Grobbelaar, B.G.

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19 Oktober 1957 S.A. TYDSKRIF VIR GENEESKUNDE 1069that the joint space has become completely filled by compactbone. In mine there is no such band of compact bone,merely a discontinuous zone of fine-meshed cancellous bone.This might simply mean that the fusion is of longer standingin my specimen, but there is no way of proving this.Although there is no gross evidence of inflammatoryreaction in my specimen, I do not think that a pathologicalbackground can be excluded. Indeed a pathological de-struction of the joint and the adjacent growth cartilagesduring childhood, followed by bony repair, is in manyrespects the most intelligible explanation.From the foregoing it will be evident that no final answerto many of the questions raised by this study can as yet begiven. It is clearly necessary for cases showing either defec-tive sacral development or juvenile sacro-iliac arthritis tobe followed through life and if possible to autopsy. Thedifficulty is that in many cases the anomaly, if not discoveredaccidentally in the course of some other investigation, maybetray itself only as a well-establi hed deformity or maypas unrecognized throughout life.REFERE CESBaird, D. (1950): Combined Text-book of Obstetrics and Gynaeco-logy, 5th ed. Edinburgh: Livingstone.Brailsford, J. F. (1953): The Radiology ofBones and Joints, 5th ed.London: Churchill.Brooke, R. (1924): J. Anat., 58, 299.Greenhill, J. P. (1955): Obstetrics, 11th 00. Philadelphia: Saunders.Heyns, O. S. (1955): Modern Trends in Obstetrics and Gynae-cology (2nd Series), ed. Bowes, K. pp. 1-19. London: Butter-worth.Payton, C. G. (1935): J. Anat., 69, 326.Schunke, G. B. (1938): Anat. Rec., 72, 313.Shore, I. R. (1930): J. Anat., 64, 503.Todd, T. W. (1921): Amer. J. Phys. Anthrop., 4, I.Whillis, J. (1940): J. Anat., 74, 277.COLD HAEMAGGLUTINATION IN PRIMARY ATYPICAL PNEUMONIAB. G. GROBBELAAR, M.B., B.Of. (RAND)Blood-Group Research Laboratories, South African Institute for Medical Research, JohannesburgCold haemagglutination has been the subject of investigationby many workers, and has been shown to occur in healthyhuman beings as well as in many animals. It has also beendemonstrated in association with many diseases, usuallyto a much higher titre than in normal, healthy people.Li-Chen-Pien1 described it in a patient suffering from hyper-trophic cirrhosis of the liver. It has been found in associationwith leukaemia by Alexander and Thompson,2 Boxwell andBigger,3 and Manheims and Brunner. t Dameshek5 men-tioned its association with infectious mononucleosis, andStats and Wasserman8 and MuscheF described its occurrencein pregnancy. Increased titres of cold haemagglutinins,however, have been found consistently only in trypanoso-miasis (York8) and in primary atypical pneumonia.Qough and Richter,S in 1918, were the first to describea raised cold haemagglutinin titre, in association with acondition which would now be diagnosed as primary atypicalpneumonia. They did not associate this serological ab-normality with the respiratory condition, and thought itto be coincidental. Since 1943, however, numerous referenceshave been made in the literature to this association betweenraised cold-haemagglutinin titres and primary atypicalpneumonia. Turner et aUo investigated 83 cases of primaryatypical pneumonia. Of these, 44 (53 %) had titres of atleast 32, and 23 patients had titres of 128 or higher. In theircontrol series, consisting of 132 patients suffering fromvarious other diseases, in only 5 (3·7 %) did the titre exceed16. Horstrnann and Tatlockll investigated 43 cases andfound an incidence of 67·5 % of significantly raised cold-haemagglutinin titres. Peterson et al.l2 mention that thegreat majority of the patients with primary atypical pneu-monia which they had encountered showed cold haemag-glutinins in dilutions of serum ranging from 1/10 to 1/10,000.Young,13 in studying a large series of cases, reported anincidence of over 51 % in which the titre was 128 or higher,whilst his normal controls and other respiratory diseasesshowed an incidence of only O· 7 %. Finland and Barnesuinvestigated 676 patients suffering from a wide variety ofacute respiratory infections. They came to the followingconclusions: (1) The great majority of uncomplicated casesof primary atypical pneumonia develop significantly