A practical study of malaria

Front matter

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Preface

While there is a number of good books on malaria, I believe there is a place for a work written by one engaged entirely in private practice largely in country districts, in the home of the severer forms of the disease.

In the endeavor to make the work as practical as possible especial attention has been devoted to that mystic paramalarial syndrome, hemoglobinuric fever, and to the diagnosis and treatment of malaria. Prophylaxis has been considered in the light of Ross' epoch-making discovery.

The parthenogenetic cycle of the parasite, whose significance was first recognized by Schaudinn, and which affords the only rational explanation of latency and relapse, is described for the first time, perhaps, in our language.

While I have not hesitated to draw from the literature for the illustration of practical points, due credit is given in the reference portion. I am especially indebted to the works of Ewing, Dock, Barker, Marchiafava and Bignami, and Kelsch and Kiener for pathologic data.

I am grateful to my wife for copying the manuscript and for assistance in reading the proof, to Mr. W. C. Seckler for the photographic work, and to the W. B. Saunders Co. for courtesies throughout the publication of the book.

W. H. D.

Marianna, Arkansas, October, 1909.

Introduction

A certain dusky tropical queen was wont to say that she did not fear the invasion of the white man, for she had two mighty generals, The Fever and The Forest.

Malaria has been one of civilization's greatest foes, both in time of war and in peace. Where shot and shell have slain their thousands, malaria has slain its tens of thousands. Malaria is the chieftain of the army of disease. Even Napoleon acknowledged its supremacy when he wrote his minister of war on the occasion of the disastrous English Walcheren expedition : "We are rejoiced to see that the English themselves are in the morasses of Zealand. Let them be kept only in check, and the bad air and fevers peculiar to the climate will soon destroy their army." It is said that the French crowed over the expedition "with the force of reason, the bitterness of sarcasm, and the playfulness of ridicule." How accurately Napoleon's prediction was verified is well known.

In the tropics the man who works the soil digs his own grave. Gigantic commercial enterprises have been undertaken and then abandoned on account of the havoc wrought by this scourge. Only recently has it been recognized that the medical man must precede and prepare the way for the engineer and the laborer.

But warring and canal-digging are not the only stages upon which the malarial tragedy is enacted. Within the family, at

2 17 home, the disease appears in a varied succession of forms, rapidly fatal, or slowly sapping the vitality, influencing the birth-rate, longevity, and even the intelligence and morality of entire countries.

In highly malarial regions, as the mortality increases the natality diminishes on account of abortions and sterility. Premature senility is frequent and advanced age is not so commonly attained.

Malaria, leaving its subjects anemic and neurotic, is responsible for inertia, loss of will power, intemperance, and general mental and moral degradation. Jones, who maintains that malaria was a potent factor in the decline of Greece and Rome, concludes that "malaria made the Greek weak and inefficient; it turned the sturdy Roman into a bloodthirsty brute." Monfalcon attributes abortion, infanticide, universal libertinism, drunkenness, want of religion, gross superstition, assassination, and other crimes to the direct influence of malaria.

Malaria costs the South incalculable wealth. Besides loss through untilled acres, diminished earning capacity, loss of time, and death, it produces in its victims a disinclination for work whose influence cannot be estimated in money. A conservative computation of the loss to the Southern States through malaria is fifty millions of dollars annually.

The importance to the world at large of the subject of malaria is evidenced by the fact that two of the seven Nobel prizes in medicine which have been awarded have been granted for discoveries in malaria — to Ross in 1902, and to Laveran in 1907.

The history of malaria may be traced to the age of fable. The story of Hercules and the Hydra is a familiar one. This monster dwelt in the morasses in the neighborhood of the Lake of Lerna, where Hercules was dispatched to destroy him. As each of the nine heads was struck off two new ones appeared. With the aid of his faithful servant, Iolaus, who burned each wound caused by the removed head, the beast was finally conquered. Even before the birth of Christ this myth was construed to typify the reclamation of swamp lands, uninhabitable on account of the prevalence of malaria. Antipater wrote,

"Hercules, the greatest subduer of the foggy atmosphere in times past, was placed among the gods for having destroyed the Hydra; in other words, for having reclaimed the marshy desert." The slaying by Apollo of the Python which arose from the fertile ground after the recession of the flood is similarly interpreted.

