An outbreak of Hemophilus influenzae type b meningitis in an enclosed hospital population

36

January 1976 The Journal o f P E D I A T R I C S

An outbreak of Hemophilus influenzae type b meningitis in an enclosed hospital population Five cases o f H I T B maningitis occurred within six months in an enclosed population o f 28 to 32 chronically ill children. Studies o f nasopharyngeal carriage and serum H I T B anticapsular antibodies were started after the third ease occurred. Two patients had low ( < 0.04 and 0.05 t~g/ml) antibodies and were not carriers when studied prior to onset o f their disease. The carriage rate was approximately 20% among the children. Carriage was usually prolonged, and acquisition was not prevented by high antibody levels. Attempts to arrest this outbreak with type b polysaceharide immunization and ampieillin therapy are discussed in the context o f H I T B meningitis as a contagious disease.

Mary P. Glode, M.D.,* Mark S. Schiffer, M.D., John B. Robbins, M.D.,

Bethesda, Md., Waheed Khan, Ph.D., Constance U. Battle, M.D., and Eduardo Armenta, M.D., Washington, D. C.

HEMOPHILUS INFLUENZAE type b, the leading cause of bacterial meningitis in children, is not listed as a "notifiable" contagious agent. 1 No HITB epidemic disease has been reported, although three cases of meningitis within a 2-month period in a day care center have been reportedY Three series of 106, 110, and 255 cases of HITB meningitis do not mention multiple occurrence in families,a-5 although there are reports of intrafamilial HITB disease. 6-18 We report five HITB meningitis cases occurring within six months in an enclosed population of approximately 30 chronically ill children. After three cases had occurred, we attempted to identify susceptible individuals and NP carriers. Subsequently, two additional children, who had low anticapsular antibody and who were noncarriers, acquired HITB meningitis. We report our observations of the spread of HITB carriage and disease in relation to age and antibody level. Although it was not possible to conduct a controlled clinical trial in this small population, From the Division o f Bacterial Products, Bureau o f Biologics, Food and Drug Administration; Children's Hospital National Medical Center," and The Hospital for Sick Children. *Recipient o f N I C H D Postdoctoral Research Fellowship Award No. 1F22HD02034-O1. Reprint address: Bureau of Biologics, 8800 Rockville Pike, Bethesda, Md. 20014.

Vol. 88, No. 1, pp. 36-40

we describe our efforts to attenuate this outbreak of HITB meningitis. METHODS

AND PATIENTS

Microbiology. Posterior NP cultures were plated on Levinthal HITB antiserum agar, incubated at 37 ~ C for 24 hours and then at 4 ~ C for 24 hours, and observed for haloed colonies.TM Confirmation of the HITB and antibiotic sensitivities performed by a microtube dilution method 1~were done by the Microbiology Service, Clinical Pathology Department, Clinical Center, National Institutes of Health. All HITB isolates were sensitive to ampicillin at 0.4/~g/ml or less. Abbreviations used HITB: Hemophilus influenzae type b NP: nasopharyngeal

Serum antibodies. Antibodies to the HITB capsular polysaccharide were assayed by radioimmunoassay.16 Immunization. Twenty-five micrograms of HITB polysaccharide vaccine was injected subcutaneously after informed parental consent had been obtained? 6 Patients. The population consisted of inpatients at a small pediatric hospital in Washington, D. C., which cares for children with chronic conditions, especially central nervous system disease. All cases of meningitis occurred

Volume 88 Number 1

H. influenzae type b outbreak

37

DURATION OF NASOPHARYNGEAL CARRIAGE OF H I.T.B, PATIENT

RESULTS OF NP CULTURE FOR H.I.T.B IMMUNIZATION

14 15

Pos. Pos.

Pos. POS,

Pos Neg

16

Pos.

17 18

Pos. Neg

Pos Eos. Pos.

Pos. Pos.

19

Pos.

Pos.

Neg.

20

Neg.

POS.

Pos,

I

1 (8-20-74)

I 2

I 3

Pos

I 4

Pos,

Neg

Ampicillin

Pos Pos

Pos. Pos

Ampicillin Ampicillin

Pos.

Pos,

Ampicillin

Neg. Neg

Pos. Ne 9

Pos

Pos

JAmpicill[n[

Pos, Neg Neg. Neg.

