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Studies on the Weltmann reaction in malaria cases
221
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. XXXIX. No. 3. December, 1945.
S T U D I E S ON T H E W E L T M A N N R E A C T I O N I N M A L A R I A CASES. BY
J. KLEEBERG, M.D. (BONN),
Head of the Medical Department _4, Hadassah-Rothschild University Hospital, Jerusalem, Palestine.
The literature of tropical medicine cites a number of blood reactions, mostly globulin reactions, which indicate certain groups of diseases rather than being pathognomonic for one alone.. (BRAHMACHARI, 1917; CHORINE, 1938 ; Formol-gel reaction, HENRY, RAY, 1931 ; SIA, 1921 and 1924 ; WOLFF, 1939). T h e Weltmann test is also a globulin reaction, but it is not at all specific for malaria or any other disease. However, I shall attempt to point out its advantages. In 1930 WELTMANN described a simple coagulation reaction (W.C.R.) of blood proteins by calcium chloride. This unspecific test makes it possible, according to its discoverer, to distinguish between acute inflammatory and chronic proliferative processes. Only a few articles followed in the German literature concerning the general clinical significance of this coagulation test. In America, since 1938-1939, rLEvINSON has made extensive studies on the subject. In the American literature papers appeared on the W.C.R. in the fields of pediatrics, neurology and tuberculosis. Together with Dr. UNNA and Dr. EINHO~, we have used the W.C.R. during 3 years on about 1,000 patients. We can confirm the results outlined by WELTMANN himself, LEVlNSON and others, concerning its general clinical importance. I n England the reaction is hardly used and in tropical medicine the standard books of CRAIG and FAUST, M.ANSON-BAHR, ROGERS, MEGAW and STRONG-STITT.do n o t mention the Weltmann reaction. I have so far been able to find only three articles from 1930 until now dealing with W.C.R. and malaria. There is LANDEIRO (1935), whose paper
222
WELTMANN
is available in Portuguese only.
REACTION
IN MALARIA
More recently LEVINSONand MCFATE (1943),in their
Clinical Laboratory Diagnosis, mention malaria (among the detailed schemes for other diseases).. A Bulgarian author, TSCHILOW(1931) examined forty cases of malaria in 1931. His results are the same as mine. However, I t h o u g h t it worth while, 13 years after this apparently forgotten paper, to report m y studies in twenty-five cases of malaria: because they confirm the results of TSCHILOW and of LEVlNSON ; because the reaction seems to me of diagnostic value, as indicating the possibility of a haemolytic process ; and because I believe this simple reaction m i g h t become an interesting test in the field of tropical medicine in general. T h e technique as published by LEVINSON and MCFATE (1943)* is as follows : 1. Stock calcium chloride solution. Dissolve in water 50 grammes of dry crystals of reagent CaCl2 . 6H20 and dilute to 500 c.c. in a volumetric flask. 2. Dilute calcium chloride solutions. Transfer 5 c.c. of stock calcium chloride solution to a 500 c.c. volumetric flask and dilute to 500 c.c. with water. Mix and transfer to a bottle numbered " 1." In turn, transfer 4.5, 4.0, 3.5, 3-0, 2.5, 2-0, 1.5, 1-0, and 0"5 c.c. of stock solution to the volumetric flask and dilute each to 500 c.e. Mix and transfer to bottles numbered 2 to 10 respectively.
Apparatus. 1. Metal test-tube racks, to hold 13 × 100 mm. test-tubes. 2. Boiling water-bath.
Procedure. Place ten test-tubes, 13 × 100 mm. in a metal test-tube rack and number consecutively from 1 to 10. Into each tube pipette 5 c.c. of the similarly numbered solution of calcium chloride. Then add 0.1 c.c. of the haemoglobin-free serum. Shake the tubes so the contents will be mixed and place in a boiling water bath for 15 minutes. Remove from the bath and read. The contents of the tubes may be clear, faintly opalescent, turbid, or there may be flocculation. There is usually a sharp and easily noted difference between flocculation and turbidity. T h e n u m b e r of the tubes in w h i c h flocculation occurs was designated by WELTMANN as the coagulation band (C.B.). I f there is very slight or doubtful flocculation in one tube, a rare occurrence, the reaction is interpreted as being intermediate between that tube and one before ft and is designated by the figure ½. T h e blood s h o u l d be taken in the morning, before breakfast, t h o u g h a cup of coffee or tea or even a rusk does not alter the result. S e r u m after a heavy meal cannot be used, nor can haemolytic serum be used. SCHWEINBURG and EVANS (1941) emphasize that there should always be one " normal serum " to test as a control. T h e bottles must be protected from the CO2 of the air b y k e e p i n g t h e m t h o r o u g h l y closed. T h e stock solution can be kept for a very long t i m e ; the dilutions should be discarded after 2 months. T h e reading of the coagulation tube must be made immediately after removal f r o m the water bath. * I thought it useful to give details of the procedure, because at the present time it may be difficult to get the original literature.
