XII. BACILLARY DYSENTERY…

XII. BACILLARY DYSENTERY

HISTORY AND GEOGRAPHICAL DISTRIBUTION

=History.=—Epidemics of dysentery have been noted since ancient times, the widespread and fulminating nature of such outbreaks in times of war and famine having impressed observers in all ages. The disease is mentioned in the Ebers Papyrus (1600 B. C.).

Herodotus referred to an epidemic of dysenteric nature in the Persian Army and Hippocrates described the dysenteric syndrome. It has been known in India since remote times.

While the etiology of amoebic dysentery was thoroughly investigated and its connection with amoebae fairly well established during the decade from 1880 to 1890 it was not until 1898 that Shiga isolated the causative organism of bacillary dysentery. It is true that Chantamesse and Widal drew attention to a bacillus isolated from large intestines, mesenteric glands and spleen of cases of tropical dysentery but the organism was not clearly differentiated from Bacillus coli. Celli isolated an organism which coagulated milk and produced gas in glucose media. This organism which Celli called B. coli dysentericus, differs culturally from B. dysenteriae.

=Geographical Distribution.=—Bacillary dysentery differs from the amoebic form in that it tends to appear in extensive epidemics spreading over temperate as well as tropical and subtropical parts of the world.

It is peculiarly liable to follow the movements of armies in any part of the world and like typhoid fever its distribution is one of hygienic rather than geographical influence.

Infections with various strains of dysentery bacilli are important factors in morbidity among infants and young children in whatever part of the world the question has been investigated. The disease is prone to prevail in lunatic asylums whether in temperate or tropical parts of the world.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—During a very fatal epidemic of dysentery in Japan Shiga isolated an organism, Bacillus dysenteriae, from dysenteric stools of 36 cases, which bacillus he found to be agglutinated by the serum of the patients. He reported this work in 1898. In 1900, Kruse isolated an organism from patients in an epidemic of dysentery in Germany which corresponded to that of Shiga. In 1900, Flexner, Strong and Musgrave, working in Manila, not only encountered an organism similar to that of Shiga but also an organism of wider fermentative action. Dysentery has resulted from accidental laboratory infections and Strong produced dysentery in a prisoner condemned to death through ingestion of cultures.

In 1903, Hiss and Russell isolated an organism from a fatal case of diarrhoea in a child to which they gave the name “Y”.

On the whole, dysentery bacilli correspond culturally with the typhoid bacillus except in showing slightly weaker fermentative action on carbohydrates. The main point of difference however is their absolute nonmotility.

The characteristic of nonmotility is of greatest differentiating value and the reports of slight motility are probably from misinterpretation of molecular movement as motility. The dysentery bacilli do not form those thread or whip-like filaments so characteristic of typhoid cultures and are somewhat plumper. The dysentery bacillus is not found in the blood and hence is not eliminated in the urine, although recently there have been reported rare cases where dysentery bacilli were isolated from the blood. It is found in mesenteric glands. In dysentery patients agglutination phenomena do not show themselves until about the tenth day from the onset. Hence, this procedure is of no particular value in diagnosis. It is of value, however, to identify an organism isolated from the stools at the commencement of the attack, using serum from an immunized animal or a human convalescent for the agglutination test.

There seems to be only moderate agglutination power in the serum of convalescents from Shiga strains. Flexner strains give higher agglutinations, but early in convalescence the serum is not apt to have a titre of more than 1-150.

Dysentery bacilli produce a coagulation necrosis of the mucous membrane of the large intestine and occasionally of the lower part of the ileum. Polymorphonuclears are contained in the fibrin exudate.

It was formerly thought that these lesions were of local origin, but the present view is that toxins are produced which, being absorbed, are eliminated by the large intestine with resulting necrosis. Flexner, by injecting rabbits intravenously with a toxic autolysate, produced characteristic intestinal lesions. The toxin withstands a temperature of 70°C. without being destroyed. The toxin may cause joint trouble.

There are two main types of dysentery bacilli:

1. Those producing acid in mannite media—the acid strains (Flexner-Strong types).

2. Those not developing acid in mannite (Shiga-Kruse types). The Shiga type is very toxic in cultures, while the Flexner type seems to be less so. An organism resembling the Shiga bacillus but producing indol is the Schmitz bacillus. It does not appear to be pathogenic.

In immunizing horses for the production of antidysenteric serum it is customary to use both Flexner and Shiga strains, thus producing a polyvalent serum.

Lentz recognizes 4 types of dysentery bacilli for the differentiation of which he uses mannite, maltose and saccharose bouillon with litmus as an indicator.

------------+-------------+---------+--------+------- | Shiga-Kruse | Flexner | Strong | “Y” ------------+-------------+---------+--------+------- Mannite | Blue | Red | Red | Red Maltose | Blue | Red | Blue | Blue Saccharose | Blue | Blue | Red | Blue ------------+-------------+---------+--------+-------

The following table gives the more important cultural characteristics of the intestinal bacilli which might be confused with the various strains of dysentery bacilli.

Key for column headings: A - Motility B - Milk coagulation C - Glucose D - Maltose E - Lactose F - Mannite G - Saccharose H - Glucose neutral red bouillon I - Butt J - Slant K - Indol ------------------+---+---+-------+---+---+---+---+---+----+--------+--- | | |Litmus | | | | | | |Russel’s| | | | Milk | | | | | | | Medium | | | |-------| | | | | | |--------| | | |1st|3d | | | | | | | | | A | B |day|day| C | D | E | F | G | H | I | J | K ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. faecalis | | | | | | | | | | | | | alkaligines | + | - |Alk|Alk| O | O | O | O | O | O | O | O | - ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. typhosus | + | - | A | A | A | A | O | A | O | O | A |Alk | - ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. dysenteriae | | | | | | | | | | | | | (Shiga-Kruse) | - | - | A |Alk| A | O | O | O | O | O | A |Alk | - ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. dysenteriae | | | | | | | | | | | | | (Flexner-Strong) | - | - | A |Alk| A | A | O | A | O | O | A |Alk | - ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. dysenteriae | | | | | | | | | | | | | “Y” | - | - | A |Alk| A | O | O | A | O | O | A |Alk | + ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. Morgan No. 1 | + | - | O | O |A G| O | O | O | O | G | | | + ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. paratyphosus A | + | - | A | A |A G|A G| O |A G| O | G |A G|Alk | - ------------------+---|---+---+---+---+---+---+---+---+----+---+----+--- B. paratyphosus B | + | - | A |Alk|A G|A G| O |A G| O |G Fl|A G|Alk | - ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. enteriditis | | | | | | | | | | | | | (Gaertner.) | + | - | A |Alk|A G|A G| O |A G| O |G Fl|A G|Alk | - ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. coli | + | + | A | A |A G|A G|A G|A G| O |G Fl|A G| A | + ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. lactis | | | | | | | | | | | | | aerogenes | - | + | A | A |A G|A G|A G|A G|A G|G Fl|A G| A | - ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. cloacae | + | + | O | A |A G|A G|A G|A G|A G|G Fl|A G|Alk | + ------------------+---+---+---+---+---+---+---+---+---+----+---+----+--- B. proteus | | | | | | | | | | | | | vulgaris | + | | O |Alk|A G|A G| O | O |A G| G |A G|Alk | - ------------------+---+---+---+---+---+---+---+---+---+----+---+----+---

Of the above tabulated nonspore bearing, Gram-negative, intestinal bacilli only B. lactis aerogenes shows capsules and only B. cloacae and B. proteus vulgaris liquefy gelatin. In the table + = positive, - = negative, O = no change, A = acid, Alk = alkaline, G = Gas and Fl = fluorescence in neutral red bouillon.

=Epidemiology.=—There is probably no disease, with the possible exception of cholera, where those attending a patient are so liable to have their hands contaminated with infectious material.

The terrible frequency of the stools and the tendency of the mucilaginous mucoid mass to become smeared over the buttocks and clothing of the patient make it onerous for an attendant to carry out methods of personal protection. In a family, where the mother may have to care for a sick child, and prepare food for the other children and herself, the opportunities for the spread of the infection in the family are great. In military barracks, as well as in other institutions where large numbers make use of the same water-closet accommodations, the chances of contamination of the seat by a patient responding to the frequent and imperious demands for evacuation are most probable, with subsequent transference of the infectious material to others. Bacillary dysentery is peculiarly an institutional disease and tends to spread in jails, orphan asylums and the like. A carrier is a particular source of danger in such an institution.

Not only is there the danger from a patient ill with bacillary dysentery but as well that from the convalescent or chronic carrier. Such carriers are particular sources of danger where they take part in the preparation of food for others. It is now thought that the striking prevalence of the disease in insane asylums is associated with the difficulty of making such patients observe the proper care of their hands as well as their persons.

Friedmann has recently noted an outbreak of dysentery due to the Shiga type of bacillus which was instituted by a soldier returning to the barracks from a furlough.

There resulted 86 cases in the man’s regiment of which 49 belonged to his own squadron. The spread of the disease was traced to the latrines. The epidemic was suppressed by the enforcement of the most rigid rules of cleanliness especially as regarding washing of the hands after leaving the latrines.

The stools of the convalescents were examined and no man was discharged from hospital until his stools were negative for dysentery bacilli upon 3 successive tests in fourteen days.

Isolation of the bacilli from convalescents was obtained in 40 patients only for periods under fourteen days while with 27 others such carrying of bacilli lasted from two weeks to one month.

As the dysentery bacillus does not invade the blood stream we do not find it in the urine so that to a certain extent the dysentery bacillus carrier is less dangerous than the typhoid one.

There have been reports of isolation of Flexner and “Y” type bacilli from monkeys and rabbits but there is nothing to indicate that any other host than man is of importance.

Flies are undoubtedly of as much importance in the spread of bacillary dysentery as of typhoid.

The possibility of infection through the medium of soiled clothes, sent out for washing, is to be thought of.

There have been several instances of transference of the disease by the water supply.

In times of war, with large forces of soldiers, bacillary dysentery tends to become the most important disease encountered by military surgeons. During the Civil War there were 285,000 cases of dysentery in the Federal army.

It is possible that infectious material may be disseminated as dust and thus contaminate food.

PATHOLOGY

Injection of dysentery bacilli into the peritoneal cavity of guinea pigs causes a muco-sanguinolent diarrhoea with congestion of and haemorrhage into the caecum. There is also a haemorrhagic peritoneal exudate.

In the rabbit lesions similar to those in man are obtained as well as paralysis of the limbs.

It is therefore thought that there are two toxins concerned in the pathology of bacillary dysentery, one a neurotoxin which may cause a peripheral neuritis or joint trouble and the other a toxin which acts on the lower bowel, especially the caecum, with the production of congestion and coagulation necrosis of the mucosa.

Cases have been reported where the adrenals showed congestion and necroses, as if subjected to the action of a toxin.

In man we have an acute inflammation of the mucosa of the large intestines and, in the tropics, we frequently find the lower third of the ileum involved as well. In amoebic dysentery the process rarely extends beyond the ileo-caecal valve. A catarrhal process with hyperaemia and sero-purulent exudate is first noted, to be succeeded by fibrin formation in the mucosa, a process of coagulation necrosis. When the process invades the ileum there is no involvement of Peyer’s patches. Virchow noted the greater intensity of the process in the region of the rectum, sigmoid flexure and ileo-caecal valve.

As a rule, however, the entire large intestine is grayish red, looking like lustreless red velvet. Later on we may have irregular islands of grayish membrane formation surrounded by the red swollen congested gut. The solitary glands are usually swollen and may soften and ulcerate, having the submucosa as a base. Ulceration in bacillary dysentery is superficial rather than deep as with amoebic dysentery. The ulcers of bacillary dysentery involve the free folds of the intestine and extend transversely while amoebic ulcers run longitudinally. The intervening mucosa is unaffected in amoebic ulcerations while in bacillary ones it is inflamed.

Microscopically we note marked congestion of the blood vessels of the mucosa and submucosa with dilated lymph spaces full of polymorphonuclear cells.

In the mucosa we find an outpouring of pus cells which are entangled, along with the glandular structures of the mucosa, in a fibrinous exudate which causes necrosis of the mucosa (coagulation necrosis).

In chronic bacillary dysentery, according to Rogers, the lesions are limited to the lower portion of the large gut and rarely extend above the descending colon.

In this region one finds serpiginous ulcerations separated by islands of mucosa. Willmore and Savage have noted autopsy findings of what was practically a large granulating surface over the whole large intestine, in cases which had apparently recovered, with the exception of a prolonged convalescence.

SYMPTOMATOLOGY

Bacillary dysentery usually runs an acute course, rarely relapsing and but occasionally going on to a chronic condition. The period of incubation is usually from two to seven days although accidental infection with bacilli in the laboratory has given an incubation period approximating twenty-four hours. Periods of incubation longer than a week can probably be explained as for cholera, such cases being in those who are healthy carriers, but by reason of some gastro-intestinal upset the quiescent bacilli take on pathogenic activity.

In temperate climates and in particular when the infecting organism is a Flexner type the case may appear as a watery diarrhoea associated with colicky pains and anorexia. The stools soon become more scanty in amount, frequent in number and associated with straining. This is followed by mucous stools more or less tinged with blood. The temperature is normal or but slightly elevated and the patient does not seem ill.

In the tropics and in temperate climates where the Shiga type bacillus is the infecting organism the onset is usually rather sudden with malaise, abdominal pain and a diarrhoea, which only temporarily relieves such pain. This initial diarrhoea is soon followed by the characteristic dysentery stool and the pains, which latter tend to centre about the umbilicus and to become continuous. There is usually loss of appetite and slight nausea and the patient may at times show a very slight tendency to flightiness. The mind however is usually clear. Fever of moderate degree is not uncommon and it may be quite marked,—up to 104°F. Ingestion of food or drink or any movement of the body brings on a desire for defecation.

The number of stools, which in mild cases number 15 to 30, may become excessive, even more than one hundred in twenty-four hours, and the tenesmus most torturing, so that excoriations around the anus and at times prolapse of the bowel intensify the distressing clinical picture. In acute cases the stool may be almost pure blood with only an admixture of mucus.

Vesical tenesmus may be present and the urine may be diminished in amount.

There is a toxic effect on the heart so that the pulse tends to become accelerated and weak. Bacillary dysentery may show a moderate leucocytosis with increased polymorphonuclear percentage instead of a large mononuclear one as with amoebic dysentery.

At times, however, the lymphocytes may be the leucocytes showing the greatest relative increase.

Collapse Types.—In the most severe types of dysentery we may have an abrupt onset with rigors and vomiting and a high fever. This fever gives way to a subnormal temperature and the patient shows signs of collapse and such a case may die without having passed dysenteric stools. The abdomen is rigid and very tender on palpation.

Entero-dysentery.—In those cases where the process extends to the lower portion of the small intestine the general symptoms are much more severe although the tenesmus is less and the stools less frequent and more voluminous. They contain much blood and mucus mixed with feculent material. Shiga calls such cases entero-dysentery.

In severe cases of the more typical dysentery or colodysentery, as designated by Shiga, the stools may change from the mucopurulent mass to a serous discharge which is very rich in albumin and of an albuminous odor. In such cases emaciation of the patient is very rapid. Such cases may show signs of collapse with cold clammy skin and the clinical picture one associates with cholera.

It has been suggested that such cases may be due to action of the dysentery toxins on the adrenal.

This serous fluid may contain the flesh-like particles which the French liken to gut scrapings. During convalescence there may be an arthritis, which however does not impair the function of the joint.

=Complications.=—In addition to the arthritis there may be neuritis, which, in severe cases, may go on to muscular atrophy. In the arthritis the knee joint is that most frequently involved. This complication appears late in the course of the attack. Arthritis may be frequent in one epidemic and absent in another. The joint swelling usually clears up completely. Some of the reported joint involvements are undoubtedly serum reactions from antidysenteric serum treatment. Rarely in Shiga infections we may have an irido-cyclitis. Subnormal temperature may follow severe attacks.

In some epidemics of dysentery gangrenous manifestations have been common. This is a very fatal type and is recognized by the passage of dark-brown serous discharges containing ashy gray to black sloughs or even tubules of gangrenous mucosa, the stool having a putrid odor. The general symptoms are pronounced, there being a dry glazed tongue, and low muttering delirium with a thready pulse. It is the typhoid state.

It is usual to consider bacillary dysentery as a self-limited disease, running on to convalescence within ten days or two weeks.

Rogers has called attention to the importance of bearing in mind a chronic condition as well as the acute one. In these chronic cases the ulcerations are usually located in the descending colon, sigmoid flexure or rectum and give rise to frequent stools containing blood and mucus and causing a progressive loss of strength and weight. There is marked digestive disorder and the patient becomes weak, anaemic and neurasthenic.

DIAGNOSIS

In the presence of the dysenteric syndrome of tormina, tenesmus, frequent scanty stools of muco-purulent or muco-sanguinolent character, one must keep in mind the various conditions which may give rise to such manifestations of dysentery and not diagnose a bacillary dysentery until we have excluded tuberculous, cancerous and syphilitic processes as well as those connected with schistosome or other helminthic infections.

=Clinical Diagnosis.=—Amoebic dysentery is differentiated clinically from bacillary dysentery by the usual absence of manifestations of toxaemia and by its insidious onset and chronic course.

It is important however to remember that either bacillary or amoebic dysentery may show gangrenous manifestations and in such cases the clinical picture of the typhoid state is the same whether the process is amoebic or bacillary. Fulminant bacillary dysenteries may greatly resemble cholera in its algid stage.

Tropical liver abscess is a complication exclusively occurring in the amoebic form of dysentery while joint manifestations and evidences of multiple neuritis may be noted in some epidemics of bacillary dysentery. Again, the toxins of the dysentery bacilli have a tendency to damage the myocardium. At present we consider the good effects of the administration of emetine as important in the diagnosis of amoebic dysentery.

It is important to remember that chronic dysentery may result from bacillary as well as amoebic infections, although a chronic process is more a feature of amoebic dysentery.

The muco-purulent stool of bacillary dysentery is more of a milky whiteness and flecked or streaked with blood or a very viscous bright blood-tinged mucus rather than the homogeneous, grayish brown, gelatinous mixture of disintegrated blood and mucus of the amoebic one. The odour is apt to be foetid in amoebic stools but rather albuminous with bacillary dysentery ones.

