105

T H E VACCINE TREATMENT OF PNEUMONIA IN CHILDHOOD. ~

B y JOHN M0WBRAu

T H E R E are severa l reasons , a p a r t f r o m the more obvious ones, w h y I should no t b r i n g f o r w a r d a communica t i on on the vacc ine t r e a t m e n t of p n e u m o n i a in chi ldhood, t he mos t

i m p o r t a n t be ing t h a t I have no t as y e t dea l t w i th sufficient cases .on which to base conv inc ing conclusions, n o r have I h a d suff icient controls . Th is p a p e r is, a d m i t t e d l y , be ing p r o d u c e d pre - m a t u r e l y , a n d i t is on ly a r a sh p r o m i s e w r u n g f rom me a t o u r Oc tobe r Mee t ing b y ou r Cmsarean S e c r e t a r y t h a t has p lucked i t so u n t i m e l y . I have no m e s s a g e f o r t he P ~ d i a t r i c Clnb, n o r f o r t h e wor ld . I s i m p l y w a n t y o u to be s y m p a t h e t i c wi tnesses of m y t r ava i l .

I have become accus tomed to see ing a ease of tubercu lous m e n i n g i t i s come in to one of m y beds, the re to be d i agnosed ~ such a n d to die. I n m y s t u d e n t d a y s I h a d deve loped a stoic ca lm when one of m y t eachers f in ished h is c l in ica l l e c tu re on a ne rvous sys tem case on the d i agnos t i c note, b u t I c anno t ge t accus tomed to seeing d e a t h ensue i n a case of p n e u m o n i a w i t h o u t t he u n c o m f o r t a b l e feel- i n g t h a t i t m i g h t have been saved. The re was no specific d r u g to employ . I n t r a v e n o u s m e r c u r o c h r o m e , de sp i t e t he d i f f icu l ty of i t s a d m i n i s t r a t i o n a n d i t s r i sks of f a t a l n e p h r i t i s a n d i n t e s t i na l ulcera.- t ion, was m y s t a n d - b y f o r a t ime, b u t when i t was b o r n e in on me t h a t a c o n c e n t r a t i o n capab le of. k i l l i n g the m i c l v - o r g a n i s m s m u s t a t t he same t i m e i n j u r e t he leucocytes a n d the re t i cu lo -endo the! ia l sy s t em on which the p a t i e n t was d e p e n d i n g fo r p ro tec t ion , a n d t h a t a n y w a y the m a x i m u m c o n c e n t r a t i o n a n d a m o u n t I w o u l d r i sk w o u l d g ive m e a concen t r a t i on in t he blood of on ly about I g r amme in 75,000 c.es., whe reas fo r e x t e r n a l use as a n an t i s ep t i c we a r e n o t con t en t w i th less t h a n a 2 p e r cent. solut ion, I r e a l l y could no t go on. T h a t was the pos i t i on when e a r l y l a s t y e a r in a more t h a n u s u a l l y consc ien t ious review of t he f i rs t vo lume of Trea~en t in Genera~ Practice ( r e p r i n t e d f r o m the British Medica~ Journa,l) I came across the fo l lowing in an a r t i c l e on p n e u m o n i a b y W y n n of B i r m i n g h a m .

" During the preconsolidation stage when the circulation through the tu~.g is not yet impeded and toxeemla is slight, m~ch can be done to control the infection by the t imely use of a vaccine or serum. We should think in te~ms of immunity; a pa t ien t recovers from pneumonia by pro- duei~g sufficient immune bodies.

'~ ~[t is not possible to find out beforehand those who will succeed in this, and 20 per cent. to 30 per cent. fail utterly. By early specific t rea tment a reduction of the mortal i ty to 5 per cent. is within the bounds of possibdlity.

