New
Haemophilus
influenzae
Type
b Control
Strategy:
Premature
Commitment
to Prophylaxis?
Jonathan M. Mann, MD, MPH, and Harry F. Hull, MD, FAAP
From the Health Services Division, New Mexico Health and Environment Department, Santa Fe
ABSTRACT. Recent promulgation of an official policy on
prevention of secondary cases of Haemophilus influenzae
type b disease illustrates the challenges and frustrations
inherent in the policy-making process. Despite evidence that H influenzae type b disease is “contagious” in house-holds and probably also in day care centers and despite demonstration that rifampin eradicates nasopharyngeal
H influenzae type b carriage, the single field study of rifampin use to prevent secondary cases of H influenzae type b disease remains unpublished and has yet to receive broad critical scrutiny. Promulgation of the rifampin strategy prior to publication of this critical study is unfortunate, as public and private providers are now committed to a policy that will be difficult to evaluate or alter. Now that the strategy has been issued, the central question regarding rifampin prophylaxis has changed from “Is this strategy effective?” to “Can this strategy be shown to be ineffective?” When policies are issued prior to publication of key supporting data, or when such studies are either missing or highly controversial, the policy-making committee might publish, along with its
recommendations, explicit criteria for continuation,
mod-ification, or withdrawal of the new policy. This structured reassessment approach could accomodate the critical need to proceed with disease control recommendations-even though based on incomplete information-yet un-derscore the policy’s tentative nature and provide direc-tion for future assessment and study. Pediatrics
1983;72:118-121; Haemophilus influenzae type b, “Red
Book” committee, rifampin, chemoprophylaxis.
The American Academy of Pediatrics’ strategy for prevention of illness among household and day cane center contacts of Haemophilus influenzae type
b disease’ illustrates both the challenges and
frus-Received for publication Jan 14, 1983; accepted March 16, 1983. Reprint requests to (J.M.M.) Health Services Division, New Mexico Health and Environment Department, P0 Box 968, Sante Fe, NM 87503.
PEDIATRICS (ISSN 0031 4005). Copyright © 1983 by the American Academy of Pediatrics.
trations of official policy-making. Policies are often promulgated at a critical moment in the study of a particular disease when striking or sufficient new data prompt hopes for disease prevention.
Never-theless, however reasonable the proposed disease control measures may appear, certain key
support-ing studies may be lacking. Often these missing studies are incomplete or never undertaken because they may be extremely time-consuming, logistically difficult, costly, or perceived as ethically improper.
Faced with this situation, policy-making bodies
may elect to proceed with preventive strategies while acknowledging intrinsic uncertainties.2 The
AAP Red Book committee adopted this course in promulgating the new H influenzae type b control strategy. This paper discusses the major steps
lead-ing to the H influenzae type b control policy, illus-trates the practical impact of the new policy on current and future H influenzae type b control efforts, and proposes lessons to be learned from this
experience.
Five concepts underlie the recommended strategy for H influenzae type b disease prevention in house-holds and day care centers. First, household and day care center contacts of patients with H influ-enzae type b disease had to be recognized to be at
increased risk of acquiring H influenzae type b
disease. Despite early suspicions based on disease clustering in families,3 H influenzae type b was not thought to be “contagious” until a recent renewal of interest led to studies of H influenzae type b
occurrence in households and day care centens.3’#{176} Actually, the recent popularity of day care centers, which brought many children into household-like contact, facilitated recognition of H influenzae type
b disease risks among attendees.3
ARTICLES 119
influenzae type b disease which exceeded age-spe-cific background rates. In households, an elevated
risk was confirmed for contacts of patients with H influenzae type b disease during the 30 days
follow-ing onset of the illness of the index case. The risk
was found to be highly age dependent.35 For
ex-ample, one large retrospective study with a 30-day follow-up of household contacts found H influenzae type b disease occurring in 6% of contacts less than
1year old, 1.5% of those aged 12 to 47 months, and
0.1% of contacts 48 to 71 months of age.5 Overall,
H influenzae type b disease rates among young household contacts of index cases with H influenzae type b ranged between 200 and 800 times greater than age-adjusted background rates.35
Similarly, an increased risk of H influenzae type b disease was noted among day care center
atten-dees following onset of H influenzae type b disease
in a child from a day care center.3’’#{176} A summary of five H influenzae type b disease outbreaks in day cane centejs found that 7% of day care center contacts developed H influenzae type b disease; the
oldest associated case was that of a 27-month-old child who had outbreaks that lasted for up to 57 weeks.3 However, this estimate is derived from day
care centers reporting clusters of H influenzae type
b disease cases. Therefore, due to the lack of
sys-tematic study of this problem, neither the extent
nor the magnitude of a generally increased risk of secondary cases of H influenzae type b disease in
the day care center setting is well established at this time.