=Laboratory Diagnosis.=—The chief point is to determine whether we are dealing with an amoebic or bacillary infection. While these two kinds of dysentery may coexist it is practical to consider a case in which amoebae with long, rapidly extruded, finger-like pseudopodia and containing red blood cells are found, as one of amoebic dysentery.

A fresh specimen of the muco-purulent stool of bacillary dysentery shows, in addition to pus cells, numerous large, phagocytic cells, which may show vacuolation and strikingly resemble amoebae. Such cells never show motility but, under conditions of lowered temperature of specimen or from prolonged standing and beginning disintegration, the amoebae too fail to show motility. If mounted in Gram’s iodine solution these large cells show a much larger nucleus than that of amoebae and take the yellow staining of iodine more intensely. The best method, however, is to make a smear, fix it by heat and stain by Gram’s method or with Loeffler’s blue or dilute carbol fuchsin. These confusing cells stain easily and perfectly and in the Gram specimen we note the Gram-negative bacilli in the cytoplasm. Giemsa’s stain, with methyl alcohol fixation, or the usual Wright or Leishman technique answer equally well. On the other hand it is rather difficult to obtain satisfactorily stained amoebae in this way, it usually being necessary to fix moist thin smears of the stool with some bichloride fixative, as Zenker’s fluid, and then carry out the staining with haematoxylin.

The Stained Smear.—The presence of pus cells as well as endothelial cells in a stained smear of material from a bacillary dysentery stool is of value in differentiating from an amoebic stool smear in which pus cells are rarely seen. The amoebic dysentery smear gives more the picture of granular débris.

We should always examine a stool as soon after it is passed as possible.

If the microscopical examination indicates a bacillary infection we should take a small mass of the stool, wash it in sterile water and then drop it in a tube of sterile bouillon or salt solution. After emulsifying in this tube of bouillon we take up 2 or 3 loopfuls of the emulsion and deposit them on a poured plate, later smearing out with a glass rod, either by successive parallel strokes or by revolving the plate while smearing the surface with the glass rod. It is in the first two or three days of an attack of acute dysentery that we obtain the best cultural results, often noting a pure culture of dysentery bacilli from proper material taken at the onset. Manson-Bahr states that he has never recovered true dysentery bacilli from a purely faecal stool. Even faecal contamination of the mucoid mass makes it difficult to recover the organism. Dysentery bacilli rapidly die out if the stool is acid so that it has been recommended to make the stool strongly alkaline where it has to be sent to a laboratory from a distance.

It has seemed to me that litmus lactose agar gives results more surely than the more restraining faeces-plating media. Still I generally use Endo’s fuchsin agar because it is always at hand for typhoid or paratyphoid culturing and gives good results. The dysentery bacillus colonies on this medium are like those of typhoid—grayish white. In England they prefer MacConkey’s neutral red bile salt agar while others use the Conradi-Drigalski medium. We are now using the Teague medium, which is taken up in the chapter on Faeces. On all these media the colonies resemble those of typhoid and the differentiation is most easily made by examining for motility. At the same time one not infrequently finds lack of motility in bacilli from colonies just isolated on Endo’s medium which later on in subculture show motility and are found to belong to the typhoid or paratyphoid group. For the sure determination of dysentery bacilli or for differentiating the Flexner and Shiga strains one should carry out agglutination tests.

The isolation of dysentery bacilli from chronic cases or from convalescents is more difficult as a rule and agglutination tests may be more practical. A trouble is that an agglutinating effect may be connected with a prior infection.

Although some observers have noted the appearance of agglutinins in the serum of cases of acute bacillary dysentery within three or four days from the onset of the disease, yet it is usual not to obtain agglutination with the patient’s serum before the tenth day. With the Shiga strains agglutinating power in 1 to 50 is usually accepted as evidence of specificity but for Flexner strains we generally have a higher titre so that a dilution of 1 to 150 should be required for the test.

Ritchie has recently tested the sera of 792 normal persons and found that 30% of these individuals agglutinated Shiga bacilli in 1 to 32, while with Flexner strains 41% agglutinated in 1 to 64 and 30% in 1 to 128. For comparison Ritchie’s results with typhoid showed that only 6% agglutinated such bacilli in 1 to 16. There is some evidence that typhoid vaccination increases the agglutinating power of the serum against dysentery organisms. These findings are remarkable, as the usual advice is to consider an agglutination of 1 to 30 as fairly specific for Shiga infections and 1 to 100 for Flexner ones.

Willmore and Savage tried heating serum to 56°C. for thirty minutes, but found that such a procedure was of no practical value with dysentery, thus differing from Malta fever serum where such a procedure is of value in destroying coagglutinins and thus increasing the specific action. The work of Ohno would indicate that we should trust to the acid-producing effect on mannite for differentiating Flexner and Shiga strains rather than on agglutination because it was found that agglutinins for an acid strain were not always more specific for such strains than for nonacid ones.

At the same time it is the rule for a Flexner type bacillus to show specificity for its serum and the Shiga type for the serum of the more toxic, nonacid-fast Shiga strain cases. The statement of Willmore and Savage that the differentiation of bacillary dysentery infections is a refinement of technique seems a proper view because with a polyvalent serum for treatment one only needs to know that the case is one of bacillary dysentery for proper treatment. Of course with a monovalent serum, effective only for the Shiga bacillus, one would have to determine whether the organism producing the dysentery was of that strain.

As a matter of fact it takes considerable time and laboratory skill to carry out reliable cultural and serological tests.

From a practical standpoint we can use the therapeutic polyvalent serum for agglutination and any organism recovered on the plate made from the faeces which agglutinates in 1 to 50 or 1 to 100 may be considered as diagnostic of bacillary as against amoebic dysentery. Often one does not see a case of dysentery until late in the disease and then, provided the condition is serious and the diagnosis points to a bacillary infection it would be better to inject the curative serum rather than await laboratory confirmation.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—The ease with which water-closet seats may be contaminated should make us pay great attention to their disinfection during an outbreak of bacillary dysentery. The same applies to the bedclothes of such patients sent out for laundering.

Great care should be given to the washing of one’s hands prior to eating. The greatest care must be taken with rectal tubes when used for treatment. It is better to make an invariable rule to confine the use of a single tube to a single patient, as the rubber tubes are difficult to disinfect other than by boiling and such treatment, especially in the tropics, soon ruins the tube. For disinfecting tubes a 5% solution of liquor cresolis compositus is good. The tubes should be thoroughly washed of the disinfectant before using again. For disinfection of faeces one can use an equal portion of the above disinfectant to a similar amount of stool leaving the disinfectant to act on the stool at least one hour before emptying the receptacle. Soiled clothes should be disinfected in a 2½% solution of the compound cresol solution. Flies must be kept in mind and water and milk supplies boiled. The carrier is of as great importance here as in typhoid or cholera, especially when assisting in preparing food.

=Vaccination.=—Vaccination against dysentery does not seem to have made much headway owing to the very severe reactions following injections of killed cultures of the Shiga bacillus. By injecting such bacilli treated with an immune serum (sensitized) the reaction is less severe.

Dean reports the value of treating the emulsion of organisms with an equal amount of 1 to 1000 eusol. Gibson treated a suspension of dead organisms with an equal amount of serum, mixing in the syringe at the time of injection. Although this method was used during the war its immunizing value was not settled.

The question of the best method of preparing vaccines for prophylactic use is still unsettled. The greatest difficulty has been experienced in making vaccines of the Shiga bacillus on account of the great toxicity of such preparations.

The serum alone is used almost exclusively for curative rather than prophylactic purposes.

=Treatment.=—In the treatment of bacillary dysentery absolute rest in bed is important to keep up the strength of the patient and also to protect the heart which tends to be more or less damaged by the toxic action of the Shiga bacillus. Some prefer to prop up the patient in bed, considering a strict dorsal decubitus as undesirable. It is important to use sufficient covering on the patient to avoid chilling. A light wool blanket spread over the abdomen is often all that is needed in the tropics.

Some authorities deal with the subject of treatment without referring to any other means than the administration of serum. This probably is the proper attitude when the very fatal Shiga type infections are encountered. It must be remembered that certain epidemics, which as a rule are associated with the Shiga type bacillus, give a very high mortality (20 to 40%) while other epidemics seem associated with a less virulent strain of this bacillus.

At any rate when a case is seen early it would seem advisable to give about 2 grains of calomel in divided doses of ¼ grain every half hour and then follow it up with saline treatment. Most authorities recommend a preliminary dose of castor oil. During the first day or two enemata of normal saline, boric acid or 1½% sodium bicarbonate solution in 2 pint amounts would seem indicated as assisting the salines in the elimination of toxic material. After that time the tenesmus and rectal irritation make the use of the rectal tube too trying to the patient. I have used the Murphy protoclysis method with a certain degree of success, but this procedure cannot be kept up long. Hot fomentations to the belly relieve the griping pains.

The saline treatment is highly recommended by Buchanan who gives 60 grains of sodium sulphate every two or three hours until the dysenteric character of the stool disappears.

Bahr in the Fiji islands treated 53 consecutive cases, of which 41% had marked constitutional symptoms, with a mortality of 13.2%. He gave 1 dram of sodium sulphate every hour for the first day and subsequently the same dose every four hours.

In a second series of 106 cases, of which 42% had marked constitutional symptoms, he treated 34 with salines plus the administration of capsules of cyllin. The remaining 72 cases received in addition to this treatment injections of a polyvalent serum obtained from the Lister Institute. The mortality in this series was 1.8%. He notes that 5 of the cases in this second series were of the severest type as evidenced by the gangrenous stools and toxic condition and yet not one of these five serum-treated cases died. He notes that the stools of those who received serum injections became normal in five days for an average while for those treated with saline alone the average period was eight days.

Bahr strongly recommends the combined treatment of salines and serum. In very severe cases Bahr used 50 to 70 cc. of the serum but ordinarily 20 cc. for adults and 10 cc. or less for children.

Willmore and Savage think one obtains the best results by injecting from 80 to 120 cc. of a polyvalent serum into the subcutaneous tissues of the flank or abdomen or intravenously. They think that anaphylaxis is less liable to follow a massive initial dose of serum.

In the use of serum Shiga recommends a dose of 10 cc. for a mild case or two injections of 10 cc. at intervals of ten hours for cases of medium severity, while in very toxic cases he uses 60 cc. in 3 daily doses of 20 cc. each. It is important to use serum early as it has little or no effect if used after the 7th day (Klein).

The best known sera are those of Shiga, Dopter and that prepared by the Lister Institute.

Animal charcoal and bolus alba are considered of value by some physicians. Opium should be avoided. Intravenous saline injections are of value in cases showing collapse signs. Again, such cases, from the standpoint of possible adrenal insufficiency, may be helped by adrenalin. Where there is a very small rapid pulse with marked cardiac weakness injections of camphor in oil may be of value.

Subcutaneous injections of ordinary or hypertonic saline containing about 10 drops of 1 to 1000 adrenalin solution is of value in collapse.

Ross considers opium as of value in dysentery and states that he regards ipecac as of value not only in amoebic but in bacillary dysentery as well. I have often given salol-coated pills containing 1 grain of ipecac and ⅙ grain of calomel every two hours to cases of bacillary dysentery with apparent benefit.

For the diet of cases of acute bacillary dysentery albumin water or barley water sweetened with lactose is to be preferred to milk, which is usually not well borne by such patients. Kendall has noted the value of sugar of milk in lessening the toxicity of various organisms. Tea sweetened with lactose is usually well borne. Meat juice expressed from a piece of lightly broiled steak is good. Various jellies or sago pudding are of value. Willmore and Savage praise yoghurt.

Unless given in small amounts liquid diet is apt to increase evacuations and some cases seem to do better on ordinary diet.

In the tropics there are many brands of sterilized natural milk and these can be inoculated with a culture of B. bulgaricus.

In chronic bacillary dysentery Rogers recommends 1 to 1½ pint enemata of albargin in strength of 1 to 500. Protargol seems to be equally efficient in the same strength. Owing to the effect of organic material on silver nitrate this salt does not seem so reliable as the organic silver compounds. It has also been recommended to flush the colon with warm boric acid solution. Another recommendation is to use milk for this purpose. Vaccine treatment has been employed, in cases of chronic bacillary dysentery. Either eusol-treated organisms or those sterilized by 0.25% trikresol are to be preferred.

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XIII. PLAGUE

DEFINITION AND SYNONYMS

=Definition.=—Plague is primarily a disease of rats or other rodents and is caused by a bacterium of the haemorrhagic septicaemia group, Bacillus pestis. The disease exists in the rodent in both an acute and chronic form. Acute plague of the rat is apt to be septicaemic, so that when certain species of fleas which infest the rat feed on the blood of their host they ingest plague bacilli. These seem to multiply in the region of the proventriculus and cause thereby an obstruction to the stomach. As a result the flea makes vigorous and repeated but ineffectual efforts to feed. Regurgitation of the contents of the oesophagus occurs, thereby inoculating plague bacilli. When the rats die these fleas will attack man and cause human plague. The ordinary type in man is bubonic plague, characterized by extremely tender glandular enlargements. This form of the disease is thought to be exclusively transmitted from man to man by fleas or possibly bedbugs. A second type is pneumonic plague which is a surely fatal pneumonia which is transmitted from man to man by droplets of sputum expelled in coughing. Either the bubonic or pneumonic types may become septicaemic or this form may exist from the start.

Plague shows a marked clouding of the consciousness from the onset and is characterized by toxic action on the heart and endothelial lining of capillaries.

=Synonyms.=—Oriental Plague, Black Death, Pestis. French: La Peste. German: Die Peste.

HISTORY AND GEOGRAPHICAL DISTRIBUTION

=History.=—Ancient writers were accustomed to apply the designation “plague” to any disease which was epidemic in character and attended with great mortality. This explains why the plague of Athens and that of Marcus Aurelius, which epidemics did not possess the characteristics of oriental plague, were so designated. There exist however writings which show that fatal epidemic diseases attended with buboes and prostration were noted prior to the Christian era.

It is probable that the biblical description of a disease among the Philistines which was attended with buboes and killed the mice of the field referred to plague.

In the 6th century, during the reign of Justinian, a disease which was unmistakably plague started from Egypt and reaching Constantinople caused the death of 10,000 persons in one day. It spread throughout the entire Roman empire.

The “Black Death.”—The most noted epidemic of plague was that of the “Black Death” of the 14th century. The disease seems to have originated in the East, possibly in China, and eventually invaded Asia Minor, Egypt and Europe. The disease was called “Black Death” in Germany, on account of the petechial spots or “tokens” and in Italy, the “Great Mortality.”

In the records of the epidemic we note that it was attended with great stupefaction, the sick losing their speech from palsy of the tongue. Others noted buboes of groins and arms while some noted a putrid inflammation of the lungs with the expectoration of blood. In the plague at Avignon it was noted that at first, for six or eight weeks, the sick expectorated blood and that to come near them was certain death. Afterwards buboes appeared in groin and axilla and some of the sick recovered.

Quarantine.—It was during this epidemic that quarantine became a recognized procedure in Europe. The adoption of a period of detention of forty days probably originated in the medical idea that the 40th day was the last day of ardent diseases, this being one of the critical days. The lazarettos, where strangers were held in quarantine, appear to have first been established on some island near Venice, in 1485.

It has been estimated that one-fourth of the population of Europe succumbed to the “Black Death,” but estimates in certain parts of Europe would indicate a mortality approaching 70% of the inhabitants.

In 1665 occurred the Great Plague of London, during which year it was estimated that approximately 60,000 out of a population of 450,000 died. It was thought that this epidemic was introduced from the Levant by way of Holland.

There was much plague in Europe in the 18th century but it would seem to have completely disappeared by 1841 and only to have returned with the present pandemic.

The Present Pandemic.—The plague epidemic with which all parts of the world are now so concerned is supposed to have originated in China, in the province of Yunnan, and from that center to have reached Canton, in 1894, causing the death of 60,000 people in a population of 1,500,000. In the same year it extended to Hong Kong and from that great seaport has spread over the entire world. India has suffered more than any other country, there having been years when the plague deaths exceeded 1,000,000.

In a recent article by Low it is noted that the highest death rate was reached in 1907 when 1,315,892 persons died. From the time of the introduction of plague into India to the end of 1917 there were 9,841,396 deaths from this disease.

In its spread it has invaded Europe, Egypt, South Africa, Australia, Japan, Philippine Islands, California and parts of Central and South America. It has recently made its appearance in New Orleans.

=Geographical Distribution.=—At present there are only two important foci of endemicity, one Mesopotamia and another in the region of the Himalayas (India, Thibet and Yunnan). There also seem to be less important centers in Uganda, in Africa, and in the trans-Baikal region of Siberia. In view of the rather widespread infection of the California ground squirrels, from which rodents the disease has from time to time spread to man, it would seem probable that California might be considered another focus of plague.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—The bacillus of plague was first isolated by Yersin from a plague bubo, in 1894, at Hong Kong. It is true that Kitasato reported a bacillus which he had isolated from the blood of a plague patient, on July 7, 1894 (Yersin’s report was made July 30, 1894). Kitasato’s bacillus was motile, Gram-positive, coagulated milk and gave a turbidity in bouillon, characteristics which were just the opposite of those of the organism reported by Yersin.

As now recognized the plague bacillus, when in smears from pathological material, shows the form of an oval bacillus, the ends of which stain more intensely than the central portion (bipolar staining). When cultured on ordinary agar, the morphology is more rod-shaped with a tendency to pleomorphism.

These agar cultures are very sticky and mucilaginous. If 3% of NaCl is added to the agar, this pleomorphism is exaggerated, there occurring coccoid, root-shaped and various bizarre involution forms.

For obtaining the involution-form appearance on 3% salt agar one should transfer liberally from the ordinary agar growth to the salt agar rather than planting direct from the pathological material.

A bouillon culture, upon the surface of which there has been deposited drops of oil or melted butter, shows a string-like downward growth from the under surface of the oil globules. This “stalactite” growth is very fragile and is difficult to obtain.

Ordinary bouillon cultures show a rather powdery deposit at the bottom and a hanging-drop preparation from such a culture shows chains of plague organisms resembling streptococci. Gelatine is not liquefied. Bacillus pestis grows readily at room temperature as well as at 37°C, and one may be struck with the fact that colonies on agar plates may show variations in degree of development so that the suspicion of a contaminated culture may arise. Human plague material for cultures or smears is best obtained from the bubo prior to suppuration in bubonic plague, from the blood in septicaemic plague and from the watery sputum in pneumonic plague.