~" When the pat ient is seen within the first three days a vaccine or serum should be given. A vaccine has the great advantage of being immediately available. I~ must be an active one of known antigenic power, made as far as possible from youn.g pr imary cultures. The one I use contains equal numbers of pneumococcl, streptioeocci and B. influenzm (P.S.I . vaccine). Whilst i t is desirable tha t ~it should consist of the various Strains, i t is more important tha t i t should be made from virulent cultures. For an adul t the dose is 200. millions of each organism, tha t is,

Communication t a the Ir ish Peediatrie Club,

106 I R I S H J O U R N A L OF M E D I C A L S C I E N C E

600 millions in all. Larger doses can be given at this stage, as the patient is not yet sensitised. Children should have proportionately smaller doses, but even at 12 months 20 millions of each should be given. The object is to stimulate the production of non-specific antibodies in adequate amount. The specific effect is not seen for some days. If the tempera- ture does not fall after the first injection, this can be repeated every 24 hours until three doses have been administered. When such doses are injected on the first day of the illness, in the majority of eases the temperature falls rapidly during the next 24 hours, with a corresponding improvement in the general condition. With each day's delay such rapid defervescence is less easily obtained. When cases are not treated until after the third day the circulation through the affected part is inter- rupted and toxins are fixed in vital tissues; little, then, can be expected of specific treatment, whose aim is to prevent, not cure, toxic symptoms."

Now all this sounded f a r too good to be , rue, besides which it cut across all my preconceived ideas of vaccine t he rapy in acute con- ditions. No oppor tun i ty had been lost in my student days to din into me the danger of tha t dreadful negative phase, and the thought of giving six hundred million l iving organisms with the initials P.S. and I jus t gave me cold shudders.

H a d I been conscientious and read W y n n ' s article when it was first published in the B.M.J. ~in 1934, I daresay I should not have given it another thought, but immediate ly a f t e r I actual ly ,read it I came across a r ep r in t of a lecture which he delivered to the Norfolk Branch of the B.M.A. in which he successfully overcame m y objections. I n this he pointed out tha t the phase of lowered immuni ty consequent on giving a vaccine occurs only in pat ients who are sensitised, whose cells are allergic. This stage of sensitiza- t ion depends on the presence of specific antibodies, and i f these antibodies are absent there is no sensitisation and no reaction will cccur with any reasonable amount of vaccine. This is clearly seen in a case of tuberculosis; 1 c.c. of tubercul in can safely be injected into a non-tuberculous and, therefore, unsensitised infant , whereas .0000001 c.c. m a y produce a reaction in an infected and therefore sensitised person. F r o m the point of view of the t rea tment of acute infect ion it was unfo r tuna te tha t the first experiences were wi th pat ients suffering f rom chronic infections, who were therefore sensitised and who easily reacted. I t was assumed tha t the varia- t ions in th~ opsonic index found a f t e r the injection of a vaccine in chronic cases were. likewise obtained in acute infections; bu t the chronic cases, unlike the acute, possessed specific antibodies, and so the init ial doses of vaccin~ _had to be small in such conditions as chronic bronchitis, arthrit is , pyelitis, etc. I n acute infections the specific antibodies are slowly produced and are present only af ter a certain in terval has elapsed. Up to this point th~ pa t ien t ds unsensitised and m a y safely be given an adequate dose of vaccine.

I n pneumonia the curve of intoxication rises rap id ly and then remains at a high level. Specific antibodies begin to appea r only about the four th or fifth day. Thei r curve rises slowly a t first, then rapidly, and reaches the curve of tox~emia about the seventh day, when in favourable cases a crisis will occur or ]ysis will commence. Our problem in t r ea tment is to accelerate the format ion and rise of this ant ibody curve so tha t i t will rise pari pa's'su, with the toxmmic curve. These antibodies, however, are s t r ic t ly specific and injection

PNEUMONIA IN CHILDHOOD 107

of vaccine a few hours after the onset of pneumonia will still pro- duce a rise of specific antibodies only some days later, so that if we had to rely on specific antibodies it would be impossible to obtain a rapid effect in control]ing the disease. Fortunately a vaccine also has an immediate effect in producing non-specific antibodies, a rapid out-pouring of bactericidal substances, the first line of defence in the early treatment of acute infections, engaging the enemy until the specific antibodies arrive and deal with the toxins before they are fixed in any dangerous quantity in nerve and heart cells.

