529

BRUCELLOSISBy A. NELSON-JONES, M.D., M.R.C.P.Physician, St. Leonard's Hospital, London

~.........

FIG. i.-A Maltese Goat.

History and AetiologyIn I859, in Malta, Marston differentiated from

other prevalent fevers a prolonged illness withundulating pyrexia which he called Mediterraneanremittent fever. In I886 Bruce discovered thecausative organism, which he called Microcroccusmelitensis, and in I897 Hughes named the diseaseundulant fever. It was probably the same feveras one described by Hippocrates in his 'Epidemics'and recognized by Cleghorn in Minorca in I751.

In 1905 it was shown that the disease wasconveyed to man from goats by their milk. Thedisease became widely recognized on the shoresand islands of the Mediterranean under differentlocal names such as Malta fever, Gibraltar fever,Rock fever and Neapolitan fever. In I921 it wasdiscovered that similar undulating fever in mancould be caused by Bacillus abortus, which hadbeen shown by Bang in I897 to be the cause ofcontagious abortion of cattle; and later it wasfound that human undulant fever could also becontracted from swine infected by a similar

organism named Bacillus suis. These three closelyrelated organisms now take their generic namefrom Bruce and are called Brucella melitensis,Brucella abortus and Brucella suis.The usual reservoir hosts of Br. melitensis are

goats and sheep, of Br. abortus bovines such ascows and bulls, and of Br. suis swine, but all threevarieties can infect all these animals, and some ofthem have also been found in horses, mules, dogs,cats, rats and chickens, and in certain wildanimals. The disease is conveyed from some ofthese animals to man-from goats, sheep andcows by their milk and rarely by milk productssuch as cream, butter and cheese; and from goats,sheep, cattle, pigs and rarely from horses bydirect contact of infected animals or their carcaseswith a cut or scratch on the human skin. Hencefarmers, herdsmen, dairymen, tanners andveterinarians are especially liable to the disease.It is always conveyed to man from animals, or bylaboratory infection. No case of man-to-maninfection has ever been proved. All infection from

copyright. on July 6, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.28.324.529 on 1 October 1952. D

ownloaded from

530 POSTGRADUATE MEDICAL JOURNAL October 1952

'#2

FIG. 2.-An aborted calf.

milk could be prevented by pasteurization. Thenative cause in England is Br. abortus, derived fromcattle of which probably about io per cent. areinfected. The disease probably often goesundiagnosed, especially in country districts.

Such local names as Malta fever, Neapolitanfever and Gibraltar fever should now be aban-doned, and whether the disease is caused by Br.melitensis, Br. abortus or Br. suis it should becalled either undulant fever or brucellosis. Brucel-losis is the term commonly used in America, andhas the advantage of not suggesting that undulat-ing pyrexia need necessarily be present. It hasan almost world-wide distribution, being foundas far east as China, as far west as California,as far north as Russia, Scandinavia, Scotland andCanada, and as far south as New Zealand, India,South Africa and South America.

The Cliniical PictureIt is impossible to state a definite incubation

period in a disease which often starts so insidiously,but commonly it is between three days and threeweeks. The onset is often gradual or subacute,but may be acute and signalled by rigor. Thepyrexia may be undulating, continuous, irregular,remittent, intermittent, recurrent, extreme (hyper-pyrexia), slight or absent. The pulse rate usuallyfollows the temperature curve. The disease canoccur in many different forms, but with no sharpdelineation between them to justify artificialclassification into 'types.' Common symptomsare headache, backache (especially low backache),pain in the limbs (especially in the joints), shiver-

ing, sweating, easy mental and physical fatigue,loss of appetite, loss of weight, nausea and con-stipation and, in women, amenorrhoea. Thepatient is often irritable and depressed, and atnight insomnia and drenching sweats are common.In about half the cases the spleen is palpable andthe liver enlarged. In some cases there is grosstremor of the fingers and tongue or tendernessover the vertebral spines. Usually the skin ismoist or sweating. Brucellosis due to Br. meli-tensis is on the whole more severe than that dueto Br. abortus or Br. suis.

