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The older we grow the less we know. That at any rate is what I feel at times
when I come up against the blank wall of a case of fever; is it typhoid,
malaria or remittent? Now it is often a very dicult matter to make
a satisfactory diagnosis early in typhoid fever and the diagnosis is
sometimes not made.
Combined infection with typhoid and malarial germs is excessively rare,
indeed that only a single instance has been met in the John Hopkins
Hospital in ten years among nearly one thousand cases of typhoid fever.
Sir William Osler
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Typhoid fever was always a problem in war, and during the Spanish
American War there were 20,738 cases of typhoid fever and 1500 deaths
caused by typhoid. Walter Reed headed the investigation to determine the
cause of the problem. Poor sanitation and sewage contamination was the
main reason for typhoid fever in the SpanishAmerican War, according to
Reed. His recommendations of boiling water and cooking equipment,
covering latrines, and disinfecting excreta subsequently were used by the
military of many coutnries and greatly decreased the incidence of typhoid
fever among armies. The role of ies in the transmission of typhoid fever
rst was demonstrated by Hamilton in 1903 [5].
In 1874, Browicz suggested that a gram-negative bacillus was the cause of
typhoid fever [12]. In 1880, Klebs also described a gram-negative organism
associated with typhoid fever [13]. The identication of S typhi as the
causative agent of typhoid fever usually is credited to Karl Eberth in 1880.
S typhi rst was known as Eberths bacillus, and typhoid was referred to
as Eberths disease [5,14]. Gaky in 1884 was able to culture S typhi on
gelatin-coated slides [15]. Vilchur in 1887 was the rst person to culture
S typhi from a patient with typhoid fever [16]. In 1911, Mechniko used
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During the rst week there is, in some cases (but by no means in all, as
has long been taught), a steady rise in the fever, the evening record rising
a degree or a degree and a half higher each day, reaching 103 F or 104 F. The
pulse is rapid, from 100 to 110, full in volume, but of low tension and often
dicrotic; the tongue is coated and white; the abdomen is slightly distended
and tender. Unless the fever is high there is no delirium, but the patient
complains of headache, and there is mental confusion and wandering at night.
The bowels may be constipated, or there may be two or three loose movements
daily. Toward the end of the week the spleen becomes enlarged and the rash
appears in the form of rose-colored spots, seen rst on the skin of the
abdomen. Cough and bronchitic symptoms are not uncommon at the outset.
In the second week, in cases of moderate severity, the symptoms become
aggravated; the fever remains high and the morning remission is slight. The
pulse is rapid and has lost its dicrotic character. There is no longer headache,
but there is mental torpor and dullness. The face looks heavy; the lips are
dry; the tongue, in severe cases, becomes dry also. Abdominal symptoms are
more markeddiarrhea, tympanites, and tenderness. Death may occur during
this week, with pronounced nervous symptoms, or, toward the end of it, from
hemorrhage or perforation. In mild cases the fever declines, and by the
fourteenth day may be normal.
In the third week, in cases of moderate severity, the pulse ranges from 110
to 130; the temperature now shows marked morning remissions, and there is
a gradual decline in the fever. The diarrhea and meteorism may persist.
Unfavorable symptoms at this stage are the pulmonary complications,
increasing feebleness of the heart, and pronounced delirium with muscular
tremor. Special dangers are perforation and hemorrhage.
With the fourth week, in a majority of instances, convalescence begins.
The temperature gradually reaches the normal point, the diarrhea stops, the
tongue cleans, and the desire for food returns. In severe cases the fourth
week may present an aggravated picture of the third. He lies in a condition
of profound stupor, with low muttering delirium and subsultus tendinum,
and passes the faeces and urine involuntarily. Heart-failure and secondary
complications are the chief dangers of this period.
In the fth and sixth weeks protracted cases may still show irregular
fever, and convalescence may not set in until after the fortieth day. At this
time, too, occur many of the complications and sequelae.
During convalescence the pulse gradually returns to normal, and
occasionally becomes very slow. After no other acute fever do we so
frequently meet with bradycardia. I have counted the pulse as low as thirty,
and instances are on record of still fewer beats to the minutes.
