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[JUNE 6, 1953ORIGINAL ARTICLES

TREATMENT OF WHOOPING-COUGH

WITH ANTIBIOTICS

A REPORT BY THE WHOOPING-COUGH SUBCOMMITTEE OF

THE ANTIBIOTICS CLINICAL TRIALS (NON-TUBERCULOUSCONDITIONS) COMMITTEE OF THE MEDICAL RESEARCH

COUNCIL*

* The members of the subcommittee were : ROBERT CRUICK-SHANK, professor of bacteriology, St. Mary’s HospitalMedical School, London (chairman) ; T. ANDERSON,reader in infectious diseases. University of Glasgow ;E. C. BENN, consultant in infectious diseases, SeacroftInfectious Diseases Hospital, Leeds ; A. BRADFORD HILL,professor of medical statistics, London School of Hygieneand Tropical Medicine ; A. B. CHRISTIE, consultant ininfectious diseases, Fazakerley Infectious DiseasesHospital, Liverpool ; A. JOE, medical superintendent,City Hospital, Edinburgh ; F. F. KANE, medical super-intendent, Northern Ireland Fever Hospital, Belfast ;D. C. LIDDLE, consultant in infectious diseases, MonsallHospital, Manchester ; W. F. TWINING McMATH,physician-superintendent, Neasden Hospital, London;A. C. BANKIN, formerly physician-superintendent, SouthMiddlesex Infectious Diseases Hospital; R. SWSTER,consultant in infectious diseases, St. Ann’s GeneralHospital, London ; and W. C. COCKBURN, director,Epidemiological Research Laboratory, Central PublicHealth Laboratory, Colindale (secretary).

DURING 1950-51 a controlled investigation of the valueof chloramphenicol and aureomycin in the treatment ofwhooping-cough was made in eight infectious-diseases

hospitals in England, Scotland, and Northern Ireland.

Plan of the InvestigationChildren 0-5 years of age admitted to the eight hos-

pitals with uncomplicated clinical pertussis within 21

days after the onset of the earliest symptoms wereincluded in the trials. On admission the patients weredivided by sex and placed in one of three age-groups-0-11 months, 12-35 months, and 36-59 months.They were then allocated to one of three treatment

groups-the chloramphenicol group, the aureomycingroup, or the control group. Children in the control

group were given a mixture of lactose and quinine.The drugs were dispensed in cachets, and, as the chloram-phenicol was white and the aureomycin yellow, half thecontrol cachets contained white powder and half yellowpowder. To make it more difficult for the observer todetect which drug was being given to an individual

patient each of the three drugs was made up under threedifferent letters. The order in which patients were

allocated to the treatments was determined by placingthe nine letters in a randomly determined sequence. Aseparate sequence was constructed for each series of9 patients in each age and sex group.All the cases were given the appropriate treatment

for the first 7 days of the observation period, but theamount of the drug differed for each age-group. Children

aged 0-11 months were given 1-0 g. daily, childrenaged 12-35 months 1-5 g. daily, and children aged

36-59 months 2 g. daily. The drugs were administeredtwice a day in equally divided doses. Administration

presented some difficulties because of the bitter taste.Each hospital devised its own methods, and the powderfrom the cachets was mixed into honey, jam, fruit puree,milk, sweetened condensed milk, or other suitable

excipient.Each child was to be observed for 20 days. Observa-

tions were first recorded on the first day of treatment.Each day notes were made of the number of paroxysmsobserved b- the day staff and the night staff, and at theend of each day the sister of the ward was asked torecord whether the paroxysms in each case had been onthe whole mild, moderate, or severe. Records weremade of the frequency of vomiting during or after

paroxysms ; but the recorded incidence was low, and inthe analysis no useful information was obtained. Theoccurrence of toxic effects of the drugs was also noted,ineluding vomiting immediately after administration.

It was expected that, though only uncomplicated caseswere to be taken into the investigation, some childrenmight develop complications during the period of treat-ment and observation. For the purpose of the inquiry,a complication was defined as any infective conditionassociated with whooping-cough which the physician incharge considered to be severe enough to require imme-diate treatment with sulphonamides or antibiotics. Insuch cases, when they occurred during the 7-day treat-ment period, the administration of the trial drugs wasstopped. The physicians treated the cases as they thoughtbest. Observations on the number and severity of theparoxysms were continued and all the complicated caseswere included in the analysis.

Description of Treatment GroupsNumbe1"s of Cases.-Altogether records were completed

for 317 patients, but the records for 23 cases were

excluded.