Plague in the Rat.—With acute plague in the rat one finds marked injection of the subcuticular surface of an exposed abdominal flap; certain glands, especially the neck ones, show marked congestion, haemorrhagic necrosis and periglandular infiltration; the pleural cavity contains much fluid; the liver has a yellow mottled appearance liberally sprinkled with discrete, yellowish-white granules about the size of a pin’s head, while the spleen is enlarged. Smears from the spleen or affected glands, as a rule, show the bacilli in great numbers. The San Francisco findings in plague rat autopsies varied somewhat from those noted above, which held for Indian plague rats.

Confusing Organisms.—Other organisms which may be obtained from plague-suspected material are those of the proteus or colon group, which may show bipolar staining, but culturally are quite different. Klein has noted that a nonmotile rod, which gives a striking bipolar staining and named Bacillus bristolensis, may be mistaken for the plague bacillus. Its growth in bouillon is similar to that of B. coli and it coagulates milk.

An organism, B. pseudotuberculosis rodentium, resembles the plague bacillus in a striking manner but is without virulence for rats. It is virulent however for guinea pigs and these animals can be immunized against plague with this closely related organism. Litmus milk cultures of plague show a very slight acidity while with B. pseudotuberculosis rodentium there is a high degree of alkalinity produced.

Wherry has reported two cases of ulcerative conjunctivitis with lymphadenitis of cervical glands, fever and marked prostration, due to infection with B. tularense, occurring in persons who had handled rabbits which had died of this plague-like infection. The organism was first noted by McCoy in squirrels in California. The symptoms and lesions in these animals are those of plague. Guinea pigs succumb after the cutaneous inoculation of material and show lesions markedly resembling plague. The organism, however, will not grow on ordinary simple media as does the plague bacillus. As will be noted in the chapter on Tularaemia the disease has a very limited geographical distribution.

The crucial test for any plague material is the power of the plague bacillus to infect a rat or guinea pig, when the material is rubbed on the shaven skin of the animal. B. tularense will also pass through intact shaven skin and it produces lesions in the guinea pig similar to those of plague. Other organisms, however which might infect through intact skin produce lesions unlike those of plague. As a practical point it may be stated that cases showing a profusion of oval, bipolarly staining bacilli, in smears from glands or sputum, and with clinical manifestations of plague, are not likely to be other than plague; still, to be conservative, one should always inoculate animals cutaneously or subcutaneously.

=Epidemiology.=—Plague is primarily a disease of rodents, usually rats, and man contracts his infection from these animals. With the exception of pneumonic plague which, under certain circumstances, is transmitted directly from man to man, plague infections originate from the bite of fleas which have become infected from feeding on the blood of plague rats. Infected fleas act as intermediaries in plague epizootics among rats. It is true that a rat might become infected from bites received in a fight with an infected rat, or man might be infected through a cut on a finger while handling plague material, but such methods play but a small part in plague epidemiology.

Fleas and Plague.—In 1897, Ogata infected mice by inoculating them with an emulsion of crushed fleas taken from plague rats. In 1898 Simond showed that if a rat, dead of plague, were placed in a large bottle and a healthy rat confined in a small cage introduced into the bottle and suspended above the dead rat, so that there could be no contact between the dead and the living animal, the well rat would contract the disease. If however the fleas were removed from the dead rat, before the introduction of the caged rat, no infection took place.

By reason of claims that the rat flea would not bite man these convincing experiments were in a measure disregarded. The complete confirmation of the correctness of this view, as to transmission of bubonic plague, was brought about by the Indian Plague Commission. In a large number of experiments it was shown that when healthy and plague-infected guinea pigs were confined together in spaces where there were no fleas, there were no plague infections of any of these well animals.

On the other hand in 35 experiments, when fleas had access to the spaces, plague infections were the rule. Again, guinea pigs in cages which were suspended only two inches above a plague flea infected floor, became infected, but other animals, which were suspended so high that the fleas could not jump up to them, remained well. Two cages, each containing a monkey, were placed in a plague flea infected room. One was surrounded with a protecting zone of 6 inches of “tanglefoot” fly paper, this being the limit of the distance a flea can jump, while the other cage was not so protected. The monkey in the cage without the sticky paper contracted plague while the second monkey remained well. It is only when there is a great incidence of plague among rats that we have outbreaks of bubonic plague in man, and it has been noted that the greater the epizootic, the more heavily infected was the blood of the sick rats with the plague bacilli. A flea with a stomach capacity of about ½ c.mm. could take in several thousand plague bacilli in a feeding on a rat whose blood was teeming with bacilli. The blood of a rat dying with plague may contain as many as fifty million bacilli to the cc. Human blood rarely contains more than a million to the cc. There is a multiplication of the organisms in the flea, so that when it defecates, thousands of plague bacilli are deposited near the puncture wound made by the flea when subsequently feeding on a man. The infected faeces are rubbed into the wound by the man in scratching the site of the bite, so that we have here an instance of a contaminative method of infection as contrasted with the inoculative method by the mosquito in malaria.

Bacot and Martin have shown that while infection may take place as the result of the faeces being rubbed into the wound made at the time of feeding yet the ordinary way is probably by regurgitation from the oesophagus of the flea at the time of feeding.

Upon taking in plague septicaemia blood the bacilli multiply about the site of the proventriculus as well as distending the oesophagus. This makes an obstruction to the entrance of the stomach resulting in starvation of the flea. This naturally makes the flea more voracious and in the ineffectual muscular efforts to take in blood, regurgitation of the contents of the oesophagus occurs, thereby infecting the person upon whom the flea is trying to feed. This obstruction apparently may be overcome in some way as the plague-infected flea does not necessarily die. Still from lack of sufficient fluid such fleas are liable to be killed off if the relative humidity is low, as in dry weather. Further investigations have shown that the proventricular plug may be channeled, but in such case valve action is lost and the contents of the stomach are regurgitated, thus making such a flea more dangerous than one with an obstructed proventriculus. Such fleas may continue infectious for 67 days.

Very interesting in this connection is the fact that Heiser found plague-infected fleas in the desk of a European at Manila who died of plague. A mummified rat was found in one of the drawers of this desk, from which successful animal inoculations for plague were made. Heiser notes that data would indicate that these fleas probably remained alive 2 weeks after the death of the rat which brought about their infection. Another very striking finding during the same Manila plague outbreak (1912-1913) was that bedbugs found on the sleeping mat of a human victim of plague showed bipolarly staining bacilli.

Bacot has carried on experiments in which fleas infected two months previously and kept in a cool place could transmit plague. This would indicate the danger from plague-infected fleas which had been held in material packed away in boxes.

Method of Spread.—The spread of plague epizootics among rats seems to be rather by the fierce brown sewer rat, Mus norvegicus. The more delicate black house rat, Mus rattus, usually receives its infection from the sewer rat. When the rat dies the fleas leave the dead body and seek a new host, preferably one similar to the one just abandoned. The sewer rat reaching the basement of houses and dying of plague is deserted by his fleas. These will attach themselves to the house rats which go from basement to roof of the house and later these dying are abandoned by the fleas which, in the absence of a rodent host, will feed on man and infect him.

The house rat is rarely found in Europe while in many parts of the tropics it is common and in close association with man. The fact that the sewer rat avoids the upper portions of houses probably explains the greater infrequency of plague epidemics in Europe where this rodent is common. In former ages when the house rat was prevalent in Europe we had great epidemics there. Mus (Rattus) norvegicus is of stout build with a blunt nose and small opaque ears which barely reach the eyes when laid forward. The tail is shorter than the length of the head and body together (89% of such length). With Mus rattus we have a delicately built rat with a slender head and sharp nose. The ears are translucent and large and reach beyond the middle of the eye when extended. The rather delicate tail is about 25% longer than the length of the head and body taken together.

Recently it has been found that a guinea pig set free in a house suspected of having plague fleas becomes infected if such fleas are present. The fleas would probably prefer the guinea pig to man and such a measure would in some degree be protective to man. It is however for the detection of plague infection that the measure is employed and the guinea pig is termed the “Plague barometer.” In Madras there is practically an absence of Mus norvegicus although Mus rattus is present in numbers and the comparative freedom of the city from plague is striking.

The principal rat flea of the Orient is Xenopsylla cheopis. This flea is without combs like Pulex irritans, the human flea, but is of a lighter color and has an ocular bristle near the upper margin of eye and two bristles posterior to the antennae. In Europe and the United States Ceratophyllus fasciatus is the common rat flea. Many other species of fleas transmit plague and it is also possible that the bedbug may play a part in spreading infections from man to man. Vergbitski has transmitted plague from man to the rat by infected bedbugs. In Siberia, a marmot, the tarabagan, is supposed to play the part of the rat in plague transmission. In California, the ground squirrel, Citellus beecheyi, has become infected and may transmit the disease by its flea, Ceratophyllus acutus. In the Tropics plague tends to prevail only at times when the temperature is between 10° and 30°C. It is the effect on the flea of cold weather which causes the disappearance of bubonic plague at such times. The bacillus of plague can withstand freezing temperatures. Sunlight and drying are the especially inimical factors for B. pestis. Dry seasons are inimical to the spread of plague and it is especially in very rainy seasons that epidemics rage.

Chronic Plague in Rats.—The Indian investigators have called attention to the existence of a chronic plague in rats. In this we have chronic buboes, areas of necrosis in spleen and abscesses of the spleen. It is chiefly in the spleen that the lesions occur, thus differing from the acute plague in rats above described. Of 27,699 M. norvegicus, examined in Bombay, O.57% showed signs of chronic plague.

In the necrotic material plague bacilli can be found in approximately one-half of these rats although frequently the bacilli are nonvirulent. It is possible that this chronic plague in rats may serve as the reservoir of infection which keeps up plague epizootics from year to year. Plague in India, according to White is less virulent now than formerly and this is attributed to a greater immunity of the rats.

As regards pneumonic plague the origin of such epidemics is probably from pneumonia occurring secondarily in cases of bubonic plague. Provided the conditions are favorable, particularly as to moisture in the air of the room, the infection spreads directly from man to man as a result of the droplets of heavily infected sputum being sprayed into the air in the act of coughing on the part of the patient. It is an instance of Flügge’s droplet method of infection.

In the recent epidemic of pneumonic plague in North China, it was at first thought that the hunting of the tarabagan for its valuable skin, which led some of the Chinese to even capture tarabagans, possibly sick with plague, was the origin of the epidemic. This view is no longer held and we now know that the outbreak was independent of any disease in rats, tarabagans or other animals. Strong has shown that the bacillus which was isolated from these cases of pneumonic plague was identical with that isolated from cases of bubonic plague; its virulence was no greater and animals infected cutaneously or subcutaneously died of bubonic plague. Experiments by Teague and Barber, with emulsions of plague bacilli, showed that with a room temperature of 32°C. plague bacilli were quickly destroyed when the air was comparatively dry. In such an atmosphere, saturated with moisture, the viability would be greatly prolonged. In the plague wards in Manchuria the extreme cold which prevailed, together with the saturation of the atmosphere of the unventilated rooms by the moisture of the breath of the patients, made conditions most favorable for the viability of the plague bacillus. They note that in the plains of India, although about 3% of bubonic cases assume a pneumonic type, yet epidemics of plague pneumonia do not occur; this is probably due to the fact that the higher temperatures and open rooms make evaporation occur 30 times more rapidly there than was the case in the plague wards in the bitter cold weather of the Manchurian winter. The possibility of carriers of plague bacilli in those who might go on to convalescence need not be considered, as practically all cases of plague pneumonia die. Other material from the patient than sputum does not seem to be a source of danger in the spread of plague, so that there is no need for the disinfection of urine and feces. There has recently been an outbreak of septicaemic plague in Ceylon in which there was an absence of plague in the rats. The infection was possibly transferred directly through bedbugs or human fleas. As a matter of experience the transference of plague from place to place generally occurs from infected rats or infected fleas which have been transported by ships. A case of bubonic plague in a ward with other patients would not be a source of danger provided there was freedom from fleas and a lack of development of secondary pneumonias. It is very doubtful as to infection ever taking place by way of the alimentary canal, although there is some evidence that rarely the tonsil may be primarily involved. Monkeys are very susceptible to plague and the possibility of an epizootic among them should be thought of during plague epidemics.

PATHOLOGY

It is rare that one finds the primary vesicle marking the site of entrance of the plague material. Thus in 13 cases where plague was contracted by direct cutaneous inoculation of those performing autopsies on plague victims only two showed evidences of local reaction as shown by the formation of a primary vesicle.

The chief points noted in a plague autopsy are: (1) The marked involvement of the lymphatic system as shown by intense congestion and haemorrhagic oedema of the lymphatic glands. Not only are the glands tributary to the site of inoculation involved, thus forming the primary bubo, but there is secondarily more or less inflammatory change in all the lymphatic glands of the body. There is also a marked periglandular oedema, with haemorrhagic extravasations of the connective tissue surrounding the primary bubo, this mass being made up of a group of glands matted together by this periglandular exudate.

(2) The destructive effect of a toxic product of the plague bacillus, which may be designated an endotheliolysin, upon the endothelial cell lining of blood vessels as well as lymphatic ones. This causes the extensive blood extravasations so characteristic of plague as shown by petechial spots, not only of the skin but of the serous and mucous membranes as well.

There is a general congestion of all organs of the body.

The meninges of the brain are deeply congested and there may be haemorrhagic extravasations in the brain substance itself. Crowell has reported two cases of plague meningitis in which plague bacilli were found in the ventricular pus. The spleen is generally markedly congested and enlarged to 2 or 3 times its normal size.

There may be haemorrhagic extravasations throughout the spleen pulp. The bacilli are chiefly scattered throughout the venous sinuses.

There is also active congestion of the liver. The kidneys are intensely congested and we often find fibrin thrombi in the tufts of the Malpighian bodies.

The plague toxin has a marked effect on the cardiac muscle so that we usually find dilatation of the right side of the heart with fatty degeneration of the muscle fibers.

In a study of the pathology of primary pneumonic plague Strong noted pericardial and pleural ecchymoses with fibrinous pleurisy over the affected lung areas.

The process was at first lobular but later involved the entire lobe.

There was marked congestion of the bronchial mucosa with involvement of the bronchial glands. The larynx and trachea are also intensely congested. Microscopically there is a distension of the alveoli and bronchial passages with a haemorrhagic exudate. There is practically no fibrin in the alveolar exudate. The process seems to extend by continuity along the bronchi and bronchioles.

Plague bacilli pack the exudate found in the bronchi and bronchioles.

In a report on the autopsy findings of septicaemic plague in Ceylon in cases where plague bacilli were demonstrated in smears and cultures from spleen and blood, Castellani noted that other than meningeal congestion and some splenic enlargement there was nothing abnormal.

SYMPTOMATOLOGY

In a clinical study of plague it is customary to consider the disease as manifesting itself in a mild form (Pestis minor) and a severe form (Pestis major).

=Pestis Minor.=—Pestis minor, which is sometimes termed pestis ambulans, is that form of plague in which there is only slight fever and comparatively little physical prostration or mental hebetude. These cases usually show moderate enlargement and tenderness of some group of lymphatic glands. It is in this mild form of plague that we are most apt to find the primary vesicle or phlyctenule at the site of the flea bite.

Ordinarily, man is so susceptible to plague that there is no reaction at the site of inoculation but in these mild cases there is an inflammatory reaction resulting in a vesicle or pustule, which may teem with plague bacilli. In such cases it is extremely important to search for such primary vesicles and examine for plague bacilli. It is usually stated that only about 5% of cases of bubonic plague show these vesicles.

=Pestis Major.=—Pestis major can certainly be divided clinically and epidemiologically into two types, pestis bubonica, or bubonic plague, which is the common type of plague, and pestis pneumonica, or pneumonic plague, the contagiousness of which is extreme and the mortality practically 100%.

Both of these types of plague tend finally to show an invasion of the blood stream with plague bacilli, the case then becoming one of septicaemic plague. Many authors, however, recognize an overwhelming plague septicaemia in which the manifestations of buboes or pneumonia are absent and such cases are designated septicaemic plague, or pestis siderans.

In all forms of pestis major there stand out the characteristics of rather sudden onset, rigors or chilly sensations, rapidly rising but irregular fever, marked giddiness, great prostration, the mental state and speech of an intoxicated person and extreme weakness of the heart with a rapid weak pulse.

Typhus fever alone shows an equal degree of early mental hebetude, so that it is stated that Clot Bey, who had seen much plague in Egypt, when elsewhere shown cases of typhus with parotid involvement, remarked “In Egypt one would call such cases plague.”

=A Typical Case of Bubonic Plague.=—After a period of incubation of from three to seven days the disease may set in quite abruptly, or after a prodromal stage, in which malaise, giddiness, mental hebetude and pains in the back and limbs may be present. With the onset of the attack the effects of the toxaemia upon the nervous system are the most striking. The patient has a pale, drawn, anxious countenance, with injection of the conjunctivae toward the inner canthus.

The speech is thick and difficult, the gait is staggering, so that, with the stupid mental state and tendency to wander aimlessly about, one has the symptom-complex of an alcoholic intoxication. In some cases a delirious tendency may be marked, especially as the disease develops. After a few hours, or within a day, the fever begins to rise rapidly and is often associated with shivering attacks. The face now becomes hot and flushed, the conjunctivae markedly injected, the pupils dilated, and the eyes rather staring. The temperature is as a rule from 102° to 104°F., occasionally higher, with a tendency to rather marked remissions and, on the whole, of great irregularity of the fever curve. The pulse is rapid and shows early indications of the extreme toxic effect exercised upon the heart. Cardiac weakness is a marked feature of plague.

The urinary secretion is diminished but there is rarely more than a slight amount of albumin.

The Pathognomonic Bubo.—About the second or third day the development of an extremely painful bubo practically gives the diagnosis.

About 70% of these buboes are of the inguinal region, the femoral glands being more frequently invaded than those above Poupart’s ligament. The axillary glands are involved in about 20% and the submaxillary and cervical ones in from 5 to 10% of cases.

