YilltoaVTITRU!TI IN MALAYA
TTY
:COT CUON8L A ,%S. HOBSON, M.D., M.R.C.
(19to Medical Specialist, iiritish Unitary Hos-ital)
rinrqra, ,uela Lumpur. CONTENTS.
1. JR.4;FAJli, 2, INTRODUCTION. RIME OP LIVITOSPIROSIS IN I ALAYA 4. CLINICAL MATERIAL.... 9 5. SOURCE OP INFECTION... 10 6. CLINICAL PICTURE 12
P? 7. COMPLICATIONS...... •••••••• ...... • 8. LABORATQRy I NITS STIOATION3 11 9. DIMREATIAL DIAGNOSIS 10. TREATVNT El)PENICILLIN • . 27 b) RENAL FAILURE . . A t ( 0 ) GiMRAL 29
11. PROGNOSIS .... 33 12. POST-WORM FINDINGS '31/- 13. GENERAL DISCUSSION a)CLINICAL PICTURE...... *IN • II• 39 b)BLOOD ''RE; SURE...... 39 COMFTICATIONS ii-0 DIAGNOSIS. LABORATORY IN1U.STIGATIONS • 9- 3 71ROGNOSIS 14-11- 14. SPalTAL DISCUSSIONS ENICILLIN iti V TIIINTMTHaMY'' .• . S-C c) RENAL PATHOLOGY...... PATHOGENESIS OP RENAL [,'AILURE fi e) PRWENTION OF RENAL FAILURE G i- 15. SUMMARY. 69 16. REFERENCES ...... 70 17. A '!'ENDIX A.LABORATORY FINDINGS 73 B.CASE RgOORDS PREFACE.
It is since (-)rld :or IT that ellaya has become one of the malor overseas stntions for the British Army. s is only to be expected, the incidence of disese affecting service personnel will tend to vary from the well annotated pre-1939 era, when India was the main overseas base. It is essential that this change of incidence should be noted, and clinical details of any common disease affecting personnel serving in the country should be carefully recorded for the benefit of future serving medical. officers. This especially arol_les to the present day, when such a large proportion of the R.A.M.C. is composed of National Oervice Officers, who in the majority of cases have not served previously overseas and require information t;cut t disef*ses they may be taped upon to treat. It is with this object in mind, tlit I hove tal,:en the opportunity of describing leptospirosis as seen !among service personnel in Malaya. The clinical material which formed the basis for this paper consisted of 27 eases which were admitted under my care during 1950, to the British Military Hospital, Kinrara, near Kuala Lumpur. Owing to the lac% of facilities for the carrying out of leptospiral agglutination tests and the repeated failure to demonstrwte leptospira by guinea pig inoculations, the cases were diagnosed. on clinical grounds alone, However. :.era rInd successful blood c'ultures from similar cases have been sent to the U.K.- for examination by rr. J. Q. Broom p,t the elloome Research Institution, London. Re has identified some of the leptospiral strains, thus confirming the general clinical diagnosis of these cases (1951). Recently Bucklc!nd (1951) has succeeded in transmitting the disease to -hamsters (cricetus auratus) after failing with guinea pigs. The complete clinical picture, complications and prognosis are discussed and comparison made with the renorts of previous Malayan writers. The differential diagnosis of the disease as seen service personnel Is fully discussed. Treatment with penicillin was employed and from the records stntintical evidence is elicited to suggest that the nntibiotic has no effect upon the duration of fever, but does iminish the incidence of febrile relapse. The,pathogenesis of renal failure in leptonnirosis is discussed in the light of the recent advances in knowledge about acute tubular necrosis; and possible oreventitive treatment suggested. A detailed list of laboratory findings which include modern biochemical investirations„ he8 been appended, to provide a record for puroses of comparison,
ACKNODGMfOTS. I would like to express my appreciation of the invaluable assistance 71ven to me, in the maintenance of 3 detailed case sheets, by tlajor (now Lieut. Col.) R.M. VANUEIUN, R.A..C. who served as my assistant medical officer; to Major (now Dr.) J.B. L.D., t4.R.0.".0 for the many laboratory investir!ations and the post-mortem examinations: to the many ?:.A.R.A.U.C. Officers and R.A.M.C. Orderlies (some F:tilayan) who nursed so many of the cases heck to complete health. T wish to thank the Director-enernl, Meilical rervlces, for permirmion to utilize the necessary clinical records for this thesis. 2. INTR(DUOTION. wince 1886, when a German -physician named described four cases Of an acute febrile illnest, associ!vted with laundice, haemorrhages and splenic enlargement, the syndrome has been associated with his name by later observers. The disease was recognised in various parts of the world. In japan, in 191), IAADA isolated a spirochsete-like organism from cp,ses of the disease. This discovery was confirmed a year later by two R.A.W..O Officers - Stokes-and- Ryle (1916). These Officers isolated a similar organism, from cases occurring among troops of the British -army in Flanders. Noguchl (1917) considered that the morphology of this new organism was sufficiently characterstio to -warrant the creation of a new genus which he named Leptospira. tlince then, the genus has been expanded by the identification of many more species, some of Waich are not pathogenic to. man. The general term "leptospirosis" is now given to infections with the members of the genus; "eils" Disease being restricted by general usage to infection with L. ictero-haemorrhaglae. R:::7 11 L '~PTO `3IROnTS IN IIALATN.. The history of leptospirosis in alay to quite recent. As far as. can he ascertained, the description, by GALLOAY (1926)4 of four cases, was the first to be ottblished. He described the onset of the disease as being sudden, with a rigor, followed by headaohe, intense ,Tinacular rains, vomiting, prostr7tion and congested conjunctivae, Jaundice appeared on the fourth day and colncided with a fall of temperature. There was a trace of albumen in the urine and casts were present. During the following two days there was an aggravation of symptoms with rapid enlargement of the liver and the development of haemorrhages:5. A remission of the fever And symptoms-occurred on the 8th day or after. Two of the cases died of epistaxis and severe intestinal haemorrhages, a delirium of the uraemic type preceeding death. There was no mention of rashes, anuria or oliguria, or laboratory investimtions.
iMETOFBR (1923), working at the Institute of Medical Research in Yuala TampUr, on an investigation into :4crub Typhus, demonstrated the oresence of pathogenic leptospira by guinea-pig inoculation, in the blood of a case of pyrexia of unknown origin. Fe found after such inoculation, that the guinea pigs developed fever on the twelfth. day. If killed, or at death, autopsy showed subcutaneous, pulmonary and intestinal haemorrhages. The pulmonary haemorrhages tended to be in the shape of a butterfly and leotospira could be recovered from the liver and 'oineys. He escribed 32 cases, in 13 of which,- he demonstrated. leptospl.ra in the blood b guinea-pig inoculation or by direct blocA,culture before the eighth day of the fever. In 14 wses, Teptospira were demonstrated by inoculation of the urine after the eighth da or by urine culture. Fletcher stfited that his findings led him to believe that Malayan infections were due to the following leptospira:- L. Ictero-Irtemorrhagine, 1. hebdomadis, pyrogenec,. L. mellothamby4 and erythan. An analysis of his clinical findings in the 32 canes is shown in Table I. There was one fatal case, 'oath being due to toxaemia and uraemia,
LENTM'AIT (1929), described 7 canes. In six, he demonstrated leptospira by guinea-pig inoculation of blood before the eighth day of the disease or of . urine after the eighth day. He inoculated several guinea pigs daily and then re-inoculated the peritoneal fluid into a second series of •.animmls. An analysis of his clinical findinge in the 7 capes is shown in Table I. There was no mention of renal_ complication or the results of any ancillary laboratory investigations.
DANARAJ (1950), reviewed 19 cases of /eptespirosin seen in Singapore General Hospital. These cases included seven which showed sJgns of meningitis. In all the cases except one, the Alurnosis was confirmed by transrnitting the disease to guinea-nigs by intra2eritoneal inoculation of blood, Ivine or cerebra-spinal fluid. In the remaining case, which proved fotni, leptospira were demonstrated in histolofJcal ctections of the kidneys and liver. An analysis of his clinical findings is shown in Table I. Chnnges in the eerebro-spinal fluid were evident in 3 cases, in which signs of meningitis were absent. Tie pointed out, that exce7t in the fatal case whch developed renal failure, meningitis only occurred in the nnicteric cases. He considered that the most important pathological finding was the elevation of the blood urea, which was found as early as the 2nd or 3rd day of the illness. In addition, Danara3 considered that the level of the blood urea was of prognostic significance, as those patients with blood levels of over 200 mgme were more ill than the remainder. TABLE T.
A tale showing the percentnge incHence of the chief signs and s*ptoms derIcribed by ?4alsan dbservers, and including the present series for compariten.
Author Fletcher Lewthwaite Tlanaral 'resent 1928 7929 1950 -leries
To. of cases ;;-,, 7 19 77
Prostration 100. 71'
Jaundice L4 14 -1 49 tuscular , T)inn 91' 36 100 67 .
-uffuslon of eyes 961 86 ' 100 70
'evere Headache 25 86 74 r-T Immes•am.. Vomitinp7 47 297, + 56
4,/buminuria 100: 1003 ”. 77
Hrtemorrhages 19- NIL 26
eningism - - 22.- 22,
Danaral stated that "vomiting, when present, was not severe". 4. CLINICAL MAT&RIAL. The twenty seven cases which form the basic for-this paper comprise fourteen British and thirteen Gurkha soldiers. These patients were adqtted under my care during 1950, to the nilitary Hospital at Kinrara, near IC.uala Lumpur. Three cases prove fatal, of which one was British, and two Gurkhas. As mentioned previously, the diagnosis of all the cases . was made clinically, as agglutination tests were not available, and guinea—pig inoculation experiments with blood or urine proved unsuccessful. However, cera from similar cases and in some cases successful blood cultures, have, since 1950, been sent to the for examination by Dr. J. C. Broom. In an interim report (1951) he stated that he had identified from the various qiaterial, L. cantcola, L. bataviae and strain Bangkinang (autumnalls group) and obtained aerological evidence only, of infections with L. ictoro—haemorrhagiae and members of the hebdomad s group. In a number of cases, the infecting organism had yet to be identified. It will be reciated, that It is probable that the cases to be described in this paer. have been infected with various species of leptospira. This may account for variations in the clinical nietures but, Pletcher (1928), stated that he found no clinical variation between cases from whom he had isolated differing leptospiral species. 10
SoURCE (F- INFECTION. All of the cases occurred in soldiers, engaged in jungle operations, ogoinst the terrorists in the states of Selangor, Pahang, Negri lembilan and Perak. None of the soldiers served wholly ill towns. The conditions of service entailed living in the jungle and relying upon streams for water—supply. Patrols in the jungle necessitated marching over swampy and marshy ground, wading through streams and being continuously subject to insect bites, minor abrasions and septic akin conditions. In a review of the sources and methods of human infection with leptospirosis, Alston (1949) stated that in almost all circumstances, infection from animal carriers to man, is not through direct contact, but is by leptospira which have been excreted by animals on to damp ground or into water, where it is well known that the organism con survive for long periods. The route of infection in man is usually through cuts, abrasions, bites, sodden surfaces, conjunctivae and possibly by mouth. It will be appreciated that the jungle conditions are ideal for the transmission of leptosoirosis provided that animal vectors are present. As to which of the multitudinous small animals, which. abound in the jungle, are concerted as carriers, is not known for certain. Pletcher (1928) following a. survey of rr•ts trapped in the Selangor rural areas, showed in 26O, lc tospira on solenic culture. The leptosoira were chiefly of the hebdomadis /1
"'roue. In no case was L. ictero-hremorrha e demonstrated. He was to demonstrate any le too.nira in rnts of town origin. 12,
6. CLINICAL PICTUR%. The inci(3ence of symptoms and signs which were observed ln the cases is shown in Table II.
1",BLE II. (Total number of cases - 27). ever. 100y3 (27) 'uffused coniuncti”re. 7C = (19) Ueadache. 67 (18) MO, -ins. 67 (18) 'omiting. 56 (15) Muscular tenderness. 49, (13) Jaundice. 149:, (13) Abdominal pain. 44 (12) Cough. 37 (10) Backache. 33 (9) Haemoutysis. 26 (7) Abdominal tenderness. 26 (7) Meningism. 92 (6) Subconlunctival haemorrhage. 22 (6) RigorS. 19 (5) Psemotemesis. 15 (4) 15 (ti,) oeteehill Rash. 15 (4) Diarrhoea. 11 (3) Palppble Spleen. 11 (3) (2) Palpable Liver. 7 Hae,riPturia. 7 (2)
TABLE III.
• Detailed analysis of the occurence of the main symptoms and signs in the individual cases. SIGNS IN THE INDIVIDUAL CASES.
i CASE O. 4 / 2 I 5 6 9 /0 // /2 13 114 /Si /Cl/7-3 fe /9 201.•‹)/ 1+; JAUNDICE ! 4' 4- 4- 4 ! 4 f
VOMITING 4 4- +1 -3-• i 4 HJ-H * M IvaLD 1 LIMB PAINS 4 4 4 ZITS * MODERATELY SEVERE i • ABDOMINAL PAIN 4 4 14 4- • +- S * SEVERE
4I VS * VERY SEVERE SUFFUSED EYES r4-ti t D =DIED HEADACHE + -t- : ! MENIINGISM 1+1 NR RESULTS OF URINALYSIS COUGH NOT RECORDED SUBCONJUNCTIVAL 1 + 4- 4 EPISTAIIS 1 -I- i 4- i 4- -41 1 -4- 4- 1 T- 4--, , HAEMOPTYSIS -t- i -t- 1 -t- i 1 4-, ---f----t--+- --4- -t- --y-; --,f -- 4-- 1. -"- HAEMATEMESIS I -r 1 I --f- --+- -t --i-- HAEMATURIA PETECHIAL RASH 1 1 1-..4 ALBUNINORIA 1 Idle • t 1NR OLIGURIA 1- ANURIA t 1 t 1 CLINICAL * 1. M5 Vs MS, 5 M C AS! 1 MS NI ‘_)I • SEVERITY t '
TABLE IV. TABLE SHOWING DURATION OF FEVER BEFORE AND AFTER COMMENCEEENT OF PENICILLIN • THERAPY AND DURATION OF ANY "AFTER FEVER".
1 6 4 2 2. 7 6 3 iL Jevere aase 3 8 3 11
4 9 11 15-2 Very severe c-a
e, 1 5 9 6 4 3 12 7 6 6 1 7 22-53 Zievere c,,se 8 . . . . No penicil4iL, • 9 .. 13 19 Fever nenx lea Itil 19th iLy 10 7 - 4 11 11 2 10 I a-3 6evere case 12 5 4 9 A.3 5 5 3 8 14 . . - . 10 No penicillin 15 ... - - . 12 Do penicillin 10 5 - 5 10 17 0 1 7 18 Do details 19 6 - 3 9, Died on 9th day 20 11 . 1 12 21 4 . 1 5 22 - - . o pcnicillin 23 24 76 2 9 • 25 9 < 1 26 2 3 Died on 4th day '> 27 5 4 2 Eiod on llth d'ay 13
The detailed occurrence of the chief symptoms and signs in the individual cases is shown in Table III. ONSET. • In every °mem the illness had a sudden, onset. A previously healthy individual would develop fever, and in the more severe cases -become raeidly ill and toxic. Prom an early st-ee, such cases would ceuse anxiety to their medical ettendants. P.ere2e. The rise of temperature at the onset was usually rapid, and levels of 1010- 1030F were common within the first 214 hours. The fever tended to be irregular with remittent end even intermittent ehases. The duration of the fever in 24 cases varied from 5-12 days (see Table rv). Of the three remaining cases, one died on the third day, one heel a prolonged fever for 19 h'ye, and records are unavailable for the third. In L cases, after the initial fever had subsided, a secondary or "after-fever" developed. This secondary fever developed from Li.-19 days after the initial fever had subsided, and eeruisted for verying periods of time (12-32 days). In to of the four cases, a mild urinary infection was discovered, the organisms involved being eenicillin- ineensitive: but it was doubtful as to whether the infection was the cause of the fever, es successful treatment of the infect- on did not bring about the subsidence of the fever. 3U 'FUSION OF CONJUNCTIVAE. "Itiffused conlunctivae are a well known clinical finding in this condition, and are of diagnostic importance in tem-erste countries. Hnwever in nalaya, suffusjon of the conlunctivne is common in febrile patients, especially those Who have been brought out of the jungle. It is also a characteristic finding in scrub typhus, another common disease occurring in the some. area. Clinically, there did not a' pearto be any particular (lifference between the conjunctivae seen in the various conditi ns. EEADACHE. Headache occurred in 18 cases, and cvAild be very severe and persistent. Sometimes it became the predominant symptom. It should be noted, however, that it was not necessarily associated with signs and symptoms of meninx eal involvement. LIMB PAINS. Limb pains were of particular significance. They were essentially muscular and could be ver7 severe. Typically the calves were affected, but frenuently the thigh muscles were also involved. VOMITING,.
