Spread
Intrafamily Amir
\s=b\ Meningitis and epiglottitis are the clinical manifestations of severe Haemophilus influenzae serotype b infection. Compared with meningitis, epiglottitis occurs in older children. When secondary cases occur within the family, the type of clinical manifestation produced by this serotype is generally similar in siblings. This report concerns the unusual occurrence of meningitis developing in the older child and epiglottitis developing in the younger one. We discuss the possible explanations for this unusual pattern. We also survey the spread of H influenzae both within and outside the family unit and review the present status of histocompatibility antigens and Haemophilus disease. (Am J Dis Child 131:778-781, 1977)
TJaemophilus influenzae serotype JTL b, which has capsular substance polyribophosphate, is responsible for
most of the invasive disease caused by H influenzae in humans. Meningitis and epiglottitis are the important clinical manifestations of invasive H influenzae serotype b infection. It is not widely known that disease due to H influenzae type b has a potential for
intrafamily spread. We recently
H influenzae
prompted
us
en¬
of disease due to in the same family that to study the immunoge-
countered two
cases
From the Department of Pediatrics, The Methodist Hospital and State University of New York Downstate Medical Center, Brooklyn, NY. Reprint requests to the Department of Pediatrics, The Methodist Hospital, 506 Sixth St, Brooklyn, NY 11215 (Dr Tejani).
Tejani, MD;
Bohdan
REPORT OF CASES Case 1.—A 6-year-old girl was admitted a comatose state after a convulsion. The positive findings at the time of admission the presence of were neck stiffness,
in
Kernig's sign, and exaggerated deep tendon reflexes. At spinal tap, turbid fluid was obtained that had a cell count of 7,660 polymorphonuclear cells per cubic milli¬ meter. A smear of the fluid showed Gramnegative coccobacilli, and H influenzae serotype b grew from the blood and CSF cultures. Case 2.-A 3-year-old boy (brother of patient 1) was admitted three days later with fever and mild respiratory distress. The presence of Kernig's sign led to a lumbar puncture that showed normal spinal fluid findings. A lateral x-ray film of the neck showed a swollen epiglottis. Within an hour of admission, respiratory distress became marked, and a tracheostomy was done. Haemophilus influenzae type b grew from a blood culture and a culture of epiglottis taken at the time of tracheostomy. were
Haemophilus
Dobias, MD; Bhim S. Nangia, MD; Hymavathi Velkuru,
netics of the family and the epidemiol¬ ogy of the disease.
Both children
of
treated with intrave¬
ampicillin sodium and chlorampheni¬ col, the chloramphenicol being withdrawn once the sensitivity of the H influenzae nous
had been determined. The two children made an uneventful recovery.
COMMENT Disease arising from H influenzae type b infection is probably due to hematogenous spread of the organism from the nasopharynx. Both of our patients had a positive blood culture for the organism. Epiglottitis most often occurs in slightly older children than does meningitis.1 This age-
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 06/17/2015
related
pattern
was
reversed in
MD
our
patients, meningitis developing in the older child and epiglottitis developing in the younger one. In an attempt to find an explanation for this reversal of the age-related pat¬ tern, we looked at the antibody levels
two
in the two children. Patients with meningitis have been shown to have significantly lower levels of antibody to capsular polysaccharide than pa¬ tients with epiglottitis.3 Anticapsular antibody level determined 28 days after the infection in the index case showed the child with meningitis to have 600 ng/ml and the child with epiglottitis, 200 ng/ml. If the acquisi¬ tion of anticapsular antibody is agerelated as suggested,3 then it was not unusual to see the meningitis patient having a higher level of antibody in this particular instance. Predisposition toward developing a particular type of disease may be genetically controlled. Recent studies concerning histocompatibility anti¬ gens and their association with cer¬ tain diseases4 have provided insight into the workings of the immune system. The histocompatibility anti¬ gens of an individual are determined by four genes, one gene alíele at each of two gene loci on each of the number 6 chromosomes.' The two loci origi¬ nally named LA and FOUR are now renamed HLA-A and HLA-B. Nine¬ teen alíeles are now recognized at the locus. The A locus and 26 at the recognized alíele at the A locus are numbered HLA-A1, -A2, -A3, -A9, -AIO, -All, -A28, -A30, etc, and those
Type
b Infections
at the locus are numbered HLA-B5, -B7, -B8, -B12, -B13, -B14, -B17, -B27, etc.6 This nomenclature replaces the old terminology, so for example, an alíele designated as W27 in the old