More than one thousand years before the birth of Christ malarial disease is mentioned in the Orphic poems, and the tertian and quartan types are alluded to. In the Iliad of Homer and in the Wasps of Aristophanes allusions are made to a fever which was probably malarial. Paludism was probably introduced into Greece from Egypt. According to GrofT the word AAT, which is found among the inscriptions of the temple of Denderah, referred to a disease, doubtless malaria, which recurred every year at the same season.

Hippocrates divided malarial fevers into continuous and intermittent, which he subdivided into quotidian, tertian, and quartan. He recognized the etiologic influence of season, rains, and stagnant water, and the dangers of malignancy, dropsy, and affections of the spleen. Plato describes splenic enlargement, and other early Greek writers undoubtedly refer to malaria.

References by Roman writers to malaria are not numerous, the earliest being that of Plautus, who died 184 b. c. Cato speaks of "black bile and swollen spleen," and Cicero, Varro, Celsus, Livy, and others show unmistakable evidence of a knowledge of the disease.

Passing over the development during the middle ages of the knowledge of malaria, the names of Morton, Lancisi, Sydenham, and Torti appear.

Morton, 1697, gave accurate clinic descriptions of the pernicious and simple intermittent fevers, and attributed them to miasmatic effluvia. He was an ardent advocate of cinchona, whose value was at that period being hotly contested.

Sydenham, 1723, accurately described the malarial fevers. The intermittent fevers he divided into spring and autumn fevers. He justly concluded that the intermittent and continuous forms of malaria were due to the same cause. Sydenham ably defended cinchona, and, after clinic experiments with its use, formulated useful rules for its administration.

Lancisi, 171 7, stated the etiologic relationship between marshy regions and malaria, and was the first to seek for a microscopic organism as the cause of the disease.

Torti, 1753, wrote an exhaustive treatise upon the various forms of malaria. His classification of the pernicious forms has become classical. Numerous quotations from Torti's treatise are to be found even in recent works upon malaria.

Varro, 118-29 B - c v expressed the opinion that malarial fever was caused by animals so minute that they could not be seen by the naked eye, and which enter the body with the air through the nose and mouth. Similar opinions were held by Columella, Palladius, and Vitruvius. Rasori is quoted as saying, "For many years I have held the opinion that the intermittent fevers are produced by parasites, which renew the paroxysm by the act of their reproduction, which occurs more or less rapidly according to the variety of their species." Le Diberder, 1869, maintained that the fever was due to the presence in the blood of animals which preyed upon the blood, and that the paroxysms depended upon reproductive acts between which apyrexia occurred.

Mitchel, 1849, claimed to have found in the sputa of malarial subjects fungous spores in great numbers, which he believed to have been inspired with marsh air and to have caused the disease.

Salisbury, 1866, announced the discovery in the urine and sweat of malarial patients of a species of alga, palmella, common on the marshy regions along the Ohio and Mississippi Rivers, which he alleged to be the causative element.

Until the true parasite of malaria was discovered the most widely accepted parasitic theory was that proposed in 1879 by Klebs and Tommasi-Crudeli. These investigators found constantly present in the mud of the Roman marshes a short bacillus. They were able to cultivate it upon fish gelatine, and when injected into rabbits produced a fever similar to malaria. They named it the bacillus malaria.

The malarial parasites were undoubtedly seen and described

Fig. i. — Charles Louis Alphonse Laveran, the discoverer of the parasite of malaria.

before Laveran discovered them. In 1847 Meckel, who first discovered malarial pigment, described bodies containing pigment which correspond to the malarial parasites. Virchow, in 1849, in a description of the pigment, depicted cells now known to be parasites, as did also Frerichs in 1866. The pigment was observed also by Dlauhy, Heschl, and Planer. None of these investigators, however, recognized the significance of these bodies, and their parasitic nature was not suspected until 1880 by Laveran, to whom all the more honor is due.

Charles Louis Alphonse Laveran was born at Paris, June 18, 1845. He entered the military service and was assigned to Algeria, where his brilliant discovery was made on November 6, 1880, and announced to the Paris Academy of Medicine November 23, 1880. He was using a one-sixth inch dry lens when examining the blood. He says, 1 "My first researches date from 1878; at this time I was on duty in the hospital of Bone, in Algeria, and a great number of my patients were suffering with malarial fever. I had occasion to perform autopsies upon several subjects of pernicious malaria, and to study melanemia which had already been observed, but was not considered as a constant change in malaria, nor as a specific lesion of that disease. I was struck by the singular appearance of granulations of black pigment, especially in the liver and in the cerebral vessels, and I endeavored to follow, in the blood of patients suffering with malarial fever, the study of the formation of pigment. I found in the blood leucocytes charged with pigment, already seen by other observers, but besides melaniferous leucocytes, spherical bodies, varying in size, pigmented, endowed with amoeboid motion, and pigmented crescentic bodies attracted my attention. I supposed at that time that these were parasites.

