is only soluble in 1-12,000 parts of water, hence its comparative
tastelessness. It is expensive.
Quinine tannate contains only about 30% of quinine and is
practically insoluble in water. It is often given to children in
chocolate tablet form. It can often be taken by those who suffer
disagreeable effects from other salts. The dose should be 2½ times
that of quinine sulphate.
Until recently the bimuriate (72% of alkaloid and soluble in 1 part
of water) or the chlorhydrosulphate (74% of alkaloid and soluble
in 2 parts of water) have been considered the most desirable salts
for hypodermic injections or oral administration. At present,
owing to its extensive use in local anaesthesia and incident
availability, bimuriate of quinine and urea is to be recommended
for intramuscular use. It contains 60% of quinine and is soluble in
an equal amount of water.
It has been found to have a slightly greater tendency to produce
amblyopia than other quinine salts and should not be used
intravenously.
In a very important series of experiments on prisoners,
MacGilchrist found that hydroquinine (a synthetic product of
quinine) was about 20% more efficient than quinine. Cinchonine was
about the same as quinine while quinidine was about one-half as
potent as quinine.
Acton has praised the value of cinchona febrifuge (the combined
alkaloids of cinchona) given in daily doses of 21 grains for ten
days.
Methods of Administration
_By Mouth._—This is the usual method and is the one to be preferred
in all cases where other methods of administration are not
necessitated.
Golgi believes that quinine is most effective at the time of
liberation of merozoites from the bursting merocytes, hence he
administered quinine four hours before the attack with a view to
having it in its greatest concentration in the blood at such times.
When given intravenously the full concentration is obtained in a
very few minutes but with other methods this is a matter of great
variation.
It is usual to give the quinine in capsules or cachets, the pills
and tablets being often so hard that they do not dissolve in the
alimentary tract.
The method usually in vogue in military services is to give quinine
sulphate in acid solution. This method is trying to the stomach.
_By Subcutaneous Injections._—This method is liable to be followed
by necrosis and abscess formation or fibrous indurations. Quinine
and urea hydrochloride is preferable either for subcutaneous or
intramuscular injection.
Cohen holds that quinine and urea hydrochloride controls malarial
infection more rapidly and efficaciously than any other salt of
quinine when given intramuscularly. In order to prevent tetanus or
other infections he is very careful about asepsis. He recommends
that a 10 to 15-grain dose be injected every day for a week, then
once a week for a month, then once every two weeks for another
month. He considers a 33% solution as best, thus one could give 10
grains in the contents of an all-glass 2 cc. syringe.
James has recommended very dilute solutions for subcutaneous
injections (1-150). There are practical objections to this method.
It is usual to give about 1 gram (15 grains) of a soluble salt in
10 cc. of water. _The present view is that subcutaneous injections
deserve condemnation._
_Intramuscular Injections._—It is now recognized that when quinine
is not well borne when given by mouth the two modes of administration
to be followed are either by intramuscular injection or introduction
of the drug into a vein. For intramuscular use we dissolve a soluble
salt of quinine, as the bimuriate or chlorhydrosulphate, in distilled
water or sterile saline. A 50% solution is commonly used and from 6
to 10 grains of quinine is injected into the gluteal muscles of one
side about 3 inches below the iliac crest. Repeat the injection on
the other side. Repeat this daily dose of 12 to 20 grains for 3 or 4
days; then give quinine by mouth.
The solution should be autoclaved before use and the skin at the
site of injection painted with iodine. Dudgeon has called attention
to the constant production of oedema and necrosis in the area of
the injection. This tissue necrosis occurs immediately and persists
for a long time. If the injection is made in the neighborhood of an
important nerve, neuritis may ensue. Repeated injections should not
be given in the same area.
Of course in the use of quinine salts through the medium of the
hypodermic needle everything must be sterile.
_Intravenous Injections._—Bass and many others think that when
quinine cannot be administered by mouth it should be given
intravenously. Not only is there the objection of inflammatory
reactions or necrosis when the drug is given subcutaneously or
intramuscularly but the absorption of the drug is so slow that the
patient may die before we obtain the desired effect. Ross condemns
the subcutaneous method and recognizes the advantages of the
intravenous method over the intramuscular one when rapidity of action
is desirable.
In giving quinine intravenously Bass thinks that 10 grains at one
time is sufficient and that a 20-grain dose is not without danger.
He does not think it necessary to give more than 30 grains daily
in this way. Intravenous quinine seems to be entirely eliminated
within twenty-four hours and most of it within twelve hours.
When used in cerebral malaria he repeats the 10 grains
intravenously in eight hours if the drug cannot then be given by
mouth. Bass thinks that theoretically amyl nitrite might relax the
cerebral capillaries which are obstructed by parasite-infected red
cells and thus enable the quinine in the circulation to reach such
cells.
The best known method of administering quinine intravenously is
that of Bacelli. In this method 1 gram (15 grains) of a soluble
salt of quinine is given in 10 cc. of water.
MacGilchrist has shown experimentally that such a strength of
quinine (1-10) will coagulate blood serum.
In my opinion this is a dangerous method if the injection is made
rapidly. There is no doubt as to the necessity for using the
intravenous channel in cerebral or algid types of perniciousness
when intramuscular injections do not give results. The generally
accepted method is to use a salvarsan technique with a dilute
solution of quinine, giving 1 gram (15 grains) of some soluble
salt of quinine in 250 cc. salt solution. Such injections should
be given cautiously. Quinine hydrochloride, which is soluble in
40 parts of water, is the salt usually recommended. MacGilchrist
considers the very soluble acid salts as haemolytic and prefers
to give quinine base—3 pints of a solution of the alkaloid,
containing about 12 grains.
McLean has used concentrated solutions of quinine intravenously
several hundred times in cases of malaria (6 being blackwater fever
ones) without any untoward results. He autoclaves his 10-grain
solution of hydrochlor-sulphate in 10 cc. of sterile water for
twenty minutes at 15 pounds, and injects it slowly into an arm vein,
allowing about two minutes for the injection. The patients complain
of a slight cough and hot feeling in the lungs with a succeeding
dizziness which rapidly disappears. He is opposed to intramuscular
injections and found intravenous ones diluted 1 to 250 often to cause
shock and collapse.
_Rectal Administration._—Some authorities recommend the
administration per rectum of a soluble salt of quinine in about 3
times the usual dose by mouth or hypodermically. It is considered
applicable in cases where there is marked vomiting. It certainly is
the least satisfactory way of giving quinine.
_Dosage and Length of Treatment._—In Panama the standard preliminary
treatment is to give from 3 to 5 grains of calomel followed by 1 or 2
ounces of 50% magnesium sulphate.
Fayrer holds that a torpid liver interferes with the efficient
action of quinine, hence the value of calomel and salts. I prefer
to give 2 or 3 grains of calomel, in divided doses, followed by
sodium phosphate, 2 drams, every two hours, for three or four doses.
_Standard Method._—The National Malaria Committee of the United
States recommends the following treatment: Give 30 grains of quinine
daily in three 10-grain doses. Keep this up for 4 days and follow
by 10 grains every night for 8 weeks. Where the infection does not
present acute symptoms give the 10 grains daily for 8 weeks.
_Canal Zone Treatment._—So soon as the diagnosis is made give 15
grains of quinine 3 times daily (45 grains in twenty-four hours) and
continue such treatment for a week or until the temperature has been
normal for five or six days. Then give 10 grains 3 times daily for
ten or twelve days.
It is considered that by employing such thorough treatment from the
beginning the tendency to latency or relapse is prevented—in other
words the disease is really cured. It is interesting to note that
Torti recommended large single doses at the commencement of treatment.
Espach has noted that he had frequent relapses in many cases
treated by this method. In my opinion the Canal Zone treatment
should be followed by 10 grain doses daily for 8 weeks.
Tonics of iron, arsenic and strychnine are valuable in treating the
anaemia, but it is not advisable to add small doses of quinine to
such tonic mixture.
_Repeated Small Doses._—In Nocht’s method we give the quinine in
small doses repeated several times in the day, as 3 or 4 grains
given 5 or 6 times daily. Such treatment is thought advisable when
there is a tendency to haemoglobinuria or when giving quinine to
pregnant women.
In giving the small doses one should see that they are given during
the night as well as the day.
_Quinine and Pregnancy._—There is frequently hesitancy in giving
quinine to a pregnant woman but unless the malaria is controlled
the patient will be apt to abort. Potassium bromide is thought to
control the ecbolic influences of quinine.
Clark states that the experience at Ancon Hospital would indicate
that quinine can be given with impunity to pregnant women. In
malarial subjects quinine after parturition is of value not only in
controlling a fever due to malaria but it also favors involution
and aids in the healing of perineal tears. The quinine also is
beneficial in improving the quality of the mother’s milk and does
no harm to the child.
_Manson’s Method._—In a benign malarial infection Manson prefers to
wait until the hot stage has been passed and the patient is beginning
to perspire, this idea being that the headache and other symptoms
are aggravated and that very little advantage is gained by treatment
during the early part of the paroxysm. He gives 10 grains at the
onset of the sweating stage and afterward 5 grains, 3 or 4 times
daily, for the following week. He then gives a daily tonic containing
arsenic and iron, with a quinine treatment every seventh day for
about two months.
For regularity he advises the quinine treatment on Sunday giving a
dose of salts in the morning followed by three 5-grain doses during
the day.
Manson notes the danger of large doses of quinine as producing
not only serious disturbances of sight and hearing but pronounced
cardiac depression as well.
There are many who speak highly of Warburg’s tincture in treatment.
It is both laxative and sudorific. The dose is ½ ounce (15 cc.)
which contains about 5 grains of quinine sulphate and 4 grains of
extract of aloes. As a rule it is better to give the quinine and
the laxative separately.
More recently the tendency has been to give large doses of
quinine, not only for its greater curative value but, as well, for
the prevention of relapses. Craig, however, states that in his
experience with aestivo-autumnal infections he has yet to see a
single case, in which treatment was promptly instituted, that did
not recover with a daily treatment of 30 grains.