J. ~ L ~ E n ~ a O
223
Interpretations.
In normal serum, the first six tubes usually show floccul'ation. Sometimes there is slight or doubtful flocculation in the seventh tube. T h e normal coagulation band is therefore 6 to 61 and remains remarkably constant in a serum of a healthy person. T h e illustration shows the technical arrangement. Coagulation values of 6 or 7 are " normal," and higher numbers (8, 9, 10) means a " shift to the right " or a prolonged coagulation band (C.B.). V i c e - v e r s a , values 5-1 indicate a " shift to the left," o r a shortened coagulation band. WELTMANN and his co-workers drew two conclusions: the WELTMANN Coagulation Reaction (W.C.R.) has a general and a specific significance. " Shift 1
2
3
4
.5
6
7
8
9
10
to the left or shortened C.B." indicates an acute inflammatory exudative process. Shift to the right or lengthened C.B. is found in chronic proliferative process. • Concerning the s p e c i f i c importance, WELTMANN has described in several papers how all patients with liver-cirrhosis showed a prolonged C.B., indicating a toxic damage of the liver-cells, as is usually the case in hepatic cirrhosis. GENERAL APPLICATION OF W.C.R.
This simple method was employed by us in twenty-fivecaseso f malaria. We can distinguish three types of reactions : thirteen cases showed a definite
2"24
WELTMANN REACTION IN MALARIA
shift to the right, figures like 8 or 9 (prolonged C.B.) : ten cases gave abnormal C.B. (figures like 6 or 7) ; only two cases showed a shift to the left (4 or 5). The W.C.R. in cases of acute infectious diseases is nearly always more or less shifted to the left. This is the experience of many investigators (WELTM;U~N, LEVINSON) and our own results in about 1,000 cases are similar (KLEEBERG, EINHORN and UNNA). We should have expected, especially when patients had high fever, W.C.R. with figures like 4 or 5, if not even less (2 or 3) : f r o m this point of view the group with numbers such as 6 or 7 is surprising. We may say that twenty-three out of twenty-five acute malaria cases gave an unexpected result with W.C.R., a so-called " normal range," or even a definite shift to the right (ten cases). The real prolongation of the coagulation band and the " masked " one (the group with figures like 6 or 7) did not depend either on the type of the malarial parasite or on the level of the temperature. T h e results were the same during an attack with chill and fever and on days between the attacks (i.e., tertian malaria). No relation has been established with the accompanying anaemia. The chemical composition of the blood proteins of a healthy person under normal conditions is very constant (BEST and TAYLOR, KECKWICK and MCFARLANE). On the other hand diseases, especially those with high fever, rapidly change the ratio albumin-globulin (KEcKWICK and MCFARLANE) as the total protein or the globulin fraction alone. (SNAPPER,1943.) Nearly all of the :previously mentioned tests are based upon hyperglobinaemia. Thus the Henry test was simplified by CHORINE by using distilled water : the original Henry technique of adding melanin from the eye of an ox merely makes the flocculation more easily visible, but it is not essential. (STRONG* STITT, 1942.) According to MEGAW, both Henry's and Chorine's tests are globulin reactions and not specific for malaria. Likewise, the modification by WOLFF (1939) with buffers, is unspecific. (STRONG-STITT.) We know t h a t the formol-gel test, discovered by GAT~ and PAPACOSTAS (1920), is positive in all cases of hyperglobinaemia. Therefore positive flocculation may be obtained in cases of malaria, kala-azar, subacute bacterial endocarditis, trypanosomiasis, schistosomiasis, even in cases of septicaemia. (KYLIM, 1938; LEVINSON and MCFATE, 1943; STRONG,STEIN-WORTHEIMER). ROGERS (1942) cites LLOYD, who says that all formalin tests depend on an excess of altered euglobulin and a decrease of serum albumin specially in the blood in kala-azar. The aldehyde test, modified by NAPIER, has its value for chronic cases in kala-azar in certain places, where some of the above-mentioned diseases do not enter into consideration in differential diagnosis, or at least not within the first months of the disease. The W.C.R. belongs to this unspecific group of globulin-flocculation, most probably the increase of globulin being the main cause. The main production place of globulin formation and transformation is the liver (WHIPPLE).
