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THE DIAGNOSTICS
AND
TREATMENT OF TROPICAL DISEASES
BY
E. R. STITT, A. B., PH. G., M. D., SC. D., LL. D.
REAR ADMIRAL, MEDICAL CORPS, AND SURGEON GENERAL, U. S. NAVY, GRADUATE, LONDON SCHOOL OF TROPICAL MEDICINE; MEMBER NATIONAL BOARD OF MEDICAL EXAMINERS; MEMBER ADVISORY BOARD, HYGIENIC LABORATORY. FORMERLY: COMMANDING OFFICER AND HEAD OF DEPARTMENT OF TROPICAL MEDICINE, U. S. NAVAL MEDICAL SCHOOL; PROFESSOR OF TROPICAL MEDICINE, GEORGETOWN UNIVERSITY, PROFESSOR OF TROPICAL MEDICINE, GEORGE WASHINGTON UNIVERSITY; LECTURER IN TROPICAL MEDICINE, JEFFERSON MEDICAL COLLEGE; ASSOCIATE PROFESSOR OF MEDICAL ZOOLOGY, UNIVERSITY OF THE PHILIPPINES
FOURTH EDITION—REVISED WITH 159 ILLUSTRATIONS
LONDON H. K. LEWIS AND CO., LTD. 1922
COPYRIGHT, 1922, BY P. BLAKISTON’S SON & CO
PRINTED IN U. S. A. BY THE MAPLE PRESS YORK PA
PREFACE TO FOURTH EDITION
In this revision it has seemed desirable to adhere to the original plan of the manual as such an arrangement of the contents gives to the student or tropical practitioner a concise and readily accessible presentation of the subject.
Accepting the spirochaetal etiology of yellow fever, as worked out by Noguchi, I have transferred the chapter on this disease to the section dealing with protozoal diseases and have endeavored to present the more important features of the recent extensive additions to our knowledge concerning this scourge of the tropics.
There is not a chapter in the book that has not been carefully revised and brought up to date. Of the revisions made, the most important deal with advances in the study of food deficiency diseases, as will be noted under beriberi and pellagra.
I have enlarged various paragraphs on treatment, the additions including descriptions of the treatment of hookworm disease by carbon tetrachloride and of the methods of administering arsphenamine and antimony.
Six new chapters have been added to the book, viz. Epidemic jaundice, rat bite fever, tularaemia, tables of helminthic and arthropodan diseases, trench fever, in Part I, and, in Part II, a chapter on the diagnostics of tropical joint, muscle and bone lesions.
Extensive additions have been made to Chapter XLIII, “Diagnostic problems and procedures, together with cosmopolitan diseases in the tropics”; and in the chapter on blood examinations will be found a presentation of our latest views as to acidosis as well as a table giving the significance of the findings in blood chemistry.
Many new illustrations have been added and some of the older ones replaced by others of greater teaching value.
Every effort has been made to retain the feature of a pocket manual but it has been necessary to increase the number of pages from 524 to 610. The illustrations in the third edition numbered 119; in this edition, 159.
In particular I have to express my indebtedness to Commanders C. S. Butler and H. W. Smith of the Naval Medical Corps for advice and assistance in the preparation of this edition. Dr. G. W. McCoy, Director of the Hygienic Laboratory, has given me valued suggestions as to changes in some of the old chapters and in the preparation of the new chapter on Tularaemia.
Lieutenant Commander Bunker, the head of the Chemical Laboratory of the Naval Medical School, has made the revisions of the subjects dealing with physiological chemistry. Others, who have given me advice and suggestions, have been Lieutenant Commander Reed and Lieutenants Harper and Chambers of the Naval Medical School.
To Lieutenant Peterson I am indebted for assistance in the proofreading and preparation of the index as well as in going over the recent literature of tropical diseases.
PREFACE TO FIRST EDITION
There is no more striking evidence of advance in general medicine than the present attitude of the physician or rather internist in the diagnosis of the cases met with in a modern hospital ward. Instead of first considering the evidence obtainable at the bedside and then noting the laboratory findings as something apart and entirely subordinate, we now find the two aids to diagnosis so correlated that it is as difficult to note one kind of information as bedside and other as laboratory as it formerly was to separate signs from symptoms in the study of a case.
In tropical medicine, however, we have for many years made our diagnosis in the laboratory, the bedside playing a subsidiary part—the laboratory diagnosis is controlled by the bedside findings.
It was originally my idea to prepare a book which would enable students to have presented to them in intimate relation the laboratory and clinical aids to the diagnosis of tropical diseases. I was forced to abandon this plan as it did not seem possible to take up clinical diagnosis prior to the obtaining by the student of a comprehensive knowledge of the facts in connection with each separate tropical disease. There was not the same difficulty attaching to a book exclusively devoted to the diagnostic methods of the laboratory so that in 1908 a laboratory manual was published. More recently it has occurred to me that my methods in teaching tropical medicine from the clinical rather than the laboratory standpoint might be of assistance to those who are interested in this very important branch of medicine.
When we consider that a knowledge of malaria, blackwater fever, amoebic dysentery, bacillary dysentery, liver abscess, pellagra and hookworm disease is just as important for the medical man in the Southern States of the United States as for the physician in tropical colonial possessions, it will be realized that there is more of a practical side to tropical medicine than is usually admitted.
Although this is intended as a companion volume to the one on laboratory methods yet, in order to make it complete in itself, there has been prepared under each disease a paragraph dealing with the laboratory diagnosis of the disease under consideration.
Furthermore, under the sections on the blood, faeces and urine in the diagnosis of tropical diseases, the laboratory methods which are of practical application have been given.
The chief feature of the book is in presenting in Part II the clinical side of tropical diseases from a standpoint of the signs and symptoms of these diseases which are connected with anatomical or clinical groupings rather than from the side of the individual disease. Thus in Chapter XLIV the diagnostic points which may be obtained from a study of the temperature chart are given while in Chapter LII the neurological manifestations, which may be noted in various tropical diseases, are presented.
In Part I each individual tropical disease is treated as taken up in any of the well-known books on tropical medicine. It has seemed to me, however, that the paragraphs on epidemiology and prophylaxis should receive especial attention. Again, in order to bring out more strongly the symptomatology of each disease, I have followed the paragraph on symptomatology in general with a section dealing with the symptoms in detail, as shown in a consideration of the circulatory, respiratory, digestive, nervous and other systems.
The paragraph devoted to the definition of each important disease has been prepared with a view to giving the reader a brief description of the disease in its clinical and etiological aspects.
Small type has been used rather to supply headings than for the purpose of indicating less important matter because in a book so condensed it has not seemed advisable to present any subject not of practical value.
This book is written from the standpoint of the teacher who aims not only to give the essential points but to present them in a manner so cross-referenced that the student has the subject presented to him from every angle.
It has been my custom in preparing my lectures to abstract the various works on tropical medicine in order that special points in one book, not noted in the others, would stand out prominently. In this connection I am deeply indebted to the manuals of Manson, Scheube, Castellani and Chalmers, LeDantec, Jeanselme and Rist as well as to the monographs in Maladies Exotiques, Albutt’s System of Medicine, Osler’s System of Medicine, Mense’s Tropenkrankheiten and Traite Pratique de Pathologie Exotique.
In particular I am indebted to Ruge and zurVerth’s Tropenkrankheiten, to Brumpt’s Precis de Parasitologie and to the only work in the diagnosis of tropical diseases I have been able to obtain, that of Wurtz and Thiroux, entitled Maladies Tropicales.
In the section on blood examination I have advocated the adoption of the scheme of differential counting brought out in Schilling-Torgau’s work on the blood in tropical diseases.
I have freely consulted the various journals dealing with the subject of tropical medicine as to recent advances in this branch of medicine and I would particularly express my indebtedness to the Tropical Diseases Bulletin which should be in the hands of every student of tropical medicine, not only as an index to original papers but as a guide as to the advisability of consulting such papers. These abstracts are prepared by authorities in the different tropical diseases and many of the abstracts indicate the value or lack of value of the paper abstracted.
The tropical diseases are classified under those due to protozoa, those due to bacteria, those due to filterable viruses, infectious granulomata and tropical skin diseases. Sprue is classified as a food deficiency disease for the reason that the cure seems to rest solely in dietary treatment. Certain diseases which did not definitely belong to any of the above-named sections were taken up under diseases of disputed nature or minor importance. The second part of the book deals with the clinical diagnosis of tropical diseases.
I. TROPICAL DISEASES AND THEIR TREATMENT
DISEASES DUE TO PROTOZOA
II. Blackwater fever, 55
CHAPTER III.—The trypanosomiases, 66; African trypanosomiasis, 66; Brazilian trypanosomiasis, 80; Animal trypanosomiases, 84.
XI. Liver abscess, 164
DISEASES DUE TO BACTERIA
XVII. Leprosy, 246
FOOD DEFICIENCY DISEASES
CHAPTER XVIII.—Beriberi, 268; Rice and beriberi, 272; Ship beriberi, 285; Scurvy, 286; War oedema, 287.
XX. Sprue, 313; Hill diarrhoea, 316
HELMINTHIC INFECTIONS
XXI. Ancylostomiasis, 319
CHAPTER XXII.—Filarial infections, 336; Filaria bancrofti, 341; Loa loa, 352; Onchocerca volvulus, 354; Dracunculus medinensis, 355.
XXIII. The schistosomiases, 357; Japanese schistosomiasis, 364
CHAPTER XXIV.—Minor helminthic infections, 368; Paragonimiasis, 368; Clonorchiosis, 371; Intestinal distomiasis, 373; Strongyloides stercoralis, 374.
CHAPTER XXV.—Table of important animal parasite diseases, 377; Protozoal diseases, 377; Trematodes, 379; Nematodes, 380; Cestodes, 381; Arthropodan diseases, 382.
INFECTIOUS GRANULOMATA OF THE TROPICS
XXIX. Granuloma venereum, 404
TROPICAL SKIN DISEASES
XXXIII. Pinta, 416
CHAPTER XXXIV.—Minor tropical affections of the skin, 418; Dermatophiliasis, 418; Tropical impetigo, 419; Piedra, 420; Cutaneous myiasis, 421; Creeping eruption, 422; Craw-craw, 424.
TROPICAL DISEASES OF DISPUTED NATURE OR MINOR IMPORTANCE
XXXV. Verruga peruviana and Oroya fever, 425; Oroya fever, 425; Verruga peruviana, 428
CHAPTER XXXVI.—Dengue, 431; Dengue-like fevers, 438; Phlebotomus or Pappataci fever, 438; Seven-day fever, 440; Sand-fly and three-day fever, 441; Six-day fever, 441.
XLI. Heat stroke and heat prostration, 464
CHAPTER XLII.—Climatic bubo, ainhum, goundou, juxta-articular nodules and visceral mycoses, 469; Climatic bubo, 469; Ainhum, 471; Goundou, 472; Juxta-articular nodules, 472; Visceral mycoses, 474.
II. DIAGNOSTICS OF TROPICAL DISEASES
CHAPTER XLIII.—Diagnostic problems and procedures, together with cosmopolitan diseases in the tropics, 477.
XLV. Blood examinations in the diagnosis of tropical diseases, 504
CHAPTER XLVI.—The circulatory, respiratory and lymphatic systems together with anaemia, haemorrhages and oedema in tropical diseases, 547.
I. TROPICAL DISEASES AND THEIR TREATMENT
DESCRIPTION OF PLATE OF MALARIAL PARASITES
Benign Tertian Parasites
A1. Schizonts. 1. Normal red cell. 2. Young ring form. 3. Amoeboid or figure-of-eight form showing Schüffner’s dots. 4. Amoeboid form showing increased chromatin (twenty-four to thirty hours). 5. Segmentation of nucleus. 6. Nuclear halves further apart, red cells enlarged and pale. 7. Further division of nucleus. 8. Unusual division form. 9. Typical merocyte. 10. Rupture of merocyte liberating merozoites.
A2. Female gametes. 1. Young form showing solid instead of ring-form staining. 2. Half grown form. 3. Rapidly growing form with compact nucleus and clear vacuolated zone. 4. Full grown macrogamete showing eccentrically placed chromatin and much pigment in deep blue stained protoplasm. Male gametes. 1. Young form similar to female one. 2. Half grown form showing central chromatin. 3. Full grown microgametocyte showing large amount of centrally placed chromatin with light blue protoplasm surrounding. 4. Division of chromatin occurring in microgametocyte and developing in wet preparation. NOTE.—Chromatin division in gametes does not take place until blood is withdrawn. 5. Spermatozoon like microgametes developing from the microgametocyte. This only occurs in wet preparations or in the stomach of the mosquito.
Quartan Parasites
B1. Schizonts. 1. Normal red cell. 2. Young ring form. 3. Older ring form. 4. Narrow equatorial band. 5. Typical band-form. 6. Oval form showing division of chromatin. 7. Early stage merocyte. 8. Daisy form merocyte.
B2. Male gametes. 1. Young solid form. 2, 3, 4. Developmental stages microgametocytes. 5. Flagellated body in wet preparation showing microgametes developing from microgametocyte. Female gametes. 1. Young oval form. 2. Somewhat older stage. 3 and 4. Mature macrogametocytes (same as benign tertian).
Malignant Tertian Parasites
C1. Schizonts. 1. Normal red cell. 2, 3, 4, 5, 6. Young ring forms. These are hair-like rings and are the only forms besides crescents to be found in the peripheral blood. In very heavy infections or in smears from spleen the following forms are found. 7. Beginning division of chromatin. 8 and 9. Further division. 10. Merocyte.
C2. Female gametes. 1 and 2. Young macrogametes. 3. Older stage. 4. Development in red cell. 5 and 6. Fully developed female crescents showing clumping of pigment and rich blue colour. Male gametes. 1 and 2. Developing forms. 3 and 4. Fully developed microgametocytes. 5. Flagellated body developed in wet preparation.
SECTION I
DISEASES DUE TO PROTOZOA
I. MALARIA
DEFINITION AND SYNONYMS
=Definition.=—Malaria is a protozoal disease caused by three species of Plasmodium. In the clinically benign types of malaria we have that of benign tertian, due to P. vivax, with a tertian periodicity and that of quartan, due to P. malariae and showing a quartan or seventy-two hour periodicity. The clinically malignant type of malaria is due to P. falciparum, the parasite of malignant tertian or aestivo-autumnal malaria.
The benign malarial fevers are characterized by a frank chill and well marked distinctions of cold, hot and sweating stages. In malignant tertian there is an indefinite or dumb chill with prolonged hot stage. Diagnostic of malaria are periodicity, parasites and splenic enlargement. The malignant tertian parasite is the one responsible for the so-called cerebral and algid manifestations of perniciousness. Man is the intermediate host of the parasite while the sexual cycle or sporogony goes on in some species of mosquito of the anopheline subfamily, the definitive host.
=Synonyms.=—Remittent Fever, Intermittent Fever, Ague, Marsh Fever, Paludism, Jungle Fever.
French: Paludisme. German: Wechselfieber.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—Hippocrates, who considered malaria as intimately connected with bile, divided the disease into quotidian, tertian and quartan, differentiating such types of fever from continuous fevers. It is interesting to note that Celsus recognized two types of tertian fever, the one benign and similar to quartan fever, the other far more dangerous, with a fever occupying thirty-six of the forty-eight hours, not entirely subsiding in the remission, but being only mitigated.
In the time of Caesar views were expressed by Varro that swamp air might be the cause of malaria and furthermore that animals, so small that the eye could not follow them, might transmit diseases by way of the mouth or nose.
In the view of our present knowledge it is remarkable that Lancisi, in 1718, should have associated marshes with the development of gnats, which insects he thought could not only introduce with their proboscides the putrefying organic matter of such swamps but animalcules as well.
In 1638 Countess del Chinchon, the wife of the Viceroy of Peru, was cured of an intermittent fever by the employment of the bark of certain trees which bark was introduced into Europe in 1640. The origin of the name cinchona is thus explained.
While Morton and Sydenham in 1666 noted the specific action of cinchona in certain fevers it remained for Torti, in 1753, by the use of cinchona, clinically to differentiate those fevers which were cured by cinchona from those which failed to yield to this specific. Quinine was not introduced until after 1820. Audouard, in 1803, was the first to draw attention to the splenic enlargement of malaria.
The views of Nott and Beauperthuis as to transmission of malaria and yellow fever by insects are considered under the latter disease.
In 1847 Meckel announced that the dark color of malarial organs was due to a pigment and in 1848 Virchow noted that this pigment was contained in cells. In 1875, Kelsch observed pigmented bodies in malarial blood and in 1880 came to the conclusion that these pigmented cells were diagnostic of malaria.
The year 1880 is the most important one in the history of malaria for on November 6, 1880, Laveran, at Constantine, first saw the parasites of malaria while carrying on investigations as to the origin of the pigmented bodies and melaniferous leucocytes. He not only noted the findings of spherical pigmented bodies but also of crescents and in particular the flagellation of the male gamete which demonstrated to him that these were living bodies.
The name Oscillaria malariae was proposed on account of the movements of the flagellate body, but had to be dropped as not valid, the generic name Oscillaria having been previously applied.
When these bodies were demonstrated to various Italian authorities, in 1882, they were thought by them to be degenerated red cells.
It may be stated that at this time the Italians, influenced by the work of Pasteur, were convinced that an organism, Bacillus malariae, reported by Klebs and Crudeli (1879) to have been isolated from water and soil of malarious districts, was the cause of malaria. This bacillus was said to be cultivable on ordinary media and to be capable, when injected into man, of producing malaria.
By 1885 the Italians were convinced that the bodies discovered by Laveran were the cause of malaria and Marchiafava, by staining with methylene blue, noted the ring forms and the increase in size up to that of the sporulating parasites. To Golgi we not only owe the discovery that the malarial paroxysm coincides with the period when the sporulating forms (merocytes) simultaneously reach maturity but also the exact working out of the cycle of quartan malaria. He even showed three stages of development of the parasites in a triple quartan. It may be stated that Golgi, Marchiafava and Celli are the ones to whom we owe our first knowledge of the existence of different species of parasites for different kinds of malaria. In these investigations they showed that as a rule they could reproduce a certain type of malaria by injecting the blood of such a case of malaria into a well man. Gerhardt, in 1884, was the first to produce malaria by the injection of malarial blood. Laveran insisted all this time that there was but a single species of malaria. About this period a great deal of research was carried on as to the origin of malarial parasites and it was found that many animals harbored parasites similar to the malarial parasites of man. In 1891 the chromatin staining method of Romanowsky was introduced which by bringing out the variations in chromatin distribution led to more accurate study of species and cycles.
Our present exact knowledge as to the existence of 3 species of malaria is largely due to the careful examinations made by Koch of fresh and stained malarial blood preparations.
In 1894 Manson formulated the hypothesis of the mosquito transmission of malaria. He based this upon the fact that the flagellation of the male gamete does not take place for several minutes after the removal of the blood from the peripheral circulation. He also suggested that larvae might feed upon infected mosquitoes dying upon the water and thus acquire the disease.
Ross for two years had mosquitoes feed upon the blood of malarial patients which contained crescents but as he used insects of the genera Culex and Stegomyia he failed to observe development in the tissues of the mosquitoes. In 1897 he used 8 dappled-wing mosquitoes (Anopheline) and in two of these, upon dissection, he noted pigmentary bodies different from anything he had observed in hundreds of dissections of other mosquitoes. At this time he was forced to discontinue this work for about six months.
In 1886 Metschnikoff from observation of sporulating parasites in the brain capillaries at the autopsy of a malarial case considered them to be coccidial in nature. In 1892 Pfeiffer, studying the Coccidia showed that there was an endogenous cycle going on in the epithelial cells as well as the long known exogenous cycle connected with the ingestion of oocysts passing out in the feces of an animal infected with coccidiosis. He suggested that malaria might similarly have an exogenous cycle as well as the well-known endogenous one. Opie noted hyaline and granular forms of parasites in the blood of crows and MacCallum, working with this malaria-like disease of birds (Halteridium), observed the fecundation of a granular female parasite by the flagellum-like process of the hyaline male cell.
In 1898, in India, working with a malarial disease of sparrows (Proteosoma), Ross infected 22 out of 28 healthy sparrows by mosquitoes which had previously fed on sick sparrows. He noted in the culicine mosquito employed for transmission the same cycle of development as that subsequently worked out for human malaria, in anopheline mosquitoes, by Grassi and Bignami, in Italy.
Koch’s great work in connection with malaria was to demonstrate that the malaria-like infections of other animals had no part in the causation of human malaria and that the malarial parasite could only circulate between man and certain mosquitoes.
In order to demonstrate conclusively the connection between infected mosquitoes and malaria Sambon and Low lived for three of the most malarious months of 1900, in one of the most malarious sections of the Roman Campagna, in a mosquito screened hut and did not contract malaria.
Infected mosquitoes were also sent to London from Italy and allowed to feed upon Doctor P. T. Manson and Mr. George Warren. After a period of incubation these volunteers came down with typical malaria with parasites in the blood.
