CHAPTER IV

THE TROPICAL RELAPSING FEVERS

DEFINITION AND SYNONYMS

=Definition.=—There is a group of tropical fevers more or less identical clinically with European relapsing fever and caused by spirochaetes closely allied to _Spironema recurrentis (Spirillum obermeieri)_. It seems probable that the relapsing fevers of East and West Africa are caused by a single species, _S. duttoni_, which is transmitted by a tick, _Ornithodoros moubata_, while that of Northern Africa is caused by another species, _S. berbera_, which is transmitted by lice, either _Pediculus vestimenti_ or _Pediculus capitis_. Another species of spirochaete, _S. carteri_, is supposed to cause the relapsing fever of India and it seems probable that its transmission is brought about by infected lice.

Besides the above species of spirochaetes others have been reported, as _S. novyi_ for American and _S. persica_ for Persian relapsing fever. The view taken by Nuttall, that these various names may be of convenience in the study of relapsing fevers but that there is no adequate morphological difference to justify them as species, seems worthy of acceptance. It has been shown that the separation of these spirochaetes on the basis of susceptibility of laboratory animals and cross immunity reactions is untenable. Agglutination of certain strains by their specific sera, however, is a reliable means of separation. As with European relapsing fever, these fevers are characterized by a sudden onset, intense frontal headache, and pain of back and limbs. This fever remains high for three to five days and falls by crisis, to be succeeded by an apyrexial interval of approximately one week. There may be several of these alternating febrile and afebrile periods. The spirochaetes are in the peripheral circulation during the febrile period but not in the afebrile one. The spleen is enlarged and tender. Cases showing jaundice seem more grave.

=Synonyms.=—Febris recurrens. Tick fever. French: Typhus recurrent. German: Rückfallfieber.

HISTORY AND GEOGRAPHICAL DISTRIBUTION

=History.=—Although Hippocrates described the clinical features of relapsing fever quite accurately this knowledge seems to have been lost until about the eighteenth century.

The causative spirochaetes were first seen by Obermeier in the blood of a patient in 1868 but he did not publish his discovery until 1873.

Ross and Milne, in 1904, found that African tick fever was a spirillar fever while Dutton and Todd established the fact of its transmission by ticks.

=Geographical Distribution.=—Relapsing fever was epidemic in the U. S. in 1869, since which time it has not reappeared. There have been many epidemics in Ireland, Russia, Turkey and other parts of Europe. It was a disease of importance during the Balkan War of 1912-1913. China and India have frequently been visited by epidemics as well as the Philippine Islands and the Dutch East Indies. Uganda, Congo State and German East Africa, as well as Egypt and Algeria, are important centers. There is also a relapsing fever of Colombia and Central America.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—Relapsing fevers are caused by organisms generally considered as protozoal in their nature and belonging to the flagellates.

[Illustration: FIG. 36.—Spirochaetes of relapsing fever from blood of man. (Kolle and Wassermann.)]

_Transmission by the tick._—The generic name _Spiroschaudinnia_ is preferred by some to the more commonly accepted _Spirochaeta_. Recently, authorities give these organisms the name _Spironema_. East and West African relapsing fever, or tick fever, is caused by _Spironema duttoni_ and the transmission is through the bite of an argasine tick, _Ornithodoros moubata_. Not only does the tick itself become infected by the taking in of blood-containing spirochaetes but likewise transmits the infection to its progeny. Leishman considers that when the spirochaetes are taken into the alimentary tract of the tick there is a breaking up of the spirochaetes into small granules which reach the Malpighian tubules. They also invade the ovary and the ova. It was thought that these granules were the infecting agents and that they were excreted in the fluid of the coxal glands or passed out with the faeces. More recently it has been claimed that these granules have no relation to the infection, which is due to spirochaetes as such.

It may be stated that spirochaetes as such may be found in the secretion of the coxal glands as well as in the faeces. This coxal fluid dilutes the thick faeces and makes an emulsion which is smeared out by the body of the tick in the area of the bite puncture.

[Illustration: FIG. 37.—_Spirochaeta novyi._ (Todd.)]

