A review of Haemophilus influenzae infections in Cambridge 1975–1981

Journal of Infection (I984) 9, 3o-42

A review of

3°

Haemophilus influenzae i n f e c t i o n s

in Cambridge

I975-I981

S h e e n a J. B r o u g h t o n and R. E. W a r r e n

Clinical Microbiology Laboratory, Addenbrooke' s Hospital, Cambridge Accepted for publication IO January I984 Summary Invasive Haemophilus influenzae infections diagnosed in Cambridge between January I975 and December I98I are reviewed. Altogether, 8I sites in 77 patients were infected. Of these patients, 4I had meningitis, 20 epiglottitis, 8 bone or joint infections (2 with concurrent meningitis), 4 cellulitis, 5 pneumonia (2 with concurrent epiglottitis) and 3 septicaemia in the absence of documented localised infection. Most patients (88 %) were children less than 5 years of age. Only 8 adults with such infections were identified. Of these, 6 had an identifiable predisposing condition. The incidence of meningitis was i8 cases per iooooo children less than 5 years of age. There were 3 deaths. Of the strains of H. influenzae isolated, I6% were ampicillin-resistant. The unusual age-specific incidence of epiglottitis and the incidence of deafness after meningitis are emphasised.

Introduction Culture of H. influenzae from blood, cerebro-spinal fluid (CSF), pleural, bone and joint aspirates is evidence of invasive infection. Associated invasive diseases include meningitis, epiglotitis, septic arthritis or osteomyelitis, cellulitis, p n e u m o n i a , endocarditis and septicaemia o f u n k n o w n source. T h e s e infections are f o u n d p r e d o m i n a n t l y in children u n d e r the age of 5 years. 1' 2 T h e y are usually caused by capsulated strains of H. influenzae of P i t t m a n type b. Infections in adults are often associated with conditions such as diabetes or malignancy. Worldwide, H. influenzae is probably the c o m m o n e s t cause of bacterial meningitis in children u n d e r 5 years of age. A recent report of a series from B i r m i n g h a m 3 suggests that the meningococcus is a c o m m o n e r cause in Britain, b u t this is not our local experience. I n f o r m a t i o n on the incidence of H. influenzae meningitis in defined rural populations is scarce. T h e r e is also not very m u c h data to be f o u n d on the relative frequencies of the various other diseases caused by H. influenzae in the U . K . I n this article we review our experience of invasive H. influenzae infections diagnosed in C a m b r i d g e over the last 7 years.

Materials and methods Microbiological and post-mortem records as well as case notes were searched for invasive H. influenzae infections. Cases in which the microbiological diagnosis was m a d e in other centres and the patient referred to Cambridge for n e u r o s u r g e r y or for other t r e a t m e n t o f suspected complications were excluded. G r a m - n e g a t i v e cocco-bacilli for which dependence on both X and V factors oi63-4453/84/o4oo3o+ 13 $o2.oo/o

© I984 The British Society for the Study of Infection

Haemophilus influenzae infection in Cambridge

3I

could be shown by disc test on Brain Heart Infusion Agar (Difco oo37-oi-6) were identified as H. influenzae. Strains were serotyped by slide agglutination with H. influenzae antisera first obtained from Hyland and later from Difco Laboratories. Ampicillin resistance was determined initially by testing with discs containing 2 ~tg ampicillin and additionally, since I978, by detecting the production of beta-lactamase acidimetrically by means o f ' Intralactam' strips obtained from Mast Laboratories. Susceptibility to chloramphenicol was determined by means of a Io #g disc. Since I98O the two-disc method for demonstrating enzymic destruction of chloramphenicol~ has been used also. T h e volume of blood added to paediatric blood cultures was not standarised. This volume may be critical because in haemophilus bacteraemia only a single bacterium may be present in each millilitre of blood that is sampled. 5 T h e aerobic blood culture medium used throughout the period was Difco Brain heart infusion broth with added cysteine hydrochloride (o'o5%), paraaminobenzoic acid (o.I g/l), Liquoid (0"25 g/l) and Whatman beta-lactamase (500 U/I). T h e basal medium, without supplement or addition of blood, enables the recovery of 75 % of strains o f H . influenzae after I4 days' incubation and ranked equal second in a recently published survey of 23 blood culture media. 6. In addition, thioglycollate broth (either Difco Thiol or Oxoid U S P thioglycollate) was inoculated with blood.