In 7 the appropriate drug was not available at the time ofadmission or the wrong dosage scale was used ; in 3 the

diagnosis was doubtful. 1 child had been treated with chlor-

amphenicol and 1 with aureomycin before admission. 2children developed salmonella infections and 1 developedSonne dysentery within 4 days of the start of treatment ;these patients were removed to other wards. 1 child was foundto be infected with Haemophilus parapertussis. 3 childrenwere removed from hospital by their parents early in theobservation period. 4 children (3 on aureomycin and 1 on

chloramphenicol) vomited the drug repeatedly and attemptsto continue administration had to be abandoned.

The analysis was therefore made on the records for294 cases. The distribution of cases by age and by treat-ment group is given by hospitals in table 1. 98 patientswere in the chloramphenicol group, 96 in the aureomycingroup, and 100 in the control group. The number ineach treatment group was similar for all hospitals togetherand for each hospital separately. The number of childrentreated in Neisden, St. Ann’s General, and NorthernIreland Fever Hospitals was small and these hospitalswere grouped together.

TABLE I——NUTUBBRS OF CASES TREATED, DIVIDED BY AGE. HOSPITAL, AXD TYPE OF TREAT’)1.E..’BT

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, Sex-distribution.-More females than males were

treated in the investigation. In the chloramphenicolgroup 53-1% were females, in the aureomycin group56-3%, in the control group 55.0%, and in all groupstogether 54-8%. As the proportion of females in eachgroup was similar, no separate analysis by sex was made.From inspection it did not appear that females faredbetter or worse than males.

Confirmation of Diagnosis.-All suitable cases which onclinical grounds were considered to be suffering fromwhooping-cough were taken into the investigation. Inorder to confirm the clinical diagnosis swabs were takenon admission and an attempt was made to get a history ofother cases in the family or neighbourhood. H. pertussiswas isolated from 47% of the cases-44% in the

chloramphenicol group, 49% in the aureomycingroup, and 47% in the control group. A history ofassociated cases was obtained from 60-59% in thechloramphenicol group, 65% in the aureomycin group,and 56% in the control group.

Duration of Observations.-The intention was toobserve each case for 20 days from the beginning oftreatment, but some patients were discharged beforethe full period of observation was completed. The numberslost at various stages in each group were similar (seetable 111). The records of these cases were included upto the time the patients left hospital.

Results

The results in the three groups were assessed byanalysing (a) the number of paroxysms per case per day,(b) the severity of the paroxysms, (c) the number of

complicated cases, (d) the number of deaths, and (e) thebacteriological findings at intervals during the period of

Fig. 2-intermediate cases.

observation. The cases were divided into three types,depending on the duration of symptoms before treatmentwas begun :

Early cases were defined as those with symptoms for 1-8days before treatment began. There were 85 early cases-28 on chloramphenicol, 29 on aureomycin, and 28 controls.

Intermediate cases were defined as those with symptoms for9-15 days before treatment began. In this category there were147 cases-50 on chloramphenicol, 49 on aureomycin, and 48controls.

Late cases were defined as those with symptoms for 16-21days before treatment began. 62 were placed in this category- 20 on chloramphenicol, 18 on aureomycin, and 24 controls.The date of the beginning of the illness was taken as theday on which the earliest symptoms-cough or coryza-began, and not as the day when the cough becameparoxysmal. Complete accuracy in ascertaining the dayof the onset of the first signs of illness was not alwayspossible, but cases on all three treatments were subjectto the same degree of error.A separate analysis of the records of children on

chloramphenicol and aureomycin was made. No cleardifference between the effects of the two antibiotics wasobserved ; this is illustrated in the graphs. Except forconsideration of complications and deaths, the two groupswere combined and are referred to as the " treatedgroup."

NUMBERS OF PAROXYSMS

The average number of paroxysms per case was

calculated separately for each of the 20 days of observa-tion. The results for each day are shown in the graphsand by 4-day periods in table 11. The average number ofparoxysms per case in the treated group was less than inthe control group for the early, intermediate, and latecases, and the differences were consistent throughoutthe period of observation. In the day-by-day analysis,the differences in the average number of paroxysms percase on days 6, 7, 8, and 9 (i.e., around the end of thetreatment period on day 7) were : for early cases 3-2,5.2, 5.7, and 3-7 ; for intermediate cases 1-0, 1-9, 1.4, and1.6 ; and for late cases 2-3, 1-8, 1-5, and 0-8. The onlylarge differences were those observed in the early caseswhere for example on day 8 the average difference was5-7 paroxysms. This finding was statistically significant(difference/standard error =3-2). In the intermediateand late cases the treated children had on the averageabout 2 paroxysms per day less than the controlchildren.The information on paroxysms was then analysed by

calculating for the 2nd, 8th, 14th, and 20th days ofobservation the percentages of cases with 0-9, 10-19,and 20 or more paroxysms (table ill). By this method

