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T H E E V O L U T I O N OF C L I N I C A L PATI- IOLOGY--A R E V I E W

By DR. WILLIAM BRIGGS

CLIniCAL pathology is an integrat ion o f several sciences--diagnostic sciences-- which have been developed from elaborations of the old ward " side room " tests. These tests, up to the beginning of world war No. 1, had been practically the only available laboratory aids to diagnosis. True, bacteriology was established as an integral p a r t of hospital ancillary service, but h~ematology was more or less confined to blood counts, and biochemistry to the detection of sugar and albumin in urine. To-day, these three depar tments of science have been combined into one specialty, which stands as a specialty in its own right.

The clinical pathologist must be hsematologist, bacteriologist and bio- chemist. A sort of Jack-of-all-Trades but generally master of one. As few men can be masters of all three subjects we usually find the clinical pathologist specializes in at least onc a sort of " specialist " within the specialty. And, in a manner analogous to general practice, he m a y come up against a problem which necessitates his referring to certain of his colleagues.

The purpose, then, of clinical pa thology is to bring the laboratory into effective use in clinical medicine. The resources of the laboratory are directed t o unravelling the phenomena of disease.

The da tum line starts at those years of war 1914-1918, w.hen trench fever offered an object lesson on the failure of British medicine to make use of its, a t t ha t time, available resources. I t is t rue tha t this was an entirely non-lethal disease but the disabling effects were very serious. There was much speculation about its ~etiology, b u t little was done about it till the arrival of the American Red Cross Society in 1917. The problem was immediately tackled by them, and in 1918 a report was published showing the louse to be the vector. I have little doubt t ha t had this, or a similar problem, occurred during the recent war, the R.A.M.C. would have speedily solved it.

The importance of the laboratory was underlined during the between-war years by the work of Bant ing and Best ; and the Medical Research Council in London (and the Rockefeller Ins t i tu te in U.S.A.) established clinical units in certain of the teaching hospitals. Even then, they were given a poor reception by certain of the clinicians who regarded them as excrescences or worse. But these units served to lay stress on pathology. That stress which marked the work of Addison, Hunter , Bright and other giants of the past. The establish- ment of the public health laboratories, with the postal service, ra ther retarded the growth of hospital laboratories. " W h a t was the use," said hospital boards, " of having a laboratory when the service could be had more cheaply, or for nothing, elsewhere ? " Tha t was a sterile a rgument as is amply proved to-day. Clinical pathology can only be properly carried out by those in close touch with clinical work. I t can only be done to a very limited extent in ecntres una t tached to hospitals. Clinical pa thology is an aid to diagnosis and demands liaison with the clinician.

Many doctors, even to-day, regard the laboratory as a sort of super slot machine. You push in a specimen and out comes a diagnosis. As I said before, it is only an aid to diagnosis, and I stress it now ; only one more tool in the a rmament of the clinician, and, in many cases, as impor tan t as thes te thoscope. Dr. J. Harold Burn, in the preface to his new book, The Background of Thera- peutics, tells us how interested he was when he visited America in 1942-43, and how much impressed, b y tl~e development of labora tory and clinical research going on there . He says " t h e great need in medicine to -day is of young people trained for at least two, preferably for five, years in the laboratory "

The tendency, in m a n y eases, is for the homceopathie physician to rely only on his six senses. When I say six I am including his " clinical sense "

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This is also true of orthodox medicine, but I am more in touch with the homceo- pathic side; but all doctors owe something to their patients in the way of accurate diagnosis and prognosis, and it is here that the clinical pathologist can help. He !s not only a laboratory assistant, he is also a clinical assistant. He is much more in touch, unlike his brother the morbid pathologist, with the living patient. This reminds me of the story of the famous pathologist, on holiday in the Highlands, who was-called to vis~it the scene of a mountaineering accident. When he arrived there he addressed the victim. " I am a patho- logist, but I am ~lso a doctor. I really feel I could do more for you dead than alive."