In 1911 Bass first cultivated the parasites of malaria.
=Geographical Distribution.=—Malaria is so widely distributed over all parts of the tropical and subtropical world that it would require too much space to give its geographical distribution other than as given in the accompanying chart. The malaria belt may be said to extend from 60° N. to 40° S. Many of the islands of the Pacific are exempt.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—There are at least three species of animal parasites which produce human malaria, Plasmodium vivax, the cause of benign tertian, P. malariae of quartan and P. falciparum of aestivo-autumnal. These parasites belong to the haemamoeba type of the order Haemosporidia, of the class Sporozoa and of the phylum Protozoa.
This type of Haemosporidia is characterized by invasion of red cells, amoeboid movement, pigment production and the extrusion of flagellum-like processes from the male sporont after the blood is taken from the animal and allowed to cool.
Other Haemosporidia which are very important in diseases of domesticated animals, but not for man, are those of the piroplasm type.
These parasites of the red cells do not produce pigment and do not “exflagellate.” It is to parasites of this type that some authorities have ascribed the cause of blackwater fever, a condition undoubtedly connected with malaria.
It has been thought proper by some to consider the malarial parasites as belonging to two genera, the genus Plasmodium, characterized by round sexual forms and including P. vivax and P. malariae and the genus Laverania, characterized by crescent-shaped sexual forms and including but one species L. malariae, that of aestivo-autumnal malaria.
Craig recognizes a quotidian form and a tertian form for the aestivo-autumnal parasite. Manson formerly held the view that three different species of crescent-bearing parasites were concerned in malignant infections; one, of tertian periodicity, Laverania malariae, and two, of quotidian periodicity, L. praecox, a pigmented form, and L. immaculata, a form in which pigment is only observed in the crescent formation and does not exist in the ring form schizonts. He has abandoned this view. Stephens has noted a parasite which has more nuclear material than P. falciparum (P. tenue).
Malaria of Animals.—Other Haemosporidia of the haemamoeba type are found in birds, monkeys, bats, squirrels and possibly in reptiles (the parasites of reptiles, while intracorpuscular and pigment producing, do not exflagellate). Of particular interest is the so-called bird malaria or Proteosoma, a parasite very similar to the human malarial ones.
The life cycle of this parasite was demonstrated before that of the malarial parasites of man.
Although Koch in his work showed that these malaria-like parasites of other animals were not infectious for man, Fermi has recently carried out well-controlled experiments, by feeding laboratory bred anophelines on the blood of various animals showing such infections, and subsequently on men, with invariably negative results.
Accumulated experience shows that man is not susceptible to any of the animal malarias and that the three human species can only exist in man as an intermediate host and in certain species of anopheline mosquitoes as definitive hosts. Culicine mosquitoes never transmit malaria.
Malaria-Transmitting Mosquitoes.—In the United States, Cellia albimana, C. argyrotarsis, Anopheles crucians, A. quadrimaculatus and A. pseudopunctipennis are efficient transmitters of malaria. Rather remarkable is the experience of Beyer in New Orleans that A. crucians will only transmit P. falciparum while A. quadrimaculatus will transmit P. vivax and P. malariae, but not P. falciparum. Further experiments have shown that A. crucians will transmit P. vivax as well as P. falciparum.
As showing the uncertainty attaching to the question of a certain anopheline species being efficient hosts for malaria may be cited the case of A. punctipennis. This species has been frequently reported as incapable of transmitting malaria and quite recently Mitzmain reported experiments on 219 females of the species which had fed on crescent containing blood and which were dissected from three to thirty-eight days after such feedings with negative findings in stomach and salivary glands. Furthermore, these mosquitoes failed to transmit malaria to healthy persons. Control experiments with A. quadrimaculatus and A. crucians were successful. In June, 1916, Dr. King reported 33% of positive findings after dissection of A. punctipennis which had fed on malignant tertian cases and 85% of success where the man bitten had benign tertian malaria. These results showed as high a degree of success as that obtained with the control A. crucians and A. quadrimaculatus.
From the above it must be evident that there are other factors involved besides that of the host species as both Mitzmain and King are expert epidemiologists.
A species which may be the chief transmitter in one country may be unimportant, though present, in another country. Thus Cellia albimana is the chief malarial transmitter of Panama although C. argyrotarsis is present. In Brazil the conditions are reversed, probably due to C. albimana thriving best where slightly brackish pools of standing water abound, as in Panama.
In the Philipines A. febrifer seems the important transmitter. It freely enters houses and is a vicious biter.
In India the species which seem most active in transmitting malaria are Myzomyia culicifacies and M. listoni; while in Africa, M. funesta is very efficient.
In Europe A. maculipennis and A. bifurcatus are important.
The following species of anophelines selected from the different genera are important transmitters of malaria.
Anopheles maculipennis.—Wings with four spots located at bases of both forked cells and of second and third longitudinal veins. No costal spots. Palpi yellowish brown and unbanded. Legs unbanded.
Anopheles punctipennis.—Wings with black costa showing yellow spots at apical third and at apex. The apical spot involves the first long vein and upper branch of first fork cell. The larger spot at the apical third passes through the first long vein and to the second vein just before it branches. In A. pseudopunctipennis the markings are as above but the fringe has yellow spots.
Myzomyia funesta.—Wings with four yellow spots on a black costa and two black line spots on third longitudinal vein. Palps with three white rings. Proboscis unbanded. Legs with faint apical bands.
Pyretophorus costalis.—Costa black with five or six small yellow spots. Palps with two narrow white bands and white tip. Femora and tibiae with yellow spots. Apical tarsal bands.
Myzorhynchus pseudopictus.—Black costa with two pale yellow spots. Wing fringe unspotted. Black palps with four pale bands. Apex of palps white.
Nyssorhynchus fuliginosus.—Black costa with three large yellow spots. Numerous black dots on the longitudinal veins. Palpi black with white tip and two narrow white bands. Last three hind tarsal segments white.
Cellia argyrotarsis.—Black costa with two distinct and several smaller white spots.
While anophelines are usually rural or at any rate preferring the suburbs of cities yet we can differentiate between domesticated and wild anophelines, these latter keeping away from man and consequently not playing a transmitting rôle.
Another factor in their becoming an efficient host appears to rest in the feeding habits of such anophelines, one which is voracious and fills and then ejects by rectum the blood taken from the malarial patient is more apt to be a transmitter than a species less greedy.
By an efficient host is meant a species in which full development of the parasite takes place.
LIFE HISTORY OF THE MALARIAL PARASITE
Malaria can be transmitted by subcutaneous or intravenous injection of the blood of a patient with the disease into a well person, the same type being reproduced.
=Transmission of Malaria.=—Such a method of transmission is only of scientific interest and the regular method is as follows: An infected anopheline at the time of feeding on the human blood introduces through a minute channel in the hypopharynx the infecting sporozoite of the sexual cycle.
When man is first infected by sporozoites we have starting up a nonsexual cycle (schizogony) which is completed in from forty-eight to seventy-two hours, according to the species of the parasite. The falciform sporozite bores into a red cell, assumes a round shape and continues to enlarge (schizont). Approaching maturity, it shows division into a varying number of spore-like bodies. At this stage the parasite is termed a merocyte. When the merocyte ruptures, these spore-like bodies or merozoites enter a fresh cell and develop as before.
=Malarial Toxin.=—At the time that the merocyte ruptures it is supposed that a toxin is given off which causes the malarial paroxysm.
Rosenau, by injecting, intravenously, filtered blood, taken from a patient at the time of sporulation of the parasites caused a malarial paroxysm. No parasites developed later. Another man who received a small amount of unfiltered blood allowed a slight paroxysm and four days later showed parasites in his blood. Hence the parasite will not pass through the pores of a Berkefeld filter.
=Schizogony.=—The nonsexual cycle goes on by geometric progression from the first introduction of the sporozoite, but it is usually about two weeks before a sufficient number of merocytes rupture simultaneously to produce sufficient toxin for symptoms (period of incubation). This cycle is termed schizogony. It is considered that there must be several hundred parasites per cubic millimeter sporulating to be capable of producing symptoms.
=Gametes.=—After a varying time, whether by reason of necessity for renewal of vigor of the parasite by a respite from sporulation, or whether from a standpoint of survival of the species, sexual forms (gametes) develop. Some think that sporozoites of sexual and nonsexual character are injected at the same time. It is usually considered, however, that sexual forms develop from preexisting nonsexual parasites. The developing gametes are often termed sporonts. Strictly, the sexual parasites in the blood should be called gametocytes. The gametes take about twice as long to reach maturity as schizonts. The life of a crescent has been estimated as about ten days and that of the gametes of benign tertian and quartan about one-half this period.
=Sporogony.=—The gametes show two types the one which contains more pigment, has less chromatin, and stains more deeply blue is the female—a macrogametocyte; the other with more chromatin, less pigment, and staining grayish green or light blue is the male—a microgametocyte. When the gametes are taken into the stomach of the Anophelinae, the male cell throws off spermatozoa-like projections, which have an active lashing movement and break off from the now useless cell carrier and are thereafter termed microgametes. These fertilize the macrogametes and this body now becomes a zygote. (Following nuclear reduction with formation of polar bodies the macrogametocyte becomes a macrogamete). This process of exflagellation can be observed in a wet preparation under the microscope. There is first seen a very active movement of the pigment of the male gamete and finally long delicate bulbous-tipped flagellum-like processes are thrown off (exflagellated) and push aside the red cells by their progressive motion. MacCallum saw a female Halteridium fertilized by the microgamete, after which it was capable of a worm-like motion (vermiculus or ookinete).
By a boring-like movement the vermiculus stage of the zygote goes through the walls of the mosquito’s stomach, stopping just under the delicate outer layer of the stomach or mid-gut. In three or four days after fertilization the zygote becomes encapsulated and is then often called an oocyst. It continues to enlarge until about the end of one week it has grown to be about 50µ in diameter and has become packed with hundreds of delicate falciform bodies. Some only contain a few hundred, others several thousand.
=Zygotes.=—In some of his observations Darling has noted that the zygote of benign tertian malaria grows larger and more rapidly than that of aestivo-autumnal and that the pigment is clumped rather than in belts or lines as with aestivo-autumnal. Darling has also noted that mosquitoes do not tend to become infected unless the gamete carrying man has more than 12 gametes to the cubic millimeter of blood. Rouband notes that the oocysts of P. vivax are feebly refractile with fine granules of gray pigment in loose chains while P. falciparum ones are highly refractile with large grains of black pigment. At a temperature of 25°C. vivax completes its cycle in 11 days while the zygote of the crescent requires 14 days. Apparently it is possible for a mosquito to carry both types of parasites.
The capsule of the mature zygote ruptures about the tenth day and the sporozoites are thrown off into the body cavity. They make their way to the salivary glands and thence, by way of the veneno-salivary duct, in the hypopharynx, they are introduced into the circulation of the person bitten by the mosquito, and start a nonsexual cycle. As the sexual life takes place in the mosquito, this insect is the definitive host and man only the intermediate host. The sexual cycle or sporogony in the mosquito takes about ten to twelve days.
=Efficient Mosquito Hosts.=—It must be remembered that only certain genera and species of Anophelinae are known malaria transmitters; thus Stephens and Christophers, in dissecting 496 mosquitoes of the species M. rossi, did not find a single gland infected with sporozoites.
With M. culicifacies, however, 12 in 259 showed infection. A mosquito which is capable of carrying out the complete sporogonous cycle is an efficient host and in the case of malaria the mosquito is the definitive host (sexual life of parasite).
=Malarial Index.=—Mosquito dissection is one method of determining the endemicity of malaria or the malarial index. There are two other methods: 1. by noting the prevalence of enlarged spleens, and 2. by determining the number of inhabitants showing malarial parasites in the blood. This index is best determined from children between two and ten years of age, as children under two show for a general average too high a proportion of parasites in the peripheral blood while those over ten years of age show too great an incidence of enlarged spleens.
Barber working in the Philippines with children from five to ten years of age obtained a spleen index of 13.3 and a parasitic index of 11.
=As Before Stated there are Three Species of Malarial Parasites:= 1. Plasmodium vivax, that of benign tertian—cycle, forty-eight hours; 2. Plasmodium malariae, that of quartan—cycle, seventy-two hours; and 3. Plasmodium falciparum, that of aestivo-autumnal or malignant tertian—cycle of forty-eight hours.
=Multiple Infections.=—Variations in cycles may be produced by infected mosquitoes biting on successive nights, so that one crop will mature and sporulate twenty-four hours before the second. This would give a quotidian type of fever. In aestivo-autumnal infections anticipation and retardation in the sporulation cause a very protracted paroxysm, lasting eighteen to thirty-six hours; this tends to give a continued or remittent fever instead of the characteristic intermittent type.
=Plasmodium Vivax.=—In fresh, unstained preparations, taken at the time of the paroxysm or shortly afterward, the benign tertian schizont, or nonsexual parasite, is seen as a grayish white, round or oval body, whose outlines cannot be distinctly differentiated from the infected red cell. They are about one-fifth of the diameter of the red cell and are best picked up by noting their amoeboid activity. In about eighteen hours fine pigment particles appear and make them more distinct. After twenty-four hours the lively motion of the pigment and the projection of pseudopod-like processes, in a pale and swollen red cell, make their recognition very easy. When about thirty to thirty-six hours old the amoeboid movement ceases. Approaching the merocyte stage the pigment tends to clump into one or two pigment masses and one can recognize small, oval, highly refractile bodies within the sporulating parasite.
The gametes or sexual forms do not show amoeboid movement, but the fully developed gamete, which is generally larger than the red cells, has abundant pigment, which is actively motile in the male gamete and nonmotile in the female. The male gamete is more refractile, is rarely larger than a red cell and shows yellow-brown, short rod-like particles of pigment. About fifteen minutes after the making of a fresh preparation these male gametes throw out four to eight long, slender, lashing processes, which are about 15 to 20 microns long. These spermatozoon-like bodies now break off from the useless parent cell and with a serpent-like motion glide away in search of a female gamete, knocking the red cells about in their passage through the blood plasma.
The female gamete is larger than a red cell, is rather granular and has more abundant dark-brown pigment than the male.
=Stained Smears.=—In dried smears, stained by some Romanowsky method, as that of Wright, Leishman or Giemsa, we note small oval blue rings, about one-fifth of the diameter of the infected yellowish-pink erythrocyte. One side of the ring is distinctly broader than the rather fine opposite end, which seems to hold a round, yellowish-brown dot, the chromatin dot, and has a resemblance to a signet ring. These small tertian rings of the nonsexual parasites (schizont) are seen about the time of the commencement of the sweating stage of the paroxysm. Two chromatin dots in the line of the ring are rare as is also true of more than one ring in a red cell.
When the parasite is about twenty-four hours old we note that it contains much pigment and has an amoeboid or multiple figure-of-eight contour, is about three-fourths the size of a red cell and that the infected red cell is about one and one-half times as large as in the beginning and presents a washed-out appearance. It is an anaemic-looking cell. We also note, as characteristic of a benign tertian infection, reddish-yellow dots in the pale red cell, which are known as Schüffner’s dots. These, practically, are characteristic for benign tertian.
A few hours before the completion of its forty-eight-hour cycle the contained pigment begins to clump, the chromatin to divide and, finally, we have a sporulating parasite, in which the 16 to 20 small, round, bluish bodies, with chromatin dots, are irregularly distributed over the area of the merocyte.
The gametes, or sexual parasites, show a thicker blue ring and have the chromatin dot in the center of the ring. The pigmentation of the half-grown gametes is more marked than that of schizonts of equal size. The shape of the gametes is not amoeboid, as is that of the twenty-four to thirty-six-hour-old schizont, but round or oval. The full-grown gametes have the pigment distributed and the chromatin in a single aggregation—just the opposite of nonsexual parasites. The male gamete stains a light grayish blue and has a very large amount of chromatin, usually centrally placed. The female gamete stains a pure blue, has only about one-tenth as much chromatin as plasma, with the chromatin often placed at one side. The pigment of the female gamete is dark brown while that of the male is yellowish brown.
=Plasmodium Malariae.=—In fresh preparations the young quartan schizont has only slight amoeboid movement and, as development proceeds, the rather dark brown, coarse pigment tends to arrange itself peripherally about the band-shaped or oval parasite.
The infected red cell shows but little change. At the end of seventy-two hours the rather regular daisy form of the merocyte is more distinct than that of the benign tertian merocyte.
The distinctions between the male and female gametes are similar to those of the benign tertian gametes. In Romanowsky-stained smears it is difficult to distinguish the young quartan schizont from the benign tertian one but, after twenty-four hours, the tendency of the quartan schizont to assume equatorial band forms across a red cell of normal size and staining characteristics and without Schüffner’s dots makes the differentiation easy. In the fully developed sporulating parasite or merocyte the eight merozoites assume a regular distribution, giving it a daisy appearance.
The gametes show practically the characteristics of the benign tertian ones but are smaller.
=Plasmodium Falciparum.=—The young schizont of malignant tertian is extremely difficult to detect in fresh preparations, there being noted early in the rather long continued, hot stage, as small crater-like dots, about one-sixth of the diameter of a red cell which, however, show an active amoeboid movement.
Malignant tertian blood tends to show rather marked vacuolation of the red cells and these central vacuoles have a resemblance to young ring forms. The malarial parasites are most often peripherally placed and they do not enlarge and diminish in size on focusing up and down as do the vacuoles.
Later on in the hot stage these ring-like dots enlarge to become about one-third of the diameter of a red cell, most often occupying the periphery of the infected red cell. About this time, or at the very commencement of the pigmentation, the schizont-containing red cells disappear from the peripheral circulation so that the further development is rarely observed in blood specimens.
The infected cell is brassy in color and shrunken in shape—it shows evidences of degeneration. The gametes appear as crescent-shaped bodies, which are absolutely characteristic of malignant tertian, the male gamete being more hyaline and delicate while the female one is more granular and larger.
In Romanowsky-stained preparations we see, while the fever is sustained, small hair-like rings, with geometrical outline, with frequently two chromatin dots in one end of the ring and a single red cell often showing two or more of these young rings. The rings are often seen as if plastered on the periphery of the red cells or as if having destroyed a rounded section of the rim of the red cell. As the fever declines the rings tend to disappear from the peripheral circulation. The infected red cells often show polychromatophilia and distortion.
In old aestivo-autumnal cases, or those with severe infection, we may see adult rings and merocytes, which latter are smaller than those of benign tertian, show from 10 to 12 irregularly placed merozoites and a sharply clumped mass of pigment.
The gametes are the striking crescent-shaped bodies and these show the distinctions of blue-staining for the female, with lighter gray-blue to purplish staining and abundance of chromatin for the male. The chromatin staining of crescents does not stand out so well as that of the round form gametes of benign tertian and quartan.
The black pigment of the female tends to be clumped toward the center while the rather generally distributed pigment of the male is reddish brown rather than black in a stained preparation.
This variation of pigment color may be due to the effect of chromatin staining, as the black of the pigment is the same in male and female gametes in fresh blood preparations.
Stained Smear Preferred.—As regards differentiation of species and cycle the examination of stained smears is more satisfactory and definite, as well as less time consuming. Still, one obtains many points of differentiation in the fresh preparation and should study such a preparation while carrying out the staining of his dried smear.