_Koch’s Method._—Koch recommended 15 grains each day for a week,
then three days without quinine. Then three days with 15-grain doses
each day. Then one week without quinine, followed by three days of
treatment. This plan of a weekly interval followed by three days of
treatment is continued until not fewer than 30 15-grain doses are
given over nine or ten weeks.
_Drugs Other than Quinine._—Salvarsan and neosalvarsan have been
extensively used and with some success in benign infections but
without material effect in malignant tertian ones.
_Intermittent Treatment._—There are those who consider a treatment
in which days of quinine administration are followed by days
without quinine as equally efficient and less trying on the
patient. Some of the experiences of Stephens and his colleagues
indicated that 45 grains on two consecutive days of each week and
continued for 8 weeks gave better results than 30 grains daily over
such a period. In their experiments a dosage above 45 grains in a
day did not seem any more efficient than 45 grains, so that this
may well be considered as a maximum dose. On the whole however
there seems to be a greater tendency to relapse following an
intermittent treatment and Acton, as a result of his comparison of
intermittent and continuous methods, deprecates the intermittent
one.
Some have thought that salvarsan aided the specific action of
quinine.
Many physicians recommend arsenic in the form of Fowler’s solution
or as sodium cacodylate. It is most useful in chronic cases. Some
preparation of iron is, of course, indicated in malarial anaemias.
It has been claimed that radium and X-ray treatment, when directed to
the spleen, assist the action of quinine.
Methylene blue, next to quinine, has been considered as the most
valuable drug. It is given in 2-grain doses every four hours. It is
also given intravenously.
The form of methylene blue to use is that labelled “Medicinal.”
It is often stated that the opium fiends of the tropics are immune to
malaria and some physicians have claimed antiperiodic properties for
the drug. Dover’s powder is lauded by some as of value in symptomatic
treatment.
Surveyor has recommended picric acid in the treatment of malaria in
doses of 2 grains two or three times daily.
Recently hectine, a remedy somewhat similar to the cacodylates,
has been strongly recommended by the French. It is given
intramuscularly in 2-grain doses. It is said to be valuable when
there is a leucopenia as it has a tonic action. It has been
recommended to combine this treatment with quinine.
It is said to be a good substitute for quinine in blackwater fever.
Rogers has recently noted the value of tartar emetic injections in
eradicating the sexual parasites of carriers.
After rather extended trial of this drug for the above purpose and
as a method of treating ordinary infections the general opinion is
against its value.
_General and Symptomatic Treatment._—During the course of the
fever the patient should remain in bed and given only broths.
In the intermissions of the benign forms one may allow a more
generous diet. It is important that the patient be not allowed
to become constipated and as a laxative one grain of calomel in
divided doses followed by effervescing phosphate of soda is very
satisfactory.
For the nausea sips of an ice-cold alkaline mineral water or
cracked ice will generally prove effective. In more refractory
cases spirits of chloroform or even a hypodermic of morphine
may be necessary. Counterirritation to the epigastrium is often
a help. Phenacetine may be given for the headache although ice
water compresses are generally sufficient. In algid states hot
water bottles should be applied to the body. During convalescence
excesses in food or drink should be avoided as well as fatigue or
exposure to wet or cold.
CHAPTER II
BLACKWATER FEVER
DEFINITION AND SYNONYMS
=Definition.=—Blackwater fever is a disease of disputed etiology
but recently there has seemed to be rather general agreement that it
is connected with repeated attacks of malaria. It is prone to affect
the old European residents of parts of the tropics where malignant
tertian is rampant.
On the basis of lowered integrity of the red cells, by reason of
repeated attacks of malaria, we may have extensive lysis of the red
cells following the administration of a dose of quinine or as the
result of refrigeration, excessive exposure to the sun or great
fatigue.
Clinically we have a prostrating chill of asthenic type
associated with early jaundice and the passage of porter-colored
urine—haemoglobinuria.
=Synonyms.=—Haemoglobinuric Fever, Bilious Haemoglobinuric Fever,
Haemorrhagic Malarial Fever.
French: Fièvre Bilieuse Hemoglobinurique. German: Schwarzwasserfieber.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—There is no reasonable doubt that the explanation of
the fact that blackwater fever was first brought to the attention
of the medical world, by Lebeau and other French naval surgeons,
in Madagascar, in 1850-1853, was due to the confusion of this
disease with the bilious remittent type of pernicious malaria as
well as with yellow fever. Even after the clinical picture was well
recognized, disputes as to the nature of the coloring matter of
the characteristic urine were frequent, some considering that the
dark color, which we now know to be due to haemoglobinuria, was due
to haematuria or that the color was due to bile. Blackwater fever
must have been the condition referred to in medical literature
of the period, 1850 to 1870, under the names “Fièvre bilieuse
haematurique,” “haemorrhagic malarial fever” and “febris remittens
haemorrhagica.”
It was first described in the U. S. by Cummings of Louisiana
in 1859. Other American physicians during the next ten years,
described the disease from various other Southern states.
Veretas noted the presence of the disease in Greece, in 1858.
It is rather remarkable that the disease was not noted by so keen
an observer as Torti, if it existed in his time, and Manson states
that it is strange that it should not have been recognized in India
if it had existed there prior to recent times. Some think that its
introduction into Africa has been of recent occurrence. There are
two explanations of the recent greater prominence of the disease in
Africa and other tropical areas, where malignant malaria prevails
extensively, which are (1) that there has been a great influx of
susceptible Europeans into such areas during the past twenty or
thirty years and (2) that the more frequent and excessive dosing of
malarial patients with quinine is responsible.
[Illustration: FIG. 23.—Geographical distribution of blackwater
fever.]
=Geographical Distribution.=—It is in tropical Africa that the
disease is of prime importance as a cause of death and invaliding.
Here it prevails chiefly in West, Central and East Africa from
about 12° N. to 12° S. latitude. It is less frequent in Northern
Africa although a considerable number of cases have been reported
from Algeria. It is unknown in Egypt, a country where malaria is
very rare in Europeans.
In India it occurs in several districts and Stephens states that
in the Duars (Bengal) he saw more cases in a fortnight than he
had seen in the same time in Africa. In Europe it occurs chiefly
in Southern Italy, Sicily, Sardinia and Greece. Blackwater fever
was frequently noted among the British forces in Macedonia and
Palestine during the World War.
It is common in Central America and Northern South America,
especially in the regions of the Amazon basin, in Brazil.
In the U. S. it is chiefly found in the most malarious sections of
Arkansas, Mississippi, Louisiana, Texas, Alabama, Georgia, Florida
and South Carolina. It would seem that it is becoming more rare in
the Southern States.
As a result of malarial prophylaxis among the Americans working in
the Panama Canal Zone it has almost disappeared among them although
still common among the white Europeans in the same region who
neglect quinine prophylaxis and mosquito protection.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—There seem to be cases where from very heavy infection
with the malignant tertian parasite, as from 12 to 20% of the red
cells, one can expect the appearance of a more or less dark urine,
the color of which is due to haemoglobinuria. Such cases give support
to the old view that haemoglobinuric fever was simply a type of
pernicious malaria.
Brem has proposed for such cases the designation, pernicious
malarial fever with haemoglobinuria.
The idea as to etiology which now seems most generally accepted
is that blackwater fever occurs almost solely in those who have
resided for considerable periods of time in districts where malignant
tertian malaria is very prevalent and intense and who have repeatedly
suffered from such malarial attacks. Rarely blackwater fever may
be connected with benign tertian infections or exceptionally with
quartan ones. As a result of the damage done the patient by the
malarial attacks there is a tendency on the part of his red cells
to haemolysis which may be due to the production of a hypothetical
autolysin or to anaphylactic sensitizations, as has been suggested
recently.
Malaria is the predisposing cause and the exciting cause may be
any of a number of different factors capable of lowering body
resistance such as the occurrence of another malarial attack,
the administration of quinine, particularly of the acid salts of
quinine in rather large doses, refrigeration, as brought about by
one’s clothes becoming wet and then later subjected to the chilling
influence of a sea breeze, to excessive fatigue or dietetic or
alcoholic excesses.
Quinine administration, particularly if associated with
refrigeration, is the most common exciting factor.
As regards the association of malaria and blackwater fever
Stephens, in a study of 390 cases of blackwater, found that 73%
of the cases showed malarial parasites on the day preceding the
haemoglobinuria, 47.5% on the day of the attack and 23% on the day
following the appearance of the dark urine. Other workers give
higher figures as 95, 70 and 20%.
Where one utilizes the methods of examining for increased
percentage of large mononuclears or for melaniferous leucocytes,
in those cases not showing malarial parasites, the percentage
of evidence of malaria is greatly increased. It is necessary to
understand that a small percentage of cases diagnosed as blackwater
fever do not show evidences of malaria at autopsy and cases are
recorded where blackwater has attacked persons who had never had
malarial fever, such instances, however being exceptional.
_The Quinine Theory._—This idea as to the causation of blackwater
fever first originated with Veretas, in Greece, in 1858. Later
Tomaselli supported this view in Italy and more recently it was
advocated by Koch. Just as in connection with the influence of
Koch’s great prestige much harm was done in prophylaxis against
bovine tuberculosis so in this matter of quinine in the causing of
blackwater the influence was unfortunate because many persons with
severe malaria now refuse to take the specific quinine for fear of
bringing on haemoglobinuria.
It may be stated that quinine alone, even in doses which are
capable of producing profound toxic effects such as disturbances
of sight and hearing, weak heart and collapse does not, other than
exceptionally, cause haemoglobinuria. It has even been stated
that quinine base and quinine tannate tend to prevent haemolysis,
haemoglobinaemia and haemoglobinuria. Blackwater fever may develop
without the previous administration of quinine.
_Theory as to Acidosis with a Damaged Liver Plus Malaria and Acid
Salts of Quinine._
MacGilchrist has recently advanced the idea that blackwater fever
is brought about by an acidosis in one with a damaged liver plus
malaria and the administration of acid salts of quinine. He thinks
that one can safely give the quinine when alkalis are being given
and that quinine base is protective against haemolysis.