The clinical pathologist meets his patients face to face during the perfor- mance" of function tests, or in ]0rocedures used to estimate progress, and this gives him some sort of personal relationship. He must take certain precautions in this relationship just as you do in everyday practice. H e must take an interest in the patient as a whole and not merely in his liver or kidneys. I would like to .quote from Dr. Cuthbert Dukes' address on the occasion of the Association of Clinical Pathologists' twenty-first birthday meeting, the occasion of his taking the presidency of the A.C.P. last January. I am sure you will detect the homceopathic flavour of the philosophy in the first paragraph--a philosophy which is slowly permeating the orthodox school to-day. Here it is :

I~ELATIOlgSItIP TO PATIENTS

" The extent to which a pathologist enters into any sort of personal relationship with patients varies very greatly according to the nature of his work, but whether he meets the patient personally, or only a bit of the patient, the existence of the patient as a living individual must not be overlooked. I t is easy to make the mistake of thinking of the patiemt only as an example of a pathological condition with which one is more or less familiar, as though he were an actor in a tragedy instead of its victim. Our patients are the subjects and not the objects of our skill.

Also from time to time we need to be warned against too exclusive a preoccupation with our own particular line of enquiry. I f a patient is parcelled out among different specialists as may be necessary in the investigation of some diseases, it is very desirable that the pathologist should modestly recollect that others beside himself have a say in the final diagnosis. Perhaps we are warned about this too often and fee] that the counsel might be more appropriately addressed to young house physicians who imagine that a diagnosis can be made by collecting reports from different departments and correlating them together. I t is always worth while reminding these raw recruits to medical science of the old chestnut about the young houseman'who presented his chief with a large collection of laboratory reports and was greeted with the remark : " But, my boy, have you examined the patient naked-eye ? "

Of course the public in general adopt a very foolish attitude to pathologists just as they do to all scientists. We are either belittled or " built up " too much, so that patients either take the point of view that nothing of any value will come of our activities or else that the pathologist is the real scientist , the one and only hope~ I am not averse to exploiting to some extent this " child- like " faith in laboratory mysteries. I t may be good treatment to foster the hope that everything possible is being done, that no stone is left unturned and no avenue unexplored. A thorough examination alone often does a patient a lot of good. We are not likely to forget this but may quite easily overlook a possible danger arising from putting too much emphasis on the importance of the work on which we are engaged. Patients often assume that laboratory tests have been resorted to because of the existence of some serious condition which has not yet been diagnosed, and therefore begin to be a~nxious. Sensible doctors know quite well that harm may be done by displaying an excessive

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interest in a patient 's symptoms and similarly even such simple laboratory tests as blood counts may create a feeling in the pat ient 's mind tha t he must have some serious or mysterious malady : otherwise so much interest would not b e t a k e n in his case.

- B u t let us get back to the evolution of clinical pathology, an evolution which it owes to the great increase in knowledge which has taken place in each of its component sciences. Some of the greatest advances are only milestones on the road and give us but a foretaste of even greater progress in the future. Perhaps it would simplify matters if I were to take each subject in turn and illustrate it with one or two examples.- I will start with Bacteriology as it is my favourite sphere of activity.

BACTERIOLOGY. Jus t forty years, ago this month I stained my first specimen by Ziehl-

Neelsen's method. This method was worked out by Ziehl, Ehrlich, and l~eelsen in 1882. The story of this work always underlines, in my mind, the ingenuity of the human brain. For over sixty years this method for demonstrating the tubercle bacillus has gone practically unmodified and unchallenged. Several other techniques have appeared from time to t ime but to-day Ziehl-Neelsen's method retains its superiority. Recently, however, within the past four or five years, a new method has been developed. Still in the experimental stage it is claimed by some to be superior to Ziehl-Neelsen's. I refer to the method of fluorescent microscopy. Under the oil immersion lens the area of field examined is very small (about "03 mm.). Where tubercle bacillus are very scanty it becomes a long and tedious job to search a large smear, and, the organism may be missed. With fluorescent microscopy the ~ inch objective is. used, thus enormously increasing the area of the field and making it very expeditious to examine the whole smear. Briefly the smear is stained w i t h auramine-phenol, decolorized with acid alcohol and examined by ultra violet light. The bacilli, fluorescing brightly, are easily detected against the dark background. If any of you are interested you will find an article by Lempert .in the second volume of the 1944 Lancet. I do not think the time has yet come when this method will entirely displace Ziehl-Neelsen's method, but I think it will be useful in checking over specimens which have hitherto been labelled tubercle bacillus negative, with carbolfuehsin.

