Postgrad Med J: first published as 10.1136/pgmj.22.254.405 on 1 December 1946. Downloaded from

THE INVESTIGATION OF PROLONGED PYREXIA By T. W. PRESTON, M.D.(LOND.), M.R.C.P.(LOND.) Physician, Croydon General Hospital; Hon. Lieut.-Col. R.A.M.C., lately Officer i/c of a Medical Divisiont India Command Preliminary Considerations Br. abortus of Bang. A single reading against the enteric group will frequently be inconclusive By prolonged pyrexia will be understood pyrexia (especially if the patient has been innoculated), but of over ten days' duration. For the purposes of a series of three tests at two-day intervals may show this article itiwill be assumed that a careful clinical a rising titre of diagnostic significance. examination has failed to reveal physical signs (4) A bloodfilm should be examined for malarial of a definite character. parasites if the patient has lived in a tropical or Confronted with such a case it will rarely be sub-tropical country; if necessary this should be possible to make an immediate diagnosis and repeated several times, if possible during a rigor. investigation resolves itself into carrying out the result of Pending these investigations, theProtected by copyright. certain routine tests which will reduce a large case will be carefully reviewed, a study made of number of "possibles" into a lesser number of the type of fever as shown by a four-hourly chart, "probables" from which the final diagnosis can and inquiry made into the patient's recent and finally be determined by some specific test. The remote movements. This is particularly important late Sir Raymond Crawford was fond of saying to at the present time when so many men and women his students, "Rare things are rare and common have recently returned from military service over- things are common," and this is an adage which seas. In considering residence overseas it is may profitably be borne in mind in this type of case. desirable to ascertain with some accuracy the At this stage, the following investigations should particular location and in obscure cases to consult be carried out as routine. the relevant authorities as to the diseases endemic (i) Leucocyte and differential leucocyte count.- and epidemic. A general statement that the A high polymorphoneucleocytosis will make it patient has been "in Africa" or "in India" may extremely probable that the patient is suffering lead those unfamiliar with these countries to waste from some pyogenic infection-very probably a time looking for diseases which in fact never occur hidden collection of pus, and further investiga- in the areas concerned. tions should be concentrated in this direction. A http://pmj.bmj.com/ leucopenia, especially with a relative lymphocytosis, An ex-soldier was suffering from an obscure pyrexia. will indicate an entirely different field for further Information that he had served in India led the doctor in inquiry, whilst large numbers of monocytes or charge to institute investigations for Kala-azar. More detailed inquiry showed that in India he had been stationed eosinophiles will definitely narrow the field. exclusively in Hyderabad state and Bombay Presidency- Where the picture is indefinite, repeated counts at areas in which Kala-azar is as little prevalent as in the three-day intervals should be made. It must be Isle of Wight. remembered that the picture may vary from day to day and, moreover, the picture may be mis- After these preliminary considerations, the various on October 1, 2021 by guest. leading if the patient has been having a course of diseases likely to be the cause of prolonged pyrexia sulphonamide. may be enumerated and briefly reviewed. They (2) Blood culture.-One sample of blood should may conveniently be subdivided into the following be cultured on glucose broth, a second on a medium, groups: suitable for the isolation of the Enteric Group (e.g. McConkey's medium). A positive culture will (a) Diseases of World-Wide Incidence. usually be conclusive but a negative result excludes i. Likely to be associated with a polymor- nothing. phonucleo-leucocytosis. ii. Likely to be associated with a leucopenia. (3) Agglutination reactions against B. typhosus iii. Likely to be associated with an indefinite blood and B. paratyphosis A. and B.; M. melitensis and picture. .406 POST-GRADUATE MEDICAL JOURNAL December, I946Postgrad Med J: first published as 10.1136/pgmj.22.254.405 on 1 December 1946. Downloaded from (b) Diseases peculiar to certain areas. person. If the patient has been previously inno- culated however (even twenty years previously) (a) (i) Diseases of World-Wide Incidence H-agglutination is valueless. Associated with Polymorphonucleo- "O" agglutination is not specific for separate leucocytosis. members of the "E" group but is not produced by i. Septicaemia (including Bacterial Endocar- innoculation. Hence, a rising titre in serial tests ditis). is of diagnostic significance of enteric infection, ii. Pyaemia. but is not specific. iii. Hidden collection of pus.