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BRITISH M{EDICAL' JOURNAL LONDON SATURDAY NOVEMBER 21 1942 THE TYPHUS GROUP OF FEVERS CLASSIFICATION, LABORATORY DIAGNOSIS, PROPHYLACTIC INOCULATION, AND SPECIFIC SERUM TREATMENT* BY A. FELIX, D.Sc. (From the Emergency Public Health Laboratory Service) The " typhus group of fevers," comprising a number of upon which immunity, and immunity reactions depend. The different varieties of the disease, is now firmly established. antigenic analysis of the various typhus rickettsiae has, how- Typhus researches during the past few years have revealed ever, not yet passed its infancy. The most widely studied the occurrence of typhus-like diseases in of of these organisms is R. prowazeki, the causal organism of many parts Old World and New World typhus of type X 19. It is known the world. Not a few endemic diseases of various tropical that R. prowazeki possesses a heat-labile and a heat-stable and subtropical countries, some of which had long been antigen (Castaneda and Zia, 1933), that the latter is common known under the label " unclassed fevers," have now been to R. prowazeki and Prot,eus OX 19 (Weil and Felix, 1921), recognized as members of the typhus fever group. This and that this 0 antigenic component is alkali-stable (Bruce recent development is mainly due to the application of White, 1933). The antigenic structure of the rickettsiae of serological and immunological methods to the study of the other varieties of typhus and their relationship to each these diseases. The so-called Weil-Felix reaction has pro- other have not been studied as yet, owing to the great diffi- vided in almost every instance the 'first evidence of the culty in obtaining pure suspensions of rickettsiae in sufficiently large quantities. This difficulty has been overcome only quite generic relationship of the unknown disease, to classical recently, thanks to the discovery of two methods of growing louse-borne typhus, and thus opened the way for the rickettsiae-namely, in the yolk sac of the developing chick experimental study which has led to the demonstration (Cox, 1938) and in the lungs of infected rats and mice' of the corresponding rickettsia. Some of the best-known (Castaneda, 1939). There is good reason for believing that instances of this sequence of events are: the endemic typhus as a result of these important advances the gaps in our of the United States of America (Maxcy and Havens, knowledge will be filled very soon. 1923); the tropical' typhus of the Federated Malay States So far the serology of the typhus group has been based (Fletcher and Lesslar, 1925); the " fievre exanthematiqiie' on the antigenic relationship between the rickettsiae of the of Marseilles, and " fibvre boutonneuse " of Tunis (Buirnet different varieties of the disease and 'corresponding serological and Olmer, 1927; Felix and Rhodes, 1931 ; Durand, 1932); varieties of Proteus X. This relationship is most strikingly demonstrated by the close correlation between cross-immunity Sao Paulo typhus (Piza et al., 1931 ; Monteiro, 1931; and agglutination reactions with the three types of Proteus Felix, 1933a); and the tick-bite fever of Sbuth Africa X (Pijper and Dau, 1930, 1931, 1932). TABLE I.-Provisional Classification of the Typhus Group of Fevers The terms " rickettsial infections " and " typhus group of . _ fevers" are not synonymous, the former being much wider Immuno ogica Type OX 19 Type OX K Type undetermined than the latter. If the rickettsial infectionsIthat occur in certain Subgroup3. TpOX1 domestic animals are excluded and only those that affect man Name ofdisease.. Classical epidemic Tsutsugamushi Spotted fever ofRocky are considered, there still remain some rickettsial diseases of typhus fever of Japan, Mountains Tabardillo (Mexi- FMo r m o sa, osfted U.S.A. man which, according to our present knowiedge, seem to be co) Dutch, East eastern U.S.A. unrelated to the typhus group of fevers. Arnong these diseases Brill's d is e a s e Indies SSio Paulo typhus may be mentioned the " Q " fever of Queensland (Derrick, (U.S.A.) Scrub typhus of Fi&vre boutonneuse 1937; Burnet and Freeman, 1937) and of certain parts of the Endemic typhus of Malay, Dutch (Mediterranean) U.S.A. and Aus- East Indies, F U.S.A. (Davis, Cox, Parker, and Deyer, 1938), and the " trench tralia, Greece, India, French tivre exanthema- fever" which became known in 1916 as a wartime infection Syria,Manchuria, Indo - China, tque of Marseifles Malay (shop ty- Australia Febbre errutiva (Italy) but has not again made its appearance in epidemic form, even phus), India, Bur- Tick-bite fever of during the present war. ma, Philippines, South. Africa Hawaii, Toulon Classification (fievre nautique), Epidemic and en- >etc. demic typhus of Megaw '(921, 1930) was the first to attempt to classify . South Africa the typhus'-&ec fevers as members of one group of diseases Tick-borne typhus of and suggest, a.subdivision according to the transmitting insect l_______________ India, Kenya,etc. vector. 