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Pathology
Department of Pediatrics
To the Editor.—
Before the introduction of Haemophilus influenzae type b (Hib) vaccines in the United States, 
20 000 cases of Hib invasive disease occurred annually.1 Conjugate vaccine use began in 1987 and, subsequently, the prevalence of invasive Hib disease decreased by 99%.1 This accomplishment has led to the speculation that elimination of Hib disease may be achievable. Thus, we were surprised to observe a cluster of 3 cases of Hib bacteremia over a 12-month period. These examples provide insight into the kinds of cases that may still occur in the Hib vaccine era.
The first case was a 3-year-old boy who presented with a 1-day history of fever and rigors. The temperature was 39.2°C, and the leukocyte count was 8000 per mm3 with 88% neutrophils. He was discharged without antibiotic therapy. The patient was recalled and hospitalized the next day because a blood culture yielded Gram-negative rods subsequently identified as Hib resistant to ampicillin and susceptible to ceftriaxone. A second blood culture performed on the day of admission was sterile. Examination of the cerebrospinal fluid (CSF), including latex agglutination for Hib capsular polysaccharide antigen (obtained after 2 doses of ceftriaxone) was normal. The patient received 3 days of ceftriaxone and was discharged to complete 7 days of cefpodoxime. He had been immunized with a Hib conjugate vaccine at 2, 4, 6, and 18 months of age. He lived at home with his parents and did not attend day care. Immunologic studies revealed normal total serum immunoglobulins, subclasses, and total hemolytic complement. The concentration of serum antibody to the serotype b H influenzae capsule obtained during the second day of the hospitalization was 0.45 µg/mL by enzyme-linked immunosorbent assay (Specialty Labs, Santa Monica, CA). Two months later, the level was 2.0 µg/mL. The serum anti-hepatitis B surface antibody was in the protective range.
The second case was an 11-month-old boy who presented in respiratory distress. Physical examination revealed a pulse of 217 beats/minute. The temperature was 39.7°C, and the oxygen saturation was 73% while breathing room air. Chest auscultation revealed wheezing, and retractions were apparent. Bilateral conjunctival injection was present. A chest radiograph demonstrated bilateral parenchymal infiltrates with hyperinflation of the lung fields. A nasopharyngeal washing yielded respiratory syncytial virus antigen by direct fluorescent antibody. The patient was admitted and empirically treated with ceftriaxone and azithromycin. The following day, Hib, susceptible to ampicillin, was isolated from the blood. CSF obtained on the third hospital day was normal. The patient received a 10-day course of ceftriaxone and recovered without sequelae. He had received an Hib conjugate vaccine at 3 and 5 months of age. A third dose was administered 6 days before admission. The patient resided in an apartment with his mother and a 4-year-old brother who was attending a day care center at that time.
The third case was a 28-week-gestation baby girl who was admitted to the neonatal intensive care unit. She was delivered vaginally 15 minutes after spontaneous rupture of the maternal membranes. A blood culture on day 1 of life yielded Hib, susceptible to ampicillin. Examination of CSF was normal. The infant received a 10-day course of ampicillin and gentamicin without complications. The mother had received no prenatal care during pregnancy. She lived in a shelter with one other child in a private room and shared meals in a community dining room.
All three isolates were identified as H influenzae by standard techniques and were serotyped using a latex agglutination reagent for the detection of Hib antigen (Murex Diagnostics, Inc, Norcross, GA) and by slide agglutination (Bacto H. influenzae Antiserum Type b, BD Biosciences Microbiology Products, Sparks, MD). The New York City Department of Health Bureau of Laboratories further confirmed the identity of the isolates from patients 2 and 3 using slide agglutination with type b antibody (Difco antisera). The isolate from patient 1 was not viable on arrival at the Department of Health Laboratories.