While on the subject of the tubercle bacillus, I am reminded that we have, in the past, relied, almost entirely, on the finding of the organism in the sputum for a positive diagnosis. The tubercle bacillus is a most difficult organism to culture. One difficulty has been the suppression of other commensals which tend to overgrow the tubercle bacillus. This is being overcome by methods of selective media and concentration. The tubercle bacillus is surrounded by a fa t ty capsule which is impervious to the action of acids and alkalis, at a strength which destroys the other organisms. But even when we have secured the organism without contamination there still remains the difficulty of securing a good culture within a reasonable time. Under the best conditions and with the best media it takes some four to six weeks to get good growth. This delay decreases its value as a diagnostic :procedure. Recently, however, methods have been worked out for getting results in about a week's time. One of these is a very interesting procedure. The slide culture method. Price published this method in 1941. Briefly i t consists of incubating a slide smear of sputum, acid treated and washed, and immersed in a culture medium of citrated blood. Clumps of the bacillus can usually be demonstrated within a week of incubation.

Soltys in 1942 described a medium of chick embryonic tissue which gave excellent growth after three to seven days.

These cu/ture methods in conjunction with concentration of the specimen, be it sputum, pus or other substance, are said to yield results which compare favouxably with animal inoculation.

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BIOCHEMISTRY. As with bacteriology so with biochemistry. The clinical pathologist is

not directly concerned with chemistry a~ applied to physiology but more so with the biochemistry of disease and, in the orthodox school, with treatment. I do not think it would be of much general interest to go into details of specific procedures but rather confine myself to generalities which will illustrate the advances in this subject. The control of chemotherapeutics is entirely a matter for the laboratory in conjunction with the physician. I, fortunately, see very little of this branch. But we are all physicians and many of us believe, rightly or wrongly, that we have, in the interests of the patient, to use all methods of treatment. Thus it comes about that I have on Occasion to test the sensitivity of organisms to penicillin and the sulphonamides. I have my own views on the subject of chemotherapy but, like a good doctor with his patient, I have no polities where my colleagues are concerned.

The carrying out of so-called " function tests " has always interested me. Here we have objective evidence of functional disturbances. Evidence in a quantitative form. The side room tells us there is sugar or albumin present but the clinical pathologist shows the amount of disturbance which is present. You all know that the amount of albumin present in the urine is no measure of the disability of the kidneys. But, combine the amount of the urine secreted and its urea content with the amount of urea in the blood and we have the basis of the delicate test devised by Van Slyke. I t is said that the urea clearance test shows kidney defects sooner than any other test so far devised. I t must be remembered that no test will measure the r e s e r v e power of the kidneys. No evidence of renal dysfunction is obtMned until a large part of the reserve has disappeared. In other words, a n o r m a l result may mean that the kidneys are healthy, slightly damaged or moderately deficient in function. The results from chemical tests must always be assessed in the light of the clinical examina- tion. The most recent advances in biochemistry are concerned with the vitamins and nutritional deficiencies. We have very few references on these in the literature before the immediate pre-war years. In this field the clinical pathologist is able t~) reveal nutritional deficiencies unsuspected by the clinician. Such deficiencies are seldom single even though the signs may be characteristic of one of the classical diseases. Most of these procedures are carried out on blood and this brings me without a violent break to the subject of h~ematology.

H2EMATOLOGY. The recent advances in this subject are so g rea t that I find it difficult to

give a short review of them. Of outstanding importance was the discovery of the Rh factor in 194:0 by Landsteiner and Wiener. This previously unsuspected antigen in human ery~hrocytes is of first importance in the setiology of h~emolytic disease of the foetus. I t was previously known that the blood of some animals contained antigens related to the "agglutinogens of human erythroeytes.