In a large number of cases there are additionalsymptoms and signs due to localization of thedisease in various organs. These and othercomplications will be mentioned under appro-priate headings.

Bone. Spondylitis occurs frequently, often withmarked spur formation, and is especially commonin the lumbar spine. Disc degeneration is commonand many of the neuralgias found in the diseaseare due to these two things. Osteitis of the spinemay rarely proceed to abscess formation. Thepus may discharge anteriorly and compress thecord and so cause paraplegia, or it may track afterthe fashion of a tuberculous abscess to form a cold(or warm) abscess in the lumbar region or (afterspreading along the psoas sheath) in the groin.Long rest on plaster cast may be necessary, oreven Albee graft. Osteitis may also occur in thelong bones or the skull, ribs, ilium, scapula andcarpus.

Joints. Apart from the common joint painstrue polyarthritis can occur, with localized swelling,but not usually redness or warmth, of the joints.Occasionally, usually late in the disease, a singlelarge or small joint may be the site of. suppurativeand destructive arthritis and Brucella organismsmay be grown from the pus. Arthritis is prob-ably commoner in cases due to Br. melitensis, forHughes recorded joint effusion in 40% of hismelitensis cases, although often of short duration.

Nervous System. Meningitis, encephalitis, mye-litis, radiculitis, neuritis, or any combination ofthese, may occur, either in the course of knownbrucellosis after a number of pyrexial undulations,or at the onset overshadowing all else, or in con-valescence, or months or years after recoveryfrom brucellosis has been presumed. In thenervous system the disease has a special affinityfor the meninges, and many of the neurologicalmanifestations are thought to be due to involve-ment of vessels of the brain and cord where theytraverse inflamed meninges. There is thus atendency to recurrences of focal lesions of shortduration in the same or different places, so thatthe patient may at different times have hemi-

copyright. on July 6, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.28.324.529 on 1 October 1952. D

ownloaded from

October I952 NELSON-JONES: Brucellosis 53 1

L~ -

a.. ........

........ u..........

;t~.-..Z

..' .. ......0

FIG. 3.-Severe brucellosis with paraparesis.

paresis, hemidysthesia, numbness of one arm andthe homolateral half-face and half-tongue,asphasia, homonymous hemianopia, or cranialnerve palsies. Any cranial nerve can be affected,and fits and myoclonus may occur, or (rarely)Parkinsonism, chorea, athetosis, cerebellar lesions,internal hydrocephalus, diabetes insipidus ormigraine. There is a tendency to late develop-ment of paraplegia in neurobrucellosis, due eitherto myelitis, radiculitis, or rarely to adhesivearachnoiditis or cord compression from hyper-trophic pachymeningitis, arachnoid cyst or abscessfrom spinal osteitis. Brucellar meningitis isusually lymphocytic. It may be the sole mani-festation of brucellosis and may resemble tuber-culous meningitis.

Psychological illness can occur. Many patientsare depressed and irritable and neurasthenic, butsome become maniacal, schizoid, paranoid andeven suicidal. If in mental illness there arerecurring slight fevers with chilly feelings andsweating, brucellosis should be thought of,especially in country districts.

Liver. Hepatitis always occurs, with granu-lomata in the parenchyma. It is suspected thatsometimes it may go on to cirrhosis. Liverabscess is rare.

Reproductive system. Orchitis occurs as a latemanifestation in about 5 to io per cent. of cases,and can cause testicular atrophy, sterility in rarebilateral cases, and rarely suppuration. It is much

more likely to occur in cases due to Br. melitensisthan in those due to Br. abortus or suis. Theepididymis may be involved and tuberculousepididymo-orchitis may be simulated. Impotenceis common. In the human female abortion is un-common, but amenorrhoea is common andmetrorrhagia may occur.