There is a question whether the tonsil ever serves as the site of infection from which cervical buboes result. It would seem that the greater frequency of inguinal buboes is because a greater area of skin drains into these glands. There may be multiple buboes and it must not be forgotten that the lymphatic glands of any region may become enlarged. There may also be lymphangitis. Only one gland of a group may be involved or the whole group may show enlargement. Very characteristic for plague buboes is the oedema of the periglandular tissues, which is largely responsible for the great size of some of these buboes; they may vary from the size of an almond or walnut to that of a child’s head. The patient tends to assume an attitude to relieve any tension on the very painful bubo. Particularly over these buboes, but at times elsewhere, the skin may show areas of inflammation, often several inches in diameter. Necrosis of this area occurs and a slough separates. These lesions are often termed carbuncles but are really not such, but only gangrenous patches of skin.

When these areas of cutaneous necrosis are a marked feature the designation of cellulo-cutaneous plague is at times given.

Petechiae or large purpuric spots may be conspicuous in some epidemics and it was from these “tokens,” as they were called, that plague received the designation “black death.”

As the case progresses, the anxious countenance gives way to one of apathy, the control of speech and cerebration become more and more impaired and the patient may go into a typhoid state.

Cases with buboes in the axillae give the gravest prognosis, as for example, 80% mortality for axillary, and 70% for inguinal. The buboes may suppurate towards the end of a week or they may undergo a slow resolution. Secondary broncho-pneumonia may develop in the course of bubonic plague. Pulmonary congestion is however not infrequent and may cause dyspnoea, accelerated respiration and cough. Owing to the tendency to degeneration of the endothelial lining of capillaries, various haemorrhagic manifestations, other than those of the skin, may be observed, such as epistaxis, haematuria, etc. There is usually a rather marked leucocytosis in which the increase is chiefly of the polymorphonuclears.

=A Typical Case of Pneumonic Plague.=—Besides those cases where pulmonary involvement sets in during the course of an attack of bubonic plague and which are classified as secondary plague pneumonias we have sporadic cases and epidemics when the clinical course of the disease is predominantly and primarily pulmonary.

Although the characteristics of pulmonary involvement, with expectoration of blood, were noted by many observers of the 14th century and later as manifestations of plague, yet in the present pandemic, which started in 1894, such cases were at first overlooked as being plague. The recognition of a primary pneumonic plague was made by Childe in 1897. The onset is sudden, with a rise of temperature to 103°F., or higher, during the first day. The marked physical exhaustion and clouding of the consciousness, characteristic of any type of pestis major, are intensified in pneumonic plague. In fact the occurrence of manifestations of such profound toxaemia in the presence of only slight physical signs, should make one suspicious. Crepitation over small areas, without demonstrable dulness on percussion, may be the only sign. There is often early dyspnoea and rapid shallow respiration. Cough, with the expectoration of rather abundant watery sputum, which soon becomes blood-stained or absolutely sanguineous, may be present by the second day.

There is never the rusty, tenacious sputum of lobar pneumonia. Herpes never appears, according to Childe. Heart failure is a very prominent feature of plague pneumonia.

It is fortunate that this watery sputum teems with bacilli early in the disease as smears from such sputum give an early and sure diagnosis of this terribly contagious and fatal malady. The knowledge that this infection is transmitted from man to man by the droplets of sputum expelled in coughing demands the protection by some form of mask of anyone coming near such a patient. Some observers noted splenic enlargement and tenderness over the superficial lymphatic glands. Strong has noted that the course of the disease rarely extends beyond the fourth day and that death is the invariable termination.

In 1919 thirteen cases of plague pneumonia occurred in California starting from an at first unrecognized case of bubonic plague of squirrel origin. These pneumonias were diagnosed as influenza pneumonias but later the true diagnosis was determined. McCoy notes in this connection that there is a strong tendency to pulmonary localization of plague in the squirrel which is not true of the rat.

=Septicaemic Plague.=—As regards the clinical manifestations of septicaemic plague, if such be considered as a separate type, Choksy states that there is no clinical sign by which such a septicaemia can be recognized without the help of the laboratory, although the presence of a thready or imperceptible pulse, in one showing the characteristic toxaemia of plague, should cause suspicion.

The patient may be so overwhelmed from the start that there may be only a slight rise of temperature. Occasionally, plague bacilli may be recognized in blood smears, a finding that practically never obtains in any other bacterial disease. At the same time blood cultures are solely to be depended upon in diagnosis and even such examinations may be negative. Liston has noted that plague patients always die if more than 40 bacilli per cc. are present in the blood. In a recent outbreak of septicaemic plague in Ceylon the only clinical manifestations were intense headache, and fever. The patients died within forty-eight hours. Until properly diagnosed bacteriologically the disease was thought to be pernicious malaria.

The Symptoms in Detail

General Appearance.—The face is at first drawn and pallid, the eyes injected and the expression one of fear or anxiety. As the temperature rises the pallor is succeeded by a flushed and dry hot skin. Later on in the disease the expression is more one of apathy. The staggering gait and the tendency to wander give the impression of alcoholic intoxication.

Temperature Curve.—The fever course of plague is very irregular. The temperature usually rises rapidly to 103° to 104°F., but tends to exhibit marked remissions by the third day. After a fall, it may rise to a very high degree just before death. Cases which recover often show a fall by lysis.

Nervous System.—Very characteristic for plague is the intense and early disturbance of the mental condition. The patient presents the characteristics of alcoholic intoxication, thick speech, lack of mental concentration and giddiness which causes a staggering gait. Later on an apathetic or stuporous stage may ensue or there may be delirium.

Rarely a case of bubonic plague may show marked involvement of the meninges, giving the clinical picture of meningitis.

Circulatory System.—The pulse is at first soft, dicrotic and rapid, 110 to 120 beats per minute. Later on, as the heart begins to show the toxic effects of the disease, the pulse becomes thready and irregular, to be followed by cardiac failure. There is a marked tendency to congestion of various internal organs and to haemorrhages from the capillaries.

Respiratory System.—Pulmonary congestion and even broncho-pneumonia may supervene in bubonic plague. In pneumonic plague, however, the lungs seem to be the primary seat of the bacterial development. Plague pneumonia is characterized by intense toxaemia and few physical signs. The abundant, watery sanguineous sputum is loaded with plague bacilli. Dyspnoea and cyanosis appear early.

The Lymphatic System.—It is the presence of the plague bubo which differentiates bubonic plague. There is no relation between the size of the bubo and the severity of the attack. Axillary buboes are the most fatal. A characteristic of these buboes is their extreme tenderness, the pain causing the patient to draw up the legs or assume any attitude which will relieve tension upon the bubo. The size is mainly due to the periglandular infiltration or oedema, which causes the glands of a group to be matted together.

The elevation of a plague bubo is rather diffuse, not pointed as with venereal buboes. Femoro-inguinal buboes are about 6 times as frequent as cervico-maxillary ones. There may be lymphangitis as well as lymphadenitis.

Cutaneous System.—The skin over the buboes often tends to become necrotic and slough off. This however may occur elsewhere and such lesions are termed “carbuncles.” Capillary haemorrhages of the skin may cause petechiae and when the area is large they have been designated “tokens.” In about 5% of cases there is a small vesicle or pustule at the site of the flea bite as an indication of reaction. The contents teem with plague bacilli. It is often termed the primary lesion.

The Liver, Spleen and Alimentary Tract.—The spleen may show enlargement and tenderness on deep pressure, as may also the liver, these organs being markedly congested. The tongue at first is coated, with clean tip and sides. Nausea and vomiting frequently occur and, as a rule, there is constipation. Haemorrhages from the bowel may occur.

DIAGNOSIS

=Clinical Diagnosis.=—It is well to remember that we have a sure and simple means of diagnosis by bacteriological means so that in the first cases during an epidemic we should rest the determination of the case as one of plague solely upon such methods.

One should be suspicious of any case of fever of rapid onset in which there is marked dulling of intellect and impairment of speech, as of one intoxicated, together with evidences of rapidly developing heart weakness. In septicaemic plague we practically have no other symptoms to guide us—there is not the exquisitely tender bubo of bubonic plague nor the abundant, watery, sanguinolent sputum of pneumonic plague.

Typhus fever probably more nearly resembles plague at its onset than any other disease. There is marked clouding of the consciousness and intense prostration as with plague and the eruption does not appear before about the fourth day.

An influenza pneumonia may show the general prostration and cardiac weakness of plague. In influenza pneumonia we have an onset with the features of ordinary influenza, which, however, in the influenza epidemic in 1918 was often short. In plague pneumonia we have pneumonia from the start. The pulse in plague is early weak and rapid and the tendency to a stuporous state more marked. The early appearance of thin watery sputum, which quickly becomes blood-tinged and always contains plague bacilli is noted in plague pneumonia. Only a few hours elapse before we have bloody sputum which in influenza is a later and not constant sign. The dyspnoea is earlier and much more pronounced in the pneumonic plague. At autopsy Crowell notes the almost invariable presence of pleural exudates in plague while an acute vesicular emphysema is a feature of influenza pneumonia.

Malaria and septicaemic conditions may be confused with septicaemic plague. The sudden onset and prostration of relapsing fever may make one think of plague.

Many have thought climatic bubo a form of ambulant plague but the gradual onset, only slight tenderness of the swollen glands and slight prostration should differentiate. Venereal bubo cases are apt to be regarded with suspicion during epidemics.

Markedly toxic cases of typhoid fever with an exceptionally rapid onset may give rise to confusion.

=Laboratory Diagnosis.=—If the patient has a bubo we should introduce a hypodermic syringe needle into the swollen, oedematous glandular mass in order to obtain some of the gland juice. Smear a drop of this on a slide, stain with Loeffler’s blue or dilute carbol fuchsin and examine for bipolarly stained oval bacilli. When the bubo begins to soften we may not obtain plague bacilli.

Probably the best stain for plague bacilli is that recommended by Archibald. There are two solutions, one made by dissolving 0.5 gram of thionin and 2.5 grams phenol crystals in a 1% aqueous solution of formalin; the other solution is made by dissolving 0.5 gram methylene blue and 2.5 grams phenol crystals in a 1% formalin solution. Let these stock solutions stand 24 hours before using and then mix equal parts of each solution; filter, and stain smear for 10 seconds. Wash and dry.

In a case of suspected pneumonic plague we stain the smear of watery or thin blood-tinged sputum as above.

The same procedure may be followed with a rather heavy blood smear of a drop of the 5 or 10 cc. taken from a vein for culturing in a case suspected of septicaemic plague.

Plague is practically the only bacterial disease where there is likelihood of finding the causative organism in smears. In septicaemic plague the blood culture is the proper procedure and one should take 5 to 15 cc. of blood in 15 to 25 cc. of normal saline containing 1% of sodium citrate. This prevents coagulation and at one’s leisure 1 or 2 cc. can be added to tubes of melted agar and plates poured or other portions added to bouillon or 3% salt agar. This same blood emulsion can be used to infect guinea pigs subcutaneously or to infect them cutaneously by rubbing on the shaven surface.

In smears from material from buboes, from sputum, or in blood smears, as well as from blood or spleen smears from experimental animals, we obtain the typical morphology of a cocco-bacillus (1.5 × 0.5 microns) with very characteristic bipolar staining, there being an intermediate, unstained area. Very characteristic also is the appearance in these smears of degenerate types which stain feebly and show coccoid and inflated oval types. The presence of these involution forms associated with typical bacilli is almost diagnostic for one with experience. Inoculating tubes of plain agar and 3% salt agar with this same material, we obtain in plain agar cultures organisms which are, typically, small, fairly slender rods, which do not stain characteristically at each end and are not oval. The smear obtained from the salt agar presents most remarkable involution forms—coccoid, root-shaped, sausage-shaped forms, ranging from three to twelve microns in length, more resembling cultures of moulds than bacteria. Another point is that on the inoculated plain agar we are in doubt at the end of twenty-four hours whether the dew-drop colonies are really bacterial colonies or only condensation particles. By the second day, however, these colonies have an opaque grayish appearance, so that now, instead of questioning the presence of a culture, we consider the possibility of contamination.

Blood cultures in septicaemic plague may show from 5 to 500,000 bacilli per cc. Smears from the blood in such cases are positive in only about 17%.

The plague bacillus grows well at room temperature—its optimum temperature being 30° instead of 37°C., as is usual with pathogens. Next to the salt agar culture, the most characteristic one is the stalactite growth in bouillon containing oil drops on its surface. The culture grows downward from the under surface of the oil drops as a powdery thread. These are very fragile, and as the slightest jar breaks them, it is difficult to obtain this cultural characteristic.

Albrecht and Ghon have shown that by smearing material upon the intact, shaven skin of a guinea pig, infection occurs. This is the crucial test. Smear the material on a shaven surface about 1 inch square.

A pocket made by cutting the skin of a guinea pig with scissors and extended subcutaneously with scissors or forceps, into which a piece of the suspected plague tissue is thrust with forceps, is more practical than injecting an emulsion with hypodermic syringe.

Mice inoculated at the root of the tail succumb quickly. Rats, this being primarily a disease of rats, are of course susceptible.

When a guinea pig is inoculated with plague material the animal should be placed in a galvanized iron garbage can or other similar container and the opening covered with cheese cloth to prevent the fleas or other vermin which it might harbor from escaping. Again a 6-inch band of tanglefoot fly paper should be attached around the interior of the upper part of the can to further prevent escape of fleas. It must be remembered that every precaution must be taken in the laboratory to prevent the escape of plague-infected fleas. The guinea pig usually dies in from two to five days and shows glandular enlargements, and marked congestion of viscera with a swollen spleen, smears from which may show a profusion of plague bacilli.

The subcutaneous tissues about the site of inoculation show a haemorrhagic oedema.

If guinea pigs are not available one may use white mice which die within forty-eight hours or white rats which live about as long as guinea pigs.

One of the most important points in fighting plague is the detection of plague in the rats and, from noting the locality in which such plague-infected rats were caught, to direct our rat destruction efforts to that particular section of the city. These dead rats should be dropped into a bichloride solution or petroleum preparation in order to destroy the rat fleas. In the laboratory they are dissected and plague-infected ones most easily recognized by the marked subcutaneous injection of the widely reflected skin flap. Oedematous or haemorrhagic glandular swellings are characteristic. The liver shows a yellowish appearance, and as if sprinkled with small whitish dots and the spleen is swollen and congested. There may be effusion into the pleural cavities. Material from the swollen glands or spleen should be stained, cultured and inoculated into animals as for a human case.

If glandular, splenic or other material from human or rat autopsies has to be sent to a distant laboratory the specimen should be placed in a strong salt mouth bottle containing 20% glycerine in water with 2% calcium carbonate.

Agglutination is not very practical owing to the frequent absence of agglutinins from the serum of plague patients. Then, too, there is a marked tendency to spontaneous agglutination on the part of the plague bacilli. Strong states that culturing at 37°C. lessens this tendency to spontaneous agglutination. Again, even when present, the titre of plague-agglutinating sera is usually quite low so that one must work with dilutions of from 1 to 10 or 1 to 20.

PROGNOSIS

Pneumonic and septicaemic plague give an almost absolutely unfavorable prognosis, many stating that every such case dies.

As regards bubonic plague the mortality averages 75%. The Egyptian epidemic of 1900 gave an average mortality of 50%. The mortality in natives is much higher than that among Europeans, these latter often showing death rates under 25% while in the same epidemic natives show from 75% to 95% mortality. Plague pneumonia, however, is absolutely fatal for Europeans as well as natives.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—In pneumonic plague it is the human patient and not the rat which has to be considered. The infection is spread by means of droplets of plague bacilli-laden sputum which are sprayed from the mouth of the patient in the act of coughing. As a result any person entering a ward containing plague pneumonia cases is extremely liable to contract the pneumonic form of plague.

The attendants are protected by bag-like masks or successive layers of gauze and cotton wool applied as bandages over face and neck. Motoring goggles make a good protection for the eyes and small rolls of cotton should be placed along the sides of the nose to absolutely prevent the possibility of bacilli being drawn down to the entrance of nose or mouth. These masks should not have any weak spot in their armor.

Spread of plague pneumonia.—It has been noted that when secondary pneumonia develops in the course of bubonic plague in India, the Philippines, or other hot countries, it is not followed by primary plague pneumonia outbreaks. This is thought to be due to the fact that the windows are wide open and the relative humidity low, conditions which are the opposite of those which existed in Manchuria where the intense cold made the closing of windows necessary and where the air of rooms or wards was saturated with the moisture from the occupants. As the main consideration for the spread of pneumonic plague seems to be high relative humidity it would seem that hospital wards could be constructed so that the air supplied by artificial ventilation would be very dry.

The recent outbreak of septicaemic plague in Ceylon at a time when there was no plague noted in rats would indicate that other transmitting agents than infected rat fleas were operative. The most probable transmitting insects to be suspected would be the bedbug and human flea.

Spread of bubonic plague.—With bubonic plague, unless it should in its course become pneumonic or septicaemic, there is almost solely the question of the rat and its fleas. Many authorities consider that pure bubonic plague can be treated safely in a general ward of a hospital provided there is sure freedom from bedbugs or other verminous insects.

The various species of fleas which the rat may harbor may be attacked by the use of various petroleum preparations containing naphthalene. One preparation known as pesterine, which consists of kerosene 20 parts, soft soap 1 part and water 5 parts, the soap being dissolved in the water and the oil being gradually stirred into the hot mixture, is often recommended as a flea insecticide. A 5% solution of compound cresol to which naphthalene has been added is also of value.

It is always well to combine flea destruction with rat extermination because, as rats are reduced in numbers, there are fewer hosts, so that man is more liable to infection with fleas deprived of a sufficient number of rat hosts.

This may explain why a high death rate among rats, as the result of a plague epizootic, may act as a factor in the outbreak of human plague.

Rat destruction.—As a matter of fact, however, it is best to attack the problem from the side of rat extermination which, it must be understood, is most difficult owing to the highly developed suspicious nature of the rat. A successful rat catcher or rat exterminator must have the mind of a detective.

The first measure in rat extermination is the regulation of the disposal of garbage. It is most important that only cans with securely fitting tops be used so that rats cannot secure any food from the contents of the can. Again no particle of food should be left accessible to the rat. Unless the ordinary food supply of the rat is denied him he will not eat poisoned bait or bait in traps. Again rats are not only carnivorous but will eat any kind of cereal or vegetable, in fact they will eat almost anything and in addition are cannibals. In a plague outbreak especial attention should be directed to flooring in stables, under surfaces of board walks, sealed-in attics of houses, wharves and sewers. Where sewers have catch-basins at street openings the rat has a means of egress from the sewer. These sedimenting catch-basins also serve as a breeding place for mosquitoes. It has been estimated that a sewer rat can jump 2 feet but not 3 feet.