Vomiting occurred in 15 cases and was a mar red fey tore especially in- the severe csen. It was not continuous in noture, but intermittent, with appreciable periods between. MUSCULAR TENDERNESS •Muscular tenderness especially in the calf muscles was Most charecteistic of the disease, .Thereas in many . acutely if febrile conditions gentle squeezing of the calf muscles between the thumb and forefinger causes mild discomfort, in leptossiresis it causes acute min, and the patient will withdraw his leg rasidly. JAUNDICE. Cl inicx I. jaundice occurred in thirteen cases. In ten At made its appearance between the 5th and 7th day of the it in two cones on the 4t11 day, and the remaining case on the ^th day.
,Sue to the associated erythema of the skin, the Jaundice appeared as an orange-red colour as opposed to the classical yellow colour of infective hepatitis. However this appearance was not so noticeable in the dark skinned races, such as the. Gurkhas. 1l3Iss‘SIN.A1, PAIN AND TYINDIMISSffl. Abdominsl pains were comnlnined of in twelve csses and could be a prominent symptom. In only four cases was there associated abdominal tenderness. In three other cases, abdominal tenderness was discovered on examinatien, but there sere no sublective symptoms of pain. Of the seven oases in which abdominal tenderness was present, it was found to be generalized in three, epigastric in three, and in the right Hine fosses in one. en palpation, one gained the impression that the tenderness was maecular in origin. The cases in- which the tenderness was enigastric in location, were marked by reverted vomiting and retching. It is possible that muscular strain from the vomiting was the most likely cause of the tenderness. id
In case-So.19 there. was generalized abdominal tenderness, but always more marked on the right side of the abdomen. It. is interesting to note, that st the autopsy of this case a large retroperitoneal haemorrhage was found on the same side. OCUGH. Cough occurred An ten onses and was associated with sub- sternal discomfort. In five cases, the srmtum was streaked with blood. BACKAGHF1. Backache was a symptom in nine coscll nc9 could be quite severe. The impression gained, was that it was similar in nature to the muscular limb painS. HAEMOIVYSIS. Haemoptysis occurred in seven cases before the sixth clay of the illness. In six cases it was associated with a persistent cough and substernal discomfort. In the remaining cse (N0.19) it appeared. an a manifestation of severe generalized hnemorrha7es.
neningism was found in six cases and then only slight. In none of the cases was lumbar puncture considered to be justified. SUBCOMINCTIVAL HMMORTIWY.r. Subconjunctival haemorrhages occurred in six cases. The day of appearante varied between the 4th to 17th days. l?
RIGORS. Rigors occurred in five cases within the first forty eight hours of the ilinesr3, prior to admission to hospital. HAEMATEMI Haematerle is occurred in four cases, all of whom were critical)y ill, two proving fatal. The time of occurrence varied from the 2nd-12th ay. Tn one cse ( To.4) the patient vomited blood en the twelfth lay and elected a piece of tissue which preVed to be a piece of gastric mucosa about 6 arms x
4 S. EPIOTW.3. Epistaxis occurred in four cn.ses, of whom two died. In two eases it was the only haemorrhagic symptom. The tirce of onset varied from the .11d-13th days. nTS011741, RASH. Petechial raShes occurred in four c sea. The time of occurrence varied from the nth-loth days. DIARpCiA. Diarrhoea occurred in three oases, but being mild it was not considered to be of nn:: significance. STURIC MILARGEMENT. The spleen was found to be clinically enlarged in three cases, in two of which it was described as being '7alpable, and two fingers-breadths in the third case. The latter case ;;roved to be fatal and et autopsy the spleen was found to be greatly enlarged. RIMMT. The liver was found to be palpable i o two rases and then only on fullful tnnrirntion, HAMATURIA. Haematuria occurred in two cases, in both f which smoky-red urine was found on the fifth day and persisted for a day. 7. CqVIPLICWION3. The complications which occurred were as follows-
160*0,40 4J4 (12 ANURIA 26 °LIGURIA ...... 19 TEMPORARY ISOTHENURI4 ..... 30s TTTAWY ...... 7
7pechromic anaemia occurred in 12 cases and was not necessarily related to any haemorrhages. 77or example, in case No.2.„ on the 34th day of the illness the blood picture' showed 1fl 12.7 Tris. RBC = 2.55 x 106 per cu.mm. and no -Clinical haemorrhage had occurred. AITURIA. (4' the seven cases which developed anuria, five commenced on the 4th or 5th days, the others on the 6th and 8th days respectively. The durotion varied from 7-6 da-o. The anuria was practically comrlete, though occasionally, entheteri7ation might Produce one or two ounces of urine. OLIGURIA. Oliguria occurred in five cnses. It was defined as being the voluntary passage of less then ten ounces of urine per 24 hours. In alaya, se in other tronical area, the normal volume of urine excreted per day is less than in temperate areas. atients tend not to complain provided they pass urine at an. Thus oli;Turia is only recognised by the maintenance of fluid balance charts. Oliguria developed between the 6th-ath Onys in three CR568 and on t] 4th day in two. za
TEMPORASY InTTIENURIA. In eight cases the specific r,12avity of the urine excreted bacaNe constant at about 1010 for varying periods of time up to the 78th day. All cases recovered and before final discharge, water concentration and dilution tests were found to be within normal limits. TETAVY. Tatany occurred in one case. This case developed severe jaundice (serum bilirubin = 31.2 mgns. on :Ali day) and on the 17th day developed generalized musciAar twitchings and carpopedal spasms. On that day, the serum calcium was found to be 6.4 mgms:. The symptoms disappeared ra idly after the intrErvenous administration of calcium gluconate. 21
8. LABORATURY INVESTIGATIONS. Detailed findirrs in individual coses are rthown in the appendix. (a) JHITE BLOOD CELL COUNT. Less than 10,000 per cu.mm. 25"4, (7) - 15,000 per cu.mm. .. 37 (10)
15,000 - 20,000 per cu.mm. •0004.4. 19% (5) Eore than 20,000 per cu.mm. 19.: (5) It will be noticed that a leucocytosis was found to be present in 75 of canes. The averare.e W.B.O. count was 16,600 per cu.mm.; the lowest count being 7,,hx:A. p(ir cu.mm. with -M. polymorphs and the highest, 33,000 per cu.mm. with 73 polymorphs. Theo figures relate to the initial counts performed after admission. (b) URINALr-JS. PR —. qSNT nBg-PMT DIMTNTRTA 77 23 GTONUTAP CAM'S 71 ' 291, R.B.C. 50 The results of urinalysis were not recorded in three cases and the above flg,ures therefore relate to 74 cases. Albumlnuria was not pre2ent in six ofses, of which five were assessed as being clinically mild. (0) IILMT URA. An elevation of the blood urea was the most important laboratory finding and was present in 23 cases (851. 22
in many acute febrile caee where the diagnosis of leetospirosis was considered unliely cltnicel [reeends, the blood urea wa found to be normal. Therefore it was not considered that dehydration with chloride denleti on elayed much part in the elevation of the blood urea. Actually in Malaya. troops operating in the lunele were provided with /flaily salt tablete and cases of chloride denletien were rare. In seventeen of the twenty-three cases the blood urea reached its highest level between the 8th-12th days of the desenne, though it had begun to rise ac early as the 4th day, and had fallen to normal by about the 14th day. it was apparent that the highest level of the blood urea coincided with the end of the anuric or otiguric period (i.e. at the time of maximum nitrogen retention). Of the four remnining cases, the blood urea wa 40 migme on the 9th dey in one ceee, no records being available for the others. (d) 'MLITT711- N. serum bilirubln eritimat1ons were carried out in fourteen cases. in eleven caeee, levels above 2.0 mgt were round. The individual maximum values varied from 2.35 mgles% to 3%2 mgms.:1,. This latter value was recorded on the 8th day in Case No.7. (o) ?LAMY, i20T/N. The plasma proteins were estlected in sixteen cases and twice in five cases. The remelts showed the following 13 variations:- Total "olnsma iroteins 5.0 - 8.5 mein (Mean 6 . 1 3 gins') flernm Albumin 3 2 - 6.0 grns r) Olean 4.4 gme I) eri_tin Globulin 1 0 - 4.1 gn*.; (Mean 1.9 gms •) It will be noticed that the plasma proteins remnined within normal limits,
() Tirr,LIOI TURBIDITY ,\I'M These investigations were carried out in seven ef7ses. It was found that the values were within norrrnl limits in all oases. The results varied as follows: Thytool Turbidity . 1-4 units (, ean 2.2). (Normal 0-5 units). Alkaline Phosphatase 4-12 units (Mean 6.0). (Normal t.-13 unite).
(g) SRIJITT CHOLESTROL. The serum cholesterol was estimoted in fourteen oases including severe enses. C:n two occesions, values of below 120 mons were recc,rcled and both were in the sy,Tae case (Case 140,13) . cm the 5th day the level was 112 mg= and :.-41 the 13th day 1!:7 mgrs . The case was moderately severe, but not so severe as case No.7 in which on the eighth day, Y.:hen the iaundice was at its deepest, the serum cholesterol vas 125 morn' Ind four %lays later when the blood urea was 540 mgms: the serum cholesterol had risen to 28r, mgras 9. DIMRENTIV, DIAGNOsIG. The clinical diagnosis of the established case with the chsracteristic ornnse-red colouration of the skin, fever, calf tenderness, aibuminuria, polymorphonuclear leucocytosis and a raised blood urea presents no difficulties. Difficulty arises in cases in Which it:mild:Ice does not develop and in the Trpecteric phase of cases which ester develop jaundice. Except for the mild case which presented as a mild pyrexia of unicnown origin with some calf tenderness and perhaps aihuminuria or suffused eyes and were only diagnosed in retrospect, the average case appeared to be ill on ndmission, with vomiting a.cowion symptom. This ill and toxic appearnce was always a contrast to cases of mnlaria or scrub typhus which could be as acutely febrile but not so Blood films were always ernmined as a routine to exclude malariatinfection. The ms;ri differentstion was from scrub typhus, typhoid and flute hepatic necrosis. Headache cauld be very severe and persistent and appear to be the pre(7sminant symptom as is so cherscteristic in scrub typhus. in addition, transient maculo,-erythematous- rashes, similar to the common rash seen in 'Allan scrub typhus, mild suffusion of the eyes, enlarged lymph glands (so common in jungle troops due to minor sensis) could simulate scrub typhus. Leptospirosis was differentiated by the degree of prostration, presence of muscular pains, calf tenderness, any haemorrhegic symptoms, development of renal failure and elevation a the blood urea. The 11.1ill and toxic looking case with a furred tongue, vogue abdominal pains end tenderness, constipation, high fever and some ill—defined red spots due perhaps to prickly hest or insect bites, could suggest typhoid fever. Lestospirosis was differentiated by the rapidity of development of the established disease as opposed to the slower deteriorstion of a csse of typhoid, the leucocytosis, usual absence of sslenic enlargement, raised blood urea, calf tenderness end negstive blood culture. The severely Ill, jaundiced patient with fever, leucocytosis and haemorrhagic symptoms might simulate acute hepatic necrosis. Lestospirosis was differentiated by the sudden onset with 'ugh fever for some days before the development of jaundice, the absence of any progressive diminution of hepatic dullness on percussion, the rresence of calf tenderness, the early elevation of the blood urea and the persistently normal levels of the plasma proteins and liver function tests. Apart from these three conditions, the abdominal and pulmonary :,...-tiintorias sometimes csused early diagnostic problems. In one case (No.4) constipation, pain and tenderness in the right iliac fossa and vomiting caused the patient to be edmitted to hossital with a provisional singnosis of subacute aSsendicitis. Examination showed the abdominal pain to be more generalised, nncl not associated with rigidity. The duration of the history (5 days), high fever (102.50P), pains in the legs and suffused conjunctivae suggested the true diagnosis., In another case (jo.21) an onset with fever, cough and !me optysis sue:gested a pulmonary condition but examination showed thnt the nine name were not working and there was no dyspnoev. lbuminuria presence of granular wets nnd red blood cells, leucooytosis nd raised blood urea indicated the correct diagnosis. 21
10. TIWTM01. (a) PENICIL,IN. In view of the favourable reports of the treatment of human leptospirosis with penicillin (Bart 1944: Oarragher 1945: Bulmor 1945: rAatterson 1947) such therapy was employed. On making the clinical diagnosis of leptospirosis, aqueous 2encillin was administered intramuscularly in a dosage of 500,000 units six-hourly. Owing to geographical and transort difficulties experienced in the evacuation of the sick, the mlority of the patients were not admitted to hospital until after the third day of the disease (range 3-10 days) and the commencement of therapy was correspondingly delayed. Details as to the any of commencement of therapy in the individual cases are shown in Table IV. of the 27 eases, aenicillin was used in 22 cases aid no specific therapy in the remaining five cases. Olinically„ one gained the impression that the patient improved subiectively in some cases following penicillin administrtion hut it is doubtful, as to whether it had a direct effect on the fever. Sxamination of Table IV shows that in 7 cases the temperature became normal. after I day, and 5 cases after two days. In the remaining cases the period varied from 3-5 days elccept case No.9 in which the fever persisted for 13 days. i,s4 will be discussed later, it appeared as though the fever ran Ito natural course in spite of peWcillin therapy. 2r
(b) RENAL PAILUR4. In one case, which became anuric (Cse No.12) treatment with an intragastric drip of a glucose-peanut oil suspension was tried (Bull et al 1949). Owing to the increased loss of fluid by sweating in the tropics, it war decided empirically, to double the amount of fluid recommended, vi7 2 litres instead of 1 litre. 6thercasea were treated with intravenous saline therapy, taking cre to avoid overloading the pulmonary circulation.
TI oases appeared to resnond equally well. As the cases did net remain anuric for more than 4-5 days with either treatment, it is not considered that any comparison can be made. Ahen the period of anuria .cea.ses, a period of diuresis follows. During :this phase it is believed that tubular reabsorption is in abeyance and the patient is excreting the glomerultAr filtrate. Thus the volume of urine passed, may be enormous and unless the intake is correspondingly increased, dehydration may result. This urine carries with it in elution, sodium chloride in large qaantities because tubular reabsorption of this salt is defective, and this may intensify the drain on the extracellular electrolytes. It is possible, by mensuring the daily volume of the urine passed, and its chloride content, to calculate the chloride loss. This may then be replaced orally or intravenously as saline. tiller (1949) suggested, that half the volume of urine excreted daily, replaced as normal saline by mouth, Should cover the chloride loss, and that it was not nauseating to patients. In Case 2?