UNSTAINED SPECIMEN (FRESH BLOOD) --------------+-------------------+------------------+-------------------- | P. vivax | P. malariae | P. falciparum | (benign tertian) | (quartan) |(malignant tertian) | | | (aestivo-autumnal) --------------+-------------------+------------------+-------------------- Character of |Swollen and light |About the size and|Tendency to distor- the infected | in color after | color of a normal| tion of red cell red cell. | eighteen hours. | red cell. | rather than crena- | | | tion. Shriveled | | | appearance. (Brassy | | | color.) --------------+-------------------+------------------+-------------------- Character of |Indistinct amoeboid|Distinct frosted |Small, distinctly young | outline. Hyaline. | glass disc. Very | round, crater-like schizont. | Rarely more than | slight amoeboid | dots not more than | one in r.c. Active| motion. | one-sixth diameter | amoeboid movement.| | of red cell. Two to | One-third diam. of| | four parasites in | r.c. | | one red cell common. | | | Shows amoeboid move- | | | ment until appear- | | | ance of pigment. | | | --------------+-------------------+------------------+--------------------- Character of |Amoeboid outline. |Rather oval in |Only seen in over- mature | No amoeboid | shape. Sluggish | whelming infections. schizont. | movement. | movement of | Have scanty fine | | peripherally | black pigment | | placed coarse | clumped together. | | black pigment. | --------------+-------------------+------------------+--------------------- Pigment. |Fine yellow-brown, |Coarse almost |Pigmented schizonts | rod-like granules | black granules. | very rare in peri- | which show active | Shows movement | pheral circulation | motion in one- | only in young to | except in over- | half-grown | half-grown | whelming infections. | schizont. Motion | schizont. | Tends to clump as | ceases in full- | | eccentric pigment | grown schizont. | | masses almost black | | | in color. --------------+-------------------+------------------+---------------------
STAINED SPECIMEN --------------+-------------------+------------------+--------------------- | P. vivax | P. malariae | P. falciparum | (benign tertian) | (quartan) | (malignant tertian) | | | (aestivo-autumnal) --------------+-------------------+------------------+--------------------- Character of |Larger and lighter |About normal size |Shows distortion and infected red | pink than normal | and staining. | some polychromato- cell. | red cell. Shows | | philia and stippl- | “Schüffner’s | | ing. Rarely we have | dots.” | | coarse cleft-like | | | reddish dots-- | | | Maurer’s spots. --------------+-------------------+------------------+--------------------- Character of |Chromatin mass |Rather thick round| Very small sharp young | usually single and| rings which soon | hair-like rings, schizont. | situated in line | tend to show as | with a chromatin | with the ring | equatorial bands.| mass protruding from | of the irregularly| | the ring. Often | outlined blue | | appears on periphery | parasite. | | of red cell as a | | | curved blue line | | | with prominent | | | chromatin dot. | | | Frequently two | | | chromatin dots. --------------+-------------------+------------------+--------------------- Character of |Vacuolated or Fig. |More marked band | Not often found in half-grown | 8 loop-like body | forms stretching | peripheral circula- schizont. | with single | across r.b.c. | tion. Chromatin | chromatin aggrega-| | still compact. | tion. Schüffner’s | | | dots. | | --------------+-------------------+------------------+--------------------- Character of |Fine pigment rather|Coarse pigment |Very rarely seen in mature | evenly distributed| rather peripher- | peripheral circula- schizont. | in irregularly | ally arranged in | tion in ordinary | outlined parasite.| an oval parasite.| infection. Pigment | | | clumps early. --------------+-------------------+------------------+--------------------- Character of |Irregular division |Rather regular |Sporulation occurs in merocyte. | into 15 or more | division into | spleen, brain, etc. | spore-like | eight or ten | Rarely in peripheral | chromatin dot |merozoites--Daisy.| circulation. 6 to 10 | segments. | | irregularly placed | | | merozoites. (In | | | culture 32.) --------------+-------------------+------------------+--------------------- Character of |Round deep blue. |Round, similar to |Crescentic, pure blue macrogamete. | Abundant, rather | P. vivax but | pigment clumped at | coarse pigment, | smaller. | center, chromatin | chromatin at | | scanty and in | periphery. | | center. --------------+-------------------+------------------+--------------------- Character of |Round, light green-|Round like P. |More sausage-shaped microgamet- | blue, pigment | vivax. | than crescent. Light ocyte. | less abundant, | | grayish blue to | chromatin abundant| | purplish. Pigment | and located | | scattered | centrally or in a | | throughout. | band. | | Chromatin scattered | | | and in greater | | | quantity but diffi- | | | cult to stain. --------------+-------------------+------------------+---------------------
Central vacuolation of red cells is common in malarial anaemia and may be mistaken for nonpigmented parasites.
Malarial rings are usually peripheral and do not vary in size as one focuses up and down as do the central vacuoles.
Quinine-affected Parasite.—A very puzzling but well-recognized finding in cases treated with quinine or salvarsan is the so-called quinine-affected parasite. Such parasites lack definiteness of outline and show poor chromatin staining. The gametes do not seem to show these effects from the drug.
=Certain questions connected with the life history of the malarial parasite in man which are of interest.=
1. Extracellular location.—It is usual to consider the parasite as developing within a red cell and in this position to destroy the red cell. Rowley-Lawson, however, thinks that the parasites are exclusively extracellular and that they adhere to the red cells by loop-like pseudopodia which encircle a portion of the red cell and digest the haemoglobin of such an area.
2. Relapses.—There are several views as to the etiology of relapses in malaria. These views are taken up under relapses (see page 35).
3. Malarial toxin.—Nature of the toxic material thrown off by the parasite at the time of simultaneous sporulation. Rosenau’s experiments tend to show that there is a fever-producing toxin thrown off at this time. Other authors have thought that a haemolysin and an endotheliolysin were thrown off at the same time. Brown considers that the pigment produced by the parasite, in its metabolism of the haemoglobin of the red cell, may act as a haemolysin, he having found that intravenous injections of haematin were capable of producing marked anaemia. It is well known that a far greater number of red cells are destroyed in a paroxysm than would be accounted for by the actual percentage of red cells destroyed by parasites. The endothelial cells take up actively this malarial pigment or haemozoin and are damaged or destroyed thereby. Haematin injections also tend to destroy leucocytes and platelets.
Rowley-Lawson is of the opinion that the greater red cell destruction than would be represented by percentage of cells showing parasites is explained by parasites migrating from cell to cell so that many red cells may be destroyed by a single parasite.
4. Transmission to larvae.—There has been an idea that sporozoites might enter the ovaries and ova as well as the salivary glands so that a second generation of mosquitoes might transmit malaria. There is no proof that such a method is ever operative.
5. Congenital malaria.—There has been some question as to the possibility of congenital malaria. Heiser has recently reported the case of an infant which showed crescents in its blood by the end of one week from birth. The mother showed the same infection and the child must have been infected through the placental circulation.
Clark in numerous examinations of the blood of the new-born failed to find infection even when the mother’s blood teemed with parasites. In one case where the child showed infection shortly after birth there had been an accident to the placenta and he believes that instances of so-called congenital malaria are to be explained in this way.
6. Cultivation of parasite.—As to cultivation of malarial parasites. Bass takes from 10 to 20 cc. of blood from the malarial patient’s vein in a centrifuge tube which contains 1/10 cc. of 50% glucose solution. A glass rod, or a piece of tubing extending to the bottom of the centrifuge tube is used to defibrinate the blood. After centrifugalizing there should be at least one inch of serum above the cell sediment. The parasites develop in the upper cell layer, about 1/50 to 1/20 inch from the top. All of the parasites contained in the deeper-lying red cells die. To observe the development, red cells from this upper 1/20 inch portion are drawn up with a capillary bulb pipette.
Should the cultivation of more than one generation be desired, the leucocyte upper layer must be carefully pipetted off, as the leucocytes immediately destroy the merozoites. Only the parasites within red cells escape phagocytosis. Sexual parasites are much more resistant. Bass thinks he observed parthenogenesis. The temperature should be from 40° to 41°C. and strict anaerobic conditions observed. Aestivo-autumnal organisms are more resistant than benign tertian ones. Dextrose seems to be an essential for the development of the parasites.
Bass considers that P. vivax has a disc-like structure which enables it to squeeze through the brain capillaries while adult schizonts of P. falciparum have a solid oval form which causes them to be caught in the capillaries.
The Thompsons have rather simplified the method of Bass. They draw 10 cc. of blood into a test tube containing the usual amount of glucose solution. They then defibrinate the blood by stirring with a thick wire for about five minutes and remove the wire with the adhering clot. They then pour this defibrinated blood into several small sterile test tubes, which should contain at least a one-inch column. Rubber caps are adjusted over the cotton plugs and the tubes placed in the incubator. They note the tendency of cultures of P. falciparum to agglutinate which is not true of P. vivax.
They think this agglutination the great cause of the plugging of capillaries in pernicious malaria. They note 32 merozoites as maximum number in sporulation of P. falciparum while P. vivax has usually 16 or more, but never as many as 32.
This would explain the shorter incubation period of malignant tertian. The pigment of P. falciparum clumps much earlier in the developing schizont than that of P. vivax and is much coarser and more discrete.
While Bass thought he noted parthenogenesis in cultures others have failed to observe any evidence of it.
7. Immunity.—As to immunity. There is no real immunity to malaria, it is a continuance of the infection, but the parasites are not in sufficient numbers to give rise to fever. If, however, the patient becomes chilled or fatigued or otherwise depressed, fever results.
This apparent immunity is also kept up by reinfection, because if natives leave the locality for a length of time they lose it. Patients who show this apparent immunity to one form of malaria have no such resistance to the other types. Bass states that immune bodies are produced in malaria and that immune processes contribute to control of the infection, but that it is not lasting and is not effective against new infection.
8. Perniciousness.—Causes of perniciousness. This is taken up under perniciousness in malaria. (See page 31.)
9. Quinine-affected parasite.—Effect of quinine on malarial parasites. It is usually thought that the merozoites at the time of being thrown off from the merocyte are most vulnerable, while the gametes are only slightly affected, if at all. Still, the young forms from which gametes develop are destroyed. Quinine causes parasites to disappear from the peripheral circulation and produces degenerative changes in such parasites as may remain. Bass thinks that quinine makes the red cell permeable to the lytic action of serum. Anaemia may cause degenerative changes in parasites similar to that from quinine.
10. Anaphylaxis and the paroxysm.—Abrami has brought forward evidence in favor of the malarial paroxysm being due to the outpouring of merozoites into the blood plasma which act as foreign antigen. It is noted that the dissemination of merozoites takes place some hours before the cold stage which is one of the manifestations of anaphylactic shock. They note a leucopenia and lowering of the blood pressure preceding the paroxysm as evidence of a haemoclastic crisis.
The Anopheline Mosquito
The ova of culicine mosquitoes are usually deposited in a scooped-out raft-like mass of about 250 eggs set vertically. The raft is easily seen with the eye, being about ⅕ inch long. The anopheline eggs are oval in shape with pleated air cell projections laterally. They are laid upon the surface of the water, to the number of about 100, in star, triangle or ribbon patterns. The egg stage is two to four days but shorter, however, in the tropics.
The larval stage is the most important one to be acquainted with because in this stage one can most readily distinguish the anopheline or possible malaria transmitter from a culicine species. One can more readily and quickly make a survey for anophelines by examining the collections of water for larvae than in any other way. The anopheline larva seems to prefer the surface, on which it lies flat and out of the water. To keep it from turning over on its long axis, it has little rosette-like hair tufts on the dorsal surface of the 5 or 6 middle abdominal segments (palmate hairs). There are feathered lateral hairs projecting from thorax and abdominal segments. The head is very small in comparison with the thorax and can be rotated with lightning-like rapidity. There is no projecting breathing tube or syphon from the next to the last abdominal segment, as is characteristic of Culex, Stegomyia or any other culicine genus.
In addition, culicine larvae do not float parallel to the surface of the water, but hang suspended at an angle, with only the tip of the syphon pushed upward to the surface. The lateral hairs or bristles are not feathered and the head is much larger than that of the anopheline larvae. It is the fact of the surface position of these anopheline larvae which enables them to worm their way over film layers of water or between blades of grass, in grass or rush studded pools or swamps.
In the pupal stage it is rather difficult to differentiate species of mosquitoes from each other, so that, other than to recognize that the bloated shrimp-like body is a mosquito pupa, is unnecessary.
DIFFERENTIATION OF CULICINAE AND ANOPHELINAE
It is impossible even for an entomologist to determine the species of mosquitoes without recourse to elaborate keys and tables. It is a comparatively easy matter, however, to decide as to whether the mosquito is a probable malaria transmitter or not.
The male anopheline.—While certain characteristics of the male are used to separate the Aedinae from other subfamilies, yet it is only with the female that we concern ourselves in differentiating the Culicinae from the Anophelinae. Therefore, it is first necessary to distinguish the male from the female. If the antennae have not been torn off, this can be decided by the highly adorned plumose antennae of the male, those of the female being sparsely decorated with short hairs. The palpi of the male Anopheles tend to be clubbed, while those of the Culex are straight. If the antennae have been broken off, look for the claspers at the end of the abdomen.
Male mosquitoes do not feed on blood but on fruits and flowers instead. The puncturing parts of the male are not sufficiently resistant to penetrate the skin.
The female anopheline.—Having determined that the insect is a female, we then proceed to place it either in the subfamily Culicinae or Anophelinae by a study of the relative length of the palpi to the proboscis. If the palpi are much shorter than the proboscis, it belongs to the Culicinae; if about as long or longer, to the Anophelinae. The palpi of the female Megarhininae are also long, but the proboscis is curved.
Having settled on the subfamily, we separate the genera by considering such points as character and distribution of scales on back of head, wings, thorax, and abdomen; banding of proboscis, legs, abdomen, and thorax, shape of scales on wings, and location of cross veins.
Anophelinae show abundant upright forked scales on occiput. The mesothorax shows sparse hairs or scales with a smooth scutellum. As a rule, the wings are spotted (dappled) and the location of these spots gives the best clue to the different species of the genera. With the exception of Bironella the first submarginal cell is large. This cell is longer than the second posterior one.
In the resting position Culex allows the abdomen to droop, so that it is parallel to the wall. The angle formed by the abdomen with head and proboscis gives a hunchback appearance.
Anopheles when resting on a wall goes out in a straight line at an angle of about 45°. It resembles a bradawl.
The scutellum of Anopheles is simple, that of Culex trilobed. Anopheles has but one spermatheca; Culex has three.
=Anophelinae=
{ 1. Scales on wings, large and lanceolate. 1. Scales on head only; { Anopheles. Palpi only slightly scaled. hairs on thorax and { 2. Wing scales small and narrow and lanceolate. abdomen. { Myzomyia. Only a few scales on palpi. { 3. Large inflated wing scales. { Cycloleppteron.
2. Scales on head and { thorax (narrow curved { 1. Wing scales small and lanceolate. scales). Abdomen with { Pyretophorus. hairs. {
{ 1. Abdominal scales only on ventral surface. { Thoracic scales like hairs. Myzorhynchus. { Palpi rather heavily scaled. 3. Scales on head and { 2. Abdominal scales narrow, curved or thorax and abdomen. { spindle-shaped. Abdominal scales as tufts Palpi covered with { and dorsal patches. Nyssorhynchus. thick scales. { 3. Abdomen almost completely covered with { scales and also having lateral tufts. { Cellia. { 4. Abdomen completely scaled. Aldrichia.
NOTE.—Of the above genera only Cycloleppteron and Aldrichia are unproven malarial transmitters.
The female anopheline mosquito alone bites man, the male feeding on fruits and flower juices. The female absolutely requires blood for the development of her eggs after fertilization by the male mosquito.
The anopheline mosquito bites at night or toward evening and selects some dark place or dark colored wall to sleep against during the day. Hence the advantage of a buff colored wall interior. It is well to remember that the malarial incidence may be kept down by killing the mosquitoes inside of a house by striking them with a folded paper or piece of wire gauze on a handle (fly swatter).
It is not a bad plan to have a dark colored surface in a room to attract them and make their destruction easy.
Anophelines do not like wind and seek protection of underbrush. As regards distance of flight from breeding places Metz has noted that A. crucians were not distributed generally over 7000 feet and rarely were found between 7000 and 9000 feet beyond which distance they were not found. Some anophelines get accustomed to feeding exclusively on animals. Mosquitoes may hibernate through the winter and possibly cause new infections the following spring. Cases of malaria in the spring are however usually due to relapses. Mitzmain’s negative experiments with hibernating mosquitoes prove man to be the winter carrier.
The malarial zygote will not develop in the stomach of the mosquito if the temperature is below 16°C. (60°F.). It would seem that the zygote of P. malariae will develop at a lower temperature than that of the other two species, P. falciparum requiring the highest temperature.
Our views as to temperature requirements for the development of zygotes in the mosquito must be changed as King has recently shown that P. vivax sporonts will survive exposure to temperatures of 30°F. for two days and P. falciparum temperatures of 35°F. for one day. This proves that temperatures approximating freezing ones will fail to destroy the parasites of hibernating mosquitoes.
Wenyon has found experimentally that mosquitoes which had fed on malarial blood and kept at incubator temperatures for a week to allow development of zygotes showed inhibition of development of zygotes when kept at temperatures corresponding to hibernating ones. This treatment did not kill the zygotes but complete development took place when subsequently the mosquitoes were again subjected to incubator temperatures. From this it would seem that the zygotes remain viable during the winter hibernation. This is at variance with Mitzmain’s views who regarded hibernation as destructive to zygotes.
The mosquito does not seem to suffer from her malarial infection—quite different from the serious affection that filariasis causes in the mosquito.
=Epidemiology.=—This matter has been considered rather extensively under the historical and etiological discussions.
It may be stated however that the requirements for the spread of malaria are: (1) Men who have sexual forms of the malarial parasite in their peripheral circulation; (2) efficient anopheline hosts, and (3) an atmospheric temperature above 60°F. (16°C.).
It is a well recognized fact in the tropics that the natives seem to have an immunity to malaria yet may carry parasites in their circulation and serve as carriers. The native children to a striking degree harbour parasites and to them malaria is a prime cause of death. After repeated infections, if not fatal, a temporary immunity is acquired. Many localities in the tropics owe freedom from malaria to an absence of anophelines, as for instance Barbadoes. Again malaria-bearing mosquitoes may acquire the habit of feeding on animal blood other than that of man. It is well recognized that rural populations are more liable to malaria than those of towns and as the population of a country moves to the industrial centres human blood may become difficult to obtain and the anophelines turn to other sources of blood supply. It has been suggested that mosquitoes may suffer from other infections which may be inimical to the development of malarial zygotes (black spores of Ross). Anophelines bite chiefly at sunset and at night from which fact there would seem to be some value in shutting the windows towards nightfall as is the custom in many malarious parts of the world.
Pools containing a border growth of grass or rushes are often selected by anophelines for depositing eggs. The small fish or tadpoles, which prey on the larvae, cannot work their way through the obstacles and, again, petroleum oil cannot be easily distributed in a network of grass. Anophelines of different species and of different countries seem to vary in their selection of water for depositing their eggs. We should not generalize but go out and search for breeding places.
Anophelines seem to prefer small collections of water or sluggish clear streams. The pools made by excavations following railway or other similar construction are favorite breeding places. Proper cultivation of rural districts makes the country more healthful and Carter has stated that tile drainage is the key to rural malaria control.
The most practical method for the identification of anopheline species is to collect the larvae and later to study the adults which develop from the pupae. On the whole culicines do not seem to object to foul collections of water while anophelines avoid such breeding places.
PATHOLOGY AND MORBID ANATOMY
The pathological lesions are those connected with the destruction of enormous numbers of red cells, not only each infected red cell being destroyed but others not so parasitised. There has been an idea that at the time of sporulation and rupture of the merocyte a pyrogenetic toxin was given off and along and with this there were haemolysins and endotheliolysins. Following Brown we are justified in thinking that the malarial pigment (melanin or haemozoin) can act as a haemolysin and by being taken up by endothelial cells bring about their degeneration with associated capillary haemorrhages. All three factors—red-cell destruction by parasites, haemolytic action on red cells and capillary haemorrhages lead to anaemia.
The brain has a leaden hue caused by the black pigment. As discussed under pernicious manifestations the blocking of the capillaries may be explained in several ways. When examining sections of a malarial brain one often encounters punctiform haemorrhages.
The spleen is enlarged and the surface dark. In acute cases it may be diffluent instead of hard, as in ague cake. Microscopic sections show a striking absence of pigment in the Malpighian corpuscles, the haemozoin being pushed off into the surrounding spleen pulp. Bone marrow is dark from deposit of pigment. In the liver the endothelial and Kupfer cells are packed with black pigment. The parenchymatous cells do not contain this pigment but may show grains of a yellow pigment, haemosiderin, which gives the iron reaction. Haemozoin, although it contains iron, does not give this reaction. Haemozoin is soluble in alkalis, but not in alcohol while haemosiderin is soluble in alcohol but not in alkalis.
The splenic blood is more rich in haemozoin than that of the other vessels, this indicating the spleen as the place of destruction of infected red cells or as the nursery for the development of malarial parasites. As a matter of fact splenectomy may cure an old malarial cachectic.
The finding of pigmented mononuclears or pigmented parasites in a cross section of a blood vessel makes for a diagnosis of a malarial infection.
Malarial manifestations are common in tropical autopsies and one must be very chary about reporting malaria as the real rather than contributing cause of death.
There is usually a marked increase in large mononuclears in malaria and if this is noted along with a leucopenia it is very suggestive. Melaniferous leucocytes occur in malaria only.
The kidneys may show degenerative changes and the presence of urobilin in the urine is an important indication of latent malaria.
SYMPTOMATOLOGY
CLINICALLY, WE HAVE TWO TYPES OF MALARIAL PAROXYSMS, (1) Those presenting a cold stage, followed by a hot stage, with a terminal sweating stage. Such attacks are brought about by the benign infections which include the benign tertian and the quartan. Owing to the fact that in such paroxysms the temperature makes a critical fall to normal or subnormal readings such fevers are frequently designated intermittent fevers.
While these benign infections rarely or never exhibit pernicious manifestations, they may, equally with the more dangerous aestivo-autumnal parasite, lead to the production of malarial cachexia, in which the clinical manifestations are similar whether produced by a benign or malignant species.
(2) Those in which the succession of cold, hot and sweating stages is lacking. There is not the frank well-defined chill of the former group, so that the term dumb chill is frequently applied. With the possible exception of the first paroxysm the temperature tends to remain well above normal giving a continuous, or at any rate a remittent type of fever, instead of the intermittent temperature curve of the benign infections. The designation remittent fever, is often applied to such fevers. Clinically there is a resemblance to typhoid fever.