In rat-proofing houses, double walls should be eliminated and houses raised well from the ground—at least 18 inches. In plugging up rat holes with concrete we should add broken glass to the concrete. Sheets of galvanized iron driven down several feet have been used as a protecting barrier around grain elevators or warehouses. Concrete is the proper material to use in rat proofing.

Where rats are on board ship fumigations with sulphur dioxide, carbon monoxide or funnel gases are usually employed.

Hydrocyanic acid gas is a most efficient destroyer of rat and flea life. The great objection to its use is its danger to those using it in fumigation. Liston allows this gas, developed from ½ ounce KCN, to act for four hours in a space of 100 cubic feet. The great danger from the use of this gas in holds of ships is that it tends to collect in detached spaces or pockets and remains following ventilation of the hold so that persons entering such spaces suffer the poisonous effects of the gas. Some cargo ships have a rat-run built to extend fore and aft and leading to a receptacle in which the rats are caught. Rats naturally choose a tube or similar opening so they get into this little passageway which is so constructed that their return is obstructed. This scheme is used in setting traps, either covering the traps with hay and leaving a small opening or placing the trap under an inclined plank or placing it at the end of an iron or terracotta pipe. There is not much danger of rats getting aboard a ship lying out from the dock. It is when a ship goes alongside a dock that we can expect rats to come aboard.

Phosphorus paste made up with a glucose base and containing about 4% of phosphorus is spread on pieces of stale bread, 1 inch square and ¾ inch thick. Whatever poison is used, whether strychnine, arsenic or phosphorus, it should be placed in boxes which have openings large enough to let the rats in but too small for domesticated animals. Barium carbonate is a useful rat poison.

Cats will very rarely attack the fierce sewer rat.

Danysz virus.—Many workers, during plague outbreaks, have tried to exterminate rats by impregnating bread or other bait with bacterial cultures. The best known of these viruses, as they are called, is that of Danysz. The organism is closely related to B. enteriditis of Gaertner and is supposed to bring about a fatal infection in the rats. As a matter of fact the cultures quickly cease to be virulent and their use has been generally abandoned. Simpson, however, thinks well of this measure and employed it with success in South Africa. He kept up the virulence of his cultures by frequent passage through animals.

In rat extermination it is advisable to employ Heiser’s Manila plan. In this, the location in the city of the plague rats brought into the laboratory is noted and radiating lines made from such foci. Plague-infected rats are rarely found more than a few squares from the focus. The periphery of the infected area is then considered as an outer zone for the fight and the house-to-house extermination is carried on toward the center of the area. If, on the other hand, one should start at the center and work peripherally the infected rats might be spread all over the city.

Prophylaxis by Immunization.—The best-known bacterial prophylactic is that of Haffkine. Stalactite bouillon cultures are grown in flasks for five to six weeks. The organisms are then killed by heat at 65°C. for one hour. Phenol (½%) is then added and from 0.5 to 4 cc. injected according to the age and size of the individual. Ten days later a still larger amount is injected. The reaction following these injections is apt to be quite severe.

Recent reports show that of 118,148 inoculated persons the plague incidence was approximately 8 per 1000 while among 321,621 noninoculated the incidence was 34 per 1000.

Statistics from Sagaing show 19 cases with 7 deaths among 4284 inoculated persons while there were 134 cases and 128 deaths among 4467 not inoculated.

The plague mortality in cases which had previously been inoculated was 40% while that among the noninoculated was 78%.

From the above it will be seen that incidence is reduced to about one-fourth and mortality about one-half as the result of the use of Haffkine’s prophylactic.

Besides this killed culture other material has been used. Lustig and Galleotti used the nucleo-proteid from plague bacilli for subcutaneous injection. Kolle and Strong have recommended a vaccine of living but nonvirulent plague bacilli. A higher degree of immunity seems to be conferred by this living vaccine but there are certain dangers in the use of living organisms which outweigh the advantage noted above.

Yersin’s antiplague serum, which is prepared by injecting horses at first with killed cultures and later with living plague bacilli, may be used as a prophylactic as well as in treatment. One point to consider is that such serum, if used immediately after taking from the horse, might contain living plague bacilli. The phenol preservative prevents this. It must be remembered that this is a passive immunization as against the active one with Haffkine’s prophylactic, hence the protection is very short, only ten days or two weeks as against the more enduring immunity of a year or so following Haffkine’s prophylactic. It must be remembered that anaphylactic manifestations may follow the repeating of the dose of Yersin’s serum. It is probably advisable for one who is to be exposed to plague for a short time only to receive an injection of the serum. As regards pneumonic plague there seemed to be little protection attaching to either active or passive immunization.

=Treatment.=—It may be stated that the only treatment which has any curative value is that with antiplague serum. This would appear to be of considerable value in bubonic plague provided it is administered in the first day or two of the disease. It must be given in large amounts, from 50 to 100 cc. or even to the extent of 250 cc. Then too such enormous doses apparently require to be repeated. Intravenous administration gives a better chance for success in desperate cases. In septicaemic and pneumonic plague the use of serum has been without result.

Salvarsan, as might be expected, has been tried but did not prove of any value.

Connor has reported success with the intravenous injection of one dram of a dilution of 1 part of tincture of iodine in 10 parts of sterile water. He gave 6 such injections to a severe case with good result.

In the way of symptomatic treatment one should use ice-bags to head and cold sponging to the body.

Morphine seems to be the best drug to calm the patient. Cardiac stimulants, especially strychnine, are indicated for the heart weakness so much a feature of plague. Some consider incision or enucleation of the bubo of value in treatment but it has always seemed to me that the going into the periglandular exudate might serve to set up a septicaemic condition when otherwise it might not supervene.

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XIV. TULARAEMIA

DEFINITION AND SYNONYMS

=Definition.=—This is a plague-like disease of various rodents, transmissible to man, caused by an organism Bacterium tularense, which is not closely allied to any other species. A number of human cases have been reported from Utah, where the disease is prevalent among the jack rabbits, and the transmission to man is through the bite of a horsefly, Chrysops discalis, which has previously sucked the blood of infected jack rabbits.

The site of the bite in man is usually marked by a punched-out ulcer, which is associated with swelling and suppuration of the glands draining the area. The general symptoms are sudden onset, with rigors, followed by an irregular fever of three or four weeks’ duration and by a prolonged convalescence. Several cases have been reported in the middle west due to handling infected rabbits. There have been a number of infections in laboratory workers where the local signs have been absent. In man death rarely results from the disease.

=Synonyms.=—Deer-fly fever (in man). Plague-like disease (in rodents).

HISTORY AND GEOGRAPHICAL DISTRIBUTION

=History.=—In 1911 McCoy and Chapin discovered the B. tularense in a plague-like disease, first described by McCoy in the California ground squirrel. They described the organism, succeeded in cultivating it on special media, transmitted the infection to various rodents by feeding, nasal inoculation and injection of infected blood, and demonstrated the probable natural mode of transmission by the squirrel flea.

In recent publications, Francis, Lake and Mayne, and Wayson have recorded the transmission of the disease experimentally by the house fly (Musca domestica), the horsefly (Chrysops discalis), the stable fly (Stomoxys calcitrans), the rabbit louse, the mouse louse and the bedbug, and have shown that the freshly recovered organism can be grown on other than the special media previously recommended.

=Geographical Distribution.=—The first case of infection occurring in man was reported from Ohio by Wherry and Lamb in 1914. Since then a number of cases have been reported by Francis among rural residents of Utah and by Francis and Lake among laboratory workers handling animals infected with B. tularense.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—Bacterium tularense is a small nonmotile Gram-negative cocco-bacillus, from 0.3 to 0.7µ long and gives the appearance in stained preparations of being surrounded by capsular material. It is very difficult to cultivate and until recently it has been grown only on coagulated egg yolk as used by McCoy and Chapin.

Recently Francis has shown that the organism will grow scantily on serum or blood agar. However, by adding a piece of fresh sterile spleen to such media he has obtained a more satisfactory culture medium, although for routine work the egg yolk medium is preferred. The organism refuses to grow on ordinary media such as nutrient broth or agar. Material from a culture, or pus from bubo, or an emulsion of the spleen of an infected guinea pig, when rubbed into the abraded skin of an experimental animal brings about infection, in this respect showing a similarity to plague infection. Upon autopsy of such an experimentally infected guinea pig we find haemorrhagic oedema at the site of inoculation with caseation of lymph glands and small necrotic foci in spleen and liver. Smears from the spleen show the organism in varying numbers. In infected rodents the organism is often found abundantly in the blood and in man a bacteriaemia may occur.

=Epidemiology.=—The infection of ground squirrels with this organism was noted by McCoy in his plague work in California. Francis in studying the disease in man in Utah found infection of the jack rabbits and ground squirrels of the region and showed that the transmission of the disease could be carried out by a biting fly (Chrysops discalis) and reported this fly as the common transmitting agent of the human infection. He regarded the sick and dying jack rabbits as the reservoir of virus. Tularaemia is chiefly a disease of the rural population attacking those at work in the fields.

As a result of accidental laboratory infections it would seem that almost 100% of those carrying on extensive animal experimentation with this organism become infected.

The louse infesting jack rabbits Haemodipsus ventricosus, can transmit the infection from rabbit to rabbit so that the infection in the jack rabbits is probably kept up by this agency. Recent experiments have shown that the infection in white mice can be transferred by the bites of the mouse louse and also by bedbugs. Again if the mice are fed on infected bedbugs transmission is found to take place by such feeding experiments. The faeces of such bedbugs prove infectious. Guinea pigs injected subcutaneously with the urine of white mice suffering from the disease die acutely with typical lesions of tularaemia.

Mice fed on the liver of a rabbit dying of the disease succumbed to the infection within five days.

As noted under etiology the most important method of spread of the disease to man is by the bite of an infected horsefly (Chrysops discalis). From experimental studies it would seem that any biting arthropod might prove a transmitting agent. In view of the fact that the infected deer fly tends to lose its infectivity after about five days Francis is of the opinion that the fly is only a mechanical transmitter of the organism.

Wherry reported the infection as manifested by conjunctivitis with glandular involvement and due to handling infected wild rabbits.

Lake and Francis have reported that of six investigators from the Hygienic Laboratory working with this infection all have contracted the disease. There were fortunately no fatalities. Such an experience demonstrates the great infectivity of this virus and must lead to the conclusion that the few cases so far reported of the disease do not represent the importance of tularaemia in man. With a knowledge of the existence of such an infection and with satisfactory methods of laboratory diagnosis we shall probably have other reports of the infection. We now know that the ground squirrels of California and Utah, the jack rabbits of Utah and the wild rabbits of the middle west furnish important reservoirs of virus.

PATHOLOGY

In experimental animals we have lesions which cannot well be differentiated from those of plague. There is not sufficient data for a statement as to the pathology in man.

In experimental animals we have a definite bacteriaemia but in man the organism has only in rare instances been obtained from the blood.

SYMPTOMATOLOGY

It has been difficult to determine the period of incubation but in one laboratory infection the disease set in seven days after the patient began tularaemia work. There do not seem to be any prodromata.

In Utah most of the cases showed local lesions at the site of the fly-bite and subsequent swelling and suppuration of adjoining lymph glands. The local lesions were generally observed about the head or on parts of the body not covered by the clothing. There is a rather sudden onset with chilliness or rigors, generally associated with dizziness, prostration and malaise. Headache is usually present and there may be complaints of pains in the back and limbs. The temperature rises rapidly and when first taken during the rigors may reach 103° or 104°F. An irregular fever course follows for two or three weeks. There is practically no apathy, thus differentiating the mental state of typhoid fever or the marked clouding of the consciousness of plague. At times we may have rhinitis and epistaxis.

Physical examination is almost invariably negative. The spleen is not palpable. The pulse is rather rapid and the blood pressure uninfluenced.

The white and differential counts vary but little from normal.

The main feature of the disease, aside from local lesions when these are present, is prostration and this continues marked during the several weeks or months of convalescence.

It is a disabling illness rather than a dangerous one though a fatal case is recorded.

In the six laboratory infections above referred to, there were no local lesions except in the case of one man who had had previously an attack of the disease. In the second attack, two years after the first one, there was noted a papule on one finger with subsequent involvement of the epitrochlear and axillary glands. A guinea pig inoculated with blood taken from the papule became infected and showed the typical lesions of tularaemia.

There was no fever or malaise in this second attack, thus showing a degree of immunity. In cases showing conjunctival ulcerations with glandular involvement Wherry and Lamb obtained cultures of B. tularense from inoculated animals.

DIAGNOSIS

There is very little in the clinical picture, other than the local lesions, to indicate a diagnosis.

Material from ulcers or glands should be inoculated into guinea pigs or white mice. The organism is almost invariably absent from the blood of human cases so that blood cultures or animal inoculation from such blood are almost always negative.

Complement fixation and agglutination tests are the methods of diagnosis to be relied on. In the Hygienic Laboratory an antigen is prepared by washing off the 72 hour growth from egg yolk medium with small amounts of saline. The suspension is heated for 30 minutes at 56°C. and then preserved by the addition of O.3% tricresol. Such an antigen is used for each type of test.

PROGNOSIS

This disease is but rarely followed by death. It is however a most incapacitating disease by reason of the three or four months of convalescence during which time the strength and energy of the patient are markedly affected.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—In view of the very great liability to infection of those carrying on autopsies of animals experimentally infected with the disease it would seem advisable to wear rubber gloves when doing such work. It would appear that house flies, stable flies and horseflies may transmit the disease in nature and we know that bedbugs and lice can transmit the disease among experimental animals. When we consider the natural infection of ground squirrels and jack rabbits in California and Utah and wild rabbits in the middle west, the problem of prophylaxis looms to great proportion.

=Treatment.=—At present treatment is entirely symptomatic. Those who go to bed at once and remain in bed during the stage of fever seem to be less seriously affected.

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XV. CHOLERA

DEFINITION AND SYNONYMS

=Definition.=—Cholera is a disease caused by a spirillar type of bacterium, Spirillum cholerae asiaticae. The organism multiplies in the small intestines and, undergoing lysis, liberates an endotoxin, which is responsible for the desquamation of the epithelium of the mucosa and other manifestations of the disease. Cholera appears to be endemic in the delta of the Ganges and the various world-wide epidemics can generally be traced to that source. The rice-water stool of cholera teems with the spirilla, and infections of water or food supplies can be traced to such a contamination. The importance of the cholera carrier has been thoroughly demonstrated from the time of the Hamburg epidemic of 1892. The clinical course of the disease is divided into a stage of evacuation, in which we have diarrhoeal discharges of rice-water character along with very painful cramps of the muscles. Following increasing cyanosis we have almost a cessation of circulation often associated with anuria, the algid stage. With the return of activity of circulation and urinary secretion we have the stage of reaction.

=Synonyms.=—Cholera Asiatica.

HISTORY AND GEOGRAPHICAL DISTRIBUTION

=History.=—Although the word χολέρα, meaning flow of bile, is found in the writings of Hippocrates, it certainly does not refer to the disease we now recognize as cholera. The older writers noted the characteristics of bilious discharges in the disease they termed cholera, which could not apply to the bile-free rice-water discharges of what we now term cholera. Koch rather doubted the antiquity of cholera but Susruta, in India, in the 7th century A. D., described a disease in which there were diarrhoea and vomiting, stabbing pains, cyanosed lips and nails, with sinking in of the eyes and weak voice.

Detailed accounts of the presence of cholera in India were published from the 16th to 18th centuries when the Portuguese, English and French were carrying on their wars of conquest in India. These wars naturally spread the disease all over India.

It is thought that true cholera did not exist in China until 1669 when it was carried there from India. It is first described from Japan in 1821 although an epidemic which devastated Tokyo in 1718 may have been cholera.

A great pandemic of cholera started in India, in 1817, extending over Asia but not invading Europe. The second great pandemic is of importance as being the first to invade Europe. It started in India in 1826 and advancing slowly reached Persia in 1829, going thence by way of Astrakhan to Russia, Sweden, Northern Europe and England. By 1832 it had spread over the whole of Europe.

In the same year, 1832, it reached Canada and thence spread to Fort Dearborn where it infected the soldiers who subsequently carried the disease down the Mississippi valley. It was also introduced into New York and spread thence South and West so that by 1836 cholera was present all over the U. S., not disappearing until 1838. It disappeared from Europe in 1839.

The next European outbreak or third pandemic lasted from 1846 to 1862 and was traced to India by way of land and sea, that by land following the caravan route by way of Persia and Russia and that by sea from Indian pilgrims going to Mecca and there causing the infection of Mahommedan pilgrims from Egypt and European Turkey. This pandemic reached the U. S. in 1848, starting at New Orleans and going up the Mississippi valley. Central and South America and the West Indies were also invaded by the third pandemic.

The fourth great pandemic invaded Europe by the usual routes and continued from 1863 to 1875. During its continuance there were two outbreaks in the U. S., one in 1867 and another in 1873.

That in 1873, when it was introduced into three widely separated parts of the country, was the last appearance of cholera in the U. S.

The fifth pandemic began in 1883 and affected particularly the Mediterranean seaports of France, Spain and Italy. It was during this epidemic, in 1883, that Koch, working in Egypt, discovered the cause of cholera, the Spirillum cholerae asiaticae.

A very serious outbreak of cholera, which originated in 1891, in pilgrims from the delta of the Ganges, reached Europe in 1892, almost a million deaths occurring in Russia. It was during this epidemic that cholera appeared in Hamburg and gave opportunity for those careful studies as to transmission of the disease to be later referred to.

It is usual to recognize a sixth pandemic which began in 1902 and spread over India, China and the Philippines. This pandemic continuing was a cause of great mortality among the soldiers of the recent Balkan war. During the World War there was much cholera among the Austrian forces in Galicia. It also prevailed in Bulgaria, Greece and Turkey.

=Geographical Distribution.=—Practically every pandemic when studied can be traced back to India and particularly to the delta of the Ganges, which may be considered the enduring focus of the disease.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—The cholera vibrio, Spirillum cholerae asiaticae, was discovered by Koch in 1883 and is a short curved organism which, from its shape, is often called the comma bacillus. In addition to single spirilla there may be “S” shapes from attachment of pairs. In cultures in peptone solutions long filamentous forms may be seen which however are exceedingly rare in the rice-water stools. A stained smear from a fleck of mucus gives the fish-in-the-stream appearance. Besides comma-shaped organisms we may have coccoid or rod-shaped forms. In old cultures marked pleomorphism is often seen.