No.! such a diuresis followed a period of anuria. The details of the daily fluid intake and output are shown in Table V. It will he noticed that there was a markedly negative fluid balance between the 12th-16th days (i.e. let-5th days after cessation of nAuria), when the insenotble fluid loss vit skin, lungs etc., nmounting to ap!-ToxiMetely 1500 ml. 18 Included. It was found that the patient concerned, would not tolernte normal saline by mouth and N/4 saline was used instead, to the salt losc. In addition, it will be noticed that the specific gr,-mity of the urine passed, did not Ball below 1006 until the 17th day, i.e. 6th post-anurie day. This was in keeping with the theory that the urine excreted, is practically a pure glomerular filtrate. (c) VITA2IN Kt THERAM In view of the haemorrhagic symptoms being frequently associated with jaundice, it is recommended to administer Vitamin K (1:4 napthoquinone). In all cases, 15 rngms daily was given intramuscularly. (d) IzakrAiurr..__ As with all acutely iii patients, reneral nursing was of supreme importance. Durin,g the diuretic phase, continuous encouragement of the patient to drink fluids was essential. Insomnia was common, but resonded to the administration of barbiturates. Amytal gr iii , fleconal gr iii or Soneryl 30
ill were most frequently used. Blood transfusions ere required on several occasions usually to combat the anaemia but in Case U0.4 as a necessity owing to severe haemateme is. ruritns an occasionally troublesome and treatment not very satisfactory. sedation with phenobarbitone, external application of anti—pruritics, e.g. calamine, and anti— histaminic drugs such as benadryl, anthisan etc. were tried but none -proved very satisfactory. Persistent hiccou Was troublesome in the deeply Jaundiced cases and proved irresnonsive to treatment.
3/ TABLE V. showing fluid intak:e and output in 0r,..se P.4.
21AY OF _,LTID fl,(.. OUTrir I 1 ,T Ri13.0 INTAKE URINE U INE i VOMIT BALM10.1:- (-m1) 1) 1 (m1)
x C4IL
rodi...... r,
X - , -.... .550 360 ÷ 20 90
10 4080 ,.. :75.00 4- 3765 .....„ ii x - -
7 5850 1008-10 2600 1530 720
8730 _ 5850 4..,,80 - 2100 4
111 2700 1006 2160 71J: 330 4- ...... 3300 1006 3;370 - 570 4,
6900 1003 50 So 10 50 - 210 4.
17 5700 1004-10 3960 420 1.320
13 9720 1002-06 6810 + 2910
r 8 820 6390 + 2430
10 5 0 1001-0 6 5700 ¢ - + 4840
21 9120 1001-014 8040 - + 1080
. awn.w.oww.1•0011.V.010.110.1245. 22 8280 - - 7260 - 4-, 1020
3 7660 1004 6180 - • 1470
2 657, - 5100 - + 1470
25 3(1,0 1002-04 7020 i 1_5 25 5530 4200 •i 13 So , 27 3050 7150 1 x No detai , available. hen the insensible fluid loss of 1000-1500 ml is taken into account it will be noticed that there is a marked negative balance between the 12th-16th days. 33
11. PROGNOSI There were three deaths among the twenty seven cases, two einp richas and one British, Of the three fatal cases, two were non-iaundiced and one laundiced. One of the former (Case No.26) died of acute toxaemia on the 4th day of his illness and so it was imposr ible to say whether jaundice might have developed or not. The remaining two cases died of urnemia associated Jith multiple haemorrhages. Renal failure was the most serious complication which could develop. Al the coven anuric cases, two died, one was critically 11.1 (Case No.4) and the regrinder were clinically severe. Haemorrhagic symptoms were associated with severe cases. An analysis of the incidence of such smptoms and the clinical assessment of the respective cases is shown in'Table VI. TABLE VI.
CLINICA `MdiNT !%4FIC Rg GIC "TOM .OD;MATET VII;RY 7:.TLD ',7,'W-1.11R7.. ITV ig !"1';'WQ,IS .....1.1.40. DI EsITSCIIAL RASH - i 1111111111111111 - SUBCONjUR NCTIVAL tEMOR4AGE ------,- EPISTAXIS - 2 HAAT,"JITIIIi-i _ _ J___1_ HAEWATURIA 1 _ — 1t appears that eoista s and/or hae pternesi are of serious import. 39-
12. POST-MORTEM FINDINGS. short-clinical sumaries snd post-mortem findings of three fatal eases were as follows- (a) Case '10.1,9 Ptc. L. (5ritish). Admitted with three day history of left-sided abdominal pain, fever (T.102.3°F), headache and pain in the calves. On the day prior to admission vomiting and epistaxis occurred. On admission, the urine showed heavy albuminuria with many granular casts, and the Count was 13 600/cu mm with 85: polymorphs. Anuria developed on the day of admission and persisted for 96 hours. Blood Urea on 5th day was 180 mgms rising to 430 mgme on 7th day. On 2nd day in hospital (5th day of illness), he became drowsy and started to hiccough. Had further opistaxis. On 3rd day showed deterioration of genera/ condition. On 4th day had haemoptysis and passed 14 07. of urine for the first time. Became dyspnoeic and cyanosed. 5th day he remained dyspnceic, had further haemoptysis and died. A)T-MoRTSM. 'eart : Both ventricular cavities dilated. Lungs : Both showed many subpeural haemorrhages and on section showed extreme oedema and congestion. Abdomen The peritoneal cavity showed a small amount of blood-stai ned fluid. There were extensive 30-
retro-peritoneal haemorrhages in the bowel wall, in the meSentery and around both kidneys. Around the right kidney there was extensive blood clot. Liver : No apparent abnormality. Spleen : Normal. Kidneys t Both kidneys were swollen, with bulging of the cut surface. The cortex was very pale, showed gross swelling with some distortion of pattern. Differentiation between cortex and. Medulla was good, end accentuated by the cortical pallor. The casule striped easily, leaving a smooth surface . Uicroscorical Appearclaces. Liver ections showed normal liver tissue. reptospiro dould not be seen in sect one stained by Levaditits method. Kidneys : The glomeruli appeared normal while the daMage was confined to the tubules. The primary con- voluted tubules showed universal destruction and disintegration of the epithelium. The difference between the intact glomeruli and the damaged convoluted tubules was most marked.
(b) Case No.26, Rfn, S. (GUrkha). :Admitted with three day history of fever and headache (the history was sketchy owing to language difficulties). 3‘
On admi Sion he was feverish, eyes very suffused, axillary and inguinal glands were moJemtely enlv.rged, moderate nuchal rigidity, oedema of skin ,xere present and the nulse impalpable at the wrist. Heart rate 160 per minute.. B.?. 55/4o mms - 33,00 per cu mm ('.73%) Blood Urea - 90 mgms ,.. The same evening he became comatose and died the next morning. POST-MORTai. Heart : Pale and flabby. 3mall haemorrhagic areas in the muscles. Lunr7s : Both congested and showed aubpleural and interstitial haemorrhages. 9tomach : Mucosa presented small haemorrhagic spots. Liver : Enlarged, with mottled surface showing some peteehial haemorrhages. On section the organ bulp:ed markedly and the cut surface was mottled with some arena yellowish brown and others a deep red. Kidneys : Both kidneys pale and swollen. The cortex wae. widened and well-differentinted from the medulla. Spleen : Enlarged about five times. Beefy consistency and colour. Follicles viJqble. Pectoral Yuscles haemorrhagic areas visible. C.N.". tformal. 37
(a) Ceee NO.27, Cpl. B. (Gurkha). Admitted with four day history of fever, muscular pains, right sided abdominal pain, and passing dark urine. On admission - T. 1010P - eyes suffUeed and icteric looked Ill - celf muscles very tender. Bee anuric on evening of admission snd remained co, apart from catheterization of 5 oz. urine on two occasions, for five days. Became very deeply jaundiced and on the sixth day he suddenly collapsed and died. 11,600/cu mm (?.30/): Urine elbumen„ granular Casts end red blood cells present: Blood Urea rose from 125 mgmsZ on the second day in hospital to 550 mgma on the fifth day. eeT-MORTSM. ell tissueo with ti exception of the were deeply Icteric and there were numerous petechiae. Lunge nhowed multiple recent hemorrhages. • Heart : There were large haemorrhages into the tipS of the papillary muscles of the left ventricle. numerous eeicardial eetechtee present. Liver : Some reduction 1n size with capsular wrinkling. Surface showed subserous haemorrhages. Cut surface was greasy, deep yellow in colour and showed obvious fatty changes. eurn : Large submucous haemorrhages in the lower end of the ileum. 39'
Kineys : The cut surface bulged slightly. There was (leep inlection of the cortical gone with name 72etechiae. 13. GSNERAL DI1CUSSION. (a)Clinical Picture. There is a close correlation between the clinical picture seen in the present series and that described by previous Observers. All have stresse the sudden onset of the .illness with early prostration, high fever, 7encral37ed pains, vomiting and albuminuria. (b)Blood Pressupe. The level of the blood pressure found in cases of leptospirosis has been the subject of varying reports. Dawson and Hurne (1917) stated that the systolic blood pressure never fell below 100 mmn Hg. Gauld (1947) described one case which developed oliguria for eight days. The blood: pressure rose suddenly to 200/120 mme Hg on the eighth day. A diuresis commenced on the twelfth, day and the blood-pressure fell to 155/100 eras Hg. It fell further as the genernl condition improved. Cayley (1949) rePorted e rending of 130/80 ms Hg in one case. uchett-Xaye (1951) reporteda reading of 110/70 Trims Hg in a case which developed anuria on the fourth day. Broom & Robertson (1951) state that the blood pressure is low and tends to fall in severe caner). The blood pressure readings in some of the severe cases are shown in T:lale VII. Apart from Case no.19 the blood pressure appeared to be very low in the severe cases. As to whether Case No.19 suffered from hypertension prior to admission was not known, but it would be extremely unlikely.
fl ' VII.
Ocse o. ading . mms .
-56/40: 9-64/40: 1 -76/4 : vere 4Ja9e. M55: 12.100 r. auria '
7-')./58: 9-`32/60. Modest e c co. "iPuria j.
° 7-7V50. e rere c.se. M.F.
7'.`T/5.%. -eveve case. nuria 5-7.
. 4...ps3/70: 5--90/61.;: 8-1 3V73. severe ease, Anuria 4.3.
1.9 4-145/115: 6 148/115: 'ied. 7-135/110: 3-155/30. qoxia 40-0.
( r, 4-5')/4 • C
Oompli -tions. 1) QisAAL. Dawson and Uume (1917) dencribea retention of 2-3 days, in three cases but node no particular comment. (1921) made no men 1"a in 55 cases. P:utchin3on et (1946) describer five cases o anuri which three rrovec1 fatal, in a series oi 17 cases. They str (ii) AJAgIA. There have been varying reports about the development of an anaemia in leptospirosis. Davison and ITU= (1917) reported that anaemia was common and some cases developed red cell counts as low as 2.5 x 106 per Cu. mm. Ryle (1921) stated that secondary anaemia never occurred nnd the lowest red blood cell count reported in his series vas 4.24 x 106 per cu. mm. Oince then, cases showing anaemia have been reported by various observers; RBC - 3.74 x 106: Trb - 9.5 gms% (Cross 1945); ABC - x 106: Hb 59 (cayiey 1949); RBC 3.50 - 4.50 x 106: - 70 (Hutchinson et al 1946). Recently, Broom and Robertson (1951) have emnhasised that anaemia is a constant finding with red cell counts of about 3.00 x 106 per Cu. mm. and a corresponding fall in the haemoglobin levels. 1/-2 in the present sereles an anaemia developed in teelve cases (144). The lowest blood onunt was found in Case No.7. on the 13th -day - RBC - 1.81 x 1O per ca. mm: fib 4.9 gins. (iii) L;TAJY. es far as can be ascertained the only previous reference to tetany occurring as a complication, was by Gauld (19477).. He described the development of convulsions and carpopedal spasm on the eighth day in a case and recorded that the serum calcium was only 5.0 mgme per 100 ml. Bayley '(194.9) reported the finding of a serum calcium of 8.6 mgms per 1C.: ml, on approximately the sixteenth day of a case but did not mention any associated symptoms. (d) Diacnosis. Ryle (1921) discussed the difficulty of differentiating typhoid fever associated with jaundice, 'ux stated that the most important feature, was that a ease of •Iseese developed rapidly within the first few days whereas a similar case of typhoid would still apeeer indefinite at a similar stage of the illness. This difference in speed of development of the diseases was found to be a most important feature. Robertson (1946) stressed the importance of a rased blood urea in diagnosis and remarked that the urine could be normal. N)th of these statements were confirmed in the present 4-3 series. The blood urea was raised in 23 out of 27 cases and the urine was normal in 5 out of 27 cases. Robertson also found that the estimtion of the urea content 411 all lymphocytic cerebro-spinal fluids containing a norms/ nrnount of chlorides, a great help in detecting cnrly lertonpirecis. s no case in the nresent series was lumbar punctured, this findin was not verified. It is riot considered sufficient to diagnose leptospironis clinically. ?he agglutination test is the most widely, used and the rest useful procedure to the clinician for confirmation of his clinical diagnosis. Beginning about the seventh clay antibodies appear in the blood of the infected individual and show a rising titre. In alaya, unfortunately, laboratory facilities for tl-le test are, as yet, unnvnllable and rniinea pig inoculaticn has been moinly used to prove the human infection. riifficiaties have arisen owing to the varying degree of ',-thonenicity of the various strains of leptosnira towards guinea-pigs. Recently, the golden hamster (Cricetue auratue, hos been used with greater success and woe,: is proceeding (i3uckiand 1051). ( e) Laboratory investigations. (1) Leucocytesis. =7)01ymorphonuclear leucocytosis has been a constant finding-.by all observers.-. Dawson and llama (1917) stated that it was invariably present, with counts of up to 25,000 per cu. mm. (75-3C polymorphe). rutchineon et al (1946) described counts of 11-34,000 per cu. mm. in 10 cases and in 5 crises, where the initial Counts were below 10,000 per cu. mm, nn inereose to 13-.20,000 per Cu. mm. by the 9th-15th days was recorded. Gauld (1947) reported that only tee caes out of 13 had counts of less than 11,000 per rime mm. (ii)plood Urea. The findings of e raised blood urea and the importance as a diagnostic feature has been repeatedly stressed by many Obeervers. Robertson (1946) stete,1 that he had never seen a blood urea of over 25e mgms per 100 ml in non-leundiced cases unless they proved fatal. In the present series there were four non-icteric cases in which levels of over 250 mgm were recorded (Nos.4, 9, 12, 19). Of these cases one died (no.19). Two cases (Nos. 4, 9) showed levels of between 250-300 mgms eer 100 ml and one (No.12), level of 30 mgm per 100 ml on the llth day. (iii)Liver notion Tests. All Observers have reported that the liver function tests remain within nornel limits (Cayley 1949: nroom end Robertson 1g51). yley (1949) in addition, seggeeted that the normal values obtained, ere of assistance in excluding the diagnosis of ecute hepatic necrosis. (f) 'rognesis. The opinion ' the ma:, r ty of observers is that the associntion of 4aund ice with renal of reel'u proenoctic Import. It ha been etreesed on many occasions that, though non-leuneiced cases may be as ill on the Jeendice nee do not prove fetal except In rare ceses (Pyle 1921: chilffner 1934: Robertson 1946: Broom 1951). That the onset of renal failure in of serious import has been stressed by verious alethere. rroom and Robertson (1951) state that r eovary is unusual, once andA qls developed. iiutchinsoe et el (1946) gained the impression that unless oliguria eould be rapidly abolished, fatal outcome was certain. :hey reported 3 deaths out of 5 anuric caees. Gaule (1947) deocribed two cases which developed oliguria for 8 and 10 days respocttvoly and of whom the latter died. These opinionc have been conf.rmed in the eresent series. The mortality rates of Jaundiced and non-jaundiced cases of the present series, are compared with those of ether ealayan rnd 'uropean authors in Tebles Vi I. Tt elll be seen thy!, the uertality rate of non-jaundiced eescc is negli Able. ref the seven fetal coses in the Malaynn series, six died of urea:11a, the seventh (No.26 of rresent series) dying of acute toxaemia before uraemia could have eeeeloped. n the other hand if recovery eccure, the kidney apparently reg ins normal function. 