The third step leading toward a preventive
strat-egy focused on the epidemiology of nasopharyngeal H influenzae type b carriage. Culture surveys of households and day care centers in which a H influenzae type b disease had occurred generally
found a higher prevalence of H influenzae type b carriage compared with control households on day
care centens.3’8’9”’5 In addition, day care centers
with two or more cases of H influenzae type b disease had higher carriage rates compared with day care centers reporting only a single case of H influenzae type b disease.3 However, these general relationships were not uniformly seen, as instances of both high group carriage rates without disease and low group carriage rates with H influenzae type b disease cases were documented.3”2 Nevertheless, the association between H influenzae type b disease in one member of a household on day cane center and elevated H influenzae type b carrier prevalence
among the household or day care center contacts
suggested that a reduction in nasopharyngeal H influenzae type b carriage among contacts might lower their risk of H influenzae type b disease.
Further exploration of this possibility required an acceptable method for terminating
nasophar-yngeal H influenzae type b carriage. Therefore, the
fourth step toward a preventive strategy involved testing various antibiotics for their ability to enad-icate H influenzae type b carniage.8”5’7 At present, nifampin at 20 mg/kg orally in a single daily dose (up to a maximum of 600 mg/dose) for four days appears the most effective means of accomplishing
this objective,9”4”8 although failures generally occur
in at least 5% to 10% of the children.9”8
These data set the stage for the fifth step, an effort to document that nifampin administration to
household and day care center contacts of index cases of H influenzae type b disease would
signifi-cantly reduce the contacts’ risk of acquiring H influenzae type b disease. A multicenten field trial
coordinated by the Centers for Disease Control
(CDC) was carried out in 1979-1980. The study was
prospective, placebo-controlled, and examined both carriage rates and H influenzae type b disease oc-cunnence in household and day cane center settings. According to preliminary information, published
only in abstract form,’9 the risk of H influenzae type b disease among nifampin-treated contacts less than 6 years old was significantly lower than the risk for placebo-treated contacts. Specifically, 1,356 household and 584 day care center contacts of 325 index patients with H influenzae type b disease were involved in the study. Households and day cane centers received one of two nifampin regimens on a placebo, until partway into the study when one of the nifampin schedules was found to be superior, whereupon use of the other nifampin regimen was discontinued. Of 839 placebo-treated contacts, four
(0.5%) developed H influenzae type b disease in contrast to none of the 1,101 nifampin-treated con-tacts. This difference was statistically significant at the P = .03 level. However, the small number of
secondary cases (significance at the P
<
.05 levelwould not survive the occurrence of a single case in the nifampin-treated group non deletion of a single case from the placebo-treated group) generates
con-cern about the use of these data as the scientific
basis for a national disease control policy. Never-theless, critical analysis of this study and its results
must await its publication.
Accordingly, the Red Book mentions that the H influenzae type b control strategy’s effectiveness is “currently under investigation” and that “the present recommendations may be modified when additional data becomes available.” Nevertheless,
the promulgation of national recommendations for
a nifampin-based strategy to prevent H influenzae type b disease in household and day care center contacts of index patients with H influenzae type b disease prior to publication of the critical field trial of this approach is unfortunate. Public agencies and private providers are now committed to a policy that will be exceedingly difficult to evaluate or alter. If the CDC study results are clear and convincing,
at Viet Nam:AAP Sponsored on September 7, 2020
www.aappublications.org/news
at least one study will support the nifampin prophy-lactic approach. However, if the CDC study is
de-ficient or highly controversial, the nifampin
nec-ommendations will be correspondingly weakened.
Yet even if the CDC study is seriously flawed, the
current strategy will likely remain. This apparent
contradiction stems from consideration of data that
would be required to modify or refute the current
strategy, given the terms in which the problem is
now presented. In other words, now that the
strat-egy has been promulgated, the key question has
changed from “Is this strategy effective?” to “Can
this strategy be shown to be ineffective?”
Anecdotal case reports of nifampin prophylaxis
failures2#{176} cannot do more than emphasize the strat-egy’s fallibility, but complete protection was never
claimed in any case. The prospects seem remote for
a second large study of nifampin prophylaxis of H
influenzae type b disease among household and day
care center contacts of patients with H influenzae
type b disease in this country. Now that nifampin
is recommended, the use of placebo in these “high
risk” settings may be considered unethical by in-vestigators and simply unacceptable by
partici-pants’ parents and physicians. International
stud-ies could be useful, but only to the extent that such
data could be reasonably generalized to the nursery
school and day care center environment in this country.