-It is neither "VV" agglutinins are highly specific. practicable nor desirable to discuss the numerous It is suggested that the terms "+ Widal" and conditions included under this heading, but special "- Widal" should be abandoned as valueless mention may be made of perinephric abscess and and misleading; the only report of clinical value is "carbuncle of the kidney." There are probably a rising titre in at least two and preferably three few clinicians of experience who have not at some tests done at two-day intervals. time had under their care cases of obscure pyrexia 2. Undulant Fever (Abortus type) is seen occa- which have long eluded diagnosis and which have sionally in all parts of the world. Clinically it is ultimately turned out to have had a perinephric milder than Melitensis infections (see under (B)); it abscess. In view of the obscure signs, special has few characteristic features of diagnostic signi- attention should always be concentrated on the ficance and it is rarely diagnosed until it has run exclusion of this most difficult condition. A for many weeks and numerous investigations previous history of boils will lead to a suspicion of made with negative result; if the pyrexia assumes the closely allied condition of "carbuncle of the the characteristic undulant type the case may be Kidney." (En passant, a warning may be uttered suspected clinically; but frequently the fever is at the too facile dismissal of a staphylococcus continuous or irregular. Diagnosis is established grown from blood or urine culture as a contamina- by agglutination of I-IOO or more to Br. AbortusProtected by copyright. tion. Mention may be made of a case ultimately of Bang. Infection is due to ingestion of infected diagnosed as carbuncle of the kidney which had milk or contiguity to infected animals, but often it remained undiagnosed for many weeks. Perusal is impossible to trace any connection and the -of the case papers revealed that early after ad- clinical history may be most misleading. mission a urine culture had grown a staphylococcus A soldier was admitted to a Military Hospital in Scotland -and disregarded.) with the following history: Six weeks previously whilst stationed in the English Midlands he had been admitted to hospital with acute tonsillitis: contrary to established (a) (ii) Diseases of World-Wide Incidence practice his tonsils had been enucleated during the stage Associated with Leucopenia. of acute infection. After a stormy convalescence he was sent on leave to his home in Scotland where he spent most I. Enteric Group of Fevers.-It is essential to of the time in bed feeling unwell and running irregular exclude this group in any case of prolonged pyrexia. fever. At the expiration of his leave he consulted a local Characteristically.the temperature chart will show doctor who sent him to the nearest Military Hospital as a a step-like rise and a relatively slow pulse, but all "P.U.O." Physical examination was negative and although blood culture was sterile a provisional diagnosis types of fever may occur. Although commonest of streptococcal septicaemia seemed, under the circum-http://pmj.bmj.com/ in tropical countries, especially when associated stances, not unreasonable. This diagnosis seemed streng- with faulty hygiene, it occurs sporadically and in thened when the temperature subsided coincidentally with -minor epidemics in this country. the exhibition of sulphonamide. After a few days, however, the temperature rose again, and the diagnosis The surest method of diagnosis is by blood was only established several weeks later when agglutina- -culture. This is most likely to be positive in the tion to Br. Abortus was obtained in high dilution. early stages but is well worth carrying out at any stage. 3. Agranulocytosis.-This condition is to be

Failing a positive blood culture, isolation of the borne in mind especially in view of the prevalent, on October 1, 2021 by guest. -bacilli from the stools is successfully undertaken and sometimes injudicious, use of the suphonamide in many cases when an efficient technique is group of drugs. Differential diagnosis may be employed; although most likely to give positive difficult from aplastic anaemia, acute aleukaemic results after the third week, an increasing number leukaemia and acute mononucleosis. Examination of bacteriologists are now successful in the early of sternal marrow by a skilled haematologist may stages. help. Agglutination Reactions: (A) (iii) Diseases of World-Wide Incidence "H" agglutination is indicative of infection with with Indefinite-Blood Picture. -the homologous organism in an uninnoculated i. Atypical Pneumonia. Usually the fever sub- December, 1946 INVESTIGATION OF PROLONGED PYREXIA 407Postgrad Med J: first published as 10.1136/pgmj.22.254.405 on 1 December 1946. Downloaded from sides within io days, but in more prolonged cases 30,000 per c.mm. is unusual and raises suspicion of the absence of physical signs will make diagnosis a leukaemia. A positive Paul-Bunnell reaction in difficult. There may be an increase of monocytes. a titre of I-64 is diagnostic. (There is no doubt The diagnosis can only be established by radio- that this group calls for further clarification.) graphy. 