"In 1880, at the military hospital of Constantine, I discovered, besides the spherical pigmented bodies, in the blood of a malarial subject filiform elements resembling flagella, which writhed with great, vivacity and displaced the neighboring corpuscles. From then I had no further doubt as to the parasitic nature of these elements which I had found in the blood."

Laveran's discovery was not accepted by the medical world until several years later; now it has been confirmed the world over. Among Americans who first corroborated Laveran's views may be mentioned Sternberg, Councilman and Abbott, Osier, James, Dock, Thayer and Hewetson, Barker, Woldert and Welch.

The discoveries of Golgi in 1885 were of great importance with reference to the life history of the parasite. He was able to follow tertian and quartan parasites throughout the endogenous cycle of development, and showed that a close relationship existed between certain phases of parasitic growth and certain stages of the paroxysm. Other Italian investigators proved the same for the estivo-autumnal parasites.

A vague suspicion that malaria and mosquitoes were in some indefinite way connected has been entertained in certain countries for a long period. A definite mosquito theory, however, was born in America. While reference is sometimes made to a paper on the "Mosquital Origin of Malarial Disease," supposed to have been published by Dr. John Crawford in the Baltimore Observer, 1807, no such article has been found, and the reference is probably erroneous.

In 1848 Dr. Josiah Nott, 2 of Mobile, published a paper upon yellow fever, in which he maintained the dissemination of that disease by insects, and suggested that malaria was spread by the "mosquito of the lowlands."

The most complete theory was proposed by King 3 in 1883. His views are supported by nineteen arguments, most of which are incontestable at the present day.

That mosquitoes are agents in the spread of malaria was advanced by Koch in 1884, by Laveran in 1884, by Fliigge in 1 89 1, by Manson in 1894, and by Bignami in 1896.

Undertaking the work at Manson's suggestion, and after several years (1895-1898) of toil and discouragement, Ross proved conclusively that certain species of mosquitoes are concerned in the dissemination of malaria. The debt owed him by mankind was acknowledged by the gift of a Nobel prize; his own feelings over the discovery are expressed in these lines, which he wrote :

Fig. 2. — Major Ronald Ross, the discoverer of the role of the mosquito.

"This day relenting God

Hath placed within my hand A wondrous thing, and God Be praised. At his command

"Seeking His secret deeds,

With tears and toiling breath, I find thy cunning seeds, Oh million-murdering death.

"I know this little thing

A myriad men will save ; Oh, death, where is thy sting, Thy victory, oh grave?"

A discovery, secondary in importance only to those of Laveran and of Ross, was made by MacCallum in 1898, who demonstrated that the flagella represent male sexual elements, analogous to spermatozoa.

HISTORY OF HEMOGLOBINURIC FEVER

It is probably unique in historical pathology that a complex of symptoms so striking as hemoglobinuric fever should have such an obscure history. As this obscurity is intimately associated with the etiology and symptomatology of the condition an investigation of some of the factors in its history is not without interest. After a short statement of the history of hemoglobinuric fever we will briefly consider how far it has been influenced by (1) its confusion with bilious remittent fever and yellow fever, (2) the introduction of cinchona bark and its alkaloids into the treatment of malaria, and (3) the advent of Europeans into endemic regions. .

In the years from 1850 to 1853 blackwater fever was described by Lebeau, Daulle, and Leroy de Mericourt, physicians of the French navy, who observed it in Madagascar, and especially on the Island of Nossi Be, off the northwest coast of the former island. They named the condition icteric pernicious fever. In 1861 cases observed in the Antilles, Guiana, and Senegal were described by Dutrouleau as hematuria bilious fever. In the early sixties Barthelemy-Benoit also described hematuric bilious fever, and in 1874 appeared the monograph of Berenger-Feraud on melanuric bilious fever. This writer states that the disease has existed in Goree since 1845, an d in St. Louis, in Senegal, according to the hospital records of that city, at least since 1820, shortly after the settling of the Europeans there. The first twenty-three settlers at Gabun, in 1843, were attacked with blackwater fever and almost all of them died. A great increase in frequency has occurred since 1850.