Neg.

i

i

i

~

I

I

I

I

6

7

8

9

10

II

12

13

N T, N T, I 14

Neg. Neg, Neg

Neg. Neg. Neg

Neg.

Neg.

Neg. Neg, Neg.

Neg. Neg Pos

Neg.

Pos

Ne~, N.T N,T.

NT N.T

]

I

I

I

I

15

t6

17

18

29 ( 3= 12~75 I

WEEK TESTED

Fig. 1. Duration of nasopharyngeal carriage of HITB. T a b l e I. Cases of HITB meningitis

Onset Case No.

Age

Sex

l

4 yr, 8 m o

M

2

1 yr

M

9.9

3 4

32 mo 4 mo

F M

13 4.3

5

15 mo

F

6.5

Weight

18

Underlying disease

Date admitted

meningitis

Rubella syndrome Lead intoxication Asthma CHD* with asplenia and cleft palate Hydrocephalus with shunt CHD*

3-29-74

4-10-74

6-13-74

7-15-74

4-13-74 9-3-74

8-12-74 9-9-74

1-25-74

10-11-74

of

*CHD = congenitaheart disease. in two adjacent wards housing 30 children, ages 3 months to 7 years. One child had a meningomyelocele, three had hydrocephalus with shunt, and one had asplenia. The child with asplenia and a child with hydrocephalus and shunt developed HITB during this outbreak. No meningitis occurred in the older children housed in other wards; they are not considered in this report. RESULTS Cases of meningitis . The five cases are summarized in Table I. Children with meningitis were transferred to the Children's Hospital National Medical Center. Cases 1 to 4 survived, and Case 5 died shortly after transfer. Cases 1 and 3 returned to the chronic care hospital where later studies revealed high levels of serum antibody (3.4 and 3.1/~g/ml) and negative NP cultures. The disease in Cases 1, 2, and 3 occurred before our studies were initiated. Case 2 was discharged to home. Cases 4 and 5, studied prior to their onset of meningitis, had low TM levels of serum antibody ( < 0.04 and 0.05/~g/ ml). Neither child was a carrier when studied 3 and 32 days, respectively, before the onset of meningitis. These five children were not among those immunized

on September t2, 1974. Case 4 acquired meningitis before results of antibody levels were available. Case 5 was not immunized because the parents refused consent. NP carriage. On August 20, 1974, an NP culture and blood sample were obtained from each of the 31 children in the two wards where three cases of meningitis had occurred. By September 6, 1974, there had been four new admissions to the hospital and six discharges; NP cultures were again obtained. During this month cultures were taken from all 160 adult employees and volunteers working with these children. Additional cuItures and blood samples were obtained only from certain groups of children as specified below. On August 20, 1974, 5 of 31 children (16%) were found to have positive NP cultures. On September 6, 1974, 7 of 29 children (24%), including all five of the previous carriers, carried HITB. Further cultures, listed in Fig. 1, showed that two of these children remained carriers for at least eight weeks. Of the ten children under 12 months of age, only one, Case 20, age 9 months, was found to carry HITB. Of the 25 children over 1 year, six (24%) were carriers. None of the 160 adults was carrier.

38

Glode et al.

The Journal of Pediatrics January I976

Table II. HITB carriage and serum antibodies in i m m u n i z e d children 23 days preimmunization

Case No.

Sex

Age

NP culture

A ntibody level (t~g/ml)

Day of immunization

NP culture

Group I: Antibody level < 0.24 #g/ml 6 M 5 yr Neg 0.066 Neg 7 M 3 yr, 10 Neg 0.137 Neg mo 8 M 24 mo Neg < 0.04 Neg 9 F 23 mo Neg NT Neg 10 F 23 mo Neg 0,082 Neg 11 F 11 mo Neg 0,087 Neg 12 F 3 mo Neg 0.132 Neg 13 M 1 mo Neg < 0.04 Neg Group H: Positive NP culture.for HITB prior to immunization 14 M 32 mo Pos 1.35 Pos 15 M 14 mo Pos 0.4 Neg 16 M 26 mo Pos 0.535 Pos 17 F 32 mo Pos 0.818 Pos 18 M 5 yr Neg 3.0 Pos 19 M 39 mo Pos 1.33 Neg Group Ili: Antibody level < 0.24 ~g/ml and HITB carrier 20 M 9 mo Neg 0.05 Pos

33 days post immunization

12 days post immunization

Antibody level (p,g/ml)

NP culture

Antibody level (llg/ ml)