The presence of the l~h factor was first demonstrated by testing different human bloods agMnst an anti-rhesus serum prepared by injecting the erythrocytes of rhesus monkeys into rabbits. I t was found that the majority of human bloods were agglutinated by the anti-rhesus serum. Approximately 85 per cent. (in this country) are agglutinated and called Rh positive, 15 per cent. are l~h negative. This property is quite independent of the A.B.O. and M.N. types. The importance of this factor in blood transfusion was shown by Weiner and Peters who described four eases of h~emolytic reactions occurring after repeated transfusions with blood compatible by group. They showed that the blood of the patients contained atypical agglutinins which gave reactions identical with the anti-rhesus serum. Some of the patients were l~h negative and the blood responsible was l~h positive. This formation of ant i -gh

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agglutinins by negative persons as a response to transfusion with Rh positive blood is comparatively rare. But much more frequent is the formation of anti-Rh agglutinins by Rh negative women as a result of stimulation by an R'h positive infant i n utero. At an early stage in the investigation Jt was noted that when these atypical agglut~nins were formed in the mother's serum, the infant was often stillborn and it was soon recognized that there was a special association with er~throblastosis foetalis, now termed hsemolytic disease of the foetus which includes the clinical conditions, hydrops foetalis, i~terus gravis --neonatorum, congenital ansemia of the new born, and a certain group, not yet defined, of stillbirths.

I t was shown that in some 91 per cent. of cases where the infant was affected the mother was l~h negative. All the fathers and infants tested were Rh positive, and in many eases the anti-Rh agglutinins were demonstrated in the m o t h e r ' s s e r u m .

I t had been recognized all along that there were different Sub groups of t~h. The nomenclature is very difficult to memorize as there are many sub-types and only a few different antigens which occur in different combinations in the various sub-types. Also there is the phenomenon of " blocking " antibodies. Some sera contain anti-l~h antibodies which are capable of' combining with Rh antigens but not of causing agglutination. Although they do not agglutinate i n vi tro they may give rise to hzemolytie disease in the foetus. This complicates the process of blood testing.

This very brief account of the latest discovery in hmmatology underlines the importance of the clinical pathologist in obstetrics. I t also poists to the responsibility of the physician when, in ordinary practice, blood transfusions have to be given to women and children. Taylor, in 1944, stated that mankind can be divided into 792 blood types ! Who knows, that in the future it may be found that the blood is as individual as the thumb print. We have advanced far from Landsteiner's and Moss's four simple groups !

I have touched on many points of the clinical pathologist's work, each of which would provide material for many papers, yet I have said nothing about diagnostic histology which is the oldest branch of clinical pathology and was in existence before bacteriology (when hsematology was still unexplored). This branch of the work is generally performed by the morbid pathologist who seems to prefer the peace and calm of the laboratory to going out into the wards. But with the introduction of aspiration biopsy the clinical pathologist is finding one more subject to incorporate into his sphere of interests. Shall I call it child, for each of his subjects are children who are growing up fast. Soon, maybe, they will be able to stand on their own legs and each go out into the world as an independent specialty in its own right.

So far I have spoken only about the diagnosis of the disease and the patient. What about the diagnosis of the remedy ? Our worthy President /rod I, ilk collaboration, are shortly starting a large scale research on the bowel flora which may throw some light on this. At the least, we hope it may throw some light on the action of our remedies. The way may be long but rest assured that, as facts emerge, we will keep you informed.

I must thank you for your attention this afternoon to what I originally intended to be an informal talk but which has turned out to be a rather scrappy paper, attempting to put volumes into a few words. As a slight compensation for the inadequacies of my paper I have brought with me a few of the simple tools of my trade which each one of you might find useful in your everyday practice. They are not by any means new, some of you may have seen them before, and I am afraid they fall into the " hints and tips " class. However, it is always refreshing to learn what the other fellow is doing or using and so I make no apologies.

Demonstration : i. Hsemoglobinometer, colorimetrie comparator and cell.

