TRANSCRIBER’S NOTE

The cover image was created by the transcriber and is placed in the public domain.

Some minor changes to the text are noted at the [end of the book.]

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.

CONTENTS

PART 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.

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).

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.

PLATE OF MALARIAL PARASITES

SECTION I
DISEASES DUE TO PROTOZOA

CHAPTER 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.

Fig. 1.—Geographical distribution of malaria.

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.

Fig. 2.—Sexual (sporogony in mosquito) and nonsexual (schizogony in man) cycle of the malarial parasite. The sporogony diagram to the left shows in lower portion the fertilization of the female gamete by the microgamete. The vermiculus stage of the zygote is shown boring into the walls of the mosquito’s stomach to later become the more mature zygote packed with sporozoites as shown in the upper diagram of the developmental processes in the mosquito’s stomach.

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.

Fig. 3.—Plasmodium vivax.(Benign tertian) Development of schizonts of nonsexual cycle in peripheral blood of man. Red cell swollen and stains feebly. Note Schüffner’s dots. X 2200. (MacNeal after Doflein.)

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.

Fig. 4.—Plasmodium vivax. (Benign tertian.) Double infection of a red blood cell which is enlarged and shows Schüffner’s dots. X 2200. (MacNeal after Doflein.)

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.

Fig. 5.—Plasmodium vivax. Mature schizont and merocyte. Found in the blood just before and at onset of chill. X 2200. (MacNeal after Doflein.)

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.

Fig. 6.—Plasmodium malariae. (Quartan.) Development of nonsexual parasite in blood of man. X 2200. (From MacNeal after Doflein.)

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.

Fig. 7.—Plasmodium falciparum. (Malignant tertian) Nonsexual cycle in blood and internal organs of man. Note multiple infections of single red cell. (From MacNeal after Doflein.)

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.

Fig. 8.—Tertian malarial parasite, one red cell showing malarial stippling. (Todd.)

Fig. 9.—Estivo-autumnal malarial parasites, and small ring forms and crescents. (Todd.)

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.

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.

Fig. 10.—In the above figure note the culicine egg raft, 45° angle position of syphonate larva, parallel attitude of resting mosquito, nonbulbous palpi of male and short palpi of female as contrasted with the anopheline star or ribbon arrangement of eggs, horizontal attitude of asiphonate larva, bradawl attitude of resting mosquito, spotted wings, bulbous palpi of male and long palpi of female mosquito. (From Jordan after Kolle and Hetsch.) MacNeal.

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.

Fig. 11.—Resting posture of mosquitoes; 1 and 2, Anopheles; 3, Culex pipienes. (After Sambon.) From P. H. Reports.

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.

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.

Fig. 12.—Asiphonate (Anopheline) larva Anopheles. 2 Siphonate (Culicine) larva Stegomyia

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.

Fig. 13.—Anatomy of the mosquito. No. 6 shows various types of scales.

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.).

Fig. 14.—Anopheles maculipennis (quadrimaculatus), female. (Castellani and Chalmers, after Austen.) From P. H. Reports.

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.

Fig. 15.—Anopheles maculipennis (quadrimaculatus), male. (After Castellani and Chalmers.) From P. H. Reports.

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.

Fig. 16.—Digestive tract of Anopheles the stomach of which is covered with numerous zygotes or oocysts of Plasmodium falciparum. c, cloaca; mt, malpighian tubules; o, oocyst; s, stomach; sb, sucking bladders or pumping organ; sg, salivary gland. (MacNeal from Doflein, modified after Ross and Grassi.)

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.

Fig. 17.—Diagram of the temperature chart of a double tertian malarial fever showing the succeeding development of two generations of parasites, causing thereby a quotidian fever. The solid line, A, shows the development of the generation of parasites first introduced and the dotted line, B, the cycle of the generation introduced later on.

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.

Fig. 18.—Typical fever charts of the 3 types of malaria.

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.