J. KLEEBERG
225
WELTMANN always held to his opinion that, in all toxic liver cell damage, the C.B. is prolonged and shifts to the right, as in certain cases of jaundice and always ill cirrhosis. There is liver damage in malaria infection by the invading parasites which is either anatomical (BOYD, FAIRLEY, 1937 ; SMITH and GAULT, STRONG-STITT, 1942), or functional (Ou, 1941 ; ORLINA, 1941 ; MANSON-BAHR, 1940; KoPP and SOLOMON, 1943). We had no cases of pregnancy in malaria where, according to WICKRAMASURIYA(1937), the cloudy swelling and the " fatty degeneration " is very pronounced. I suppose the W.C.R. in such cases might give quite interesting results. However, if we do not go into details on liver damage it is because I do not think that liver changes are the decisive factor for our unexpected results in the W.C.R. in malaria. It is difficult to explain such a coagulation result due to a parasitic liver invasion, compared with the opposite reactions of the C.B. in nearly all the other infectious diseases with high fever. There, too, the liver is highly involved (e.g., pneumonia) and the W.C.R. goes to the left. Then the rapidity with which the W.C.R. swings to the right; even on the first day of chill and fever we found in several cases already results of " 8 " o r " 9." In 1931 WELTMANN already explained the results of TSCHILOW (1931) as a possible haemolytic reaction. He came to this conclusion as a result of his observation on cases of pernicious anaemia. I also believe that haemolysis is the most probable factor producing this peculiar coagulation reaction. One can easily produce this phenomenon with every normal blood serum which gives a normal range of W.C.R. If one makes by any procedure such a serum haemolytic, the new coagulation test shows one or two tubes more to the right ; therefore clear unhaemolysed sera only are to be carefully examined. We have examined two cases with acute haemolytic anaemia due to sulphanilamide and dagenan. Both cases whose C.B. had been shifted to the left (surgical cases) swung during the haemolytic crises to " 9." When the recovered patients left the hospital, they had W.C.R. " 6." We have proved that the ;sulphanilamide group alone has no effect on the W.C.R. We therefore think that it is the haemolytic effect of the malaria infection which causes the prolongation of the C.B. I should like to suggest that perhaps the number of the coagulation tubes, 8 or 9, or 10, or only 6 or 7, may be a quantitative indication of the degree of the haemolysis. If this holds good it may be a very helpful method in addition to, or instead of, reticulocyte counting (FAIRLEY) and especially in watching patients with threatened blackwater fever. No satisfactory explanation can as yet be offered as to why two patients with malaria had a C.B. of 4 o r 5. They had no other complications, which could have changed the C.B. Other investigators, and we, too, have observed that patients, suffering from typhoid, for instance, had a C.B. of 5. As soon as they got any complications (broncho-pneumonia, thrombophlebitis, otitis, cystitis), the W.C.R. changed and swung to the left,
226
WELTMANN REACTION IN MALARIA
2 or 3, returning to its former level when the complication had passed away. As has been said, no such complications occurred in these two patients with malaria. We are commencing investigations on a larger scale and hope to discover the reasons for the exceptional results. One case is worth reporting in detail: The patient, S., with tertian malaria, presented a coagulation hand of 9. He received quinine-atebrin treatment and left the hospital after 8 days with no fever, no plasmodia, and in a satisfactory condition, After another 7 days he had to be re-admitted on account of high fever, headache, a sensation of burning in the eyes. A relapse was suspected but no plasmodia could be detected although the blood was thoroughly searched during 2 days. The coagulation band was 7 instead of 9 as it had previously been. The temperature chart and the positive Weil-Felix reaction after 10 days indicated that the patient had in the meantime contracted typhus of the mild murine type prevailing in this country. Thus the change in the W.C.R. had given a hint that the diagnosis should be revised. All these facts show that in a given case of high acute fever the W.C.R. has a certain diagnostic value, especially as the result is obtainable on the very first day of the fever. Influenza, tonsillitis, pneumonia would give always a marked shift to the left " and even typhoid (not easily identified in the first $ew days) would not show a shift to the right : typhoid mostly gives the figures " 5," maximum 6." Only infectious jaundice might come in for special consideration as it has a W.C. ÷ Reaction though probably for other reasons (liver damage). As far as I could find in the available literature, the W.C.R. has not been used in the field of tropical medicine. Theoretically, judging from what is known of the W.C.R. in other infectious diseases, one might expect in patients with schistosomiasis or kala-azar at the time of high fever a shift to the left." Only when liver-cirrhosis has definitely set in, a swing to the right should be obtained. But to examine the two mentioned, and other tropical diseases, by the Weltmann method may lead to another advantage. WELTMANN (1931) has pointed out the value of repeated W.C.R. in the course of a given disease in obtaining a prognostic view. Since the W.C.R. is uninfluenced by the height of fever, or by any accompanying anaemia, the W.C.R. may sometimes be more helpful in prognosis than the sedimentation time. (W~.LTMANN, LEVINSON,KLEEBERG). Taking into consideration the very simple technique, may I again be allowed to urge that this Weltmann Reaction be tried in the field of tropical medicine. "
"
"
SUMMARy.