2 11 renal efficiency tests return to normal within 2-3 months (teetchinson et al 194 Gauld 1947). This was confirmed in the eresent series. TABLE VI IvalaYan Series. - Cl'as s ,,,- hs ' , lis Jaund ,ed N n.J nd fY. .y 1.! - ___,..,--11926\ , 4 PATH&R L. 28) ' TAWTHWATTE (1929'1 (951) , , R8BENT 1 Totls 78 5 : 2 7 (*) ' ) ( r ) f. Includes Case No.26 who died on t,1,0 /4..th day. TABLE IX. Mows connorlson etween !,%711ayan Series and 14, n Series. --___--._ Author _ ' c 1 Jaundiced n-Jaunr. e bined DA/ HUM$ - 4.5-7 (191` 1 _..--- 13 NIL 1 4.i 5J-V) ' 4 Ct 1 k.r2 AL - 20.4% AULT) 7.7 _ 7.7% BII:k.;OL (1951) To penicillin 2 'cnicillln -treated. --- nb i ne , ....es. 4? 14. SPECIAL DISCUSSIONS. (a) TWATMENT ITH eeNICILLn. In experimental infection of animals with L. ictero- hoemorrhagiae, Koilman end llerrell (1944) and Alston and Broom (1944) showed that penicillin could prevent the appenrance of symptoms in guinea es, provided that treatment was begun within 24 hours. These observers and Auguotne et al (1944) however, found the drug completely inactive If it ens withheld until the animals showed signs of illness. en the contrary, Borg Petersen and Gchmidt (1945) were able to cure the disease in guinea-pigs even when treatment was delayed until the fourth day after infection and the animals were manifestly sick. Joshua and Preale (1947) noted very little response to penicillin therapy in dogs, infected with L. ietero- haemorrhagiae. This was in marked contrast to the dramatic improvement effected by the drug in the early stages of canine cenicola fever. In a similar manner, renorts on the action of eenteillin therapy in human leptospirosis have been variable. Hart (1944), Cerragher (1945), Bulmer (1945) and Patterson (1947), have commented favourably on the clinical use of narenteral penicillin in eill s hieense; they flave noticed the reeid disaopeorance of leptospira from the urine and an absence of febrile relap e but no apparent effect on the jaundice or nephritis. On the contrary, Yetchinson et al (1946) did not consider that there was any obvious benefit from the use of penicillin on the fever, toxaemia* pulse or .urinary output. Robertson (19)46) considered that penicillin ohortened the course of severe ceses, protected the liver but not the kidneyS. fenith (1949) thought that penicillin had little effect in toxie petients. Broom (1951) from a statistical study of 51 cases in which the tiny of diseese* on which penicillin treetment was comeenced, was lelown, concluded that the patients concerned, obtained no benefit from the administration of eenicillin et ewr stage of the disease. euchett-Kaye (1951) considered that the beneficial effect of penicillin given early, was shown by the rentd fall of the temperature and by the disappearance of such symptoms as headache, myelgia, epigestric pain, and apathy. He also considered that the urinary output, blood urea, white cell count, and E.S.R. returned to normal quicker than in untreated cases. Leptospira could not be found in the urine 24 hours after the first dose of penicillin, en the other hard gneketteF4eye thought that though penicillin did not seem to have any effect on the course of eeteblished hepatitis, the drug probably protected the liver as well as the kidneys from further assaults by lepto pits. eummarizing these observations, it nears thet eenicilltn has been reported to be of benefit in the treatment of human leetospirosis because it results in:- (1) A ahortened febrile course. (ii) More ran16 return of blood urea level to normal. (ill) Rapid return of white blood cell count to normal. (iv)Rapid disappearance of leptospira from the urine. (v)Rapid return of urinary output to normal. (vi)Diminution in the Incidence of febrile relapse. (vii)Rapid improvement in eublectiVe Tempteme such as heaenchee, menleias etc. it is proPosen to eiscuss these ntatements in more detail. shortened f,Orile course. 7iefore it can be asserted that penicillin Shorteno the febrile course of tbe diseese, consideration must be given to the duration of fever in untreated'casee. it Would then be necesnary to compere the totel duration of fever in treated and nntrented comes end to submit the findings to statistical investigation. The following details of duration of fever in penicillin trested and untreated cases have been elicited from the literature. Details of such cases are shown in Table X. TABLE X. CA1S8 UCT TREATED JTH PgNICILLIN. Author No. of Cases Mean ruration of Range, :)evee in Da;g1n. 1-rfLE (1921) 59 7-14 reVeClISR (1923) 26 8.4 6-12 r 17 „.. ni\TTo (1929) 7 9-12 DAV/DSON (1934) 15 7.5 6-9 GAD1D (1947) 11 7.0 PATTERSON (1947) 44 .9.0 S2.R72i2 ic 1r)-12 Totcl.. 162 Oafl -.3 CASE2 1. R; TITH T)ENSOILLIN. Author No. of Cases Mean 37uration of Range. Fever in nays. PATTERSON (19L.7) 6 9.5 (,-13 IM1AW (1950) 17 9,0 5-13 SUGESTT-KAYE (1951) 4 6.8 5-8 PRESBOT -SERIES 21 9.7 5-19 •••••••••.• Total 148 Wean 9.2 It will be seen that there is no:appreciable difference between the mean duration of fever in the two series of cases. •The conclusion must be drawn that the duration of fever in leptoopirosis is not influenced by penicillin thery. (ii) "ore rrlid return of blood urea te. normal level. 11 observers are a7,reed that the elevation of the blood urea is the most significant finding in leptospirosis and can be demonstrated as early as the 2nd or 3rd day of the disease. The elevation of the blood urea is dqe to renal fa lure, and its duration will depend upon the degree and duration of such failure. As will be discussed later, the renal failure may vary from a temporary reduction in glomerular filtration pressure with minimal absent tubular lesions, to a•more sustained reduction, associated with a widespread diversion of blood-flow from the renal cortex. This result8 in ischaemic damage to the parts of the nerhrons depending upon such cortical blood- flow. 57 For penicillin to effect the return of the blood urea level to normal, it would need to 1:e postulated, that lepteseira are themselves the direct cause of the renal failure, end that upon their inhibition or destruction, renal function woul} resume. It would appear to be eetremely improbeble that such a direct action by the leetoeetre occurs. ?hough their action on the epithelium of ne first convelutoe tubules eight be direct, renal I:unction- should only improve following heeling of such damage, and this could not lee influenced by penicillin therapy. It is ConsiOered that the evidence suggests, that the return of the blood urea level to normal depends upon the recovery of renal function. 721ae time involved in such return, varies with the degree of initial renal damage. , and penicillin therapy could not have any direct effect on the shortening of such a period of time. (iii) keeele_return or white 'blood cell count to nor Perueal of the literature shows that the white blood cell count Is very veriable in leptonriroels. 14utchtneon et el (1e46) descrebed 'five ceoes 1.n which the tnitial counts were less thnn 1G00:,u per cu. nun. and eet roe to 13-20,060 per cu. mm. by the 8th-5th days rIcseite penicillin therapy. Otyley (1949) described nennoe'in which the count W2S still 184,000. per cu. mm, -on the 3th day. A similar cane was described be eteuld (1747), Tn the eresent series, seven cises had initial counts of below le,100 per Cu. TTO.' tbe -.r.c. count stowing such vrriation it is difficult to believe that it be used as a measure of the effect of 'enicilltn therapy. ?arid dleapT)earance of leptespim fL on the urine. to '1117 the disappearance of lectosp ra from the urine, hi been iggested as a measure of the ,-)enefit of therapy Is difficult to understnd, in view of the prey' Dina Ino741e(1Fre reined aboUt the urinary excretion of le7tespira. Pletcher (1:;28) maintained that owing to the excretion of immune bodies in the urine the leptosoira are motionless or deod and so dark-ground examinations ore of little vie and at the same time frue,ht v:ith error. He advised repented intracerltoncal inoculations of centrifuged urine into 7uinea pigs. He stted that positive results could he obtained rfter the 15th-1(7th days. Manson-Bahr (1948) stater th9t positive results can be atelned flfter the 12th day. In addition he quotes Davidson as saying that leptoscira may disa7pear comoletely in acid urine. Thus, at the stage of the illness during which penicillin is adminiltered, -renence of leptospira in the urine, is not to be expected. The only nner in which le-oton7Aral excretion could be used ns a measure of benefit of penicillin therapy In cases, we/11d be, for daily urinary examination to be rerformed, and the repeated absence of such ors:7nisme to be considered a positive effect. A comparison between penicillin-treated and untreated cases should then be mde to discover whether leptosiva are found less in the former (i.e. Penicillin treated) tAan the latter cases. far as can be ascertained, no uuch series have bean reported. (v) 4a0d return of urinarY output to normal. The return of the urinary output to normal in any single case will deDend upon the extent and type of renal failure. As will be described later, the extent of the renal lesion leptospironis praably depends upon the duration of the diversion of the cortical blood flow. It is doubtful If this is entirely due to the LIction of leptospirn and so it is difficult to believe that the actual destruction of leptospiro by penicillin will have a direct effect upon the return of urinary (utut to normal. • (vi) Diminution in the iqpidongq pf febrile relapses,. For purposes of discussion, a febrile relapse in leptospirosis i defined as a fever of 99°? or more which is maintained for four or more days, an6 which develops four or more days aft the initial fever has subsided. It will be seen in Table XI that the reourted incidence of febrile relapses has been variable. Dawson and :lume (1917) reported 10.: relapses in 14 severe eases and only 22.4 in 58 mild eall=. Davidson Smith (1934) reported 405 relapses in 15 severe c,z,ses. Lewthwaite (1929) observed one febrile -'elapse in seven cases, and stated that the case yas the iminCiced and presumably the most severe. Ignoring this variation in incidence with clinical severity reported by some observers, it will be seen that the overall incidence of febrile relapses has been 2%C , in the pre-penicillin series as opposed to 10.6. in the penicillin treated cases. :his difference is statistically significant and su73.ests that penicillin diminishes the incidence of felaille relapses in lepte Piro .is. each an effect would be expected to shorten the convalescence and speed the recovery of cases. That this might be so, has been suggested by::.groom (1951). (vii) Rapid improvement in subJecti7e This can only be an individual clinical impression. My impression was, that in the milder cases, there was a rapid subjective improvement, but in the severe cases, symptoms persi.sted and improved in duo course, without any apparent rentionship to the concurrent penicillin therapy. TABLE XI. Table showing incidence of febrile relapses in series of eases treated with and without penicillin. 7ENIOILLIN TREATED NO. 07 NO. OP OASES ADTKoR CA . 11TH RaiRILE RELAPSES DANARAJ (195911 1 SUOHETT-hAYE (1951) 6 1 PRESENT SERIES 1 - SEVERE 15 4 - MILD 2 0 TOTALS 47 5 (10.6 ''', 4 wITHOUT PENICILLIN AO. OF No. OF CASES UTHoR ITH MBRILS RHI,L,3 -,), e, EWE (1917) - 13VnEE lb .L.,.. - MILD 58 13 ...--- RYLB (1921) 59 1" GALLMAY (1926) 2 ,,) LEWTIMATTE (1929) -7 1 DAVTDSoN (1934) 15 6 fl-I.ULD (1947) 13 0 70T7',LS 1(1., 746 (23.0 standard Error of 1.fference = 70.9 r It is to be concluded that penicillin therapy reduces the incidence of febrile relapses in leptospirosis. (b) - PTHOLOGY OF LIV1R. Though laundice can be a most Obvious clinical finding in leptospirosis it has been considered that hepatic failure contributes little to the fatal outcome. Most observers have agreed that the berctic leaions appear to be minimal. StOkes quoted by 7)awson an0 Hume (1917) described the naked-eye appearance of the liver to be normal. !Acrosoopically he noticed dissociation nnd enlargement of some of the liver cells and portal infiltrtion with mononuclear cells. ylie (1946) found that necrosis of the liver was an inconstant feature of experimental leptospirosis. Hutchinson et al (1946) remarked on the absence of hepatic damage in five fatal canes. leAcroseopionlly they did not find any trace of recent or healing necrosis or eeeeneration. They thought that there were proereesive changes in pigment deposition and in the eucleer appearences. Jeckson end 0/eesky (1946) noted the absence of macroscopic hepatic necrosis in their cape. eAcroscopieellY they found areas of fatty eegeneration, and areas of regeneration with enlarged binucleated liver—cells. Herington and ehillips (1947) described considerable disorgenisation of the liver pattern with moder- te vecuolization and swelling of liver cells; the formation of continuous cords of liver cells instead of the normal groups of two or three cells. hlmsworth (1947) wrote that the essential cherecter of the lesion would never be fully understood until a series of observations are made of biopsy material at different stages.of the disease. Ouch biopsies have been performed by Ostertag (quoted by Broom 1951) in eleven cases. He took no special precautions against the dangers of haemorrhaee and experienced no untoward incidents during the performance of the biopsies. Be found there was a disorganisation of the cord system and also, signs of regeneration were eresent at an early stage, even before the onset of laundice. The minimal chawres seen in the liver would explain the normal yrilues found after the performance of liver function tests. On the other band, it 13 well recognised that liver damage mast be considerable, before such tetits show significant abnormal. The pathologi ci material avai7Rble In the present series. is too scnty to tiae- any rtIcul r coMment.. In Case No.19,- the liver th.owed . no naked-eye Onormaliti s. This was -confiedicroscopierty. in'..Case'No.716 the liver was enlarged, and on section, the out eurfnce was mottmed wit same are%s yenewish brown and others a CCOp ren -In colour. o microscopical details are available. In Case.e.27 tho liver howed some reduction in si7le with capsular Wrinklin. The surface showed. tome sqbserous haemorrhages. The cut surface was.staJned deep yellow., was greasy and showed obvious' fatty chanze. o microscopical rive RYaiable. •. • Tt . is considered that the appearance in Osse No.26 Were suggestive of.a . subscute necrosis. Cse No.lq who was .aniotero chowet no changes, in his liver. Case go.27 was a Gu'ekha ni it II- Considered that the fl.tt7 chancres were non- (0) srilYOLOGY 4'.'T YID nrr The renal lesion in letosp1rori t,,s been the sublect or vf,rying re,.-orts. post ol)serverr7 agree that the glomerull furoear to remain intact while the tubules bear the brunt of the damage. it is the site and type of tubular damage which has not been agreed. 