Results Altogether 8x foci of invasive haemophilus infection were found among 77 patients (see Table I). By comparison, only 15 cases of meningococcal infection in the same period were identified. Of all patients 62 ~o were male. A similar sex incidence was found for meningitis, epiglottitis, and infections in other sites. Ampicillin resistance was noted in the strains from 9 of 4I patients with meningitis but in that of only I in 2o patients with epiglottitis and 2 in 20 of those with infections in other sites.

Meningitis

Patients Forty-one patients with meningitis were identified. Of these, two were adults. Addenbrooke's Hospital, Cambridge, has a catchment area larger than its former Health District, but was the only hospital admitting patients with meningitis from this area over the period of this study. When cases referred from other health districts are excluded, the incidence of meningitis over the period of the study was I8 cases per iooooo children less than 5 years of age per year. It is essential to use age-specific incidence figures as the denominator for comparing incidence in our area with that of another because of the restricted age-range over which infection with H. influenzae occurs and the variation in the age structure of various populations. All except one of the 39 children with meningitis were between the ages of 4 months and 4 years (Fig. I). T h e exception was an 8-year-old girl, with a history of previous pneumococcal meningitis, who was subsequently shown

32

S. J. B R O U G H T O N A N D R. E. W A R R E N

Table I

Sites of infection and antibiotic resistance No.

No. (percentage males)

Deaths

ampiciUinresistant

41 (61) 20 (65) 20 (61) 5 8

2 i o o o

9 I 2 i o

Meningitis Epiglottifis Miscellaneous Pneumonia Bone/joint Cellulitis

4

o

o

Septicaemia

3

o

o

81

3

13

Total

Table II

Early antibiotic regimens for meningitis

Antibiotic Benzylpenicillin Chloramphenicol Sulphonamide Benzylpenicillin Ampicillin Chloramphenicol Sulphonamide Intrathecal streptomycin Benzylpenicillin Chloramphenicol Sulphonamide Intrathecal penicillin and streptomycin Benzylpenicillin Chloramphenicol Sulphonamide Intrathecal penicillin and streptomycin Benzylpenicillin Chloramphenicol Sulphonamide Benzylpenicillin, Chloroamphenicol, Sulphonamide

Duration of treatment (in days)

8}

No. of patients

Complications

8 3

14 14 2

I IO IO

14 14 14

2

8

Deafness

2

i2h

Death

Haemophilus influenzae infection in Cambridge

33

to have a CSF leak into her middle ear that required a dural repair. Only one child was i m m u n o d e f i c i e n t - an 8-month-old boy with meningitis who was later found to have an undefined immunodeficiency associated with recurrent Pseudomonas septicaemia and pneumococcal osteomyelitis. His brother also had haemophilus septic arthritis with a strain of different ampicillin susceptibility and subsequently died of pseudomonas septicaemia and synergistic bacterial gangrene after appendicectomy. One adult patient, a 34-year-old man, previously fit and well, was not investigated for predisposing factors. Haemophilus influenzae was isolated from the CSF in all cases, and Gramnegative bacilli were seen in the stained deposit of the CSF in all but two patients, both of whom had received oral ampicillin before admission. Blood from 38 patients was cultured and H. influenzae was recovered from 36. Neither of the two patients with negative cultures had received antibiotics before admission. All strains were Pittman type b, except for a single non-typable isolate from the CSF and sinus washout-fluid of the second adult of the series, He was another 34-year-old man with frontal sinusitis and meningitis, who had fractured his skull in a road traffic accident 7 years previously.

Treatment No uniform regimen of antimicrobial therapy was used for treating meningitis. In the earlier years of the survey chloramphenicol together with penicillin and a sulphonamide, occasionally with intrathecal streptomycin, were given (Table II). More recently either ampicillin or penicillin was usually combined with chloramphenicol for the first 48 hours, chloramphenicol alone then being continued for I o - I 4 days (Table III).