At any rate this infection of man seems to be the contamination method, the material from faeces and coxal glands being rubbed into the wound made by the tick-bite. The ticks hide in the cracks about the old native huts and bite the sleeping inmates. There may be quite a local reaction at the site of the bite. _Spironema duttoni_ has been cultured by Noguchi, by utilizing his methods for culturing the organism of syphilis. In such cultures he has noted longitudinal division rather than transverse, this fact rather favoring a protozoal as against a bacterial nature. This spirochaete is from 24-30 microns long, about 0.45 micron broad and has a corkscrew motility. It is readily transmissible to a number of laboratory animals, as monkeys, white rats, etc. The spirochaete of Northern African relapsing fever, _S. berbera_, causes the disease as seen in North Africa and Egypt. It is transmitted by lice, Nicolle and others having shown that the spirochaetes make their way from the alimentary tract to the body cavity of the louse. They have shown that the bite alone of an infected louse is innocuous and also that the faeces are non-infective, when injected into monkeys. Emulsions of infected lice, however, when rubbed into wounds, produce the disease in monkeys.

_Transmission by the Louse._—The spirochaetes taken in by a louse disappear in a few hours and the insect remains harmless until about the fifth day, when it becomes infectious, and so remains until the twelfth to fifteenth day. Spirochaetes reappear in the coelomic fluid of the louse about the sixth day and continue present until about the twentieth day.

A striking fact is that infection can be brought about a day before spirochaetes appear and that after a period of a few days these spirochaete-containing lice lose their power to infect. It would seem that the infecting stage was an invisible one. Have we then a symbiosis between a spirochaete and an invisible virus, possibly filterable? Wolbach has shown that certain spirochaetes will pass through a Berkefeld filter as spirochaetes but this would not affect the possibility of the existence of some granule or chlamydozoal stage. It may be that the infecting stage is not an invisible one but a granule one.

_Mode of Infection._—It is by crushing the louse, by scratching or otherwise, that the spirochaetes contained in the coelomic fluid reach and penetrate the wound of the bite. This is therefore a contaminative method of infection. Mackie has shown that the Indian relapsing fever, which is caused by _S. carteri_, is probably transmitted by the louse, and it is probable that the conditions under which the infection takes place are similar to those occurring with _S. berbera_ infections. With the European relapsing fever, bedbugs may possibly act as transmitting agents. The probabilities however are that this infection is transmitted by lice alone.

[Illustration: FIG. 38.—_Ornithodoros moubata._ (Murray from Doflein.)]

A relapsing fever of Persia is transmitted by a tick of the genus _Ornithodoros_, which is also true for the relapsing fever of Panama. There is great variation in the description of the different spirochaetes, and frequently measurements are given for short forms and long forms. They also vary from wave-like lines to corkscrew spirals. Again, different species have different types and different activities of movement. As a rule they are about 20 × 0.4 microns. The spirochaetes of the relapsing fever of Panama varied in length from 4.6µ to 22µ. Of these the most common were those measuring 13µ. Transverse division of the longest forms was seen in dark-field preparations. The monkey is susceptible to all species of relapsing fever spirochaetes. White mice and white rats are readily infected by _S. duttoni_ and the Panama spirochaete but are refractory to _S. recurrentis_ except after passage through monkeys. _S. carteri_ causes only a transient infection in these small rodents.

=Epidemiology.=—With tick fever the epidemiology rests upon the life history of the tick _O. moubata_. This tick infests the rest houses along the route of travel, hiding in the crevices of floors and walls during the day and coming out at night to bite the sleeping inmates. The feeding occupies a long time, more than an hour. Both sexes bite man. The female lays about 100 eggs, from which nymphs emerge in about twenty days. The larval stage takes place in the egg. Shortly after emerging the nymphs suck blood. An important fact is that the female transmits the spirochaete to its ova, so that the ticks from such ova may transmit the disease.

[Illustration: FIG. 39.—Siphunculata and Rhynchota. 1. _Pediculus capitis._ 2. _Pediculus vestimenti._ 2_a_. Protruded rostrum of _Pediculus_. 3. _Phthirius pubis._ 4. _Acanthia lectularia._ 5. _A. rotundata._ 6. _Conorhinus megistus._]

Natives seem to suffer severely from tick fever in childhood but in adult life possess a sufficient degree of immunity so that the disease shows itself in a very mild form in those harboring spirochaetes.

The immunity conferred by an attack is not lasting and a second infection may occur within a year. Such second attacks, however, do not present the relapses so important in a clinical diagnosis. As a matter of fact there may be no symptoms and such cases with spirochaetes in their blood make ideal carriers for the infection of ticks or lice. Ticks can be infected by these carriers. In some of the rest houses 50% of the ticks may be infected. While the tick does not tend to leave its habitation it may be transported in the bundles of native porters. The transmitting agent of the North African relapsing fever and probably of the Indian type is the louse. The body louse deposits about 75 eggs in the clothes of the host, which hatch out in about four days and become adults in about two weeks. The head louse deposits its eggs or nits on the hair of the host’s head. Hagler has noted that, in Servia, typhus fever disappeared when lice were gotten rid of but relapsing fever continued to prevail until they also exterminated the bedbugs.