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ii. Blood gun. iii. Rubber disc bottle (a) for plasma, (b) for culture. iv. Venule. v. Tube seal for b loodpipet tes .

vi. B.S.I%. tube and glass ink.

D i s c u s s i o n

The PRESIDENT said tha t Dr. Briggs had a great habit of bringing things out of his pocket like a conjurer. He was sure the audience had been struck by the detailed points in his clinical pathology. He thought there had been too little connection between the orthodox homceopathie physician and the orthodox clinical pathologist, t Iomoeopathy had been apt to fight shy of laboratory tests but Dr. Briggs was a clinical physician and he laid stress on the point tha t there was definite connection between what was done in the laboratory and what the physician saw in the pat ient and tha t the inter- pretation, of the laboratory findings should be by the clinical physician. In other words, the clinical physician must make use of the information from the tests, the tests must not master or compel the physician to take any point of view, that is, the physician came first.

Dr. LEES TE~aPLWTO~ said tha t Dr. Briggs was an example of the Scotsman who said, " Here's to us and all like us." That was his own feeling about clinical pathology. H e found it difficult to understand the separation of pathologists and clinical pathologists unless it was tha t one dealt with the dead and the other with the living. He would agree that they must not allow the clinical pathologist to .influence them in their diagnosis. One found tha t one went along with pathology and got nowhere, and at the end he came to the conclusion and said that he thought the patient looked like so-and-so; it was possible to have too much pathology. He thought tha t the pathologist or the radiologist should be asked for confirmation of what was suspected. That was the danger of the mass radiography technique. Some of the members would have read the article which gave an account of how five or six different X-ray plates were shown to five or six radiologists and five or six different diagnoses were made, but later they were shown the same plates and they altered

, their diagnoses again. This was the danger of X-rays and to some extent of pathology.

He thought tha t McKinlay was responsible for the discovery of the louse carrier in trench fever and not the Americans. Of Course, as homoeopaths their interest lay in the study of the patient before there was any pathology ; tha t might be the saving grace, he did not know.

There was the question of the pathologist being hocussed. Some of them would remember the disseminated sclerosis hoeus. A pathologist who was not qualified medically discovered a microbe in the cerebrospinal fluid which she said was the cause "of disseminated sclerosis. I t was discovered later that .she had put something into the cerebrospinal fluid and found it !

I t was his experience that the most important clinical finding was the lymph hmmostasis of whooping cough. I t was not invariably correct but it was nearly always correct. They all found secondary anaemias which came from bleeding piles, and they were apt to get too much in the laboratory and too little in the ward. There was too much faith placed on a differential diagnosis bg the administration of penicillin ; if it did not work, it was so-and-so, and he thought this was rather dangerous. I t was very recefitly tha t the discovery was made tha t the myeloblasts of the pernicious type of blood disease should now be recognized as not being a normal cell inefficiently developed but as a complete new cell suffering from a deficiency disease. He was glad that Dr. Briggs said tha t the Rh factor was difficult to memorize. He also agreed tha t the simple blood count was the most useful of all investigations in clinical pathology if it was done for a particular purpose. He would suggest

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t h a t for the sake of the clinician the pathologists should keep their pathology simple, not giving too much detail.

Dr. B.RIGGS said that the whole purpose of his Paper was to point out how closely related clinical pathology should be to the clinician in charge of the case. There were numerous examples of the young houseman who collected his reports. Even many older members of the profession seemed to think that it was a kind of penny-in-the-slot machine. With regard to the myeloblasts there was a good deal of trouble. They had been discovered in marrow examinations and the whole matter was not quite settled. He would point out that the value of the blood count was in the maerocytie anaemias, pernicious anaemias, and carcinoma of the stomach. He had a patient whose blood he had examined in January. He had a maorocytic anmmia with a eolour index of 0.8. He was given iron but did not d o very Well and he examined his blood again later, this time to establish a picture of macroeytic ansemia. I t turned out that he had carcinoma of the stomach, so that there was a valuable means of differential diagnosis.

