STUDIES UPON THE ETIOLOGY OF DENGUE FEVER
Authors: William H. Harris, Charles W. Duval
Journal: The Journal of Experimental Medicine (1924)

The dengue cases studied during this epidemic were, as a whole, typical examples of the disease. The onset was sudden, often of a violent character, ushered in with severe headache and backache, vague pains throughout the body, and fever ranging from 101-105 degrees F. On the 2nd or 3rd day a maculopapular eruption appeared, generally on the neck, chest, and arms, but sometimes more widely disseminated. In most instances the fever remained for 3 or 4 days, after which it dropped to normal to rise again in 24 to 48 hours. The secondary rise, while occasionally higher than the primary one, was as a rule of a milder character. A few cases occurred in which marked jaundice existed. As reported for previous epidemics, no fatalities were recorded and hence no human material for histological study was available. Those cases caught in the fastigium of the disease were selected when possible as a source of material. The leucocytic count in all of the observed human cases was below normal. The experiments herein reported upon the transmission of dengue fever to the guinea pig are based upon the use of material secured from sixteen typical human cases of the disease, and upon the inoculation of many animals. Of the 143 animals used for the initial transmission, 42, representing eleven human cases out of the sixteen studied, reacted in a characteristic manner. The reaction occasioned in these animals by the inoculations closely resembles the symptoms seen in human dengue, differing only in the absence of exanthem. The primary pyrexia following regularly after a definite incubation period of 2 to 5 days, the secondary rise in temperature after a 24 to 48 hour remission ("saddleback"curve), and the concomitant fall in the circulating leucocytes present a syndrome identical with that of the human disease. Dark-field and special tinctorial studies of the dengue material, both human and experimental, have failed to reveal any visible spirochetal microorganism. It seems unlikely that an organism of any proportion other than a minute body is the excitant of dengue fever. In the experimentally induced infection of the guinea pigs by the inoculation of dengue virus there occurs a rather constant and characteristic gross alteration of the lymphoid tissues, and of the spleen especially, which latter organ often attains a size three to four times that of the normal. Enlarged lymph glands in the peritoneal areas are also a fairly constant finding. The adrenal glands occasionally show marked enlargement. The histopathology consists of an endothelial proliferation occurring chiefly in connection with the Malpighian bodies of the spleen and the germinal centers of the lymph nodes. Experiments performed with a view of demonstrating the protection afforded the recovered guinea pig were somewhat confused by delayed fatalities or later intercurrent infections to which the dengue-inoculated animal seems highly susceptible. The constant and uniform results for all the positive cases indicate that the virus of dengue fever is not only transmissible to the guinea pig but is susceptible to propagation in this species through an undetermined number of successive generations. After certain of the virus strains had been propagated through four or more generations they were discontinued. Two strains, however, have been continued for 36 and 45 generations respectively. The equally successful results with Berkefeld filtered material and whole defibrinated blood indicate that the excitant of dengue fever belongs in the group of filterable viruses.