8. Lymphadenoma may be associated with pyrexia 2. Influenza.-Except in epidemics, this diag- of a relapsing type (Pel-Ebstein) or irregular. nosis should never be made until other conditions The blood picture is not characteristic and diag- .have been excluded; the diagnosis should only be nosis can only be established by biopsy of a gland. provisional so long as fever persists and investi- Great difficulty in diagnosis may occur when the gations must be continued. There may be leuco- mediastinal or mesenteric glands are enlarged with penia and the pulse relatively slow, but these no appreciable superficial adenitis. findings are inconstant. If fever persists for more 9. Leukaemias.-Atypical leukaemias with than two weeks it is wise to assume either that the pyrexia and aleukaemia may present difficulty. diagnosis is wrong or that there are complications Diagnosis depends on repeated blood examinations (especially pneumonia or empyaema). and examination of sternal marrow by a skilled 3. Acute Miliary Tuberculosis. haematologist. 4. Relapsing Fever.-Although commonest in the East, it occurs in Europe and is reported from time (B) Diseases Peculiar to Certain Areas. to time in Ireland (The (louse-borne). tick-borne i. Malaria. With a history of relapse in a occurs in Central Africa.) It is characterised by tropical or sub-tropical country it is always five to seven days of high fever followed by a necessary to exclude malaria. The following crisis and ten to fourteen days remission followed practical points should be borne in mind: by relapse. This may be repeated once or-several Duration of liability to relapse: M.T., rare after times. Diagnosis is established by detection of common to two the spirochaete in thick blood films taken during eighteen months; B.T., up yearsProtected by copyright. fever. and may be up to three or four years; Quartan, 5. Rat-Bite Fever produces a relapsing type of very persistent-four years or more. fever difficult to distinguish from relapsing fever. Well-authenticated cases have occurred of There may be a polymorphonucleocytosis. The apparent first attacks in this country in persons history, local lymphangitis and a raised erythe- who have not had clinical malaria overseas. matous rash will direct the diagnosis. The One negative blood film does not exclude causative spirillum may be found in the blood but Malaria; it may be necessary to examine many its isolation is difficult. films before parasites are found-preferably taken 6. Typhus Fevers.-The true louse-borne or during a rigor. epidemic typhus is world-wide. Tick-borne, mite- A soldier was admitted to hospital in India with per- borne and flea-borne varieties occur endemically, sistent pyrexia. Six blood films were taken and examined various sub-types in various districts. In endemic by an experienced pathologist with negative results. A areas and in epidemics diagnosis on clinical grounds seventh film was literally swarming with M.T. parasites. is easy, otherwise diagnosis is established by the Occasionally parasites (especially M.T.) may be Weil-Felix reaction. (Note: sporadic cases are discovered on sternal puncture which have eludedhttp://pmj.bmj.com/ unlikely.) detection in blood films. 7. Glandular Fever.-The common glandular It is emphasised that the characteristic regular types and the rare Anginose tvpe do not call for intermittent fever may be replaced by a fever description in a discussion on Prolonged Pyrexia. irregular or continuous. The febrile type, however, may present extreme Occasionally it is justifiable to try the therapeutic difficulties in diagnosis. Adenitis may be transi- effect of Quinine in spite of negative films. tory and too slight to be significant, and clinically the course and symptoms may be uncharacteristic. on October 1, 2021 by guest. Pyrexia may be prolonged with recurrences and 2. Kala-azar (Leishmaniasis).