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Joint Infectious Diseases Conference:
Venkata G. Meka
October 17, 2001
Case Presentation:
CC: “Rash all over”
HPI: Patient was a 36 year-old white male HIV + (CD4 19, viral load 450K as of July
10, 2001). Approximately 2 weeks prior to presentation, he was exposed to 2 toddlers
who had not had their vaccinations and subsequently developed measles. Then, 7 days
ago, he developed coryza and cough. Then, 5 days ago, he developed a maculopapular
rash that began on his chest and then moved to his face, back, and extremities. The rash
eventually became pruritic, blanching, and then confluent. It subsequently moved into
his palms and soles. He also experienced fever and intermittent headaches. He denied
photophobia or nuchal rigidity.
Review of systems was otherwise unremarkable. In terms of vaccinations, he
remembered getting a killed measles vaccine as a child.
PMH: 1. HIV:
diagnosed in 1987
history of PCP pneumonia in 1992, requiring intubation and ICU
stay
followed at the Fenway Clinic
2. Asthma
3. No surgical history
Allergies:
Penicillin (angioedema)
Medications: 1. Bactrim DS 1 tablet orally once daily
2. Diflucan 100 mg tablet orally once daily
3. No HAART therapy (to start new regimen soon, has been off meds
since December 2000)
Social History:
Homosexual, lives with his partner
Denies tobacco, illicit drug use
Alcohol socially (occasional beer or glass of wine at parties)
Physical Exam:
Vitals
99.6 106 133/85 20 97% (RA)
Gen
resting comfortably
HEENT
no scleral icterus, no sinal tenderness, no conjunctivitis
anterior cervical lymphadenopathy bilaterally
posterior pharynx without erythema, exudates, or Koplik’s spots
Heart
regular rate and rhythm; no murmurs, rubs, or gallops
Lungs
clear to auscultation bilaterally
Abdomen
soft, nontender, nondistended, bowel sounds present
no masses or organomegaly
Extremities no edema
blanching rash confluent on face and trunk
morbilliform on extremities and involving palms, soles
Labs:
none drawn at this point
Imaging:
none done at this point
Background:
Given this presentation, our differential included a drug reaction to Bactrim,
atypical measles, or classic measles. He had already taken his Bactrim that day, but we
held any subsequent doses.
Given the history of receiving the killed vaccine, this could have been atypical
measles. This is a syndrome described in people that were administered the killed
measles vaccine and then years later were exposed to wild measles virus. In the setting
of undetectable or very low measles antibody titer, these patients developed unusual
manifestations of measles followed by the appearance of extremely high measles
antibody titers. The symptoms included a prodrome of fever and pain for 1-2 days and
then the appearance of a rash. Differing from classic measles, the rash began peripherally
and could be urticarial, maculopapular, hemorrhagic, and/or vesicular. Patients also had
edema of the extremities, interstitial pulmonary infiltrates, hepatitis, and occasionally a
pleural effusion. The syndrome had a prolonged course and could be fatal. Of note, no
measles virus has been isolated from these patients, and they do not appear to transmit
measles to others. (1,2,3)
In regards to the possibility of classic measles, there are three questions that will
be addressed. First, how does HIV infection affect immunity to measles? Second, how
does measles infection present in HIV-infected individuals? Third, should HIV-infected
individuals be vaccinated for measles?
How does HIV infection affect immunity to measles? :
In 1990, the CDC reported 27,786 cases of measles; and although this new
epidemic mainly affected children, 15%-20% of those cases were in adults. Also, the
associated case fatality rate of 3.2 deaths per 1,000 cases reported was the highest rate
reported in 30 years. (4)
Then in 1991, Glaser et al. conducted a study of the prevalence of measles
antibodies among HIV-infected New York State prison inmates. (5) Fifty-one HIVinfected inmates consented to measles antibody testing. Fifty of the inmates had a history
of intravenous drug use. CD4 counts ranged from greater than 500 cells/mm3 (13 of 51),
200-500 cells/mm3 (16 of 51), and less than 200 cells/mm3 (22 of 51). Six of 51 (11.8%)
were seronegative for measles. This included 3 born after January 1, 1957 and 3 born
before 1957. None of the inmates could readily provide proof of vaccination.