Such malarial fevers are caused by the small hair-like ring parasite with its crescent sexual forms. There are many designations for this type of malarial fever of which the best recognized are: malignant tertian, subtertian, aestivo-autumnal and tropical. It is preëminently the malarial fever of the tropics and, from its appearing in temperate climates chiefly in the late summer and through the autumn months, received from the Italians the designation aestivo-autumnal.
Such fevers were called subintrant by Torti because the succeeding paroxysm set in before the completion of the long-continued preceding one. This type of fever was greatly dreaded. The designation malignant tertian is to be preferred as indicating the greater seriousness of this type of malaria.
INCUBATION PERIOD
Depending in great part on the number of sporozoites introduced by one or more infecting anophelines at the time of biting we have with quartan fever (8-12 merozoites) a period of incubation of approximately three weeks, for benign tertian (16-24 merozoites) two weeks and for malignant tertian (32 merozoites in culture) eight to twelve days. These periods however may be much longer.
PRODROMATA
There may be prodromata of the nature of malaise, vague muscular pains, headache and anorexia, possibly showing a periodicity in their appearance or intensity.
It is only when a sufficient number of parasites sporulate simultaneously and pour out into the circulation sufficient toxic material to cause a well-marked paroxysm that such occurs—with less poison we may only have vague suggestions of an attack of ague.
In a large proportion of cases there are no prodromata, they begin with a sudden onset.
Malarial paroxysms show a preference for the forenoon or at any rate tend to occur in the early afternoon, rather than in the evening.
MIXED AND MULTIPLE INFECTIONS
When there are two generations of tertian parasites, each maturing on successive days, we have a paroxysm every day—a quotidian fever. Such a tertian infection is called a double tertian. In quartan infections, with the seventy-two-hour cycle of development, if we have two generations of parasites sporulating on succeeding days, but with an apyretic day intervening, we have a double quartan. If three generations of quartan parasites sporulate on three successive days we have a triple quartan infection. When two species of parasites are present in the same case we have a mixed infection. Mixed infections of malignant tertian and benign tertian are the most common, next, those of quartan and malignant tertian and very rarely those showing quartan and benign tertian. All three species have been found in a single individual.
CLINICAL TYPES
A Typical Benign Tertian or Quartan Paroxysm.—(Other than for the difference in periodicity the paroxysms of these two malarial infections are alike.)
The ague attack generally commences with malaise and slight headache, frequently accompanied by yawning and stretching. Chilly sensations radiating from the spinal column to the extremities and the jaws give way to actual chill with shaking body and chattering teeth, face pinched and bluish and cutis anserina.
The pulse is frequent, small and of rather high tension, there is increased frequency of urination and nausea and vomiting may be present.
Notwithstanding the fact that the rectal temperature is steadily rising five or six degrees during this cold stage there is a desire on the part of the patient to cover himself with all the wraps obtainable.
The cold stage, which usually lasts from twenty to sixty minutes, is succeeded by the hot stage.
At first there is a feeling of slight relief from the misery of the chill but this is soon lost sight of in the increasing headache and feeling of intense heat.
The previously welcome blankets are cast aside. The face now becomes flushed, the eyes shining, and the pulse more full. Epigastric discomfort, nausea and vomiting are apt to become more prominent in this stage. The patient often complains of a throbbing headache. It is at this time that he may become slightly delirious. A sense of tension or even pain may be experienced in the region of the spleen, which organ will be found tender even if not already palpable. Herpes about the nose and lips is almost as common as in lobar pneumonia.
An attending bronchitis is not uncommon.
The fever remains high, from 105° to 106°F., and continues so elevated for from four to six hours to be succeeded by the sweating stage. In this the dry skin becomes moist and perspiration breaks out first on the forehead to be followed by a more or less marked profuse sweating of the entire body. The pulse becomes slower, the temperature falls rapidly and the patient falls asleep to awake slightly exhausted but feeling well.
This feeling of well-being continues during the fever-free day which is often referred to by a patient as “my good day.”
The sweating stage lasts usually about four hours so that the entire paroxysm of cold, hot and sweating stages occupies approximately eight to twelve hours.
While most cases of the benign infections show the typical stages yet we meet cases where the cold and sweating ones are absent or but slightly marked.
Blood examination will show the parasites of the benign infections to be in the peripheral circulation during the entire apyrexial period. During the paroxysm we have a moderate leucocytosis and during the afebrile period a leucopenia with an increased percentage of large mononuclears.
Billet thinks that quartan paroxysms can be distinguished from benign tertian ones by their showing a less abrupt fever rise and a more rapid fall of temperature with a shorter duration of the paroxysm, four or five hours as against eight to twelve hours for benign tertian.
A Typical Malignant Tertian Paroxysm.—The characteristic features of the paroxysm are slight chilliness instead of a frank chill, prolonged and intensified hot stage, lack of marked terminal sweating and a tendency to exhibit a continuous or at least remittent fever curve instead of the distinct intermittence, with an apyrexial period, of the benign infections.
During the period of the remittence the patient fails to experience a sense of well-being. He is sick and does not have a “well day.”
The temperature of a malignant tertian paroxysm may fall to normal during the first attack but succeeding attacks only show the tertian periodicity by an exacerbation of the more or less continuous fever.
In these cases the temperature rise is gradual rather than abrupt and the fall rather by lysis than crisis.
The paroxysm lasts from twenty to thirty-six hours instead of ten hours.
To explain the continuous type of fever it is often stated that anticipation and retardation are characteristic of malignant tertian infections. This simply means that the new paroxysm tends to come on before the tertian periodicity of forty-eight hours has expired and, having appeared, tends to delay its termination. At any rate there is an extreme irregularity in the course of the paroxysm. These attacks are often termed “dumb chills” and are greatly dreaded.
The onset is insidious, occurring as a rule in the forenoon or early afternoon, with rarely a chill but only chilly sensations. The headache and backache are severe, the face is flushed, the pulse quickened and the thirst urgent.
The patient feels more prostrated and ill than does one in a benign paroxysm and there is a distinct tendency to mental confusion or delirium. Nausea and vomiting may be prominent features of an attack. At times an apathetic state may suggest typhoid fever. In these malignant malarial attacks the spleen is palpable and very tender. There is also a sense of weight in the region of the liver.
In a blood examination one is not apt to find any other parasites than the young hair-like ring forms which begin to appear a few hours after the onset of the paroxysm. The rings may be observed to broaden, but prior to that development in which pigment would appear in the ring, the parasite-containing red cell is caught in the capillaries of spleen or other organs. The finding of young ring forms while fever continues is suggestive of a malignant tertian infection.
In the absence of quinine administration the finding of parasites is to be expected in benign tertian and quartan infections, but with the tropical parasite a smear may fail to show any organisms where a few hours previously a blood examination would have shown a large percentage of infected red cells in every field of the microscope.
=Pernicious Manifestations of Malaria.=—These grave manifestations arise almost exclusively in the course of malignant tertian infections. In his study of malaria Stott had about 1% of his cases showing well-marked pernicious symptoms.
As explanations of perniciousness are given: (1) the very large number of red cells infected and destroyed by the malarial parasites; (2) the throwing off at the time of sporulation of the merocyte of a large amount of toxic material owing to the presence of such a large number of disintegrating merocytes, and (3) from the plugging of the capillaries of important internal organs by adult parasites. This may arise as the result of (a) the sporulating parasites acting as emboli, being too large to pass the lumen of the capillary; (b) from degenerative changes or distension with pigment of the endothelial cells lining the capillaries, or (c) as the result of an ovoid shape on the part of the malignant tertian parasite there is an inability to pass through capillaries which the flattened benign parasites can do by infolding (Bass), or (d) resulting from the tendency of malignant tertian parasites to agglutinate.
Types of Pernicious Malaria.—It is customary to divide pernicious malaria into the following divisions—(1) Cerebral, (2) Algid, (3) Bilious Remittent and, possibly, also (4) Pneumonic and (5) Cardiac types.
Blackwater fever is often included in the grouping but would appear to be best considered as a separate disease although almost surely brought about by malaria.
We do not understand why in one case sporulating parasites should plug the capillaries of the central nervous system, with the production of conditions resembling well-recognized nervous diseases, while in another case the damage is done the intestinal mucosa, pancreas or lungs. At any rate these pernicious manifestations of malaria should always be kept in mind when a case of sudden cerebral involvement or acute abdominal disease shows itself in a patient in a malarious country and a blood examination should be promptly made.
Cerebral Manifestations of Pernicious Malaria.—Various authorities give different clinical pictures but the more commonly accepted types are:
(1) The hyperpyrexial, when the symptoms are those of heat stroke, with a temperature going up as high as 110°F. or even higher. Such patients rapidly become comatose and as a rule die.
(2) The delirious and comatose forms are apt to be associated, the comatose condition following a delirious state. Such manifestations may or may not set in with a chill. Cases belonging to this group may arise from a typical malignant tertian infection in which the headache and restlessness have been unusually marked. The pulse is full and fast with sighing respiration, hot dry skin and flushed face. There may be rigidity of the neck muscles.
(3) Such terms as epileptiform, tetanic, aphasic, cerebellar and bulbar have been applied to malarial manifestations and are self-explanatory.
Cerebral malaria may give rise to a delusional insanity. Various psychoses or amnesia at times follow cerebral types of pernicious malaria.
Algid Manifestation of Pernicious Malaria.—In such cases we have a small thread-like pulse and a cold clammy skin. There are signs of collapse. The respiration is slow and shallow and the voice weak. It is customary to consider some of these cases, when there is vomiting and diarrhoea, with painful cramps of the legs and scanty or suppressed urine, as of choleraic type, while other cases, with blood and mucus in the stools and marked abdominal pain are termed dysenteric. Most dysenteric types only show a diarrhoea with the presence of blood.
The dysenteric type is more common but the question always arises whether the case may not have been really dysentery lighting up a latent malaria or the lowering of resistance from the malaria favoring a dysenteric infection. Stott had five algid cases of dysenteric type but not one of choleraic. The choleraic types have often been reported during outbreaks of cholera.
When epistaxis and haemorrhages from the intestines or stomach are marked features of an attack the cases are termed haemorrhagic and, if a prostrating, collapse-producing sweat be a characteristic feature, they are called diaphoretic.
Cases have been observed when the excessive sporulation was apparently taking place in the pancreas, giving the symptomatology of acute haemorrhagic pancreatitis.
Bilious Remittent Fever.—This is the most common and the least dangerous of the pernicious manifestations but tends rapidly to produce malarial cachexia. Slight jaundice and bilious vomiting may appear in the course of an ordinary malignant tertian paroxysm and only severe types, with fatal tendency, should be classed as pernicious. It sets in with marked nausea followed by bilious vomiting and bile-rich stools. Jaundice shows itself by the second day; earlier than in yellow fever, but much later than the rapidly appearing jaundice of blackwater fever. The urine shows bile pigment and a yellow foam. Epigastric distress and liver tenderness are marked features and there may even be gastric haemorrhage.
Pneumonic and Cardiac Types.—Other recognized types are when, with the symptoms of a broncho-pneumonia, we find an element of periodicity and a response to quinine—the so-called pneumonic type.
Again, usually in elevated regions, dilatation of the right heart and death have been noted as occurring in cardiac types of pernicious malaria.
Another type is one in which the sweating stage is excessive, the so-called diaphoretic type. These cases may result in collapse and such a termination may be syncopal in character.
=Relapses.=—Relapses are distinct features of malarial diseases, the tendency being most marked in quartan and least so in malignant tertian. A relapse after an interval of two years is very rare in malignant tertian but periods as long as nine years may intervene between attacks of quartan fever.
Relapses are intimately associated with conditions which tend to lower the body resistance, so that exposure to cold or wet or hot sun may bring on an attack. Alcoholic or venereal excesses, as well as errors of diet, may be provocative. Persons returning home from the tropics often experience relapses as they approach the cooler climate of the temperate zone. It has been well stated that the old resident of the tropics owes his condition of health rather to education than acclimatization—experience has taught him discretion.
There are three explanations of relapses of which the one supported by Ross and Bignami seems more reasonable and is that the disappearance of nonsexual parasites is only apparent and that they continue their cycle but in insufficient numbers to excite symptoms.
Parthenogenesis.—Schaudinn thought that, either spontaneously or as the result of treatment, there was a disappearance of the nonsexual forms and the male gametes, the female gametes however surviving and, eventually, through the process of parthenogenesis, producing a set of spores or merozoites which set up a nonsexual cycle. It would seem probable that Schaudinn saw red cells containing a merozoite along with a female gamete and interpreted his findings as a sporulating sexual form.
Craig thinks that as the result of the conjugation of two young schizonts a more resisting parasite is evolved, which under favorable circumstances for its development may start anew a nonsexual cycle.
=Latent Malaria.=—The persistence of a malarial infection, in the absence of clinical and to a great extent of laboratory manifestations, is shown by the occurrence of relapses, so that the section treating of malarial relapses applies equally to this paragraph. In addition to the factors influencing relapses, such as exposure to sun, rain and excesses of various kinds, we note a particular tendency for a latent malaria to develop activity following surgical operations and childbirth. In untreated latent cases we may have delayed healing of surgical operations.
In another paragraph there is noted the importance of examining placental smears for evidence of a latent malarial infection. Persons returning to a cool climate from the tropics, who may not have shown evidence of active malaria for months, may come down with a paroxysm upon encountering cool weather (refrigeration). Latency may be complete or there may be vague manifestations of ill health such as anorexia, malaise, irritability, headaches, anaemia and alimentary tract disturbances. Not infrequently tropical residents without symptoms may show crescents in their blood and such cases are of prime importance in connection with infection of mosquitoes. To a certain extent they are the typical carriers and should be actively treated from a standpoint of malarial prophylaxis.
=Masked Malaria.=—While as a rule one should not accept such a diagnosis, unless the possibility of some other explanation than malaria is excluded, yet there are manifestations, chiefly neuralgic, gastro-intestinal or in the form of varied skin eruptions which at times show periodicity and which respond to treatment with quinine.
=Malarial Cachexia.=—As the result of repeated attacks of any type of malaria a condition of anaemia and physical and mental incapacity may be produced. The skin has a dirty earthy hue, particularly of the face, and the sclerae show a yellowish tinging. The patient is sensitive to the slightest cold and is the victim of mental depression with deterioration of memory or at any rate lack of concentration.
There may be long periods in which the temperature is normal or subnormal but slight febrile accessions may occur from time to time and at such times the blood may show parasites.
The spleen is enlarged as may also be the liver. Twisting of the pedicle of the spleen or its rupture from even slight blows may necessitate surgical intervention.
There is anorexia and alimentary tract disturbances. A very important feature of malarial cachexia may be the occurrence of haemorrhages, particularly serious being those from the retinal vessels.
It is probable that hookworm infection has frequently been confused with the anaemia of malarial cachexia as in both of these conditions we may have a high-grade anaemia with swelling about the ankles, palpitation of the heart and shortness of breath. Some authorities have recently called attention to splenic enlargement in hookworm disease, but this is not generally accepted. There may be also ascites in malaria. Urobilinuria is an important sign in malaria where other causes for red cell destruction are excluded.
=The Sequelae of Malaria.=—The anaemia and other manifestations of malarial cachexia have been described above. The enlarged spleen not only is a source of danger from rupture but it may cause sensations of pain or tension. The skin of those with chronic malaria tends to ulcerate from slight wounds and phagedenic lesions may occur. There may be various disorders of the nervous system varying from mental confusion or lack of mental concentration to melancholia. Neuritis and possibly peripheral neuritis may have origin in repeated attacks of malignant tertian malaria. Ulceration of the cornea is the most frequent of the ocular sequelae although even this is rare. It only occurs after many relapses. It is painful, heals slowly and tends to recur with relapses. Iritis may accompany it. Abortions are frequent unless the malaria is adequately treated.
Symptoms in Detail
General Appearance.—In the cold stage of the benign infections the face is pinched and blue to become decidedly flushed when the hot stage sets in. In malarial cachexia there is an earthy color with the pigmentation more marked about the face and knuckles. In the algid forms of pernicious malaria the skin is pale, cold and clammy, in a measure simulating cholera. Herpes labialis is very common in the benign infections, but less so in the malignant tertian ones. Jaundice is a feature of bilious remittent fever.
The Temperature.—Even in the cold stage the temperature is steadily rising and may have reached 105°F. or higher by the time of onset of the hot stage. It remains elevated during the four to six hours of the hot stage and then falls rapidly to normal during the sweating stage. The paroxysm tends to occur in the forenoon or early afternoon. In 793 typical paroxysms Stott found only 37% to occur before noon. Intermittent fever curves are characteristic of benign infections. In malignant tertian a prolonged hot stage (fifteen to thirty-six hours) is a marked feature. The onset also is more gradual and the fever tends only to remit or may remain continuous over several days, but even with such a chart there are apt to be indications of slight rises every other day.
In the hyperpyrexial form of cerebral perniciousness the temperature may rise to 112°F. and the case resemble sun stroke. In the algid forms the axillary and rectal temperatures are usually elevated.
The Circulatory System.—The pulse is small, rapid and of high tension in the cold stage to become full and bounding in the hot stage. A cardiac type of perniciousness in which the right heart dilates has been referred to.
The Alimentary Tract.—Nausea and vomiting are common manifestations of malarial paroxysms and in bilious remittent fever the bilious vomiting is an especially distressing feature.
So-called choleriform and dysenteric manifestations of perniciousness of the algid type are rarely observed.
Cases with the clinical picture of acute haemorrhagic pancreatitis have been reported as incident to excessive sporulation of malarial parasites in the capillaries of the pancreas.
The Respiratory System.—There may be a slight bronchitis in ordinary types of malarial fever. In the cerebral types of perniciousness the breathing may be markedly altered—even of Cheyne-Stokes character.
A broncho-pneumonia which shows a periodicity and responds to quinine is often considered as a pernicious type of malaria.
The Skin.—Herpes labialis is a common manifestation of benign tertian and not rarely of malignant tertian infection. Urticaria may also be noted. The skin of malarial cachexia is earthy. Of course, one must always keep in mind the skin eruptions due to quinine administered in treatment, and of these urticaria is probably the most frequent.
The Nervous System.—In both the benign and malignant infections headache is a marked feature and is accentuated during the hot stage. There may be a “flighty” condition in the hot stage of benign tertian and quartan but in aestivo-autumnal infections there may be actual delirium.
Delirious and comatose states are prominent features of cerebral pernicious attacks. At times there may be an apathetic condition suggesting typhoid fever.
Almost any type of central nervous system disease may be simulated as the result of focal sporulation so that we have aphasic, epileptiform, hemiplegic, bulbar and other clinical types.
Some authors have recorded cases of multiple neuritis of malarial origin. Catto has recently examined the blood of a number of cases of multiple neuritis in Jamaica and has obtained negative malarial findings in every case. Neuralgic manifestations are features of latent malaria. Some loss of memory may be apparent after severe malaria.
The Special Senses.—Plugging of the retinal arteries may lead to blindness which may be either transient or lasting. The discs are grayish red instead of white as is the case with quinine amblyopia. The ringing in the ears is connected with the quinine treatment.
The Genito-urinary System.—In the cold stage there is apt to be frequent urination with increased secretion. Later on, there is a scanty febrile urine.
Albuminuria is rather common in aestivo-autumnal attacks and true nephritis occurs in about 2% of cases.
Plehn attaches great importance to the examination of the urine for urobilin as showing malarial infection when parasites cannot be found. The pigment particles in urinary sediment (Uriola) do not give reliable information. Bile in the urine is an important sign of bilious remittent fever.
Orchitis has been reported as a malarial complication.
The Liver and Spleen.—There is very little of importance to note in connection with the liver except tenderness and jaundice in bilious remittent fever. The spleen, however, is the organ in which centers the infection and its tenderness and enlargement are of special diagnostic value in malaria.
Even in comatose conditions pressure on the spleen may bring about indications of pain. The liability to rupture of the friable spleen of aestivo-autumnal infections is a real danger and the patient should not expose himself to injury.
The Blood Examination.—This is of prime value in the recognition of malaria, and one should examine both fresh blood preparations and stained films as well. More information is gotten from the stained films but we should also avail ourselves of the different characteristics of the 3 malarial species, which can be noted in a preparation made by taking up a small drop of exuding blood on a cover-glass and allowing it to drop on a slide and run out without any pressure on the cover-glass.
The crescents, when found, show a malignant tertian infection but there may also be present one of the benign parasites. A stained film should be used to identify malignant tertian young ring forms.
Pigmented rings are rarely observed in aestivo-autumnal fever, such parasites being caught in the capillaries as they enlarge to the stage where pigment begins to be present. Flagellated forms only develop in fresh blood preparations, 15 to 20 minutes after the taking of the blood. Of the greatest differential value is the swollen pale infected red cell of benign tertian, the normal red cell of quartan and the distorted shrunken red cell of malignant tertian.