becomes HLA-B27. For this report, the new nomenclature is given with the previous in paren¬ theses in Table 1. Most persons inherit two different alíeles at each locus (are heterozygous). The particular combi¬ nation of alíeles at locus A and locus on the same chromosome is called the haplotype. The two loci of the HLA system are located very close together on chromosome 6, and the HLA haplotypes are generally transmitted with¬ out change from generation to gener¬ ation.* Altered frequencies of HLA anti¬ gens have been recorded in a large number of diseases.7 Very few studies have been done regarding the associa¬ tion between HLA and influenzae disease.'·-·" " Whisnant and his col¬ leagues1-' have studied HLA antigens in 65 patients with influenzae disease, and Table 1 shows the frequency of various HLA antigens among their patients compared with controls. The distribution of all second series antigens (B5 to Bw40 [A5 to W10]) differed from the expected normal. We studied the haplotype of all of the members in the family of our two patients (Table 2), and it can be seen that each patient did inherit at least one antigen that is more frequently associated with influen¬ zae disease (Bw35 and Bwl7 [W5 and W17]). It was interesting to note that
terminology
now
Table 1 .—HLA Antigen Frequencies in Patients With Haemophilus influenzae Type b Epiglottitis or Meningitis and in Blood Bank Controls* HLA HLA
Antigen Frequency, %
Controls·
Epiglottitis
Meningitis
Total
A1
31.5
A2 A3 A9 A10 A11 A28
43.7 23.1
33.3 50.0 16.7
31.4 37.1 25.7 20.0 14.3 17.1 14.3 8.8 2.9 17.1 17.1
32.3 43.1 21.5
25.7 5.7
27.7 9.2 24.6
(W28)t Aw19(W19) B5 (A5) B7 (A7) B8 (A8) B12 (A12) B13 (A13) Bw35 (W5) Bw22 (W22) B14 (W14) Bw15 0/V15) Bw17 (W17) B18(W18) Bw40 (W10)
22.4 12.9 9.3 6.2 11.3
16.7 16.7 3.3 20.0 13.3 13.3 20.0 10.0 30.0 13.3 20.0
22.4
22.8 26.2 4.0
13.3 10.0 13.3 3.3 10.0
2.4 15.3
10.8 7.7 18.5 13.8
28.8 5.7 11.4 5.7 11.4
5.1
6.7 8.4 3.2
18.6 15.4 10.8 16.9
12.3 7.7 12.3 1.7 16.9
2.9 22.9
"From Whisnant et al.2
tControls were 451 normal blood bank donors. tSpecificities in parentheses are previous nomenclature. Table
2—Tissue-Typing Report HLA
Father
First (LA) Series or A A1
Mother
A2
Elder
sibling
Patient 1
(meningitis)
A1
Patient 2
(epiglottitis)
A2
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Phenotype Second (FOUR) Series or Bw35
A9
B8
A9
B8
A9
Bw35
HLA
Haplotype Bw35
Bw17
B17
B8
Bw35
Bw17 Bw17
Table
3.—Intrafamily Spread
of
Haemophilus influenzae Disease of Haemophilus Flu Infection
Type Age Author Davis" Herzog et alíc
Index Case 5 days 2 yr
Cooperstock21
2yr
Carabelle et al2!
14
Rothman and Nahil" Kline2Kline2" Kloss25 Coulter et al'
6 mo 1 yr 2 V·· yr 28 mo 11 mo
Sinclair2' Good et al21
3yr
Present report
6 yr index
5 yr 5 yr 11 mo 1V4 yr 6 yr 19 mo* 19 mo" 3 yr
3 days 5 days 3 days 5 days 1 day 30 days 1
2
day days
3 wk
Cellulitis
2
days
Epiglottitis Epiglottitis Epiglottitis
2
mo
Arthritis
1 3
specified day day days
Not 1
Epiglottitis
case.
the two children did not share any recognizable HLA antigens. Whether this could account for their exhibiting different types of disease is specula¬ tive. Mechanism of involvement of leuko¬ cyte antigens in the pathogenesis of disease is yet to be defined. One postulate is that the antigens on the cell surface may function as a receptor for a virus. Haemophilus influenzae meningitis is often associated with a high incidence of antecedent viral upper respiratory tract infection." An association between antecedent viral infection and subsequent bacterial meningitis has been suggested.1" If this association can be established, then surface receptors for viruses may play an important role in the patho¬ genesis of disease such as H influen¬ zae meningitis. An alternate postulate is that of molecular mimicry wherein it is suggested that invading organ¬ isms are able to escape immune attack because of cross reactivity with the HLA antigens on normal cell sur¬ faces. ' ' In
mo
12 mo 12 mo Not specified
2V4 yr
Ginsburg31
addition, haplotype analysis sug¬ common HLA haplotypes
gests that
2yr
Not specified
Whisnant2'
siblings of the
4 yr 5
Sibling Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Epiglottitis Epiglottitis Epiglottitis
Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Epiglottitis Epiglottitis Epiglottitis Epiglottitis Epiglottitis Meningitis Meningitis Meningitis Meningitis
3yr 2yr
mo
3V4 yr 4 yr
Index Case
Sibling days
4 yr
3yr 3yr
Addy2' Addy21 Addy2i
'Twin
5
Time Interval Between the Disease in the Index Case and Sibling Same day 3 days 1 day
may be associated with resistance to many diseases.12 Further HLA studies in families where an index case of H influenzae occurs and other siblings escape the disease may clarify wheth-
Table
4—Spread of Haemophilus influenzae Disease Outside No. of Children in the
Population Author Schiffer et al25 Glode et al3' Melish et al3'
Day
ill children in pediatrie ward Day care center
Chronically
31
3 (all
30
48
this is true for H influenzae disease. The rising incidence of H influen¬
meningitis as suggested by recent
surveys13-1" necessitates
a
Flu Disease Cases
Haemophilus
Survey
Involved care center
er
zae
No. of
review of
secondary cases. Haemophilus in¬ fluenzae meningitis is not listed as a notifiable contagious disease,17 and therefore, the risk of spread is diffi¬
cult to calculate. Smith13 reports finding multiple infections in 3% of the families wherein an index case of H influenzae meningitis had occurred. Table 3 lists all demonstrated cases of intrafamily spread of H influenzae disease. These numbers exceed the demonstrated reports of nonepidemic intrafamily spread of meningococcal meningitis.1131 No epidemics of H influenzae meningitis have been re¬ ported, but in recent years, there have been reports of spread of H influenzae