_Theory as to Its being Caused by a Piroplasm._
Sambon has thought by reason of the clinical resemblance of
blackwater to certain haemoglobinuric diseases in cattle, dogs and
sheep that such a cause might be operative. These parasites of the
red cells are easily discernible in the animal infections but have
never been seen in blackwater fever.
_The Chlamydozoal Hypothesis._
Leishman has recently noted appearances in the large mononuclear
cells of the blood of blackwater patients of certain cell
inclusions which he thought to be of chlamydozoal nature and that
these chlamydozoa might be etiological factors. Such appearances
may not only be absent in marked cases of blackwater but may be
seen in conditions other than blackwater fever.
=Epidemiology.=—There seems to be a consensus of opinion that when
malaria is kept in check by proper and persistent quinine prophylaxis
or by other antimalarial measures blackwater fever becomes mild in
character or even nonexistent. It is those who are careless about
quinine prophylaxis or those who expose themselves to depressing
influences as cold, wet, excessive fatigue or alcoholic debauches in
whom blackwater shows itself.
Overexertion leading to fatigue and chilling seem to be the most
common exciting factors. Those in bad health from disease or lack
of proper diet seem more susceptible. A peculiar feature of the
disease is that it may not be present in a district for a number
of years and then assume almost epidemic proportions. Europeans
are usually exempt from attacks during their first year in endemic
tropical areas. Dudgeon obtained a malarial history in every one of
a hundred cases observed by him in the Balkans.
PATHOLOGY AND MORBID ANATOMY
As a result of the excessive destruction of red cells the liver
cannot convert the great amount of haemoglobin outpouring into bile
pigment so that haemoglobinaemia and haemoglobinuria result. It has
been estimated by Ponfick that if ⅙ of the red cells are destroyed
the liver is unable to dispose of the liberated haemoglobin and
haemoglobinuria results. A damaged liver would be less competent.
Various discussions as to autolysins and complement content of serum
have arisen.
Dudgeon has demonstrated active haemolysins in the tissues and
urine of blackwater fever cases which bodies he was unable to note
in other conditions including malaria. There was no evidence of
increased fragility of the red cells. There was no evidence of
auto-haemolysis. Bile pigment in the plasma occurred in most of the
cases which ended fatally.
As a rule we have the pathological findings which go with malaria.
As peculiarities of blackwater noted by Whipple and others may
be mentioned congestion of the kidneys with purple-colored
pyramids. In the spleen the Malpighian bodies are prominent and
sharply outlined. Very striking are the necroses of the Malpighian
corpuscles of the spleen and focal necroses of the liver. Whipple
considers that this speaks for a powerful circulating toxin in
blackwater fever which is not present in malaria.
The liver cells in the area of the central veins show the most marked
destruction. The myocardium shows fatty change and the fat lipoid
content of the adrenal is reduced.
The anuria is thought to be mechanical and due to the plugging up
of the tubules by haemoglobin casts.
The urine shows a reddish to black color and has a sediment made up
of granular débris with haematoidin crystals and only rarely a red
cell. It is not a haematuria.
The absorption bands of methaemoglobin are usually noted
spectroscopically.
Urobilin and albumin are present in large quantities.
SYMPTOMATOLOGY
=A Typical Case.=—In a person who has lived in an intensely
malarious region for one or two years or even long after he has left
such districts and who has had several malarial attacks, there comes
on what is considered as another malarial chill, which may or may not
definitely be connected with some resistance-lowering influence, as
exposure to tropical sun or rain, or indulgence in dietary or other
excesses, or following in one to six hours the accustomed dose of
quinine. This chill, however, is more prostrating than those formerly
experienced and upon passing his urine the patient notes its reddish
to black coffee color and himself makes the diagnosis of blackwater
fever. The attack comes on suddenly with a very severe chill, marked
prostration and pain over the region of the kidneys. The temperature
in a typical case rapidly goes up to 104° to 105°F.
Rather profuse sweating accompanies the fall of the fever and the
patient is markedly debilitated after the subsidence of the fever.
There may be a recurrence of the paroxysm the following day. The
fever course, however, may be more or less continuous or remittent.
In other words it tends to be irregular and atypical.
Nausea and bilious vomiting come on early with epigastric distress.
Almost as pathognomonic as the haemoglobinuria is the early and
intense jaundice. This comes on within a few hours or almost
simultaneously with the haemoglobinuria and usually lasts for two or
three days after the haemoglobinuria and fever have ceased. Itching
of the skin of this jaundice is not noticeable.
The spleen and liver are enlarged and tender. Albuminuria comes
on with the haemoglobinuria and shows from 1/10 to 4/10 of 1% of
albumen by weight.
The pulse is rapid, 110 to 120, from the first but soon becomes
feeble and of low tension. In severe cases the very rapid almost
thready pulse, with pallor and cold extremities, may resemble a
severe haemorrhage. Epistaxis is not uncommon. A very unfavorable
symptom seems to be hiccough. Another frequent cause of death and
the one against which we chiefly direct our therapeutic measures
is anuria with subsequent uraemic symptoms, such as coma and
convulsions. At times a nephritis may develop in the course of a
blackwater attack and the case subsequently run as one of severe
nephritis.
Very striking is the rapidly developing anaemia, some cases showing a
loss of two million red cells in twenty-four hours.
The mind is usually clear throughout an attack, the patient showing
restlessness and marked anxiety.
In mild cases the fever course and haemoglobinuria is over within
twenty-four hours leaving the patient far more prostrated than
would a malarial paroxysm. In severe cases, however, the fever
runs a remittent course over several days, with more marked
haemoglobinuria and jaundice.
There may be cases which only show haemoglobinuria. These apyretic
cases have been considered by some as quinine haemoglobinuria.
Symptoms in Detail
_Fever Course._—This resembles that of a malarial paroxysm and may
be intermittent in character or last several days as a remittent
fever. The rigor which accompanies the febrile rise is intense.
_The Liver and Spleen._—As a result of the marked blood
destruction the liver is unable to dispose of the haemoglobin
outpouring and icterus, which usually comes on in a few hours and
is intense, is almost constant together with epigastric distress,
bilious vomiting and tenderness and slight enlargement of the
liver. The spleen is also somewhat enlarged and quite tender.
_The Circulatory System._—At first the pulse is rapid with tension
but soon it becomes weak, compressible and of low tension. In
severe cases it may have a rate of 150 or more or even become
thready.
_The Genito-urinary System._—The dark colored urine is
pathognomonic of the disease and gives it its name. The reddish
to almost black color is due to haemoglobin and not to bile.
Bile pigments do not appear in the urine. There is but rarely
a red cell to be found in the granular débris with occasional
haematoidin crystals which forms the urinary sediment, hence it is
haemoglobinuria and not haematuria.
The urine resists decomposition for a long time. Albumin is present
in large amount and comes on with the onset of haemoglobinuria.
Casts are abundant and urobilinuria is marked. As a result of the
blocking up of the renal tubules with haemoglobin casts pain over
the loins and anuria may occur. There may be vesical tenesmus.
_The Blood._—Cases have been reported where as many as 2,000,000
red cells have been destroyed within twenty-four hours, so that
rapid and marked anaemia characterizes the disease. The blood is
thin and the serum tinged. The degenerative changes of the red
cells are not as commonly seen as one would expect but this is
probably due to the fact that degenerated cells are first destroyed
in the excessive haemolysis. Hb percentage reduction generally
parallels the reduction in red cells. Melaniferous leucocytes may
be found and during the leucopenia, which follows the paroxysm, the
large mononuclears and transitionals may be increased to 20%. There
is a reduction in the alkalinity and coagulability of the blood.
DIAGNOSIS
=Clinical Diagnosis.=—An unusually asthenic prostrating paroxysm,
similar to that of a malarial chill, but with more intense rigor,
during which haemoglobinuria, early jaundice and marked bilious
vomiting are features, makes for a diagnosis of blackwater fever.
The two diseases which are most likely to be confused with
blackwater fever are yellow fever and bilious remittent malarial
fever.
In infectious jaundice the jaundice does not appear for 48 to 72
hours, the pulse is slow, there is no haemoglobinuria, although
there may be a haematuria, and we have a polynuclear leucocytosis.
A case of paroxysmal haemoglobinuria occurring in a blackwater
district would be impossible to differentiate from a very mild
case of blackwater fever. Chlorate of potash or carbolic-acid
poisoning, or snake bite, or severe burns, may produce
haemoglobinuria.
-----------+-------------------+-------------------+--------------------
| Blackwater fever | Yellow fever | Bilious remittent
-----------+-------------------+-------------------+--------------------
Onset |Sudden but asthenic|Sudden but asthenic|Comes on more
| with marked | for two or | slowly.
| rigor. | three days. |
-----------+-------------------+-------------------+--------------------
Urine |Haemoglobinuria. |No blood in urine |Bile in urine.
| Pink foam to | before 3d or 4th | Yellow froth on
| urine. Albuminuria| day and then | shaking urine.
| from first day. | haematuria. | Albuminuria
| | Albumin from 2d | slight and
| | day. | not common.
-----------+-------------------+-------------------+--------------------
Icterus |Early and intense. |Does not appear |Jaundice develops
| Comes on in a few | before 3d day | slowly about 2d
| hours. | and gradually | day.
| | intensifies. |
-----------+-------------------+-------------------+--------------------
Spleen |Somewhat enlarged |No enlargement of |Splenic enlargement
| and tender. | spleen. | is marked; may
| | | have ague cake.
-----------+-------------------+-------------------+--------------------
Pulse |Rapid from start |Stationary pulse |Pulse not so rapid
| and becoming | with rising temp- | as in blackwater.
| more so as disease| erature or falling|
| progresses. | pulse with |
| | stationary temp- |
| | erature. (Faget’s |
| | law.) |
-----------+-------------------+-------------------+--------------------
Vomit |Early marked |Mucus-like followed| Bilious vomiting
| bilious vomiting. | by black vomit | and gastric distress
| | about 4th day. | less than in
| | | blackwater.