1. The technically simple procedure of the " Weltmann Coagulation Reaction" (W.C.R.) was employed by us in twenty-five cases of malaria. 2. Nearly always in acute infections with high fever the Coagulation Band (C.B.) is shortened and the W.C.R. is shifted to t h e left. But although a
J. KLEEBERG
227
malaria attack clinically produces all the features of an acute inflammatory process, the W.C.R. is shifted to the right (thirteen cases) or stays normal (ten cases). Very similar results were obtained by TSCHILOW (1931). 3. T h e W.C.R. is an entirely unspecific protein-globulin reaction; but considering all above-mentioned facts, it gives in tropical countries a certain hint in the diagnosis of acute fevers. 4. It is suggested that haemolysis may be responsible for the occurrence of the lengthened C.B. in malaria. 5. T h e Weltmann test is particularly valuable in all haemolytic processes. It might prove to be of special help in blackwater fever. 6. A repeated W.C.R. in the course of a disease can, like the sedimentation time, be of help in prognosis. Therefore interesting results might be obtained in other tropical diseases besides malaria. REFERENCES BINC, JENS. (1937)• Acta reed. scan., 91,336. BOYD, W. (1932). Textbook of Pathology. London : Henry Kimpton. B~m~ACHAaI, U . N . (1917): Indian med. Gaz., 52, 319. CHOaINE, V. (1938). Arch• Inst. Prophy. Phris, 10, 202. C~Ic, C. F. & FAUST,E.C. (1937). ClinicalParasitology. Philadelphia : Lea & Febiger. FAIPa~.Y, H . N . (1937)• Trans. R. Soc. trop. Med., 30, 9. (1938). Trop. Dis. Bull., 35, 265. GATfi ~ PAPACOSTAS. (1920). Compt. R. Soy. Biol., 83. K~cXWmK, R. A. & McFAaLANE,A.S. (1943). Ann. Rev. Bioch., 12, 93. ~EaG, J., EINHOm~, V. & UNNA, G. Clinical value of Weltmann reaction in internal diseases. In press. Koee, ISaA,~L& SOLOMON,H . C . (1943). Amer. ft. Med. Sci., 205, 90. KYLIN, E. (1938). Die Eiweisak6rper des Blutplasmas. In Blennhold-Kylin-Ruszniyak. LANDEIRO,F. (1935). Lisbon med., 12, 771. LEVINSON, S. A. & KLEIN, Z. I. (1938). Amer. Rev. Tuberc., 37, 200. • (1939). Ann. intern. Med., 12, 1948. - & McFArE, R• P. (1943). Clinical Laboratory Diagnosis. London : Henry Kimpton. MANSoN-BAx-m, P. (1940). Manson's Tropical Diseases. llth Ed. Baltimore: Wm. Wood & Co. NAPmR, L . E . (1927). Kala-azar. Oxford University Press• ORLINA, N . M . (1941). Trans. Kuibyshev Milit. med. Acad. Red Army, 5, 29. Abstract Trop. Dis. Bull., 39, 519. Ou, T. (1940). Taiwan Igakkai Zasshi, 39, 1125. Abstract Trop. Dis. Bull., 38, 507. RAY, C.B. (1921). Indian reed Gaz., 56, 9. • (1924). Ibid., 59, 387. RocEns, L. & M~GAW,J. W.D. (1942). Tropical Medicine. London : J. & A. Churchill. SIA, R. H• P. (1921). China reed. aT., 35, 397• • (1924). Ibid., 38, 35. SNAPPER, J. (1943). Medical Clinics on Bone Diseases. New York: Interscience Publishers. SCHWEXNBtmG,B. & EVANS,L . Z . (1941). ft. Lab. Clin. Med., 366. STRONG, R. P. (1942). Stitt's Diagnosis, Prevention and Treatment of Tropical Diseases. 6th Ed. London : H. K. Lewis.
')28
WELTMANN REACTION IN MALARIA
TIRUMURTI,T. S. 8: RADHAKRISHNARAO. (1936). Indian ft. reed. Res., 24; Abstract in Trop. Dis. Bull., 34, 152. TSCHILOW, K. (1931). Wien. Klin. Wschr., 37. WELTMANN, 0 . (1930). Med. Klinik, 26 (February), 240. • (1930). Wien. Klin. Wschr., 43 (October), 1301. WHITBY, L. E. H. 8: BRITTON, C. J . G . (1942). Disorders of the Blood. London : J. 8: A. Churchill. WICKRAMASURIYA, G. A . W . (1937). Malaria and Ankylostomiasis in the Pregnant Woman. Oxford University Press. WOLFF, E . K . (1939). Trans. R. Soc. trop. Med., 32, 707. YOUNG, C . W . (1923). China med. ft., 38, 797.