3-tokes (quoted by Dawson and Hume 1917) described the microscopical rearance of the kidneys of fatal eases of eilt s 73ease, as showing swelling and - granular 10,7,encration 0-7 t'ae tlthnlar orrIthellum, affectin the proximal convoluted tubules and ascending loops of 7:ionic. He described the exudation of leucocyte between, and haemorrhages into the tubules. ne stted tot the gloms,rull showed no appreciable changes, and he was unnle to dernonstrute the presence of leptospira In the kidneys. Ash an spitz (1:94) (lesoribed sliOliar microscopical sppearances. .They stated that the epithelium of the proximal convoluted tubules was necrotic cute to the presence of large numbers of leptospira. Hutchinson et al (1946) descried the glpmeruli as being of normal arpearnnce; the epithelium of the proximal convoluted tubules showed a finely granular cytoplasm and tended to hnve a foamy anpearance. They found cr,:sts in the distal convoluted tubules and connecting tubules land marled epithelial destrqction. The microscopical appearaneen of the kidneys of Case 7o.19 in the present ertes chow nOrlsi glomcruli surrounded by necrotic 7)roximal convoluted tubUlcs. This is in eeping with nrevtons (e -:,1110G107,1Tg OT? 7",TrUR7,. Renal ftlilure is one of the outst.,,nling features of leptospirosin and is the most frequent cause of death. The pathegenests of the renal lesion is not completely understood, though in the past it has been assumed trat the lesions were due to the direct action of leptosptra. This explanation has been difficult to accept when the microscopical- aopearances of kidneys in leptosplrosis have been staf7ied. Tho facts which have required further explanation ere (a) the almost universal sparing of the glomeruli: (b) the lack of apparent relationship between the nresence of leptosoira and the renal lesions: and (c) the similfn.ity of the renal lesions to those occurring in clinical conditions, other than leptospirosis, when acute renal foilure nqflervenes. ithin recent years It has been noted that acute renal failure, occurimg in a variety of clinical conditions is associated with similar microscopical renal lesions. Parmady (1950) hen .classified these conditions into seven groups:— (a)shock following accidents, certoin opera _one and gun—shot wounds. (b)Oases associated with disturbances of water and/or electrolyte balance, as in acidosis, alkalosis and diabetic comic. Cases associated with intrwiscular haemolysis following shock and/or excessive loss of fluid or salt as in the "crush" syndrome, incompatible blood transfusion, blackwater fever, and after certain drugs. (d) Allergic reactions such as fovism etc. G0 (e)Capes in Which the acute anaemia is associated with known nephrotoxinn. (f)Cases with etther systemic infections, &Leh as pyeloneohritis, typhUs, Dise..,,se, etc. (g)Cases assoeiated with obstetrical conditions, orotein depletion and water intoxications. Though all these conditions are clinically distinct, once nnuriA hnS developed the clinical course is similar in all types. The clinical course hps been described an being in three phases rilirhend 1943). The first phase in which renal failure is determined fild which lasts a few hours or less; the second, in which life continues in the absence of renal function, the blood urea mounting daily and electrolytic disturbances gradually increasing; the third and final phase in which renal recovery starts and continues with resultant diuresis and excretion of-large quantities of salt in what is almost a glomerular filtrate. The renal lesions occurring in loptospirosis are similar to those occurring in these allied conditions associated with acute renal failure. Apart from when cortical necrosis occurs, the lesions are oredominnntly tubular in site. There has been however, varying reports as to the site nntl extent of the lesions along the course of the tubules. Bywiters (1944) and later Dible (1950) described the main rennl lesion in oases of "crush" syndrome as affecting the epithelium of the ascending loops of Henle and the distal convoluted tubules. Govan and WeGillivray (1950) described the occurrence of patchy cortical necrosis and hydropic degenerwtion. of the epithelial cells of the proximal coaeoluted tubules in three fatal cases of "ouerperal uraemia. ebeehan (1951) escribing the lesions he found in a neries of women who died at varying times following accidental .haemorrhage of pregnancy, classified the lesions into nine grows, which included colloid degeneration of the tubules, necrosis of the proximal convoluted tubules and patchy or gross cortical necrosis. liver (1951) by means of a special micro—dissection technique in which he separates the individual nephrons of a kidney, has demonstrated the occurrence of two types of tubular lesion in cases of acute renal failure. One lesion he found in all cases, and called it "tnbulorrhexis". This lesion consisted of a localized necrosis of tubular epithelium associated with disinteeration of the basement meObrane at the same point and consequent disruption of the tubule. This lesion was found to be irreeularly distributed among and along the ne:ehrons from the origin - Of the proximol convoluted tubule to the connecting tubule where it joins the collecting ducts. Though the lesion could be found anywhere along the course of the nephron, it was always most prominent in the terminal portion of the proximal convoluted tubules and the distal convoluted tubules. 42. The second lesion, which was - less commonly seen, consisted of necrocis of the epithelium of the proximal convoluted tubules and was. distributed evenly among all the nephrons. Oliver ohowed that known nephrotoxins such as mercuric chloride, carbon tetrachloride etc., produced the latter lesion predominantly though there viere..lso signs of the tubulorrhexis. This tubulorrhexis was found in all cases. The concept that these tubular lesions could be due to ischaemis caused by a redistribution of the renal blood-flow was proposed by Maegraith & Vindlay (1944. They noted that the main tubular lesions were located in the cortex and suggested that n redistribution of the blood-flow to by-pass the cortex was partly responsible for degenerative changes in the highly specialized tubule cells, Experimental demonstrEtion in animals, of Ouch a diversion of the renal blood-flow was shown by Truete et al (1947). They showed that the diversion could be produced by various neural and toxic stimuli. Puring t):1e, experiments, the cortex of the kidneys was seen to blanch, suggestive that it was being by-passed. The appearance of bright-red arterial blood in the renal vein was also indicative of some shunt mechanism. That such a diversion occurs in man has not been definitely proVed but there - is a large amount of circumstantial evidence forthcoming, to suggest that it does so occur. aumerous cases of bilateral renal cortical necrosis have been described in which the only normal areas have been the subcapsu hi oh is cnown to be suonlied by capsular blood and the lux -medullary (which is known to be supplied urge vea ci which run in that area). Thane findin, o ould be expected if the necrosis was of iaohaemie .stribution of the cortical blood supply. Do & ngupta (1951) using an inane technique have demonstrated appearances which could only be explained by the occurrenco of such a redistribution. Jeffcoate (quoted by Franklin 1950) described the appearance at operation of a Xieney in a case of concealed o.ecirental h r or_hage with anuria of 28 hours duration. The kidney looked eote d on superficial appearnnce but the capsule and cortex did not bleed on being incised. 'gin the contrary as soon as the medulla was ranched, there was bleeding. On the lc th day the tient died end at autoney both kidneys showed typical cortical aocrosis. It is suggested that this diminution i'.a corticol bloodis en important factor in the occurrence of °lig ria or onuria. The diminution in glomerular blood-flow will lower the filtration pressure and thus diminish the excretion of urine. This diversion of the renal blood-flow is claimed to have a Physiological purpose (Oophian 1g52). Any noxious substance which is filtered through the glomeruli will be absorbed by the proximal convoluted tubules. aboorption may cause damage to the tubular epithelium and evoke the renal blood flow diversion mechanism by some reflex type f action. a divers could be of a protective mechanism to pr nt damage to further nephrons. The effect of dehydration alone, causing diminution of blood volume and renal blnod-flow with consequent reduction of glomerular filtration pressure and diminution of urinary e7cretion without involving a renal blood-flow diversion mechanism was emphasized by roy et al -(1943) Renal 'Pailure in Leotosoirosis. The similarity between the renal lesions in leptospirosis which 71ave been described by the various Observers and seen in the one case of this series (Case i0,19) on the one hand, and those discovered in the allied conditions mentioned previously, is most striking. In the erly stges of leptos-pirocis there is a. generalized leptospirsemis, Which can be proved by animal inoculation, up to about the 7th day. In the severe cases there is a marked peripheral vaso-dilatation (shown by the intense erythema of the sin). This peripheral v*.so- dilatation may be so marked, that Oedema of the skin occurs (Case No.26). The heart is affected with other organs in this early stage and toxic myocarditis develops. ln Case - No.26 who died on the 4th day the myocardium - was flabby and showed haemorrhagic areas. It is to 'be expected that this association of toxic myocarditis and intense neripheral vaso-dilatation will result in a diminished blood-pressure. The reduced blood-oressure will by itself tend to cause reduction in renal glomerular filtration pressure and affect urinary excretion. Circulating leptoepira entering the kidneys will first pats through the glomerular vessels where they may escape into the tubules, or paea via the efferent glomerular vessels to the epithelium of the Proximal convoluted tubules. In either case it is probable that the epithelum of the proximal tubules will absorb the majority of circulating leptospira and be damaged in the process. This damage to the proximal convoluted tubules will invoke the diversion of the renal blood-flow from the cortex ophian 1952), This diversion will protect other nephrone from further damage by leptospira, but will also cause ischaemic lesions among the tubules. It is suggested that these tubular lesions are as described by Oliver (1951) as F'tubulorrhexis". The extent of the two types of lesions which might occur in any inglividual case would be expected to depend upon the varying influence of the direct leptospiral action and the ischaemic factor. Diminution of systemic blood-presure would implement guy renal ischaemia, though vaso-constriction of the glomerular efferent vessels would tend to offset such reducti on. The renal changes found at autopsy would be expected to vary and this might exTlain the conflicting reports of previous observers. (e) PRENZUTION OP RENAL FAILURE. AS has been described, the onset of renal failure 44 is the most serious complication in leptoopirosis and one which is the most common cause of deuth. Thus, any treatment which night prevent such a complication, would in itself improve the prognosis of the disease. essaming that the pathos of the renal lesion to be aS described in the previous section, treatment to be of preventitive value should be direct towards- (a)The eradication or inhibition of leptospira from or in the blood and tissues as soon as possible. (b)The maintenance of the cortical blood-flow to prevent ischaemic lesions of the tubules. Dible (1950) showed in the "crush4 syndrome that renal changes could occur as early as 20 hours after the crushing and be fully developed in 48 hours. Wylie (1946) demonstrated, in experimental leptospirosis, a diminution of the cortical hlood-flow as early as the first day of infection. Thus the eradication of Teptospiral infection Should occur within the first 24-48 hours of the illness, otherwise it would be expected that any renal changes initiated would continue to develop despite the later destruction of leptospirs. That this does haPPen ;las been the usual experience of clinicians. The maintenance of the cortical blood-flow ha been tried by two methods. (:fl the assumption that vascular spasm plays a part in the production of cortical ischeemioet paralysis of the sympathetic nervous system by high spinal anaesthesia up to '7 the level of D7 was tried by Robertson (1946) in three cases with varying success. Williams (1947) combined similar spinal anaesthesia with plasma infusion an6 intramuscular administration of methedrine (30 mgms), in one case, with resultant restoration of urine excretion. Both observers mentioned that the known propensity of the kidney to resume function spontaneously makes it difficult to assess the effects of any treatment. The duration of time of renal isohaemia, required to cause irreversible damage in man, has been estimated to be about six hours. (Badenoch and Darmady (1947). Thus any procedure desimed to prevent such damage, should presumably be put into effect at least within the first 24 hours. However, it iS doubtful in man, whether the renal iachaemia which occurs, is always so dramatic as that seen in animal experiments, except in very severe infections. it would seem however, that treatment should consist of an anti-leotospiral drug given within the first 24-48 hours, associated, with plasma infusion ane intramuscular methedrine to combat hypotension. In this manner it would be hoped that renal changes might be avoided. The chief difficulty Which arises, would be in making a dianosis, sufficiently early to achieve the maximum effect of such treatment. Tht3 would place a premium on early evacuation of cases in Malaya. 15. SINUARY% 1. A review of the literature appertaining to leptospirosie in lalayu hat been made. 2. The source of Infection, clinical picture, complications, laboratory findings and trestmont of 27 cases of clinical leptospirosis admitted to a military he PitRl in Malaya have been discussed in detail. 3. The differential diagnosis of leptospiroole as neen amongst service personnel in !alaya io described. 4. The post-mortem findings in three fatal cases are described. 5. The clinical picture, blood pressure, complications, diagnosis, laboratory findings and prognosis are compared with those reported by previous observers and generally discussed. 6. ; critical review of the literature appertaining to nenicillin therapy In human 1 etespirosin has been made, and statinticW1 evidence produced, to show that such therapy does not influence tie duration of fever of cases, but diminishes the incidence of febrile relapses. 7. The pathology of the liver and kidneys are discussed. 3. The similarity of the renal lesions in leptospirosis to those found in certein other clinical conditions, associated with acute renal failure, is emphasized. The pathogeneols of these renal lesions habean discussed in detail and its application to leptpspirosis considered. mode of treatment relying upon early diagnosis, 4? Oesigned to prevent or minimi7e renal changes in leptospirosis has been discussed. 16 aqrXRgWria3. ALSTON, J.M. (1949). Proc. Roy. Soc. Med., 42, 707. ALSTON, and BROOM, J.0. (1944). Brit. 14A. J. It, 718. ASH, J.E. and SLIM, S. (1945), "Pathology of Tropical Diseases", W.B. Saunders & Co. (PHILAD&LPHIA) p.68. AUGUSTINE, n.L., !IRITIMAN, D., and Mc:JALISTER, J. (1944). New Enpj, J. ied., 231, 358. BADENOCH, A.X., and DARMADY„ E.M. (1947). J. Path. &lot., 59, 79. BORG PETANSSN„ C. and SCHMIDT, (1945). Acta. Path. tkicrolliol. Ieand., 22, 462. BROOM, J.C. (1951). Brit. Med, J. ii, 689. BROOM, J.X. (1951). "LEPTOSPIROSIS IN MALAYA" - INTERIM REPORT. 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Ba t 58, 351. 23 APPL1TIDTX "A" The detailed results or laboratory investigations Ivrformed in each case and the day of the disease to which each refers are shown in the following tables. 1. B1,007) (a) rill Cases Case Day 4.§.C. Day !lb. RN ro. x 10 /ou.mm. gms., x lou/ou.i. (, Poly) (Sanli) 8 1 19.5 (90) 6 8.8 (74) 10 7 14.5 (85) 14 9 19.0 (86) 14.5 5.17 15 8 10.0 (56) 16 5 9.8 (80) 9 12.0 4.1J 20 11 8.0 (67) 17 11.8 3.65 22 8 15.4 (86) 23 7 12.0 (61) 23 11.2 3.60 24 2 11.8 (94) 14 13.8 4.41 8 13.4 (90) 25 9 8.8 (6';) 9 12.9 4.95 ------ ) 1------.------r- Case Day '!.n.c. Day Hb . n.ne }:o . x 1()3/cu o lTIm o gms .;" x 10°1cuomm. (" Po l y ) ( 3ah1i.) " - 3 7 21 .0 ( 9 2) ------1--.------5 8 19 . 6 ( 'Y.) ------'- 6 6 2 '34 3 .D? ------1------t 9 11 . 2 45 12 . 2 _._------11--- -- ._------42 I - - -_.---- '--'------. .- <") I n 6 1;0 02 ( 60) ! 8 14 . 8 . ';0 I -- - 11------15 34 11. 2 3 .80 - -- - 11------f 21 4 17 .0 (98) --- -- ___--'11- ..::. • .1-- _ 71" (c) Severe Cases. Case ')ay ;..C. )ay Jib. no. x 103/cu.mm. gms.',, x 10Vcii.mm. (,) Poly) (:.;ahli) 1 6 12.4 (85) 35 10.6 4.00 02 8 8.'± (88) 34 7.2 2.55 42 8.0 2.75 19 8.5 2.95 78 15.5 5.35 * 4 5 21.0 (91) 11 10.8 3.30 8 13.0 (87) 27 10.6 3.67 11 12.8 (78) 52 12.0 3.83 100 13.7 4.50 7 6 12.6 (69) 8 12.2 3.98 18 4.9 1.81 25 7.2 2.73 36 7.3 2.76 53 8.1 2.88 J2 14.4 5.00 9 5 7.8 (71) 'This case ,was very severe. (c) Severe Cases (cont), __ Case W.Bxq Rh. V°. 7-)ay x 106Au.mm fLay gms.