-----------+-------------------+-------------------+--------------------
Evidences |Usually present as |Negative unless |Some evidence at
of malaria| parasites or | yellow fever | some time almost
| melaniferous | occurs in a | always obtainable.
| leucocytes or | malarial case. |
| increased large | |
| mononuclear | |
| percentage. | |
-----------+-------------------+-------------------+--------------------
=Laboratory Diagnosis.=—Other than the noting of evidences of
malarial infection, rapid reduction in red-cell count and haemoglobin
percentage there is little information to be derived from the blood
which is thin and shows delayed coagulation time. It is difficult to
make good blood smears. In the urine we note the granular sediment of
débris of red-cell destruction with at times haematoidin crystals.
Spectroscopically we get absorption bands of methaemoglobin and more
rarely oxyhaemoglobin.
[Illustration: FIG. 24.—The most important clinical spectra.
(_Monographic Medicine._ D. Appleton and Co., New York.)]
Albumin is present in quantity and urobilin is usually present in
large amount.
One can examine the urine for blood by the haemin-crystals, guaiac
or benzidin tests.
Burkitt has noted that his cases of blackwater have shown a very
acid urine with large amounts of acetone bodies.
The serum shows haemoglobinaemia and may show reduced alkalinity.
PROGNOSIS
So far as statistics go the mortality rate would appear to be
influenced by the delicateness of the tests used for determining the
presence of haemoglobinuria. When a diagnosis is only made with the
presence of marked haemoglobinuria, showing porter-colored urine, the
mortality rate is, of course, higher than when slight haemoglobinuria
is taken into consideration.
In cases treated with quinine, Deaderick, in statistics of various
authorities, gives a death rate of 25.9%; in cases not so treated,
of 11.1%.
Marked and persistent vomiting and hiccough are very unfavorable
signs. In particular, however, it is anuria that gives us our
greatest concern in the care of a case. A severe attack is followed
by a marked anaemia and convalescence is usually protracted.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The view now generally entertained is that where
malarial prophylaxis is properly carried out there will not be any
blackwater fever. In persons who have had a previous attack of
blackwater fever quinine prophylaxis should be with quinine tannate
or quinine base, avoiding the acid salts of quinine.
In particular any exposure to chilling influences or conditions
which lower resistance should be avoided. As blackwater fever is
more prevalent among those who have been for 2 or 3 years in highly
malarious, tropical regions than among recent arrivals, the former
should exercise the greater care as to errors in diet, alcoholic
excesses, exposure to wet and irregularity in quinine prophylaxis.
=Treatment.=—There is less unanimity of opinion as to the
advisability of giving quinine during an attack of blackwater fever
than exists as to any other therapeutic measure.
Of course if it be true that quinine base is devoid of haemolytic
influence the fear of increasing haemolysis by giving quinine would
not have to be considered. At any rate any red cells containing
parasites will surely be destroyed in the general haemolysis and
with them their contained parasites, so that it does not seem
reasonable to give quinine during the first day or two of the
attack. Quinine, if given, should not be by mouth for fear of
increasing the nausea and vomiting. The majority of authorities
hold that if parasites persist after two or three days from the
onset quinine is indicated. Some give quinine during the first day
if parasites are present but otherwise they withhold quinine.
Absolute rest in bed, avoidance of chilling and good nursing are the
prime considerations in treatment.
The patients should be given alkaline waters freely, as Vichy
or water containing 30 grains of bicarbonate of soda to the
pint. Cracked ice often tends to lessen the nausea and vomiting.
Albumin water or barley water may be retained better than milk or
broths. As the condition is so asthenic one cannot disregard the
nourishment of the patient during the first two or three days as is
true of the sthenic first stage of yellow fever. Hot fomentations
to the loins are indicated for relief of pain and the effect on the
renal congestion.
Saline enemata are of particular value and may suffice in mild
cases. In severe cases subcutaneous or intravenous saline
injections are necessary. Sorel recommends the intravenous
injection of lactose or glucose solutions in quantities of about
300 cc. (Crystallized glucose 47 grams, water 1000 cc. or C. P.
lactose 92.5 grams, water 1000 cc.) He also uses these sugar
solutions as enemata. Dry cupping or hot fomentations over the
loins are the usual remedies in threatened suppression of the
urine. If blackwater fever should be shown to be accompanied by
diminished alkalinity of the serum then the intravenous injection
of a 1 or 2% solution of bicarbonate of soda would be indicated.
Some have recommended calcium lactate in doses of 20 grains every
four hours. There is little evidence however to indicate that it
is of value. Transfusion of blood has been practised but reports
of such treatment indicate that while temporary improvement occurs
yet this is followed by a return of haemoglobinuria. From Dudgeon’s
work it would seem that the existing haemolysins would destroy the
foreign red cells.
Burkitt claims excellent results by intravenous injections of
alkaline solutions, similar to those recommended under “cholera.”
He also finds neosalvarsan of the greatest value in treatment, as
cases so treated convalesce most rapidly.
Hearsey advocates a mixture in which there is contained 10 grains
of bicarbonate of soda and 1/30 grain of bichloride of mercury in
each dose, to be given every two hours.
Cholesterin has been given in 15-grain doses in suspension in thick
milk every four hours with the idea that it is anti-haemolytic. The
dose is repeated 2 or 3 times.
Calomel in large doses has been recommended by some tropical
practitioners but it would seem advisable only to use calomel to
keep the bowels open and then in small divided doses.
Antipyretics should not be used from their depressing action on the
heart.
For the urinary suppression, Wallace recommends salines as hot
as can be borne, administered high in the colon by a double-flow
tube. Since he found this treatment effective after intravenous and
rectal injections had failed, it is to be inferred that the results
obtained were due not to the further administration of fluid but to
the action of heat applied directly to the splanchnic area.
CHAPTER III
THE TRYPANOSOMIASES
DEFINITION AND SYNONYMS
=Definition.=—African trypanosomiasis is an important protozoal
disease of Central and West Africa, due to a flagellate, _Trypanosoma
gambiense_, and transmitted by a tsetse fly, _Glossina palpalis_.
The trypanosome undergoes a developmental cycle in the fly which
does not become infective until after about twenty days. The period
of incubation is about two or three weeks, after which an irregular
fever with approximately normal morning temperature and high evening
rise appears, attended with a rapid pulse rate at all times. This is
called the stage of trypanosome fever and may show trypanosomes in
the peripheral blood. Later on the glands enlarge and gland juice
shows trypanosomes. With the appearance of a fine tremor of the
tongue, a state of apathy or lethargy, known as sleeping sickness,
sets in, attended with trypanosomes in the cerebro-spinal fluid.
Gradually increasing mental deterioration marks the almost invariable
course to death. A more virulent type of trypanosomiasis is found in
Rhodesia.
In Brazil there is a disease caused by a flagellate,
_Schizotrypanum cruzi_, which resembles a trypanosome and is
transmitted by a bug, _Lamus megistus_. The disease runs an acute
course with a high fever and great mortality in infants showing
chiefly manifestations of involvement of brain or thyroid gland. In
adults it runs a chronic course showing neurological manifestations
or signs of myxoedema or even of Addison’s disease.
=Synonyms.=—Sleeping sickness; Negro lethargy. French: Maladie du
sommeil. German: Schlafkrankheit. For the Brazilian trypanosomiasis,
Schizotrypanosomiasis; Chagas’ disease.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—In describing sleeping sickness, in 1803, Winterbottom
brought out the importance of enlargements of the posterior
cervical glands (Winterbottom’s sign).
In 1880 Evans had found a trypanosome in the blood of horses
affected with surra and several years afterward Bruce discovered
that nagana, a fatal disease of cattle, was due to a trypanosome,
_T. brucei_. In 1890 Nepveu found a trypanosome in the blood of a
man in Algeria but owing to vagueness of description the discovery
did not attract attention.
[Illustration: FIG. 25.—Geographical distribution of African
trypanosomiasis.]
In 1901, Forde found a parasite in the blood of a patient in the
River Gambia Colony who had a fever and in 1902 Dutton recognized
the parasite as a trypanosome and gave it the name _T. gambiense_.
In 1902, Castellani, finding a trypanosome in the cerebro-spinal
fluid of a patient with sleeping sickness, brought about the
establishment of the connection between the trypanosome in the
blood (trypanosome fever) and the trypanosome in the cerebro-spinal
fluid (sleeping sickness). In 1903, Bruce and Nabarro reported that
this disease was spread by a tsetse fly, _Glossina palpalis_.
In 1910 Stephens and Fantham brought forward the existence of a
more virulent trypanosome, _T. rhodesiense_.
=Geographical Distribution.=—The disease exists on the West Coast
of Africa, from Senegal to Mossamedes. It is also present in the
Congo basin and particularly in Uganda. The more virulent form is
found in Rhodesia.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—The African trypanosomiases follow infection with two
species of trypanosomes; the more virulent type of the disease,
occurring in South Central Africa, being due to _Trypanosoma
rhodesiense_, transmitted by _Glossina morsitans_ and that of
less severe type, but of more general distribution, being due to
_T. gambiense_ and transmitted by _Glossina palpalis_. The very
important _Trypanosoma brucei_, which is the devastating agent in the
African horse, dog and cattle disease, nagana, is also transmitted
by _Glossina morsitans_ and there exists the opinion that this
trypanosome is identical with _T. rhodesiense_.
Macfie has reported a new trypanosome, _T. nigeriense_, from
young persons in Nigeria. It is said to be less virulent than _T.
gambiense_, and to be transmitted by _Glossina tachinoides_.
[Illustration: FIG. 26.—_Trypanosoma gambiense_ (slide presented by
Professor F. G. Novy) (From Todd.)]
Bruce considers _T. nigeriense_ as being _T. gambiense_. Macfie
noted many short stumpy forms in animals inoculated with _T.
nigeriense_.