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TABLE II-AVERAGE NUMBERS OF PAROXYSMS PER CASE PER DAY IN 4-DAY PERIODS

also the differences between the control and treated

groups were greatest in the early cases. For instance on

day 2 the percentages of early cases with 0-9, 10-19,and 20 or more paroxysms were similar in the two

groups; but on days 8, 14, and 20 respectively 72%,80%, and 90% of the treated children had fewerthan 10 paroxysms per day compared with 40%, 58%,and 64% of the control children. These differences were

statistically significant (differences/standard errors =

2.6, 2.2, and 2-7).

SEVERITY OF PAROXYSMS

As mentioned earlier, the sister of the ward, who didnot know which drug was given to individual patients,was asked to record each day during the observationperiod whether she considered the paroxysms in eachcase had been on the whole mild, moderate, or severe.For the analysis of this information the 20-day observa-tion period was divided into the five 4-day periods. Theresults for the early, intermediate, and late cases aregiven in table iv. The greatest differences between thetreated and control groups were in the early cases. For

example the proportion of early control cases in whichthe paroxysms were described as absent or mild increasedfrom 22% in the first 4-day period to 29% in the fifth4-day period, but in the treated cases the percentagesincreased from 17 to 66. Between the first and fifth

4-day periods the proportion of control cases with severeparoxysms fell from 41 to 23% while the proportion oftreated cases fell from 27 to 4%.In the early cases the differences between treated and

control groups in the percentages of cases where the

TABLE III-PERCENTAGES OF CASES WITH 0-9, 10-19, AND 20OR MORE PAROXYSMS ON THE 2ND, 8TH, 14TH, AND 20THDAYS OF OBSERVATION

paroxysms were absent or mild were statistically signifi-cant for the third, fourth, and fifth 4-day periods(differences/standard errors = 4-4, 5-8, and 6-2). In theintermediate cases the differences in the percentages ofcases where the paroxysms were absent or mild werestatistically significant for the same three periods(differences/standard errors = 2-7, 3-1, and 3-9). It

appeared that the drugs influenced the severity of theparoxysms to a greater degree than they affected thenumbers of paroxysms in the intermediate cases.

TABLE IV-PERCENTAGES OF CASES WHERE THE PAROXYSMS

WERE DESCRIBED AS ABSENT OR MILD, MODERATE, OR SEVERE

(IN 4-DAY PERIODS)

COMPLICATED CASES AND DEATHS

19 patients developed respiratory complications duringthe observation period-7 in the control group (3bronchopneumonia, 2 bronchitis, 1 lobar pneumonia,and 1 pleural effusion with atelectasis), 7 in the aureo-mycin group (2 bronchopneumonia, 2 bronchitis, 2 lobarpneumonia, and 1 pleural effusion with atelectasis), and5 in the chloramphenicol group (3 bronchopneumoniaand 2 bronchitis). 3 cases in the control group and 2 casesin the chloramphenicol group occurred during the periodthe drug was being administered. All cases in the

aureomycin group and the remaining cases in the othergroups occurred after the end of the treatment period.In addition 3 cases, 1 in each treatment group, were fatal ;in the control group a male aged 6 wteks developedbronchopneumonia on the 5th day of observation and inspite of treatment with sulphonamides and penicillindied on the 10th day of observation ; in the aureomycingroup a male aged 7 months developed convulsions onthe 14th day of observation and died the following day ;in the chloramphenicol group a female aged 1 yeardeveloped widespread collapse of the lungs about the7th day of observation and died on the llth day ofobservation. None of the complicated or fatal casesoccurred in patients treated within 8 days of the onsetof symptoms.

BACTERIOLOGICAL RESULTS

Most cases were swabbed on or about the 1st, 2nd,3rd, 8th, and llth days of observation. In the third

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TABLE V——BACTERIOLOGICAL RESULTS

* I = 1st day of observation (day 1) or day -1 or day -2 or day -3.II = 2nd day of observation (day 2).III = 3rd day of observation (day 3) or day 4.IV = 8th day of observation (day 8) or day 7 or day 9.V = llth day of observation (day 11) or day 10 or day 12 or day 13.

and fourth intervals (see footnote to table v) the per-centage of positive cases was less in the treated thanin the control groups for early, intermediate, and latecases. The differences for cases of all types at theseintervals were statistically significant (differences/standard errors = 2.3 and 3-4). In the treated groupof early cases the percentage of cases from whichH. pertussis was isolated increased from 4.4 in intervaliv to 10-4 in interval v. As the same children were notswabbed in the two intervals this did not meari thatsome cases became swab-positive after treatment hadbeen completed. When the cards were scrutinised it wasfound that none of the children who became swab-

negative were positive when swabbed later.