Now, all that was calculated to dispose of my objections to giving large amounts of vaccine in an acute condition like pneumonia, but I was still curious as to the vaccine itself. It transpired that this was a plain straightforward emulsion of germs, sterilised bY heat and as far as possible prepared from young primary cultures. Above all, the vaccine must be active. I t appears that when organisms are sub-cultured colonies separate out into rough and smooth varieties, of which only the smooth are pathogenic and have antigenic power. The more one sub-cultures them, the more numerous become the roughs and the more inert the culture. I gathered that I could count on my vaccine. The way seemed clear, but there arose before me on~ or two obstacles yet. I f this form of treatment were to be safe the patient must be given it before sensitisation has taken place. I had just been .won over to the allergic theory of the pneumonias as expressed by Lauche, particu- larly in the lobar variety, viz., that either as a result of measles or whooping cough, or a mild upper respiratory catarrh, a special sensitisation of the body takes place, which in the course of a few days permits the invading bacteria to colonise in the lungs. Why lobar pneumonia should develop in one case, and lobular in another could not be explained, but probably the age (up to 3 years in lobular, and from 3 years on in lobar) had something to say in deciding the reaction. Now, if that theory were correct, and it is widely held by the German school, the patient was sensitised before he developed pneumonia at all, and it would be manifestly impos- sible to get him in time. Wynn definitely stated that the tempera- ture fell and the patient's condition improved after the administra- tion of the vaccine, and the only thing to do was to give the theory a back seat at the performance of practice.

The next difficulty to be overcome was to get hold of the patient before the fourth day of the disease.

Now, the mothers who bring their offspring to Temple Street can be divided into two main groups.

There is first the group who dramatically carry large well- nourished Bolsheviks into my dispensary on a Monday morning gasping out " I don't know what's the matter with him," the gasp being due in equal parts to the innate Irish sense of stagecraft, and the exertion caused by the strain of carrying a heavy weight. I t usually transpires that nobody can really be sure of the diagnosis except the Bolshie himself who has developed Monday morning megrims to avoid compulsory Irish. I~ this group is also included

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the night-hawk mother, who can detect ,the symptoms of meningitis or pneumonia, or what have you? always in the small hours. The house surgeon who receives her, being young, is obviously no match for that type, who usually wins the night with the old iormula : " Well, if the child dies, I ' l l know what to do." " Bury it,'-' seems too simple and callous an answer, and another bed is filled with a f~ecal fraud. These cases do not require a vaccine. The other group carry in moribund marasmic mites whose only function during their few hours' stay in the ward seems to be to ruin hospital .reports. I may say, in passing, that I do not allow them to ruin mine. They are ruthlessly eliminated from the series with which I will deal in this paper, but, please be assured that that applies only to obviously dying infants who survive a very few hours. I submit they should be admitted to a special ward for the dying and should not appear in hospital reports at all, except perhaps in a special section headed " moribund." Cases of loba~ or lobular pneumonia are seldom brought to hospital on the first or second .day of illness, yet it was from these that I had most to hope for this treatment. I have also included those cases who came on the 3rd, 4th and 5th days of illness (as far as these particulars can be relied on from the history of distraught and untrained mothers). I t will be argued that the onset of broncho- pneumonia in particular is a very indefinite thing, sometimes appearing after a few days of symptoms of gradually increasing severity or suddenly after a period of mild negligible ea,tarrh. That is all admitted and possibly the hospital accusation of " why did you not bring the child sooner and give the doctors a chance?" is not always merited, but it is good sound prophylactic practice to make the accusation all the same.