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Families Time Interval of the
Survey
meningitis)
2
mo
6
(all meningitis)
6
mo
4
(3 meningitis and 1 pneumonia)
5 wk
disease outside a family unit, and Table 4 lists these reports. Nasopharyngeal carriage of H in¬ fluenzae is common in homes in which cases of clinical infections with the organism have recently occurred. Good and his colleagues'-'7 recovered H influenzae type b from members of two out of three such homes and in one case, recorded a secondary intrafami¬ ly spread of infection. Turk33 recov¬ ered serotype b from members of five out of six homes where an index case of H influenzae meningitis had occurred. We cultured all of the members of the family (father, moth¬ er, and an older sibling, aged 9 years) and five other children who were in intimate contact with our two pa¬ tients. The parents and the sibling were negative for H influenzae serotype b, but all the contact children had
positive throat culture for serotype b. These frequencies greatly exceed those found in most population sur¬ veys since capsulated strains recov¬ erable from the nasopharynx or throat of healthy children are in the range of 3% to 5%.38 The higher recovery rate from homes with patients with H influenzae infections suggests that either high concentration of carriers of serotype b precede and give rise to cases of H influenzae meningitis and epiglottitis, or that the affected chil¬ dren in the early stages of the disease are potent sources of infection for others in the household. Chemoprophylaxis of immediate household contacts of an index case of H influenzae meningitis has been recommended by some authors.1'3·34·3"·40 The development of a successful vaccine against H influenzae would a
solve the dilemma of close contacts, however, recent evidence114L> suggests that immunization with the capsular polyribophosphate does not produce adequate antibody levels in infants— the group that is at highest risk for developing H influenzae disease. Par¬ tially successful eradication of the organisms from the carriers in a pedi¬ atrie ward was achieved by Glode et al36 by using ampicillin sodium (125 to 250 mg four times a day for ten days). Four of the five children so treated became culture-negative, showing limited efficacy of oral ampicillin in eradicating carriage. Melish et al37 also succeeded in eradicating the carrier state in a day care center by
using
sulfamethoxazole-trimetho-
prim for four days. Carriage was eradicated in their study from all treated children wtien surveyed ten
later. The numbers involved in both of these studies are small and uncontrolled, but till a more effective vaccine is available,13 protecting the infant in close contact with an index case of H influenzae disease with one of these antibiotics may not be an unreasonable solution.
days
Porter W. Anderson, PhD, of the Children's Hospital Medical Center, Boston, performed the radioimmunoassay for antibody studies, Mari¬ lena Fotino, MD, of the New York Blood Center performed HLA typing on the family, and Jane Pitt, MD, of the College of Physicians and Surgeons of Columbia University, New York, reviewed the manuscript.
Nonproprietary Name and Trademarks of Drug Ampicillin soàmm-Alpen-N, Amcill-S, Omnipen-N, Penbritin-S, Polycillin-N, Principen / .
References 1. Whisnant JK, Rogentine GN, Mann DL, et al: Human cell-surface structures related to H influenzae type b disease. Lancet 2:895-898, 1971. 2. Whisnant JK, Rogentine GN, Gralnick MA, et al: Host factors and antibody response in H influenzae type b meningitis and epiglottitis. J Infect Dis 133:448-455, 1976. 3. Feigin RD, Stechenberg BW, Chang MJ, et al: Prospective evaluation of treatment of Hemophilus influenzae meningitis. J Pediatr 88:542\x=req-\ 548, 1976. 4. Schaller JG, Omenn GS: The histocompatibility system and human disease. J Pediatr 88:913-925, 1976. 5. Lamm LU, Friedrich U, Petersen GB, et al: Assignment of the major histocompatibility complex to chromosome No. 6 in a family with pericentric inversion. Hum Hered 24:273-284, 1974. 6. Meeting report of Sixth International Histocompatibility Workshop, in Kissmeyer\x=req-\ Nielsen F (ed): Histocompatibility Testing 1975. Copenhagen, Ejnar Munksgaard Forlag, 1976, pp 5-11. 7. Ryder LP, Svejgaard A: Association Between HLA and Disease. Copenhagen, HLA and Disease Registry of Copenhagen, 1976. 8. Coulter D, Whisnant JK, Marks IM: Hemophilus influenzae b meningitis in identical twins of a triplet sibship. Pediatrics 54:502-504, 1974. 9. Tejani A, Fotino M, Khan R, et al: HLA and Hemophilus influenzae disease. Edit Inst Natl Sante Recherche Med 58:264, 1976. 10. Young LS, LaForce FM, Head JJ, et al: A simultaneous outbreak of meningococcal and influenza infections. N Engl J Med 287:5-9, 1972. 11. Dausset J, Hors J: Some contributions of the HLA complex to the genetics of human diseases. Transplant Rev 22:44-74, 1975. 12. Teraski PI, Mickey MR: HLA haplotypes of 32 diseases. Transplant Rev 22:105, 1975. 13. Michaels RH: Increase in influenzal meningitis. N Engl J Med 285:666-667, 1974.