_The Relapsing Fever of Panama._—Bates, Dunn and St. John have demonstrated that a tick, _Ornithodoros talaje_, transmits the relapsing fever of Panama. This tick seems to prefer the crevices and open joints of bamboo beds, laying its eggs and moulting in the hiding places. It comes out at night to feed on the occupants of the bed. Two white rats were inoculated with an emulsion made from ticks taken from a suspected bed. Both rats developed a spirochaete infection. A man inoculated with blood of one of these rats developed relapsing fever on the sixth day. A second man was inoculated subcutaneously with an emulsion of ticks collected from a bed and showed spirochaetes in his blood on the eleventh day.

Another man was bitten by ticks from the same source and was instructed not to scratch the bite. The ticks engorged in about 15 minutes, some of them secreting coxal fluid which mixed with blood from the bite made a scab. This man was positive for spirochaetes on the fifteenth day.

PATHOLOGY AND MORBID ANATOMY

The spirochaetes disappear from the peripheral circulation during the apyrexial period, notwithstanding which such spirochaete-free blood, when injected into monkeys, may bring about infection. Either a granule stage or an invisible stage of the parasite may be present. The relapse is probably due to the existence of resistant strains which are not destroyed by the lytic substances, developed during the attack.

Agglutinating and lytic substances show themselves chiefly during the apyretic intervals.

The spleen is enlarged and soft. There are frequent infarctions. The spirochaetes are found phagocytized in the macrophages of the spleen and elsewhere. Parenchymatous degeneration of kidney and heart muscle, and especially of liver, may be noted.

SYMPTOMATOLOGY

_East and West African Relapsing Fevers._—In African tick fever after a period of incubation of from three to ten days the disease sets in rather suddenly with dizziness, marked headache and general body pains. The temperature quickly rises to 104°-105°F. and remains elevated during this primary febrile period, except for slight morning remissions. Vomiting is quite a feature of this disease and may be bilious in character.

There may be rather marked praecordial oppression and a bronchial catarrh. The pulse in particular and the respiration in less degree are accelerated. Herpes and epistaxis may be noted. The bronchial manifestations seem to occur chiefly in the first febrile accession. The spleen is somewhat enlarged and tender but in many cases this is not noted. Spirochaetes are found in the peripheral circulation during the febrile accessions but not during the apyrexial intervals. There is great variation as to the abundance of spirochaetes. In some cases we may have to search several hundred fields before finding a single spirochaete. Severe cases may show them in abundance. A rather marked leucocytosis may be present in cases showing high fever and bronchitis. After about four days the fever falls by crisis, often below normal, and possibly with great prostration and cardiac weakness.

A critical sweat is a feature of this rapid fall of temperature. During the afebrile period, which lasts from three or four days to eight to ten days, the patient feels much better and his appetite and strength return. With the onset of the second pyrexial wave the severe symptoms of the first days are repeated, as with the first febrile period. This second one terminates by crisis. Iritis is not uncommon. Manson and Thornton have reported transient cranial nerve involvements coming on late in the course of the disease.

In European relapsing fever the second febrile accession is usually shorter and of less severity than the first. Furthermore there are rarely more than 2 or 3 relapses. In tick fever, however, there may be as many as 10 of these febrile recurrences, although there are usually only 4 or 5. In natives there is usually only one febrile period, this probably being due to an immunity resulting from previous infections.

_North African Type._—In the relapsing fever of North Africa the attacks are less severe and the number of relapses rarely exceeds three. A fever of Egypt, generally known as the _bilious typhoid of Griesinger_, is believed to have been a form of relapsing fever. In this there was marked bilious vomiting with great tenderness of the liver, late jaundice, albuminuria, bone pains, especially about the knees, and a high death rate. The symptoms rather suggest yellow fever but this disease has never been reported from Egypt.

_Indian Type._—In the relapsing fever of Asia there is a marked tendency for the patient to collapse at the time of the crisis. There are rarely more than two relapses and in probably 25% of cases there is no relapse. There seems to be a greater tendency to liver complications in the Asian types than elsewhere and such cases form a large part of the death rate from this disease. Bilious vomiting and jaundice, with a typhoid-like state and the occurrence of various inflammatory complications, especially parotiditis, are noted. The mind is usually clear, but delirium may be present in severe cases.