Crosse 4 believes his own case, in 1888, to be the first on record in the Niger Territories, though he states that the disease was said by old coasters to have existed in the Niger Delta since 1882. F. Plehn 5 does not believe the disease to be of recent introduction into West Africa, but attributes its comparatively late recognition to two facts — first, that the susceptible population, who formerly lived as traders on anchored hulks, began to take up their abode on the shore; second, that the disease was formerly confounded with yellow fever. It has been known in Senegambia since 1855, 6 and in the Dutch East Indies since the Atjeh War, 1874-78. 7 Calmette saw a number of cases in Gabun in 1886-87, an d Fluit, in San Juan del Stir, has seen numerous cases since 1850. 8 The condition was not described in India until 1855, and Sambon 9 regards this as conclusive of its recent introduction, as "it would be absurd to think that it could have escaped the attention of such men as Annesley, Chevers, Carter, Martin, Fayrer, Morehead, and Maclean had they met with it."

Dr. Elliotson, 10 in 1832, mentioned a case of ague accompanied by a discharge of bloody urine during the cold stage.

Todd, 110 in 1849, asserted that "a state of general cachexia, such as often occurs in scurvy, may bring on hematuria, or such as results from an aguish state brought on by the malaria of marshy districts."

In the United States hemoglobinuric fever was first described by Dr. J. C. Cummings, ia of Monroe, Louisiana, in 1859. He reported 6 cases, and refers to numerous cases during the previous season. Faget 12 treated the disease as early as 1859, and states that cases with hematuria and hematemesis had frequently been seen in New Orleans and been mistaken for yellow fever. Inasmuch as Faget considered hematemesis a common symptom of hemoglobinuric fever, it is possible that he himself confounded the two diseases in some instances. In 1867 Dr. T. C. Osborn, 13 of Greensboro, Ala., observed 10 cases, 5 of which ended fatally, some with anuria and uremia. All the patients had been repeatedly attacked with malaria. A few months later his son, Dr. J. D. Osborn, 14 read a paper before the Greensboro Medical Society, from which it is evident that the disease was becoming more prevalent, and that the country people were regarding it as yellow fever. Dr. H. C. Ghent, 15 of Port Sullivan, Texas, in 1866 reported hemoglobinuric fever endemic in parts of Texas. In March, 1869, Dr. R. F. Michel, of Montgomery, Ala., read a paper before the Medical Association of the State of Alabama in which he spoke of the disease as "a malignant malarial fever, following repeated attacks of intermittent, characterized by intense nausea and vomiting, very rapid and complete jaundiced condition of the surface as well as most of the internal organs of the body, an impacted gall-bladder, and hemorrhages from the kidneys.

These phenomena presented themselves in an almost uninterrupted link, attended by remissions and exacerbations. It is a fever peculiar to the United States." He recorded the morbid anatomy in one of his fatal cases. In Arkansas hemoglobinuric fever was first recorded by Dr. E. R. Duvall, of Fort Smith, in a paper read before the State Society in 1871. He believed the case he recorded to be the first to occur in the State. This paper is said to be a model of accurate clinic observation. In 1880 Dr. G. B. Malone, in Monroe County, Arkansas, reported 155 cases met in his practice. The affection was first reported in Georgia by Dr. W. A. Greene, of Americus, in 1872, and in North Carolina by Dr. Norcom, of Edenton, in 1874. Norcom asserts that the disease did not, as some claimed, make its first appearance a few years ago, but that it had long been recognized. Dr. McDaniel, 10 of Camden, Alabama, described hemoglobinuric fever in 1874, and says, "In calling up my own reminiscences, I am sure that I have occasionally ever since my boyhood seen isolated cases of what was considered intense bilious fever with the surfaces and under tissues stained deeply yellow and with the urine deep red. They were nearly all fatal, and were called in older phrase "bilious congestive," and in more recent "pernicious bilious." I have also, but more rarely, known groups of similar cases associated, say 3 or 4 cases occurring on the same premises or in the same family, about the same time. All such cases, in addition to the deep so-called bilious color and the red urine, had jactitation, suspirous breathing, inordinate thirst, and vomiting of various shaded and tinted so-called bilious matters. By diligently inquiring I have ascertained that very many old physicians, some of whom have now retired from practice, are satisfied that they have observed similar cases, sometimes singly and sometimes in groups.