Typhus fever
Oslers description of typhoid fever was careful and complete [20,21].
Less-astute clinicians at the time often confused typhoid fever with malaria
and to a lesser extent with typhus. Oslers description of typhus in his
textbook leaves no doubt that he was readily able to distinguish between these
two similar-sounding but dierent infectious disease processes [22,27].
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Typhus fever, known as spotted fever, jail fever, hospital fever, and camp
fever, was rare in Oslers era, but an outbreak occurred in Montreal in 1877,
a large outbreak occurred in New York in 1881 to 1882, and a small epidemic
occurred in Philadelphia in 1883 [28]. Osler understood the relationship of
typhus to lack of cleanliness, overcrowding, and poverty. At the time, typhus
was regarded as essentially a European disease, but it also occurred in the
most blighted parts of large American cities [2931]. It is apparent from his
description of typhus that Osler was familiar with the infection [27]. His
writings concentrated on the dierential diagnostic points that separate
typhus from typhoid fever, which was much more common at the time [22].
The following section is condensed (authors italics) from Oslers chapters on
typhus and typhoid fever in Curschmanns 1901 book [22].
Even in quite severe cases of typhus fever the development of the associated
eruption may be extremely imperfect or almost completely absent. The
typhoid roseola is almost from the beginning slightly elevated, papular, and,
throughout its entire duration, purely hyperemic, constantly circular, and
sharply dened. The spots of typhus fever are less sharply limited and are ill
dened; at rst pale, the majority soon become hemorrhagic, so that they
are then simple, not elevated, spots of from a dusky, coppery redness, only
in part disappearing on pressure, to a dark livid color, which then distinctly
exhibit their petechial character.
The diagnosis is facilitated by the fact that the spots of typhus fever
appear earlier than the typhoid roseolabetween the second and, at the
latest, the fth day of the disease.
The dierences in the distribution of the eruptions over the surface of the
body in both diseases are also noteworthy. While in cases of typhus fever the
trunk and the extremities are quite uniformly covered, in cases of typhoid
fever only the parts of the extremities adjacent to the trunk are involved.
Even from the beginning it is diusely red and turgid, the conjunctivae are
vividly injected, subsequently often ecchymotic, while, in addition, the face
has a wild and startled expression, which is in marked contrast to the
indierent, dull expression of the typhoid patient.
Not less important than observation of the skin in the dierentiation of
the two diseases is the course of the fever. Step-like ascent in cases of
typhoid fever, the temperature in cases of typhus fever generally, after one or
rarely several chills, rises rapidly to it height with slight interruption, so that
within from twenty-four to thirty-six hours a level of from 40.5 to 41 C is
reacheda far higher level than in cases of typhoid fever at this time. Its total
duration does not exceed from fourteen to seventeen days even in the most
severe cases of typhus fever. It generally terminates with a critical or a rapid,
step-like decline.
The pulse in all cases of typhus fever, without reference to age and sex, is
exceedingly frequent from the beginning. In women and children it may be
120 and more during even the rst days; also, in previously healthy young
men a frequency of pulse is sometimes encountered at the beginning, such as is
rarely observed at the height of the disease in cases of typhoid fever.
Enlargement of the spleen is far less constant in cases of typhus than in those
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Malaria
For Osler, typhoid fever cannot be confused easily with typhus because of
important dierences in temperaturepulse relationships, splenomegaly,
rash, and pathologic ndings (eg, the presence or absence of ulcerative
Peyers Patches in the ileum). His writings show that his pointcounterpoint
dierential diagnostic approach is characteristic of a master diagnostician.
Osler believed that typhoid fever was more likely to be confused with
malaria than with typhus fever. Whereas typhus was rare in North America
during Oslers time, typhoid fever and malaria were common. No other
disease caused as much diagnostic confusion as malaria, which shared many
common clinical features with typhoid fever [5,32]. In an article on the
features of malaria written by Osler in 1897, he described the clinical
manifestations of malaria and emphasized the critical dierential diagnostic
points to discern malaria from typhoid fever. Parts of from Oslers original
article (authors italics) are excerpted [20]:
Clinical Forms of Malarial Fever. (1) Intermittent Fever.