% x 10Vcu.77111. (A Poly) (Sahli) 11 6 29.0 (85) 12 5 7.4 (74) 24 12.6 3.78 13 7 8.6 (64) 14 11.6 4.02 17 b 11.0 (93) 13 13.2 4.50 77 . ' r 1L'" .... -.1 ,t.,) . --- Case Day a.H.C. Day JIb . . 13 . • f No . x l O3/eu •mrn • emS . O x l Oo/eu. rom . ( ~ '. -'ol y) {Sahl i ) - 19 8 13 . G ( 85 ) 8 _ 1.0 . 0 3 . 60 26 4 33 .0 (73) I--- 27 6 11. 6 ( 80 ) 2 . ) T; The bl ,)el urea estimations are shown in rqgns, per 160 ill. or blood. The day on which the estimations were performed is indicated over each value. C,',.5c; :ro. 10 14 16 20 23 24 25 8 9 4 11 7 7 9 71-1,0 45 40 b 240 220 85 70 ..d.',.....t.t2 10 10 40 25 C ,,.; r:o. 3 5 4: 18 21 11 8 9 8 5 .-Y 12,1,Y 240 140 feAu 220 50 18 14 7 40 60 50 0 6-9 :;,,.....7, c). 1 2 4 7 9 11 12 13 17 6 7 7 6 5 6 5 5 4 368 60 25 70 20 230 240 200 80 ; 8 10 10 8 7 9 8 7 5 528 WO 20 360 27,- 440 340 340 190 LITT ;:Z; 14 11 12 16 11 8 13b 280 040 125 390 360 12 13 j 210 520 420 11 40 52k 15 40 c) A , ,,,„ ,, 0 0 4-;) 8-3 6-1% -1C 547 4-8 4-5 6-9 KlY Anuria. 0 6117urta. Very s,were case. 7? 2. Ai (cont) C'f,;. No. 19 2,-: 27 6 4 5 160 90 126 7 7 FATAL 180 2410 a ! 8 430 480 10 CA2 550 A % 4-18 5-11 A Anuri a 3 MOOT) (37 I.4i1ISTRY„ (a) IfiLLD CAS Case PLASMA P '1.0 TA Ili S' Serum Serum Bilirubin Cholestero No. Day Total Alb. Glob. Day flay gins % gas % gins '- . mgms ,:fio mgms ''S 14 9 0.5 9 170 16 10 5.5C) ‘.1.00 1.50 20 11 2.25 11 300 23 7 5.75 4.00 1.75 7 1.20 7 167 24 7 6.60 5.10 1.50 25 9 6.00 4.60 1.40 9 5.30 9 124 (b) MORATZY CAS6. PLASTU POTHUNS Serum Serum Case Billrubin Cholesterol ay Total Alb. Glob. Day Day No. gms;L gm gms.cit% mgms,1; mgms70 3 11 8.50 4.40 4.10 11 6.8 11 250 24 7.00 4,80 2.20 24 1.4 5 8 7.00 6100 1.00 6 9 6.00 4.40 1.60 18 8 6.20 4.20 2.00 8 13.1 14 375 41 270 21 4 5.50 3.60 1.90 9 0.50 4 125 (c) S. CASS. Serum Serum Case PIA:3NA PAOTAINS Bilirubin Cholesterol NO. nay Total Alb. Glob. Day ,-,, Day gins % , s gilis %mgms A mgms 1 26 6.25 3.60 2.65 9 15.0 26 4.0 2 6 5.50 3.60 1.90 17 8.0 15 250 1 4 12 5.00 3.20 1.80 12 3.2 7 8 7.00 5.80 1.20 8 31.2 8 . 125 12 280 36 6.50 4.40 2.10 15 220 18 223 9 7 5.30 4.00 1.30 6 200 11 6 5.25 4.00 1.25 6 16.0 9 160 16 7.75 5.20 2.55 16 3.8 16 156 5 210 12 11 3.00 5.60 2.40 11 156 - - 5 , 112 13 7 5.50 3.60 1.90 5 7.5 13 107 17 7 3.4 9 181 19 6 6.75 4.00 2.00 6 343 At . Very severe case. 4. LITiit Fl -NC 1017 T.: Case CLX7ICAL T1 IYI:101., i-U..,ictUJ I:: DAY IT RJ-3 EU TY P110 SPIIATA No. SZ,VII.ZITY (0-5 Units) (0-13 Units) 7 Severe 36 2 4 9 II 7 3 8 11 u . 6 2 5o 16 4 - 12 u 11 2 4 13 ff 5 3 10 14 laid 9 1 12 24 u 7 1 5 APP1MIX "13". Th c&se 1Astorie3 of 11 non-fatal cases were as follows: -• Case 1121.1: Pte., A7e 20, jyri ti .dmitted 18.12.49 with three day history of severe headache and fever followed by pains in the lower abdomen and lumbar reg:ion. On the day prior to admission he vomited blood on three occasions. 0n admission he gyres mildly confused skin was icteric and erythematous. There was tenderness on deep palpation of the abdomen but no muscular guarding. On 20.12.49 he had become deeply laundiced and a petechial rash appeared. ES had become oliguric and only eight ounces of urine were passed in the first 24 hours after admission. Investigations showed WPC 12,400 per cu. ran. (N 85 L 14 1); Urine contained albumen, bile, red blood cells, pun cells and granular casts; Blood Urea 368 mgms. •,enicillin (IT mega unit six-hourly) commenced. On 21.12,149 a small subconjunctival haemorrhage developed in the left e7e. By the 22.12.49 the temperature was normal and 49 oz, of urine was passed. He felt much better and was drinking freely. Dn this day the blood urea had risen to 528 mgms , and the Van den Bergh reaction was immediate and direct and the serum bilirubin 15 mgme. Pruritus became troublesome on the 23.12.49 hut was eased with clamine lotion. On 26.12.49 an erythematous macular rash appeared on the trunk and arms. Improvement continued and penicillin was discontinued after a total dosage of 20 mega unite on 29.12.49. urea had then fallen to 135 mgms. By 10.1.50 the laundice had almost disappeared but the specifie grity of the urine had remained more or less constant at 1010. The (3G urine began to vary by 16.1.50. On 21.1.50 a blood count showed Hb = 10.6 grdEl RBC L. z 106/cu. mm. On 24.1.50 he was transferred to:convalescent depot. On 27.3.50 he was returned to duty after renal efficiency tests had proved normal. Case £To,2: Are 24. ipriticitl. Admitted 4-2.5C with history of general malaise and drowsiness of three days duration. On 2.2.50 he developed severe lumbar backache, with nausea and vomiting. In oddition he had a mild cough associated with substernal discomfort. On admission he looked ill, hi eyes were suffused, there was vague epigactric tenderness on abdominal palpatlon and his chief complaint use of general muscular painS. On 6.2.5C the sputum was blood-stained but there were no abnormal signs in the chest. The urine showed no albumen or oasts. serum proteins normal. By the next day (7.2.50) jaundice had developed and he was complaining of pain in his calf muscles, Penicillin (1 mega unit six-hourly) was comenced. Blood urea was Go mgort*:; Oliguria develcred and only 9 oz. urine was passed in the 24 hours 8/9.2,50. Hiccough became persistent on the 9.2.5. 7B.C,' count on 8.2.50 was 8,400 per cu. mm. (N 33 L 10 2). He was afebrile- on 10.2.50. He pained 13 urine thing the day but the blood urea had risen to 300 mgms Improveuent was progresse. "enioillin was discontinued on 17.2.50, laundice fading on 21.2.50 and appetite returning. 1G urine rerlained constant at 1010 until its transfer to convalescent depot on 31.3.5. By the tcoo for his return to duty ou 23.5.50 his renal function was uonial. Between 1.3.50 and 11.3.50 he ran an irregular fever of 980. 1010v but felt perfectly fit and was eating well. An anaemia developed, the blood count on 6.3.50 being Hb 7.2 aTs::. RBOs 2.55 x 106 per cu. rm. ?errous Allphaten tablets were given and there vas gradual improVemmt and bj 19.5.50 lib was 15.5 go. and RBOs 5.36 X 106 par cu. mm. Cane Admitted 2.2.50 with two day history of fever ,9nd cough. On admission he looked Ill, T. /030P, eyes were suffused but there were no other physical signs. Jaundice developed on 7.2.50 and investigations showed A1C 22,500 per au. mm. (N 89 L 10 M 1).1 Urine - Albumen, Urobilinogen, csts and red blood cells present, but no bile. Penicillin (21-. mega unit six-hourly) was commenced on 3.2.504 on which day the blood urea was 240 'mgms, serum proteins 8.5 mgms (Plbumin 4.1) and scrum biljrubin 6.3 re became- febrile by 11.2.50 and penicillin was discontinued on 1S.2.50. B7 24.2.50 the serum proteins had become. normal (Tot,71 7,0 Trems'f, tn L.8, Glob 2,2) and by 3.3.50 he was fit for con,r.11escence. Caze go.4: Pte. G. AN3 19 Oritish). Amitted 27.3.50 with five day history of fever and pains in his WTI. 12 hours before admission he developed acute pain in his right ilioc fosea, and as he was constipated, he was sent to hospital with the orovisional diaoeis of subacute aependicitis. There had been no vomiting. On admission he looked ill, T. 102.8°F: P 110: P 20: eyes were suffused, slight nuchal rigidity was present, no icterus and tongue was furred. Abdominal examination showed generalised tenderness on palpation, but there was no muscular guarding or hypernesthesisa. Rectal examination was more tender on the right than left side. Investigations showed: Blood films - no malarial parasites: WPC 21,900 per ca. mm. (N 91 L 8 M 1). By the next day (28.3.50) he felt mueh better though mild general abdominal pain and tenderness persisted, and calf muscles were tender. un 29.3.5e he was still tender in the calf muscles, but the headache was less and there were no signs of icterus. en 30.3.50 the fever appeared to be settling but it was Still 1000- 101°F. Frontal headache was the main complaint with photophobia. Tongue was dry and furred and footer oris present. Tenderness in calf muscles was less marked. Anuria had become evident, no urine having been passed since 0300 hours 29.).50. Abdomen was mildly distended and vomiting occurred occasionally. 1W 80/52 in the morning and falling to 58/40- b7 the evening. Glucone line drip infusion commenced. Penicillin 0 mega unit six—hourly started. Two bottles of 4.5 sodium sulphate solution given with drip. On 31.3.50 condition was unchanged. Mill. anuric. Hiccoutth persistent. Photophebia pretlent. BP 64/40. Catheterization produced 10r ml urine. Blood urea 25 mgns urine contained much albumen. Condition remained unchanged until 3.4.5o apart from persistent hen cache which was relieved by codeinesulphate gr and the developmont of two subconjunctival haemorrhages. The blood urea was 280 mgms on 2.4.50, On 3.4.50 he was afebrile and felt much better. He passed urine for the first time after 120 hours of anuria.- . BP had risen to 100/65. 7e comPlained of genen7lieed pruritus and vomited "altered" blond (coffee grounds) on two occasions. a he Sterted.taking. fluids by mouth without difficulty, the intravenous drip was dlsoontinued. On 4.4.5o he had an epistaxis," and on the following morning (5.4.50) he had two haematemeses, rune of which, included a place of tissue which was subsequently proved to be gastric mucosa. In view of the haemorrhages, he was given a blood transfusion of three pints. general condition continued to. Improve though it was found necessary to catheterize, 9-? in order to complete the emptying in the bladder after he had micturated. Between 644.50 and 10.4.50 a polyuria developed, the daily urinary excretion rising over 200 oz. It was necessary to recommend intravenous saline therapy in order to bolster up the oral intake and so prevent secondary dehydration. All oral fluids contained 15 ~rains of salt to the pint. eroeress was maintained after 70.4.50 end penicillin was discontinUed on 22.14.50 as it did not ar-ear to influence the after-fever which develoeed on 6.'4.50 and raid not subside until 4-9.50. Anaemia was evident and the blood count on 1.5.5o was Hb = 8.7 Tms- ; Rpc = 3.58 x 106 per cu. mm. He was treeted with ferrous sulphate and the blood count gradually returned to normal. en 25.5.50 a barium meal radiological eeamination showed a normal eastrio mucosa and on 26.5.50 he was trennferred to a convaloecent hospital. After five weeks convalescence, he was-returned to duty feeling very fit, and his renal function tests within normal limits. vase 110174. ege 22. (BritIsh). Admitted 12.4.5e with history of sudden onset of fever on 3.4.50 followed by several rigors, epieastric pain, vomiting, headache and pain in the calves. en admission he wee febrile, conjunctivae eere faintly icteric, and there was wild epieastric tenderneeu on palpation. Icy 15,4.5e• he did not look very well, the jaundice more - evident, vomiting freeeent, and on examination his liver was lust palpable and Calf muscles very tender. BP 8)/? Investigations: Blood Urea 14U mgms: wBO 19,600 per eu. mm. (N 65 L 23 M 9 E 3): Serum Proteins normal: Urine - Albumen nil. Bile nresent. IMprovement was rapid. The fever mabsided on 16.4.50 and on 17.4.50 the laundice was described us being of moderate intensity though the characteristic erythema was present, and s nubconlunctivnl haemorrhae had develored. He was transferred for convalescence ,7111 23.4.5G and on 10.6.5r) he was returned to duty, renal fanction tests having been found normal. Case No,6: fn L. Ar-e 17, Admitted 8.4.50 17ith history of sudden onset of fever of T. 10001-1, rains in calves and knees, and headaches seven days before. Abdominal pain developed four days before end laundice became evident one day before admission. On admission he as obviously very launRiced and ill- looking. There was marked muscular tenderness of the thighs and calves. Oligurin was present from admission. B 92/58. Penicillin ( mega unit six-hourly) was comienced. Investigations: Blood urea 220 mgms:: 4L0 11,250 per cu. mm. (N i3 L 13 L 4): brine - Albumen present, Bile present, many pUs aells:' '47 rum eroteins normal. 'regress WWII good. A diuresis commenced on 10.4.50; temperature settled on 11.4.5, epistaxis occurred on 12.4.50, jaundice began to fads by 15.4.50 and apart from a mild anaemia there were no further incidents. f'',e was transferred for ConvalescelAce on 29.5.50, hia blood count being .*-• 12.2 gma R110 3.49 x 106 per mm. Cape Noll: .LteLji...,...rre. -212,1rItisbfi. Adnitted 13.4.50 with four day history of fever, shiverinr7 attacks, headaches and pains in his neck and back. Alec) developed a cough with substernal discomfort. Vomiting developed and incresea in frequency and intenaity just prior to admission. The sputum was blood-stained for three days. On adminsion he loolced:111, T. 102.e.P, erythema of face and neck was present, axillary and inguinal glands were tender and en/arged, and eyes suffused. '.i:hore was lower abdominal discomfort with generalised moderate muscular gaarding. The following morning he developed acute pain in the muscles of his calves and thighs. Ile continued to vomit but was toning oral fluids liberally. -enicillin (11- me7a unit six-hourly) coif` anced and intr:.venous glucose-saline drip infusion set up. Later the same day. (19.4.50- lalndice became evident and anuria monifest. BP 70/501 T11,7)od Urea 70 mgms k 12,600 per cu. mm. The temersture became normal by the evening of the 19.4.50 and remained norm', The anuria persisted until 23.4.5 during which time the patient remained deeply jaundiced but quite rational. The blood urea rose to: 360 mgmis on 21.4.50 and then to 540 m7ms': on 25.4.50. q2. Theintravenous drip was discontinued on 26.4.50, and further improvement was prorTessive apart from the development • of generalized muscular twitchinr7 and cnrpopedal spasms on 3C.4.50 which resDondod to intravenous calcium gluconate. On that ,day the serum calcium was 6.4 mgmEi. An the i%undice foded, so the pallor of anaemia become most evident. Te blood count on 30.4.50 was Ub = 4.9 gas RI = 1.8 x 10° per cu. mm. A blood transfusion of 2 pints was given on 3 4,50. Further convalescence was nneventful apart from an irregular fever of up to 1010F which developed on 10.5.50 and persisted unto 10.6.50. This fever did not seem to affect patient or his progress. on 19.6.50 he was transferred for convalescence and on 2J.7.50 he was returned to duty after the renal function tents and blood count were found to be normal. Case No,8: rkha). ?iitted 23.5.50 with three day history of fever, hehe, and severe muscular pains especiRily marted in the calves. On admission there was no laundice, the eyes were suffused, renerali7ed lymphedenorathy, and intense irialgia ennecially in the calf muscles. BP 90/60. rvogress was uneventful. The fever settled by 31.5.50 and remained normal. !frine never showed the nresence of albumen. On 23.5.50 -13C was 8,80(7, per cu. mm. T 74 T., 19 M 5 I+ 2). was transferred for convalescence on 10.6.50. 93 Case Nc1,9: ilfu C. Age 22. (WrIzha). Admitted 2.6.50 with two day history of fever, headache, muscular pains, and cough. 11 admission he did not look very ill, T 100F, some tender enlargement of cervical and ucillary glands present, calf 'muscles very tender and thigh and lumbar muscles moderately tender. B.P. 35/? Un 3.„50 the sputum was blood-stained, anuria had become manifest, blood urea 2C0 mgme,,- and so a diagnosis of anicteric leptospirosis wade. n=.3nicillin Iky mega unit six- hourlyj Was caanenced. .he following day he began vomiting and developed a smalt- petechial rash over his neck, trunk and legs. Urine was passed on 5.6,50 after 411 -hours anuria. It showed large numbers of pus cells and scanty granular casts and a trace of albumen. Further progre3s was uneventful and final renal function tests normal. Cape NpAL12: 4ta, N. Age 19. (Gurk4.), elmittef.1 Owin7 to language difficulties the history was deficient, apart from a claim that he had been ill for seven days and had had pains in his legs. On admission: T 1010F, he looked 111 , but apart from exquisitely tender crlves there were no other physical signs. Investigations: "130 14,500 (N 85;): Tirine- .libumen nil, pus cells and granular casts present in deposit: Blood urea 45 rms.. 'enicillin (i mega unit) comenced. 