Urinary System. Febrile albuminuria mayoccur in the acute stage. Nephritis and cystitisare very rare. In paraplegic cases needingcatheterization infection can occur.

Respiratory System. Rarely, bronchitis, pneu-monia, pleurisy and empyema have been reported.

Cardio-vascular System. Brucellosis is a rarecause of subacute bacterial endocarditis, peri-carditis and of thrombophlebitis.

Nose. Epistaxis.Eyes. Iritis, choroiditis, retinal lesions and, in

neurological cases, papilloedema, optic atrophy,diplopia, ptosis, oculomotor palsies, mydriasis,irregularity, inequality or fixity of the pupils.

Alimentary System. Anorexia and constipationcommon, diarrhoea uncommon, ulceration andintestinal haemorrhage rare.

Skin. Alopecia has been reported in severemelitensis cases. Rarely rashes of various sortsoccur-erythematous, urticarial, papular, macular,purpuric and erythema nodosum.

Breasts. In humans, mastitis is uncommonand breast abscess is rare.

Duration of the Disease. Variable, but often

copyright. on July 6, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.28.324.529 on 1 October 1952. D

ownloaded from

532 POSTGRADUATE MEDICAL JOURNAL October 1953

..............

M,..

FIG. 4.-Brucella melitensis.

three to six months, with sometimes subsequentdebility for a year or several years, and sometimeslate localizations, for instance in the nervoussystem.

Mortality. Probably about 2 per cent. beforeantibiotic treatments were discovered; usuallyfrom hyperpyrexia, intestinal haemorrhage, in-fective endocarditis, encephalomyelitis and urinaryinfection secondary to unrecovered paraplegia.

Laboratory FindingsBlood

The white cell count is usually normal or low,with relative or absolute increase of lymphocytes.This alone in a case of pyrexia should raise thepossibility of brucellosis. Eosinophils are oftenabsent in the acute stage.Red Blood Corpuscles. In the later stages

anaemia often occurs, of varying types, and usuallynot severe.

Culture. At least 5 ml. of blood are incubatedwith special media, of which trypticase soy brothis perhaps the best, under increased (io per cent.)carbon dioxide tension. Frequent subcultures ontrypticase soy agar are made from the fourth dayfor five weeks. With good technique and sevenconsecutive daily blood cultures, positive Oloodculture can often be obtained in early pyrexialcases.Serum agglutination. A titre of i in 40 or over is

strongly suggestive and of i in ioo is diagnostic.A rising titre in serial tests is of special significance.Zonal agglutination tends to occur in which

agglutination takes place with low concentrationsof serum whilst no agglutination takes place withhigh concentrations.The complementfixation test and the opsonocyto-

phagic test are more in vogue in America than inEngland. The former is sometimes positive earlierand persists lonager than the agglutination reaction.The cerebro-spinal fluid is usually normal in theordinary case but sometimes shows a slight rise incell count and protein. When there are neuro-logical complications the cells are usually increasedto over ioo and sometimes to over i,ooo per ml.and are usually mainly lymphocytes; the proteinis usually considerably raised and may even bexanthochromic, also in such cases the cerebro-spinal fluid often agglutinates brucella in adiagnostic titre of i in ioo or over and may give apositive culture.

Intradermal test. o.i ml. of brucellin is injectedinto the skin of the forearm. A positive result isa raised red oedematous and sometimes tenderplaque, 2 to 6 cm. in diameter, appearing within48 hours. It merely indicates past or presentbrucellosis, being comparable to a tuberculin test,and as it vitiates future agglutination tests it is oflittle value.

The brucella organisms vary in morphology fromvery small cocci to delicate rods, depending on thestrain and conditions of growth. They are gram-negative, non - motile, non - spore - forming andoccasionally encapsulated.