Complications Two patients died. T h e first, the only one with neonatal H. influenzae meningitis, was a full-term male infant (fifth child in the family) who was well immediately after an uncomplicated vaginal delivery. When 13 days old he was admitted to hospital with a history of recurring fits and apnoeic attacks. Haemophilus influenzae type b was cultured from his C S F , but despite antimicrobial therapy and supportive care he died 24 days later with an intraventricular haemorrhage. A high vaginal swab for culture was not obtained from his mother who was well before and during delivery. T h e second death was of a 5-year-old boy who had been ill with 'a respiratory tract infection' for z weeks. He died from respiratory arrest, due to meningitis, only ~z hours after admission. Two children with meningitis had septic arthritis that involved the elbow and hip respectively. None was seen with epiglottitis and meningitis together. We did not prospectively study the surviving children for evidence of mild permanent sequelae, but review of case notes did not disclose any child with major neurological deficit on discharge. One child had a slight squint and two others w e r e ' irritable' but all three were in good health during surveillance over the following year. Children were generally reviewed i-2 months after discharge. Four were noted to have some degree of hearing loss at that time. Two other children were only later shown to have impaired hearing when they failed an audiographic test at school some years later. 2

JIN 9

S. J. BROUGHTON AND R. E. WARREN

34

T a b l e I I I Later antibiotic regimens for meningitis Duration of therapy (in days)

Antibiotic

No. of patients

Complications

Ampicillin

Chloramphenicol

2 } 10-14

12

Deafness in 2

Ampicillin Chloramphenicol

I0 / 5J

I

Deafness

Benzylpenicillin Chloramphenicol Benzylpenicillin Chloramphenicol Chloramphenicol Benzylpenicillin Ampicillin Chloramphenicol Benzylpenicillin Ampicillin Chloramphenicol Benzylpenicillin Ampicillin Gentamicin Chloramphenicol

IO-I4 IO Io } 10-14 a} 2 i0 2) io 2 2} 2I 2 21

13

Deafness in 2

I

o

3

o

I

0

I

o

I

Death

2

}

Epiglottitis

H. influenzae type b was shown to be the cause of epiglottitis in 20 patients b y isolation of the organism from blood cultures. O f 20 patients, I9 were children, mostly r-4-year-olds. Only one was a child less than r year of age (Fig. r). In five other children blood cultures were not done, the diagnosis being based on the clinical picture and the characteristic appearance of the epiglottis at laryngoscopy. As these cases do not satisfy our criteria for proven invasive disease they are not included in the total figures for invasive disease in T a b l e I. D u r i n g the period of the s t u d y all Suspected cases of epiglottitis arising in this area were referred b y general practitioners directly to the E N T unit. Clinically-confirmed cases were managed b y elective tracheostomy and intravenous antibiotics. T w o children required immediate emergency tracheostomy for respiratory arrest on admission. N o child died during the period of the survey. T h e only death was that of a previously fit 42-year-old man. H e had been referred directly to the E N T unit with a short history of increasing airway obstruction b u t died three minutes before reaching the unit. Haemophilus influenzae type b was recovered p o s t - m o r t e m from b o t h his heart blood and an aspirate of his swollen epiglottis. Chloramphenicol only replaced ampicillin as the antibiotic for empirical treatment in I98O. T w o children had a concomitant lobar pneumonia.