These 3 cases illustrate scenarios for Hib disease occurring in the immunization era. Presumably, the premature newborn was exposed to Hib in the maternal genital tract; the other 2 children were probably exposed to Hib in pharyngeal secretions from a close contact and developed bacteremia despite being immunized. The first patient had received 4 doses of Hib vaccine at recommended ages and had no evidence of immunodeficiency. The child did have detectable anticapsular antibody in his serum 3 days after the onset of bacteremia. No earlier specimen was available for comparison. Whether this low level of antibody was elicited by his previous immunizations or reflected an early response to the invasive disease cannot be differentiated. The second patient received 3 doses of a conjugate vaccine, which also should have been protective. Notably, the third dose was given 6 days before presentation with Hib disease. This is most likely coincidental. So-called first-generation, unconjugated, capsular polysaccharide Hib vaccines were believed to be associated with a small increase in susceptibility in the week after immunization.2 However, conjugated capsular saccharide vaccines such as polyribosylribitol phosphate-Neisseria meningitidis outer membrane protein are not believed to be associated with such a risk.3
These two cases are atypical because most reported cases occur in children who have not received vaccinations. For example, in a case-control study of confirmed Hib invasive disease among 2- to 18-month-old infants conducted in 1991–1994, 57 cases were identified; complete data were available for 40.4 Only 4 had received 
2 doses of Hib vaccine; 15 had received 1 dose and 21 had not been vaccinated. Similarly, in 1998 to 2000, there were 197 cases of invasive Hib disease reported to the Centers for Disease Control in children <5 years old. Eighty-six were <6 months old, and 72 were old enough to have completed the primary vaccination series (>6 months old) but were incomplete, unvaccinated, or of unknown immunization status.5 Thus, failure of age-appropriate immunization may be an important contributor to the continuing incidence of disease.
Infants in receipt of a full series of Hib vaccine are protected in part because priming is presumed to allow a rapid antibody response to occur after exposure to native capsular polysaccharide. The importance of priming on ensuring long-lived immunity was supported by a study of 4 million children receiving Hib conjugate vaccine in the United Kingdom.6 Although anticapsular antibody titers diminished after 3 doses of Hib vaccine at 3, 4, and 5 months, there was minimal loss of clinical protection. Patients 1 and 2 illustrate, however, that receipt of Hib vaccines is not always sufficient to protect from bacteremia even after the third or fourth dose. However, it should be noted that the bacteremia of patient 1 was self-limited, perhaps reflecting partial protection induced by immunization or, alternatively, an age-appropriate response to bacteremia.
Vaccine failure may be associated with immunodeficiency. In one study, more than a third of children vaccinated at 15 months of age who subsequently developed invasive Hib disease had subnormal serum immunoglobulin levels, particularly IgG2.7 Patient 1 had normal immunoglobulin subclass levels; patient 2 was not evaluated. The third patient was a newborn. Although H influenzae accounts for 8% of all cases of neonatal bacteremia or sepsis, most of the isolates are non-type b (80%).8 Most cases of neonatal H influenzae are encountered in premature or low birth weight infants. This case likely reflects colonization in a nonvaccinated adult as the source of the invasive disease isolate.
The reasons for the clustering of 3 cases at our institution over a 1-year period (October 1999–September 2000) are unknown. Vaccination rates in New York City are similar to those reported nationally. In 1998, 91.3% of children between 19 and 35 months old were vaccinated with 3 doses of Hib vaccine, compared with 93.4% nationally.9 Other factors such as the high immigration rate and overcrowding may play a greater role in the presence of disease in New York City than in other US populations. The occurrence of these cases suggests that despite an effective immunization program, the organism must still be circulating. If we are to achieve the goal of elimination of invasive Hib disease, additional strategies may be required. The reasons for vaccine failures, variation in persistence of carriage despite vaccination, and potential role of booster vaccinations in older children, adolescents, or adults to further decrease carriage rates should be evaluated. Rates of carriage have varied among different populations and with the use of different Hib conjugate vaccines. For example, vaccinated Alaskan Native American children had rates of carriage as high as 9.3% in rural, western Alaska. In contrast, rates were 0.9% among similarly aged Alaskan Native American children living in more urban Anchorage.10 Additional study relating pharyngeal carriage to Hib vaccine in varying populations with different vaccines may provide important information that may suggest strategies to completely eliminate residual Hib disease.
REFERENCES
This article has been cited by other articles:
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  S. R. Dominguez, J. S. Parrott, D. S. Lauderdale, and R. S. Daum On-Time Immunization Rates Among Children Who Enter Chicago Public Schools Pediatrics, December 1, 2004; 114(6): e741 - e747. [Abstract] [Full Text] [PDF]
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