The biggest fallacy that could creep into and completely stultify this paper and the findings contained in it would be in the question of d~agnosis. The fig.ures are only of importance in so far as they apply to authentic cases of lobar or bronchopneumonia as the case may be, hence I will deal with this matter of diagnosis in some detail. I simply do not believe in the abortive one-day pneumonia. I have also been in a. stronger and more comfortable position than the man in private practice, who, faced with a case which may be a severe bronchitis yet whose symptoms preclude the exclusion of bronchopneumonia either presently or in the immediate future, plunges for the more serious diagnosis, preferring rather to make a dramatic and laudable " cure " t h a n to risk the odium, either secret or expressed, if his case ofJ " bronchit is" either runs a long and dangerous course or dies. His change over to a, diagnosis of bronchopneumonia from the original one of bronchitis would inevitably raise the suspicion i,n the parents' minds: " Why did the doctor not prevent it? I t was only bronchitis when he was called in:" I was able to make a tentative diagnosis which I could either verify or throw out of court as the case progressed, and only those cases which could honestly be lubelled pneumonia are given in the series.

PNEUMONIA IN CHILDHOOD 109

We are all fully alive to the difficulty of making this diagnosis. Let us first consider lobular pneumonia. The differential diagnosis here is from bronchitis, bronchio~itis, lobar pneumonia and miliary tuberculosis of the pulmonary type.

1. From~ Labor Pneumonia:. The symptoms may not be helpful, and it is frequently difficult to determine if one is dealing with a case of benign lobular pneumonia of moderate extent, or one of lobar pneumonia with severe general symptoms. Beyond all doubt we must demonstrate the absence of consolidation in the lung. I f it~is present clinically with x-ray support" to clear up any reason- able doubt I would insist on the most severe symptoms to make a diagnosis of confluent lobular pneumonia. In my Series this differential diagnosis did not arise.

2. Bronchitis. This is most important, as this condition also may give rise to severe symptoms and high fever, but as a general rule a bronchitis remains a bronchitis, and the old idea of a descend- ing infection explains only a small minority of cases. In this series if only coarse and sibilant rhonchi were heard and heard in various areas of the lung, no matter what the symptoms, bronchitis was diagnosed. I f nothing but an occasional rale was heard and the patient made an uneventful recovery, tracheitis was put down on the chart. P.S.I. was given with startlingly good results in both tracheitis and bronchitis if the symptoms were severe, but they arc not included.

3. Branchiolitis. So competent an observer as Feer discusses ]obular pneumonia and bronchiolitis under one heading. In the first few days of bronchiolitis it is an amazing thing that there are usually no signs in the chest. Then abundant fine rales can be heard in the lower posterior portions of the lung. I admit that in this matter I cannot be considered any more competent than Feer.

4. Mi~iary or Aau.te Caseous Tuberculosis. The pulmonary form of miliary tuberculosis is characterised clinically by a cceler,~tion of respiration, dyspncea, intense waxy pallor, the most obvious mani- festation of acute circulatory failure, and, towards the end) by a profuse bronchitis with fine vesicular rales. Any case of broncho- pneumonia which was obviously going to ground was sent to the radiologist~ and in three cases that beautiful picture of a snowstorm as seen through a latticed window was returned. The x-ray diagnosis from acute miliary pneumonia is difficult, but I under- stand the, marbling in pneumonia is more intense than in miliary tuberculosis.

So much for the negative side of the picture. To make a positive diagnosis of lobular pneumonia. I insisted on the following: a very ill, weak and exhausted infant or child, usually not over two years of age. (The eldest was three.) Great apathy and great thirst, but no appetite. Dyspncea and polypncea. High temperature. Either a marked pallor, with a livid undertone or a dusky red or bluish tinge. (Two cases only had distinct cyanosis.) Practically all my cases had pallor. Cough was most uncommon and never troublesome.

