the antigens of the typhoid bacillus

2
618 routine the disease is one that will flourish. Dr. JoHANNE CHRISTIANSEN in Denmark heads an article 1 " Rickets has disappeared ! " and proceeds to demolish the assertion. Prof. ROMINGER of Kiel speaks of an increase of rickets, and quotes authorities recording the percentage of rachitic infants as 37-46 in Westphalia, 55 in Dortmund, 40 in Vienna and Paris, and 50 (in the summer) or 75 (in the winter) in Basle. These figures indicate a very high incidence but it is unlikely that they represent a recent increase ; the prob- ability is that observation has become much more complete and critical. When one considers, how- ever, the completeness of our knowledge of how to prevent and cure this disease, the state of affairs described seems very deplorable. A new piece of heavy artillery has recently been introduced into the campaign. It seems first to have been used by HARNAPP,3 but has won greater fame under the command of BRAULKE 4 of Marburg, who gave it the name of Vitamin Stoss therapy. It consists in oral administration of vitamin D in one enormous dose of about 15 mg.-that is to say, 600,000 international units, an ordinary daily dose being 3000 LU. or less. Within a very few days healing can be detected in radiograms, and this proceeds to completion without further treat- ment. In 50 cases BRAULKE saw no ill effect, and his observation is confirmed by BISCHOFF 5 of Greifswald who has treated 10 children in the same way. The use of the Vitamin Stoss is par- ticularly recommended in cases of spasmophilia and tetany, in severe rickets with risk of fracture, and in rickets associated with infection, acute or chronic ; it has had signal success in children desperately ill with pneumonia or whooping-cough complicated by rickets. Wherever a rapid result is important Vitamin Stoss therapy is considered appropriate. The suggestion is also made that it might be employed to advantage in out-patient and welfare departments where the doctor cannot rely on the child’s parents or guardians to carry out regular treatment con- scientiously-an all too common state of affairs. Obviously the method is not one to apply lightly, but it is not unpromising, and should not be rejected out of hand. A resemblance is evident between Vitamin Sto8s therapy and the injection of large doses of vitamins A and D, as described by Dr. NoRMAN LEAK on p. 599 of our present issue. Dr. LEAK has used such injections in the acute states of a variety of diseases and is deeply impressed by their value, though the circumstances of general practice have necessarily prevented him from securing the scientific controls needed to carry full conviction. He attributes the favourable reactions he has observed chiefly to the vitamin A which pre- dominates in his preparation, but one is left wondering whether such large doses of vitamin D given at the same time might not be significant. 1 Christiansen, J., Ugeskr. Lœger, 1937, 99, 683 ; Lancet, Feb. 5th, 1938, p. 336. 2 Rominger, E., Med. Klin. 1938, 34, 1. 3 Harnapp, G. O., Klin. Wschr. 1936, 15, 1043 ; Mschr. Kinderheilk. 1936, 66, 318. 4 Braulke, H., Z. Kinderheilk. 1937, 59, 18. 5 Bischoff, H., Jb. Kinderheilk. 1937, 150, 2. THE ANTIGENS OF THE TYPHOID BACILLUS STUDIES that have been carried out during the past few years on various Gram-negative bacilli, and particularly on bacteria of the typhoid- paratyphoid and dysentery groups, mark an important advance in our knowledge of the chemical substances that determine the anti- genicity and toxicity of these bacterial species. The studies of AVERY and HEIDELBERGER, and of many subsequent workers, had already demon- strated that the antigenic specificity of the various types of pneumococci depended on the presence in the bacterial capsules of a series of chemically different polysaccharides, and it was known that specific polysaccharides could also be isolated from other capsulated or non-capsulated bacteria. These polysaccharides had, however, the properties of haptens, rather than of complete antigens. They gave specific precipitation in the test-tube, when mixed with the corresponding antisera produced by inoculating animals with the intact bacterial cells ; but they failed to induce antibody forma- tion themselves, when injected in the purified state. They were almost or entirely non-toxic. In 1933 BoiviN and MESROBEANU reported the isolation from Bact. typhi-murium, by extraction with trichloracetic acid, of a complex antigenic component consisting of a polysaccharide linked to a phosphatide or nucleotide ; and in 1934 RAlSTRiCK and TOPLEY independently reported the isolation from the same organism of a similar antigenic component by the tryptic digestion of acetone-extracted bacterial cells. In both cases the crude extracts were further purified by alcohol precipitation. The interest of these new substances lay in the fact that they not only reacted speci- fically in the test-tube, but induced active immunity when injected into mice, and stimulated the produc- tion of specific antibodies in vivo. They were also found to be highly toxic, and it was shown by DELAFIELD that they induced characteristic changes in the blood-sugar concentration when injected into rabbits. Further studies by these two groups of workers have shown that antigenic components of this kind can be isolated from a variety of Gram-negative bacilli, but not from Gram-positive organisms. It has become clear that they represent the 0 (somatic) antigens of the bacterial cells, and, at the same time, constitute the principle " endo- toxin." In the particular case of Bact. dysent. Shiga BomN and MESROBEANU have been able, by their technique, to differentiate the exotoxin produced by that organism from the somatic endotoxin. W. T. J. MORGAN has recently shown that this somatic antigen can be isolated from Bact. dysent. Shiga by a third method, extraction with diethylene- glycol ; and in a still more recent paper HENDERSON and MORGAN have applied the same technique to various strains of the typhoid bacillus. This organism is of particular interest because of the demonstration by FELIX and PITT of the Vi antigen and antibody, and their importance in active or passive immunisation. It has already been shown 1 Henderson, D. W., and Morgan, W. T. J., Brit. J. exp. Path. 1938, 19, 82.