It is Gram-negative and stains best with a dilute (1-10) carbol fuchsin. There is a single terminal flagellum, which endows the organism with great motility, which may best be termed scintillating. It has been estimated that its motility is five times greater than that of the typhoid bacillus. It grows best on media with an alkaline reaction (—0.4%) and it is this tolerance for media of high alkalinity that permits the separation of the cholera spirillum from the ordinary faecal bacteria by the use of Dieudonne’s alkaline blood agar or similar media. This is equal parts of defibrinated ox blood and N/1 NaOH, 3 parts of which are added to 7 parts of nutrient agar. It thus has 15% of normal sodium hydrate, instead of the 1% acid reaction of the usual media. Unfortunately, other spirilla tolerate this high alkalinity.

The cholera organism is strongly aerobic and grows quickly and luxuriantly in the upper part of a tube of Dunham’s peptone solution, this property enabling one to separate it from other organisms of faeces by taking up loopfuls from the surface layer to plate out on agar of about 0 or -0.3% reaction. When grown in peptone solution the cholera spirillum produces a nitroso body so that one obtains an indol reaction (cholera red) by simply adding 5 or 6 drops of concentrated H_{2}SO_{4}.

When this test is employed it is necessary to determine whether the peptone used is suitable for the reaction. As a matter of fact this test is now rather discredited. Blood serum is digested. Recently much discussion has arisen as to the value of the haemolytic power possessed by noncholera vibrios on blood agar plates.

It is true that the digestive action which true cholera has on the red cells of the medium may give the appearance of a zone of haemolysis. Therefore, for the demonstration of this haemolytic action of noncholera spirilla, fluid blood media should be used. The El Tor spirillum, isolated from Egyptian pilgrims without symptoms of cholera, is haemolytic, but gives the immunity reactions of the true cholera vibrios which are not haemolytic.

Gelatine is liquefied and the stab shows an air bubble liquefaction at the summit of the stab. On gelatine plates a powdered glass center with an encircling zone of liquefaction was formerly considered characteristic of cholera, but at the present time gelatine cultures have been almost abandoned in practical work.

As a rule animals cannot be infected by feeding them cholera material unless the acidity of the gastric juice be neutralized and intestinal peristalsis checked by opium (procedure of Koch). Injected intraperitoneally, the cholera vibrio produces a fatal peritonitis. Recently monkeys have been infected after purgation with sulphate of soda and administration of bicarbonate of soda. They died in from one to forty-eight hours with symptoms of cholera.

There have been instances where cholera has been caused in laboratory workers by the accidental ingestion of cholera cultures, thus Orgel was infected from sucking up peritoneal fluid in doing Pfeiffer tests for bacteriolysis and died.

Emmerich and Pettenkofer swallowed cholera cultures, the former experiencing a severe attack of cholera and the latter a diarrhoea in which cholera spirilla were present. On the other hand similar experiments have resulted negatively but this is what should be expected from the epidemiological facts as to carriers.

The virulence of the cholera vibrio can be exalted by passage through guinea pigs—successive culturing of the peritoneal exudate of intraperitoneally infected animals alternating with culture media growth inoculations. Such a fixed virus, the virulence of which cannot be exalted, is the material used by Haffkine in his cholera vaccine. The toxicity of cholera is supposed to be due to an endotoxin which is set free when the vibrios undergo disintegration when lying between the basement membrane and epithelial lining of Lieberkühn’s glands. Others think the vibrios may enter the blood stream, there to be immediately disintegrated with toxin production. The usual idea, however, is that the cholera spirilla never invade the blood stream—they are confined to the alimentary canal. Macfadyen obtained the endotoxin by grinding the frozen spirilla. This toxin was destroyed by a temperature of 60°C.

The spirillum of cholera has but little resistance to disinfecting agents or to drying. It is also rapidly overgrown by putrefactive bacteria and tends to disappear from sewage-contaminated water in a short time. In stools the vibrio dies in about one or two days in summer and in about a week in winter.

The inoculation of animals by cholera cultures tends to produce an immune serum which is remarkable for its high agglutinating power, the titre at times going as high as 1 to 20,000. For agglutination tests in proving spirilla isolated from stools to be true cholera ones we use a serum of at least 1 to 4000 for its specific vibrio. Such a serum should agglutinate any true cholera spirillum in a 1 to 500 or 1 to 1000 dilution. The occurrence of bacteriolysis, when a small loopful of the culture emulsified in 1 cc. of 1 to 1000 dilution of the immune serum and then introduced into the peritoneal cavity of a guinea pig, is the surest proof that a suspected organism is that of cholera.

This is shown when, upon removing a drop of the peritoneal fluid fifteen to twenty minutes afterward, there is noted an absence of motility and disintegration of the spirilla (Pfeiffer’s phenomenon).

Complement fixation tests, using the rice-water stools or peptone solution cultures as antigen, are of less value than those above noted. Agglutination is the practical test and is almost as specific as that for bacteriolysis.

=Epidemiology.=—Until recently our attention as to the methods of transmission of cholera was directed almost exclusively to the water and food supply, with a certain degree of consideration of danger from fomites, especially to that connected with clothing soiled by cholera discharges, it having been noted that those who wash such clothing showed a high incidence of infection. Later on the importance of flies in the spread of the disease was strongly insisted upon. At the present time we consider the cholera carrier the most important factor in cholera epidemiology and it is to the detection and isolation of such persons that we now chiefly direct our attention in the keeping out of a country of this dread disease.

It will be remembered that Pettenkofer and Emmerich insisted upon the factors of soil and ground water in the spread of cholera. Emmerich now admits that the spirilla excreted by carriers can produce cholera but that such transference never gives origin to epidemics. For this to take place he thinks that the vibrios excreted by a carrier must come in contact with a soil which has been impregnated with a suitable medium drawn to the surface from the deeper layers of the soil by capillary suction. In such medium the vibrios flourish and acquire the property of actively producing nitrites from nitrates.

Emmerich considers that the symptoms of cholera are those of nitrite poisoning so that only such organisms as possess this nitrite-forming function in high degree can produce virulent outbreaks of cholera.

All facts in connection with the spread of cholera by land or water routes can be best explained by the cholera carrier; the individual who is excreting vibrios, while in apparent health, being far more dangerous than the one excreting such organisms in the rice-water stools of a well-recognized case of the disease.

Water Transmission.—There are two types of outbreaks of cholera according as the general water supply is contaminated or when such contamination is localized to certain wells, cisterns or other nongeneral supplies. In the former the onset is explosive and cases occur almost simultaneously and with equal distribution in all parts of the city, to disappear with almost equal suddenness.

In the latter mode of infection, cases will appear from day to day and often peculiarly localized to certain definite districts of a city or to certain definite users of a particular water supply.

As an example of the first type of outbreak the Hamburg epidemic of 1892 is most instructive.

During a period of only about two months cholera attacked about 17,000 persons causing 8605 deaths in a city with a population of 600,000. This outbreak was attributed to the washing of clothes in the water of the Elbe River by Russian immigrants. These immigrants had come from cholera-infected districts and among them there undoubtedly were cholera carriers.

The water supply of Hamburg was taken directly from the river. The adjoining city of Altona, with a population of 140,000, is further down the river but filtered its water by a slow sand process. Although the water as taken from the river contained the sewage of Hamburg yet there were only 328 deaths or 2.1 per thousand as against 13.4 per thousand for Hamburg. There were many interesting points in connection with the exemption of certain places in Hamburg, of which may be noted the instance of the entire freedom from cholera of a group of houses (Hamburg Hof), with 345 occupants. This was the only section of Hamburg which was supplied with Altona water. As Hamburg and Altona are only separated by the width of a street and hence practically form a single city, the factor of food and contact transmission could easily explain the cases in Altona.

To illustrate the second type of water transmission we have the well-known incident of the Broad Street pump.

This was about the first definitely proven connection between water and cholera. In 1854 it was noted that cholera was about 10 times as prevalent in Golden Square as in other adjacent parts of London. Various factors, such as previous droughts, stagnation of lower strata of the atmosphere, sewerage defects and subsoil drainage were found to be the same in Golden Square as elsewhere. It was noted that the number of cases increased in the neighborhood of the Broad Street well. The employees of a cartridge factory where this well water was used gave a large number of cases while an adjoining brewery, which had a well of its own and served out beer to its employees, did not furnish a single case. Very striking was the case of a lady living at Hampstead, a section of London which was then free from cholera, who had acquired a liking for the water of this well and had brought out to her regularly bottles of water from the well. This lady drank some of the water on August 31 and was seized with cholera the next day. A niece drank of the same water and died of cholera as well as the aunt. A servant also contracted the disease but recovered.

Macnamara has noted the circumstance of a vessel of water, which became contaminated with cholera stools, but which at the time it was drunk by 19 persons did not show anything suspicious in odor, color or taste. One person was stricken one day afterward, two on the third day and two others came down with cholera on the fourth day. It will be noted that only 5 of the 19 were attacked. A similar lack of susceptibility of a certain proportion of people, equally exposed, has been noted in all cholera outbreaks. It is probable that of those of the 19 who did not contract cholera there were developed a certain number of cholera carriers.

Food Transmission.—Food contaminated by dejecta from cholera patients or carriers is dangerous in proportion to its condition of moisture. Drying and the development of inimical organisms are the two chief factors in destroying the cholera vibrio. Temperature and sunshine are operative in assisting the drying process.

Lettuce and celery are particularly dangerous because of the favorable condition of moisture in their folds and imbrications. Furthermore these vegetables are eaten uncooked and may have been fertilized with night soil (human excrement) which material, if containing cholera dejecta, would infect the plants. Milk is a splendid culture medium for cholera vibrios but, upon becoming acid, sterilizes itself of these vibrios. In sterilized milk, however, they live for extended periods, as long as sixty days and, even when such milk is contaminated by faecal material containing other organisms besides the cholera vibrio, the vibrios live much longer than they do in raw milk.

Milk is liable to be contaminated by flies which have been in contact with cholera stools. Water that has been boiled and food that has been cooked should subsequently be scrupulously protected from flies or other contaminating agents. Uncooked shell fish are peculiarly dangerous in cholera outbreaks.

In India, sun-dried fish, which are frequently covered with flies during the curing process, are a factor in the spread of cholera.

Transmission by Carriers.—This is now universally recognized as the most important factor in the spread of cholera. Dunbar was the first to draw attention to the presence of virulent cholera spirilla in the faeces of apparently healthy persons during the Hamburg epidemic of 1892.

Since that time these observations have been generally confirmed. In some instances as many as 20% of those who have been in immediate contact with a cholera patient have become carriers, some showing symptoms of cholera but a larger proportion excreting cholera spirilla while continuing in health.

While cholera prevailed in Manila, McLaughlin found from 6 to 7% of carriers among healthy persons living in the infected districts.

Pottevin has recently reported that of 13,000 pilgrims examined 1.7 per thousand carried cholera vibrios. The carriers were especially common among the dysenteric patients. During the Naples epidemic of 1911 it was found that on the average 10% of healthy people in contact with cholera cases became carriers. It was estimated that 90% of the cases in this epidemic were infected by sick or healthy carriers.

Sergeant has recently reported the case of a healthy carrier who continued to excrete cholera vibrios for two months and during this time was in contact with 8 persons, 7 of whom became infected and 4 died. In Manila it was found that many of the children reported as dying of meningitis or infantile beriberi were cholera cases.

The vibrios are rarely excreted in the faeces of the cholera patients longer than seven to ten days. Frequently they disappear in three or four days.

With healthy cholera carriers the period of the continuance of vibrio excretion is equally short but cases have been reported where periods of from three weeks to two months have been noted. It is usually stated that 97% of carriers become vibrio free within a month.

Greig has found infection of the bile of the gall bladder or ducts in 80 cases in 271 cholera autopsies. When living organisms are injected into the ear vein of a rabbit they pass into the bile. An examination of the epithelial layers of the gall-bladder of such a rabbit shows destruction of the cells and the presence of vibrios in the underlying tissues. While cholera spirilla are soon crowded out by intestinal bacteria, thus explaining the short period during which cholera spirilla are excreted by convalescents, this is not true when the cholera vibrio gets into the bile ducts or gall bladder. Greig found one cholera convalescent excreting cholera vibrios forty-four days after the attack. Of 27 persons who had been in contact with cholera patients 6 were excreting cholera vibrios although apparently well.

A very important matter is that persons who fail to show cholera vibrios may begin to excrete such organisms after the administration of a purgative or following some intestinal disorder. In fact purgatives may set up an attack of cholera in a cholera carrier.

The spread of cholera is intimately connected with the great religious festivals and pilgrimages of Oriental people. Not only do those of India keep up the dissemination of the disease there but pilgrims going from the delta of the Ganges to Mecca carry the infection and transmit it to their fellow pilgrims from Egypt and Algiers. Greig examined a number of cholera convalescents who were about to return to their homes in India and found 30 per cent of these pilgrims excreting cholera vibrios in their stools.

In India cholera accounts for about 1 to 1.5 deaths per 1000 of population. Malaria and plague are other great causes of death.

The intimate commercial relations between Europe and Egypt and Algiers make the introduction of the disease into European ports an easy matter. Of particular importance is the fact that so many sick people make pilgrimages, these being peculiarly liable to act as carriers.

Excesses in eating, often of badly prepared or decomposing food, following periods of religious fasts, predispose the natives of India to cholera.

Lowered resistance, as from disease or from gastric disorder, increases the susceptibility to cholera. Errors in diet and in particular the effects of alcoholic excesses markedly predispose to infection.

PATHOLOGY

The cholera spirillum does not produce a soluble toxin, the toxic principle being intracellular. The organism rarely penetrates more deeply than just under the epithelial layer of the glands of Lieberkühn. As a result of the outpouring of the fluid into the lumen of the gut we have an increase in the red cells (7,000,000 per cu. mm.) and leucocytosis of from 12,000 to 50,000. The specific gravity of the blood is greatly raised, 1073 to 1078, and the alkalinity diminished. The blood pressure is markedly lowered, 60 mm. in very severe cases and 75 mm. in less severe ones.

The lower portion of the small intestines is the favorite location for the action of the endotoxin of cholera. Early and marked postmortem rigidity is a striking characteristic of the cholera cadaver. Muscular contractions, causing odd positions of the limbs, have at times given a basis for the idea that the victim had been buried alive.

Besides marked rigor mortis the emaciation, leaden hue of skin and shrivelled hands are noteworthy.

In opening up the body there is a striking dryness of all the structures. The dry and dark-red muscles stand out prominently. The lungs are dry and shrunken. The right heart is full of a dark, jelly-like, viscid blood. The leading changes are found in the abdomen. The omentum is dry, sticky and shrivelled looking. The intestines have a ground glass appearance with a lilac-pink color of the small intestines which is in contrast with the normal color of the large intestines.

There is congestion of the affected intestinal mucosa and the lumen is filled with the alkaline rice-water material. If the case is of some days standing we have a rather brownish, foul-smelling bowel content. There is usually a parenchymatous nephritis and on section the medullary portion is much congested.

Crowell gives the following points as indicating cholera upon autopsy: (1) Cyanotic finger nails, (2) dry tissues, (3) dry and sticky peritoneum with pink serosa of ileum, (4) contracted and empty urinary bladder, (5) shrunken dry spleen and liver, (6) rice-water intestinal contents and (7) prominence of lymphoid tissues in the ileum.

In his studies of the pathology of cholera Greig drew attention to the frequency of the involvement of the gall-bladder. He also noted the presence of small areas of consolidation in the lungs of those developing pneumonia during the early days of convalescence. In the exudates of such areas cholera vibrios could be seen thus showing their penetration of the lung. Although rare instances of recovery of the cholera spirillum from the blood have been reported Greig was unable to accomplish this in any instance. In his opinion the spirilla travel by way of the lymphatic system. In eight cases out of fifty-five cases he recovered the spirilla from the urine.

SYMPTOMATOLOGY

=A Typical Case of Cholera.=—The so-called prodromal or premonitory diarrhoea is not a feature of the onset of cholera gravis, the type of the disease which characterizes the cholera epidemic.

The period of incubation is usually from one to five days. Longer periods are possibly explained by some exciting intestinal disorder in a cholera carrier. The course of the disease is conveniently divided into a stage of evacuation, an algid one and a stage of reaction.

The Stage of Evacuation.—A profuse and frequent diarrhoea comes on without colic or tenesmus. In fact the stools are voided with a sense of relief as when an enema is gotten rid of.

The striking feature, however, of these movements is the sensation of prostration which accompanies them.

The faecal character of these diarrhoeal stools is soon lost and the typical rice-water stool is now passed. This designation is very apt and the flocculi of intestinal epithelium, in a watery, slightly opaque fluid, suggests rice-water. The odor is slightly albuminous.

Early in this stage cramps of the muscles set in. The muscles of the legs, especially the calf muscles and those of the feet, are particularly liable to these very painful contractions which may cause the patient to cry out for relief. The muscles of the abdomen and back may also be involved as may at times the muscles of the entire body.

Vomiting, at first of the contents of the stomach and later of rice-water material, is a distressing feature to the patient and by reason of the manner in which it often gushes from the patient’s mouth is liable to contaminate the attendants.

Along with the excessive loss of fluid the tissues, especially of the face, become shrunken, the eyeballs with their congested conjunctivae sink back in the orbits, and the nose becomes pinched. The pulse becomes more and more feeble and there is a steady diminution in the secretion of urine. An increasing duskiness of the skin, which is cold and clammy to the touch, denotes the setting in of the algid stage.

Algid Stage.—In this stage there is almost complete cessation of circulation, even the incision of a vein is only followed by a drop of black tarry blood. Anuria is practically complete.

The vomiting, purging and cramps may or may not subside and in the patient, with his great thirst, intense exhaustion and cadaveric appearance, with mental faculties fairly well preserved, we have an example of a living death. The temperature of the sodden, inelastic, clammy skin is markedly depressed, even below 90°F., while the rectal temperature may approximate normal or be elevated.

Some authorities consider a marked difference between the superficial and rectal temperatures as of bad prognosis.

The voice becomes husky and finally so feeble that the patient can only whisper and the breath feels cold.