_Relapsing Fever of Panama._—In three experimental cases the temperature of the first accession varied from 102°F. to 104.5°F. Frontal headache and general body aches were the chief symptoms. Vomiting was noted in one case. The spleen was not enlarged. The first relapse was cut short in each case by arsphenamine.

The Symptoms in Detail

_The Temperature Curve._—This is the chief point in the clinical diagnosis of relapsing fever. The onset of the first febrile accession is abrupt and the temperature rapidly rises to 104°F. or higher. After a continued high temperature for three or four days the fever drops by crisis, which is at times productive of collapse. Following an apyrexial period of four to eight days we have a second febrile accession, and there may be several of these wave-like alternations of fever and apyrexia.

_The Nervous System._—Very marked frontal headache is a striking feature and the pains in back and limbs may be of great severity. Cranial nerve involvement has been noted. There may be apathy, but on the whole the mind is clear.

_The Digestive System._—Anorexia and vomiting are features of the febrile periods to cease in the fever-free periods. In some types bilious vomiting may be marked.

_The Circulatory and the Respiratory System._—The pulse rate is much accelerated, and there may be some praecordial distress. A bronchial catarrh is frequently present in the first febrile paroxysm.

_The Liver and Spleen._—Splenic tenderness and moderate enlargement are fairly constant features. The liver may suffer severely in the so-called bilious typhoid and marked jaundice may ensue with a typhoid state.

_The Blood Examination._—This is the most important point in diagnosis. The spirochaetes, which are only found in the peripheral circulation during fever periods, are not so numerous in tropical relapsing fevers as in the European forms. When spirochaetes are scarce it is more satisfactory to examine Romanowsky-stained specimens, especially with the Giemsa staining. The spirochaetes show a varying number of undulations. There is no chromatin staining in the line of the spirochaetes. The disease when severe shows a well-marked polymorphonuclear leucocytosis, with at times an increase of large mononuclears. This latter, however, may be connected with malaria or amoebiasis.

DIAGNOSIS

The disease most likely to be confused with relapsing fever is malaria and for this differentiation the finding of the parasites of either disease is of first importance.

The blood of a suspected case even during the apyrexial period should be injected into a mouse or white rat (guinea pigs are refractory to infection). Spirochaetes should appear in the blood of the mouse in about twenty-two hours and persist for about two days. Relapses occur but recovery is the rule.

Dengue may be suspected, but the leucopenia, lack of splenic tenderness, lack of tendency to vomiting and presence of post-orbital pains should differentiate. As there is a leucocytosis in both relapsing fevers and smallpox, and similar headache and backache, confusion might exist were the parasites not found.

Yellow fever has many features in common with the bilious type of relapsing fever, but there is no leucocytosis in yellow fever, and there is no characteristic albuminuria and slow pulse in relapsing fever. Influenza has many points in common with relapsing fever.

In a case of relapsing fever with jaundice confusion might arise with Weil’s disease inasmuch as a blood smear might show spirochaete-like organisms.

Typhus fever shows a less abrupt onset and the marked mental symptoms (stupor) and dark macular eruptions about the trunk, on the 4th to 6th day, should differentiate. If the case is first seen in the apyrexial period one may take a drop of blood from a case showing spirochaetes and one from the suspected patient. After incubation for thirty minutes the spirochaetes should lose motility and agglutinate if the case be one of relapsing fever (Lowenthal’s Reaction).

In blood examinations we may use the dark-field illumination, although the spirochaetes stain readily with Wright’s stain. The India ink method is a good one. Hagler recommends smearing out a mixture of one loopful of blood and a collargol preparation made by diluting one part collargol with two parts water. The diluted collargol should stand 24 hours and be filtered before use.

PROGNOSIS

The mortality is usually given as about 2 to 5% with the exception of the very serious form in which jaundice is present when the death rate may exceed 50%.

A serious feature of the disease is the length of its course, this often extending from six weeks to two months.

Since salvarsan and neosalvarsan have been found to be practically specifics in the treatment of the disease the mortality has been reduced to exceedingly low figures.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—The sole question is the avoidance of places infested with ticks, bedbugs and lice. In Africa, the habitations of the natives, where infected ticks may hide themselves in cracks in floors and walls, are to be especially avoided. As the tick feeds at night a night light is of value.

Destruction of the spirochaetes by salvarsan injection is important prophylactically as well as therapeutically—the reservoir of infection for lice or ticks being gotten rid of.