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Page 1: THE ANTIGENS OF THE TYPHOID BACILLUS

618

routine the disease is one that will flourish. Dr.JoHANNE CHRISTIANSEN in Denmark heads an

article 1 " Rickets has disappeared ! " and proceedsto demolish the assertion. Prof. ROMINGER ofKiel speaks of an increase of rickets, and quotesauthorities recording the percentage of rachiticinfants as 37-46 in Westphalia, 55 in Dortmund,40 in Vienna and Paris, and 50 (in the summer)or 75 (in the winter) in Basle. These figuresindicate a very high incidence but it is unlikelythat they represent a recent increase ; the prob-ability is that observation has become much morecomplete and critical. When one considers, how-ever, the completeness of our knowledge of how toprevent and cure this disease, the state of affairsdescribed seems very deplorable.A new piece of heavy artillery has recently been

introduced into the campaign. It seems first tohave been used by HARNAPP,3 but has won greaterfame under the command of BRAULKE 4 of Marburg,who gave it the name of Vitamin Stoss therapy.It consists in oral administration of vitamin Din one enormous dose of about 15 mg.-that isto say, 600,000 international units, an ordinarydaily dose being 3000 LU. or less. Within a veryfew days healing can be detected in radiograms, andthis proceeds to completion without further treat-ment. In 50 cases BRAULKE saw no ill effect, andhis observation is confirmed by BISCHOFF 5 ofGreifswald who has treated 10 children in thesame way. The use of the Vitamin Stoss is par-ticularly recommended in cases of spasmophiliaand tetany, in severe rickets with risk of

fracture, and in rickets associated with infection,acute or chronic ; it has had signal success

in children desperately ill with pneumonia or

whooping-cough complicated by rickets. Wherevera rapid result is important Vitamin Stoss therapyis considered appropriate. The suggestion is alsomade that it might be employed to advantage inout-patient and welfare departments where thedoctor cannot rely on the child’s parents or

guardians to carry out regular treatment con-

scientiously-an all too common state of affairs.

Obviously the method is not one to apply lightly,but it is not unpromising, and should not be

rejected out of hand.A resemblance is evident between Vitamin Sto8s

therapy and the injection of large doses of vitaminsA and D, as described by Dr. NoRMAN LEAK onp. 599 of our present issue. Dr. LEAK has usedsuch injections in the acute states of a variety ofdiseases and is deeply impressed by their value,though the circumstances of general practice havenecessarily prevented him from securing thescientific controls needed to carry full conviction.He attributes the favourable reactions he hasobserved chiefly to the vitamin A which pre-dominates in his preparation, but one is left

wondering whether such large doses of vitamin Dgiven at the same time might not be significant.