In (~lasgow practitioners hesitated to use the X-ray in any ease where carcinoma of the stomach was suspected. Some physicians would not allow radiography to be used under any circumstances, usually ~giving a test meal and making a blood count. If the clinical pathologist found a maeroeytic anaemia with achlorhydria that was all he could report. The point he tried to make was that it was up to the clinician, pathology was only a guide to him. He thought his whole feeling in the matter was that these clinical tests especially should not be confined to being appendages to the pathologist's laboratory.

Dr. LEI)~I~WAN asked if the aehlorhydria would be absolute proof of carcinoma.

Dr. BmGGS said that .with carcinoma there was a gradual transition. Dr. TEMPLETON said that what decided him was the change. Dr. MONCRIEFF said that the Hendon Branch of the British 1VIedieal

Association had a lecture from one of the gynseeologists at the London City Maternity Hospital who spoke about blood transfusions in obstetrics and the Rh negative factor. The lecturer said that he started as a great protagonist of blood transfusions in obstetrics but now he looked upon it as a major catastrophe for the reason that occasionally one gave a woman the wrong kind of blood. Up to now the blood banks had been completely mixed as far as the l~h factor was concerned and if a woman who was Rh factor negative was given this mixed blood there was a bad result. With a woman with a positive Rh factor a transfusion with a certain amount of negative blood did not produce a bad result at the time but there was the liability of giving the patient Rh negative blood and she would have a Rh negative baby with bad results. He said that this should be considered carefully with regard to blood injections on little girls. I t was possible to transform Rh positive blood into Rh negative blood simply by a chance injection of whole blood. I t seemed to her that a homceopathic patient avoided a great many dangers.

The other thing she would like to ask Dr. Briggs was with regard to an article in the British Medical Journal about two months ago in which the writer said that he had noticed in TB patients there was a percentage of large mononuclear cells to lymphocy~es greater than 1 to 4 ; if there were fewer large mononuelears than 1 to 4, the lymphoeytes did not mean anything. Probably the patient was not tn, bercular. If, however, the large mononuelears were in a proportion greater than 1 to 4, that was very largely suggestive of tuberculosis. She would suggest that it would be a great help if Dr. Briggs could make a note of that in his work. She had only had one ease of (?) tuberculosis in .a child where the mononuclear cells were in the proportion of 1 to 2. T h e child had been tested with the Mantoux test and it was negative, but all the other possible conditions had also been negative. On clinical grounds she thought the child was an abdominal TB.

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There was a small boy of about 4 in the ward at present. I t was difficult to get an X-ray of the lungs at that age which would give tubercular resolution, because one could not differentiate from bronchial pneumonia. This child also had a large percentage of mononuclears to the lymphoeytes and she wondered if Dr. Briggs would make a note of that.

Dr. BRIGGS said that the large mononuclears were regarded as an indication of new tubercles being formed whereas a preponderance of lymphocytes meant that healing was'taking place. He had seen that again and again.

With regard to the question of the l~h negative and l~h positive blood, l~h negative blood remained negative always. By giving repeated transfusions of Rh positive blood a sensitivity was built up and the person became allergic with serious results. The blood never changed from l%h negative to Rh positive, in the same way that it never changed from A to B.

Dr. T~oMPso~ WALKER said that he was surprised to hear that blood taken for a sedimentation rate could be kept in a tube for three hours. What prevented separation and how could it be reconstituted ?

Dr. BRIGGS said that this was a matter introduced by ]~rof. Davis of the Royal Glasgow Infirmary. The tube was kept in one pocket. Once the column had been set up in the BSR tube it must not be shaken.

Dr. TI~OMI~SON WALKER: I t does sediment in your pocket but you can reconstitute it ?

Dr. BRIGGS : Oh, yes, by just tilting the tube ! The PRESIDENT said that the Paper had been very interesting as had been

the discussion. He thought the discussion had emphasized the point he had made and which Dr. Briggs had tried to make all along, that he regarded laboratory work as an instrument to be used by the physician. He was not a laboratory technician who said that was his opinion and one could take it or leave it. He was a physician who should make use of all these things and his clinical knowledge should take first place.

They were very grateful to Dr. Briggs for his Paper and he would offer him personal thanks as well as thanks on behalf of the members.