The sodden shrivelled hands, as those of a washerwoman, are very characteristic. Thirst is intense.

The patient now falls into a listless, motionless state in which, however, the apathy is more apparent than real. The algidity may deepen and death ensue or the stage of reaction may set in. The algid stage may last from a few hours to two or three days.

Collapse and uraemia are the two most frequent causes of death.

Stage of Reaction.—The pulse returns, urine is again secreted and the duskiness and coldness of the skin give way to normal conditions and a favorable convalescence sets in. At other times, however, the rise of surface temperature and restoration of the circulation are not attended by urinary secretion.

In such cases a typhoid state ensues with accelerated respiration, dry, brown tongue and muttering delirium.

It is customary to divide the types of cholera cases into:

1. Cholera gravis. The type above described.

2. Cholerine. In this there is a more or less marked stage of evacuation with possibly the appearance of rice-water stools. The urine, however, does not become suppressed and the algid stage is not entered upon.

3. Cholera sicca. This type of the disease is more apt to be seen in old or debilitated people. The patient dies of collapse without showing symptoms of vomiting or diarrhoea. At the autopsy one may find the bowels distended with rice-water contents.

The so-called cholera ambulans is simply another designation for the more or less ill cholera carrier.

=Sequelae.=—Following an attack of cholera we may have abscess of the parotid gland or gangrene of various parts of the body. There may be ulceration of the cornea. In pregnant women the disease almost invariably causes abortion. Post-choleraic pneumonias and renal inflammations are to be considered.

Symptoms in Detail

General Appearance.—A typical case of cholera, with its cyanosed, drawn, pinched face, cold, clammy skin and the eyes deeply sunken in the orbits, makes a picture rarely seen in other conditions. The washerwoman’s hands appearance should always be looked for.

Temperature Record.—The temperature of the skin surface is lowered from the normal while that of the rectum may be normal or even elevated. There may be a difference of 10° or more between rectal and surface temperature. In the stage of reaction the temperature may continue to rise to high fever points and this so-called hyperthermic type is very fatal.

Circulatory System.—The pulse is rapid and feeble in the stage of evacuation to become imperceptible in the algid stage. The circulation is practically at a standstill so that only a few drops of black tarry blood, which does not coagulate readily, flow from a wound of a vein when giving an intravenous injection. The blood is concentrated and has a specific gravity of 1072 to 1078. The systolic pressure falls greatly, even to 60 mm. of mercury in a severe, or 75 mm. in a less serious case. The red cell count is increased to 7 or 8 million red cells per c.mm. and the leucocyte count reaches 15,000 to 50,000.

Nervous System.—The mind is clear, even when the patient seems profoundly apathetic. The muscle cramps are characteristic of the disease.

DIAGNOSIS

=Clinical Diagnosis.=—It is customary to state that cholera nostras and infections with virulent meat poisoning bacteria of the paratyphoid group show bile in the intestinal discharges and not the typical rice-water stools of true cholera. It must be remembered that these affections can at times show as marked muscular cramps, emaciation, cyanosis and weak voice as cholera so that only the bacteriological examination can differentiate.

Algid pernicious malaria generally shows a rather high axillary temperature and the stools are rarely so profuse as in cholera.

In ptomaine or mushroom poisoning the vomiting usually precedes the diarrhoea—the opposite of the order in cholera.

Acute intestinal obstructions may simulate but here we have faecal vomiting and constipation.

With irritant poisons as arsenic or antimony there is the metallic taste and the pains are chiefly colicky rather than muscular and the stools rather dysenteric.

I have seen severe cases of bacillary dysentery which could not be differentiated clinically from cholera, and it is interesting to note that many cases of cholera occurring in the Balkan war were diagnosed as bacillary dysentery. In children cerebral manifestations are very common so that in the Philippines many such cholera cases were diagnosed as meningitis.

=Laboratory Diagnosis.=—Agglutination is the practical aid in diagnosis. The serum from cholera convalescents, or those vaccinated against cholera, show agglutinins. It has been stated that properly vaccinated cases show a titre of from 1 to 2 thousand in about 70% of cases. Normal human serum does not agglutinate in a higher dilution than 1 to 20. Greig has found that fatal cholera cases rarely give higher than 1 to 40. In cases recovering he found well-marked agglutinating power by the 6th day, titres of 1 to 500 or 1 to 1000 being frequently obtained. Janoue and Watanabe found the agglutinating power of the sera of convalescents to fall rapidly after the third week. As a rule the titre varied from 1 to 100 to 1 to 400. The highest titre noted was 1 to 10,000.

It is well to first make a microscopical examination of the stool by taking one of the whitish epithelial flakes from the rice-water material and making a straight smear which is then dried and fixed with heat. This may be stained best by a dilute carbol fuchsin (1 to 10). Methylene blue makes a good stain, or more differential is that by Gram’s method which shows the Gram-negative spirilla stained by the bismarck brown counterstain, giving the appearance of fish parallel to one another in a stream. According to Koch a diagnosis can be made in this way of one-half the cases during an epidemic.

The scintillating motility of cholera spirilla may strike one in the examination of the stool in hanging drop.

Dunbar has a quick diagnostic method in which epithelial flakes from the stool are emulsified in peptone solution. Then on a slide, according to the method to be later described, is deposited a drop of 1 to 50 normal serum dilution and on the same slide a second drop of 1 to 500 dilution of cholera serum. A loopful of the suspected stool emulsion is rubbed up in each of these serum dilutions and we should have cessation of motility and clumping in the cholera immune serum provided the organisms in the stool are true cholera spirilla.

In case of an autopsy on a suspected case of cholera one should tie off, between double ligatures, at least two 5-inch sections of small intestines, one just above the ileo-caecal valve and one taken from about the middle of the ileum. These portions of gut should be dropped into sterile salt mouth bottles, well stoppered and sent to a bacteriological laboratory as soon as possible. As the cholera spirilla, when associated with faecal bacteria, tend to die off within twelve to twenty-four hours it would probably be advisable to inoculate an agar or blood serum slant with material from the ileum at the same time the sections of gut are removed. For diagnosis of a cholera carrier with a normal stool or a cholera suspect with a diarrhoeal one inoculate 2 or 3 tubes of peptone solution with 2 or 3 loopfuls of material from the stool. With suspected carriers who are constipated and to whom one should not give purgatives we may insert into the rectum a rubber tube or a throat swab in order to obtain material immediately. The cholera spirilla grow rapidly and being strong aerobes, they grow on the surface of the fluid so that by taking a loopful from the surface, we may in three to eight hours obtain a pure culture. Should there be a pellicle present, this should be avoided in transfer by tilting the tube slightly, so that the material near the surface be obtained without touching the pellicle. Inoculate a second tube from the surface of this first and, if necessary, a third (enrichment method).

Smear the three-hour surface growth of a peptone culture on a dry agar surface in a Petri dish. From colonies developing make agglutination and, if desired, cultural tests. It is by immunity reactions and not by cultural ones that we identify cholera spirilla. The surface moisture of plates is best dried by the filter-paper top.

The cholera colony is easily distinguished from the ordinary faecal bacterial colonies by its transparent, bluish gray, delicate character.

A practical quick method is to make smears from suspicious colonies, stain for one minute with dilute carbol fuchsin and if vibrios are present to make 2 vaseline rings on a single slide allowing ample space at one end for handling the preparation safely. Inside of one ring deposit with a platinum loop a drop of salt solution and inside the ring nearest the end which is to be held by fingers or forceps deposit a loopful of 1 to 500 or 1 to 1000 dilution of cholera serum. The emulsion in the salt solution remains uniformly turbid and under a low power of the microscope (⅔-inch) shows a scintillating motility. The emulsion made into the drop of serum quickly shows a curdy agglutination and upon examination with the ⅔-inch objective shows clumping and absence of motility. Cover-glasses placed over the two vaseline rings assist in the study of the preparation.

The best-known selective medium for plating out cholera material is that of Dieudonne which is referred to under etiology. Apparently a more satisfactory medium is that proposed by Goldberger, this medium being transparent.

First prepare a 100% meat infusion by treating 500 grams of finely chopped lean beef with 500 cc. water and after three hours strain the infusion, adjust reaction to neutral with 5.3% anhydrous sodium carbonate, then add to each 100 cc. 2½ cc. of the 5.3% anhydrous sodium carbonate, sterilize in Arnold for one-half hour and filter. Next prepare a 3% meat extract agar and mix one volume of the alkaline meat infusion with 3 volumes of the hot melted 3% meat extract agar. Pour plates and cover with a piece of filter-paper and place in incubator for one-half hour until they are quite dry. The necessity for a surface without moisture applies to Dieudonne’s and Krumwiede’s alkaline egg media as well as this one. On this medium cholera grows well while faecal bacteria are restrained.

The cholera colony is clear, round and shows a brownish center but is without that striking bluish opalescence shown on ordinary agar plates.

While peptone solution is a more favorable enrichment medium and answers perfectly when cholera organisms are fairly abundant yet, when scarce, selective enrichment media may be desirable. Of these the best known is Ottolenghi’s alkaline bile. Goldberger prefers an alkaline egg peptone solution made as follows:

Shake up an egg with an equal quantity of water and add to this egg solution an equal quantity of a 5% solution of anhydrous sodium carbonate. Steam one hour. Then add 1 part of this alkaline egg medium to 9 parts of peptone solution, filter and sterilize. Recent reports on Aronson’s cholera medium would indicate its great value in stool examination for cholera. The organisms taken from such plates emulsify easily and there is no interference with their agglutinability. To prepare it add to 100 cc. of 3% nutrient agar, 6 cc. of 10% solution of exsiccated sodium carbonate and steam in Arnold sterilizer for fifteen minutes. Then add 5 cc. of 20% saccharose solution, 5 cc. of 20% dextrin solution, 0.4 cc. saturated alcoholic basic fuchsin and 2 cc. of 10% sodium sulphite. A precipitate forms which quickly settles and plates can be poured from the supernatant fluid. Cholera colonies develop in twelve hours and show as red colonies in fifteen to twenty hours.

Test for cholera red reaction. Add from three to five drops of concentrated chemically pure sulphuric acid to the first or second peptone culture after eighteen to twenty-four hours growth. Some specimens of peptone do not give the reaction. At times we only get the cholera red when we have a pure culture of cholera.

PROGNOSIS

There is the greatest variation in the mortality in different epidemics as is true of most other epidemic diseases. At any rate 50% may be considered an average mortality.

Young children and old people give a very high mortality rate as is also true of alcoholics and those with kidney disease.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—Of all the quarantinable diseases cholera is the one in which personal prophylaxis is apparently of greatest influence in protection from infection.

In the presence of cholera one should not only drink recently boiled water, which has been protected from the contaminating influence of flies, but all forms of uncooked food should be avoided. In the first rank of prohibited foods should be raw shell fish and uncooked salads. Such articles as lettuce and celery are particularly dangerous on account of the moisture retained. Fruits such as bananas and oranges can be made safe by covering them with boiling water for two or three minutes and subsequently peeling. Care must be taken that native servants do not put fish, which may have been contaminated with cholera-infected water, on the ice in an ice box and through such a source to have the butter, etc., infected. The most scrupulous attention should be given the matter of the care of the ice-box in the tropics.

If conditions are such that boiled water cannot be obtained the water may be treated with good quality chlorinated soda. As a stock solution we use 1 teaspoonful of chlorinated soda to 1 pint of water and of this 1 teaspoonful to 2 gallons of the water to be disinfected. Pottevin recommends six hours contact with hypochlorite of soda, 1 mg. per liter.

Besides care of the food and water ingested particular attention should be paid to the washing of the hands before eating and if in contact with cholera cases careful disinfection of the hands.

Experience in cholera epidemics has shown the importance of avoiding anything which might lower resistance. In particular are fatigue, excesses in alcohol or the taking of any kind of indigestible foods to be avoided. It must be remembered that the use of purgatives may set up cholera in a cholera carrier so that this possibility should be thought of.

Tea has been recommended as a prophylactic, as has also eucalyptus oil, 10 minims twice daily.

As acids have an inimical effect on the cholera spirilla some have recommended the use of acid drinks but as a matter of fact the best prophylactic is the normal gastric juice and there is a possibility that the use of such acid drinks might upset the digestion and thus defeat the object desired.

As to municipal measures for the control of a cholera outbreak the most important one is to diagnose cholera carriers, such cases often occurring in those associated with a cholera case. Such carriers should be isolated and their stools disinfected until at least 2 negative examinations show them to have ceased being cholera carriers. Of course a cholera case should be isolated and kept in a fly-screened room.

For disinfection of stools one requires an equal amount of a 5% compound cresol solution which when mixed with the same amount of stool becomes a 2½% solution. This should be in contact with the stool at least one hour before emptying the container. Chlorinated lime, 1 pound to 4 gallons, makes a splendid disinfectant for stools—equal parts of this 1 to 16 chlorinated lime solution and stool.

Bed clothing or other material contaminated by vomitus or faeces should be immersed in a 2½% compound cresol solution. All food utensils should be disinfected by boiling.

Persons attending cholera cases should wear gowns and remove the same upon leaving the room. Particular care should be exercised in hand disinfection after attending a cholera case.

There is no danger from aerial conveyance of infectious material other than the possibility of one’s coming within the danger zone of a vomiting patient. Therefore, for disinfection of a room occupied by a cholera patient we need not use formaldehyde gas but washing of floors and lower part of walls with 2½% compound cresol solution is sufficient. The stock solution of chlorinated lime, 1 pound to 4 gallons, is suitable for mopping floors and walls.

Vaccination prophylaxis against cholera has been less used than has been the case with plague or typhoid fever. The anti-cholera sera have no practical value prophylactically and the same statement applies to the use of such sera in treatment of cholera.

Ferran, in 1885, was the first one to use cholera vaccines in prophylaxis. Haffkine, in 1893, adopted the use of a preliminary subcutaneous injection of an attenuated cholera organism to be succeeded later by one, the virulence of which had been exalted by passage through animals to a fixed virulence. (Pasteur’s anthrax method.) He now only uses the fixed virulence vaccine. This vaccine is not killed by heat.

The statistics indicate quite a reduction in susceptibility on the part of vaccinated persons (probably 8 to 1) but only slight lessening of mortality rate. Of 5549 nonvaccinated 198 contracted cholera and 124 died. Of 5778 vaccinated 27 contracted cholera and 14 died.

In the recent Balkan war (1913) Kolle’s vaccine was employed with considerable success. This vaccine is killed by exposure to 58°C. for one hour. It was found that this vaccine was not only of value prophylactically but diminished case mortality as well. With 91,224 persons vaccinated and 8,968 not vaccinated, the case rate among the inoculated was 0.7% and the death rate 10.2%, while among the noninoculated the case rate was 9.3% and the death rate 27.5%.

Ottolenghi prefers to sterilize with a temperature of 53°C. He gives 500 million at the first injection and 2 billion at the second.

Among 72,653 soldiers, having 2 inoculations of this vaccine, the incidence of cholera was about 13 times less than among 14,332 who were not vaccinated.

Of 2897 Greek sanitary corps men inoculated 0.45% were attacked while of 114,805 combatants, not inoculated, about 2% were attacked by cholera. One would naturally consider the greater exposure of the sanitary forces.

Cholera vaccines made from killed cultures are the ones now generally used.

During the World War a Roumanian regiment numbering 4,500 soldiers, had 386 cases of cholera develop in the course of six days, with 166 deaths. Vaccination was commenced and during the interval between the first and second injections, new cases continued to appear. Two days after the second injection the epidemic ceased. In another regiment the commandant refused to have his men vaccinated. A group of Jewish soldiers, 200 in number, insisted on being vaccinated, which was done. Later the regiment was stricken by cholera and 450 cases developed. None of the vaccinated Jewish soldiers contracted the disease.

Some prefer sensitized living cultures for prophylaxis but such vaccines are less practical.

There is much to indicate that Strong’s cholera autolysate is of value prophylactically. In this cholera cultures are killed at 60°C. The killed culture is then allowed to digest itself in the incubator at 37°C. for three or four days (peptonization). The preparation is then filtered and from 2 to 5 cc. of the filtrate is injected.

=Treatment.=—Many of the older authorities recommended the use of various astringent medications for the checking of suspicious diarrhoeas and most of these prescriptions contained opium in some form, such as lead and opium pills or aromatic sulphuric acid and laudanum. In view of the fact that for the infection of animals Koch had to employ opium for checking peristalsis in addition to neutralization of gastric juice it would seem very undesirable to use opium by mouth. Calomel in divided doses and continued over one or two days, but not exceeding 7 or 8 grains, has been recommended.

At present the treatment which is thought to give the best results is the permanganate one proposed by Rogers. In this the patient is given calcium permanganate water ad libitum and 2-grain pills of potassium permanganate every half hour until the stools become more faecal in character. These pills are made up with vaseline and coated with a mixture of a 1 part salol and 5 parts of sandarach varnish.

Reports as to the use of kaolin in treatment and as a prophylactic have been favorable. The suspension in water is given as a drink and as an enema.

Rogers has recently been administering 1/100 of a grain of atropine sulphate morning and evening. His statistics would indicate a reduction in mortality of about one-half. Cases treated with atropine also rarely show collapse. Injections of adrenalin solutions have been recommended.

A great objection to any form of oral medication is the tendency to vomiting. This can in a measure be controlled by cracked ice or by a small hypodermic of morphia. The latter drug also relieves the very painful cramps.

One danger which must always be borne in mind in giving more than one dose of any drug subcutaneously is that with the slowing or cessation of circulation, coming on with the algid state, we have no absorption but, when the stage of reaction sets in and the drug, whether morphine or toxic stimulant, begins to be taken up, there may ensue a fatal poisoning.

However the views of authorities may conflict as to special forms of treatment, there is universal acceptance of the employment of intravenous injections of fluid to combat collapse. Normal saline is the fluid usually used, but Rogers recommends his hypertonic solution which consists of 120 grains of sodium chloride, 6 grains of potassium chloride and 4 grains of calcium chloride to the pint of water.

In the Philippines the normal saline seemed to answer as well as the hypertonic solution.

Sellards had success in combating anuria, which is one of the most dangerous conditions encountered in cholera, and at the same time answered equally well with normal saline in relieving collapse, by giving 2% sodium bicarbonate injections.

There is a marked acidosis in cholera and this form of treatment seems indicated.