These trypanosomes are blood flagellates and are typical of the
Binucleata in possessing two chromatin-staining areas, the larger
and more centrally situated mass being the tropho or macronucleus
and the smaller, but more deeply staining one, the kineto or
micronucleus (Blepharoplast). Trypanosomes have a fusiform or
fish-shaped body which stains blue. Near the less pointed,
nonflagellated end, usually called the posterior end, is the deeply
stained blepharoplast. Adjoining this is a vacuole and, taking
origin from this part of the trypanosome, is the flagellum. This
borders an undulating membrane attached to the body and then,
carried along to the other extremity, projects free as a long,
whip-like flagellum.
In fresh preparations the body of the trypanosome progresses in the
direction of its flagellated end, although occasionally it will be
observed to move in the opposite direction.
Some trypanosomes show granules at certain stages and it has been
observed that the extrusion of these granules precedes disintegration
of the trypanosome. It has been suggested that such granules might
be infective, explaining the infectivity of blood from which
trypanosomes were absent. In the separation of trypanosomes into
groups and species Bruce relies upon morphology, action on animals,
and manner of development in the tsetse fly. He does not consider
serum diagnosis and cross inoculation methods as reliable for
differentiation. The human trypanosomes are polymorphic.
_T. gambiense_ varies much in length and breadth. The normal
type, as found in the blood, varies from 14 to 20 microns, while
longer forms, 20 to 24 microns, are growth ones and, in the
longest ones (23 to 33 microns), we have those preparing to divide
longitudinally. The normal short forms are the ones from which
the development takes place in the tsetse fly. In width these
flagellates are from 1.5 to 2 microns. The blepharoplast is oval
and the nucleus situated about the center.
[Illustration: FIG. 27.—_Glossina palpalis_ in natural resting
position and with wings outstretched. (MacNeal after Doflein.)]
With _T. rhodesiense_ the nucleus is typically located almost
adjacent to the blepharoplast. As a matter of fact it may require
the passage of this trypanosome through rats to bring out these
“posterior nuclear forms,” the nuclear location being at times almost
entirely that of _T. gambiense_. In addition to the characteristic
of nucleus being near the blepharoplast, this trypanosome is more
virulent for laboratory animals than _T. gambiense_, agreeing in this
respect with the more severe clinical course in man.
When the tsetse fly, _Glossina palpalis_, feeds on a man in whose
peripheral circulation there are normal type trypanosomes we
have an accumulation of such forms in the middle and posterior
portions of the gut. From the eighth to the eighteenth day long,
slender forms develop and pass forward into the proventriculus.
None of the intestinal forms can cause infection when injected
into animals. These proventricular types work their way into the
salivary ducts and thence into the salivary glands, where further
development takes place. Here we have shorter forms developing,
which are similar in morphology to the normal blood type. It is at
this stage that the fly becomes infective by the passing of these
trypanosomes down the salivary ducts and through the channel in the
hypopharynx to the subcutaneous tissues of the person bitten. High
temperatures, 75 to 85°F., are favorable to development, while low
temperatures, 60 to 70°F., are inimical to development, but do not
kill the ingested trypanosomes. This explains the long period which
at times elapses before a fly becomes infective. Under favorable
conditions a fly becomes infective in twenty to thirty-four days
and remains infective the rest of its life, up to 185 days. The
infection is not transmitted to the pupa. This is an inoculative,
cyclical or indirect type of infection. It is usually considered
that a tsetse fly whose proboscis has just been contaminated with
trypanosome blood is capable of transferring the infection for a
few hours. This would be a mechanical or direct method of infection
and such power for infection only lasts for a few hours.
There are other groups of trypanosomes, not important for man,
in which the cyclical development does not include the salivary
glands. In the _T. pecorum_ group of small monomorphic trypanosomes
development takes place only in intestines and proboscis, while in
the _T. vivax_ group this occurs in the proboscis alone.
[Illustration: FIG. 28.—_Glossina morsitans_ before and after
feeding. Lateral view. (From Doflein after Austin.) MacNeal.]
When tsetse flies feed on animals infected with trypanosomes only
from 2 to 6% become infective. Again, it has been shown that where
the wild animals on which tsetse flies feed may show an infection
of from 16 to 50% yet not more than 2 out of every 1000 tsetse
flies, caught and tried out on susceptible animals, show themselves
infective.
Both of the human trypanosomes of Africa have been cultured by
using the N.N.N. medium in which rat’s blood was substituted for
that of the rabbit. Human blood will also serve as a substitute.
Growth however is not constant.
=Epidemiology.=—Practically the only method of transmission of the
disease is by the bite of infected tsetse flies. The female gives
birth to a single, yellowish brown, motile larva, which is almost as
large as the mother and which, upon reaching the ground, bores its
way into a coarse, sandy soil for a depth of about two inches and
then becomes a pupa. The larval stage in the mother lasts about two
weeks and the pupal stage about a month.
The tsetse fly is much like _Stomoxys_, but has a branching of
the feathering of the arista, long palps, a bulb to the proboscis
and a characteristic upbending of the fourth longitudinal vein
to meet the mid-cross vein. The female deposits her larva near a
shady place upon loose, dry, sandy soil. Moisture and sunlight are
not favorable for pupal development, the sun being particularly
injurious, so that pupae, buried only an inch deep and away from
shade, are killed. This fact has been utilized in prophylaxis by
cutting down the trees. The trouble is that the bush growth which
soon follows is favorable as providing shade for the pupae.
Male and female flies bite and transmit the disease. They bite in
the daytime, usually from 9 A.M., to 4 P.M., and will bite in the
sunlight.
It has been stated that tsetse flies are attracted by persons
wearing khaki clothing.
With a view to eradication of the disease certain areas have been
depopulated, but upon examining the flies caught in the district a
year or more later, infected flies have been obtained. This would
indicate some other reservoir than man. It is now generally conceded
that the trypanosome strain in the antelope is the same as _T.
rhodesiense_, both being transmitted by _G. morsitans_.
Taute, however, believes them different as he not only injected
blood containing such trypanosomes into himself, with negative
result, but also allowed flies which had fed on antelopes, which
were infective for laboratory animals, to feed on himself, likewise
with negative result. It is a well-known fact that men in good
condition are refractory to trypanosome infection so that this
courageous experiment does not prove the antelope strain to be
different from the human one.
One measure that has been proposed is to kill off the big game from
a certain area with a view to depriving the flies of their main
source of infection.
The probabilities of an animal reservoir for _T. gambiense_ however
is not so well settled. Many think that we may have trypanosome
carriers and that such persons in the enjoyment of health may act
as reservoirs of the virus. Koch suggested that crocodiles were
important factors in the life of the tsetse flies and recommended
the destruction of the crocodile eggs.
Koch noted the infection of 15 women in a fly-free district and
considered their infection as coming from sexual intercourse with
their husbands, who had returned home from fly districts where they
had contracted trypanosomiasis.
This same method of infection of prostitutes has quite recently
been brought to notice by Bernard.
It will be remembered that dourine, a trypanosome disease of
horses, caused by _T. equiperdum_, is transmitted by the sexual act.
All observations however indicate that the spread of the disease is
almost exclusively through the medium of the tsetse fly. Professor
Lanfranchini was infected in his laboratory by a strain which was
supposed to be _Trypanosoma brucei_.
PATHOLOGY
The chief pathological findings are the enlargements of the lymphatic
glands. The dura mater may be adherent in places and the pia mater
may show areas of thickening. The cerebro-spinal fluid is increased
in amount. The pathological process is a chronic polyadenitis which
is followed by a chronic inflammation of lymphatics of brain and
spinal cord.
We have a meningo-encephalitis in which the most characteristic
feature microscopically is a widespread perivascular infiltration
of small round cells surrounding the vessels of the pia-arachnoid
of both brain and cord. The process is most marked about vessels
of pons and medulla. The nerve cells are but little affected other
than those of the bulbar nuclei.
[Illustration: FIG. 29.—Temperature chart of trypanosome fever.]
SYMPTOMATOLOGY
_The Period of Invasion._—After an incubation period which may be
as short as ten or twelve days, following the bite of an infective
tsetse fly, the trypanosomes may be found in the blood or in gland
juice. One case has been reported where an official of the Belgian
Congo showed trypanosomes less than four weeks after his arrival in
the colony. His first symptoms were noted about ten days after his
arrival.
In natives, trypanosomes may be present in the blood for long
periods of time during which they may do heavy work; thus 7 of
Koch’s 52 native porters showed trypanosomes. In Europeans however
the course of the disease is rarely so insidious but rapidly enters
upon the stage of trypanosome fever.
_The Stage of Trypanosome Fever._—Although fever may be absent in
natives until the onset of the period of sleeping sickness, yet in
Europeans there are usually noted febrile paroxysms, lasting for a
few days, and followed, by afebrile periods varying from a few days
to two or three weeks.
The temperature curve is of a markedly remittent type, approaching
normal in the morning and going up to 103°F. or higher in the
evening—a wide daily range. Very characteristic is a low-tension
rapid pulse which often is as rapid when the temperature
approximates the normal as when it is higher. Early in the disease
there are evidences of involvement of the nervous system, as shown
by headache insomnia, difficulty of concentration for mental work
and cardiac instability.
[Illustration: FIG. 30.—Rash of human trypanosomiasis. (Photo: R.
McKay.) By permission from Manson’s Tropical Diseases.]
_Winterbottom Sign._—Very important are the glandular enlargements,
particularly of the glands of the posterior cervical triangle
(Winterbottom’s sign), which upon puncture may show trypanosomes when
the blood examination fails to reveal them. The glands are discrete,
soft, usually painless and may show but very slight enlargement.
Oedematous swellings, especially about the eyes or joints or in
localized areas upon the trunk, may be rather prominent in some
cases. In Europeans pinkish erythematous rings appearing early in
the infection may make one think of syphilis. These erythematous
patches are not visible on the skin of natives. A dryness of the skin
is rather constant and, especially in natives, papules which itch
greatly may be present. Rarely such manifestations as orchitis or
choroiditis may be observed.