Several problems may arise when a strategy is
based on a logical sequence of study whose critical
final (protective efficacy) data are either
unpub-lished or inadequate. Discussions of the practical
consequences of the Red Book strategy for H
influ-enzae type b control have recently been
pub-lished.22’ Our experience in New Mexico and re-ports from others2’ suggest difficulty in several
areas. First, when attendees of a day care center in
which a case of H influenzae type b disease has
occurred are sent to their personal physicians with
a recommendation for nifampin prophylaxis,
rea-sonable physicians may differ about the need for
nifampin. In some instances, up to half of day care
center attendees therefore do not receive nifampin,
thereby reducing or nullifying the value of
chemo-prophylaxis for attendees who do take rifampin as
well as for the entire day care center group.
Second, unwarranted extrapolations beyond the
limited AAP guidelines to other H influenzae type
b situations also occur. For example, nifampin
pro-phylaxis may be provided to casual recent or remote
contacts of patients with H influenzae type b
dis-ease. The apparent rationale is that if prophylaxis
is effective in household and day care center
set-tings, it might also reduce the risk, however small,
for casual playmates of a child with H influenzae
type b disease. This unsupported reasoning
mark-edly expands the number of children receiving
ni-fampin. Further inflation of the control
recommen-dations occurs when nifampin is administered to
contacts of children with H influenzae sinusitis and
otitis (usually due to nontypable strains).
The large numbers of household and day care
center contacts now receiving nifampin leads to
concern about nifampin toxicity and emergence of
resistant organisms. Logistic problems, including
coordination of prophylaxis in day care centers,
lack of a readily available nifampin suspension for
pediatric use, cost, and the need to avoid
adminis-tration of rifampin to pregnant women, are
nettle-some but resolvable issues.
In summary, our concern is that despite
disclai-mers that new data being developed may lead to
future modification of the household and day care
center H influenzae type b control strategy, vital
new data are unlikely given the terms in which the
issue is now framed (“Can this strategy be shown
to be ineffective?”).
We recommend
prompt
publication
ofthe
critical
CDC study data along with editorial discussion and
evaluation of the evidence. Regardless of whether
these data are sufficient to support the existing
national recommendations, a generic lesson may be
gleaned from this experience. When policy
guide-lines are issued prior to publication of key
support-ing data, or when such studies are highly
contro-versial, the policy-making committee might
pub-lish, along with its recommendations, explicit
cni-tenia for continuation, modification, or withdrawal
of the new policy. This approach to medical and
public health policy-making, by allowing for
struc-tuned reassessment of recommendations over time,
takes advantage of potential new information and
experience that would be gained during the early
phases of new policy implementation.22 In this
man-ner, the policy’s tentative nature would be better
understood while the critical need to proceed with
disease control recommendations-even though
based on incomplete information-could be
accom-modated.
Finally, if H influenzae type b resistance to
nifam-pin ever becomes widespread, a new agent to
erad-icate nasopharyngeal H influenzae type b carriage
will be sought. At that time, it will be tempting to
assume that its effectiveness in preventing H
influ-enzae type b disease among household and day care
center contacts of patients with H influenzae type
b disease would parallel its effectiveness in
eradi-cating H influenzae type b carriage (the assumption
underlying nifampin use for meningococcal disease
prophylaxis). However, the fallacy of this approach
ARTICLES 121
determine the new agent’s protective efficacy,
in-corporating lessons learned from analysis of the
CDC nifampin field study, would be both ethically
and scientifically appropriate.
ADDENDUM
In December 1982, the CDC published
recommenda-tions for “Prevention of Secondary Cases of Haemophilus influenzae Type b Disease.”’ These recommendations
parallel the Red Book in most respects, although the
terminology differs and the CDC seems to express greater
uncertainty and tentativeness regarding the need for and
the efficacy of nifampin prophylaxis in the day care center
setting. In addition, CDC provides several refinements to
the rifampin strategy by giving a prophylactic regimen
for neonates (younger than 1 month old) of 10 mg/kg once daily for four days; by recommending that patients
with H influenzae type b disease also receive a rifampin prophylactic regimen before hospital discharge; and by
suggesting that chemoprophylaxis is probably not
mdi-cated if the last contact between the index case and the contact occurred more than seven days previously.
Never-theless, the basic policy-making issues illustrated in the discussion of Red Book recommendations apply equally to the CDC policy formulation.