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. XXXIX. No. 3. December, 1945.
S T U D I E S ON T H E W E L T M A N N R E A C T I O N I N M A L A R I A CASES. BY
J. KLEEBERG, M.D. (BONN),
Head of the Medical Department _4, Hadassah-Rothschild University Hospital, Jerusalem, Palestine.
The literature of tropical medicine cites a number of blood reactions, mostly globulin reactions, which indicate certain groups of diseases rather than being pathognomonic for one alone.. (BRAHMACHARI, 1917; CHORINE, 1938 ; Formol-gel reaction, HENRY, RAY, 1931 ; SIA, 1921 and 1924 ; WOLFF, 1939). T h e Weltmann test is also a globulin reaction, but it is not at all specific for malaria or any other disease. However, I shall attempt to point out its advantages. In 1930 WELTMANN described a simple coagulation reaction (W.C.R.) of blood proteins by calcium chloride. This unspecific test makes it possible, according to its discoverer, to distinguish between acute inflammatory and chronic proliferative processes. Only a few articles followed in the German literature concerning the general clinical significance of this coagulation test. In America, since 1938-1939, rLEvINSON has made extensive studies on the subject. In the American literature papers appeared on the W.C.R. in the fields of pediatrics, neurology and tuberculosis. Together with Dr. UNNA and Dr. EINHO~, we have used the W.C.R. during 3 years on about 1,000 patients. We can confirm the results outlined by WELTMANN himself, LEVlNSON and others, concerning its general clinical importance. I n England the reaction is hardly used and in tropical medicine the standard books of CRAIG and FAUST, M.ANSON-BAHR, ROGERS, MEGAW and STRONG-STITT.do n o t mention the Weltmann reaction. I have so far been able to find only three articles from 1930 until now dealing with W.C.R. and malaria. There is LANDEIRO (1935), whose paper
222
WELTMANN
is available in Portuguese only.
REACTION
IN MALARIA
More recently LEVINSONand MCFATE (1943),in their
Clinical Laboratory Diagnosis, mention malaria (among the detailed schemes for other diseases).. A Bulgarian author, TSCHILOW(1931) examined forty cases of malaria in 1931. His results are the same as mine. However, I t h o u g h t it worth while, 13 years after this apparently forgotten paper, to report m y studies in twenty-five cases of malaria: because they confirm the results of TSCHILOW and of LEVlNSON ; because the reaction seems to me of diagnostic value, as indicating the possibility of a haemolytic process ; and because I believe this simple reaction m i g h t become an interesting test in the field of tropical medicine in general. T h e technique as published by LEVINSON and MCFATE (1943)* is as follows : 1. Stock calcium chloride solution. Dissolve in water 50 grammes of dry crystals of reagent CaCl2 . 6H20 and dilute to 500 c.c. in a volumetric flask. 2. Dilute calcium chloride solutions. Transfer 5 c.c. of stock calcium chloride solution to a 500 c.c. volumetric flask and dilute to 500 c.c. with water. Mix and transfer to a bottle numbered " 1." In turn, transfer 4.5, 4.0, 3.5, 3-0, 2.5, 2-0, 1.5, 1-0, and 0"5 c.c. of stock solution to the volumetric flask and dilute each to 500 c.e. Mix and transfer to bottles numbered 2 to 10 respectively.
Apparatus. 1. Metal test-tube racks, to hold 13 × 100 mm. test-tubes. 2. Boiling water-bath.
Procedure. Place ten test-tubes, 13 × 100 mm. in a metal test-tube rack and number consecutively from 1 to 10. Into each tube pipette 5 c.c. of the similarly numbered solution of calcium chloride. Then add 0.1 c.c. of the haemoglobin-free serum. Shake the tubes so the contents will be mixed and place in a boiling water bath for 15 minutes. Remove from the bath and read. The contents of the tubes may be clear, faintly opalescent, turbid, or there may be flocculation. There is usually a sharp and easily noted difference between flocculation and turbidity. T h e n u m b e r of the tubes in w h i c h flocculation occurs was designated by WELTMANN as the coagulation band (C.B.). I f there is very slight or doubtful flocculation in one tube, a rare occurrence, the reaction is interpreted as being intermediate between that tube and one before ft and is designated by the figure ½. T h e blood s h o u l d be taken in the morning, before breakfast, t h o u g h a cup of coffee or tea or even a rusk does not alter the result. S e r u m after a heavy meal cannot be used, nor can haemolytic serum be used. SCHWEINBURG and EVANS (1941) emphasize that there should always be one " normal serum " to test as a control. T h e bottles must be protected from the CO2 of the air b y k e e p i n g t h e m t h o r o u g h l y closed. T h e stock solution can be kept for a very long t i m e ; the dilutions should be discarded after 2 months. T h e reading of the coagulation tube must be made immediately after removal f r o m the water bath. * I thought it useful to give details of the procedure, because at the present time it may be difficult to get the original literature.