954- PrcTess was uneventful, the fever settled by 23.6.50, and transfer to convalescence took place on 5.7.50. Case Ne.11t Rfn. R. 4g0 19, (Gurkha). Admitted 5.7.50 with history of fever since 2.7.50. He was febrile (T 1010F) and some enlarged glands were found in the left exilla. No other abnormal physical signs were found. On the following morning he had a sadden aematuria, the urine containing blood, much albumen and large numbers of F.Tanular ("!!nto, The next day (7.7.50) he began vomiting and developed Jaundice. Anuria, since the previous evening became manifest. Investigations showed: Blood Urea 200 mgms: :130 9,000 per cu. mm. (N 85 L 12 M 2 A 1): Serum Bilirubin 16 mgms: Serum Cholesterol 200 mgms%: Liver Function Tests normal: Serum proteins normal. enicillin mega unit six-hourly) cornnenced. On 9.7.5o he started to pass small amounts of bile stained urine (31 oz. in all). Temperature was 1000, B.P. 86/60. Urine howed much albumen, bile, moderate numbers of pus cells and granular casts. By 10.7.50 renal excretion was normal, though the blood urea had risen to 440 mgme. The fever subsided on 11.7.50. A peteohial rash developed about this time and Vitamin K was administered intramuscularly. Desoite penicillin therapy an irregular fever developed on 15.7.50 and persisted until 4.8.50. During this period his general condition improved steadily, the blood urea having fallen to 125 mgma/, on 17.7.50. He was transferred for convalescence on 9.8.50. Before return to duty his urine was examined and found to be normal am) renal function tests satisfactory. CUEle No.12; Onre F. eee 18fi (Brit.ish). Admitted 11.5.50 with three day history of fever, occipital headache, nausea, vomiting, pains in back and lees (especially in oalf nuscles). enorexia and constipation irked. en admdssicn he looked ill end drowsy, eyes, face and neck were suffused and the axillare and cervical glands were enlergoe. There was moderate tenderness of the calf eusclec, and on deep palpation in the left hypochonerium where the neleen vas palpable on inspiration. There was also tenderness in the right renal angle. BP WI The following morning his vomit contained a few blood clots. Investigations showed: ,130 7,400 (i 75 L 12 M 12 E 1). en 13.5.50 he developed an erythemetous meculer rash described as being like that of a scrub typhus. The same day it became evident that he was enurie (since early 12.5.50). B.7'. 90/6e. enicillin (4 mega anit six-hourly) comoenced. An Intravonous dlucose-saline drip was set up. en the following deer (14.5.5e) the rash faded but the anuria continued. en 15.5.50 an intragaetric drip of glucose, peanut oil and water (Glucose L ems, ,eanut oil 100 gem, eater 2 2itres) wao instituted in lieu of the intrevenous drip. aas impossible to assess the value of this treatment ae urine was passer spontaneously on the following day 94 (16.5.50) after nearly four cla7y of anuria. The blood urea which had been 240 mgms on 13.5.50 (first day of enuria) rose to 340 mgms on 16.5,50 (tho end of the anuria). The general condition began to improve r-:nidly, he had been afebrile since 14.5.50 arart from a slight rise to 99eF on the 15th and 16th, end he began to take a ligrit diet on and penicillin via discontinued on 19.5.50. An anaemia developed and the blood count on 26.5.50 was Eb . 12.6 7ms: InC 3.73 x 10 per cu. mm. He was transferred for convalescence on 2.6.5L, and before final discharrfe on 19.7.5G his blood count and renal functirm tests were found to be normnl. ;:;%s EfuL B. he, 21. (Gurkha;. dmitted 10.10.50 with four day history of fever and pins in his legs. en admission he looked ill, fevered T 1(720 , conjunctivae wore icteric and calf muscles were very tender. He was oliguric for the: first 24 hours in hospital. Investigations ehowed: Blood Urea 200 ngtas:IC .3,1400 Cu. mm. (N 64 L 31 M 4 1: 1): F'Jerum bilirubia 7.5 mg=0*: Van den Bergh Di ect. 4arum Cholesterol 112 mgms-: Liver Function Tests :&:4ormal: Urine - Albumen 4, :11-S 0011S present. nu (i mega unit six-hourly) was corinenced on 11.10.51). -jr1 12,10.5.y he was still 111, febrile and complaining of intense calf tenderness, but ie f lt better 92 the next dee (13.10.5C) though the blood urea hed rthen to 340 memeA. is suffusion hnd dleanreared on this ?lay and the fever was subcidine. 7e was now feeling hungry end Pieced nn a light diet. erogrese was raid, be become afebrile as from 14.1e.50, jaundice w obviously deereacing on 16.10.5el en which dr,Y penicillin wan discontinuee. tk mild annemia developed, the blood count on 19.1(.5e being n.11.6 gmme R.ree. 4.02 x 1O per cu . me. He was tranaferred foe convalescence on 2.11.50 and returned to duty after the renal function tuts ard blood counts had bean found to be normal. !_S!0 .1k -eee._ee Ireeeeeeerajz. ee !elmittee V.le.ee with sie day history of lleedache and painsein the lees. n admismien he wan fevered (T /030V but ei, not look very 111. eere moderatele euffesede There was no calf teneernese Ile 124/90 sne no other abnormal physieel niw "ft fever remained finternettent (96°- v'2307 ene! on 12.10ee he compleined of - ins in els thighs and lege. Teveetigatione ehovedt Jrine - Albumen + 'Large audber of ram eelle are moderate putber of grenular c-eto in deposit. -nc le,Oee per cu. mm. (N 86 L 12 2). 13.1t:.5e he complained bitterly of in thighs and knees and to a Tweet extent in his celves. He had intermittent heedecele, eyes wore neffesed and eomo posterior cervical elandm eelea enlarged. Mood urea 40 memo orur 9t unolesterol 170 mgms%: Liver function tests normal. At this stage the diagnosis of scrub typhus was still being entertained owing to the suffused eyes, headache, no laundice, normal blood urea and enlarged cervical glands. In addition the On. agglutination titre on 12.10.50 was 1 : l& which though not diagnostic, was suggestive. s, on the following day (14.1C.50) the fever settled, and the chief complaint was still of the rains in the legs, it was realized that the case was an anicterie leptospirosis with leucocytocis, urinary findings of albumen and casts, and pains in the legs. On 20.10.50 he was discharged feeling perfectly fit. Case No.la: Rfn. D Age 26. (purna). [dmitted 18.10.51) with seven dfty history of fever, headache and general 9chos and pains. 7omiting had been persistent and occurred daily. on admission he was fevered (.T 1000P), loohed quite his eyes were suffused and his cervical, axillary and inguinal glands were enlarged. There wan tenderness on palpation in the epigr!.strium and both hypochondria. It was thought that this was probably of muscular origin and due to the repeated vomiting. Investigations showed: WBC 10,0(10 per au. mm. (N 56 L 39 M 2 g 3): Urine - Albumen trace, modexate number of pus cells in deposit. By 23.10.50 he was afebrile, though he still complained of some backsche, and, on 26./0.50 he was discharged. It wan considered that this was a mild case of ieptospirosis. 99 Case No.16: 'eta. D. ((,Airkha). Admitted 10.11.50 with twe day history of delirium and coma. In his unit R.4.t. he had been thought to be a cerebral malaria and was given an intranuseular injection of quinine (10 grains). adeession he eee coneeices, febril ( 103°F), with no signs of meningism. There was a slicht cough but no other abnormal ehysicel signs. eL0 9,8ee ecr cu. mm. (N 80 He was treated symptometically until the renewing day (11.11.50) olhon he loolzed very ill, and febrile (J: le30P) and complained of headache, pains in the back and front of the chest. i4-es were suffused and B.P. 86/50. Investigations showed: Urine — Albumen present, moderate number of granular casts and few pus cells present: Blood urea 55:poels tin 12.11,5C subconjunctival haemorrhaged developed in both eyes, whilst the cuffusion Ives more intense. There eae no calf tenderness and no other myalgias. Tempereture was still about 103°F. It was the development of the suboonjunctival haemorrhages that decided the diagnosis, as the clinical— picture had only teen one of fever, headache, suffusion of eyes and albuminuria, with a normal 7:BC count.- Penicillin G mega unit sixehourly) eee come-Lanced on 12.11.50 and the temperature reached normal on the morning of 14.11.50 but rose again and wae around 99P — 10.0°P On 16.11.50, but became normal as from 17.11.50. Penicillin was discontinued the following day (13.11,50). /00 The blood urea was within noluul limits on 17.11.50 (25 mgms); rl mild anaemia developed, the blood count being Hb = 12 gms:: ROC 4.19 x 106 per cu. mm. on 16.11.50, He was trnsferr d to convniescence on 23.11.50 and returned to duty perfectly fit on 14.12.50. case R. Age. 21. Oritigh). ?Omitted 27.11.50-with four clay history of fever, headache, abdominal pain in loft hypOchondrium, vomiting and rigors of sudden onset. - On admisoion, he was fevered, T 1020 103°F, Oyes Suffused, fauceo injected, and tonsillar glands enlarged. There Wore no other abnormal physical eigns. Investigations Showed: Blood urea 30 ralpEC: Urine — Albumen + +, moderate number of pus cells, and few granular casts present. •By 29.11.50 he had been afebrile for 24 hours but did not look well. He was still nauseated and vomiting and his eyes were very mffusea.. A repeat blood urea showed 190 mgms and -101.0 count of 11,GC6 per cu. mm. (A 93 L 7). eniciilin (i mega unit six—hourly) was commenced. The following day (30.11.50) he was afebrile but his general condition was not much improved, though he felt better. hiccoughing was persistent. lie was oliguric from 23.11.50 to 3u.11.50. l'he blood urea rose to 1.90 mgms on 28.11.5f), 420 mgms.,; on 30,1i.5.;and 520 mgms: on 2.12.50. The urine on 29.11.50 contained much albumen, and a heavy deposit of granular Lind cellular cuts with a moderate number of pus cello. / 0 / He was afebrile by 2.12.50 and began to improve rapidly. The blood urea was within normal limits on 6.12.50. He vas transferred for convalescence on 14.12,50 and diechnrgod early in erder to be repatriated to the U.K. Case 'Tfo.1. Rfn. T. ;eqV 20. (Gurkl1q)e dieitted 23.2.50 with a fourteen d history of abdominal pain, rain n the limbs and constipation, On adelissien he was afebrile, icteric and tender on palpation of the upper abdomen. Neither liver nor spleen were palpable. His coif munoles were exquisitely tender on palpation. Investigations showed: WBC 10,200 per cu. Mee. (N 61 L 18 M 16): Blood urea 220 mgmse: serum biltrubin 13,1 mgmse: Urine - Albumen present, bile present, pus cells, red blood cells and granular oasts in deposit. 7e improved rapidly, except that the seecifio gravity of the urine did not begin to vary from leie until 18.3.5e. He wae returned to duty on 8.5.5c, his renal function tents and blood count were shown to be normal. (Fato.) nee --!1,11 Pindines. Case 1W20: Ter, R. Age 22. (British). Admitted 1.11.5o with ten day history of headache, anorexia, and vomiting, Two days prior to admission he developed: pains in his legs, and noticed that his urine had been dark and red in colour. Pe also had a small haemoptytis four days prior to admiseion. /0 2. On admission he was febrile (T 100.2°P), not very ill, eyes suffused and a su.bconjunctival haemorrhage was present in the right eye. There was abdominal tenderness in the right hypochondrium but the liver wf...s.s not palpable. Investigations Showed: WBO 3„0-.)/ c.mm. 67 L 24 3 9): Urine - ,:lbumen preset. scanty pus col s in deposit: Blood urea 240 mgms: Serum Cholesterol 30C, 'r-rzas:,: Serum bilirubin 2.25 cone,. he was afebrile on the 2.11.5,, and apart from a slight fever of 99.201' about 6th-k.th remained so. discontinued on 3.11.50. He developed a mild anaemia, the blood count on 7.11,50 being hb . 11.8 gas-;: itlie 3.65 x 106 per cu. ram. He was transferred for convalescence on 16.11.50 and returned to duty on 27.11.50. opse_Nr,.P1: 'Amtin B. Age20. Amitted 21.10.50 with three day history of irever z•id genoml malaise. Developed productive cough with pleuritic pain in the left side of the chest. Also complained of headache anC photophobia. on admission he was fevered (r 101°P) and had a productive cough with hcsvtly blo-d-stnined snutum. Fis eyes were suffused, but there was no calf tenderness rrid no nuchal rigidity. The alae nasi were not working and he was not dyspnoeic. There were some tender inguinal glands. 4xam1nation of the chest showed normal movements arm percussion note but universal rhenchi with some coarse raies were hoard - on auscultation. /03 Invest!getiole ehowod: X-! ay, - HAD: VW 17,000 per cu, (P 98 L 2): Urine - Albumen + + granular casts, pus cells, and red blood cells in deposit. Leter on the day of admission, he heti a rigor and began coughing up brit red blood. It was considered that the urinary findings, leucocytosis, heemortysis and the lack of dysinnoea suggested a cause other than pulmonery disease, e.g. leptospirosis, Penicillin ( mega unit six-hourly) was commenced. Blood urea on 22.10.5e Was 50 mgms. By 23.10.5 he was very mak but had been afebrilo for 18 hours. Marked bronchoneasm was still prenent in the chest. n 27.10.5D he was much better and penicillin was discontinued. irinar eeaminatione.showed repeated17 the presence of much albumen and eany granular casts and run eels. 1.11.50 he wan fit and transferred for conenieseence. On 15.11,50 he was returned to duty eerfeetly fit. Oeoe ee.22e 1nr, MI go 41. (British). Admitted 27.10.50 with seven days history of fever, headache, nausea, vomiting (for first two days), diarrhoea (for three days) and some cough. On edmission he was febrile (T 100.50F) not very ill looking, moderate suffusion or face and eyes, and few enlarged cervical and let axillery glands. The c lf Ausclee were not tender though the patient complaineu of tenderness. There was eioderate to on palpation in the right iliac fosse. /09 Investigations Showed: 'eBC 15,400 per eu. mm. (N 86 L. 14). On the following day the urine examination showed the p sence of scanty pus cells in the deposit, but albUM071 WRG abeent. Stool examinatlens wcro negative. On 31.10.50 he was still running a low grade fever of 990 — 100cV but felt well apart from mill headache. en this day albuminuria was present. By 2.11.5C the fever had settled and improvement was raid. Ea vas transferred to convalescence on ?.11.50.. The diagnosis in this case was between scrub typhus and loptospirosis, but the leunocytosis„ suffusion, albuminuria, stiffness of calf muscles, slid a eellerelix Agelutination Titre (eXK) which never rose above 1 : 160, suggested a mild case of leptoseiresio. nc; Case te. G. —t•ea (Britielf). 'eaelltted 23.1u.5o with six day history of fever, headache, pain in the right groin, marked cough with blood— stained sputum, occasional vomiting ar4 some generalized abdominal pain. Cr, admission he was ill, fevered (T lel and suffused. There vas generalized lymphadenopat J.'he chest moved evenly and the percussion note and air entry were normal. There were universal rhonchi and basal rales on ansenitation. neve wgs slieht meningism; the calf musoles were not tender. avestigati ns showed: WBO 12,000 per eu. mm. (N 61 L 29 1.1 5 5): Blood urea 220 mgms : Urine - Albumen Preeant• heav deposit of granular cast and pus cells. Cn 24.10.. e running low grade fever and pe (1- 0 unit six-hourly) was coll oenced. The temPeratire retched normal on 25.1'4,55,and he felt much better apart _rom mild headache. 