The late-lamented Dr. A. G. Mabry, in a report of a case of intermitting icterode hematuric fever made to this association in 1870, says, "It is a mistake to suppose that this is a new form of disease. More than twenty-five years ago I treated, in the vicinity of Selma, cases of intermitting fever presenting in a marked degree all the symptoms characteristic of these cases at the present day."

The acrimonious dispute of the earliest writers on the subject of what constituted the coloring matter of the urine is parallelled only by that occurring later concerning quinine in the treatment. While Daulle and Berenger-Feraud stoutly maintained that the dark color was due to the presence of bile in the urine, Dutrouleau, Pellarin, Barthelemy-Benoit, Antoniades, and Corre ascribed it to blood. It is remarkable that none of the first American writers attributed the color of the urine to bile, but considered it due to blood. Corre ( 1881 ) and Karamitsas (1882) proved that the process was a hemoglobinuria instead of a hematuria.

The credit of first directing attention to the etiologic relation between quinine and hemoglobinuric fever is generally credited to Tomaselli, who published his first observations in 1874, but this is an error. At a meeting of the Greek Medical Society, November 6, 1858, Veretas 15 reported that the majority of physicians practising in the marshy regions of Greece had noticed hematuria following the administration of quinine. He adds, "Among these observers my father has a place, having attentively observed this action of the medicament not only in several other persons, but in himself also, unfortunately, as he was for a long time tormented with intermittent fever during his long residence at Vonitsa." Konsola 15 is said to have observed similar cases in 1858. During this year, also, Antoniades published an article on "Hemorrhages and Particularly Hematuria in Intermittent Fever," in which he opposes the theory that quinine is a cause. Other Greek physicians whose observations were published before those of Tomaselli are Papavassilou, Rizopoulos, and Karamitsas.

1. The close relationship between malaria and blackwater fever renders it easily understood why the latter might have been confounded with bilious remittent fever. Moreover, the early pyretologists almost completely ignored the condition of the urine in fevers. Hence, in a clinical scene, preceded by or opened with ordinary malarial paroxysms and characterized by dark urine, between the color of which and the bilious urine of bilious remittent fever there are all degrees, it is slight wonder that the two conditions were confounded.

This probably occurred chiefly in India and to a less extent in certain portions of Africa and America. One is struck, on reading accounts of the Indian fevers, with the description of the intense jaundice of the skin and scleras, out of all proportion to this symptom in the bilious remittent fevers of the present day. In fact, some of these descriptions — for instance, Johnson's 16 of his first case in India — lack only the mention of the characteristic urine, about which the author is altogether silent, to make a fairly complete case of hemoglobinuric fever. Cleghorn 17 graphically depicts what he regards as a form of tertian fever, accompanied with hemorrhages, dark urine, deep jaundice, and other symptoms of hemoglobinuric fever. Since it is reasonably certain that there was no yellow fever in Minorca during the period of Cleghorn's sojourn in the island, namely from 1744 to 1749, it may reasonably be inferred that he saw cases of blackwater fever.

The fact that the early history of hemoglobinuric fever opens with disputes as to whether the coloring matter of the urine was due to blood or to bile is evidence of the confusion by some observers between hemoglobinuric fever and bilious remittent fever, since formerly bile and malaria were practically synonymous.

It has been mentioned that the first reliable records of the existence of hemoglobinuric fever were, according to Berenger- Feraud, those of the hospital of St. Louis in Senegal, where it is shown to have existed as early as 1820. It is a singular coincidence that this city afforded, in 1778, the first epidemic of yellow fever occurring in Africa. 18 Later Plehn 5 gave as one of his reasons for believing that hemoglobinuric fever was not a new disease in West Africa, that it had formerly been mistaken for yellow fever. Besides Senegal, two of the other regions where hemoglobinuric fever was first seen, the West Indies and Guiana, were yellow-fever foci. In the United States we have the early statement of Dr. J. D. Osborne that the condition was then regarded as yellow fever.

The similarity of the symptoms and the relative immunity of the black race to both diseases render the mistake somewhat excusable. As recently as 1897 Below 448 maintained the identity of yellow fever and blackwater fever.