Does the presence of HIV infection identify a group that is at high risk for
measles infection, as measured by a lack of serum antibody to measles? Also, does HIVrelated immunodeficiency over time lead to a loss of measles antibody and thereby, leave
the HIV-infected individual vulnerable to measles infection? (6)
Brunell et al. looked at the measles antibody response in HIV-infected babies,
children, and adults. They hypothesized that severe measles occurs in immunized as well
as nonimmunized HIV-infected individuals and suggested that both immunologic
memory and the initial response to measles may be impaired by HIV infection. That the
initial response is affected was supported by the finding that post-measles immunization
titers of HIV-infected babies were significantly lower (p=0.01) than those of normal
babies. Poor immunologic memory was evidenced in HIV-infected children by lower
titers than in normal children (p<0.001) and by a continuing decline in measles antibody
that was not arrested by reimmunization. Impaired memory appeared to be associated
with defective avidity maturation. HIV-infected babies and infants or children had a
significantly lower avidity index (AI) than age-matched normal children (p<0.01). AI
increases during the first few months after infection and has been used to differentiate
recent from remote infections. HIV-infected adults, who were infected with HIV after
exposure to measles, did not have AI values significantly different from normal adults
(p=0.18) but had significantly greater values than did HIV-infected babies and children
(p<0.01). They concluded from this that the adult immune response to measles was less
affected. (7)
Several studies subsequently looked at the prevalence of measles antibody in
HIV-infected adults. (8,9,10,11) Zolopa et al. conducted a retrospective cohort study
involving 172 HIV-negative and 299 HIV-positive homosexual men. They found no
relationship between changes in the CD4 cell count and measles antibody level. Sha et
al. looked at 105 asymptomatic HIV-seropositive adults and screened them for measles
antibody. They found that neither the presence nor the level of antibody were predictable
from patient age, history of measles or immunization, CD4 count, percentage of CD4
cells, or CD4:CD8 ratio. Kemper et al. looked at the seroprevalence of measles antibody
in 619 HIV-infected adults and evaluated risk factors for lack of antibody and presumed
susceptibility to measles. Neither minority status, stage of HIV infection, CD4 cell
count, nor a history of opportunistic infection was found to be related the
presence/absence of antibody. Finally, Wallace et al. conducted a prospective survey of
210 HIV-infected adults and found that 95% of the adults had demonstrable antibodies
using a standard ELISA technique.
How does measles infection present in HIV-infected individuals? :
Severe measles may occur in patients with compromised or deficient cellular
immunity such as those with HIV infection. Kaplan et al. looked at measles cases
occurring in immunocompromised patients from 1989-1990. They also combined this
with cases recorded in the literature. They found that the case fatality rate for severe
measles in children and young adults was calculated to be 70% in 40 oncology patients
and 40% in 11 HIV-infected patients. In the oncology patients, 40 percent had no rash,
58 percent had pneumonitis, and 20 percent had encephalitis. In the HIV-infected
population, 27 percent had no rash and 82 percent had pneumonitis. (12)
In addition, measles virus can cause 3 major CNS syndromes. Acute encephalitis
is thought to be an autoimmune process occurring during recovery from measles and
involves a recrudescent fever, headaches, seizures, and changes in mental status.
Subacute sclerosing panencephalitis (SSPE) presents after a latent period and presents
with the insidious onset of mental deterioration and later of motor dysfunction.