[Illustration: FIG. 31.—Swelling of the glands of the posterior
cervical triangle—Winterbottom’s sign. (Ruge and zur Verth after
Koch.)]
_Kérandel Sign._—Recently great prominence has been given to a
deep hyperaesthesia, which shows itself as a lively pain, often
retarded, after some slight blow upon a bony projection of the
body. Kérandel, who suffered from trypanosomiasis, noted that
the fear of striking against objects became with him an absolute
obsession. It is called the Kérandel sign. It is during this first
stage, when the trypanosomes are to be found only in the blood or
gland juice that the disease would appear to be curable. Upon the
appearance of the trypanosomes in the cerebro-spinal fluid (second
stage) we have practically a hopeless prognosis.
There may be a latent period of several months in which health
seems normal, to be followed by the sleeping-sickness stage. It has
also been noted that untreated cases, as well as those receiving
more or less treatment, may remain in good health for periods up to
several years. There is therefore reason to believe that certain
cases may not enter upon the sleeping sickness stage.
[Illustration: FIG. 32.—Cases of trypanosomiasis showing the edema
especially about eyes. (Ruge and zur Verth after Koch.)]
_The Stage of Sleeping Sickness._—In this stage the mentality
becomes more weakened. The native from being happy and willing to
work becomes morose and apathetic. This change of disposition is
frequently the first thing to be noted in a patient by his family.
There is a tendency to gaze into the distance. The speech is rather
low and tremulous like that of a tired, sleepy child. The tongue
especially shows a decided tremor which may also be present in the
lips and hands.
The gait is one of weakness and apathy—a shuffling gait. The
reflexes may be exaggerated. Romberg’s sign may be present but
the Argyll-Robertson pupil has not been noted. There may be an
alternation of periods of crying and laughing which with the
occasional exhibition of intention tremor and rarely nystagmus may
make one think of multiple sclerosis. The patient tends to sleep
even when lying in a bright sunlight. Again he may go to sleep
with a morsel of food in his mouth. Notwithstanding the apparent
stupid state of the patient, he will, when aroused, answer fairly
intelligently but with apathy and retardation. The hebephrenic and
catatonic manifestations of dementia praecox may be exhibited in
some cases.
Finally the patient becomes weaker and more emaciated. The pulse
becomes rapid and feeble, the blood pressure being extremely low.
The mouth becomes dry, the teeth covered with sordes and bed sores
develop. There may be convulsions. The coma and general weakness
become more marked and the patient dies. Frequently terminal
pneumonias or dysenteries bring about the end.
The sleeping sickness stage rarely lasts longer than a year and
even with treatment not more than two years.
The Symptoms in Detail
_The Nervous System._—Headache and lack of mental concentration
may be early features of the disease. Deep hyperaesthesia, or
Kérandel’s sign, often present. Patients tend to be morose and
apathetic. Tremor of tongue and lips are rather constant signs
about the commencement of the stage of sleeping sickness. Early
insomnia gives way to the drowsiness that characterizes the second
stage. There is very little disturbance of sensory or motor
functions until near the end. Epileptiform convulsions may be late
manifestations. Coma deepens as the end approaches.
_The Temperature Curve._—The febrile paroxysms, which may not be
present in natives until the sleeping-sickness stage, show great
irregularity of course and a marked remission in the morning. The
fever may be absent for several weeks to return later. Trypanosomes
are more apt to be present in the peripheral circulation during the
fever than when the temperature is normal.
_The Circulatory System._—The pulse tends to run from 90 to 120
beats per minute and is fast even without fever. The tension is
low and the systolic pressure tends to be extremely low during the
later stages of the disease.
_The Lymphatic System._—Most important in diagnosis is the
enlargement of the lymphatic glands, especially those of the
posterior cervical triangle (Winterbottom’s sign). Other enlarged
glands may be the supraclavicular, epitrochlear and axillary
glands. The inguinal glands suffer enlargements so frequently
as the results of wounds and infections of the foot that their
enlargement is of less diagnostic value. The natives of certain
parts of Africa not only attach great diagnostic importance to
gland enlargement but they imagine they cure the disease by
removing the glands with various primitive cutting tools. The
glands are not painful, do not become matted together and rarely
suppurate. Our best means of diagnosing trypanosomiasis is by
withdrawing gland juice with a syringe and examining the smears.
_The Skin._—Erythematous areas may be present in Europeans.
Localized oedemas are rather marked features. The skin may be very
dry and itch markedly.
_Other Manifestations._—The spleen may be enlarged, the
respirations may be more rapid than normal and the blood show a
secondary anaemia. In a blood examination the large mononuclears
show an increase with a normal white count.
The eye may show keratitis or irido-cyclitis in trypanosomiasis.
Trypanosomiasis seems to favor abortion and still-births, in this
respect resembling syphilis.
DIAGNOSIS
In making a survey of a native population Schwetz considers gland
palpation as almost as reliable as gland puncture and of course more
expeditious. The typical gland should be large and soft or elastic
although he admits trypanosomes may be found in small hard glands.
When the glandular enlargement is distinct, with the erythema and
headache, there is much that suggests syphilis. Another point of
confusion is that positive Wassermann tests are often obtained in
sleeping sickness.
The increase in large mononuclears goes with malaria, kala-azar and
syphilis as well as with trypanosomiasis so that such findings are
of little assistance in differential diagnosis.
An early history of attacks of fever, with marked fluctuation of
temperature, associated with rapid pulse, even with the apyrexial
morning fall, is suggestive. Then with the glandular enlargements
we think immediately of laboratory examinations. As with pellagra
the history is very important in the diagnosis of trypanosomiasis.
_For the laboratory diagnosis_ we may use peripheral blood with
some thick film method. The examination of preparations from the
peripheral blood is usually very discouraging. Very much better
results (in fact some prefer this method to any other) can be
obtained by taking 10 to 20 cc. of blood in about 25 cc. of citrated
salt solution, centrifuging 2 or 3 times and examining the sediment
of the third centrifugalization. Dutton and Todd prefer to centrifuge
citrated blood and to collect the leucocyte layer for examination as
is done in opsonic work.
_Gland Puncture._—The English workers usually prefer the gland
puncture method, using a sterile but dry hypodermic needle. Water
in the needle distorts both leishman bodies and trypanosomes.
In the sleeping-sickness stage trypanosomes can almost constantly
be found in the cerebro-spinal fluid.
In a diagnostic study of 336 cases Broden obtained 87% of positives
from gland puncture, 80% from centrifugalizing the supernatant
fluid left from the second centrifugalization of the blood and 4.5%
from spinal fluid examinations.
Some prefer to inoculate susceptible animals, particularly the
guinea pig or monkey, with blood or gland juice from the suspected
case. A very satisfactory material is an emulsion from an excised
gland which may be inoculated intraperitoneally into white rats.
The further course, after animal inoculation, is the examination of
the blood of these animals for trypanosomes. Usually at the time
the guinea pigs die we find numerous trypanosomes.
Other tests are: (1) Trypanolysis, when unheated suspected serum
and trypanosomes are incubated together for one hour. Normal serum
may occasionally cause disintegration and treated cases give it in
only about 45% of cases. Unfavorable untreated cases give it in
about 80% of cases.
(2) The so-called auto-agglutination test is not of much value.
In this the red cells of the blood of a trypanosomiasis case come
together in clumps when one makes a wet preparation. It is not
a rouleaux formation. (3) The attachment test is made by making
a mixture of inactivated serum, leucocytes and trypanosomes and
allowing them to be in contact for 20 minutes. A positive test
shows attachment of the trypanosomes to the leucocytes.
PROGNOSIS
If the patient cannot be removed from the infected district or cannot
receive the atoxyl or atoxyl-tartar-emetic treatment the prognosis is
almost surely that of a prolonged but fatal end.
There is very little hope of cure if the disease has gone on to the
sleeping-sickness stage.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The question of depopulation of districts and
destruction of the big game therein, when the area is infected with
_Glossina palpalis_, has been fully considered under epidemiology.
Isolation, in the fly-free districts, of infected natives has
not proven a very practical measure but that of rendering their
peripheral blood free of trypanosomes by atoxyl injections would
seem more desirable. In this we aim to cure the patient as well as
render him safe to others.
The most practical measure is that employed in Uganda of clearing
the plant and tree growth for at least fifteen feet from the
streams of water, it having been noted that the tsetse flies
confine themselves to a narrow strip not more than fifteen feet
from the water’s edge. The tsetse fly requires considerable
moisture for its existence.
The catching of flies in traps or with a sticky lime does not offer
much encouragement.
As regards personal prophylaxis, white clothes are to be worn as the
tsetse fly, along with mosquitoes, prefers dark-colored garments.
The legs should be protected by leggings and possibly one could
consider the wearing of gloves or veils. As a matter of fact,
however, the heat of the tropics precludes these latter measures. As
the fly only bites in the daytime one should choose the night for
going about, if practicable.
=Treatment.=—The general opinion is that trypanosomiasis is only
curable at a time prior to the appearance of trypanosomes in the
cerebro-spinal fluid. Consequently, the stage of sleeping sickness
offers little chance of cure by treatment.
Such cases have been treated with injections of 10 cc. of 1 to 1000
solution of neosalvarsan into the spinal canal, after withdrawing
about 15 cc. of spinal fluid, but without appreciable curative
effect. On the assumption that trypanosomes invading the central
nervous system are protected from drug action, Marshall proposed
the injection of salvarsanized serum intrathecally. Three hours
after the administration of 0.6 gm. of salvarsan enough blood is
withdrawn from a vein to give about 20 cc. of serum. Following
the withdrawal of a slightly greater amount of cerebro-spinal
fluid from 5 to 20 cc. of the serum is injected in its place.
Yorke in a critical article on the claims for this treatment is
of the opinion that there is no satisfactory evidence that such
a method sterilizes the infected cerebro-spinal fluid. He cites
cases where the trypanosomes disappeared from the spinal fluid
after ordinary treatment and where cases lived for extended periods
after trypanosomes were found in their spinal fluid. Corbus
and associates have described a new method of obtaining a high
medicinal content in the cerebro-spinal fluids. Their work was done
with neo-arsphenamine, but there seems to be no reason why other
drugs may not be similarly administered.