14. Koch R, Kogut M, Asay L: Management of bacterial meningitis in children. Pediatr Clin North Am 8:1177-1197, 1961. 15. Haggerty RJ, Ziai M: Acute bacterial meningitis. Adv Pediatr 13:129-181, 1964. 16. Riley HD Jr, Bracken EC: Empyema due to H influenzae in infants and children. Am J Dis Child 110:24-28, 1965. 17. Center for Disease Control. Morbidity Mortality Weekly Rep 23:182, 1976. 18. Smith DH: The challenge of bacterial
meningitis. Hosp
Prac 6:71-80, 1976. 19. Davis DJ: Influenzal meningitis. Arch Intern Med 4:323-329, 1909. 20. Herzog AJ, Cameron LA, Karlstorm AE: Influenzal meningitis in brothers. JAMA 124:502-503, 1944. 21. Cooperstock M: Influenzal meningitis in siblings. Am J Dis Child 68:269-270, 1944. 22. Carabelle RW, Mitchell DD, Salmon GW: Influenzal meningitis treated with chloromycetin. J Pediatr 37:37-41, 1950. 23. Rothman M, Nahil FJ: Prophylaxis in meningitis due to type b H influenzae. N Engl J Med 253:653, 1955. 24. Kline HA: H influenzae meningitis. Am J Dis Child 104:595-597, 1962. 25. Kloss LJ: H influenzae meningitis in siblings. Clin Pediatr 6:580-581, 1967. 26. Sinclair SE: H influenzae type b in acute laryngitis with bacteremia. JAMA 117:170-173, 1941. 27. Good PG, Fousek MD, Grossman MF, et al: A study of the familial spread of H influenzae type b. Yale J Biol Med 15:913-918, 1943. 28. Addy MG, Ellis PDM, Turk DC: Haemophilus epiglottitis: Nine recent cases in Oxford. Bri Med J 1:40-42, 1972. 29. Whisnant JK: Studies on mechanism of susceptibility to H influenzae type b disease, in Sell SH (ed): Hemophilus influenzae. Nashville, Tenn, Vanderbilt University Press, 1973, p 218. 30. Ginsburg CM: Epiglottitis, meningitis, and arthritis due to Hemophilus influenzae type b presenting almost simultaneously in siblings. J
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 06/17/2015
Pediatr 87:492-493, 1975. 31. Greenfield S, Feldman HA: Familial carriers and meningococcal meningitis. N Engl J Med 277:497-502, 1967. 32. Cragg J, Bennett EF: Meningococcal meningitis: A family study. Lancet 1:248-249, 1959. 33. Khuri-Bulos N: Meningococcal meningitis following rifampin prophylaxis. Am J Dis Child 126:689-691, 1973. 34. Marti GI, DeGrinney JT: Intra-familial infection with N meningitidis group C. Clin Pediatr 11:538-540, 1972. 35. Schiffer MS, MacLowry J, Schneerson R, et al: Clinical, bacteriological, and immunological characterization of ampicillin-resistant Haemophilus influenzae type b. Lancet 2:257-259, 1974. 36. Glode MP, Schiffer MS, Robbins JB, et al: An outbreak of Hemophilus influenzae type b meningitis in an enclosed hospital population. J Pediatr 88:36-40, 1976. 37. Melish ME, Nelson AJ, Martin TE, et al: Epidemic spread of H influenzae type b (HIB) in a day care center. Pediatr Res 10:348, 1976. 38. Turk DC: Hemophilus influenzae, Turk DC, May JR (eds). London, English Universities Press, 1971. 39. Mortimer EA Jr: Rational use of prophylactic antibiotics in children. Pediatr Clin North Am 15:261-273, 1968. 40. Stimson PM, Hodes HL: Manual of the Common Contagious Diseases, ed 5. Philadelphia, Lea & Febiger Publishers, 1956, p 428. 41. Anderson PW, Ingram DL, Harding L, et al: Antibody response of infants to the capsular polyribophosphate (PRP) of Hemophilus influenzae b (HIB), abstracted. Pediatr Res 10:383, 1976. 42. Parke JC Jr, Schlesselman J, Schneerson R, et al: Vaccine trial in Mecklenburg County, NC, with H influenzae type b (HITB) and meningococcal group C (MGC) capsular polysaccharides: Progress report, abstracted. Pediatr Res 10:402, 1976.
