Pediatr. 1994; 125:72-74 [CrossRef][Medline]
19. El-Sadr W, Oleske JM, Agins BE, et al. Clinical Practice Guideline Number 7. Evaluation and Management of Early HIV Infection. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, January 1994; AHCPR publication 94-0572
20. American Academy of Pediatrics, Committee on Pediatric AIDS Evaluation and medical treatment of the HIV-exposed infant. Pediatrics. 1997; 99:909-917 [Abstract/Free Full Text]
21. National Pediatric and Family HIV Resource Center and National Center for Infectious Diseases, Centers for Disease Control and Prevention. 1995 revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus. MMWR Morb Mortal Wkly Rep. 1995;44(RR-4):1-11
22. Wilfert CM, Gross PA, Kaplan JE, Quality standard for the enumeration of CD4⁺ lymphocytes in infants and children exposed to or infected with human immunodeficiency virus. Clin Infect Dis. 1995; 21(suppl 1):S134-S135
23. Gross PA, Phair JP, Kaplan JE, Holmes KK, Masur H Quality standard for the enumeration of CD4⁺ lymphocytes in adults and adolescents infected with human immunodeficiency virus. Clin Infect Dis. 1995; 21(suppl 1):S126-S127
24. Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep. 1994;43(RR-12):1-19
25. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep. 1992;41(RR-17):1-19