The basis of the method is the observation that hypertonic salt
solution, injected intravenously, will dehydrate the central
nervous system, and that restoration of fluid begins at about
the sixth hour. If a drug is injected into the circulation just
at the time when the restorative formation of spinal fluid is
taking place, it appears that a large quantity is carried into the
subarachnoid spaces with the fluid, as on a flood tide.
Method:
1. 8 A.M. Patient is put to bed.
2. 10 A.M. Intravenous injection of 100 cc. of 15% saline, warmed
and administered slowly by gravity. The symptoms produced by this
injection are mild and transitory.
3. No food is permitted at midday.
4. 4 P.M. Neo-arsphenamine is injected with the usual technic.
5. 8 P.M. Light nourishment is allowed. Patient is kept under
observation, preferably in bed, for the ensuing thirty-six hours.
_Atoxyl._—The first drug to offer hope of cure was sodium
arsanilate, atoxyl, which contains about 26% of As. This is best
given in doses of about 0.5 gram (7½ gr.) in about 15 cc. of
sterile distilled water intramuscularly. Several cases of optic
neuritis were reported but the drug is still a standard treatment.
We give the atoxyl at intervals of five days, Manson gives 3 grains
every third day.
Probably the best treatment is one in which three doses of atoxyl
are followed by from 10 to 15 daily or every other day injections
of 0.1 gram (1½ gr.) of tartar emetic. The course is repeated after
an interval of three weeks. It is advisable to give a hypodermic of
caffein a few minutes before the tartar emetic to lessen depression.
Kérandel received the atoxyl-tartar-emetic double treatment and
ascribed his cure to the tartar emetic. Tartar emetic is also given
intravenously, 0.1 gram in 150 cc. water.
Intravenous injection of arsenophenylglycin, in doses of about
1.0 gram. (15 gr.) intravenously has been highly recommended.
Recent reports from German East Africa state that of 35 treated
with this drug six died of the effects of the drug. Salvarsan and
neosalvarsan have been used but apparently without particular
success.
A combination of treatments in which salvarsan, sodium salicylate
and ethyl-hydrocuprein (a quinine derivative) have been used has
been favorably reported by Morganroth where the action of a single
drug was of little value.
Very remarkable claims in experimental animals have been made for
“trixidin,” a preparation of antimony trioxide which is given
intramuscularly. Even inunctions with this preparation have been
quite successful in curing infected mice. In larger animals abscess
formation is an objection.
Daniels has reported good results from the injection of oxide of
antimony. The preparation used is Martindale’s injectio antimonii
oxidi given subcutaneously in 30 minim doses (1/20 grain of the
oxide). Masters gives this preparation intramuscularly and notes
its greater efficiency than any other drug or combination of drugs.
He gives 3/100 grain every other day until 40/100 grain has been
given. If trypanosomes continue present he gives a .77 gram dose
of soamin. Soamin is a drug similar to atoxyl but said to be less
toxic.
In the treatment of 18 cases of _T. rhodesiense_ infections Newham
notes that tartar emetic alone was as effective as the combined
treatment with atoxyl. He gave the tartar emetic injections twice
weekly intravenously commencing with 1 grain and going up to 3
grains. An organic antimony preparation, “Stibenyl,” has been
recommended. See kala-azar.
Very favorable reports have been made from the use of galyl and
ludyl, arsenical compounds.
A drug which is reported to have exceptional trypanocidal effect
on animals infected with both human trypanosomes is “Bayer 205.”
Dogs infected with the dourine parasite and showing oedema
and eye symptoms have been cured by the injection of the drug
intravenously. A dose of 0.5 mg. causes disappearance of parasites
in mice. It is stated that the drug produces a protection against
reinfection which lasts for months.
BRAZILIAN TRYPANOSOMIASIS
=General Considerations.=—In 1909, Chagas reported the finding
of a flagellate in the intestines of _Conorhinus megistus_ or,
more properly, _Lamus megistus_. He was also able to transmit the
flagellate to laboratory animals and could culture it on blood agar.
[Illustration: FIG. 33.—_Schizotrypanum cruzi_ in blood of child
with acute type of Brazilian trypanosomiasis. (MacNeal from Doflein
after Chagas.)]
In investigating the matter of the importance of this flagellate,
_Schizotrypanum cruzi_, in Minas Geraes, Brazil, where the
above-named bug was present in great numbers in the cracks of the
houses of the poor he associated this flagellate infection, which he
at first considered trypanosomal, with a disease of the children of
that section.
The bug is a vicious feeder and, from its biting chiefly about the
face, has been called barbeiro or barber by the natives. Both the
male and female of _Lamus_ bite and can transmit the disease and
although the parasite is not transmitted hereditarily the nymph is
capable of sucking blood and becoming infected.
[Illustration: FIG. 34.—_Conorhinus megistus_, the insect carrier of
_Schizotrypanum cruzi_. (From Doflein after Chagas.)]
It requires several months for the insect to go through the egg,
larval and pupal stage to maturity. Some consider this bug to
belong to the genus _Triatoma_. The insects may live for more than
a year and tend to remain in the same house where they may have
become infected but leave such house if it be abandoned by man.
Brumpt thinks that the bedbug may also transmit the disease. A
large proportion of armadillos in the endemic areas are infected
with _S. cruzi_ but do not seem to be affected thereby. It has been
suggested that this animal may be a reservoir of virus.
[Illustration: FIG. 35.—_Schizotrypanum cruzi_ developing in the
tissues of the guinea pig. 1. Cross-section of a striated muscle
fibre containing _Schizotrypanum cruzi_: Note dividing forms. 2.
Section of brain showing a _Schizotrypanum_ cyst within a neuroglia
cell, containing chiefly flagellated forms. 3. Section through the
supra-renal capsule, fascicular zone. 4. Section of brain showing a
neuroglia cell filled with round forms of _Schizotrypanum_. (From
Low, in Sleeping Sickness Bulletin, after Vianna.)]
_S. cruzi_ is found in the blood of children during the acute febrile
stage but at other times in children, and as a rule in adults, it is
rarely present in the peripheral blood. The early blood forms are
narrow and very motile. They increase in size and slacken in motility
when they become about 20 microns long. _S. cruzi_ is characterized
by a very large blepharoplast. Dividing forms are never seen in the
blood. The common site of multiplication is in the cells of the
voluntary muscles and heart and also in the cells of the central
nervous system, adrenals, and bone marrow. In these tissues the
flagellate takes on a rounded form and undergoes binary division.
Continued division converts the infected cell into a cyst. It is this
process going on in various important structures that accounts for
the extreme variation in symptomatology and pathology.
Chagas thinks that the gametes for the cycle in _Lamus_ arise
from parasites developing in the lungs of the vertebrate host.
Flagellated parasites enter the lungs, lose the flagellum and
become oval in shape, later on dividing into 8 parts. These assume
an elongated form and enter the red cells of the host. Against this
is the statement of various observers that the flagellates are only
to be found free in the plasma, never within red cells. The forms
taken up by _Lamus_ multiply in the intestine and then pass to the
salivary glands after about 8 days. The bug is then infectious when
it bites. Brumpt notes that infection may occur from inoculation of
the faeces passed by the bug, especially through the conjunctiva.
=Symptomatology.= _Acute types._—This form of the disease usually
occurs in children under one year of age. The period of incubation is
about ten days. It is attended by a high continued fever which may
show a slight morning drop. There is marked puffiness of the face and
enlargement of the thyroid. The lymphatic glands and spleen are also
enlarged. The case may give the picture of a meningitis in which form
the disease is exceedingly fatal. During the febrile period parasites
are to be found in the blood but in the afebrile intervals which
alternate with the febrile ones parasites are not present.
_Chronic Types._—The type of the disease as seen in adults is
mainly chronic. They often show enlargement of the thyroid and
manifestations of myxoedema. The lymphatic glands are enlarged. Where
the adrenal is attacked we have the syndrome of Addison’s disease.
In the cardiac types there are present various forms of cardiac
irregularities.
In the cerebral types various neurological manifestations may be
noted.
An irregular fever may accompany the signs of involvement of the
various important organs.
The disease is attended by a marked anaemia.
=Diagnosis.=—In the laboratory diagnosis of those cases not showing
the flagellates in the blood the usual method is to inoculate a
guinea pig with the blood and in about two weeks _S. cruzi_ may be
found in the blood of the animal. The parasites may not appear,
however, in the blood, when one should resort to culturing the guinea
pig’s blood or more surely examine sections of muscle of the animal
for the forms in the muscle cells undergoing binary division.
Brumpt has recently advocated the xenodiagnostic method. Thus, in a
number of guinea pigs infected with _S. cruzi_, parasites could not
be found, but by having third stage larvae of _Conorhinus_ feed on
these animals the parasites developed in the bugs. He regards the
alimentary tract of these bugs as a most favorable culture medium.
=Prophylaxis and Treatment.=—Other than destroying the bugs by
sulphur fumigation or whitewashing there is little to note. The bugs
show a liking for leather articles, as old harness.
The same plan of treatment as for African trypanosomiasis may be
tried but such treatment is not effective with infected animals.
In the myxoedema types thyroid extract is indicated.
NOTE: Escomel has reported the finding of a trypanosome 20 to 40
microns by 3 to 4 microns which had a flagellum as long as the
body and with a very small but distinct blepharoplast (unlike _S.
cruzi_) in the blood of a native of Peru. The patient at the time
of the blood examination was afebrile and showed a generalized firm
oedema. There was noted anaemia, prostration and somnolence. This
may be a new species.