Intrafamily Amir
\s=b\ Meningitis and epiglottitis are the clinical manifestations of severe Haemophilus influenzae serotype b infection. Compared with meningitis, epiglottitis occurs in older children. When secondary cases occur within the family, the type of clinical manifestation produced by this serotype is generally similar in siblings. This report concerns the unusual occurrence of meningitis developing in the older child and epiglottitis developing in the younger one. We discuss the possible explanations for this unusual pattern. We also survey the spread of H influenzae both within and outside the family unit and review the present status of histocompatibility antigens and Haemophilus disease. (Am J Dis Child 131:778-781, 1977)
TJaemophilus influenzae serotype JTL b, which has capsular substance polyribophosphate, is responsible for
most of the invasive disease caused by H influenzae in humans. Meningitis and epiglottitis are the important clinical manifestations of invasive H influenzae serotype b infection. It is not widely known that disease due to H influenzae type b has a potential for
intrafamily spread. We recently
H influenzae
prompted
us
en¬
of disease due to in the same family that to study the immunoge-
countered two
cases
From the Department of Pediatrics, The Methodist Hospital and State University of New York Downstate Medical Center, Brooklyn, NY. Reprint requests to the Department of Pediatrics, The Methodist Hospital, 506 Sixth St, Brooklyn, NY 11215 (Dr Tejani).
Tejani, MD;
Bohdan
REPORT OF CASES Case 1.—A 6-year-old girl was admitted a comatose state after a convulsion. The positive findings at the time of admission the presence of were neck stiffness,
in
Kernig's sign, and exaggerated deep tendon reflexes. At spinal tap, turbid fluid was obtained that had a cell count of 7,660 polymorphonuclear cells per cubic milli¬ meter. A smear of the fluid showed Gramnegative coccobacilli, and H influenzae serotype b grew from the blood and CSF cultures. Case 2.-A 3-year-old boy (brother of patient 1) was admitted three days later with fever and mild respiratory distress. The presence of Kernig's sign led to a lumbar puncture that showed normal spinal fluid findings. A lateral x-ray film of the neck showed a swollen epiglottis. Within an hour of admission, respiratory distress became marked, and a tracheostomy was done. Haemophilus influenzae type b grew from a blood culture and a culture of epiglottis taken at the time of tracheostomy. were
Haemophilus
Dobias, MD; Bhim S. Nangia, MD; Hymavathi Velkuru,
netics of the family and the epidemiol¬ ogy of the disease.
Both children
of
treated with intrave¬
ampicillin sodium and chlorampheni¬ col, the chloramphenicol being withdrawn once the sensitivity of the H influenzae nous
had been determined. The two children made an uneventful recovery.
COMMENT Disease arising from H influenzae type b infection is probably due to hematogenous spread of the organism from the nasopharynx. Both of our patients had a positive blood culture for the organism. Epiglottitis most often occurs in slightly older children than does meningitis.1 This age-
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 06/17/2015
related
pattern
was
reversed in
MD
our
patients, meningitis developing in the older child and epiglottitis developing in the younger one. In an attempt to find an explanation for this reversal of the age-related pat¬ tern, we looked at the antibody levels
two
in the two children. Patients with meningitis have been shown to have significantly lower levels of antibody to capsular polysaccharide than pa¬ tients with epiglottitis.3 Anticapsular antibody level determined 28 days after the infection in the index case showed the child with meningitis to have 600 ng/ml and the child with epiglottitis, 200 ng/ml. If the acquisi¬ tion of anticapsular antibody is agerelated as suggested,3 then it was not unusual to see the meningitis patient having a higher level of antibody in this particular instance. Predisposition toward developing a particular type of disease may be genetically controlled. Recent studies concerning histocompatibility anti¬ gens and their association with cer¬ tain diseases4 have provided insight into the workings of the immune system. The histocompatibility anti¬ gens of an individual are determined by four genes, one gene alíele at each of two gene loci on each of the number 6 chromosomes.' The two loci origi¬ nally named LA and FOUR are now renamed HLA-A and HLA-B. Nine¬ teen alíeles are now recognized at the locus. The A locus and 26 at the recognized alíele at the A locus are numbered HLA-A1, -A2, -A3, -A9, -AIO, -All, -A28, -A30, etc, and those
Type
b Infections
at the locus are numbered HLA-B5, -B7, -B8, -B12, -B13, -B14, -B17, -B27, etc.6 This nomenclature replaces the old terminology, so for example, an alíele designated as W27 in the old