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For physical signs I concentrated mainly on the. left upper lobe where the layer of lung tissue is very thin "and the infiltration soon reaches the surface, and the region on both sides close to the vertebral column and below the hilus. In all the cases used for this analysis fine crepitant rales were heard and lived up to their classical description of being sharp and close to the ear. To be quite honest, I could not conscientiously demonstrate consolidation. The few cases that were sent down to the radiologist for his opinion (not the miliary cases) came back with a picture showing marked shadows at one or other hilus, or both, with irregular markings extending towards the side and some indefinite shadows in the lower" lobes.

And now for the findings in my series. I have only 20 cases of lobular pneumonia and 23 of lobar, with 14 controls in the ease of the latter. The two or three cases of bronchopneumonia which I treated here before I started using P.S.I. could obviously control nothing.

The three things which, in my opinion, we must use as criteria of any form of treatment are : - -

1. The saving of life; 2. The return to a normal temperature with the disappearance

or abatement of serious symptoms; and 3. The early discharge from hospital.

(1) The Sa;ving of Life. You will remember what- I said about moribund cases. Of three cases included on that ground, one lived for 8 hours, another for 10, and the third for 24. That leaves seventeen, including one treated in our isolation room, for co-existent whooping cough. That case died, as did another, making two deaths out of 17 bad cases of bronehopneumonia. I will not dare to talk of percentages. I f I had 100 cases they would still mean nothing.

(2) The Num~bvr of Da~s of Pyrexia, a~c~ Distress. These figures should apply only to those that lived. I f this be accepted, the average number of days is 4, the minimum being 2, and the maximum 12. I f we include the fatal cases with pyrexial days of ]0 and 16 respectively, the average is still only 5.

(3) The 1Vumber of Da~ys in Hospita~l. This is a most important figure from many points of view. The hospital authorities must consider the expense, the public only consider their own incessant demands for beds, the nurses have other cases calling for their attention, the doctor is always hoping that the next ease is going to be something out of the rut, and-- I had nearly forgotten the patient. The patient needs to get home before he contracts one of lhe infectious fevers. This figure averages 12�89 days, with a minimum of 8, and a maximum of 24, and as the minimum cost of mMntenance of a case of bronchopneumonia with the drain on drugs, oxygen, etc., must be 4/- a day, whereas the cost of three in~ections of P.S.I. for a child of one year is about 3d., from the financial side the results can only be regarded with approval.

To make these figures more convincing it would have helped if

PNEUMONIA IN CHILDHOOD 111

no other treatment had been given, but I could not take that chance. In a~ddition to injections of P.S.I. (the amount of which was fairly accurately estimated by the " age over age plus 12 " formula) they were given four-hourly injections of coramine, an expectorant mixture, and a c(~mbination of tinct, digitalis and liquor strychin~e (of each one minim, these being the dosage for one year). Adalin for insomnia, with mustard paste for counter-irritation, were used as required.

Jus t a few words about oxygen and digitalis. Oxygen first. Rapid and shallow breathing is the rule in pneumonia. Shallow breathing tends to produce anox~emia, and anox~emia tends to pro- duce rapid, shallow breathing. The cause of the anox~emia is surely an alteration in the permeability of the alveolar walls which ~e~ders them relatively impervious to the oxygen reaching them in the expired air, and the anox~emia can only be overcome by forcing a higher concentration of oxygen than atmospheric into the blood. Barach, in the U.S.A., and Haldane in England state that the optimum concentration of oxygen is 40 to 60 per cent., and that this simply cannot be obtained by discharging it through a funnel held over the patient's face. I use either a single or double nasal catheter with several vpenings and introduced well back into the posterior nares, the oxygen being bubbled through alcohol at jvst such a rate that the bubbles cannot be counted. Dr. Magennis is at the moment experimenting with an " Oxygenaire " tent and ~ow-meters from which we expect great things.