Quinine administration may cause parasites to disappear from the peripheral circulation or it may so affect the parasite that the staining would indicate a degenerated parasite—the so-called quinine-affected parasite. It is difficult to diagnose the species of malaria from such a parasite.
Large mononuclears and transitionals containing phagocytized pigment (melaniferous leucocytes) are characteristic of malaria—the pigment however must be in the leucocyte and not free. There is a leucocytosis during the malarial paroxysm with a leucopenia and increase in the large mononuclears during the apyrexial period.
Among natives of India the large mononuclears and transitionals averaged 21% in the apyrexial stage of malaria while healthy natives rarely showed as much as a 10% count (Stott).
Some authorities have reported positive Wassermann reactions in serum of malarial patients taken during a paroxysm. All agree, however, that the serum of malarial patients at other times is negative.
DIAGNOSIS
In the diagnosis of malaria the special points to consider are: (1) presence of malarial parasites, (2) periodicity, (3) splenic enlargement, (4) response to quinine therapy, (5) the presence of melaniferous leucocytes and (6) a high large mononuclear percentage when leucopenia is present. In the examination for parasites one should not only consider the species of parasite present but, as well, the stage of development and the presence of the sexual forms.
In an intensive investigation Bass has shown that 55.09% of those showing parasites in the blood give a clinical history of malaria while 44.91% of those with parasites in the blood fail to be associated with clinical manifestations.
Blood platelets are the findings most frequently mistaken for malarial parasites in stained blood, and the vacuoles in fresh blood. Quartan and tertian periodicity is only found in malaria, but quotidian periodicity is a feature of a host of diseases.
There are very few tropical diseases which have not been mistaken for malaria and many of these have been considered as of malarial etiology before the discovery of the real cause.
Of the cosmopolitan diseases, typhoid fever, septic conditions, including malignant endocarditis, tuberculosis, influenza, pyelitis and even syphilis are to be considered in a diagnosis of malaria.
As regards tropical diseases, kala-azar, Malta fever, liver abscess, filariasis, trypanosomiasis, leprosy, relapsing fever and yellow fever are to be thought of in differential diagnosis.
As was noted under the discussion of the pernicious manifestations of malaria, scores of diseases may be simulated by the sporulation of the malarial parasite in certain organs or areas of organs. One should always keep in mind the possibility of pain in the appendix region or in the gall bladder area as connected with malaria if in the tropics. A polynuclear increase negatives malaria and indicates appendicitis or cholecystitis. Malarial pancreatitis has been referred to before.
With malarial cachexia we must in particular keep from mistaking it for hookworm disease or other secondary anaemias due to intestinal parasites.
Provocative Measures.—Kohlbrugge’s recommendation to have patients suspected of malaria climb mountains and drink copiously of cold water, in order to bring on a relapse, is of value in the diagnosis. (Effects of fatigue and refrigeration.) It must always be borne in mind that quinine causes the parasites to disappear from the peripheral circulation. It is interesting to note that small doses of quinine given over ten days or two weeks may make a latent case active. Other provocative agents are subcutaneous injections of adrenalin (the best), or anti-typhoid inoculations. Certain physical methods, as hot and cold douches or alternating the hot air chamber at 55°C. for 10 minutes, followed by a cold bath for 3 minutes have been recommended. After injection of adrenalin the presence of parasites in the blood is at its height at the end of an hour. Sunlight is a factor in relapse.
The laboratory diagnosis of malaria has already been fully gone into in the section on etiology and that on blood examination under the heading of symptoms in detail.
The evenly spread stained film undoubtedly gives more accurate information as to species and stage of cycle than any other method. Still one should always examine a fresh specimen and if the parasites are very scarce, a thick film preparation. The thick film methods of Ross, Ruge and James are given under the chapter on the blood in tropical diseases. During winter parasites tend to disappear from the circulation regardless of treatment.
PROGNOSIS
The prognosis in benign tertian and quartan is most favorable when proper treatment is instituted, as such infections are never fatal in first attacks. Not only may malignant tertian kill in a first attack but it leads rapidly to a cachexia while the cachexia following upon benign infections is more gradual.
It is the tendency to perniciousness which makes us dread malignant tertian as we can never be sure that a paroxysm may not develop cerebral or algid manifestations and these show a very high death rate, 25 to 50%, even when promptly treated.
As regards relapses quartan is the malarial fever which is most apt to show this feature and aestivo-autumnal the least. Deaderick gives the percentage of cases showing relapses in quartan, benign tertian and aestivo-autumnal as 65, 55 and 45.
The great importance of malaria is rather its invaliding tendency and by thus reducing the powers of resistance it makes the death rate from intercurrent diseases higher. Tropical malaria does not seem to affect the native as it does the European but the high death rate of infants among the natives is undoubtedly largely connected with this disease.
Statistics vary greatly as to the percentage of fatal cases in malaria. Certain figures from tropical countries give fatal results as occurring in from 2 to 10% of cases, while statistics from temperate climates show a death rate below 1%. The mortality from pernicious types of malaria is about 25%.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—There are three methods in the prevention of malaria, all of which may be combined, as was the case in the Canal Zone region of Panama. These are: (1) Destruction of anopheline mosquitoes; (2) protection of the individual from the bites of mosquitoes, and (3) quinine prophylaxis.
It may be stated that it is frequently advisable to carry on the mosquito warfare without regard to the question of the kind of mosquitoes destroyed. In general terms the malarial mosquito breeds in the suburbs of towns or in districts more distinctly rural, while the transmitter of the more dreaded yellow fever, prefers breeding places in the immediate vicinity of city houses.
Bentley has recently noted that, with improvement in agricultural methods and utilization of marshy lands, malaria tends to disappear as much from the physical improvement and thereby greater resistance of the people as from the destruction of mosquitoes by the draining of the swamps. The resulting greater prosperity makes better food and shelter obtainable.
1. Destruction of Mosquitoes.
Such measures may be directed either toward the larva or fully developed insect.
(a) Measures against larvae. When practicable permanent measures should be preferred to temporary ones and when agricultural development goes along with drainage of swamps the cost is repaid.
The doing away with mosquito breeding places may be accomplished by filling in pools or by making ditches with smooth sloping sides to carry away the water. These ditches require a great deal of attention to prevent their filling up with tropical vegetation and thereby adding to breeding places. Subsoil drainage with tiled drains is better. Care should be exercised that public works operations do not raise the level of the subsoil water.
Anophelines tend to breed in sluggishly moving streams or in stagnant pools especially where there is a luxuriant growth of weeds or grass, and are not apt to be found in rapidly flowing streams, hence the necessity for constant care of ditches and the like to prevent their becoming obstructed by vegetation or silt. When filling in or drainage is not practicable the method of oiling the surface of the pool with crude petroleum is to be recommended. One uses about ½ pint for every 100 square feet of surface and the process should be repeated every two weeks.
In places where oil is not effective, Barber recommends Paris green mixed with dust and so used as to form a scant surface deposit. Anopheline larvae, being surface feeders, ingest it and are killed. It does not affect Culex larvae. On account of its ease of transportation, and adaptability to weedy places where oil does not penetrate, Paris green dust will doubtless prove a valuable selective larvicide. Mayne and Jackson recommend cresol as the best larvicide. In 1 to 1,000,000 parts it is an effective larvicide, and even in 1 to 1,000,000,000 it is destructive to young larvae.
Mixtures of soft soap and petroleum are better than petroleum alone.
Winds are apt to blow away the surface coating of oil and it is difficult to oil the surface of a pool filled with grass. Wise recommends crude carbolic acid, using 1 ounce to 16 cubic feet of water.
In using any larvicide it is well to introduce it along the banks of water collections with a long-spout can and mix it thoroughly with a stiff reed broom.
There are many enemies of mosquito larvae, such as tadpoles, water-beetle larvae and various small fish such as “millions.”
Terni suggests the using of such fish as carp and tench which have a food value as well as a larvicidal one.
(b) Measures against the mosquito. The clearing away of grass and brush from around houses exposes the mosquitoes to the sun in which they cannot live long.
When inside the house they may be destroyed by sulphur fumigation, 1 or 2 pounds of sulphur for each 1000 cubic feet and with an exposure of two hours.
It is usually stated that mosquitoes may hibernate during winter following infection in the autumn and that cases of malaria in early Spring may be explained by their bites. Examination of hibernating mosquitoes for zygotes does not give strong proof to this view but such mosquitoes, becoming active with a rise in temperature, may bite gamete carriers in the house and thus spread malaria.
Pyrethrum powder, which is set on fire with a little alcohol, may be burned, using 2 pounds per 1000 cubic feet, and an exposure of four hours. This does not certainly kill the insect and the stupified mosquitoes should be swept up and burned.
Giemsa’s spray is now considered an excellent measure for killing mosquitoes in rooms. The composition is as follows: Pyrethrum tincture (20 parts powdered pyrethrum blossoms to 100 parts alcohol), 480 grams; odorless potash soap, 180 grams; glycerine, 240 grams. Before using it dilute with 20 times its own weight of water, and spray the walls of the room with a spray pump.
The use of a small square of wire gauze on a handle (fly swatter) to kill mosquitoes as they rest on a wall is of great value in keeping them down in a screened house.
2. Protection of the Individual.
The house should be thoroughly screened with copper-wire screens which should have 18 meshes to the inch. Mosquitoes can pass through a 15 mesh screen. Screen doors should always open outward and close automatically with spring hinges.
It is almost impossible to screen a ship’s hatches effectually. Then too the screening of fan intakes and ports interferes with free circulation of air, thus adding to the discomfort of the heat of the tropics.
As malarial mosquitoes bite chiefly toward evening one should not expose himself after sunset.
Houses should be far removed from native habitations.
Mosquitoes prefer the lower floors of a house so that the upper stories are preferable for sleeping.
Mosquito nets at night, with protection by veils for the face or coverings for the hands and ankles, when going out of the house, are well-known measures.
It is stated that Emin Pascha always carried a mosquito net and never suffered from malaria. He thought that the cause of malaria was too large to go through the net.
Even when mosquito nets are intact and well tucked in there is the weak point that a person sleeping on a narrow cot is apt to put his arm or leg against the net, in which case the mosquitoes readily bite the skin presenting at the open spaces.
Oil of citronella is often used to keep away mosquitoes.
Brooks recommends Neal’s method. In this daub a solution of 1 ounce Epsom salts in 10 ounces of water on the exposed parts and allow to dry.
Application of certain pine products used as mange cures will keep away mosquitoes.
3. Quinine Prophylaxis.
The ease of application of quinine prophylaxis, as compared with the more permanent methods of mosquito destruction and screening, appeals to the sanitarian, especially in the tropics.
It is just as easy to give quinine to a man in the tropics as it is in temperate climates, but when one considers the propositions of draining tropical swamps and shutting off circulation of air on a torrid night with fine wire gauze in the windows and closely woven mosquito nets around the bed, the question is decidedly different. In consequence, the tendency is for the average man to despair of accomplishing anything in the way of mosquito destruction and screening and to seize eagerly on the inferior alternative, that of quinine prophylaxis.
Ronald Ross presents this matter concisely and to the point when he states that it is not a good policy to substitute a measure which does not exclude infection, but is merely extirpative in some cases, for positive prevention. From this it will be seen that unless it is clearly recognized that quinine prophylaxis may in some cases extirpate, but does not prevent, there might be a tendency to adopt this measure and neglect the two proper ones.
As regards the relative merits of quinine prophylaxis and protection from mosquitoes Celli gives the following figures:
Treatment Infected Mosquito protection plus quinine prophylaxis 1.76 % Mosquito protection alone 2.5 % Quinine prophylaxis alone 20.0 % No protection at all 33.0 %
With quinine prophylaxis, there is the possibility of producing an immunity to quinine on the part of the parasites which have been introduced by infected mosquitoes and held in check by the prophylactic but not curative dose of quinine. Later on when the quinine prophylaxis is discontinued the parasites begin to multiply vigorously and seem to possess an immunity to quinine.
As an instance of this, 398 marines served in 1906 for about one month on the Isthmus of Panama during which time they were given 9 grains of quinine daily as a prophylactic.
During this month there was only an occasional case of malaria among the men. At the end of the month 298 of the original 398 returned aboard ship and sailed for the North. Two days later 20 cases of malaria developed, followed the next day by 53 and the day following that by 45. The medical officer then resumed 10-grain prophylactic doses for those not down with malaria but notwithstanding this there were 215 acute malarial paroxysms, some of them of pernicious type, among the 298 men.
It was noted that these men did not respond satisfactorily to quinine treatment even when the drug was administered intramuscularly.
Of the greatest value have been the observations of Stott. Using native Indian troops he gave one group (3931) prophylactic quinine while the other (3906) did not take quinine prophylactically. He continued this experiment one year giving 15 grains 3 times weekly for five months, and 10 grains 3 times weekly for the remaining seven months. Those taking quinine gave 170 primary admissions while those not taking it gave 179 (43.2 per thousand strength for the former as against 45.8 per thousand for those not taking quinine prophylaxis). Further observations were that those taking quinine prophylaxis showed a greater tendency to relapse, had somewhat longer fever, and required more quinine for treatment.
Linnell states that he used quinine prophylaxis among 2000 coolies for a year, giving 5 grains or more daily with most discouraging results. It seemed to act as a slow poison and did not protect.
Quinine Immunity.—Bignami thinks that malarial relapses may be connected with insufficient initial treatment so that quinine-resisting forms survive and later, when some factor lowers the patient’s resistance, active multiplication of parasites, which are not readily destroyed by quinine, follows.
While quinine prophylaxis may not be desirable on board ship, where one is in a position to readily recognize and treat the onset of malaria and to more or less efficiently carry out mosquito protection methods, or in a wealthy seaport, where sufficient interest in and funds for draining and screening exist, yet on military expeditions or exploring trips in tropical or subtropical countries it is the only practical method of keeping a force efficient.
Of course, one should also utilize mosquito nets as assisting in protection from malaria, and as effective for yellow fever, dengue and filariasis.
Methods of Prophylaxis.—There are innumerable methods of carrying out quinine prophylaxis among which may be noted.
(a) Celli’s method. In this there is given 3 grains of quinine each morning and 3 grains each night. Taken in this way Celli thinks that harmful effects from quinine are avoided, that quinine immunity does not occur and that there is no danger from quinine haemoglobinuria. For children he recommends the tannate in chocolate tablets.
(b) In 1909 Bertrand and other members of a French Commission recommended two consecutive doses of 5 to 10 grains every seventh and eighth day for benign infections and two consecutive prophylactic doses of 10 to 15 grains every third and fourth days where malignant tertian was prevalent.
(c) Ziemann gives 15 grains every fourth day with the idea that the quinine is entirely eliminated in four days. Nocht gives about 12 grains on two succeeding days of each week in divided doses of 2 or 3 grains instead of the entire amount in one dose.
Koch gave 15 grains on tenth and eleventh days.
(d) Castellani’s method of 5 grains daily and a double dose once a week is the one I recommend.
Sterilization of Carriers.—In addition to quinine prophylaxis for those not infected we also have quinine disinfection for native or other carriers of malaria. For these infected persons Koch recommends 15 grains on two to three successive days of each week, the course to be continued for three months. This plan of extirpation of the parasites of malarial carriers is of great practical application. Gill uses 10 grains of quinine daily for six months after discharge from hospital. The effect of tartar emetic on malarial gametes may prove of value.
=Treatment.=—Cinchona bark was first introduced into Europe in 1640 and has its name from Countess Chinchon, wife of the Peruvian Viceroy, who was cured of a fever by this bark in 1638.
Much of our knowledge of the therapeutics of cinchona bark is due to Torti. In giving the drug he used a large dose the first day and the same for the subsequent two days. After that he administered smaller doses for a week and then still smaller doses for two or three weeks. Quinine was not introduced until 1820.
At present quinine or some salt of the alkaloid is used in malaria instead of preparations of cinchona bark.
Toxic Effects of Quinine.—The most important untoward manifestations of cinchonism are the very common scarlatiniform, eczematous or urticarial rashes, gastric disturbances and vertigo. Impairment of vision may be brought about by quinine and quinine haemoglobinuria is a recognized possibility. In quinine amblyopia the pupils do not react to light and the optic disc is very pale, thus distinguishing the impairment of vision due to the plugging of the retinal vessels by the malarial parasite, in which condition the pupils do react to light and the disc is a grayish red.
Quinine Idiosyncrasy.—Fortunately the taking of quinine is well borne by the great majority of persons but in exceptional cases we may have developing, even after doses as small as one grain, of (a) severe nausea vomiting or diarrhoea, (b) various skin eruptions, usually of a scarlatiniform or urticarial type, (c) marked ringing in the ears, dizziness or deafness, (d) impairment of vision, (e) dyspnoea and (f) malarial haemoglobinuria. To determine an idiosyncrasy make a scratch on the flexor surface of the forearm and apply a drop of a 1 to 10 solution of quinine. Oedema with a wide zone of erythema in about 5 minutes shows idiosyncrasy. A control with normal saline should be made. It is well to make this skin test before giving quinine intravenously. For desensitization we give 1/10 grain of quinine combined with 5 grains of bicarbonate of soda and in about 1½ hours we give 1 grain with 5 grains of bicarbonate of soda.
The cheapest and most generally obtainable salt is the sulphate. It is soluble in 720 parts of water and contains 74% of alkaloid. The opinion now prevails that this is one of the less desirable of forms for the administration of quinine. It is frequently obtained in pill or tablet form and it must not be forgotten that such preparations may be almost stone-like and pass through the alimentary tract without absorption. If used it is best to give it in acid solution made by dissolving 5 grains of quinine sulphate in one teaspoonful (1 dram) of water with one drop of concentrated hydrochloric acid.
Dosage of Quinine.—The ordinary full dose of quinine for an adult is 10 grains repeated three times in a day or 30 grains daily. Some authorities recommend 15 grains three times daily (45 grains) at the commencement of treatment and such dosage seems to be just as efficient as the larger dose of 60 grains in a day. In cinchonism we have ringing in the ears, fullness in the head, deafness and dizziness. For children Bass recommends 1/20 of the adult dose for each year of age so that a child of 5 years age would receive ¼ of the adult dose. Beyond 15 years of age the dose is that of an adult.
There now seems to be a tendency to use the alkaloid itself instead of its salts, it having been found that the alkaloid and its very insoluble tannate are absorbed from the digestive tract equally as well as the soluble salts. Quinine is almost insoluble in water (1-1560) and hence has less bitter taste than the soluble salts. It is also less haemolytic so that it may be used with greater safety where blackwater fever is feared.
Euquinine or ethylcarbonate of quinine contains 81% quinine, and is only soluble in 1-12,000 parts of water, hence its comparative tastelessness. It is expensive.
Quinine tannate contains only about 30% of quinine and is practically insoluble in water. It is often given to children in chocolate tablet form. It can often be taken by those who suffer disagreeable effects from other salts. The dose should be 2½ times that of quinine sulphate.
Until recently the bimuriate (72% of alkaloid and soluble in 1 part of water) or the chlorhydrosulphate (74% of alkaloid and soluble in 2 parts of water) have been considered the most desirable salts for hypodermic injections or oral administration. At present, owing to its extensive use in local anaesthesia and incident availability, bimuriate of quinine and urea is to be recommended for intramuscular use. It contains 60% of quinine and is soluble in an equal amount of water.
It has been found to have a slightly greater tendency to produce amblyopia than other quinine salts and should not be used intravenously.
In a very important series of experiments on prisoners, MacGilchrist found that hydroquinine (a synthetic product of quinine) was about 20% more efficient than quinine. Cinchonine was about the same as quinine while quinidine was about one-half as potent as quinine.
Acton has praised the value of cinchona febrifuge (the combined alkaloids of cinchona) given in daily doses of 21 grains for ten days.
Methods of Administration
By Mouth.—This is the usual method and is the one to be preferred in all cases where other methods of administration are not necessitated.
Golgi believes that quinine is most effective at the time of liberation of merozoites from the bursting merocytes, hence he administered quinine four hours before the attack with a view to having it in its greatest concentration in the blood at such times. When given intravenously the full concentration is obtained in a very few minutes but with other methods this is a matter of great variation.
It is usual to give the quinine in capsules or cachets, the pills and tablets being often so hard that they do not dissolve in the alimentary tract.
The method usually in vogue in military services is to give quinine sulphate in acid solution. This method is trying to the stomach.
By Subcutaneous Injections.—This method is liable to be followed by necrosis and abscess formation or fibrous indurations. Quinine and urea hydrochloride is preferable either for subcutaneous or intramuscular injection.
Cohen holds that quinine and urea hydrochloride controls malarial infection more rapidly and efficaciously than any other salt of quinine when given intramuscularly. In order to prevent tetanus or other infections he is very careful about asepsis. He recommends that a 10 to 15-grain dose be injected every day for a week, then once a week for a month, then once every two weeks for another month. He considers a 33% solution as best, thus one could give 10 grains in the contents of an all-glass 2 cc. syringe.