becomes HLA-B27. For this report, the new nomenclature is given with the previous in paren¬ theses in Table 1. Most persons inherit two different alíeles at each locus (are heterozygous). The particular combi¬ nation of alíeles at locus A and locus on the same chromosome is called the haplotype. The two loci of the HLA system are located very close together on chromosome 6, and the HLA haplotypes are generally transmitted with¬ out change from generation to gener¬ ation.* Altered frequencies of HLA anti¬ gens have been recorded in a large number of diseases.7 Very few studies have been done regarding the associa¬ tion between HLA and influenzae disease.'·-·" " Whisnant and his col¬ leagues1-' have studied HLA antigens in 65 patients with influenzae disease, and Table 1 shows the frequency of various HLA antigens among their patients compared with controls. The distribution of all second series antigens (B5 to Bw40 [A5 to W10]) differed from the expected normal. We studied the haplotype of all of the members in the family of our two patients (Table 2), and it can be seen that each patient did inherit at least one antigen that is more frequently associated with influen¬ zae disease (Bw35 and Bwl7 [W5 and W17]). It was interesting to note that
terminology
now
Table 1 .—HLA Antigen Frequencies in Patients With Haemophilus influenzae Type b Epiglottitis or Meningitis and in Blood Bank Controls* HLA HLA
Antigen Frequency, %
Controls·
Epiglottitis
Meningitis
Total
A1
31.5
A2 A3 A9 A10 A11 A28
43.7 23.1
33.3 50.0 16.7
31.4 37.1 25.7 20.0 14.3 17.1 14.3 8.8 2.9 17.1 17.1
32.3 43.1 21.5
25.7 5.7
27.7 9.2 24.6
(W28)t Aw19(W19) B5 (A5) B7 (A7) B8 (A8) B12 (A12) B13 (A13) Bw35 (W5) Bw22 (W22) B14 (W14) Bw15 0/V15) Bw17 (W17) B18(W18) Bw40 (W10)
22.4 12.9 9.3 6.2 11.3
16.7 16.7 3.3 20.0 13.3 13.3 20.0 10.0 30.0 13.3 20.0
22.4
22.8 26.2 4.0
13.3 10.0 13.3 3.3 10.0
2.4 15.3
10.8 7.7 18.5 13.8
28.8 5.7 11.4 5.7 11.4
5.1
6.7 8.4 3.2
18.6 15.4 10.8 16.9
12.3 7.7 12.3 1.7 16.9
2.9 22.9
"From Whisnant et al.2
tControls were 451 normal blood bank donors. tSpecificities in parentheses are previous nomenclature. Table
2—Tissue-Typing Report HLA
Father
First (LA) Series or A A1
Mother
A2
Elder
sibling
Patient 1
(meningitis)
A1
Patient 2
(epiglottitis)
A2
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Phenotype Second (FOUR) Series or Bw35
A9
B8
A9
B8
A9
Bw35
HLA
Haplotype Bw35
Bw17
B17
B8
Bw35
Bw17 Bw17
Table
3.—Intrafamily Spread
of
Haemophilus influenzae Disease of Haemophilus Flu Infection
Type Age Author Davis" Herzog et alíc
Index Case 5 days 2 yr
Cooperstock21
2yr
Carabelle et al2!
14
Rothman and Nahil" Kline2Kline2" Kloss25 Coulter et al'
6 mo 1 yr 2 V·· yr 28 mo 11 mo
Sinclair2' Good et al21
3yr
Present report
6 yr index
5 yr 5 yr 11 mo 1V4 yr 6 yr 19 mo* 19 mo" 3 yr
3 days 5 days 3 days 5 days 1 day 30 days 1
2
day days
3 wk
Cellulitis
2
days
Epiglottitis Epiglottitis Epiglottitis
2
mo
Arthritis
1 3
specified day day days
Not 1
Epiglottitis
case.
the two children did not share any recognizable HLA antigens. Whether this could account for their exhibiting different types of disease is specula¬ tive. Mechanism of involvement of leuko¬ cyte antigens in the pathogenesis of disease is yet to be defined. One postulate is that the antigens on the cell surface may function as a receptor for a virus. Haemophilus influenzae meningitis is often associated with a high incidence of antecedent viral upper respiratory tract infection." An association between antecedent viral infection and subsequent bacterial meningitis has been suggested.1" If this association can be established, then surface receptors for viruses may play an important role in the patho¬ genesis of disease such as H influen¬ zae meningitis. An alternate postulate is that of molecular mimicry wherein it is suggested that invading organ¬ isms are able to escape immune attack because of cross reactivity with the HLA antigens on normal cell sur¬ faces. ' ' In
mo
12 mo 12 mo Not specified
2V4 yr
Ginsburg31
addition, haplotype analysis sug¬ common HLA haplotypes
gests that
2yr
Not specified
Whisnant2'
siblings of the
4 yr 5
Sibling Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Epiglottitis Epiglottitis Epiglottitis
Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Meningitis Epiglottitis Epiglottitis Epiglottitis Epiglottitis Epiglottitis Meningitis Meningitis Meningitis Meningitis
3yr 2yr
mo
3V4 yr 4 yr
Index Case
Sibling days
4 yr
3yr 3yr
Addy2' Addy21 Addy2i
'Twin
5
Time Interval Between the Disease in the Index Case and Sibling Same day 3 days 1 day
may be associated with resistance to many diseases.12 Further HLA studies in families where an index case of H influenzae occurs and other siblings escape the disease may clarify wheth-
Table
4—Spread of Haemophilus influenzae Disease Outside No. of Children in the
Population Author Schiffer et al25 Glode et al3' Melish et al3'
Day
ill children in pediatrie ward Day care center
Chronically
31
3 (all
30
48
this is true for H influenzae disease. The rising incidence of H influen¬
meningitis as suggested by recent
surveys13-1" necessitates
a
Flu Disease Cases
Haemophilus
Survey
Involved care center
er
zae
No. of
review of
secondary cases. Haemophilus in¬ fluenzae meningitis is not listed as a notifiable contagious disease,17 and therefore, the risk of spread is diffi¬
cult to calculate. Smith13 reports finding multiple infections in 3% of the families wherein an index case of H influenzae meningitis had occurred. Table 3 lists all demonstrated cases of intrafamily spread of H influenzae disease. These numbers exceed the demonstrated reports of nonepidemic intrafamily spread of meningococcal meningitis.1131 No epidemics of H influenzae meningitis have been re¬ ported, but in recent years, there have been reports of spread of H influenzae