raisedcold-haemagglutinin titres; (2) the demonstration of high-titre cold haemagglutinins is almost always associated withprimary atypical pneumonia, although the finding of thisdisease was sometimes obscured by complicating conditions;(3) patients with acute respiratory infections other thanprimary atypical pneumonia fail to develop high-titre coldhaemagglutinins; (4) the demonstration of high-titre coldhaemagglutinins is of considerable value in the diagnosis ofprimary atypical pneumonia.The spate of articles describing the occurrence of high-titre cold haemagglutinins in primary atypical pneumoniaappearing in the medical press in 1943 and at sporadicintervals afterwards originated mainly from the USA. Invirtually every article the significant incidence of high-titre cold haemagglutination was stressed. It has, in fact,become customary for cold-agglutinin investigations to becarried out as an aid to diagnosis in cases of atypical re-spiratory infections.The demonstration of high-titre cold haemagglutinins inprimary atypical pneumonia, or any respiratory infection forthat matter, is a rare occurrence in the experience of ourlaboratories during the past 11 years, and it is probable thatphysicians in this country have been struck by the monoto-nous regularity with which such inve tigation have givennegative results. The investigations described in this paperwere carried out in order to confirm these findings.The differentiation between 'normal' cold haemagglutininpresent in many normal, healthy people, and 'abnormal' coldhaemagglutinins as ociated with disease, depends to a largeextent on the concentration in which the cold haemagglutininare present in the serum. The exact dividing line between1070 S.A. MEDICAL JOURNAL 19 October 1957'normal' and 'abnormal' cold haemagglutinins is debatable,although a titre of 16 is the most generally accepted upperlimit of the normal range. This figure is questionable; manyworkers consider the upper limit of normal to be 128, andtitres as high as 500 have been deseribed in apparently normal,healthy people (Kyuhei akadate15). The confusion isincreased by variations in technique. It is probable that beforedefinite pathological significance can be attached to coldhaemagglutinins the titre would have to be well in excess of16, but for purposes of this investigation the latter figure wasaccepted as the upper limit of the normal range.Cold-haemagglutinin technique:A clotted specimen of the patient's blood is incubated at37°C for 2 hours to allow elution of cold haemagglutinins totake place. The serum is separated immediately after thespecimen has been removed from the incubator. Twofoldserial dilutions of the serum in saline are prepared, and a dropof each dilution is added to each of two tubes. One drop ofa washed 2 %suspension of the patient's cells in isotonic salineis added to each tube in one row of serum dilutions, and onedrop of freshly prepared, washed 2 % suspension of groupo cells in isotonic saline is added to each tube in the otherrow. The cells and diluted serum are mixed, and then refri-gerated at 4°C for 12-18 hours. The results are read macro-scopically, and scored from + + + + (solid agglutinate) to+(visible granularity). The highest titre- at which visiblegranularity can be detected is taken as the end-point of thetitration.The investigation consisted of a 160 patients tested for coldhaemagglutinins (Table D. Of these patients 27 had beendiagnosed clinically as virus or primary atypical pneumonia,33 as pulmonary tuberculosis, 12 as some other pulmonaryinfection (lobar pneumonia or bronchopneumonia), and 88as suffering from various non-respiratory conditions. It isapparent from an analysis of these figures that the incidenceof high-titre cold haemagglutinins in primary atypicalpneumonia (7.6%) is insignificant when compared withfigures quoted by American authors, in which the incidenceranged from 51 % to 67.5 %. The incidence compares moreTABLE I. 160 PATIENTS TESTED FOR COLDHAEMAGGLUTININSVariousPrimary Pul- Other nOIl-atypical mOllary respira- respira-pneu- tubercu- tory torymonia losis con- dis-ditions easeso. of cases investigated 27 33 12 88o. in which cold haemag-glutinin titre exceeded 16 2 I 0 2Incidence 7'6% 3% 0% 2'3%favourably with that of their control series, consisting ofvarious respiratory infections other than primary atypicalpneumonia. The