-Although fairly apyrexial periods. Undulant fevers, lymphade- wide-spread this condition has a somewhat patchy noma and leukaemia may be suspected. Although distribution and is practically unknown in some monocucleosis is characteristic (and probably areas in close proximity to others where it is always occurs at some stage), the blood picture is common. In Africa it is mainly found on the extremely variable and may change from day to East coast, in Sudan and the Blue Nile, Ethiopia day. There may be leucopenia or leucocytosis and and on the Mediterranean coast; in Europe, on polymorphs, lymphocytes or monocytes may pre- the south coast of Spain, Malta and Crete, Sicily, dominate. In suspected cases repeated blood and the "toe" of Italy. In India-a few cases examinations should be made. A count of over occur in Madras-then passing north the country 408 POST-GRADUATE MEDICAL JOURNAL December, 1946Postgrad Med J: first published as 10.1136/pgmj.22.254.405 on 1 December 1946. Downloaded from is free of it until we come to the Ganges delta; it is for the material to be examined by a pathologist common in Bengal and Assam, but is never met experienced in Kala-azar. west of Lucknow, Western India being free. It Napier's Aldchyde test is valuable and easily occurs in parts of China, Manchukuo, Mongolia, carried out, but it rarely gives a positive result Transcaucasia, and Russian Turkestan, and in until the disease is of three to four months duration. parts of South America. It is therefore useless for early diagnosis, buit a The fever is characteristically remittent, dropping negative reaction in a case of long-standing illness in the morning, rising in the early afternoon, falling can be safely taken to exclude Kala-azar. Doubt-. again towards evening, and rising again during ful positive reactions are stated to occur in certain the night. This will be shown by keeping a three- other diseases (advanced tuberculosis, and leprosy). hourly chart. This may continue for many weeks 3. Undulant Fever (Melitensis type) is wide- followed by a period of partial apyrexia followed spread in goat-rearing districts of the tropics and by a relapse. This may continue for many sub-tropics. The undulant character of the fever months. is more constant than in the Abortus type and Absence of malaise and symptoms may be usually the patient is more ill. Sweating may be striking. It is a clinical experience never to be profuse and there is complaint of headache, a forgotten to visit a hospital where cases of Kala- picture which may be mistaken for acute rheu- azar are being treated; to inspect first the tem- matism. The spleen may be enlarged. The pulse perature charts showing fever to I030 and I040, is relatively slow. There is usually leucopenia and then to see the patients sitting up in bed with relative lymphocytosis. Agglutination to eating a hearty meal and demanding to be allowed I-ioo or over to M. Melitensis establishes the up! It is frequently difficult to persuade Indian diagnosis. and African patients to remain in hospital and A soldier was invalided home from North Africa as a often impossible to confine them to bed. case of Pulmonary Tuberculosis. His prolonged fever Leucopenia is a striking and constant feature- seemed inconsistent with the apparently healed andProtected by copyright. usually below 3,000 per c.mm. and often down to inactive tuberculous focus seen radiologically. Agglutina- I,ooo per c.mm., the deficiency being mainly in tion reactions gave a strong positive to M. Melitensis. polymorphs. 4. Amoebiasis.-It may appear that reference to Enlargement of the spleen occurs approximately this condition is out of place in a paper on pro- at the same rate as the pregnant uterus in the longed pyrexia since localising symptoms and opposite direction. Thus in early cases the spleen signs might reasonably be anticipated. It is will be just palpable, in a case of six months duration emphasised, therefore, that Amoebic Dysentery is it may be expected in the region of the umbilicus. occasionally an insidious disease and bowel Diagnosis can only be established by demon- symptoms may occur ten years or longer after strating L-D bodies in material obtained by original infection (which may never have been sternal or splenic puncture. Although less reliable, diagnosed). When, therefore, obscure pyrexia sternal puncture should always be tried first on occurs in persons with a past record of tropical account of its greater safety and the material residence, examination of the stools and careful cultured as well as examined in direct films. palpation of the liver is indicated. Sometimes a

Splenic puncture should be performed by a rapid liver abscess may occur in an impalpable liverhttp://pmj.bmj.com/ thrust with a fine-bore needle; the drop of fluid and only recognised by "humping" of the dia- thus obtained is quite sufficient for examination. phragm revealed by screening. (Note: such a Prolonged aspiration through a wide-bore needle is liver, however, would usually be painful on pressure unnecessary and dangerous. It is emphasised over the intercostal spaces.) It may be noted that that recognition of L-D bodies requires the whilst a leucocytosis (with increased polymorphs) familiarity which is only gained by experience. is usual it may be only of moderate degree and It is futile for the clinician to subject his patient may be absent. In Endemic areas the therapeutic to the inconvenience (and possible danger) of effect of emetine is sometimes regarded as a useful on October 1, 2021 by guest. sternal or splenic puncture unless he has arranged and justifiable test.