J. ~ L ~ E n ~ a O
223
Interpretations.
In normal serum, the first six tubes usually show floccul'ation. Sometimes there is slight or doubtful flocculation in the seventh tube. T h e normal coagulation band is therefore 6 to 61 and remains remarkably constant in a serum of a healthy person. T h e illustration shows the technical arrangement. Coagulation values of 6 or 7 are " normal," and higher numbers (8, 9, 10) means a " shift to the right " or a prolonged coagulation band (C.B.). V i c e - v e r s a , values 5-1 indicate a " shift to the left," o r a shortened coagulation band. WELTMANN and his co-workers drew two conclusions: the WELTMANN Coagulation Reaction (W.C.R.) has a general and a specific significance. " Shift 1
2
3
4
.5
6
7
8
9
10
to the left or shortened C.B." indicates an acute inflammatory exudative process. Shift to the right or lengthened C.B. is found in chronic proliferative process. • Concerning the s p e c i f i c importance, WELTMANN has described in several papers how all patients with liver-cirrhosis showed a prolonged C.B., indicating a toxic damage of the liver-cells, as is usually the case in hepatic cirrhosis. GENERAL APPLICATION OF W.C.R.
This simple method was employed by us in twenty-fivecaseso f malaria. We can distinguish three types of reactions : thirteen cases showed a definite
2"24
WELTMANN REACTION IN MALARIA
shift to the right, figures like 8 or 9 (prolonged C.B.) : ten cases gave abnormal C.B. (figures like 6 or 7) ; only two cases showed a shift to the left (4 or 5). The W.C.R. in cases of acute infectious diseases is nearly always more or less shifted to the left. This is the experience of many investigators (WELTM;U~N, LEVINSON) and our own results in about 1,000 cases are similar (KLEEBERG, EINHORN and UNNA). We should have expected, especially when patients had high fever, W.C.R. with figures like 4 or 5, if not even less (2 or 3) : f r o m this point of view the group with numbers such as 6 or 7 is surprising. We may say that twenty-three out of twenty-five acute malaria cases gave an unexpected result with W.C.R., a so-called " normal range," or even a definite shift to the right (ten cases). The real prolongation of the coagulation band and the " masked " one (the group with figures like 6 or 7) did not depend either on the type of the malarial parasite or on the level of the temperature. T h e results were the same during an attack with chill and fever and on days between the attacks (i.e., tertian malaria). No relation has been established with the accompanying anaemia. The chemical composition of the blood proteins of a healthy person under normal conditions is very constant (BEST and TAYLOR, KECKWICK and MCFARLANE). On the other hand diseases, especially those with high fever, rapidly change the ratio albumin-globulin (KEcKWICK and MCFARLANE) as the total protein or the globulin fraction alone. (SNAPPER,1943.) Nearly all of the :previously mentioned tests are based upon hyperglobinaemia. Thus the Henry test was simplified by CHORINE by using distilled water : the original Henry technique of adding melanin from the eye of an ox merely makes the flocculation more easily visible, but it is not essential. (STRONG* STITT, 1942.) According to MEGAW, both Henry's and Chorine's tests are globulin reactions and not specific for malaria. Likewise, the modification by WOLFF (1939) with buffers, is unspecific. (STRONG-STITT.) We know t h a t the formol-gel test, discovered by GAT~ and PAPACOSTAS (1920), is positive in all cases of hyperglobinaemia. Therefore positive flocculation may be obtained in cases of malaria, kala-azar, subacute bacterial endocarditis, trypanosomiasis, schistosomiasis, even in cases of septicaemia. (KYLIM, 1938; LEVINSON and MCFATE, 1943; STRONG,STEIN-WORTHEIMER). ROGERS (1942) cites LLOYD, who says that all formalin tests depend on an excess of altered euglobulin and a decrease of serum albumin specially in the blood in kala-azar. The aldehyde test, modified by NAPIER, has its value for chronic cases in kala-azar in certain places, where some of the above-mentioned diseases do not enter into consideration in differential diagnosis, or at least not within the first months of the disease. The W.C.R. belongs to this unspecific group of globulin-flocculation, most probably the increase of globulin being the main cause. The main production place of globulin formation and transformation is the liver (WHIPPLE).