1 Christiansen, J., Ugeskr. Lœger, 1937, 99, 683 ; Lancet,Feb. 5th, 1938, p. 336.

2 Rominger, E., Med. Klin. 1938, 34, 1.3 Harnapp, G. O., Klin. Wschr. 1936, 15, 1043 ; Mschr.

Kinderheilk. 1936, 66, 318.4 Braulke, H., Z. Kinderheilk. 1937, 59, 18.5 Bischoff, H., Jb. Kinderheilk. 1937, 150, 2.

THE ANTIGENS OF THE TYPHOID BACILLUS

STUDIES that have been carried out during thepast few years on various Gram-negative bacilli,and particularly on bacteria of the typhoid-paratyphoid and dysentery groups, mark an

important advance in our knowledge of thechemical substances that determine the anti-

genicity and toxicity of these bacterial species.The studies of AVERY and HEIDELBERGER, and ofmany subsequent workers, had already demon-strated that the antigenic specificity of the varioustypes of pneumococci depended on the presence inthe bacterial capsules of a series of chemicallydifferent polysaccharides, and it was known thatspecific polysaccharides could also be isolated fromother capsulated or non-capsulated bacteria. These

polysaccharides had, however, the properties of

haptens, rather than of complete antigens. Theygave specific precipitation in the test-tube, whenmixed with the corresponding antisera producedby inoculating animals with the intact bacterialcells ; but they failed to induce antibody forma-tion themselves, when injected in the purified state.They were almost or entirely non-toxic.

In 1933 BoiviN and MESROBEANU reported theisolation from Bact. typhi-murium, by extractionwith trichloracetic acid, of a complex antigeniccomponent consisting of a polysaccharide linkedto a phosphatide or nucleotide ; and in 1934RAlSTRiCK and TOPLEY independently reportedthe isolation from the same organism of a similarantigenic component by the tryptic digestion ofacetone-extracted bacterial cells. In both casesthe crude extracts were further purified by alcoholprecipitation. The interest of these new substances

lay in the fact that they not only reacted speci-fically in the test-tube, but induced active immunitywhen injected into mice, and stimulated the produc-tion of specific antibodies in vivo. They were alsofound to be highly toxic, and it was shown byDELAFIELD that they induced characteristic changesin the blood-sugar concentration when injectedinto rabbits. Further studies by these two groupsof workers have shown that antigenic componentsof this kind can be isolated from a variety of

Gram-negative bacilli, but not from Gram-positiveorganisms. It has become clear that they representthe 0 (somatic) antigens of the bacterial cells, and,at the same time, constitute the principle " endo-toxin." In the particular case of Bact. dysent. ShigaBomN and MESROBEANU have been able, by theirtechnique, to differentiate the exotoxin producedby that organism from the somatic endotoxin.W. T. J. MORGAN has recently shown that this

somatic antigen can be isolated from Bact. dysent.Shiga by a third method, extraction with diethylene-glycol ; and in a still more recent paper HENDERSONand MORGAN have applied the same technique tovarious strains of the typhoid bacillus. Thisorganism is of particular interest because of thedemonstration by FELIX and PITT of the Vi antigenand antibody, and their importance in active orpassive immunisation. It has already been shown

1 Henderson, D. W., and Morgan, W. T. J., Brit. J. exp.Path. 1938, 19, 82.

Page 2: THE ANTIGENS OF THE TYPHOID BACILLUS

619

by TOPLEY and RAISTRICK that the antigeniccomponents isolated by tryptic digestion fromVi (O+Vi) and non-Vi (0) strains of Bact.

typho8um show the same differences in immuno-logical behaviour as the corresponding bacterialcells ; so that it would appear that the Vi antigenbelongs to the same chemical category as the0 antigen, at least in regard to its resistance totryptic digestion and its behaviour to alcohol

precipitation, though the two antigens show minordifferences in their reaction to certain other

precipitants. HENDERSON and MORGAN haveobtained similar results with the componentsisolated by extraction with diethyleneglycol. Theywere, however, able to include in their studies tworough strains of Bact. typhosum, isolated by FELIXand his colleagues, which contained the Vi antigenbut were entirely, or almost entirely, free from the0 antigen. They conclude from their findings,and particularly from the results of cross-precipi-tation tests, that the Vi antigen is not a modified0 antigen, but a separate chemical entity. Their

paper includes a series of interesting observationson certain differences between the antisera pro-duced by immunisation with the isolated Vi antigen,or with the intact bacterial cells. Although bothreagents induce the formation of Vi agglutinins tohigh titre, the protective value of the antisera

produced by the partially purified antigen wasfound to be less, as judged by the minimal pro-tective dose, than that of antisera produced inresponse to the intact bacterial cells.