'The suggestion was undoubtedly a step in the right Vector .. Lice and rat fleas Mites Ticks, lice, and rat direction, and so long as the group was composed of only fleas a few diseases the differentiation according to vector seemed Reservoir of virus Rats. Man Field mice and Rodents. Dogs. to -fit' the known facts. This, however, no longer holds good. rats ? Ticks. Man A satisfactory classification of the typhus group can be based Agglutination .. OX 19+++ OX 19 OX 19 + OX2 + OX2- OX2 + solely on the-ant4cnic type of the corresponding rickettsiae, OX K- OXK +++ OXK + * A report to the Medical Research Council. 4272 BRITISH 598 Nov. 21, 1942 THE TYPHUS GROUP OF FEVERS MEDICAL JOU RNAL strains, known as OX 19, OX 2, and OX K (Felix, 1933b). The rickettsiae (Cox, 1938; Castaneda, 1939) have not, for the conception of serological varieties of typhus, based on the time being at any rate, materially altered the position. work of Fletcher and Lesslar (1925) and formulated by Felix The published data on the agglutination of R. prowazeki and Rhodes (1931), led to the subdivision of the typhus group by the serum of typhus patients and convalescents present into three immunological subgroups. a rather confusing picture. Some workers have reported almost Table I shows that the suggested scheme (Felix, 1935) com- complete parallelism between agglutination of R. prowazeki prises at present only two well-defined main types-namely, and Proteus OX 19 (Weigl, 1930; Zinsser and Castaneda, types OX 19 and OX K' The third subgroup, provisionally 1932), whereas others obtained quite different results (Liu, Zia, designated "type undetermined," probably contains several and Wang, 1938; Hudson, 1940). Obviously the confusion different types. Further subdivision will be made possible is due to the fact that agglutination of rickettsiae can be by the use of pure cultures of the corresponding rickettsiae, adequately described only in terms of two separate reactions- which will disclose the interrelationships of both the heat- namely, those which occur between the heat-labile and the stable and the heat-labile rickettsial antigens. heat-stable antigens and their respective antibodies. According The most important of these diseases is the louse-borne to Castaneda and Zia (1933), living or formolized rickettsiae typhus of type OX 19, known as the classical epidemic typhus are not agglutinated by the OX 19 antibody, but become and caused by R. prowazeki. The subsequent sections of this agglutinable after heating at 750 C.; phenol seems to produce paper deal mainly with this variety of the disease, though a similar effect to heat. Differently prepared rickettsial suspen- some of the conclusions are applicable also to the other typhus- sions, such as have been employed by various workers, do not like fevers. A few remarks on nomenclature may not be out therefore indicate the same antigen-antibody reaction when of place here. In the past some confusion has arisen from tested against typhus sera that contain, or may contain, the two the tendency to use a number of different names to designate different antibodies. the same disease. In recent papers published in this country What has been said about agglutination of rickettsiae (Findlay, 1941a, 1941b) this tendency has reappeared, and the applies also to complement-fixation with these organisms louse-borne epidemic typhus has been given a new name- (Castaneda, 1936b; Mosing, 1938; Bengtson, 1941; Bengtson viz., "exanthematic" typhus. It cannot be said that there and Topping, 1941). Either of the two reactions may be used was need of a new name. The one chosen by Findlay certainly for the demonstration of the antibody corresponding to the does not offer any advantage over the generally' accepted heat-labile rickettsial antigen pro-vided that a technique is old names. There is nothing distinctive in the name devised by means of which the heat-stable 0 antigen is pre- " exanthematic" typhus, since all the varieties of typhus are cluded from taking part in the reaction and thus obscuring exanthematous diseases. Louse-borne typhus occurs as an the results. endemic disease in many parts of the world, but gives rise Although the technique of the customary test-tube agglutina- to widespread epidemics only under exceptional conditions, tion with Proteus OX 19 is very simple, still simpler procedures chiefly in the wake of war, famine, or other major disasters have been adopted by workers in the U.S.A. (Welch, 1937) that favour louse-infestation. The term "louse-borne typhus," and in Mexico (Castaneda et al., 1940) in the form of, slide used throughout this paper, applies to both the epidemic and agglutination tests, German workers even employ a slide the endemic form of the disease. test using dried drops of whole blood instead of the separated serum. Extensive surveys are being carried out by this method Laboratory Diagnosis in endemic areas in occupied Poland, with a view to detecting and cases The clinical diagnosis of typhus is not altogether easy, so missed ambulatory patients of so-called inapparent The infection.