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.

_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.

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.

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.

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.