DiagnosisIn a disease with such varying clinical manifesta-

tions how is the diagnosis approached? Obviouslyone cannot wait for undulating pyrexia which, inany case, may not occur. The following steps leadto the diagnosis:

i. Awareness of the possibility of the diseaseand especial alertness in country districts whereraw milk is drunk and where the patient's occupa-tion may bring him into contact with the animalsmentioned or their carcases.

2. Suspicion. This should especially bearoused:

(a) In a case of pyrexia with normal or lowwhite blood count, especially if there is back-ache, headache, sweating or enlarged spleen orliver. The differential diagnosis of such casesmust be worked out in each part of the worldafter consideration of what other local diseasescause a similar picture.

(b) In cases of headache and backache andjoint pains not explained by commoner causes.

(c) Chronic ill health associated with recurringshivering and sweats or low pyrexia.

(d) In any case of lymphocytic meningitis.

copyright. on July 6, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.28.324.529 on 1 October 1952. D

ownloaded from

Octob2r 1953 NELSON-JONES: Brucellosis 533

29M&r April April April 2 m JMyMawE - 30Ma June June June Jun Ju!y3Apr 4-10 31-17 13-24 1 2-0 9 16 6- 23-29 SJun -1-2 1319 20'23 July 4

305

304

103 1

102 L3

1-ho- L EES E- =-100 1i I99

l ___ 1111T

97

96

2000

3000

0

FIG. 5.-Showing temperature and agglutination curves. There was abrupt termination of thepyrexia after the second dose of vaccine and a rapid recovery.

(e) In neurological diseases with recurringfocal symptoms with the same or differentlocalizations or in unexplained paraplegia,especially if there is a history of pyrexial illnessmonths or years previously.

(f) If any of the things mentioned under'clinical picture ' such as cold abscess or in-fective endocarditis cannot be shown to be dueto one of their common causes.3. Laboratory tests. Diagnosis depends on

these, although in a typical case those who haveseen brucellosis previously may feel fairly sureclinically. The most satisfactory proof is, ofcourse, blood culture, but practically the first stepwill be agglutination reaction of the serum, andin neurological cases of the cerebro-spinal fluidalso. It is wise to start several cultures and if theagglutination test is negative to repeat it to lookfor a rising titre. Brucellin intradermal testshave many pitfalls and if used at all should onlybe used by those with full knowledge of these.

Treatmenti. Streptomycin with sulphadiazine. Start sul-

phadiazine, i gm., four-hourly by mouth, andafter three days give also streptomycin, i gm.b.d., intramuscularly. Continue both for twoto six weeks if well tolerated. The disadvantagesare drug toxicity and an occasional Herxheimer-like reaction.

2. Chloramphenicol or aureomycin often cause

remission but relapses are common and they areprobably not as good as early reports suggested.

3. Terramycin and erythromycin are under trial.Isonicotinic acid is worth a trial.The resistance of Brucella organisms to chemical

and physical agents is comparable to that of othernon-spore-formers such as the tubercle andtyphoid bacilli.

4. Brucellin (a mixed toxic filtrate of the threeBrucella organisms) injected intramuscularly atintervals of five days, starting with o.i ml. andincreasing according to condition of patient andreaction to previous dose. In chronic cases whichdo not clear up on antibiotics this is still worthtrying.

5. Brucella (antibacterial) vaccine, also worthtrying in such cases, starting with 0.5 millionintramuscularly and giving increasing doses everyfive days

6. Human Immune Serum. Some temporarypassive immunity may be achieved by injecting10 to 20 ml. intramuscularly or even intravenouslyand may help to tide over a fulminating or hyper-pyrexial case until antibiotic treatment couldbecome effective. In neurological cases somecould also be given intrathecally.

7. Complications.Spinal Osteitis. Rest on plaster cast may be

necessary and, if disintegration of bone shouldoccur, Albee graft.