Haemophilus influenzae infection in Cambridge

35

Pneumonia

Haemophilus influenzae type b was accepted as a cause of pneumonia only if the organism was isolated from blood or pleural fluid. T h e incidence of pneumonia in our study is therefore likely to be unduly low. Trans-tracheal aspiration is not used in our paediatric practice and strains of H. influenzae otherwise isolated from the respiratory tract are not routinely typed. Two of the five patients were children, both under 5 years old, with lobar pneumonia associated with epiglottitis. Two patients were adults who were clearly immunocompromised. One was a 6I-year-old man with hairy-cell leukaemia and whose spleen had been previously removed; the other, a 69-year-old man with chronic myeloid leukaemia, had H. influenzae bacteraemia associated with clinical and radiological evidence of pneumonia. In one case the strain isolated was of Pittman type b; in the other case the strain isolated could not be serotyped. T h e fifth patient was a 76-year-old woman who had had a mastectomy for carcinoma of the breast two years previously and who presented with cough and dyspnoea. A chest X-ray showed a large empyema. Haemophilus influenzae type b was recovered from both a blood culture and a purulent pleural aspirate. All the patients with pneumonia recovered on treatment. Septic arthritis and osteomyelitis All the strains involved in septic arthritis or osteomyelitis were of capsular type b. Six patients had septic arthritis involving a single large joint. In two children less than 5 years of age with meningitis, a single joint (elbow and hip respectively) was involved. O f two other children, a 3-year-old boy with septic arthritis of his left hip was later shown to be immunodeficient; the other child, a I-year-old boy, had septic arthritis of the knee. T h e two remaining patients with septic arthritis were adults, both of whom had infection in the knee. One was a 7o-year-old man with myeloma, the other a 59-year-old woman with rheumatoid arthritis. Two boys of I I months and 13 months respectively had osteomyelitis of the distal end of the humerus. All these patients recovered without residual disability. Cellulitis One cannot be sure that H. influenzae is the causative organism in periorbital ceUulitis when it is isolated only from the upper respiratory tract or conjunctiva, especially when the organism is part of mixed flora. We therefore restrict our report to patients with proven bacteraemia. All were children aged less than 5 years. T h r e e of the children had a unilateral periorbital cellulitis in association with H. influenzae type b bacteraemia. None of them had associated otitis media. T h e y were all treated initially with empirical intravenous flucloxacillin and ampicillin or penicillin. A fourth child presented with an abscess of her right thigh (not involving the hip joint) together with an area of cellulitis on her cheek. Haemophilus

36

S. J. B R O U G H T O N

16 , - -

A N D R. E. W A R R E N

]

Patientswithoutepiglottitis

]

Meningitis

•

Epig/otlitis

14" 12. ~ 10" ,L'

z

4 :;!!::

.. 2 ...<

0-I

1-?

2-3

3-4

4-5

5-6

6-7

7-8

> 16

Years

Fig. z. Age incidence of invasive Haemophilus influenzae infection.

influenzae type b was grown from her blood b u t material aspirated from the abscess of the thigh was 'sterile' on culture. It was not, however, cultured on heated blood agar.

Septicaemia T h r e e patients had septicaemia in the absence of any recorded localised infection. T w o children, b o t h boys with acute lymphocytic leukaemia, one aged 6 years and the other 4 years, had septicaemia with n o n - t y p a b l e strains of H. influenzae. O n e of t h e m had s y m p t o m s suggestive of frontal sinusitis, b u t nose swabs were not taken; the other had clinical signs of resolving chest infection at the time of his septicaemia. T h e third patient was a full-term male infant who developed a severe respiratory distress-like s y n d r o m e only 2 hours after an uncomplicated vaginal delivery. Haernophilus influenzae type b was isolated from his blood, nose, throat and eye swabs b u t not from C S F . T h e child i m p r o v e d with supportive antibiotic therapy and was discharged after 5 weeks w i t h o u t any obvious sequelae. Unfortunately, a high vaginal swab was n o t obtained from his mother, w h o was clinically well and apyrexial at the time of delivery. N e i t h e r overwhelming septicaemia associated with splenectomy, W a t e r h o u s e - F r i d e r i c h s e n s y n d r o m e nor endocarditis were seen.

Discussion T h e s p e c t r u m of disease caused b y invasive H. influenzae infection in this series (see T a b l e I) is similar to that previously described. 1, ~ Eighty-eight per cent of infections were in children less than 5 years of age and were with capsulated type b strains. T h e yearly incidence of invasive H. influenzae infection rose during the period of the study, reflecting a similar national u p w a r d trend from I975 to I98I. 7 T h e incidence of meningitis among children less than 5 years of age was 18 cases per i o o o o o children per year. This figure is higher than that of i x per IOOOOO children aged less than 5 years per year previously reported in I976. 8 This last figure was related to an u r b a n population in N o r t h - W e s t L o n d o n . Rates of 35-45 per i o o o o o have been reported from the U . S . A . , where