J. KLEEBERG
225
WELTMANN always held to his opinion that, in all toxic liver cell damage, the C.B. is prolonged and shifts to the right, as in certain cases of jaundice and always ill cirrhosis. There is liver damage in malaria infection by the invading parasites which is either anatomical (BOYD, FAIRLEY, 1937 ; SMITH and GAULT, STRONG-STITT, 1942), or functional (Ou, 1941 ; ORLINA, 1941 ; MANSON-BAHR, 1940; KoPP and SOLOMON, 1943). We had no cases of pregnancy in malaria where, according to WICKRAMASURIYA(1937), the cloudy swelling and the " fatty degeneration " is very pronounced. I suppose the W.C.R. in such cases might give quite interesting results. However, if we do not go into details on liver damage it is because I do not think that liver changes are the decisive factor for our unexpected results in the W.C.R. in malaria. It is difficult to explain such a coagulation result due to a parasitic liver invasion, compared with the opposite reactions of the C.B. in nearly all the other infectious diseases with high fever. There, too, the liver is highly involved (e.g., pneumonia) and the W.C.R. goes to the left. Then the rapidity with which the W.C.R. swings to the right; even on the first day of chill and fever we found in several cases already results of " 8 " o r " 9." In 1931 WELTMANN already explained the results of TSCHILOW (1931) as a possible haemolytic reaction. He came to this conclusion as a result of his observation on cases of pernicious anaemia. I also believe that haemolysis is the most probable factor producing this peculiar coagulation reaction. One can easily produce this phenomenon with every normal blood serum which gives a normal range of W.C.R. If one makes by any procedure such a serum haemolytic, the new coagulation test shows one or two tubes more to the right ; therefore clear unhaemolysed sera only are to be carefully examined. We have examined two cases with acute haemolytic anaemia due to sulphanilamide and dagenan. Both cases whose C.B. had been shifted to the left (surgical cases) swung during the haemolytic crises to " 9." When the recovered patients left the hospital, they had W.C.R. " 6." We have proved that the ;sulphanilamide group alone has no effect on the W.C.R. We therefore think that it is the haemolytic effect of the malaria infection which causes the prolongation of the C.B. I should like to suggest that perhaps the number of the coagulation tubes, 8 or 9, or 10, or only 6 or 7, may be a quantitative indication of the degree of the haemolysis. If this holds good it may be a very helpful method in addition to, or instead of, reticulocyte counting (FAIRLEY) and especially in watching patients with threatened blackwater fever. No satisfactory explanation can as yet be offered as to why two patients with malaria had a C.B. of 4 o r 5. They had no other complications, which could have changed the C.B. Other investigators, and we, too, have observed that patients, suffering from typhoid, for instance, had a C.B. of 5. As soon as they got any complications (broncho-pneumonia, thrombophlebitis, otitis, cystitis), the W.C.R. changed and swung to the left,
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2 or 3, returning to its former level when the complication had passed away. As has been said, no such complications occurred in these two patients with malaria. We are commencing investigations on a larger scale and hope to discover the reasons for the exceptional results. One case is worth reporting in detail: The patient, S., with tertian malaria, presented a coagulation hand of 9. He received quinine-atebrin treatment and left the hospital after 8 days with no fever, no plasmodia, and in a satisfactory condition, After another 7 days he had to be re-admitted on account of high fever, headache, a sensation of burning in the eyes. A relapse was suspected but no plasmodia could be detected although the blood was thoroughly searched during 2 days. The coagulation band was 7 instead of 9 as it had previously been. The temperature chart and the positive Weil-Felix reaction after 10 days indicated that the patient had in the meantime contracted typhus of the mild murine type prevailing in this country. Thus the change in the W.C.R. had given a hint that the diagnosis should be revised. All these facts show that in a given case of high acute fever the W.C.R. has a certain diagnostic value, especially as the result is obtainable on the very first day of the fever. Influenza, tonsillitis, pneumonia would give always a marked shift to the left " and even typhoid (not easily identified in the first $ew days) would not show a shift to the right : typhoid mostly gives the figures " 5," maximum 6." Only infectious jaundice might come in for special consideration as it has a W.C. ÷ Reaction though probably for other reasons (liver damage). As far as I could find in the available literature, the W.C.R. has not been used in the field of tropical medicine. Theoretically, judging from what is known of the W.C.R. in other infectious diseases, one might expect in patients with schistosomiasis or kala-azar at the time of high fever a shift to the left." Only when liver-cirrhosis has definitely set in, a swing to the right should be obtained. But to examine the two mentioned, and other tropical diseases, by the Weltmann method may lead to another advantage. WELTMANN (1931) has pointed out the value of repeated W.C.R. in the course of a given disease in obtaining a prognostic view. Since the W.C.R. is uninfluenced by the height of fever, or by any accompanying anaemia, the W.C.R. may sometimes be more helpful in prognosis than the sedimentation time. (W~.LTMANN, LEVINSON,KLEEBERG). Taking into consideration the very simple technique, may I again be allowed to urge that this Weltmann Reaction be tried in the field of tropical medicine. "
"
"
SUMMARy.