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Families Time Interval of the
Survey
meningitis)
2
mo
6
(all meningitis)
6
mo
4
(3 meningitis and 1 pneumonia)
5 wk
disease outside a family unit, and Table 4 lists these reports. Nasopharyngeal carriage of H in¬ fluenzae is common in homes in which cases of clinical infections with the organism have recently occurred. Good and his colleagues'-'7 recovered H influenzae type b from members of two out of three such homes and in one case, recorded a secondary intrafami¬ ly spread of infection. Turk33 recov¬ ered serotype b from members of five out of six homes where an index case of H influenzae meningitis had occurred. We cultured all of the members of the family (father, moth¬ er, and an older sibling, aged 9 years) and five other children who were in intimate contact with our two pa¬ tients. The parents and the sibling were negative for H influenzae serotype b, but all the contact children had
positive throat culture for serotype b. These frequencies greatly exceed those found in most population sur¬ veys since capsulated strains recov¬ erable from the nasopharynx or throat of healthy children are in the range of 3% to 5%.38 The higher recovery rate from homes with patients with H influenzae infections suggests that either high concentration of carriers of serotype b precede and give rise to cases of H influenzae meningitis and epiglottitis, or that the affected chil¬ dren in the early stages of the disease are potent sources of infection for others in the household. Chemoprophylaxis of immediate household contacts of an index case of H influenzae meningitis has been recommended by some authors.1'3·34·3"·40 The development of a successful vaccine against H influenzae would a
solve the dilemma of close contacts, however, recent evidence114L> suggests that immunization with the capsular polyribophosphate does not produce adequate antibody levels in infants— the group that is at highest risk for developing H influenzae disease. Par¬ tially successful eradication of the organisms from the carriers in a pedi¬ atrie ward was achieved by Glode et al36 by using ampicillin sodium (125 to 250 mg four times a day for ten days). Four of the five children so treated became culture-negative, showing limited efficacy of oral ampicillin in eradicating carriage. Melish et al37 also succeeded in eradicating the carrier state in a day care center by
using
sulfamethoxazole-trimetho-
prim for four days. Carriage was eradicated in their study from all treated children wtien surveyed ten
later. The numbers involved in both of these studies are small and uncontrolled, but till a more effective vaccine is available,13 protecting the infant in close contact with an index case of H influenzae disease with one of these antibiotics may not be an unreasonable solution.
days
Porter W. Anderson, PhD, of the Children's Hospital Medical Center, Boston, performed the radioimmunoassay for antibody studies, Mari¬ lena Fotino, MD, of the New York Blood Center performed HLA typing on the family, and Jane Pitt, MD, of the College of Physicians and Surgeons of Columbia University, New York, reviewed the manuscript.
Nonproprietary Name and Trademarks of Drug Ampicillin soàmm-Alpen-N, Amcill-S, Omnipen-N, Penbritin-S, Polycillin-N, Principen / .
References 1. Whisnant JK, Rogentine GN, Mann DL, et al: Human cell-surface structures related to H influenzae type b disease. Lancet 2:895-898, 1971. 2. Whisnant JK, Rogentine GN, Gralnick MA, et al: Host factors and antibody response in H influenzae type b meningitis and epiglottitis. J Infect Dis 133:448-455, 1976. 3. Feigin RD, Stechenberg BW, Chang MJ, et al: Prospective evaluation of treatment of Hemophilus influenzae meningitis. J Pediatr 88:542\x=req-\ 548, 1976. 4. Schaller JG, Omenn GS: The histocompatibility system and human disease. J Pediatr 88:913-925, 1976. 5. Lamm LU, Friedrich U, Petersen GB, et al: Assignment of the major histocompatibility complex to chromosome No. 6 in a family with pericentric inversion. Hum Hered 24:273-284, 1974. 6. Meeting report of Sixth International Histocompatibility Workshop, in Kissmeyer\x=req-\ Nielsen F (ed): Histocompatibility Testing 1975. Copenhagen, Ejnar Munksgaard Forlag, 1976, pp 5-11. 7. Ryder LP, Svejgaard A: Association Between HLA and Disease. Copenhagen, HLA and Disease Registry of Copenhagen, 1976. 8. Coulter D, Whisnant JK, Marks IM: Hemophilus influenzae b meningitis in identical twins of a triplet sibship. Pediatrics 54:502-504, 1974. 9. Tejani A, Fotino M, Khan R, et al: HLA and Hemophilus influenzae disease. Edit Inst Natl Sante Recherche Med 58:264, 1976. 10. Young LS, LaForce FM, Head JJ, et al: A simultaneous outbreak of meningococcal and influenza infections. N Engl J Med 287:5-9, 1972. 11. Dausset J, Hors J: Some contributions of the HLA complex to the genetics of human diseases. Transplant Rev 22:44-74, 1975. 12. Teraski PI, Mickey MR: HLA haplotypes of 32 diseases. Transplant Rev 22:105, 1975. 13. Michaels RH: Increase in influenzal meningitis. N Engl J Med 285:666-667, 1974.