NP culture

0.521 0.247

NT NT

> 2.5 > 2.5

NT NT

4.7 34.0

< 0.04 0.085 0.205 0,042 0.165 < 0.04

NT NT NT NT NT NT

0.042 NT 0.43 0.066 0.079 0.055

NT NT NT NT NT NT

< 0.038 16.0 0.39 < 0.038 < 0.038 < 0.038

0.438 0.351 0.788 0.545 4.0 0.165

Pos Pos Pos Pos Neg Neg

0.485 0.487 1.23 1.51 > 2.5 0.15

Neg Pos Pos Pos Pos Neg

0.31 0.31 0.62 0.75 17.0 0.23

0.184

Pos

0.093

Pos

A n tibody level (Izg/ml)

0.038

NT = not tested.

Immunization and antibody levels (Table II). Initial antibody levels for the entire group of children ranged from < 0.04/zg/ml to 19.7/~g/ml with a m e d i a n level o f 0.685/~g/ml. The median age of the entire group was 32 months. Two groups of children were immunized on S e p t e m b e r 12, 1974_ The eight patients in G r o u p I were selected because of an a n t i b o d y level less than 0.24/zg/ml. A level greater than 0.24 /xg/ml is considered to be protective against HITB meningitis, s o that these children were considered potentially susceptible to H I T B disease?" N o n e of these children was an HITB carrier. Their median age was 24 months. G r o u p II consisted of six children chosen for immunization because they were carriers of HITB. Although these six children were a m o n g those with initial antibody levels greater than 0.24 b~g/ml, they were immunized in an attempt to erradicate the carrier state. Their median age was 32 months, and their median antibody level was 1'.074 /xg/ml. An additional carrier, Case 20, age 9 months, was immunized, but is considered separately because he had an a n t i b o d y level less than 0.24/~g/ml. In the G r o u p I patients there was a rise in H I T B antibody level after immunization, comparing either the 12- or 33-day postimmunization level either with the immediate preimmunization levels or with the average o f

the two preimmunization levels. By the Wilcoxon Signed Rank Correlation Test, these differences were significant with p = 0.06 for the 12-day level and p = 0.08 for the 33-day level. Response to immunization appeared to b e age related. The three children under one year of age had no antibody rise after immunization. The five remaining children in G r o u p i were approximately 2 years of age or older. Three had at least an 8-fold increase, and one had a 2-fold increase in antibody level following i m m u n i z a t i o n (Table II). The six children in Group II had preimmunization titers ranging from 0.4 to 1.35/~g/ml. No significant rise occurred after immunization. In addition, five of these six carriers continued to carry HITB at 12 or 33 days after immunization. The 9-month-old child, Case 20, who was a carrier but who had low antibody levels showed no response to immunization and continued to be a carrier. Antibiotic therapy of carriers. In a further attempt to eliminate HITB, five of the six remaining carriers, excluding Case 20 who was kept in a separate isolated room, were treated with ampicillin suspension, 125 mg (or if over 20 kg, 250 rag) four times a day for 10 days. Therapy began on N o v e m b e r 2, 1974, except for one child who was treated earlier for otitis media. Three days after therapy was discontinued, four of the five treated children

Volume 88 Number 1

had negative cultures. The child who was then still positive for HITB later became negative; the untreated isolated child also became negative (Fig. 1). Follow-up. The 28 children in the two wards were cultured again on March 12, 1975; eight of them were new children. Among these were two of the five carriers who had been treated with ampicillin, both of the nontreated carriers, and 11 of the 15 who had been immunized. Three of the 28 children (10.7%) were found to be carriers on March 12, 1975. None of the previous carriers who had been treated with ampicillin had positive cultures. However, both of the carriers who had converted to negative without treatment were again carriers (Fig. 1). Case 10 had been immunized in September, 1974, because of a low antibody level and had responded with an increase to 0.43 ~g/ml. At the March survey, she was found to be a carrier for the first time. As of June, 1975, no additional HITB meningitis had occurred. DISCUSSION We report five cases of HITB meningitis that occurred within six months in a slowly changing enclosed population of 30 chronically ill children, a prevalence 750 times that reported in children 6 years of age or less. 1~ We observed an average carriage rate of 20% in this population. Previous studies by Turk TM and by Mpairwe ~9 have reported carriage rates as high as 50 to 70% in orphanages, in contrast to 3 to 4% in open populations of children. However, they observed no HITB disease in their orphanages despite the high carriage rate. In our population, there was both a high HITB carriage rate and a high incidence of HITB meningitis. Two of the children in our study who acquired meningitis had underlying predisposing conditions; one had hydrocephalus with shunt and one had congenital asplenia. ~~Another explanation for the high disease rate may be the virulence of the strains involved, although there is currently no method to compare HITB strains. Both Turk ~ and Mpairwe '~ observed that when susceptible children moved into closed populations with high carriage rates, they acquired the organism after a lag period of weeks or months, implying that H ITB carriage is not highly contagious. These studies and our own demonstrate that NP carriage can be prolonged several months. These observations serve to explain the higher carriage rates in enclosed populations, where a single carrier may infect a large group over a prolonged period of time. HITB carriage was associated with high antibody levels) 2. ~ However, one of the seven children who were carriers had a low antibody level of 0.05/~g/ml which later