Symptoms progress to seizures, coma, and death within 1-2 years. Finally, acute
encephalitis of the delayed type (also called subacute measles encephalitis, SME) is
usually seen in immunocompromised patients. Encephalitic signs and symptoms such as
seizures, myoclonus, stupor, and coma usually develop 1 to 10 months after measles
infection. (13, 14)
Should HIV-infected individuals be vaccinated for measles? :
Recognizing the potential for serious complications from measles infection in
HIV-infected people, the Advisory Committee on Immunization Practices (ACIP)
addressed this in their report in 1998. (15) Among HIV-infected patients with no
evidence of severe immunosuppression (see Table 1), there have been no reported serious
adverse events after measles vaccination. (16) The current recommendation, therefore, is
that MMR vaccination is recommended for all asymptomatic HIV-infected patients who
do not have evidence of severe immunosuppression. Also, MMR vaccination should be
considered for all symptomatic HIV-infected patients who do not have evidence of severe
immunosuppression.
Table 1. Age-specific CD4 T-lymphocyte count and percent of total lymphocytes as
criteria for severe immunosuppression in persons infected with human
immunodeficiency virus (HIV)
Total CD4 T-lymphocytes
or
CD4 T-lymphocytes (as
% of total lymphocytes)
<12 mos
<750/uL
or
<15%
1-5 yrs
<500/uL
or
<15%
Age
6-12 yrs
<200/uL
or
<15%
≥13 yrs
<200/uL
or
<14%
Of note, transient increases in HIV viral load have been observed after
administration of other vaccines to HIV-infected patients. (18, 19) This hasn’t been
studied in reference to the MMR vaccination, so the clinical significance of this
observation is not known.
Measles vaccine is not recommended for HIV-infected persons with evidence of
severe immunosuppression (as outlined in Table 1) for several reasons. This includes a
case of progressive measles pneumonitis in patient with HIV and severe
immunosuppression to whom the MMR vaccine was administered. (18)
In this case, on September 3, 1992, a 20 year-old man with hemophilia A and HIV
infection received the MMR vaccination to fulfill a college prematriculation vaccination
requirement for a second dose of measles vaccine. He had gotten a previous dose of
measles vaccine in 1973. His CD4 count was reported as “too few to enumerate” as of
August of the same year. Also, at the time of the second dose, he did not have any HIVrelated symptoms, was not taking any antiretroviral therapy, or taking prophylaxis for
Pneumocystis carinii. On August 31, 1993, he was hospitalized for worsening dyspnea,
fever, nonproductive cough, and weight loss. Eventually, he underwent an open-lung
biopsy on October 6 that revealed numerous multinucleate giant cells, and some
contained both intranuclear and cytoplasmic eosinophilic inclusions suggestive of viral
infection. On October 22, measles virus was identified from tissue-culture cells
inoculated with the lung biopsy tissue. The patient was started on ribavirin therapy on
October 23, and his condition slowly stabilized. He later was discharged home. He was
readmitted on November 12th for increasing shortness of breath and found to have
bilateral pulmonary infiltrates. Following the onset of encephalopathic changes, he died
on December 17th.
Although the reported immediate cause of death was cytomegalovirus (CMV)
encephalitis, pulmonary measles and Mycobacterium avium complex (MAC) infection
were listed as contributing causes. Also, further analysis of the measles virus isolate
recovered from the lung biopsy tissue showed a high degree of similarity between the
patient’s virus isolate and the Moraten vaccine virus strain.
Summary:
1. Atypical measles is a syndrome described in people that were administered the killed
measles vaccine and then years later were exposed to wild measles virus. The symptoms
differed from classic measles, and the clinical course could be prolonged, possibly even
fatal.
2. HIV-infected adults have a level of immunity to measles that appears to be
comparable to that found in non-HIV-infected populations. Once measles immunity (as
determined by the presence of protective antibodies) is established in the HIV-infected
patient, it is maintained despite progression of HIV-related immunodeficiency.
3. The presentation of measles in HIV-infected patients can be severe and include
complications such as giant cell pneumonitis and subacute measles encephalitis (SME).