14. Koch R, Kogut M, Asay L: Management of bacterial meningitis in children. Pediatr Clin North Am 8:1177-1197, 1961. 15. Haggerty RJ, Ziai M: Acute bacterial meningitis. Adv Pediatr 13:129-181, 1964. 16. Riley HD Jr, Bracken EC: Empyema due to H influenzae in infants and children. Am J Dis Child 110:24-28, 1965. 17. Center for Disease Control. Morbidity Mortality Weekly Rep 23:182, 1976. 18. Smith DH: The challenge of bacterial
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Prac 6:71-80, 1976. 19. Davis DJ: Influenzal meningitis. Arch Intern Med 4:323-329, 1909. 20. Herzog AJ, Cameron LA, Karlstorm AE: Influenzal meningitis in brothers. JAMA 124:502-503, 1944. 21. Cooperstock M: Influenzal meningitis in siblings. Am J Dis Child 68:269-270, 1944. 22. Carabelle RW, Mitchell DD, Salmon GW: Influenzal meningitis treated with chloromycetin. J Pediatr 37:37-41, 1950. 23. Rothman M, Nahil FJ: Prophylaxis in meningitis due to type b H influenzae. N Engl J Med 253:653, 1955. 24. Kline HA: H influenzae meningitis. Am J Dis Child 104:595-597, 1962. 25. Kloss LJ: H influenzae meningitis in siblings. Clin Pediatr 6:580-581, 1967. 26. Sinclair SE: H influenzae type b in acute laryngitis with bacteremia. JAMA 117:170-173, 1941. 27. Good PG, Fousek MD, Grossman MF, et al: A study of the familial spread of H influenzae type b. Yale J Biol Med 15:913-918, 1943. 28. Addy MG, Ellis PDM, Turk DC: Haemophilus epiglottitis: Nine recent cases in Oxford. Bri Med J 1:40-42, 1972. 29. Whisnant JK: Studies on mechanism of susceptibility to H influenzae type b disease, in Sell SH (ed): Hemophilus influenzae. Nashville, Tenn, Vanderbilt University Press, 1973, p 218. 30. Ginsburg CM: Epiglottitis, meningitis, and arthritis due to Hemophilus influenzae type b presenting almost simultaneously in siblings. J
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Pediatr 87:492-493, 1975. 31. Greenfield S, Feldman HA: Familial carriers and meningococcal meningitis. N Engl J Med 277:497-502, 1967. 32. Cragg J, Bennett EF: Meningococcal meningitis: A family study. Lancet 1:248-249, 1959. 33. Khuri-Bulos N: Meningococcal meningitis following rifampin prophylaxis. Am J Dis Child 126:689-691, 1973. 34. Marti GI, DeGrinney JT: Intra-familial infection with N meningitidis group C. Clin Pediatr 11:538-540, 1972. 35. Schiffer MS, MacLowry J, Schneerson R, et al: Clinical, bacteriological, and immunological characterization of ampicillin-resistant Haemophilus influenzae type b. Lancet 2:257-259, 1974. 36. Glode MP, Schiffer MS, Robbins JB, et al: An outbreak of Hemophilus influenzae type b meningitis in an enclosed hospital population. J Pediatr 88:36-40, 1976. 37. Melish ME, Nelson AJ, Martin TE, et al: Epidemic spread of H influenzae type b (HIB) in a day care center. Pediatr Res 10:348, 1976. 38. Turk DC: Hemophilus influenzae, Turk DC, May JR (eds). London, English Universities Press, 1971. 39. Mortimer EA Jr: Rational use of prophylactic antibiotics in children. Pediatr Clin North Am 15:261-273, 1968. 40. Stimson PM, Hodes HL: Manual of the Common Contagious Diseases, ed 5. Philadelphia, Lea & Febiger Publishers, 1956, p 428. 41. Anderson PW, Ingram DL, Harding L, et al: Antibody response of infants to the capsular polyribophosphate (PRP) of Hemophilus influenzae b (HIB), abstracted. Pediatr Res 10:383, 1976. 42. Parke JC Jr, Schlesselman J, Schneerson R, et al: Vaccine trial in Mecklenburg County, NC, with H influenzae type b (HITB) and meningococcal group C (MGC) capsular polysaccharides: Progress report, abstracted. Pediatr Res 10:402, 1976.