TRYPANOSOMIASES OF ANIMALS
=Trypanosoma brucei.=—This trypanosome causes a surely fatal
disease in horses and one from which few cattle recover. It is
called “nagana” or the fly disease, from being transmitted by
the tsetse fly, _Glossina morsitans_. All animals except man and
possibly the goat seem susceptible. The disease is characterized
by fever, oedematous areas about neck, abdomen and extremities,
progressive anaemia and emaciation. It is an important disease of
domesticated animals of many parts of Africa.
=Trypanosoma evansi.=—This is the cause of a very fatal disease
of horses in India and the Orient and known as “surra.” It also
affects camels and even cattle. It is thought to be transmitted
by biting flies (_Stomoxys_). The symptoms are fever, emaciation,
oedematous areas and great muscular weakness.
=Trypanosoma equinum.=—This trypanosome causes a fatal disease in
horses in South America. There is paralysis of the hind quarters of
the horse which gives the disease the name “mal de caderas.”
=Trypanosoma equiperdum.=—This trypanosome causes a disease of
horses in many parts of the world. It is known as “dourine” and is
transmitted by coitus. The genital organs show marked oedema which
is followed by anaemia and paralysis.
=Trypanosoma dimorphon.=—This trypanosome causes a disease of
horses in Gambia. It is also found in horses and cattle in other
parts of Africa. The parasite shows marked variation in morphology.
=Trypanosoma lewisi.=—Rats in many parts of the world show this
infection which is rarely fatal to them. It is transmitted by the
rat flea by a process of regurgitation. It can also be transmitted
by the rat louse.
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.
CHAPTER V
YELLOW FEVER
DEFINITION AND SYNONYMS
=Definition.=—Yellow fever is an important epidemic disease of the
West Coast of Africa and tropical America caused by a spirochaetal
organism, _Leptospira icteroides_. The spirochaete is contained
in the peripheral blood only during the first three days of the
disease. A mosquito, _Stegomyia calopus_ (_Aedes calopus_), biting
a patient during this period of his illness, takes in the organism
which undergoes some developmental cycle of the nature of which we
are ignorant, but we do know experimentally that a minimum period of
twelve days is requisite for the completion of the cycle which makes
the mosquito infectious for man.
When a susceptible individual is bitten by an infected mosquito
there develops, after a period of incubation of from two to five
days, a rapid rise of fever, with markedly congested face and
severe pains of back and head. About the end of the third day the
sthenic manifestations are succeeded by asthenic ones in which
jaundice, haemorrhages, particularly black vomit, and anuria are
the important features.
Faget’s sign of a lack of accordance between pulse and temperature
is of great diagnostic importance.
=Synonyms.=—Febris Flava, Typhus Icteroides. Spanish: Fiebre
Amarilla, German: Gelbfieber, French: Fièvre Jaune.
History and Geographical Distribution
=History.=—It would seem probable that yellow fever was the
disease from which those of Columbus’ second expedition suffered
in San Domingo, in 1495. At the same time the first definite
description of the disease was that of Dutertre, in Guadaloupe, in
1635. There has been much discussion as to whether the West Coast
of Africa may not have been the original endemic centre and the
importation to the West Indies the result of the slave traffic.
While there is very little support given this view the recent
recognition of the extent and importance of the African endemic
area, as brought out by Boyce, is somewhat suggestive. Spinden
advances evidence to show that a devastating epidemic disease,
attended with bleeding from the mouth and nose, raged among the
Mayas and Aztecs in pre-Columbian periods. One such epidemic is
recorded as of 1454. There have been numerous severe outbreaks
in the United States, that occurring in Philadelphia, in 1793,
being the most celebrated and that centering in Memphis, in 1878,
probably the most terrible. Yellow fever has been a scourge in
Brazil since its introduction in 1849, until quite recently. Lisbon
experienced severe outbreaks of the disease in 1723 and in the next
century in 1850 and 1856. Many of the Spanish cities have also
suffered from time to time.
The history of the connection between yellow fever and the mosquito
is discussed under etiology.
[Illustration: FIG. 40.—Geographical distribution of yellow fever.]
=Geographical Distribution.=—As will be seen from the chart the
chief epidemic centers are the islands and coasts of the Gulf of
Mexico and the West Coast of Africa. The disease has at times
extended down the West Coast of South America and is now rather
prevalent in Ecuador. The last epidemic in the United States was
that in New Orleans.
The disease has never invaded Asia or Australia and there is fear
that the opening of the Panama canal may bring this about.
Guiteras, who has recently returned from an investigation of the
problem of yellow fever on the West Coast of Africa, was unable to
find evidence of its existence there at the present time. He notes
an absence of the extreme heat and abundance of mosquitoes which
are features of yellow fever ports of South America.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—It is now generally accepted that the cause of yellow
fever is a spirochaete, _Leptospira icteroides_, which is very
similar to but slightly smaller than _L. icterohaemorrhagiae_ of
infectious jaundice. Noguchi injected 74 guinea pigs with about
5 cc. of blood from 27 cases of yellow fever. The blood from 6 of
these cases proved infectious, producing in 8 guinea pigs fever,
conjunctival injection, albuminuria, a leucocytosis followed by
leucopenia and, after a few days, a subsidence of the fever to normal
or subnormal. At this time jaundice and haemorrhages occurred.
[Illustration: FIG. 41.—Dark-field view of _Leptospira icteroides_
in a culture 16 days old. × 1000. (After Noguchi.)]
Autopsies of the guinea pigs showed a fatty and yellow liver with
nephritis. Some of the injected guinea pigs showed only fever
but seemed to have acquired an immunity to subsequent injections
of a virulent virus. In the blood, liver and kidneys of the
animals showing the jaundice and albuminuria Noguchi was able
to demonstrate spirochaetes by dark-field illumination. He also
obtained cultures from such animals. Leptospiras were demonstrated
in the blood of 3 out of 27 human cases but only after prolonged
search. Cultures have been obtained from human yellow fever
blood. For culturing, a medium is used consisting of 1 part of
serum and 3 parts of Ringer’s solution made semisolid with 0.3%
agar and contained in tall tubes. One cc. citrated yellow fever
blood is introduced into the lower part of the medium. A thin
layer of liquid petrolatum is poured on the top of the medium. We
need partial oxygen tension but not anaerobiasis. Optimum growth
temperature is 33°C. _L. icteroides_ is from 4 to 9 microns long
by 0.2 wide and tapers gradually to extremely thin sharp points.
These organisms will pass the pores of V and N Berkefeld filters
thus placing them in the group of filterable viruses. The virulence
of different strains varies, with some strains as little as 0.00001
cc. of culture proving fatal for guinea pigs. Monkeys, rabbits and
birds were not susceptible to infection but the marmoset and puppy
seemed to respond as did the guinea pig.
By having _Stegomyia_ (_Aedes calopus_) feed on infected guinea
pigs as well as the human case of yellow fever, and subsequently
allowing these mosquitoes to bite normal guinea pigs, the disease was
transmitted in a few cases. In certain infected mosquitoes Noguchi
found leptospiral organisms with dark-field illumination. Mosquitoes
fed on infected guinea pigs became infectious in 8 days, this shorter
period over human feedings being due, probably, to the greater
abundance of organisms in the blood of the infected guinea pigs over
human yellow fever blood.
Guiteras doubts the etiological relation of Noguchi’s leptospira to
yellow fever on the ground that in view of the susceptibility of
animals to this organism the disease should exist as an epizootic,
which is improbable in view of the ease with which yellow fever is
eradicated when measures applied solely to man and the mosquito are
practiced. Among other points of objection he notes the recovery
of the spirochaete from the blood later than the third day of the
disease.
[Illustration: FIG. 42.—_Leptospira icteroides_ in blood of a guinea
pig inoculated with a culture × 1000. (After Noguchi.)]
_Infection by Injection of Blood._—The subcutaneous injection of as
little as 0.1 cc. of the blood of a yellow fever patient in the first
three or four days of the disease, or the serum of this blood, which
has passed through the pores of a Chamberland filter (F but not B
according to the French Commission), will bring about the infection
of a susceptible person after an incubation period of from one day
and fifteen hours to twelve days and eighteen hours.
In the natural method of transmission the mosquito, _Stegomyia
calopus_, is the intermediary. In order that the female of this
culicine species may transmit the disease it is necessary that
she bite a yellow fever patient in the first three days of his
illness, after which a period of approximately twelve days must
elapse before the mosquito can transmit the disease. In such case
the period of incubation varies from two days one hour to six days
two hours. Carroll was bitten by a mosquito which had fed on a
yellow fever patient twelve days previously, and four days later
experienced a very severe attack, this fact being against the views
of the French Commission that the disease shows a less severe form
in those who may be bitten in the first period of the infectivity
of the mosquito. A second case bitten five days later by the same
mosquito that infected Doctor Carroll had a mild attack. Persons
bitten by experimentally contaminated mosquitoes before an interval
of twelve days had elapsed escaped infection.
Prior to the investigations of the American Commission our views as
to the incidence and spread of yellow fever were chaotic.
Rush, in 1793, thought that the Philadelphia epidemic originated
from “damaged coffee which putrefied on a wharf near Arch Street.”
In 1883, Doctor Friere reported that yellow fever was caused by
a coccus, _Cryptococcus xanthogenicus_ and claimed that he could
confer immunity by vaccination with attenuated cultures. Carmona
y Valle of Mexico and Carlos Finlay of Havana considered that the
_Micrococcus tetragenus_ was the cause but Sternberg, investigating
these claims, showed that these cocci had nothing to do with
yellow fever. In his work Sternberg isolated an organism which he
designated “X.”
=Bacillus Icteroides.=—In 1897, Sanarelli isolated an organism which
he named _Bacillus icteroides_. In investigating this organism Reed
and Carroll found that it was closely related to the hog cholera
bacillus. Certain American investigators substantiated the claims of
Sanarelli. Sternberg, however, doubted these findings.
To further investigate the relation of _B. icteroides_ to yellow
fever Army surgeons were sent to Cuba in 1900.
=American Commission.=—In addition to Reed and Carroll, Lazear and
Agramonte were also members of the Commission.
The Commission first cultured the blood of 18 yellow fever patients
with negative results for _B. icteroides_ in every case.