H. influenzae type b outbreak

39

rose to 0.148 /~g/ml. It appears that additional factors were determinant in his resistance to disease. The two patients who became carriers during the study had a rise in antibody titer. One of these new carriers, Case 18, had a high antibody level of 3.0/~g/ml prior to acquisition of carriage. Either his carriage was missed at the first survey or his high antibody level did not prevent carriage. Several children showed a change in their preimmunization antibody levels which was greater than that attributable to the variation of the radioimmunoassay. 16 Three children in Group I, who were noncarriers, demonstrated a rise in preimmunization antibody levels. This phenomenon has been previously reported in a population with HITB disease. ~1 We documented low antibody ( < 0.04/~g/ml and 0.05 /~g/ml) in two children prior to their onset of meningitis consistent with the hypothesis that anticapsular antibody confers immunity. Neither patient was a carrier when tested at 3 or 32 days, respectively, prior to onset of disease. In the current study only 10% (1 of 10) of the children under one year were carriers compared to 24% (6 of 25) of the older children. In Turk's TM study of a day nursery, ten children under one year of age were all noncarriers, while carriage ranged from 5 to 12% in children ages 1 through 4 years. Mpairwe ~ found a 4% (l of 26) HITB carriage rate among orphans under one year of age as contrasted to an average rate of 29% for a group of children ranging to 4 years housed separately in the same institution. Johnson and Fousek ~ found a high carriage rate among toddlers and older children, but low carriage among infants and nurses in a small convalescent hospital. ~2 Michaels and associates, ~4 studying outpatients, found no carriers among children under six months of age, as compared to a 3% carriage rate among children from 6 months 1o 4 years~ In contrast, children from 3 months to 1 year of age have the highest age-related incidence of HITB meningitis? ' It may be important, therefore, when attempting to contain HITB disease in an institutionalized population, to separate children under one year of age from older children. This study suggests that HITB meningitis is a contagious disease when susceptible children are in prolonged contact with carriers of the organism. Carriage does not identify children in danger, as individuals with negative cultures may rapidly develop meningitis. One child (Case 4), who developed meningitis three days after a negative culture, illustrates this point. Conversely, although most carriers are immune to meningitis, positive culture does not exclude a child from danger, since potential cases of meningitis might acquire positive throat cultures prior to onset of clinical disease. Similiar observations regarding

40

Glode et al.

the spread o f m e n i n g o c o c c a l meningitis were recently reported b y Kaiser a n d colleagues. 2'~ Several authors h a v e advocated antibiotic p r o p h y l a x i s of y o u n g susceptible contacts of cases o f H I T B m e n i n g i tis.7, 9. 29However, older carriers m a y persist as a c o n t i n u a l source o f H I T B for y o u n g e r sibs. In this study, antibiotic therapy was used in a n a t t e m p t to rid the p o p u l a t i o n o f HITB. Our uncontrolled data suggest only limited efficacy of oral ampicillin in erradicating carriage. I m m u n i z a t i o n with HITB polysaccharide vaccine was associated with s e r u m a n t i b o d y increases a m o n g n o n c a r tiers with low p r e i m m u n i z a t i o n levels. W e c a n n o t conclude f r o m this small a n d uncontrolled study w h e t h e r i m m u n i z a t i o n was related to disease p r e v e n t i o n . I m m u n i zation o f age-susceptible children a n d antibiotic treatm e n t o f carriers, on a n investigational basis, m a y b e considered if a n o u t b r e a k of H I T B meningitis s h o u l d occur. We thank Marie MacDonald for her help in preparing the manuscript, the staff of the Clinical Microbiology Laboratory at the National Institutes of Health, Dr. James Schlesselman for statistical analysis of the data, and Marena Gibbons, R.N., B.S.N, for her help through the study. REFERENCES