BRONCHIECTASIS AND PULMONARYCOLLAPSE

MOST of the speakers at a discussion reportedon another page seem to have found convincingclinical and bronchoscopic evidence that post-operative massive collapse of the lung is mostlydue to obstruction by a plug of tenacious secretion.Dr. MAXWELL pointed out justly that the chiefdanger of this condition rests in the liabilityof the patient to develop lung abscess or

bronchiectasis and that the speedy re-expansion of,the lobe affected should thus be the first aim intreatment. LEE LANDER and DAVIDSON have

recently approached the subject of pulmonarycollapse from the other side and believe itsassociation with early bronchiectasis to be muchmore significant than is generally recognised.The classical text-book description of bronchi-ectasis was based on autopsy findings afteryears of an increasingly foul infection had led topremature death. The introduction of lipiodolhas led to a recognition of a very different picturesince bronchial dilatation can be detected at astage when physical signs are absent and symptomsminimal. The old view of fibrotic contraction

following infection as the factor responsible forthe dilatation is no longer tenable, and the

pathology of bronchiectasis is being studiedafresh. The same observers have recently setforth their grounds for believing that pulmonarycollapse is the invariable antecedent of bronchi-ectasis, the atelectasis being due to the aspiration and

retention of viscid sputum.1 They maintain, more-over, that in the absence of infection bronchiectasisis reversible ; the bronchi are capable of resumingtheir original shape and size if the lung becomesreinflated, and when this occurs the disease is

regarded as benign. LEE LANDER and DAVIDSONbase their conclusions partly upon lipiodol investiga-tion of medical and surgical cases in which a massiveatelectasis has been diagnosed on clinical grounds,and partly on the experimental production ofbronchial obstruction in - cats, opaque oil beinginstilled into the trachea before and after theatelectasis is produced. Further evidence againstinfection as the cause of the dilatation is pro-vided by the examination of lobes removed forbronchiectasis at the Brompton Hospital. Theseshowed no adhesions between the affected lobe andthe chest wall or between two bronchiectaticlobes, and histologically many of the affectedbronchi were seen to have an intact epitheliallining.

Of particular interest is what LEE LANDER andDAVIDSON have styled the " black lobe." Thosewith experience in pneumothorax work are familiarwith the sudden change in appearance some-

times observed in the diseased upper lobe, whenit seems to diminish in volume and to assumea homogeneous density greater than that of the

surrounding lung. This phenomenon commonlymanifests itself after the apex of the lung has beencompletely freed by the division of adhesions andhas been hailed by the operator as a perfect result.The authors believe this " black lobe " to indicatemassive lobar atelectasis and with the aid of

lipiodol they have demonstrated bronchial dilata-tion within it. Their theory is attractive and seemsto fit the facts. The crux of the problem is themechanism whereby atelectasis, once it has

occurred, is compensated. The first effect of amassive collapse is an increase in the intrapleuralnegative pressure, which, if it becomes pronounced,leads to contraction of the spaces between the

ribs, a shift of the mediastinum, a rise of the

diaphragm, and compensatory emphysema of thelung. If the negative pressure is still not relievedthe bronchi dilate. A concrete example is furnishedby the catastrophe that sometimes follows anextensive apical thoracoplasty. After the operationcoughing is painful and the sputum collects andblocks the bronchus to the lower lobe, causing amassive collapse. Often compensation cannotbe achieved by the falling in of the thoracic wallbecause the mobility of the mediastinum and

diaphragm is limited by adhesions due to thedisease and the remainder of the lung has been putout of action by the surgeon. It is left, therefore,to the bronchi to relieve the excessive negativepressure ; this they do by dilating and, if thelower lobe is not reinflated and if infection occurs,the classical picture of foetid bronchiectasis soonbecomes established. The mechanics of the

development of the " black lobe " are different.Here the presence of a pneumothorax is a safe-

1 Lander, F. P. Lee, and Davidson, Maurice, Brit. J. Radiol.February, 1937, p. 65.