Digi ta l i s . Since pulse irregularities, dilatation of the right heart, and toxic changes in the heart muscle are at least potentialities in all cases of pneumonia, there seem to be good theoretical grounds for giving digitalis, and, although practical proof of its value is lacking, I believe in giving it, always provided that one ~stops well short of the toxic doses that would be permissible in heart failure as such. I f serious circulatory failure threatened (as it did in a few cases) I used subcutaneous adrenalin (according to age) every 4 hours, one minim for a child of one year. In those cases the effect was remarkably good. In fact I succeeded in bringing one of the fatal cases back to life for a few hours with an intra-cardiae injection, but that type of D a i l y MLa~l dramatics is only permissible as the culmination of steady painstaking routine treatment long before circulatory toxmmia has fully developed.

t tere I must emphasise that the relief from tortured dyspncea and the change from a seriously ill subject to a state of comparative ease and safety even after the first injection of the vaccine has to be seen to be believed. I f the sisters and nurses in charge of their cases were to be allowed to give their judgments one would imagine that the initials of the vaccine stood for " Powerful, Stupendous and Incredible."

Lobar pneumonia must obviously be dealt with separately because in this condition, as is well known to p~ediatricians, recovery may take place with, without and in spite of treatment. The difficulty of keeping these sturdy children lying down in their cots is almost

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the major problem of nursing in many cases, but the great majority of eases in this series were quite ill on admission and they simply grunted out the diagnosis which, depending as it does, on the demonstration of consolidation clinically or with radiologica~ assistance, was in only two-thirds the cases possible when first seeL~ although in all cases it was obvious immediately after the first injection. The results of vaccine treatment in 23 cases were as follows : - -

(1) Moxtality. Two died out of 23, one complicated by bilateral empyema, unilateral on admission, in the controls, the deaths were two out of 14.

(2) Days of Pyrexia. An average of six, ranging from a minimum of 3 to a maximum of 16 (the empyema case). I f this be omitted the average is 5�89 days, a figure which is not particularly good. I t makes out a very poor case for P.S.I. in the lobar variety i n children, as the average in the controls was 5�89 days; but then, atJart from the non-specific effect, the streptococcal and influenzal ingredients are theoretically useless, and since the type of pneumococcus is unknown in the case and unmentioned in the vaccine, the specific effect should be a very mild quantity. The symptomatic relief, however, was so definite in all cases that I intend to continue with its use. I may mention that in all the 23 cases, apart from that with the initial empyema, there was only one complication (an otitis media). After the second day, although there were still pyrexia and localised consolidation either in the base, right apex or axilla, the children were well and required no oxygen, coramine or medicine of any sort. I searched hard for a left apical infection, because the theory of a primary complex as in tuberculosis only with a more rapid tempo rather fascinates me. I f one concedes a primary complex forming and spreading ont to ihe lung as an infiltration all in the course of a~ few days, one has a perfect analogy between pneumonia and tuberculosis. Now~ the regional lymph nodes for the left upper lobe lie outside the lung so "that perihilar infiltration of the lung from these nodes cannot oee l l r .

(3) Days i~ Hos~p~ta~. The average here is 14, with a minimum of 7 and a maximum of 30 (a migratory case). In fact, I had two migratory cases in whom the temperature fell after the administra- tion of P.S.I., to rise again in 4 or 5 days. ~ P.S.I. was not given for the second focus. There was also the greatest difficulty in getting the parents to take the cured children home. Practically every one of these cases could have been safely taken home in ten days from the date of admission.

In conclusion, I would draw your attention again to the absence of empyema or other complication. Delayed resolution did not bother us either, so that although the s tay in hospital for the cob- trols was 16 days, only two extra days, the children were all very ill until their crisis, and two died, one on the second day and the other on the 7th. There was also one case of unresolved pneumonia which had to be left for 20 days in hospital.