1. Center for Disease Control: Reported morbidity and mortality in the United States, 1973, Morbidity and Mortality Weekly Rep 22:2, 1973. 2. Schiffer MS, MacLowry J, Schneerson R, Robbins JB, McReynolds JW, Thomas WJ, Bailey DW, Clarke ES, Mueller EJ, and Escamilla J: Clinical, bacteriological and immunological characterization of ampicillin-resistant Haemophilus influenzae type b, Lancet 1:257, 1974. 3. Smith ES: Purulent meningitis in infants and children, J PEDIATR 45:425, 1954. 4. Crook WE, Clanton BR, and Hodes HL: Haemophilus influenzae meningitis observations on the treatment of 1 l0 cases, Pediatrics 4:643, 1949. 5. Cavanaugh JJ, and Kline AH: Unpublished data cited, Am J Dis Child 104:595, 1962. 6. Good PG, Fousek MD, Grossman MF, and Boisvert PL: A study of the familial spread of Hemophilus influenzae type b, Yale J Biol Med 15:913, 1943.

The Journal of Pediatrics January 1976

7. 8.

9. 10.

11. 12.

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22. 23.

Hertzog AS, Cameron IL, and Karlstrom AE: Influenzal meningitis in brothers, JAMA 124:502, 1944. Carabelle RW, Mitchell DD, and Salmon GW: Influenzal meningitis treated with chloromycetin, J PEDIATR 37:37, 1950. Kline AH: Hemophilus influenzae meningitis, Am J Dis Child 104:595, 1962. Rothman M, and Nahil FJ: Prophylaxis in meningitis due to type b Hemophilus influenzae, N Engt J Med 253:653, 1955. Kloss JL: Hemophilus influenzae meningitis in siblings, Clin Pediatr 6:580, 1967. Coulter D, Whisnant JK, and Marks MI: Hemophilus influenzae type b meningitis in identical twins of a triplet sibship, Pediatrics 54:502, 1974. Ginsburg CM: Epiglottitis, meningitis, and arthritis due to Haemophilus influenzae type b, presenting almost simultaneously in siblings, J PEDIATR 87:492, 1975. Michaels RH, Stonebraker FE, and Robbins JB: Use of antiserum agar for detection of Haemophilus influenzae type b in pharyngeal cultures, Pediatr Res 9:513, 1975. MacLowry JD, Jaqua MS, and Selepak ST: Detailed methodology and implementation of a semiautomated serial dilution microtechnique for antimicrobial susceptibility testing, Appl Microbiol 20:46, 1970. Robbins JB, Parke JC Jr, Schneerson R, and Whisnant JK: Quantitative measurement of "natural" and immunizationinduced Haemophilus influenzae t y p e b capsular polysaccharide antibodies, Pediatr Res 7:103, 1973. Parke JC Jr, Schneerson R, and Robbins JB: The attack rate, ag e , incidence, racial distributio n , and case fatality rate of Haemophilus inftuenzae type b meningitis in Mecklenburg County, North Carolina, J PEDIATR 81:765, 1972. Turk DC: Naso-pharyngeal carriage of Haemophilus influenzae type b, J Hyg (Camb) 61:247, 1963. Mpairwe Y: Observations on the nasopharyngeal carriage of Haemophilus influenzae type b in children in Kampala, Uganda, J Hyg (Camb) 68:337, 1970. Kevy SV, Tefft M, Vawter GF, and Rosen FS: Hereditary splenic hypoplasia, Pediatrics 42:752, 1968. Greenfield S, Peter G, Howie VM, Ploussard JH, and Smith DH: Acquisition of type-specific antibodies to Hemophilus influenzae type b, J PEDIATR 80:204, 1972. Johnson RD, and Fousek M: Study of the spread of H. influenzae type b, J Bacteriol 45:197, 1943. Kaiser AB, Hennekens CH, Saslaw MS, Hayes PS, and Bennett JV: Seroepidemiology and chemoprophylaxis of disease due to sulfonanide-resistant Neisseria meningitidis in a civilian population, J Infect Dis 130:217, 1974.