7ho fever however peroistednd did LAOt finally settle until 3G.1(_. Penicillin was discOntinued on .1u.50. The cough and blOod-stained sputum ceased on 26.1 .50. The urine ho,d cleared on 4.11..,k,. they inyestigationz on 23.10,50 showed serum proteins - Normal: "erum bi1irub1n 1.2 3er1im cholesterol - 167 The gene al condition improved raidIy from •a mild annenia. The blood count on 8.11.5 Bhowed - Hb = 11.2 P.T3C x 1O pe.o on, we was transferred to eclIvn ,1 and discharged•to on 24.11,:)u 'ter function to t„ end• count zzich ir=is y ormal. Case , I Si 71, Age 19t (British'. r~aittoo 17.5 50 with five day history of fever , headache, pains the neck, back and legs, nausea and vomiting. aomission he was fever ed (T 100.80P)„ eyes suffused, glands enlarged in left axilla, and in groins, nlight meningism was present, but calf Tuscles were not tender. /6 Investlg' tions shoxed: 'BC 13,400 per cu. mm. (J L ,,, 1): Urine - oClbulaent moderate number of grJ-,nalar casts an5 puo follouing aay (11.5.5C) jaundice develo;)ed on an erythematoas loe'r.ground giving the chlracteri,stic oranfr,e-red colour. ?he temper,lture wls P- 11ing. investigations showed: blood area 35 mgms.: erum :roteins - Normal: Liver Functirn :ests - Normal: 'Penicillin CI mega unit six-hourly) was commenced. The fever settled en the following day (19.5.50): penicillin wan liscontinued on 21.5.5C tad tie jaundice had disam-,earod by the 25.5.5D. A mi1'i anaemia develo-)ed, the blood count on 25.5.5.' being lib = 13.8 gms RBO = 4.41 x 106 ner cu. mm. He was tr'Insfe.2red for convEJlencence on 2.5.'10 and before finpl diAehlrge on 1.7.50 he showed normal rensl function tests aad Mood count. Case No.271: (3p1. P. Are 24. (ritish). Admitted 25.Lt.5C with two day history of fever, general malaise and severe backache. On admission he was fevered (T 1030r)t but not very ill-looking, eyes mildly sliffased, no glandular enTs.rgement and no muscuThr tenderness. BP 140/100. Investigations showed: Urine - No albumen, no cots or pus cella. On 26.4.50 the fever was intermittent, but apart from general aches and pains, and suffusion of the eyes there was nothing specific about the illness. lo7 On 28.4.50 the spleen was palpable and tender but repeated blood films were negative for malarial pnrastten. f2e. fever apenred to be nettling. On 1.5.50 the temperatUre wan 10001= and the mein complaint was pain In the calf musclec. 'r7,.rthema and lnundice had developed and the calves ,;:ere tender on palpation.' Investigations dh owed: Blood urea 70 mgrn C9,800 per cll. mm. (N 58 L 22 M t 7, Li): Urine .6. 'Albumen nil, few granular catts and pus cells in (3.enosit: 3erum iroteins - Normal: Serum Billrubin 5.3 mgmsA. enicillin (If mega unit nix-hourly) was commenced. progress was raid, be 'ti afcbrile on 2.5.50, penicillin was discontinued on 6.5.50 and lauWice had nearly disappeared on 8.5.50. He waa transferred for convalescence on 19.5.50 and discharged to duty on 13.6.5O After normal renal function tests. Case No.26: Rfn. h Are 17._(Gurill!a Case See under , findings. BRITISH 1111 MAY 24, 1952 SPECIFIC GRAVITY OF RED CELLS MEDICAL JOURNAL At the end of one hour, after each tube was filled, read- ings were taken and the haematocrit tubes centrifuged, Summary together with some of the unmanipulated " Wintrobe " Evidence has been given that the specific gravity of blood samples which were used to fill the 3-mm. tubes red blood cells falls very appreciably when the M.C.H.C. previously described. The results are given in Tables I becomes low. This might explain the slow sedimenta- and II. tion of blood from some cases of " chronic anaemia," Case 2 as it was shown that markedly hypochromic cells sedi- It was not possible, in this case, to make such a full inves- ment more slowly than do normochromic cells, and tigation to show the practical effect of marked reduction in the M.C.H.C. on the sedimentation rate. these red cells with a very low M.C.H.C. and low specific gravity may not be good " indicators " in sedimentation A man of 79. with a carcinoma of the colon, was found to have a very low corrected Wintrobe sedimentation rate, rate estimations. but the blood count showed a marked hypochromic anaemia. REFERENCES Suitable normochromic red cells were washed once in the Gregg, R. 0, (1937). J. Lab. cite,. Med., 22. 786. patient's plasma and then used to perform a Wintrobe sedi- Ham. T. H., and Curtis, F. C. (1938). Medicine, Baltimore, 17. 447. Heller, V. G., and Paul. H. (1934). J. Lab. clin. Med., 19, 777. mentation test when suspended in the patient's plasma. The Hynes, M.. and Whitby, L. E. H. (1938). Lancet, 2. 249. results are given in Table III. MacFarlane, R. G., and O'Brien, J. R. (1946). Practitioner, 157. 1. Phillips, R. A., Van Slyke, D. D., Dole, V. P.. Emerson, K.. jun., Hamilton, P. B.. and Archibald. R. M. (1943). Bull. U.S. Army med. TABLE II1.-Results in Man of 79 With Carcinoma of Colon Dept., No. 71, 66. Rogers. K. B. (1946a). Lancet, 1. 502. R.B.C. .. 2.8 mil. per c.mr). Sp. G. of R.B.C. .. 1075 Plasma proteins .. 7.2 g. % - (1946b). Ibid.. 2, 520. .. .. 4.8 „ „ Rourke, M. D.. and Ernstene, A. C. (1930). J. am. invest., 8. 545. 20 cgcir Tubercle, 19, 529. Globulin Schuster, N. H. (1938). M.C.V. .. ' .. .. 71 /45 Smith, C. J. Pedicti., 12. 684. .. .. 2: 1 H, (1938). M.C.H.C. .. 23% A/G ratio Terry, R. (1950). British Medical Journal, 2, 1296. Patient's plasma was cross-grouped with K.B.R.'s red cells-In tube at Wintrobe, M. M. (1946). Clinical Haematology, 2nd eel. Kimpton, London. 37° C. for one hour and was compatible. - and Landsberg, J. W. (1935). Amer. J. med. Set.. 189, 102. Wintrobe Sedimentation Rate-Both Cells Suspended in Patient's Serum K.B.R.'s Cells Patient's Cells Fall in 1 hour .. 47 mm. 52 mm. 20 c.cm . 34 c.cm. Corrected rate (by Hynes and Whitby's graph) .. 5 mm. 28 mm. TATTOOING AS POSSIBLE MEANS OF In this experiment it was felt that a misleading " normal " TRANSMITTING VIRAL HEPATITIS corrected sedimentation rate was due to the low M.C.H.C. of the patient's red cells. BY A. C. S. HOBSON, M.C., M.B., M.R.C.P. Discussion Lieutenant-Colonel, R.A.M.C. ; Officer in Charge of A hypothesis that red cells with a reduced M.C.H.C. Medical Division would have a lowered specific gravity has been found to be correct. Experiments showed that hypochromic red cells D. E. FRASER, M.B. sedimented much more slowly than normochromic Captain, R.A.M.C. suspended in the same plasma. In these experiments there was a correlation between both M.C.V. and M.C.H.C. and AND the sedimentation rate, which agrees with the findings of Ham and Curtis on the correlation between the sedimen- The Late N. H. NEWMAN, M.B. tation rate and the M.C.V., and with Neuberg and Snapper's Captain, R.A.M.C. correlation between it and the colour index. It does not (From a Military Hospital in Hong Kong) agree with Ham and Curtis regarding the lack of correlation between sedimentation rate and M.C.H.C., or with Win- file object of this paper is to provide statistical evidence trobe's observations on the specific gravity of red cells and to show that tattooing should be regarded as an impor- the sedimentation rate. tant means of dissemination of viral hepatitis among This work has provided an explanation of Terry's results, Service personnel in Hong Kong, This investigation was as all his cases had marked hypochromic anaemia, many with M.C.H.C. values far below those encountered in the initiated after observing that the incidence of tattooed present investigation. It does not substantiate Terry's sug- patients in the hepatitis wards appeared to be higher gestion that the plasma of such patients is deficient in than in other wards. rouleaux-forming powers. The term " viral hepatitis " was proposed by Neefe Terry argued that his slowly sedimenting hypochromic et al. (1946) ,to describe those forms of hepatitis caused anaemic bloods proved that the sedimentation rate was not by filterable infectious agents which have not yet been increased by anaemia and therefore the observed rate had routinely isolated and identified. Evidence arising from the same significance in anaemia as in normal blood states. extensive experiments, using human volunteers, has It might be more correct to state that he showed that two shown that there are at least two virus-like agents factors-the slowing due to the red cells having a low speci- fic gravity, and the accelerating effect of the lowered packed concerned in the aetiology of viral hepatitis. cell volume-may nearly cancel the influence each will have on this test. Terry's work does not prove that correction Transmission of Virus charts are fallacious in any other type of anaemia ; but the Theie two agents have been called (a) virus IH and fact that correction charts may be misleading in such hypo- (b) virus SH (Neefe, 1949). Virus IH is present in the faeces chromic anaemias does not mean that the uncorrected rate and blood, and is concerned with infectious hepatitis (incu- is any more informative. Many workers would hesitate to bation period of 15-40 days), while virus SH is found only state that the results Terry showed in his Table III (the in the blood and is concerned with homologous serum Westergren sedimentation rates of cases with a slightly raised hepatitis (incubation period of 50-150 days). It will be E.S.R.) were indications of any condition other than that noticed that both viruses appear in the blood, and, according of anaemia. to Neefe, parenteral transmission of such blood may cause It is obvious that in cases with a very marked hypochromic a hepatitis following an incubation period typical of virus anaemia the sedimentation rate may provide an inadequate Ill-that is, 15-40 days-or of virus SH-that is, 50-150 indication of active disease. days, according to the infecting virus. 1112 MAY 24, 1952 TATTOOING AND VIRAL HEPATITIS Bitrrisa MEDICAL JOURNAL By inoculation experiments it has been shown that the Discussion virus is present in the peripheral blood during the latter part of the incubation period (for a longer period in homo- It will be seen that the difference between the number logous serum hepatitis) and for about the first 14 days of of cases of viral hepatitis tattooed 51 to 150 days before the disease (Havens and Paul, 1948). Thus during this period the onset of symptoms, and the control cases (39.1 % to it is possible for the virus to be transmitted to another host 10.5%) is highly significant—the actual difference being 5.7 by transfusions of blood, serum, or plasma. Since, however, times the standard error of difference and the probability the virus may be present in the blood in such high concentra- of the occurrence being that of chance being approximateb. tion that as small a quantity as 0.001 ml. of serum can be I in 4 x 108. shown to be infectious (Scheinberg et al., 1947), transmission Robertson (1951) described how, in a British military of the virus may occur through contaminated syringes and hospital in Germany in 1947, a medical officer made a similar needles following their use on a patient with infected observation regarding the incidence of tattooing in cases of peripheral blood. Thus one would anticipate cross-infection infective hepatitis, but circumstances prevented further if numerous injections were performed on consecutive statistical investigation. He did, however, mention that patients without intervening resterilization of the syringes among 10 cases admitted during one week six were found and needles. This has occurred, for example, in V.D. clinics to have been tattooed on the same day, and by the same and in circumstances where parenteral therapy has been artist, rather less than four months before. employed. Smith (1950) described how among American Service This danger of cross-infection is now well recognized and personnel he found that 18 out of 26 cases of infective suitable. precautions are taken. When one considers the hepatitis had been tattooed 49-154 days before the onset of technique of tattooing, it will be realized that a similar symptoms whereas only 61 out of 200 non-hepatitis case,, danger of cross-infection exists. had been tattooed. He thought that the comparison of 69% The technique of a local tattoo artist is as follows: The among hepatitis cases with 30% among his controls particular area of skin is shaved and then wiped rather per- represented a significant difference. functorily with industrial spirit. The pattern transfer is We believe our series shows that the higher incidence of pressed on the skin and then the pattern is traced with the tattooing in the hepatitis cases is mainly due to the greater mechanical needle. The needle is dipped in various bottles number of cases which have been tattooed between 50 and containing the coloured dyes and then transferred to the 150 days beforehand and have become infected in that skin. During the needling a certain amount of blood oozes manner. from the area. At the end of the process the skin is given Summary a final wipe with the same cloth. Without the needle being A record of the incidence of tattooing in 143 cases cleaned, the next customer is attended to. of viral hepatitis admitted to a military hospital in Hong It will be realized that the tattoo needle can remain Kong has shown that 56, or 39.1%, were tattooed 51 infected, and that the bottles of dye may become infected. to 150 days beforehand, as against 16, or 10.5%, of 152 It is known that the virus is very hardy and can withstand the normal measures suitable for bacterial neutralization. control cases in the same hospital. Service personnel often go in pairs to be tattooed, and so It is thought that the difference is statistically signifi- one is tattooed immediately after the other. If the first cant, and that it proves that tattooing is a possible mode soldier should be incubating the disease there would be of transmission of the causative virus. every chance that the tattoo needle would be contaminated The technique of tattooing is discussed with reference with the virus and then the second soldier would be inocu- lated. According to Neefe (1949) the incubation period of to its facilitation of the transmission of the hepatitis virus homologous serum hepatitis is approximately 50-150 days, from one subject to another. and thus one would anticipate that, if tattooing was a mode We wish to thank Professor A. J. S. MacFadzean, honorary of transmission of virus SH, in any group of personnel of consultant physician to H.M. Forces in Hong Kong, for his whom a large number had been tattooed the number adorned assistance during the preparation of this paper, and the Director- 50 to 150 days beforehand should be greater among cases General. Army Medical Services, for permission to publish. of hepatitis than among others. REFERENCES Havens, W. P., jun., and Paul, J. R. (194R). In Rivers, T. M. (Editor), Investigation of a Series of Cases Viral and Ridkettsial Infections of Man, pp. 269-83. Lippincott, Philadelphia. An investigation was made on these lines among the cases Neefe, J. R. (1949). New Engl. J. Med., 240. 445. of viral hepatitis which were admitted to this hospital during — et al. (1946). Amer. J. Med., 1. 3. Robertson, K. M. (1951). Lancet. 1. 57. the period December, 1950, to June, 1951, and a comparison Scheinberg. I. H., et al. (1947). J. Amer. med. Ass.. 134, 841. made with other patients in the hospital as a control. These Smith, B. F. (1950). Ibid.. 144. 1074. other patients were exactly similar as regards units, living environment, liability to inoculations, tattooing, etc., and The 72nd Annual Congress of the Ophthalmological differed only in that they had been admitted to hospital for Society of the United Kingdom was held in Dublin at.the conditions other than that of viral hepatitis. The compara- Royal College of Surgeons in Ireland as guests of the Irish tive figures are shown in the Table. Ophthalmological Society in Ireland on April 17 to 19, and Mr. Maurice Whiting presided. On only one previous occasion—exactly 40 years ago—has the society journeyed No of Days Tattooed before Total Onset of Viral Hepatitis Total to Ireland. More than 125 members were present this time. No. of No Cases Tattooed including several from the Continent. Two of the principal 0-50 51-150 150+ speakers—Professor Alan Woods and Professor Derrick Vail tv —came from the U.S.A.; the second giving the Montgomery Hepatitis 143 5 56 38 99 (3'57) (39.1%) (26.6%) (69.2%) Lecture on diffuse collagenous diseases with ocular complica- tions, while the first opened a discussion on the value of No. of Days Tattooed before cortisone and A.C.T.H. in ocular diseases. Among the short Admission papers was one by Mr. T. Roche, who could find no 0-50 51-150 150+ evidence for the occurrence of retrolental fibroplasia in t Dublin, and an outstanding exhibition of the value of angio- Controls 152 7 16 56 79 graphy in ocular disease by Dr. Alan Mooney. The meeting (4.6%) (10-5%) (36.8%) (51.9%) was completed by a number of social functions, including • Standard error of difference.0.050 = 5.0%. the annual dinner of the Society at the Gresham Hotel, and t Actual difference, 39.1%-10.5% = 28.6%. a reception by the Eire Minister for Health.