The objection to using sodium carbonate is that the salt has a lytic action on red cells in vitro and furthermore Sellards found that it tended to cause convulsions in one of his cholera cases. Sodium bicarbonate, even in 4 or 5% concentration, does not have any haemolysing effect on the red cells. Of course it is true that in sterilization the bicarbonate tends to be converted into carbonate but Sellards found that by sterilization in an autoclave connected with live steam, at 7 pounds pressure, this was minimized, only about 25% of the bicarbonate being converted into carbonate after 1 hour.

If the temperature by rectum is about normal or slightly below, the temperature of the fluid should be 102° to 104°F. and one usually gives about 2 quarts.

Owing to the collapse of the veins it is usually necessary to cut down on them instead of inserting the needle through the skin as for salvarsan injections. The same apparatus as for salvarsan injections is suitable but with a somewhat larger container as we give from 1 to 2 quarts of fluid. At least fifteen minutes should be taken up for the introduction of 1 quart of fluid.

To determine the necessity for intravenous infusion in cholera Rogers has recently recommended the employment of small bottles containing aqueous solution of glycerine with specific gravities varying from 1048 to 1070, increasing the specific gravity in each successive bottle by 2°.

Drops of blood from the cholera patient are deposited at the center of the surface of the fluid in the bottles from a capillary pipette. If the specific gravity of the blood is 1062 at least a liter of saline or sodium bicarbonate solution is needed. If 1066, at least 2 liters. Formerly he estimated the indications by blood pressure, considering a pressure of 80 in Europeans or of 70 in natives as indicating intravenous injections.

On the whole the reports from the use of anti-cholera sera are not very encouraging. Savas, however, was favorably impressed by such treatment during the Balkan war. It should be administered intravenously and early in the attack and given in doses of 50 cc. Of 61 severe cases, so treated, the mortality was 55.7%. Of 17 severe cases, not receiving serum treatment, all died.

Hot water bottles should be used to keep up the body heat. No food should be given during the first thirty-six hours but after that time we may give broths or albumin water.

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XVI. MALTA FEVER

DEFINITION AND SYNONYMS

=Definition.=—Malta fever is a septicaemic condition due to the presence of the specific organism, Micrococcus melitensis, in the blood and various organs, especially spleen. It runs a protracted course, averaging three or four months, but is attended with very slight mortality (2%). Rare cases may run an acute course and show a high death rate. The fever course resembles that of a typhoid fever with two or more relapses, in that a step-like rise of fever for ten or twelve days is followed by a similar fall during the succeeding week or ten days, an afebrile interval of a few days then ensuing, to be followed by a second or third or even tenth febrile wave with the separating days of apyrexia. The course of the disease may last for a year or more attended with progressive anaemia and manifestations of neurasthenia. Very characteristic are sudden swellings of various joints which subside in a few hours to entirely disappear in a few days. Neuralgic manifestations, especially sciatica, are prominent features of the disease. It is chiefly spread by the milk of infected goats and can best be prevented by boiling such milk.

=Synonyms.=—Febris undulans (from the wave-like monthly accessions of fever). Mediterranean, Gibraltar or “Rock,” Neapolitan, Cyprus fever (from the geographical distribution). Febris sudoralis (from the night sweats). Mediterranean phthisis (from the bronchitis, anaemia and night sweats resembling phthisis). Melitensis septicaemia. Febris melitensis.

HISTORY AND GEOGRAPHICAL DISTRIBUTION

=History.=—It is generally considered that a disease described by Hippocrates, in which there was an irregular febrile course without crisis but showing relapses and running a very prolonged course, was probably Malta fever.

In 1861 Marston showed on clinical and pathological grounds that the disease was different from typhoid fever.

In 1887, Colonel Bruce isolated the causative organism from the spleen at autopsy and established the demands of Koch’s postulates by reproducing the disease in monkeys with cultures from the spleen and then recovering the organism from the monkeys.

Our present accurate knowledge of the epidemiology of Malta fever and its connection with the use of the milk of goats is due to the work of a Commission appointed to investigate the disease—1904 to 1907.

=Geographical Distribution.=—It is usual to consider Malta as the focus of the disease, with the cities of the Mediterranean shores showing quite a degree of infection. It is probable that the spread of the disease has been in part connected with the importation of Maltese goats, these animals being desirable on account of their superior yield of milk. It is now known that outside of the Mediterranean basin the disease exists in India, East and South Africa as well as Northern Africa, China, North and South America and the West Indies.

Mohler has shown that the disease under the names of “slow fever” and “mountain fever” has existed in Texas and New Mexico for at least twenty-five years.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—The causative organism, Micrococcus melitensis, is a small coccus, rather oval than round and about 0.4 micron in diameter. In morphology it is quite variable and may occur in pairs or in short chains and is Gram-negative. It emulsifies evenly and rapidly in a hanging-drop preparation and is nonmotile. Possibly on account of its showing a rather active Brownian motion there has been a reporting of slight motility by some authorities. Very striking is the characteristic of very slow growth so that cultures on agar fail to show colonies before the fourth day.

These minute transparent colonies become somewhat opaque and about 1/10 inch in diameter by the tenth day. Gelatine is not liquefied and litmus milk is not altered. The optimum reaction of media is about +0.75 to phenolphthalein and it grows best at the body temperature. It has great powers of resistance to drying so that it survives in dust for long periods.

Horses, cows, asses, as well as goats, are susceptible. It is very difficult to infect rabbits, mice and guinea pigs. Monkeys have been chiefly utilized in experimental work.

It would appear as if there were other organisms closely related to M. melitensis and a great deal is now being written as to confusing serum reactions from the use of M. paramelitensis.

Evans and others have studied the relationship between Bacillus abortus and M. melitensis. Morphologically and culturally these organisms are quite similar and Evans has demonstrated a marked degree of cross-agglutination. This is a probable explanation of the finding by Kennedy of agglutinating power in the sera and milk of certain cows, but inability to isolate M. melitensis from the agglutinating milk.

=Epidemiology.=—Many experiments have failed to show any mosquito, biting fly or louse as a probable factor in the transmission of the disease. The infection is readily transmitted by subcutaneous inoculation so that in a case in goat or man, with the cocci in the peripheral circulation, it is reasonable to suppose that a biting insect might transfer the infection by going directly from one animal to another. There have been several laboratory infections, but when we consider that of the great number of cases treated at Haslar hospital and elsewhere in England, with frequent elimination of the organism in the urine, and practically no infections among the friends or attendants, it would seem as if usual methods of infection were inoperative. There does not seem to be a carrier problem in this disease. Urine showing bacterial contamination, when dried and mixed with dust, has caused infection and contaminated urine applied to the glans penis of a monkey caused the disease.

As a large proportion of the prostitutes of Malta showed infection and as M. melitensis was found in urine and vaginal discharges of many of these it is possible that sexual intercourse may be a factor in transmission.

The Commission noted many cases of Malta fever among the goatherds. By agglutination tests it was found that one-half of the goats showed agglutinins in their serum. Of 28 monkeys given infected milk 26 became infected. Very conclusive was the case of the “Joshua Nicholson,” which ship carried 65 Maltese goats from Malta to the United States. Of ten of the crew who drank goats’ milk on the voyage, eight became infected. Two who boiled the milk escaped infection. It is reported, that when the goats reached the United States and were quarantined, a woman drank of their milk and became infected.

What may be deemed proof positive is the practical disappearance of the disease among the naval and military forces of Malta, as the result of boiling the milk, while still continuing among native civilians. Bassett-Smith has noted that in 1905 there were 798 cases among civilians and 245 naval cases. In 1907 there were 457 cases among civilians and only 12 cases in the naval forces.

There are however occasional cases which Shaw has considered as due to carriers. As the organisms are excreted in faeces as well as in urine, and as the course of the disease is so protracted, as well as the convalescence, it would seem that the carrier factor should be of more importance than facts would justify.

Mohler has noted that in Texas, where the disease has existed for twenty-five years, the Mexican goatherds boiled their milk and hence were rarely infected.

Gentry and Ferenbaugh, in Texas, noted that cases of Malta fever were most common in the spring and early summer months when the goats were in full milk and the ranchmen were caring for the kids and teaching them to suckle. The disease in certain areas was called “goat fever” and in others “dust fever,” this latter name coming from the idea that the dust-filled goat pens had to do with the disease.

The souring of milk does not destroy the germs of the disease, hence transmission may be brought about by butter and cheese.

Malta fever was stamped out of Port Said by destroying all infected goats.

Infection may occur: (1) By the stomach atrium (usual); (2) contaminated dust reaching lungs; (3) by subcutaneous injection.

PATHOLOGY AND MORBID ANATOMY

The germs are found early in the blood and spleen; and are also present in lymphatic glands and kidneys.

The blood is most apt to contain them at the height of the fever curve and a striking feature is the appearance in waves of the organisms in blood, urine or milk. While serum immunity reactions are striking features, there is some question as to the conference of immunity by an attack.

At postmortem we have an enlarged, congested, soft spleen with swollen Malpighian bodies. The kidneys may show a nephritis and the mesenteric glands be swollen. The intestines fail to show the characteristic lesions of typhoid fever.

There may be evidences of myocarditis.

SYMPTOMATOLOGY

A Typical Case.—Following a period of incubation, varying from ten to fifteen days, headache, malaise and anorexia set in with a step-like rise of fever from day to day.

The tongue is not heavily coated and is red at the tip and sides.

Constipation is the rule and there is an early tenderness and enlargement of the spleen. There is much to suggest typhoid fever in the gradual ascent of the remittent fever for about ten or twelve days and the gradual descent during the succeeding ten or twelve days, but the lack of apathy and slighter evidences of toxaemia differentiate. The patient is dejected rather than apathetic.

There is often a slight bronchitis, with cough, which, when associated with a profuse sweating at night, may suggest phthisis.

Following the initial period of fever there is usually a short afebrile interval of a few days to be succeeded by a second, third or many of these febrile waves, thereby making one of the names, undulant fever, appropriate. Anaemia becomes marked and cardiac weakness, as shown by palpitation and rapid, irregular pulse, apparent.

The symptoms which aid us most in diagnosis are joint manifestations and neuralgic pains. These may come on quite early in the course of the disease or be delayed until succeeding febrile waves set in. Swelling and pain, but without redness, of a single joint may come on rather suddenly, to have the acute symptoms subside in a few hours and to be entirely normal in three or four days.

Pains in the sacro-iliac region or pains resembling those of hypertrophic arthritis of the spine may be noted.

It is however the peripheral nerves, even more than the joints, for which the toxic effects of M. melitensis show a preference. The sciatic nerve seems to be most often involved and sciatica may set in suddenly and acutely, to pass off in two or three days, leaving a soreness over the course of the nerve and a tendency to recurrence. Orchitis may occasionally set in. There is usually albuminuria.

Insomnia is usually quite a prominent feature of the disease and there is a great tendency for nervous prostration to develop.

The usual course of the disease runs for three or four months but may last almost a year.

=Other Clinical Types.=—(1) The Malignant Form.—In such cases instead of the insidious onset we have the characteristics of a severe acute infection with high temperature from the beginning, ranging from 103° to 105°F. Such cases may show vomiting and early diarrhoea. This is followed by a typhoid state with cardiac manifestations in the way of irregularity of the pulse. An ordinary type of case may assume this malignant form and such cases may develop a broncho-pneumonia.

(2) The Intermittent Form of Hughes.—Here we have a type of case similar to the typical one but less severe. It is a subacute form which from time to time shows an intermitting fever. These cases may fail to show evidence of serious illness and the patient may continue his work although noting a progressive deterioration of health. Some very mild cases which only rarely show slight fever of a few days’ duration have been reported as ambulatory cases.

(3) The Disease in Infants.—Di Cristina and Maggiore have described various forms of the disease as observed in infants in Palermo. They note a hyperpyrexial type and an undulant type. A type with anaemia and marked cachexia is very severe. Another form shows cyanosis, irregular pulse and irregular respiration with marked sweats. Again the symptoms may be those of a cerebro-spinal meningitis.

=Sequelae and Complications.=—It should be borne in mind that while not serious from a standpoint of mortality this disease is to be dreaded by reason of the possibility of invalidism. The neuralgic pains, insomnia and mental depression render patients liable to the morphine habit. In pregnant women there is a tendency to abortion. In rare cases we may have intestinal haemorrhages with asthenic manifestations. Bassett-Smith has reported a case with extensive purpura. The same author in paramelitensis cases has noted the susceptibility to secondary streptococcal infections.

SYMPTOMS IN DETAIL

Temperature Chart.—Except in the malignant form of the disease, when the temperature may be rather continuous, the fever course is a step-like ascent with daily remissions for about ten days and then a similar descent. Following an evening rise of temperature night sweats may be noted.

It is the wave-like succession of such courses of fever, separated by afebrile intervals, that suggests the name undulant fever.

Circulatory System.—The disease shows rather a toxic effect on the heart as shown by palpitation and irregularity and rapidity of pulse rate.

In the beginning of the fever, however, the pulse rate is not very fast. Anaemia is a rather marked feature.

Respiratory System.—A slight bronchitis with cough tends to suggest phthisis in those cases which show rather marked night sweats.

Nervous System.—The organism seems to have a selective action on the nervous system as shown by headache, various neuralgias, insomnia, apathy and neurasthenia. Sciatica is probably the most common peripheral nerve involvement.

Joint Symptoms.—Very characteristic are the sudden and painful swellings of various joints, especially hip, shoulder, ankle and knee. Not rarely the costo-sternal articulations may be involved. The acute symptoms subside in a few hours and the joints become normal in a few days.

Alimentary Tract Symptoms.—The tongue may have a slight furring but the edges and tip are quite clean and red. Although anorexia exists with the fever the appetite tends to return with apyrexia. Constipation is usual. There is frequently tenderness of the epigastric region.

Genito-urinary System.—Other than for albuminuria and the presence at intervals of the causative bacteria in the urine, there is nothing of note, except the occurrence of orchitis in about 3 per cent. of cases.

The Blood.—The white count is about normal or slightly reduced—6500 on the average. The cells of lymphocyte type tend to show an increase in percentage with a corresponding reduction of polymorphonuclears.

There is a secondary anaemia.

The spleen shows early enlargement and tenderness.

DIAGNOSIS

=Clinical Diagnosis.=—The diseases most apt to be confused with Malta fever are typhoid fever, malignant tertian malaria, liver abscess, influenza, phthisis and kala-azar.

Besides the agglutination, complement fixation or blood culture aids, we rely upon the sudden onset of joint involvement or neuralgic manifestations as indicating Malta fever.

Usually the splenic enlargement about corresponds with that of typhoid fever but at times it may be so marked as to equal that of malaria or even kala-azar.

The presence of rose spots as well as the marked apathetic state and the tendency to diarrhoea should aid in differentiating typhoid. Unfortunately for diagnosis the leucopenia and polynuclear percentage reduction is similar in the two diseases.

In kala-azar the double temperature rise in 24 hours with the Leishmania bodies in spleen puncture material, instead of M. melitensis, are differentiating.

The short course and more sudden onset of influenza and the more marked pulmonary symptoms of phthisis should prove diagnostic aids.

Liver abscess and empyema with their tendency to anaemia and sweating may prove confusing, but the history, leucocytosis and location of pain should differentiate. Then too the joint and nerve manifestations of Malta fever are absent.

=Laboratory Diagnosis.=—Eyre obtained cultures from blood from the 2d to 300th day of the disease. He recommended the taking of at least 5 cc. from a vein and that this be done at a time when the fever is at its maximum point—the days when the fever is at its maximum and in the evening of that day. By taking 20 to 30 cc. in an equal amount of citrated salt solution, as described in chapter on blood examination, one should have as great success as had Eyre—158 positives in 235 cases or 65.4 per cent.

It must be remembered that the colonies only appear about the fourth day, becoming quite distinct by the tenth day.

Bassett-Smith takes about 10 cc. of blood in the afternoon during pyrexial waves and distributes this blood in several tubes of broth. He makes plates from these tubes every day. He also recommends the taking of 1 cc. of blood which he allows to clot and subsequently removes the serum and adds bouillon (clot culture).

Agglutination is the chief reliance in diagnosis. As result of two infections in his laboratory Widal uses emulsions killed by ¾% of formalin. He uses the microscopic method in the test with dilutions not exceeding 1 to 200. Such emulsions keep for at least a year.

In connection with agglutination tests Nicolle recommends that the serum be separated at once and removed from the clot and Nègre has shown that by heating the serum to 56°C., for thirty minutes, reactions are not obtained with nonspecific sera.

Some workers prefer the macroscopic agglutination.

Complement fixation methods are of value but the application of such tests is confined to large laboratories.

PROGNOSIS

The mortality is usually reported as 2% but there have been epidemics where the mortality, owing to the frequency of the very fatal malignant type, has exceeded 10%. It must be remembered however that the invaliding connected with the long course of the disease and protracted convalescence makes Malta fever a serious affection. Neurasthenia, susceptibility to neuralgias, cardiac weakness and formation of morphine habit may result from the disease.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—The danger from carriers seems slight but should be considered.

Disinfection of excreta, in particular urine, is important.

Boiling of goat’s milk or killing of infected goats is a prime consideration.

A rapid method of detecting infected goats is by carrying out a macroscopic agglutination of M. melitensis with the milk obtained from goats. The lacto-reaction should be confirmed by a serum one.

=Treatment.=—There is no specific treatment generally recognized as efficient. Recently, an anti-melitensis serum, from animals injected with the nucleo-proteid material from the organisms, has been used with some success.

A serum prepared by injecting horses intravenously with the specific organism has been recommended by Sergent in doses of 50 cc.

Bassett-Smith recommends an autogenous vaccine, during the afebrile period, in doses of from 50 to 200 millions. He thinks that the best results are obtained with sensitized vaccines. During acute phases the vaccine treatment is detrimental—it is only in chronic cases that such treatment is of value. Some prefer to give doses of 10 million or so at short intervals. He also thinks yeast in 2-dram doses to be of value. Phenacetin or aspirin may be given, but the heart weakness makes extensive use of these analgesics dangerous.

The diet should be that for any acute disease but the protracted course makes it necessary to have regard to an adequate food value. Care should be taken to avoid chilling or fatigue.

Some recommend moderate use of alcoholic stimulation but this treatment is questionable.

Cold sponging and local applications to joint or nerve involvements are indicated.

Morphine should be employed with great caution.

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