James has recommended very dilute solutions for subcutaneous injections (1-150). There are practical objections to this method. It is usual to give about 1 gram (15 grains) of a soluble salt in 10 cc. of water. The present view is that subcutaneous injections deserve condemnation.
Intramuscular Injections.—It is now recognized that when quinine is not well borne when given by mouth the two modes of administration to be followed are either by intramuscular injection or introduction of the drug into a vein. For intramuscular use we dissolve a soluble salt of quinine, as the bimuriate or chlorhydrosulphate, in distilled water or sterile saline. A 50% solution is commonly used and from 6 to 10 grains of quinine is injected into the gluteal muscles of one side about 3 inches below the iliac crest. Repeat the injection on the other side. Repeat this daily dose of 12 to 20 grains for 3 or 4 days; then give quinine by mouth.
The solution should be autoclaved before use and the skin at the site of injection painted with iodine. Dudgeon has called attention to the constant production of oedema and necrosis in the area of the injection. This tissue necrosis occurs immediately and persists for a long time. If the injection is made in the neighborhood of an important nerve, neuritis may ensue. Repeated injections should not be given in the same area.
Of course in the use of quinine salts through the medium of the hypodermic needle everything must be sterile.
Intravenous Injections.—Bass and many others think that when quinine cannot be administered by mouth it should be given intravenously. Not only is there the objection of inflammatory reactions or necrosis when the drug is given subcutaneously or intramuscularly but the absorption of the drug is so slow that the patient may die before we obtain the desired effect. Ross condemns the subcutaneous method and recognizes the advantages of the intravenous method over the intramuscular one when rapidity of action is desirable.
In giving quinine intravenously Bass thinks that 10 grains at one time is sufficient and that a 20-grain dose is not without danger.
He does not think it necessary to give more than 30 grains daily in this way. Intravenous quinine seems to be entirely eliminated within twenty-four hours and most of it within twelve hours.
When used in cerebral malaria he repeats the 10 grains intravenously in eight hours if the drug cannot then be given by mouth. Bass thinks that theoretically amyl nitrite might relax the cerebral capillaries which are obstructed by parasite-infected red cells and thus enable the quinine in the circulation to reach such cells.
The best known method of administering quinine intravenously is that of Bacelli. In this method 1 gram (15 grains) of a soluble salt of quinine is given in 10 cc. of water.
MacGilchrist has shown experimentally that such a strength of quinine (1-10) will coagulate blood serum.
In my opinion this is a dangerous method if the injection is made rapidly. There is no doubt as to the necessity for using the intravenous channel in cerebral or algid types of perniciousness when intramuscular injections do not give results. The generally accepted method is to use a salvarsan technique with a dilute solution of quinine, giving 1 gram (15 grains) of some soluble salt of quinine in 250 cc. salt solution. Such injections should be given cautiously. Quinine hydrochloride, which is soluble in 40 parts of water, is the salt usually recommended. MacGilchrist considers the very soluble acid salts as haemolytic and prefers to give quinine base—3 pints of a solution of the alkaloid, containing about 12 grains.
McLean has used concentrated solutions of quinine intravenously several hundred times in cases of malaria (6 being blackwater fever ones) without any untoward results. He autoclaves his 10-grain solution of hydrochlor-sulphate in 10 cc. of sterile water for twenty minutes at 15 pounds, and injects it slowly into an arm vein, allowing about two minutes for the injection. The patients complain of a slight cough and hot feeling in the lungs with a succeeding dizziness which rapidly disappears. He is opposed to intramuscular injections and found intravenous ones diluted 1 to 250 often to cause shock and collapse.
Rectal Administration.—Some authorities recommend the administration per rectum of a soluble salt of quinine in about 3 times the usual dose by mouth or hypodermically. It is considered applicable in cases where there is marked vomiting. It certainly is the least satisfactory way of giving quinine.
Dosage and Length of Treatment.—In Panama the standard preliminary treatment is to give from 3 to 5 grains of calomel followed by 1 or 2 ounces of 50% magnesium sulphate.
Fayrer holds that a torpid liver interferes with the efficient action of quinine, hence the value of calomel and salts. I prefer to give 2 or 3 grains of calomel, in divided doses, followed by sodium phosphate, 2 drams, every two hours, for three or four doses.
Standard Method.—The National Malaria Committee of the United States recommends the following treatment: Give 30 grains of quinine daily in three 10-grain doses. Keep this up for 4 days and follow by 10 grains every night for 8 weeks. Where the infection does not present acute symptoms give the 10 grains daily for 8 weeks.
Canal Zone Treatment.—So soon as the diagnosis is made give 15 grains of quinine 3 times daily (45 grains in twenty-four hours) and continue such treatment for a week or until the temperature has been normal for five or six days. Then give 10 grains 3 times daily for ten or twelve days.
It is considered that by employing such thorough treatment from the beginning the tendency to latency or relapse is prevented—in other words the disease is really cured. It is interesting to note that Torti recommended large single doses at the commencement of treatment.
Espach has noted that he had frequent relapses in many cases treated by this method. In my opinion the Canal Zone treatment should be followed by 10 grain doses daily for 8 weeks.
Tonics of iron, arsenic and strychnine are valuable in treating the anaemia, but it is not advisable to add small doses of quinine to such tonic mixture.
Repeated Small Doses.—In Nocht’s method we give the quinine in small doses repeated several times in the day, as 3 or 4 grains given 5 or 6 times daily. Such treatment is thought advisable when there is a tendency to haemoglobinuria or when giving quinine to pregnant women.
In giving the small doses one should see that they are given during the night as well as the day.
Quinine and Pregnancy.—There is frequently hesitancy in giving quinine to a pregnant woman but unless the malaria is controlled the patient will be apt to abort. Potassium bromide is thought to control the ecbolic influences of quinine.
Clark states that the experience at Ancon Hospital would indicate that quinine can be given with impunity to pregnant women. In malarial subjects quinine after parturition is of value not only in controlling a fever due to malaria but it also favors involution and aids in the healing of perineal tears. The quinine also is beneficial in improving the quality of the mother’s milk and does no harm to the child.
Manson’s Method.—In a benign malarial infection Manson prefers to wait until the hot stage has been passed and the patient is beginning to perspire, this idea being that the headache and other symptoms are aggravated and that very little advantage is gained by treatment during the early part of the paroxysm. He gives 10 grains at the onset of the sweating stage and afterward 5 grains, 3 or 4 times daily, for the following week. He then gives a daily tonic containing arsenic and iron, with a quinine treatment every seventh day for about two months.
For regularity he advises the quinine treatment on Sunday giving a dose of salts in the morning followed by three 5-grain doses during the day.
Manson notes the danger of large doses of quinine as producing not only serious disturbances of sight and hearing but pronounced cardiac depression as well.
There are many who speak highly of Warburg’s tincture in treatment. It is both laxative and sudorific. The dose is ½ ounce (15 cc.) which contains about 5 grains of quinine sulphate and 4 grains of extract of aloes. As a rule it is better to give the quinine and the laxative separately.
More recently the tendency has been to give large doses of quinine, not only for its greater curative value but, as well, for the prevention of relapses. Craig, however, states that in his experience with aestivo-autumnal infections he has yet to see a single case, in which treatment was promptly instituted, that did not recover with a daily treatment of 30 grains.
Koch’s Method.—Koch recommended 15 grains each day for a week, then three days without quinine. Then three days with 15-grain doses each day. Then one week without quinine, followed by three days of treatment. This plan of a weekly interval followed by three days of treatment is continued until not fewer than 30 15-grain doses are given over nine or ten weeks.
Drugs Other than Quinine.—Salvarsan and neosalvarsan have been extensively used and with some success in benign infections but without material effect in malignant tertian ones.
Intermittent Treatment.—There are those who consider a treatment in which days of quinine administration are followed by days without quinine as equally efficient and less trying on the patient. Some of the experiences of Stephens and his colleagues indicated that 45 grains on two consecutive days of each week and continued for 8 weeks gave better results than 30 grains daily over such a period. In their experiments a dosage above 45 grains in a day did not seem any more efficient than 45 grains, so that this may well be considered as a maximum dose. On the whole however there seems to be a greater tendency to relapse following an intermittent treatment and Acton, as a result of his comparison of intermittent and continuous methods, deprecates the intermittent one.
Some have thought that salvarsan aided the specific action of quinine.
Many physicians recommend arsenic in the form of Fowler’s solution or as sodium cacodylate. It is most useful in chronic cases. Some preparation of iron is, of course, indicated in malarial anaemias.
It has been claimed that radium and X-ray treatment, when directed to the spleen, assist the action of quinine.
Methylene blue, next to quinine, has been considered as the most valuable drug. It is given in 2-grain doses every four hours. It is also given intravenously.
The form of methylene blue to use is that labelled “Medicinal.”
It is often stated that the opium fiends of the tropics are immune to malaria and some physicians have claimed antiperiodic properties for the drug. Dover’s powder is lauded by some as of value in symptomatic treatment.
Surveyor has recommended picric acid in the treatment of malaria in doses of 2 grains two or three times daily.
Recently hectine, a remedy somewhat similar to the cacodylates, has been strongly recommended by the French. It is given intramuscularly in 2-grain doses. It is said to be valuable when there is a leucopenia as it has a tonic action. It has been recommended to combine this treatment with quinine.
It is said to be a good substitute for quinine in blackwater fever.
Rogers has recently noted the value of tartar emetic injections in eradicating the sexual parasites of carriers.
After rather extended trial of this drug for the above purpose and as a method of treating ordinary infections the general opinion is against its value.
General and Symptomatic Treatment.—During the course of the fever the patient should remain in bed and given only broths. In the intermissions of the benign forms one may allow a more generous diet. It is important that the patient be not allowed to become constipated and as a laxative one grain of calomel in divided doses followed by effervescing phosphate of soda is very satisfactory.
For the nausea sips of an ice-cold alkaline mineral water or cracked ice will generally prove effective. In more refractory cases spirits of chloroform or even a hypodermic of morphine may be necessary. Counterirritation to the epigastrium is often a help. Phenacetine may be given for the headache although ice water compresses are generally sufficient. In algid states hot water bottles should be applied to the body. During convalescence excesses in food or drink should be avoided as well as fatigue or exposure to wet or cold.
II. BLACKWATER FEVER
DEFINITION AND SYNONYMS
=Definition.=—Blackwater fever is a disease of disputed etiology but recently there has seemed to be rather general agreement that it is connected with repeated attacks of malaria. It is prone to affect the old European residents of parts of the tropics where malignant tertian is rampant.
On the basis of lowered integrity of the red cells, by reason of repeated attacks of malaria, we may have extensive lysis of the red cells following the administration of a dose of quinine or as the result of refrigeration, excessive exposure to the sun or great fatigue.
Clinically we have a prostrating chill of asthenic type associated with early jaundice and the passage of porter-colored urine—haemoglobinuria.
=Synonyms.=—Haemoglobinuric Fever, Bilious Haemoglobinuric Fever, Haemorrhagic Malarial Fever.
French: Fièvre Bilieuse Hemoglobinurique. German: Schwarzwasserfieber.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—There is no reasonable doubt that the explanation of the fact that blackwater fever was first brought to the attention of the medical world, by Lebeau and other French naval surgeons, in Madagascar, in 1850-1853, was due to the confusion of this disease with the bilious remittent type of pernicious malaria as well as with yellow fever. Even after the clinical picture was well recognized, disputes as to the nature of the coloring matter of the characteristic urine were frequent, some considering that the dark color, which we now know to be due to haemoglobinuria, was due to haematuria or that the color was due to bile. Blackwater fever must have been the condition referred to in medical literature of the period, 1850 to 1870, under the names “Fièvre bilieuse haematurique,” “haemorrhagic malarial fever” and “febris remittens haemorrhagica.”
It was first described in the U. S. by Cummings of Louisiana in 1859. Other American physicians during the next ten years, described the disease from various other Southern states.
Veretas noted the presence of the disease in Greece, in 1858.
It is rather remarkable that the disease was not noted by so keen an observer as Torti, if it existed in his time, and Manson states that it is strange that it should not have been recognized in India if it had existed there prior to recent times. Some think that its introduction into Africa has been of recent occurrence. There are two explanations of the recent greater prominence of the disease in Africa and other tropical areas, where malignant malaria prevails extensively, which are (1) that there has been a great influx of susceptible Europeans into such areas during the past twenty or thirty years and (2) that the more frequent and excessive dosing of malarial patients with quinine is responsible.
=Geographical Distribution.=—It is in tropical Africa that the disease is of prime importance as a cause of death and invaliding. Here it prevails chiefly in West, Central and East Africa from about 12° N. to 12° S. latitude. It is less frequent in Northern Africa although a considerable number of cases have been reported from Algeria. It is unknown in Egypt, a country where malaria is very rare in Europeans.
In India it occurs in several districts and Stephens states that in the Duars (Bengal) he saw more cases in a fortnight than he had seen in the same time in Africa. In Europe it occurs chiefly in Southern Italy, Sicily, Sardinia and Greece. Blackwater fever was frequently noted among the British forces in Macedonia and Palestine during the World War.
It is common in Central America and Northern South America, especially in the regions of the Amazon basin, in Brazil.
In the U. S. it is chiefly found in the most malarious sections of Arkansas, Mississippi, Louisiana, Texas, Alabama, Georgia, Florida and South Carolina. It would seem that it is becoming more rare in the Southern States.
As a result of malarial prophylaxis among the Americans working in the Panama Canal Zone it has almost disappeared among them although still common among the white Europeans in the same region who neglect quinine prophylaxis and mosquito protection.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—There seem to be cases where from very heavy infection with the malignant tertian parasite, as from 12 to 20% of the red cells, one can expect the appearance of a more or less dark urine, the color of which is due to haemoglobinuria. Such cases give support to the old view that haemoglobinuric fever was simply a type of pernicious malaria.
Brem has proposed for such cases the designation, pernicious malarial fever with haemoglobinuria.
The idea as to etiology which now seems most generally accepted is that blackwater fever occurs almost solely in those who have resided for considerable periods of time in districts where malignant tertian malaria is very prevalent and intense and who have repeatedly suffered from such malarial attacks. Rarely blackwater fever may be connected with benign tertian infections or exceptionally with quartan ones. As a result of the damage done the patient by the malarial attacks there is a tendency on the part of his red cells to haemolysis which may be due to the production of a hypothetical autolysin or to anaphylactic sensitizations, as has been suggested recently.
Malaria is the predisposing cause and the exciting cause may be any of a number of different factors capable of lowering body resistance such as the occurrence of another malarial attack, the administration of quinine, particularly of the acid salts of quinine in rather large doses, refrigeration, as brought about by one’s clothes becoming wet and then later subjected to the chilling influence of a sea breeze, to excessive fatigue or dietetic or alcoholic excesses.
Quinine administration, particularly if associated with refrigeration, is the most common exciting factor.
As regards the association of malaria and blackwater fever Stephens, in a study of 390 cases of blackwater, found that 73% of the cases showed malarial parasites on the day preceding the haemoglobinuria, 47.5% on the day of the attack and 23% on the day following the appearance of the dark urine. Other workers give higher figures as 95, 70 and 20%.
Where one utilizes the methods of examining for increased percentage of large mononuclears or for melaniferous leucocytes, in those cases not showing malarial parasites, the percentage of evidence of malaria is greatly increased. It is necessary to understand that a small percentage of cases diagnosed as blackwater fever do not show evidences of malaria at autopsy and cases are recorded where blackwater has attacked persons who had never had malarial fever, such instances, however being exceptional.
The Quinine Theory.—This idea as to the causation of blackwater fever first originated with Veretas, in Greece, in 1858. Later Tomaselli supported this view in Italy and more recently it was advocated by Koch. Just as in connection with the influence of Koch’s great prestige much harm was done in prophylaxis against bovine tuberculosis so in this matter of quinine in the causing of blackwater the influence was unfortunate because many persons with severe malaria now refuse to take the specific quinine for fear of bringing on haemoglobinuria.
It may be stated that quinine alone, even in doses which are capable of producing profound toxic effects such as disturbances of sight and hearing, weak heart and collapse does not, other than exceptionally, cause haemoglobinuria. It has even been stated that quinine base and quinine tannate tend to prevent haemolysis, haemoglobinaemia and haemoglobinuria. Blackwater fever may develop without the previous administration of quinine.
_Theory as to Acidosis with a Damaged Liver Plus Malaria and Acid Salts of Quinine._
MacGilchrist has recently advanced the idea that blackwater fever is brought about by an acidosis in one with a damaged liver plus malaria and the administration of acid salts of quinine. He thinks that one can safely give the quinine when alkalis are being given and that quinine base is protective against haemolysis.
Theory as to Its being Caused by a Piroplasm.
Sambon has thought by reason of the clinical resemblance of blackwater to certain haemoglobinuric diseases in cattle, dogs and sheep that such a cause might be operative. These parasites of the red cells are easily discernible in the animal infections but have never been seen in blackwater fever.
The Chlamydozoal Hypothesis.
Leishman has recently noted appearances in the large mononuclear cells of the blood of blackwater patients of certain cell inclusions which he thought to be of chlamydozoal nature and that these chlamydozoa might be etiological factors. Such appearances may not only be absent in marked cases of blackwater but may be seen in conditions other than blackwater fever.
=Epidemiology.=—There seems to be a consensus of opinion that when malaria is kept in check by proper and persistent quinine prophylaxis or by other antimalarial measures blackwater fever becomes mild in character or even nonexistent. It is those who are careless about quinine prophylaxis or those who expose themselves to depressing influences as cold, wet, excessive fatigue or alcoholic debauches in whom blackwater shows itself.
Overexertion leading to fatigue and chilling seem to be the most common exciting factors. Those in bad health from disease or lack of proper diet seem more susceptible. A peculiar feature of the disease is that it may not be present in a district for a number of years and then assume almost epidemic proportions. Europeans are usually exempt from attacks during their first year in endemic tropical areas. Dudgeon obtained a malarial history in every one of a hundred cases observed by him in the Balkans.
PATHOLOGY AND MORBID ANATOMY
As a result of the excessive destruction of red cells the liver cannot convert the great amount of haemoglobin outpouring into bile pigment so that haemoglobinaemia and haemoglobinuria result. It has been estimated by Ponfick that if ⅙ of the red cells are destroyed the liver is unable to dispose of the liberated haemoglobin and haemoglobinuria results. A damaged liver would be less competent. Various discussions as to autolysins and complement content of serum have arisen.
Dudgeon has demonstrated active haemolysins in the tissues and urine of blackwater fever cases which bodies he was unable to note in other conditions including malaria. There was no evidence of increased fragility of the red cells. There was no evidence of auto-haemolysis. Bile pigment in the plasma occurred in most of the cases which ended fatally.
As a rule we have the pathological findings which go with malaria. As peculiarities of blackwater noted by Whipple and others may be mentioned congestion of the kidneys with purple-colored pyramids. In the spleen the Malpighian bodies are prominent and sharply outlined. Very striking are the necroses of the Malpighian corpuscles of the spleen and focal necroses of the liver. Whipple considers that this speaks for a powerful circulating toxin in blackwater fever which is not present in malaria.
The liver cells in the area of the central veins show the most marked destruction. The myocardium shows fatty change and the fat lipoid content of the adrenal is reduced.
The anuria is thought to be mechanical and due to the plugging up of the tubules by haemoglobin casts.
The urine shows a reddish to black color and has a sediment made up of granular débris with haematoidin crystals and only rarely a red cell. It is not a haematuria.
The absorption bands of methaemoglobin are usually noted spectroscopically.
Urobilin and albumin are present in large quantities.
SYMPTOMATOLOGY
=A Typical Case.=—In a person who has lived in an intensely malarious region for one or two years or even long after he has left such districts and who has had several malarial attacks, there comes on what is considered as another malarial chill, which may or may not definitely be connected with some resistance-lowering influence, as exposure to tropical sun or rain, or indulgence in dietary or other excesses, or following in one to six hours the accustomed dose of quinine. This chill, however, is more prostrating than those formerly experienced and upon passing his urine the patient notes its reddish to black coffee color and himself makes the diagnosis of blackwater fever. The attack comes on suddenly with a very severe chill, marked prostration and pain over the region of the kidneys. The temperature in a typical case rapidly goes up to 104° to 105°F.
Rather profuse sweating accompanies the fall of the fever and the patient is markedly debilitated after the subsidence of the fever. There may be a recurrence of the paroxysm the following day. The fever course, however, may be more or less continuous or remittent. In other words it tends to be irregular and atypical.
Nausea and bilious vomiting come on early with epigastric distress. Almost as pathognomonic as the haemoglobinuria is the early and intense jaundice. This comes on within a few hours or almost simultaneously with the haemoglobinuria and usually lasts for two or three days after the haemoglobinuria and fever have ceased. Itching of the skin of this jaundice is not noticeable.
The spleen and liver are enlarged and tender. Albuminuria comes on with the haemoglobinuria and shows from 1/10 to 4/10 of 1% of albumen by weight.