records of cold-haemagglutinin investiga-tions carried out at the Blood-Group Research Laboratoriesfrom 1951 to 1954 were also analysed (Table m. These resultsare in close agreement with those of Table I. The finalanalysis is therefore based on 590 investigations comprising 79cases of primary atypical pneumonia, 33 cases of pulmonarytuberculosis, 33 cases of other types of respiratory infections,and 445 patients suffering from various non-respiratorydiseases (Table Im. The most important point which emergesfrom an analysis of these findings is that the incidence ofTABLE n. ROUTINE INVESTIGATIONS CARRIED OUT AT THEBLOOD-GROUP RESEARCH LABORATORIES 1951-54VariousPrimary Pul- Other non-atypical monary respira- respira-pneu- tubercu- tory torymonia losis con- dis-ditions easesNo. of cases investigated 52 0 21 357No. in which cold haemag-glutinin titre exceeded 16 0 2 IIncidence 0% 8% 0·28%high-titre cold haemagglutinins in primary atypical pneu-monia (2.6%) is low, being similar to the incidence in othertypes of respiratory infections (4.5 %), in contrast to the highlysignificant incidence described by American workers. Itwould appear therefore, that the presence or absence of high-TABLE ill. FINAL ANALYSIS-588 INVESTIGATIONSVariousPrimary Pul- Other non-atypical monary respira- respira-pneu- tubercu- tory torymonia losis con- dis-ditions easesNo. of cases investigated 79 33 33 445No. in which cold haemag-glutinin titre exceeded 16 2 I 2 . 3Incidence 2'6% 3% 6% 0'67%titre cold haemagglutinins is of no value in diagnosing thenature of a respiratory infection. These remarks are certainlyapplicable to the Witwatersrand area, from which most of thespecimens used in the investigation originated, and presum-ably also to the rest of Southern Africa.- It should be pointed out that the specimens used in thisinvestigation were submitted to our laboratory for routineinvestigation, and originated from many different sources.It is certain that the diagnostic criteria used in the diagnosisof primary atypical pneumonia, being the enigma that it is,were not uniform, and that in some instances the conditiondid not conform to the clinical entity described by Americanworkers. Some of the patients probably suffered from Q feveror one of the lesser known diseases which may simulate viruspneumonia. As the analysis, however, included all specimensinvestigated by our laboratory since 1949, one cannot butcome to the conclusion that either the incidence of viruspneumonia is not significant in this country or, if it is, thenthe disease process must in some way differ from that occurr-ing in the United States.Macaulay16 considers cold haemagglutination to be a non-specific response to lung-tissue destruction, occurring in alltypes of lung disease, although most commonly in primaryatypical pneumonia. In the light of the above findings itseems much more likely that the development of high-titrecold haemagglutinins can be correlated with the aetiologicalagent, presumably a virus17 different strains of which would19 Oktober 1957 S.A. TYDSKRIF VIR GE EE KU DE 1071SOME PROBLEMS OF THE EXTRACORPOREAL CIRCULATIO *be found in various geographical regions, and only ome ofwhich are capable of stimulating the formation of coldhaemagglutinins.SUMMARYAn analy is of cold-haemagglutinin investigation carried outin 79 patients suffering from primary atypical pneumonia,66 patients suffering from other respiratory conditions, and445 patients suffering from various non-respiratory diseases,show that there is no significant difference in the incidenceof high-titre cold-haemagglutinins in primary atypical pneu-monia and other respiratory infections and that, in SouthAfrica, the demonstration of the presence or absence ofhigh-titre cold haemagglutination is of no value in diag-no ing the nature of a respiratory infection.The mechanism of cold haemagglutinin formation is brieflydiscussed.This investigation was made possible by the kind permissionof the Director of the South African Institute for Medical Re-search. 