Haemophilus influenzae infection in Cambridge

37

H. influenzae is the commonest cause, overall, of meningitis. 9,10 An exceptional incidence of 409 per Iooooo has been reported in Alaskan Eskimos. 11 T h e mortality rate of 4"8 % for meningitis broadly agrees with previously published figures. 3, a, 12, 13, 14,15 Despite the fall in mortality with the advent of antimicrobial therapy some series report a high rate of permanent sequelae such as neurological deficits including intellectual impairment and psychological problems among survivors. In two studies made over the periods ~95o-i95416 and I968-I97513 high morbidity rates of 57% and 29% respectively were reported. Loss of hearing accounted for 9/26, and I5/22, survivors with residual deficits, respectively. For both studies combined the incidence of hearing deficit in survivors was 18 %. Unlike these other studies, we did not set out prospectively to assess survivors for permanent sequelae, but a review of cases notes detected six (I5 %) patients with varying degrees of hearing loss after meningitis. In one of the other series, hearing loss was severe in 15 % of survivors and it was noted that this complication was more frequent (4 of I I) in patients receiving both ampicillin and chloramphenicol compared with those who had either drug alone (6 of 52). Gamstorp and Klockhoff (I974) 17 also reported a higher incidence of deafness in patients treated with combined therapy. In one recent series 12 deafness was not noted as a complication although two deaths and four patients with severe sequelae were seen among 25 patients treated. In our series deafness was not commoner in patients treated according to any particular regimen. Furthermore, serious sequelae other than deafness were rare among our patients. Laboratory confirmation of the diagnosis of H. influenzae meningitis in our area appears to have been unusually frequent. Blood cultures were negative when CSF cultures were positive in only 2 of 38 patients compared with I3 of 33 patients in another U.K. series. 3 Moreover, organisms were seen in the Gram-stained film of CSF in 39 of 4I of our patients compared with 42 of 5I in the same U.K. series and 3oo of 386 in a U.S. series. 15 This may reflect more bacteria in the blood and CSF in our series but the relatively low incidence of sequelae does not suggest later diagnosis as an explanation. Differences in the volume of blood taken for culture or the examination of all purulent CSF samples by both technical and medical laboratory staff)be important. T h e differences could also be due, however, to different presc'n~-'~ng of antibiotics in general practice. It has been clearly established that in haemophilus meningitis there is a significant association between prior administration of any antibiotic and negative blood cultures, although microscopical detection of organisms in the CSF is reduced only if the patient has previously been given ampicillin or chloramphenicol as distinct from penicillin. Studies from the U. S.A. 18have shown that meningitis is approximately three times as common there as epiglottitis. In the U.K., figures reported to the Communicable Disease Surveillance Centre during I975-I979 give an approximate ratio of meningitis to epiglottitis of 6: I. This should be interpreted with caution, however, because in I4 % of all cases of bacteraemia reported the source o f H . influenzae was not specified. 7 In our series, the ratio was 2: I, and, since the number of cases of epiglottitis is probably an underestimate because five clinically diagnosed cases without bacteriological confirmation were ex-