1. The technically simple procedure of the " Weltmann Coagulation Reaction" (W.C.R.) was employed by us in twenty-five cases of malaria. 2. Nearly always in acute infections with high fever the Coagulation Band (C.B.) is shortened and the W.C.R. is shifted to t h e left. But although a
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malaria attack clinically produces all the features of an acute inflammatory process, the W.C.R. is shifted to the right (thirteen cases) or stays normal (ten cases). Very similar results were obtained by TSCHILOW (1931). 3. T h e W.C.R. is an entirely unspecific protein-globulin reaction; but considering all above-mentioned facts, it gives in tropical countries a certain hint in the diagnosis of acute fevers. 4. It is suggested that haemolysis may be responsible for the occurrence of the lengthened C.B. in malaria. 5. T h e Weltmann test is particularly valuable in all haemolytic processes. It might prove to be of special help in blackwater fever. 6. A repeated W.C.R. in the course of a disease can, like the sedimentation time, be of help in prognosis. Therefore interesting results might be obtained in other tropical diseases besides malaria. REFERENCES BINC, JENS. (1937)• Acta reed. scan., 91,336. BOYD, W. (1932). Textbook of Pathology. London : Henry Kimpton. B~m~ACHAaI, U . N . (1917): Indian med. Gaz., 52, 319. CHOaINE, V. (1938). Arch• Inst. Prophy. Phris, 10, 202. C~Ic, C. F. & FAUST,E.C. (1937). ClinicalParasitology. Philadelphia : Lea & Febiger. FAIPa~.Y, H . N . (1937)• Trans. R. Soc. trop. Med., 30, 9. (1938). Trop. Dis. Bull., 35, 265. GATfi ~ PAPACOSTAS. (1920). Compt. R. Soy. Biol., 83. K~cXWmK, R. A. & McFAaLANE,A.S. (1943). Ann. Rev. Bioch., 12, 93. ~EaG, J., EINHOm~, V. & UNNA, G. Clinical value of Weltmann reaction in internal diseases. In press. Koee, ISaA,~L& SOLOMON,H . C . (1943). Amer. ft. Med. Sci., 205, 90. KYLIN, E. (1938). Die Eiweisak6rper des Blutplasmas. In Blennhold-Kylin-Ruszniyak. LANDEIRO,F. (1935). Lisbon med., 12, 771. LEVINSON, S. A. & KLEIN, Z. I. (1938). Amer. Rev. Tuberc., 37, 200. • (1939). Ann. intern. Med., 12, 1948. - & McFArE, R• P. (1943). Clinical Laboratory Diagnosis. London : Henry Kimpton. MANSoN-BAx-m, P. (1940). Manson's Tropical Diseases. llth Ed. Baltimore: Wm. Wood & Co. NAPmR, L . E . (1927). Kala-azar. Oxford University Press• ORLINA, N . M . (1941). Trans. Kuibyshev Milit. med. Acad. Red Army, 5, 29. Abstract Trop. Dis. Bull., 39, 519. Ou, T. (1940). Taiwan Igakkai Zasshi, 39, 1125. Abstract Trop. Dis. Bull., 38, 507. RAY, C.B. (1921). Indian reed Gaz., 56, 9. • (1924). Ibid., 59, 387. RocEns, L. & M~GAW,J. W.D. (1942). Tropical Medicine. London : J. & A. Churchill. SIA, R. H• P. (1921). China reed. aT., 35, 397• • (1924). Ibid., 38, 35. SNAPPER, J. (1943). Medical Clinics on Bone Diseases. New York: Interscience Publishers. SCHWEXNBtmG,B. & EVANS,L . Z . (1941). ft. Lab. Clin. Med., 366. STRONG, R. P. (1942). Stitt's Diagnosis, Prevention and Treatment of Tropical Diseases. 6th Ed. London : H. K. Lewis.
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TIRUMURTI,T. S. 8: RADHAKRISHNARAO. (1936). Indian ft. reed. Res., 24; Abstract in Trop. Dis. Bull., 34, 152. TSCHILOW, K. (1931). Wien. Klin. Wschr., 37. WELTMANN, 0 . (1930). Med. Klinik, 26 (February), 240. • (1930). Wien. Klin. Wschr., 43 (October), 1301. WHITBY, L. E. H. 8: BRITTON, C. J . G . (1942). Disorders of the Blood. London : J. 8: A. Churchill. WICKRAMASURIYA, G. A . W . (1937). Malaria and Ankylostomiasis in the Pregnant Woman. Oxford University Press. WOLFF, E . K . (1939). Trans. R. Soc. trop. Med., 32, 707. YOUNG, C . W . (1923). China med. ft., 38, 797.