2. Cinchona bark was introduced into Europe in 1640 by the Countess del Cinchon, wife of the vice-regent of Peru, in whose honor it has received its name. The efficacy of the bark in malaria was first known to the Indians in the region of Loxa, in the southern portion of Ecuador. The Corregidor of Loxa, hearing of the severe illness of the countess with tertian fever at Lima, in 1638, advised her physician, de Vega, to give the bark a trial, which effected a prompt cure, and in those days was regarded as nothing short of miraculous. When the countess returned to Spain she took a supply of the bark with her. Here it seems first to have been employed chiefly by the Jesuits, who introduced it into Rome in 1649. It was then known as countess' powder, or Jesuits' powder. Its use was antagonized by other religious denominations and by the medical profession. Bark was imported into England in 1 671 by Sir Robert Talbot, an English quack, who kept the remedy a secret and sold it for one hundred louis d'or per pound. Louis XIV, who was attacked with a rebellious and severe intermittent in the year 1679, was cured by Talbot with a concentrated vinous tincture of the bark, purchased and made public the secret remedy, for which he paid £48,000 and a life annuity of £2000.

In India the remedy was employed by Bogue 20 as early as 1657. In these times in Spanish- America, where the bark was indigenous, extraordinary methods were employed to prevent the nature of the drug becoming recognized. But during the eighteenth century cinchona bark was almost universally known. Lind is said to have employed in Lower Senegal, during 1765, over 140 pounds of the bark. In 17 14 Ramazzini 21 wrote that should a fever patient die it was considered a crime not to have employed cinchona. In fact, so widespread was the use of large doses of bark that Calmenero (1647), Casati (1661), Daval (1684), Ramazzini (1714), and others wrote vehemently against the abuse of the drug.

Pelletier and Caventou, in 1820, succeeded in isolating quinine from the bark.

The institution of cinchona plantations in Java in 1854 and in Ceylon in 1859 caused a drop in the price of quinine, which had formerly sold for its actual weight in gold, to one-twentieth the original price.

Marchiafava and Bignami 22 seek to explain the seeming late appearance of hemoglobinuric fever by the use of quinine becoming prevalent at the time when the disease was first described. It is probable that this factor has caused an increase in certain localities, but a comparison of the history of the disease with that of the drug shows no very intimate chronologic relations. Further, blackwater fever is on the decrease in some regions where the use of quinine is becoming more general. This is reported to be the case in German East Africa by Meixner, 23 in Cameroon by Ziemann, 23 in Togo by A. Plehn, 24 and by Kohlbrugge 7 in the Malay Archipelago. The large number of cases occurring without the previous use of quinine should also be considered.

3. A consideration of the importance, in the history of hemoglobinuric fever, of the immigration of Europeans into regions where the condition is endemic involves the history of the tropics and subtropics. . This factor is manifestly an essential in countries where the natives are nearly immune, as in parts of Africa. Historic events, which were probably potent in the development of blackwater fever, were the discovery of America, the Portuguese discoveries and settlements on the coast of Africa, the African slave trade and the later efforts to abolish the same, the advent to Africa of missionaries and explorers, especially in the early part of the nineteenth century, and the operations of the East India Company. The accession of Europeans was influential in the history of hemoglobinuric fever in several ways — by the increase of susceptible population, by the importation of quinine, and by the advent of physicians competent to recognize and to describe the disease.

Chapter II

North America. — In the United States it is chiefly the southeastern portion in which malaria is most prevalent. Along the Atlantic coast, south of New York and especially the lowlands of Maryland and of Virginia, and in the Carolinas, Georgia, and Florida the disease occurs frequently. Along the Gulf coast and up the Mississippi River and its tributaries malaria is widely prevalent. The portions of the States lying along the Appalachian Range are almost exempt, but the disease appears as the Mississippi River and the Atlantic coast upon either side are approached. West of the Mississippi, Arkansas, Louisiana, and Texas present the most numerous foci of malaria. In portions of Pennsylvania and New York autochthonous cases are not infrequently observed. In the more" southern New England States malaria is still encountered, and in some places is even increasing in frequency. In the neighborhood of the Great Lakes malaria is very rare, excepting, possibly, that of Lake Erie and of Lake Michigan. In the Central States malaria has almost or quite disappeared, except in certain low river valleys. Along the Pacific coast the disease is not so frequent as along the Atlantic. In Washington it occurs in the Puget Sound Basin and the Columbia River, Chehalis, and the Yakima valleys. In Oregon malaria is found in the Columbia, Williamette, Rogue, and the Umatilla valleys, and in California in the Sacramento, San Joaquin, Tulare, Kern, and Santa Clara valleys. In certain parts of New Mexico malaria is occasionally met with.