38

S. J. B R O U G H T O N

A N D R. E. W A R R E N

cluded, this suggests that epiglottitis is a much commoner manifestation of invasive H. influenzae infection than is generally recognised. Our attack rate of 9 cases per IOOOOO children less than 5 years of age per year is similar to that reported from the U.S.A. It was noted in a recent review of epiglottitis that, in several large U.S.A. series, blood from patients with epiglottitis was not cultured. As there is no other laboratory index for identifying such patients for informal reporting to the U.K. National Communicable Disease Surveillance Centre, it is not surprising that previous figures underestimated the prevalence of this condition. In view of the changing pattern ofantimicrobial susceptibilities of H. influenzae, blood for culture should always be taken from patients with acute epiglottitis. In Cambridge, all patients with suspected epiglottitis are referred directly to the E N T unit by general practitioners so that possible delays in the casualty department are avoided. Elective tracheostomy is then usually possible and indeed only two patients in our series required emergency tracheostomy. It is well recognised that expectant medical management carries a higher mortality rate than electively establishing an alternative airway. 19 T h e absence of mortality with prompt referral of suspected cases by general practitioners and the immediate availability of staff trained to perform tracheostomy safely (and if necessary, at speed) in children, undoubtedly played the major part of the recovery of all children with epiglottitis seen here in the last 7 years. Such availability of staff able skilfully to perform nasotracheal intubation might be similarly effective. Children with epiglottitis are generally older than those with meningitis; our results concur with this. x, 2.19 T h e lack of patients less than I year of age in our study, however, is particularly striking (Fig. I). This difference in agespecific attack rate for meningitis and epiglottitis, which has been mentioned in a review of other series, 19 has not been explained. It is noteworthy that in an Alaskan series 1~ in which there was a very high prevalence of invasive haemophilus infection, epiglottitis was not recorded but 72 of 73 cases of haemophilus meningitis were among children less than I8 months of age. It may be that epiglottitis is much commoner in populations where invasive haemophilus strains are more likely to be encountered later in childhood, but the mechanism involved in this different localisation of infection is unknown. T h e possible roles of bactericidal antibodies, which are absent in patients with epiglottitis, and genetically determined susceptibility to differing localisations of infection, require further investigation although associations with M N blood group, with human lymphocyte antigen and with immunoglobulin allotypes have been reported in respect of the immune response to H. influenzae) °, 21 Whether populations differ in their susceptibility to epiglottitis and meningitis remains to be resolved. Extra-epiglottic complications are unusual. Although Molteni reported pneumonia in 25 % of cases, our figure was only Io %. As regards the rarer manifestations of invasive H. influenzae infection, our British experience correlates well with U.S.A. experience. In patients with cellulitis caused by H. influenzae, Daiani et al. (I979) ~s noted that the head, face, and neck were involved in 74 % of patients and that 87 % were less than 2 years of age. T h e y reported that 6 % of invasive haemophilus infections were

H a e m o p h i l u s influenzae infection in Cambridge

39

associated with cellulitis, a figure comparable to our 5 %. Bone and joint infections in our series were rather atypical in that haemophilus arthritis was seen among adults and also because in 2 of 8 patients it was associated with osteomyelitis. It is interesting to note that b o t h patients with osteomyelitis in our series and a s u b s e q u e n t patient we have seen had involvement of the h u m e r u s , an unusual site for staphyloccal and streptococcal infection b u t the c o m m o n e s t reported site for haemophilus bone infection. TM 24 Haemophilus influenzae m a y cause a pattern of invasive infection in adults similar to that in childrenfl 5, 26 albeit rarely. M o s t of such patients have a possible predisposing condition. O f the eight invasive infections in adults identified, all b u t two were caused b y capsulated type b strains and six of the patients had an underlying condition that m a y have predisposed t h e m to infection. T h e seventh patient died before the diagnosis was established and the eighth was not investigated for immunodeficiency. T o define the features that predispose adults w i t h o u t head injury to develop H. influenzae disease w o u l d be interesting. In our experience the infection is surprisingly rare in patients with myeloma. O n e was of fatal meningitis in a 13-day-old infant, the other of septicaemia in a 2 - h o u r - o l d infant w h o recovered. W e have also seen bacteraemia with H. paraphrophilus in a male infant of 36 weeks gestational age w h o developed severe respiratory distress-like s y n d r o m e and died within 2 4 hours of birth. T h e same organism was cultured from his m o t h e r ' s vagina shortly after delivery. U n f o r t u n a t e l y swabs were not taken from the mothers of the first two neonates nor was their blood examined for antibody. In all cases of neonatal infection reported b y K h u n i - B u l o s and M a c k i n t o s h in I974fl 7 Haemophilus influenzae was recovered from either the m o t h e r ' s genital tract, amniotic fluid or the placenta, thus supporting the idea that infection is transmitted to the child at or immediately before delivery. It is n o t clear, however, if m o t h e r s of such infants lack protective antibody. Recently it has been shown that a distinct non-capsulated b i o t y p e of H. influenzae is more c o m m o n l y implicated in neonatal infection, is seldom associated with meningitis, and produces a clinical s y n d r o m e similar to that p r o d u c e d b y stretococci of Lancefield G r o u p B. 28 Such infections are unusual and carry a poor prognosis. W i t h the single exception of the brothers with immunodeficiency and strains of different antibiotic susceptibility, history of contact with other cases in the recent past was not n o t e d during our review of the case notes of patients with invasive disease. Secondary cases of haemophilus disease among household contacts and those in day-care centres has led some workers to r e c o m m e n d chemoprophylaxis.29, 30 Although administration of rifampicin m a y eliminate nasopharyngeal carriage 31 it is not clear w h e t h e r this practice prevents secondary cases of disease, and we, like others, 15 do not r e c o m m e n d it at present. As regards chemotherapy, the ampicillin resistance rate of i6 % among t y p e b strains agrees with the most recent U . K . national figures of I 4 % . 32 Chloramphenicol-resistant isolates were not identified among the invasive strains in this study although such resistant strains have been reported from the U . K . 33 and elsewhere. 3~' ~ T h e y are also reported n o w at a frequency of 1% from non-capsulated strains especially from the eye. 32 T h e spread of multiply-resistant capsulated strains should be anticipated. Continuing