1 am also grateful to Dr. A. Zoutendyk for his helpfulcriticism, and for allowing me access to the records of his depart-ment.REFERE CES1. Li-Chen-Pien (1926): J. Immuno1., 11, 297.2. Alexander, H. L. and ThompsoD, L. D. (1925): J. Amer.Med. As oc., 85, 1707.3. Boxwell, W. and Bigger, J. W. (1931): J. Path. Bact., 34, 407.4. Manheirns, P. J. and Brunner, B. K. (1933): J. Amer. Med.A oc. 101, 207.5. Dam hek, W. (1943): Ibid., U3, 77.6. Stats, D. and Wasserman, L. R. (1943): Medicine, 22, 363.7. Muschel, L. H., oIte, L. B. and Keiderling, L. J. (1957):Amer. J. Clin. Path., 27, 42.8. York, ~ . (1910): Ann. Trop. Med. Parasit., 4, 529.9. Clough, . C. and Richter, I. . (1918): Johns Hopk. Hosp.Bull., 29, 86.10. Turner, J. C., Jackson, E. B., isnewitz, S. and Bemey, R.(1943): Lancet, 1, .765.11. Horstmann, D. M. and Tatlock, H. (1943): J. Amer. Med.Assoc., 122, 369.12. Peterson, O. L., Ham, T. H. and Finland, M. (1943): Science,97, 167.13. Young, L. E. (1946): Amer. J. Med. Scl., 211, 23.14. Finland, M. and Bames, M. W. (1951): Ibid., 221, 152.15. Kyuhei akadate (1956): Keio J. Med., 5, 51.16. Macaulay, D. (1951): Arch. Dis. Childh., 26,601.17. Editorial (1956): Lancet, 2, 180.H. C. CHuRCHILL-DAVIDSON, M.D., D.A.Department 0/ Anaesthesia, St. Thomas's Hospital, London.The problem of the 'dry heart' has been with us for manyyears and any progress in this subject is bound to bring withit an increase in our knowledge of the circulation. At ·St.Thomas's Hospital in London for the past 5 years mycolleagues Drs. Kent Harrison and MacMillan and I havehad a modest research programme devoted to learning some-thing of the difficulties imposed by the interruption of thecirculation.Up to 2 years ago our energy was devoted to developingand learning something of the limitations of the techniqueof surface cooling in hypothermia. The reduction in cellularmetabolism appeared to be an ideal method of achievinga temporary interruption of the circulation. It is true tosay that hypothermia has not lived up to our originalexpectations. The main problem is to explain the reasonfor the increased irritability of the myocardium as thetemperature falls. There are 4 favourite theories concerningfactors which may account for this, but in none is the evidenceconclusive.1. Anoxia-low oxygenation of the coronary blood.2. Electrolyte Changes, particularly rise in ionized calcium·3. Alterations in the pH of the Blood.4. Excess of Catechol Amines i.e. adrenaline or nor-adrenaline.Today, hypothermia is used clinically down to 30°C(normal, 37°C) and this allows the surgeon approximately10 minutes in which to carry out some intracardiac pro-cedure. Meanwhile our attention has been turned to the• A paper presented at the South African Medical Congress,Durban, September 1957.other possible line of approach to this problem, namelythe extracorporeal circulation.I feel it would be very wrong to create the impression thatwe have been or are contributing anything original in thisfield. Our aim has to be to learn the difficulties involved.and as there are so many little problems it seems clear thatprogress will be made only if each group of workers fullydiscusses its failures.There are two big subdivisions in the type of mechanicalpump that can be used. In the first, the principal aim is tosupply only a limited quantity of oxygenated blood to thebrain and vital organs, and no attempt is made to ensure anadequate flow. These machines are called 'low-flow oxy-genators' and the Lillehei machine is the best example. Theprinciple is based on the finding of Andreasen and Watson(1953) that at normal body temperature the dog requiresonly the very low flow of about 50-60 ml. per minute tomaintain life during a period of occlusion of the heart fromthe circulation. Dr. Lillehei with his bubble oxygenator hasapplied these findings to man and has now performed manysuccessful operations with this technique. Our experiencewith this type of oxygenator was very satisfactory but itwas difficult to obtain more than 200-400 ml. of oxygenatedblood per minute. Physiologically it would not seem correctto supply a very reduced flow of blood to the vital organs,but rather to try to perfuse all the body with the same flowrates as it would normally receive. Here the problem imme-diately grow, and machines of the 'high-flow' type are morecomplex.I have had the honour of working in Dr. John Gibbon'slaboratory in Philadelphia, USA. For nearly 15 years nowhe has pioneered the development of a machine capable

Cold Haemagglutination in primary atypical pneumonia

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Cold Haemagglutination in primary atypical pneumonia

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