Paraplegia, if due to spinal abscess, hvpertrophic

copyright. on July 6, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.28.324.529 on 1 October 1952. D

ownloaded from

534 POSTGRADUATE MEDICAL JOURNAL October 1952

pachymeningitis, arachnoid cyst or adhesive arach-noiditis, may require laminectomy. In these daysintrathecal streptomycin would have to beconsidered.

8. Symptoms. Analgesics for pain and head-ache, hypnotics for insomnia, aperients or enemataor both for constipation, iron for anaemia andnutritious diet in convalescence.

PreventionPasteurization or boiling of milk would eliminate

brucellosis except in those whose work bringsthem in contact with infected animals or theircarcases, and laboratory workers. Completeeradication of the disease in humans depends onits eradication in animals. This has been achievedin Norway as a result of laws which stated thataborting animals must be reported and tested, andthat the owner of infected animals must not allowhis animals to have a chance of infecting those ofother owners. Infected animals were marked andcould only leave the farm for slaughter.Methods of eradication must vary according to

the veterinary problems of the particular country,but consist essentially of (i) elimination of infectedanimals (detected by the agglutination test) and(ii) vaccination of animals. In Great Britain,brucellosis does not occur in pigs, goats or sheep.It occurs only in bovines and is almost entirelydue to Br. abortus. In bovines, vaccination withan attenuated strain of Br. abortus (Strain I9 orS.i9) has given valuable results.

AcknowledgmentsI am indebted to the Wellcome Museum of

Medical Science for illustrations I, 3, 4 and 5, andto Professor Stableforth, Director of the VeterinaryFisheries, for Fig. 2.

BIBLIOGRAPHY'Brucellosis: A Symposium' (I950), American Association for the

Advancement of Science.DALRYMPLE-CHAMPNEYS, W. (I95o), Lancet, i, 429, 477.HARRIS, H. J. (I950), ' Brucellosis,' New York.MARSTON, J. A. (I859), Army Mledical Report of I863, 3, 486.ROGER, H., and POURSINES, Y. (1938), Marseille-med., 2, 63.STABLEFORTH, A. W. (I952), Proc. Roy. Soc. Med., 45 (2),

79-86 (veterinary).

N

SURGICAL REPLACEMENT THERAPYBy MICHAEL F. A. WOODRUFF, M.S., F.R.C.S.

Department of Surgery, University of Aberdeen

Basic PrinciplesWhenever important structures are congenitally

absent or irreparably damaged by injury or disease,the problem of replacement arises. In many casesno solution can be found; recently, however,surgeons have become increasingly interested inthe problem and important advances have beenmade.The methods of replacement now being used

may be classified under three main headings:i. Autotransplantation (autografting), i.e. trans-

plantation of living tissue from some other site inthe same individual.

2. Homotransplantation (homografting), i.e.transplantation of living tissue from anotherindividual.

3. Implantation, i.e. insertion of inert material.This may consist of:

(a) Dead tissue derived from the same or anotherindividual or from an animal.

(b) Synthetic substances such as acrylic resin.Heterotransplantation, i.e. transplantation of

living tissue from an animal, has also been triedbut has now been abandoned as useless.

Transplants may be further subdivided intofree transplants, transplants by vascular anasto-mosis and pedicle transplants. A free transplantconsists of an isolated piece of tissue which, if itbecomes vascularized at all, does so as the result ofingrowth of vessels from the surrounding tissue.In transplantation by vascular anastomosis, on theother hand, continuity between the blood vesselsof transplant and host is established at the time ofoperation. In an experimental animal, for ex-ample, a kidney may be transplanted to the neckwith anastomosis of the renal artery to the carotidand the renal vein to the jugular vein. A pedicletransplant remains attached to the donor site untilan alternative blood supply has developed. Ahomotransplant which remains temporarily at-

copyright. on July 6, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.28.324.529 on 1 October 1952. D

ownloaded from