The pulse is rapid, 110 to 120, from the first but soon becomes feeble and of low tension. In severe cases the very rapid almost thready pulse, with pallor and cold extremities, may resemble a severe haemorrhage. Epistaxis is not uncommon. A very unfavorable symptom seems to be hiccough. Another frequent cause of death and the one against which we chiefly direct our therapeutic measures is anuria with subsequent uraemic symptoms, such as coma and convulsions. At times a nephritis may develop in the course of a blackwater attack and the case subsequently run as one of severe nephritis.
Very striking is the rapidly developing anaemia, some cases showing a loss of two million red cells in twenty-four hours.
The mind is usually clear throughout an attack, the patient showing restlessness and marked anxiety.
In mild cases the fever course and haemoglobinuria is over within twenty-four hours leaving the patient far more prostrated than would a malarial paroxysm. In severe cases, however, the fever runs a remittent course over several days, with more marked haemoglobinuria and jaundice.
There may be cases which only show haemoglobinuria. These apyretic cases have been considered by some as quinine haemoglobinuria.
Symptoms in Detail
Fever Course.—This resembles that of a malarial paroxysm and may be intermittent in character or last several days as a remittent fever. The rigor which accompanies the febrile rise is intense.
The Liver and Spleen.—As a result of the marked blood destruction the liver is unable to dispose of the haemoglobin outpouring and icterus, which usually comes on in a few hours and is intense, is almost constant together with epigastric distress, bilious vomiting and tenderness and slight enlargement of the liver. The spleen is also somewhat enlarged and quite tender.
The Circulatory System.—At first the pulse is rapid with tension but soon it becomes weak, compressible and of low tension. In severe cases it may have a rate of 150 or more or even become thready.
The Genito-urinary System.—The dark colored urine is pathognomonic of the disease and gives it its name. The reddish to almost black color is due to haemoglobin and not to bile. Bile pigments do not appear in the urine. There is but rarely a red cell to be found in the granular débris with occasional haematoidin crystals which forms the urinary sediment, hence it is haemoglobinuria and not haematuria.
The urine resists decomposition for a long time. Albumin is present in large amount and comes on with the onset of haemoglobinuria. Casts are abundant and urobilinuria is marked. As a result of the blocking up of the renal tubules with haemoglobin casts pain over the loins and anuria may occur. There may be vesical tenesmus.
The Blood.—Cases have been reported where as many as 2,000,000 red cells have been destroyed within twenty-four hours, so that rapid and marked anaemia characterizes the disease. The blood is thin and the serum tinged. The degenerative changes of the red cells are not as commonly seen as one would expect but this is probably due to the fact that degenerated cells are first destroyed in the excessive haemolysis. Hb percentage reduction generally parallels the reduction in red cells. Melaniferous leucocytes may be found and during the leucopenia, which follows the paroxysm, the large mononuclears and transitionals may be increased to 20%. There is a reduction in the alkalinity and coagulability of the blood.
DIAGNOSIS
=Clinical Diagnosis.=—An unusually asthenic prostrating paroxysm, similar to that of a malarial chill, but with more intense rigor, during which haemoglobinuria, early jaundice and marked bilious vomiting are features, makes for a diagnosis of blackwater fever.
The two diseases which are most likely to be confused with blackwater fever are yellow fever and bilious remittent malarial fever.
In infectious jaundice the jaundice does not appear for 48 to 72 hours, the pulse is slow, there is no haemoglobinuria, although there may be a haematuria, and we have a polynuclear leucocytosis.
A case of paroxysmal haemoglobinuria occurring in a blackwater district would be impossible to differentiate from a very mild case of blackwater fever. Chlorate of potash or carbolic-acid poisoning, or snake bite, or severe burns, may produce haemoglobinuria.
-----------+-------------------+-------------------+-------------------- | Blackwater fever | Yellow fever | Bilious remittent -----------+-------------------+-------------------+-------------------- Onset |Sudden but asthenic|Sudden but asthenic|Comes on more | with marked | for two or | slowly. | rigor. | three days. | -----------+-------------------+-------------------+-------------------- Urine |Haemoglobinuria. |No blood in urine |Bile in urine. | Pink foam to | before 3d or 4th | Yellow froth on | urine. Albuminuria| day and then | shaking urine. | from first day. | haematuria. | Albuminuria | | Albumin from 2d | slight and | | day. | not common. -----------+-------------------+-------------------+-------------------- Icterus |Early and intense. |Does not appear |Jaundice develops | Comes on in a few | before 3d day | slowly about 2d | hours. | and gradually | day. | | intensifies. | -----------+-------------------+-------------------+-------------------- Spleen |Somewhat enlarged |No enlargement of |Splenic enlargement | and tender. | spleen. | is marked; may | | | have ague cake. -----------+-------------------+-------------------+-------------------- Pulse |Rapid from start |Stationary pulse |Pulse not so rapid | and becoming | with rising temp- | as in blackwater. | more so as disease| erature or falling| | progresses. | pulse with | | | stationary temp- | | | erature. (Faget’s | | | law.) | -----------+-------------------+-------------------+-------------------- Vomit |Early marked |Mucus-like followed| Bilious vomiting | bilious vomiting. | by black vomit | and gastric distress | | about 4th day. | less than in | | | blackwater. -----------+-------------------+-------------------+-------------------- Evidences |Usually present as |Negative unless |Some evidence at of malaria| parasites or | yellow fever | some time almost | melaniferous | occurs in a | always obtainable. | leucocytes or | malarial case. | | increased large | | | mononuclear | | | percentage. | | -----------+-------------------+-------------------+--------------------
=Laboratory Diagnosis.=—Other than the noting of evidences of malarial infection, rapid reduction in red-cell count and haemoglobin percentage there is little information to be derived from the blood which is thin and shows delayed coagulation time. It is difficult to make good blood smears. In the urine we note the granular sediment of débris of red-cell destruction with at times haematoidin crystals. Spectroscopically we get absorption bands of methaemoglobin and more rarely oxyhaemoglobin.
Albumin is present in quantity and urobilin is usually present in large amount.
One can examine the urine for blood by the haemin-crystals, guaiac or benzidin tests.
Burkitt has noted that his cases of blackwater have shown a very acid urine with large amounts of acetone bodies.
The serum shows haemoglobinaemia and may show reduced alkalinity.
PROGNOSIS
So far as statistics go the mortality rate would appear to be influenced by the delicateness of the tests used for determining the presence of haemoglobinuria. When a diagnosis is only made with the presence of marked haemoglobinuria, showing porter-colored urine, the mortality rate is, of course, higher than when slight haemoglobinuria is taken into consideration.
In cases treated with quinine, Deaderick, in statistics of various authorities, gives a death rate of 25.9%; in cases not so treated, of 11.1%.
Marked and persistent vomiting and hiccough are very unfavorable signs. In particular, however, it is anuria that gives us our greatest concern in the care of a case. A severe attack is followed by a marked anaemia and convalescence is usually protracted.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The view now generally entertained is that where malarial prophylaxis is properly carried out there will not be any blackwater fever. In persons who have had a previous attack of blackwater fever quinine prophylaxis should be with quinine tannate or quinine base, avoiding the acid salts of quinine.
In particular any exposure to chilling influences or conditions which lower resistance should be avoided. As blackwater fever is more prevalent among those who have been for 2 or 3 years in highly malarious, tropical regions than among recent arrivals, the former should exercise the greater care as to errors in diet, alcoholic excesses, exposure to wet and irregularity in quinine prophylaxis.
=Treatment.=—There is less unanimity of opinion as to the advisability of giving quinine during an attack of blackwater fever than exists as to any other therapeutic measure.
Of course if it be true that quinine base is devoid of haemolytic influence the fear of increasing haemolysis by giving quinine would not have to be considered. At any rate any red cells containing parasites will surely be destroyed in the general haemolysis and with them their contained parasites, so that it does not seem reasonable to give quinine during the first day or two of the attack. Quinine, if given, should not be by mouth for fear of increasing the nausea and vomiting. The majority of authorities hold that if parasites persist after two or three days from the onset quinine is indicated. Some give quinine during the first day if parasites are present but otherwise they withhold quinine.
Absolute rest in bed, avoidance of chilling and good nursing are the prime considerations in treatment.
The patients should be given alkaline waters freely, as Vichy or water containing 30 grains of bicarbonate of soda to the pint. Cracked ice often tends to lessen the nausea and vomiting. Albumin water or barley water may be retained better than milk or broths. As the condition is so asthenic one cannot disregard the nourishment of the patient during the first two or three days as is true of the sthenic first stage of yellow fever. Hot fomentations to the loins are indicated for relief of pain and the effect on the renal congestion.
Saline enemata are of particular value and may suffice in mild cases. In severe cases subcutaneous or intravenous saline injections are necessary. Sorel recommends the intravenous injection of lactose or glucose solutions in quantities of about 300 cc. (Crystallized glucose 47 grams, water 1000 cc. or C. P. lactose 92.5 grams, water 1000 cc.) He also uses these sugar solutions as enemata. Dry cupping or hot fomentations over the loins are the usual remedies in threatened suppression of the urine. If blackwater fever should be shown to be accompanied by diminished alkalinity of the serum then the intravenous injection of a 1 or 2% solution of bicarbonate of soda would be indicated. Some have recommended calcium lactate in doses of 20 grains every four hours. There is little evidence however to indicate that it is of value. Transfusion of blood has been practised but reports of such treatment indicate that while temporary improvement occurs yet this is followed by a return of haemoglobinuria. From Dudgeon’s work it would seem that the existing haemolysins would destroy the foreign red cells.
Burkitt claims excellent results by intravenous injections of alkaline solutions, similar to those recommended under “cholera.” He also finds neosalvarsan of the greatest value in treatment, as cases so treated convalesce most rapidly.
Hearsey advocates a mixture in which there is contained 10 grains of bicarbonate of soda and 1/30 grain of bichloride of mercury in each dose, to be given every two hours.
Cholesterin has been given in 15-grain doses in suspension in thick milk every four hours with the idea that it is anti-haemolytic. The dose is repeated 2 or 3 times.
Calomel in large doses has been recommended by some tropical practitioners but it would seem advisable only to use calomel to keep the bowels open and then in small divided doses.
Antipyretics should not be used from their depressing action on the heart.
For the urinary suppression, Wallace recommends salines as hot as can be borne, administered high in the colon by a double-flow tube. Since he found this treatment effective after intravenous and rectal injections had failed, it is to be inferred that the results obtained were due not to the further administration of fluid but to the action of heat applied directly to the splanchnic area.
III. THE TRYPANOSOMIASES
DEFINITION AND SYNONYMS
=Definition.=—African trypanosomiasis is an important protozoal disease of Central and West Africa, due to a flagellate, Trypanosoma gambiense, and transmitted by a tsetse fly, Glossina palpalis. The trypanosome undergoes a developmental cycle in the fly which does not become infective until after about twenty days. The period of incubation is about two or three weeks, after which an irregular fever with approximately normal morning temperature and high evening rise appears, attended with a rapid pulse rate at all times. This is called the stage of trypanosome fever and may show trypanosomes in the peripheral blood. Later on the glands enlarge and gland juice shows trypanosomes. With the appearance of a fine tremor of the tongue, a state of apathy or lethargy, known as sleeping sickness, sets in, attended with trypanosomes in the cerebro-spinal fluid. Gradually increasing mental deterioration marks the almost invariable course to death. A more virulent type of trypanosomiasis is found in Rhodesia.
In Brazil there is a disease caused by a flagellate, Schizotrypanum cruzi, which resembles a trypanosome and is transmitted by a bug, Lamus megistus. The disease runs an acute course with a high fever and great mortality in infants showing chiefly manifestations of involvement of brain or thyroid gland. In adults it runs a chronic course showing neurological manifestations or signs of myxoedema or even of Addison’s disease.
=Synonyms.=—Sleeping sickness; Negro lethargy. French: Maladie du sommeil. German: Schlafkrankheit. For the Brazilian trypanosomiasis, Schizotrypanosomiasis; Chagas’ disease.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—In describing sleeping sickness, in 1803, Winterbottom brought out the importance of enlargements of the posterior cervical glands (Winterbottom’s sign).
In 1880 Evans had found a trypanosome in the blood of horses affected with surra and several years afterward Bruce discovered that nagana, a fatal disease of cattle, was due to a trypanosome, T. brucei. In 1890 Nepveu found a trypanosome in the blood of a man in Algeria but owing to vagueness of description the discovery did not attract attention.
In 1901, Forde found a parasite in the blood of a patient in the River Gambia Colony who had a fever and in 1902 Dutton recognized the parasite as a trypanosome and gave it the name T. gambiense. In 1902, Castellani, finding a trypanosome in the cerebro-spinal fluid of a patient with sleeping sickness, brought about the establishment of the connection between the trypanosome in the blood (trypanosome fever) and the trypanosome in the cerebro-spinal fluid (sleeping sickness). In 1903, Bruce and Nabarro reported that this disease was spread by a tsetse fly, Glossina palpalis.
In 1910 Stephens and Fantham brought forward the existence of a more virulent trypanosome, T. rhodesiense.
=Geographical Distribution.=—The disease exists on the West Coast of Africa, from Senegal to Mossamedes. It is also present in the Congo basin and particularly in Uganda. The more virulent form is found in Rhodesia.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—The African trypanosomiases follow infection with two species of trypanosomes; the more virulent type of the disease, occurring in South Central Africa, being due to Trypanosoma rhodesiense, transmitted by Glossina morsitans and that of less severe type, but of more general distribution, being due to T. gambiense and transmitted by Glossina palpalis. The very important Trypanosoma brucei, which is the devastating agent in the African horse, dog and cattle disease, nagana, is also transmitted by Glossina morsitans and there exists the opinion that this trypanosome is identical with T. rhodesiense.
Macfie has reported a new trypanosome, T. nigeriense, from young persons in Nigeria. It is said to be less virulent than T. gambiense, and to be transmitted by Glossina tachinoides.
Bruce considers T. nigeriense as being T. gambiense. Macfie noted many short stumpy forms in animals inoculated with T. nigeriense.
These trypanosomes are blood flagellates and are typical of the Binucleata in possessing two chromatin-staining areas, the larger and more centrally situated mass being the tropho or macronucleus and the smaller, but more deeply staining one, the kineto or micronucleus (Blepharoplast). Trypanosomes have a fusiform or fish-shaped body which stains blue. Near the less pointed, nonflagellated end, usually called the posterior end, is the deeply stained blepharoplast. Adjoining this is a vacuole and, taking origin from this part of the trypanosome, is the flagellum. This borders an undulating membrane attached to the body and then, carried along to the other extremity, projects free as a long, whip-like flagellum.
In fresh preparations the body of the trypanosome progresses in the direction of its flagellated end, although occasionally it will be observed to move in the opposite direction.
Some trypanosomes show granules at certain stages and it has been observed that the extrusion of these granules precedes disintegration of the trypanosome. It has been suggested that such granules might be infective, explaining the infectivity of blood from which trypanosomes were absent. In the separation of trypanosomes into groups and species Bruce relies upon morphology, action on animals, and manner of development in the tsetse fly. He does not consider serum diagnosis and cross inoculation methods as reliable for differentiation. The human trypanosomes are polymorphic.
T. gambiense varies much in length and breadth. The normal type, as found in the blood, varies from 14 to 20 microns, while longer forms, 20 to 24 microns, are growth ones and, in the longest ones (23 to 33 microns), we have those preparing to divide longitudinally. The normal short forms are the ones from which the development takes place in the tsetse fly. In width these flagellates are from 1.5 to 2 microns. The blepharoplast is oval and the nucleus situated about the center.
With T. rhodesiense the nucleus is typically located almost adjacent to the blepharoplast. As a matter of fact it may require the passage of this trypanosome through rats to bring out these “posterior nuclear forms,” the nuclear location being at times almost entirely that of T. gambiense. In addition to the characteristic of nucleus being near the blepharoplast, this trypanosome is more virulent for laboratory animals than T. gambiense, agreeing in this respect with the more severe clinical course in man.
When the tsetse fly, Glossina palpalis, feeds on a man in whose peripheral circulation there are normal type trypanosomes we have an accumulation of such forms in the middle and posterior portions of the gut. From the eighth to the eighteenth day long, slender forms develop and pass forward into the proventriculus. None of the intestinal forms can cause infection when injected into animals. These proventricular types work their way into the salivary ducts and thence into the salivary glands, where further development takes place. Here we have shorter forms developing, which are similar in morphology to the normal blood type. It is at this stage that the fly becomes infective by the passing of these trypanosomes down the salivary ducts and through the channel in the hypopharynx to the subcutaneous tissues of the person bitten. High temperatures, 75 to 85°F., are favorable to development, while low temperatures, 60 to 70°F., are inimical to development, but do not kill the ingested trypanosomes. This explains the long period which at times elapses before a fly becomes infective. Under favorable conditions a fly becomes infective in twenty to thirty-four days and remains infective the rest of its life, up to 185 days. The infection is not transmitted to the pupa. This is an inoculative, cyclical or indirect type of infection. It is usually considered that a tsetse fly whose proboscis has just been contaminated with trypanosome blood is capable of transferring the infection for a few hours. This would be a mechanical or direct method of infection and such power for infection only lasts for a few hours.
There are other groups of trypanosomes, not important for man, in which the cyclical development does not include the salivary glands. In the T. pecorum group of small monomorphic trypanosomes development takes place only in intestines and proboscis, while in the T. vivax group this occurs in the proboscis alone.
When tsetse flies feed on animals infected with trypanosomes only from 2 to 6% become infective. Again, it has been shown that where the wild animals on which tsetse flies feed may show an infection of from 16 to 50% yet not more than 2 out of every 1000 tsetse flies, caught and tried out on susceptible animals, show themselves infective.
Both of the human trypanosomes of Africa have been cultured by using the N.N.N. medium in which rat’s blood was substituted for that of the rabbit. Human blood will also serve as a substitute. Growth however is not constant.
=Epidemiology.=—Practically the only method of transmission of the disease is by the bite of infected tsetse flies. The female gives birth to a single, yellowish brown, motile larva, which is almost as large as the mother and which, upon reaching the ground, bores its way into a coarse, sandy soil for a depth of about two inches and then becomes a pupa. The larval stage in the mother lasts about two weeks and the pupal stage about a month.
The tsetse fly is much like Stomoxys, but has a branching of the feathering of the arista, long palps, a bulb to the proboscis and a characteristic upbending of the fourth longitudinal vein to meet the mid-cross vein. The female deposits her larva near a shady place upon loose, dry, sandy soil. Moisture and sunlight are not favorable for pupal development, the sun being particularly injurious, so that pupae, buried only an inch deep and away from shade, are killed. This fact has been utilized in prophylaxis by cutting down the trees. The trouble is that the bush growth which soon follows is favorable as providing shade for the pupae.
Male and female flies bite and transmit the disease. They bite in the daytime, usually from 9 A.M., to 4 P.M., and will bite in the sunlight.
It has been stated that tsetse flies are attracted by persons wearing khaki clothing.
With a view to eradication of the disease certain areas have been depopulated, but upon examining the flies caught in the district a year or more later, infected flies have been obtained. This would indicate some other reservoir than man. It is now generally conceded that the trypanosome strain in the antelope is the same as T. rhodesiense, both being transmitted by G. morsitans.
Taute, however, believes them different as he not only injected blood containing such trypanosomes into himself, with negative result, but also allowed flies which had fed on antelopes, which were infective for laboratory animals, to feed on himself, likewise with negative result. It is a well-known fact that men in good condition are refractory to trypanosome infection so that this courageous experiment does not prove the antelope strain to be different from the human one.
One measure that has been proposed is to kill off the big game from a certain area with a view to depriving the flies of their main source of infection.
The probabilities of an animal reservoir for T. gambiense however is not so well settled. Many think that we may have trypanosome carriers and that such persons in the enjoyment of health may act as reservoirs of the virus. Koch suggested that crocodiles were important factors in the life of the tsetse flies and recommended the destruction of the crocodile eggs.
Koch noted the infection of 15 women in a fly-free district and considered their infection as coming from sexual intercourse with their husbands, who had returned home from fly districts where they had contracted trypanosomiasis.
This same method of infection of prostitutes has quite recently been brought to notice by Bernard.
It will be remembered that dourine, a trypanosome disease of horses, caused by T. equiperdum, is transmitted by the sexual act.
All observations however indicate that the spread of the disease is almost exclusively through the medium of the tsetse fly. Professor Lanfranchini was infected in his laboratory by a strain which was supposed to be Trypanosoma brucei.
PATHOLOGY
The chief pathological findings are the enlargements of the lymphatic glands. The dura mater may be adherent in places and the pia mater may show areas of thickening. The cerebro-spinal fluid is increased in amount. The pathological process is a chronic polyadenitis which is followed by a chronic inflammation of lymphatics of brain and spinal cord.