40

s . j . B R O U G H T O N AND R. E. W A R R E N

assessment of new antibiotics that m a y be alternative first-line agents for treating invasive disease is therefore indicated. Cefuroxime has p r o v e d effective in childhood meningitis. 3s Consideration should be given also to newer third generation cephalosporins of greater potency against haemophilus, e.g. cefotaxime, in the initial t r e a t m e n t of meningitis. T h e use of these agents in epiglottitis has not been widely suggested but m a y need to be considered in the future. Until recently, vaccination appeared to offer the best hope of controlling better to polyribitol phosphate carbohydrate vaccines without B. permssis as adjuvant. Such vaccines m a y or m a y not prevent epiglottitis which, as we have confirmed, is largely confined to children in this older age-group. Carbohydrate vaccines with B. pertussis p r o d u c e protective amounts of antibody in y o u n g e r children and appear to have potential for preventing haemophilus meningitis. Recently, a significantly impaired I g G antibody response to such vaccines in siblings of children with a past history of haemophilus meningitis, including especially those who were born after the episode of meningitis, has been described. 3v This, together with the lack in antibody production after epiglottitis, 2° suggests that invasive infection is often superimposed on a background o f subtle, genetically-determined, immunodeficiency. Vaccines, therefore, m i g h t not directly protect the subpopulation who actually suffer from invasive haemophilus infection. F u r t h e r studies of the efficacy o f vaccines and the epidemiology of h a e m o philus acquisition are needed, especially of families in which there has been a case of epiglottitis. T h e specificity of a poor i m m u n e response to haemophilus antigens also requires analysis in such families with meningitis and epiglottitis. T h i s is in order to see if specificity for carbohydrate or protein antigens relates either to the age distribution or the site of invasive infection. W i t h o u t this background information it will be difficult logically to design i m m u n o p r o p h y laxis against invasive haemophilus infection. T h e cost-effectiveness of a p r o g r a m m e of vaccination for invasive h a e m o philus infection m a y be unreasonably high despite the apparently rising incidence of dramatically invasive infections. Although there is a high rate of deafness among children who have had haemophilus meningitis, epiglottitis appears to cause little mortality and morbidity if diagnosed and treated p r o m p t l y with tracheostomy and appropriate antibiotics. Prevention of otitis media caused by non-capsulated H. influenzae might be a m o r e significant, albeit less dramatic, achievement for the n e w vaccines. (We are most grateful to all our paediatric and surgical colleagues for permission to report on patients under their care and especially to Dr N. D. Barnes for helpful discussion and advice.) References

I Turk DC, May JR. Haemophilus influenzae, Its clinical importance. London: English Universities Press, I967. Turk DC. Haemophilus influenzae. PHLS Monograph Series. no. I7. London: H.M.S.O., I982.

3 Davy PG, Cruickshank JK, McManus IC, Mahood B, Snow MH, Geddes AM. Bacterial meningitis - ten years experience. J Hyg (Camb) I982; 88: 383--4OI.

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