TOXIC EFFECTS

Presumed toxic effects were noted in 28 cases=12 inthe chloramphenicol group, 15 in the aureomycin group,and 1 in the control group. The effects noted were :

Vomiting.-7 on chloramphenicol, 11 on aureomycin, and1 control.

Anorexia.-3 on chloramphenicol and 2 on aureomycin.DCM-OM.—2 on choramphenicol.Redness of Buttocks.-l on aureomycin.Urticarial Rash.-l on aureomycin.

Summary and Conclusions

In a strictly controlled investigation 98 children 0-5years of age were treated with chloramphenicol, 96 withaureomycin, and 100 with an inert powder (lactose andquinine). The patients were given the drugs twice dailyfor 7 days. For 20 days from the 1st day of treatmentthe number and severity of paroxysms and the occurrenceof toxic effects and complications were noted. In

addition, swabs for isolation of H. pertussis were taken onadmission and at intervals afterwards.When cases which had symptoms for 1-21 days before

the beginning of treatment were considered together, thebenefit to the treated cases, though consistent during-the period of observation, was small. If attention hadbeen directed solely to the straightforward comparisonof the whole of the treated and control groups it wouldhave been concluded that the results were disappointingand that chemotherapy failed to produce a clear-cutclinical cure. In cases which were treated within 8 daysfrom the onset of the earliest symptoms the differencesbetween the groups were greater, and some of thedifferences were statistically significant. Even with earlycases, however, the effect of the drugs was not dramatic.No difference was detected between the effect of aureo-

mycin and chloramphenicol.On the 3rd and 8th days of observation, but not on

the 1st, 2nd, and 11th days of observation the proportionof patients from whom H. pmtussis was isolated wasgreater in the control group than in the treated group.

These findings are in general agreement with those ofWehrle et al. (1951) and LaBoccetta and Dawson (1952),and it may be reasonable to speculate on the significanceof the results in relation to our scanty knowledge of thepathogenesis of the disease. In an acute infectiousdisease it might be expected that elimination of the

infecting agent would be followed by rapid disappearanceof the signs which that agent initiated. The failure toobserve such an immediate amelioration in whooping-cough might support a view that infection withH. pertussis sets in train a sequence of events which,once it has started, is not greatly affected by eliminationof the pathogen. The present study suggests that earlyrecognition and early antibiotic therapy of whooping-cough may help to reduce the severity of the infection,but that little is to be gained from antibiotic treatmentof cases in which even slight symptoms have been presentfor more than a week.

REFERENCES

LaBoccetta, A. C., Dawson, K. E. (1952) Amer. J. Dis. Child. 84,184.

Wehrle, P. F., Lepper, M. H., Bundesen H. N. (1951) J. Pediatrics,39, 435.

FAMILIAL CRETINISM

DOUGLAS HUBBLEM.D. Lond., M.R.C.P.

PHYSICIAN, DERBYSHIRE ROYAL INFIRMARY ANDDERBYSHIRE HOSPITAL FOR SICK CHILDREN

WHEN cretinism occurs in regions where goitre is notendemic it is known as sporadic cretinism. This is thecommon type of cretinism seen in this country, and it isusually accompanied by no evidence of a goitre. HiltonFagge, of Guy’s Hospital, observed in 1871 that no

vestige of a thyroid gland could be found in sporadiccretins, and he contrasted this with the " bronchocele"seen in endemic cretinism. The published reports of thehistology of the thyroid gland confirm that there is anatrophy of this gland without any evidence of colloidformation or other active gland structure. It may beassumed, as a working hypothesis, that such atrophy ofthe thyroid gland could either be due to a primary failureof the thyrotropic hormone or else to some failure in thegland, either developmental or destructive. A primaryfailure of the thyrotropic hormone has not yet beenestablished as a cause of cretinism. Where there is a

primary failure of the gland, it may be assumed thatthere is an excess of thyrotropic hormone circulating,because the secretion of this anterior-pituitary hormoneis inversely regulated by the amount of circulating thy-roxine. The gland, however, is incapable of response tothis stimulus.

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Endemic cretinism occurs in regions where goitre isendemic because of a deficiency of naturally occurringiodine. The goitrous thyroid resulting from severe iodine