=Treatment.=—We have in salvarsan, or neosalvarsan, a specific. The drug should be given so soon as the spirochaetes are found—in the period of onset of the fever. If given at the end of the fever it may intensify the critical manifestations, especially collapse. Unless given early it does not abort the relapse. Neosalvarsan, being less toxic, is better adapted to the treatment of the icteric type of the disease. Atoxyl has practically no value in treatment and the same is true of antimony.

Conseil has treated cases with galyl and ludyl, in doses of 4 to 7 grains, with results as good or better than with salvarsan. The pains in the head and back are relieved by aspirin, although a hypodermic of morphine may be necessitated. Cool sponging and fresh-air treatment are desirable. On the whole, treatment, other than the specific one, is symptomatic.

_Administration of the Arsphenamines._—Although arsphenamine (salvarsan) is probably the drug of choice when immediate therapeutic effect is desired, neo-arsphenamine is more popular because it is more simply prepared and administered, is tolerated better by the patient and has a slightly higher therapeutic index. It is, however, less stable, and both the powder and its solutions should be inspected carefully for signs of decomposition, namely, a darkening in color, a strong odor, and insolubility. Ampules containing either drug should be immersed in 95% alcohol for 15 minutes in order to detect any crack. Should a breach be found, or suspected, the ampule should be rejected.

Myocarditis, advanced non-syphilitic renal or hepatic disease, advanced arteriosclerosis and Addison’s Disease are regarded as generally contra-indicating the employment of these drugs. Cases in which the syphilis is of long standing should receive mercurials for at least a week prior to the first injection of arsenic, in order to avoid the possibility of activating lesions in vital organs (Herxheimer), and should be closely questioned regarding the occurrence of symptoms following previous injections (idiosyncrasy).

Prior to each injection, a patient should have a complete uranalysis, receive a cathartic on the evening preceding, and be allowed only liquids for the meal preceding. Subsequently to the injection, he should be allowed only liquids for the succeeding meal, and be retained under observation for at least twelve hours. Untoward symptoms following the injection are treated usually with epinephrin solution (0.6 to 1.2 cc.) or atropin.

Arsphenamines are administered intravenously, usually in the median cephalic or the median basilic vein at the bend of the elbow. This method requires aseptic technic throughout. All apparatus should be thoroughly washed before sterilization, since it is believed that symptoms may arise from substances extracted from glassware and rubber tubing. The water used must be distilled, preferably twice, and freshly boiled. The dose of arsphenamine is 0.3 to 0.6 gm., that of neo-arsphenamine is 0.3 to 0.9 gm. Until tolerance is ascertained, the dose should be small and not repeated in less than a week.

NEO-ARSPHENAMINE

1. Only a single ampule should be dissolved at a time. The powder should be dusted over the surface of a small portion of the water and permitted to dissolve without agitation. The solution is then made up to bulk. Specimens which do not dissolve readily are to be rejected.

2. Cold water only is to be used.

3. The solution should not be stronger than 0.1 gm. of the drug in 2 cc. of water.

4. A very small needle should be used, and the time of the injection should not be less than five minutes.

ARSPHENAMINE

1. _Cold Water Should be Used in all Cases._—(Exception. “Arsenobenzol” requires hot water. Consult instructions issued by individual manufacturers for possible departures from these directions.)

2. _Neutralization and Alkalinization of the Solution._—With a graduated pipette or burette add 0.9 cc. of normal NaOH, standardized against normal acid, for each 0.1 gm. of the drug. The alkali should be added all at once, the amount specified being slightly in excess of that required to redissolve the flocculent precipitate first formed.

3. _Concentration of the Drug._—It is important that the concentration of the drug is not greater than 0.1 gm. to 30 cc., _i.e._, 180 cc. of water for the usual dose of 0.6 gm.

4. _Method of Injection._—The gravity method only should be employed. When several patients are to be injected from the same solution, the container for the solution should be graduated. A glass stopcock is of value in controlling the flow of solution, but in its absence the rate of injection can be governed by the elevation of the fluid and by the size of the needle. A needle of 18 or 20 B. & S. gauge is best.

5. _Rate of Injection._—Operators should pay particular attention to the rate of administration since it is believed that rapidity of injection accounts for more unfavorable results in the use of arsphenamine than any other one thing. In no case should the rate exceed 0.1 gm. of drug (30 cc. of solution) in two minutes, _i.e._, twelve minutes for the average dose of 0.6 gm.

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