We have a meningo-encephalitis in which the most characteristic feature microscopically is a widespread perivascular infiltration of small round cells surrounding the vessels of the pia-arachnoid of both brain and cord. The process is most marked about vessels of pons and medulla. The nerve cells are but little affected other than those of the bulbar nuclei.
SYMPTOMATOLOGY
The Period of Invasion.—After an incubation period which may be as short as ten or twelve days, following the bite of an infective tsetse fly, the trypanosomes may be found in the blood or in gland juice. One case has been reported where an official of the Belgian Congo showed trypanosomes less than four weeks after his arrival in the colony. His first symptoms were noted about ten days after his arrival.
In natives, trypanosomes may be present in the blood for long periods of time during which they may do heavy work; thus 7 of Koch’s 52 native porters showed trypanosomes. In Europeans however the course of the disease is rarely so insidious but rapidly enters upon the stage of trypanosome fever.
The Stage of Trypanosome Fever.—Although fever may be absent in natives until the onset of the period of sleeping sickness, yet in Europeans there are usually noted febrile paroxysms, lasting for a few days, and followed, by afebrile periods varying from a few days to two or three weeks.
The temperature curve is of a markedly remittent type, approaching normal in the morning and going up to 103°F. or higher in the evening—a wide daily range. Very characteristic is a low-tension rapid pulse which often is as rapid when the temperature approximates the normal as when it is higher. Early in the disease there are evidences of involvement of the nervous system, as shown by headache insomnia, difficulty of concentration for mental work and cardiac instability.
Winterbottom Sign.—Very important are the glandular enlargements, particularly of the glands of the posterior cervical triangle (Winterbottom’s sign), which upon puncture may show trypanosomes when the blood examination fails to reveal them. The glands are discrete, soft, usually painless and may show but very slight enlargement. Oedematous swellings, especially about the eyes or joints or in localized areas upon the trunk, may be rather prominent in some cases. In Europeans pinkish erythematous rings appearing early in the infection may make one think of syphilis. These erythematous patches are not visible on the skin of natives. A dryness of the skin is rather constant and, especially in natives, papules which itch greatly may be present. Rarely such manifestations as orchitis or choroiditis may be observed.
Kérandel Sign.—Recently great prominence has been given to a deep hyperaesthesia, which shows itself as a lively pain, often retarded, after some slight blow upon a bony projection of the body. Kérandel, who suffered from trypanosomiasis, noted that the fear of striking against objects became with him an absolute obsession. It is called the Kérandel sign. It is during this first stage, when the trypanosomes are to be found only in the blood or gland juice that the disease would appear to be curable. Upon the appearance of the trypanosomes in the cerebro-spinal fluid (second stage) we have practically a hopeless prognosis.
There may be a latent period of several months in which health seems normal, to be followed by the sleeping-sickness stage. It has also been noted that untreated cases, as well as those receiving more or less treatment, may remain in good health for periods up to several years. There is therefore reason to believe that certain cases may not enter upon the sleeping sickness stage.
The Stage of Sleeping Sickness.—In this stage the mentality becomes more weakened. The native from being happy and willing to work becomes morose and apathetic. This change of disposition is frequently the first thing to be noted in a patient by his family. There is a tendency to gaze into the distance. The speech is rather low and tremulous like that of a tired, sleepy child. The tongue especially shows a decided tremor which may also be present in the lips and hands.
The gait is one of weakness and apathy—a shuffling gait. The reflexes may be exaggerated. Romberg’s sign may be present but the Argyll-Robertson pupil has not been noted. There may be an alternation of periods of crying and laughing which with the occasional exhibition of intention tremor and rarely nystagmus may make one think of multiple sclerosis. The patient tends to sleep even when lying in a bright sunlight. Again he may go to sleep with a morsel of food in his mouth. Notwithstanding the apparent stupid state of the patient, he will, when aroused, answer fairly intelligently but with apathy and retardation. The hebephrenic and catatonic manifestations of dementia praecox may be exhibited in some cases.
Finally the patient becomes weaker and more emaciated. The pulse becomes rapid and feeble, the blood pressure being extremely low. The mouth becomes dry, the teeth covered with sordes and bed sores develop. There may be convulsions. The coma and general weakness become more marked and the patient dies. Frequently terminal pneumonias or dysenteries bring about the end.
The sleeping sickness stage rarely lasts longer than a year and even with treatment not more than two years.
The Symptoms in Detail
The Nervous System.—Headache and lack of mental concentration may be early features of the disease. Deep hyperaesthesia, or Kérandel’s sign, often present. Patients tend to be morose and apathetic. Tremor of tongue and lips are rather constant signs about the commencement of the stage of sleeping sickness. Early insomnia gives way to the drowsiness that characterizes the second stage. There is very little disturbance of sensory or motor functions until near the end. Epileptiform convulsions may be late manifestations. Coma deepens as the end approaches.
The Temperature Curve.—The febrile paroxysms, which may not be present in natives until the sleeping-sickness stage, show great irregularity of course and a marked remission in the morning. The fever may be absent for several weeks to return later. Trypanosomes are more apt to be present in the peripheral circulation during the fever than when the temperature is normal.
The Circulatory System.—The pulse tends to run from 90 to 120 beats per minute and is fast even without fever. The tension is low and the systolic pressure tends to be extremely low during the later stages of the disease.
The Lymphatic System.—Most important in diagnosis is the enlargement of the lymphatic glands, especially those of the posterior cervical triangle (Winterbottom’s sign). Other enlarged glands may be the supraclavicular, epitrochlear and axillary glands. The inguinal glands suffer enlargements so frequently as the results of wounds and infections of the foot that their enlargement is of less diagnostic value. The natives of certain parts of Africa not only attach great diagnostic importance to gland enlargement but they imagine they cure the disease by removing the glands with various primitive cutting tools. The glands are not painful, do not become matted together and rarely suppurate. Our best means of diagnosing trypanosomiasis is by withdrawing gland juice with a syringe and examining the smears.
The Skin.—Erythematous areas may be present in Europeans. Localized oedemas are rather marked features. The skin may be very dry and itch markedly.
Other Manifestations.—The spleen may be enlarged, the respirations may be more rapid than normal and the blood show a secondary anaemia. In a blood examination the large mononuclears show an increase with a normal white count.
The eye may show keratitis or irido-cyclitis in trypanosomiasis.
Trypanosomiasis seems to favor abortion and still-births, in this respect resembling syphilis.
DIAGNOSIS
In making a survey of a native population Schwetz considers gland palpation as almost as reliable as gland puncture and of course more expeditious. The typical gland should be large and soft or elastic although he admits trypanosomes may be found in small hard glands.
When the glandular enlargement is distinct, with the erythema and headache, there is much that suggests syphilis. Another point of confusion is that positive Wassermann tests are often obtained in sleeping sickness.
The increase in large mononuclears goes with malaria, kala-azar and syphilis as well as with trypanosomiasis so that such findings are of little assistance in differential diagnosis.
An early history of attacks of fever, with marked fluctuation of temperature, associated with rapid pulse, even with the apyrexial morning fall, is suggestive. Then with the glandular enlargements we think immediately of laboratory examinations. As with pellagra the history is very important in the diagnosis of trypanosomiasis.
For the laboratory diagnosis we may use peripheral blood with some thick film method. The examination of preparations from the peripheral blood is usually very discouraging. Very much better results (in fact some prefer this method to any other) can be obtained by taking 10 to 20 cc. of blood in about 25 cc. of citrated salt solution, centrifuging 2 or 3 times and examining the sediment of the third centrifugalization. Dutton and Todd prefer to centrifuge citrated blood and to collect the leucocyte layer for examination as is done in opsonic work.
Gland Puncture.—The English workers usually prefer the gland puncture method, using a sterile but dry hypodermic needle. Water in the needle distorts both leishman bodies and trypanosomes.
In the sleeping-sickness stage trypanosomes can almost constantly be found in the cerebro-spinal fluid.
In a diagnostic study of 336 cases Broden obtained 87% of positives from gland puncture, 80% from centrifugalizing the supernatant fluid left from the second centrifugalization of the blood and 4.5% from spinal fluid examinations.
Some prefer to inoculate susceptible animals, particularly the guinea pig or monkey, with blood or gland juice from the suspected case. A very satisfactory material is an emulsion from an excised gland which may be inoculated intraperitoneally into white rats. The further course, after animal inoculation, is the examination of the blood of these animals for trypanosomes. Usually at the time the guinea pigs die we find numerous trypanosomes.
Other tests are: (1) Trypanolysis, when unheated suspected serum and trypanosomes are incubated together for one hour. Normal serum may occasionally cause disintegration and treated cases give it in only about 45% of cases. Unfavorable untreated cases give it in about 80% of cases.
(2) The so-called auto-agglutination test is not of much value. In this the red cells of the blood of a trypanosomiasis case come together in clumps when one makes a wet preparation. It is not a rouleaux formation. (3) The attachment test is made by making a mixture of inactivated serum, leucocytes and trypanosomes and allowing them to be in contact for 20 minutes. A positive test shows attachment of the trypanosomes to the leucocytes.
PROGNOSIS
If the patient cannot be removed from the infected district or cannot receive the atoxyl or atoxyl-tartar-emetic treatment the prognosis is almost surely that of a prolonged but fatal end.
There is very little hope of cure if the disease has gone on to the sleeping-sickness stage.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The question of depopulation of districts and destruction of the big game therein, when the area is infected with Glossina palpalis, has been fully considered under epidemiology.
Isolation, in the fly-free districts, of infected natives has not proven a very practical measure but that of rendering their peripheral blood free of trypanosomes by atoxyl injections would seem more desirable. In this we aim to cure the patient as well as render him safe to others.
The most practical measure is that employed in Uganda of clearing the plant and tree growth for at least fifteen feet from the streams of water, it having been noted that the tsetse flies confine themselves to a narrow strip not more than fifteen feet from the water’s edge. The tsetse fly requires considerable moisture for its existence.
The catching of flies in traps or with a sticky lime does not offer much encouragement.
As regards personal prophylaxis, white clothes are to be worn as the tsetse fly, along with mosquitoes, prefers dark-colored garments. The legs should be protected by leggings and possibly one could consider the wearing of gloves or veils. As a matter of fact, however, the heat of the tropics precludes these latter measures. As the fly only bites in the daytime one should choose the night for going about, if practicable.
=Treatment.=—The general opinion is that trypanosomiasis is only curable at a time prior to the appearance of trypanosomes in the cerebro-spinal fluid. Consequently, the stage of sleeping sickness offers little chance of cure by treatment.
Such cases have been treated with injections of 10 cc. of 1 to 1000 solution of neosalvarsan into the spinal canal, after withdrawing about 15 cc. of spinal fluid, but without appreciable curative effect. On the assumption that trypanosomes invading the central nervous system are protected from drug action, Marshall proposed the injection of salvarsanized serum intrathecally. Three hours after the administration of 0.6 gm. of salvarsan enough blood is withdrawn from a vein to give about 20 cc. of serum. Following the withdrawal of a slightly greater amount of cerebro-spinal fluid from 5 to 20 cc. of the serum is injected in its place. Yorke in a critical article on the claims for this treatment is of the opinion that there is no satisfactory evidence that such a method sterilizes the infected cerebro-spinal fluid. He cites cases where the trypanosomes disappeared from the spinal fluid after ordinary treatment and where cases lived for extended periods after trypanosomes were found in their spinal fluid. Corbus and associates have described a new method of obtaining a high medicinal content in the cerebro-spinal fluids. Their work was done with neo-arsphenamine, but there seems to be no reason why other drugs may not be similarly administered.
The basis of the method is the observation that hypertonic salt solution, injected intravenously, will dehydrate the central nervous system, and that restoration of fluid begins at about the sixth hour. If a drug is injected into the circulation just at the time when the restorative formation of spinal fluid is taking place, it appears that a large quantity is carried into the subarachnoid spaces with the fluid, as on a flood tide.
Method:
1. 8 A.M. Patient is put to bed.
2. 10 A.M. Intravenous injection of 100 cc. of 15% saline, warmed and administered slowly by gravity. The symptoms produced by this injection are mild and transitory.
3. No food is permitted at midday.
4. 4 P.M. Neo-arsphenamine is injected with the usual technic.
5. 8 P.M. Light nourishment is allowed. Patient is kept under observation, preferably in bed, for the ensuing thirty-six hours.
Atoxyl.—The first drug to offer hope of cure was sodium arsanilate, atoxyl, which contains about 26% of As. This is best given in doses of about 0.5 gram (7½ gr.) in about 15 cc. of sterile distilled water intramuscularly. Several cases of optic neuritis were reported but the drug is still a standard treatment. We give the atoxyl at intervals of five days, Manson gives 3 grains every third day.
Probably the best treatment is one in which three doses of atoxyl are followed by from 10 to 15 daily or every other day injections of 0.1 gram (1½ gr.) of tartar emetic. The course is repeated after an interval of three weeks. It is advisable to give a hypodermic of caffein a few minutes before the tartar emetic to lessen depression. Kérandel received the atoxyl-tartar-emetic double treatment and ascribed his cure to the tartar emetic. Tartar emetic is also given intravenously, 0.1 gram in 150 cc. water.
Intravenous injection of arsenophenylglycin, in doses of about 1.0 gram. (15 gr.) intravenously has been highly recommended. Recent reports from German East Africa state that of 35 treated with this drug six died of the effects of the drug. Salvarsan and neosalvarsan have been used but apparently without particular success.
A combination of treatments in which salvarsan, sodium salicylate and ethyl-hydrocuprein (a quinine derivative) have been used has been favorably reported by Morganroth where the action of a single drug was of little value.
Very remarkable claims in experimental animals have been made for “trixidin,” a preparation of antimony trioxide which is given intramuscularly. Even inunctions with this preparation have been quite successful in curing infected mice. In larger animals abscess formation is an objection.
Daniels has reported good results from the injection of oxide of antimony. The preparation used is Martindale’s injectio antimonii oxidi given subcutaneously in 30 minim doses (1/20 grain of the oxide). Masters gives this preparation intramuscularly and notes its greater efficiency than any other drug or combination of drugs. He gives 3/100 grain every other day until 40/100 grain has been given. If trypanosomes continue present he gives a .77 gram dose of soamin. Soamin is a drug similar to atoxyl but said to be less toxic.
In the treatment of 18 cases of T. rhodesiense infections Newham notes that tartar emetic alone was as effective as the combined treatment with atoxyl. He gave the tartar emetic injections twice weekly intravenously commencing with 1 grain and going up to 3 grains. An organic antimony preparation, “Stibenyl,” has been recommended. See kala-azar.
Very favorable reports have been made from the use of galyl and ludyl, arsenical compounds.
A drug which is reported to have exceptional trypanocidal effect on animals infected with both human trypanosomes is “Bayer 205.” Dogs infected with the dourine parasite and showing oedema and eye symptoms have been cured by the injection of the drug intravenously. A dose of 0.5 mg. causes disappearance of parasites in mice. It is stated that the drug produces a protection against reinfection which lasts for months.
BRAZILIAN TRYPANOSOMIASIS
=General Considerations.=—In 1909, Chagas reported the finding of a flagellate in the intestines of Conorhinus megistus or, more properly, Lamus megistus. He was also able to transmit the flagellate to laboratory animals and could culture it on blood agar.
In investigating the matter of the importance of this flagellate, Schizotrypanum cruzi, in Minas Geraes, Brazil, where the above-named bug was present in great numbers in the cracks of the houses of the poor he associated this flagellate infection, which he at first considered trypanosomal, with a disease of the children of that section.
The bug is a vicious feeder and, from its biting chiefly about the face, has been called barbeiro or barber by the natives. Both the male and female of Lamus bite and can transmit the disease and although the parasite is not transmitted hereditarily the nymph is capable of sucking blood and becoming infected.
It requires several months for the insect to go through the egg, larval and pupal stage to maturity. Some consider this bug to belong to the genus Triatoma. The insects may live for more than a year and tend to remain in the same house where they may have become infected but leave such house if it be abandoned by man. Brumpt thinks that the bedbug may also transmit the disease. A large proportion of armadillos in the endemic areas are infected with S. cruzi but do not seem to be affected thereby. It has been suggested that this animal may be a reservoir of virus.
S. cruzi is found in the blood of children during the acute febrile stage but at other times in children, and as a rule in adults, it is rarely present in the peripheral blood. The early blood forms are narrow and very motile. They increase in size and slacken in motility when they become about 20 microns long. S. cruzi is characterized by a very large blepharoplast. Dividing forms are never seen in the blood. The common site of multiplication is in the cells of the voluntary muscles and heart and also in the cells of the central nervous system, adrenals, and bone marrow. In these tissues the flagellate takes on a rounded form and undergoes binary division. Continued division converts the infected cell into a cyst. It is this process going on in various important structures that accounts for the extreme variation in symptomatology and pathology.
Chagas thinks that the gametes for the cycle in Lamus arise from parasites developing in the lungs of the vertebrate host. Flagellated parasites enter the lungs, lose the flagellum and become oval in shape, later on dividing into 8 parts. These assume an elongated form and enter the red cells of the host. Against this is the statement of various observers that the flagellates are only to be found free in the plasma, never within red cells. The forms taken up by Lamus multiply in the intestine and then pass to the salivary glands after about 8 days. The bug is then infectious when it bites. Brumpt notes that infection may occur from inoculation of the faeces passed by the bug, especially through the conjunctiva.
=Symptomatology.= Acute types.—This form of the disease usually occurs in children under one year of age. The period of incubation is about ten days. It is attended by a high continued fever which may show a slight morning drop. There is marked puffiness of the face and enlargement of the thyroid. The lymphatic glands and spleen are also enlarged. The case may give the picture of a meningitis in which form the disease is exceedingly fatal. During the febrile period parasites are to be found in the blood but in the afebrile intervals which alternate with the febrile ones parasites are not present.
Chronic Types.—The type of the disease as seen in adults is mainly chronic. They often show enlargement of the thyroid and manifestations of myxoedema. The lymphatic glands are enlarged. Where the adrenal is attacked we have the syndrome of Addison’s disease.
In the cardiac types there are present various forms of cardiac irregularities.
In the cerebral types various neurological manifestations may be noted.
An irregular fever may accompany the signs of involvement of the various important organs.
The disease is attended by a marked anaemia.
=Diagnosis.=—In the laboratory diagnosis of those cases not showing the flagellates in the blood the usual method is to inoculate a guinea pig with the blood and in about two weeks S. cruzi may be found in the blood of the animal. The parasites may not appear, however, in the blood, when one should resort to culturing the guinea pig’s blood or more surely examine sections of muscle of the animal for the forms in the muscle cells undergoing binary division.
Brumpt has recently advocated the xenodiagnostic method. Thus, in a number of guinea pigs infected with S. cruzi, parasites could not be found, but by having third stage larvae of Conorhinus feed on these animals the parasites developed in the bugs. He regards the alimentary tract of these bugs as a most favorable culture medium.
=Prophylaxis and Treatment.=—Other than destroying the bugs by sulphur fumigation or whitewashing there is little to note. The bugs show a liking for leather articles, as old harness.
The same plan of treatment as for African trypanosomiasis may be tried but such treatment is not effective with infected animals.
In the myxoedema types thyroid extract is indicated.
NOTE: Escomel has reported the finding of a trypanosome 20 to 40 microns by 3 to 4 microns which had a flagellum as long as the body and with a very small but distinct blepharoplast (unlike S. cruzi) in the blood of a native of Peru. The patient at the time of the blood examination was afebrile and showed a generalized firm oedema. There was noted anaemia, prostration and somnolence. This may be a new species.
TRYPANOSOMIASES OF ANIMALS
=Trypanosoma brucei.=—This trypanosome causes a surely fatal disease in horses and one from which few cattle recover. It is called “nagana” or the fly disease, from being transmitted by the tsetse fly, Glossina morsitans. All animals except man and possibly the goat seem susceptible. The disease is characterized by fever, oedematous areas about neck, abdomen and extremities, progressive anaemia and emaciation. It is an important disease of domesticated animals of many parts of Africa.
=Trypanosoma evansi.=—This is the cause of a very fatal disease of horses in India and the Orient and known as “surra.” It also affects camels and even cattle. It is thought to be transmitted by biting flies (Stomoxys). The symptoms are fever, emaciation, oedematous areas and great muscular weakness.
=Trypanosoma equinum.=—This trypanosome causes a fatal disease in horses in South America. There is paralysis of the hind quarters of the horse which gives the disease the name “mal de caderas.”
=Trypanosoma equiperdum.=—This trypanosome causes a disease of horses in many parts of the world. It is known as “dourine” and is transmitted by coitus. The genital organs show marked oedema which is followed by anaemia and paralysis.
=Trypanosoma dimorphon.=—This trypanosome causes a disease of horses in Gambia. It is also found in horses and cattle in other parts of Africa. The parasite shows marked variation in morphology.
=Trypanosoma lewisi.=—Rats in many parts of the world show this infection which is rarely fatal to them. It is transmitted by the rat flea by a process of regurgitation. It can also be transmitted by the rat louse.