4. Current recommendations for measles vaccination of HIV-infected patients is based
on the degree of immunosuppression. It is not recommended for HIV-infected patients
with evidence of severe immunosuppression.
References:
1. Ramh LW. Schmidt R. Measles immunization with killed virus vaccine. Am J Dis
Child. 1965;109:232.
2. Fulginiti. VA, Eller JJ, Downie AW, et al. Altered reactivity to measles virus.
JAMA. 1967;202:1075.
3. Frey HM, Krugman S. Atypical measles syndrome: unusual hepatic, pulmonary, and
immunologic aspects. Am J Med. 1981:281:55.
4. Centers for Disease Control. Measles- United States, 1990. MMWR 1991;40:369-72.
5. Glaser JB. DeCorato Dr. Greifinger R. Measles antibody status of HIV-infected
prison inmates. J AIDS 1991;4:540-1.
6. Zolopa AR. Kemper CA. Shiboski S., et al. Progressive immunodeficiency virus does
not lead to waning immunity to measles in a cohort of homosexual men. Clin Infect Dis
1994;18:636-8.
7. Brunell PA. Vimal V. Courville TM., et al. Abnormalities of measles antibody
response in human immunodeficiency virus type 1 (HIV-1) infection. J Acquired
Immune Defic Syndr Hum Retroviral 1995; Dec 15;10(5):540-8.
8. Zolopa AR. Kemper CA. Shiboski S., et al. Progressive immunodeficiency virus
does not lead to waning immunity to measles in a cohort of homosexual men. Clin Infect
Dis 1994;18:636-8.
9. Sha BE, Harris AA, Benson CA, et al. Prevalance of measles antibodies in
asymptomatic human immunodeficiency virus-infected adults. J Infect Dis 1991;
164:973-5.
10. Kemper CA, Ganger M, Arias G, Kane C, et al. The prevalence of measles antibody
in human immunodeficiency virus-infected patients in northern California. J Infect Dis
1998 Oct;178(4):1177-80.
11. Wallace MR, Hooper DG, Graves SJ, et al. Measles seroprevalence and vaccine
response response in HIV-infected adults. Vaccine 1994 Oct;12(13):1222-4.
12. Kaplan LJ, Daum RS, Smaron M, et al. Severe measles in immunocompromised
patients. JAMA 1992 Mar 4;267(9):1237-41.
13. Gazzola P., MD, Cocito L., MD, Capello E., et al. Subacute measles encephalitis in
a young man immunosuppressed for ankylosing spondylitis. Neurology 1999;52:107480.
14. Mustafa MM, Weitman SD, Winick NJ, et al. Subacute measles encephalitis in the
young immunocompromised host: report of two cases diagnosed by polymerase chain
reaction and treated with ribavirin and review of the literature. Clin Infect Dis 1993
May;16(5):654-60.
15. Centers for Disease Control: Recommendations of the Advisory Committee on
Immunization Practices (ACIP). Measles, Mumps, and Rubella- Vaccine Use and
Strategies for Elimination of Measles, Rubella, and Congenital Rubella Syndrome and
Control of Mumps: MMWR 1998:47:1-57.
16. Sprauer MA. Markowitz LE. Nicholson JKA, et al. Response of human
immunodeficiency-infected adults to measles-rubella vaccination. J AIDS 1993; 6: 10131016.
17. Centers for Disease Control: Recommendations of the Advisory Committee on
Immunization Practices (ACIP). Measles, Mumps, and Rubella- Vaccine Use and
Strategies for Elimination of Measles, Rubella, and Congenital Rubella Syndrome and
Control of Mumps: MMWR 1998:47:21.
18. Centers for Disease Control: Recommendations of the Advisory Committee on
Immunization Practices (ACIP). Measles Pneumonitis Following Measles- MumpsRubella Vaccination of a Patient with HIV infection, 1993: MMWR 1996:45(28):603606.