REFERENCES
1. American Academy of Pediatrics: Report of the Committee on Infectious Diseases, ed 19. Evanston, IL, 1982
2. Fulginiti VA: Point: Recommendations for rifampin prophy-laxis of Haemophilus infections by the Committee on Infec-tious Diseases of the American Academy of Pediatrics. Pe-diatr Infect Dis 1982;1:377-378
3. Granoff DM, Daum RS: Spread of Haemophilus influenzae type b:Recent epidemiologic and therapeutic considerations.
J Pediatr 1980;97:854-860
4. Glode MP, Daum RS, Goldinann DA, et al: Haemophilus influenzae type b meningitis: A contagious disease of chil-then. Br Med J 1980;2:899-901
5. Ward JI, Fraser DW, Baraff U, et al: Haemophilus influ-enzae meningitis: A national study of secondary spread in household contacts. N Engl J Med 1979;301:122-126
6. California State Department of Health: What should be done about contacts to Hemophilus influenzae meningitis?
Calif Morbidity, October 1979, No. 40
7. Campbell LR, Zedd AJ, Michaels RH: Household spread of
infection due to Haemophilus influenzae type b. Pediatrics 1980;66:115-117
8. Granoff DM, Gilsdorf J, Gessert C, et al: Haemophilus
influenzae type b disease in a day care center: Eradication of carrier state by rifampin. Pediatrics 1979;63:397-401 9. Cox F, Trincher R, Rissing JP, et al: Rifampin prophylaxis
for contacts of Haemophilus influenzae type b disease. JAMA 1981;245:1043-1045
10. Ward JI, Gorman G, Philips C, et al: Haemophilus influen-zae type b disease in a day-care center. J Pediatr
1978;92:713-717
11. Daum RS, Glode MP, Goldmann DA, et al: Rifampin chem-oprophylaxis for household contacts of patients with inva-sive infections due to Haemophilus influenzae type b. J
Pediatr 1981;98:485-491
12. Lerman SJ, Kucera JC, Brunken JM: Nasopharyngeal car-riage of antibiotic-resistant Haemophilus influenzae in healthy children. Pediatrics 1979;64:287-291
13. Michaels RH, Norden CW: Pharyngeal colonization with Haemophilus influenzae type b: A longitudinal study of families with a child with meningitis or epiglottitis due to
H influenzae type b. J Infect Dis 1977;136:222-228
14. Gessert C, Granoff DM, Gilsdorf J: Comparison of rifampin and ampicillin in day care center contacts of Haemophilus influenzae type b disease. Pediatrics 1980;66:1-4
15. Yogev R, Melick C, Kabat K: Nasopharyngeal carriage of
Haemophilus influenzae type b: Attempted eradication by cefaclor or rifampin. Pediatrics 1981;67:430-433
16. Shapiro ED: Persistent pharyngeal colonization with Hoe-mophilus influenzae type b after intravenous chloramphen-icol therapy. Pediatrics 1981;67:435-437
17. Homer HB, McCracken GH Jr, Ginsburg CM, et al: A comparison of three antibiotic regimens for eradication of
Haemophilus influenzae type b from the pharynx of infants and children. Pediatrics 1980;66:136-138
18. Shapiro ED, Wald ER: Efficacy of rifampin in eliminating pharyngeal carriage of Haemophilus influenzae type b.
Pe-diatrics 1980;66:5-8
19. Band JD, Fraser DW: Prevention ofHaemophilus influenzae
type b disease by rifanipin prophylaxis (abstract 17). Read before the 21st Interscience Conference on Antimicrobial Drugs and Chemotherapy, Chicago, Nov 4-6, 1981
20. Boies EG, Granoff DM, Squires JE, et al: Development of
Haemophilus influenzae type b meningitis in a household contact treated with rifampin. Pediatrics 1982;70:141-142 21. Daum RS, Halsey NA: Counterpoint: The Red Book opts
for red urine. Pediatr Infect Dis 1982;1:378-381
22. Neustadt RE, Fineberg HV: The Swine Flu Affair: Decision-Making on a Slippery Disease. US Dept of Health, Educa-tion, and Welfare, 1978
23. Centers for Disease Control: Prevention of secondary cases of Haemophilus influenzae type b disease. MMWR
1982;31:672-680
at Viet Nam:AAP Sponsored on September 7, 2020
www.aappublications.org/news
1983;72;118
Pediatrics
Jonathan M. Mann and Harry F. Hull
Prophylaxis?
Type b Control Strategy: Premature Commitment to
Haemophilus influenzae
New
Services
Updated Information &
http://pediatrics.aappublications.org/content/72/1/118
including high resolution figures, can be found at:
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtml
entirety can be found online at:
Information about reproducing this article in parts (figures, tables) or in its
Reprints
http://www.aappublications.org/site/misc/reprints.xhtml
1983;72;118
Pediatrics
Jonathan M. Mann and Harry F. Hull
Prophylaxis?
Type b Control Strategy: Premature Commitment to
Haemophilus influenzae
New
http://pediatrics.aappublications.org/content/72/1/118
the World Wide Web at:
The online version of this article, along with updated information and services, is located on
American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1983 by the
been published continuously since 1948. Pediatrics is owned, published, and trademarked by the
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
at Viet Nam:AAP Sponsored on September 7, 2020
www.aappublications.org/news