This form is characterized by recurring paroxysms of what are known as
ague, in which, as a rule, chill, fever, and sweat follow each other in orderly
sequence. The stage of incubation may be very short. Attacks have occurred
within twenty-four hours after exposure. Usually the time of incubation is
from seven to fourteen days. On the other hand, the ague may be, as is said,
in the system, and the patient may have a paroxysm months after he has
removed from a malarial region, though I doubt if this can be the case
unless he has had the disease when living there.
Description of the Paroxysm. The patient generally knows he is going to
have a chill a few hours before its evident by unpleasant feelings and uneasy
sensations, sometimes by headache. The paroxysm is divided into three
stagescold, heat, and sweating.
Fever may rise during the chill to 105 or 106 . Of symptoms associated
with the chill, nausea, and vomiting are common. There may be intense
headache. The pulse is quick, small, and hard. The chill lasts for a variable
time, from ten to twelve minutes to an hour, or even longer.
The hot stage is ushered in by transient ushes of heat; gradually the
coldness of the surface disappears and the skin becomes intensely hot. The
contrast in the patients appearance is striking: The face is ushed, the hands
are congested, the skin reddened, the pulse is full and bounding, the hearts
action is forcible, and the patient may complain of a throbbing headache.
The rectal temperature may not increase much during this stage; in fact, by
the termination of the chill the fever may have reached its maximum. The
duration of the hot stage varies from half an hour to three or four hours. The
patient is intensely thirsty and drinks eagerly of cold water.
Sweating Stage. Beads of perspiration appear upon the face and
gradually the entire body is bathed in a copious sweat. The uncomfortable
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feeling associated with the fever disappears, the headache is relieved and
within an hour to two the paroxysm is over and the patient usually sinks into
a refreshing sleep. The sweating varies much. It may be drenching in
character or it may be slight.
Types of the Paroxysm. The periodicity of the paroxysms is one of the most
striking features in malarial fever. They occur with regularity, either at the
end of twenty four, forty-eight, or seventy-two hours.
Twenty-four hours the paroxysm is daily, hence the name quotidian.
Paroxysm occurs at the end of forty-eight hours, it happens upon the third
day; hence the term tertian applied to this form. This is the next most
frequent form. Seventy-two hours the paroxysm is on the fourth day, hence
the name quartan ague. This is rare.
Course of the Disease. After a few paroxysms, or after the disease has
persisted for ten days or two weeks, the patient may get well without any
special medication. In cases in which we have been studying the haematozoa
I have repeatedly known the chills to stop spontaneously. Such cases, however,
are very liable to recurrence. Persistence of the fever leads to anemia and
a haematogenous jaundice, owing to the destruction of the red blood-disks
by the parasites. Ultimately the condition may become chronic, and will be
described under malarial cachexia. Cases of intermittent fever yield
promptly and immediately to treatment by quinine.
Symptoms. The disease may set in with a denite chill, or may be preceded
for a few days by feelings of malaise. As seen in this latitude, the patient has
either chilliness or a distinct rigor in the beginning. When seen on the
second or third day of the disease he has a ushed face and looks ill. The
tongue is furred, the pulse is full and bounding, but rarely dicrotic.
The temperature may range from 102 to 103 , or is in some instances
higher. The general appearance of the patient is strongly suggestive of
typhoid fever, a suggestion still further borne out by the existence of acute
splenic enlargement of moderate grade.
The similarity of the cases at the outset to typhoid fever is most striking, more
particularly the appearance of the facies, and the patient looks very ill. The cases
develop, to, in the autumn, at the very time when typhoid fever occurs.
There are only two forms of these continued fevers in the Souththe one
due to the typhoid, and the other to the malarial infection. The typhoid fever
of Philadelphia and Baltimore presents no essential dierence from the
disease as it occurs in Montreal, a city practically free from malaria. Dock
proved conclusively that cases diagnosed in Texas as continued malarial
fever were really typhoid fever.
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Soon after the beginning of the fever, and progressively from this time
on, there occurs an often considerable reduction in the number of white
blood-corpuscles; this does not occur in a number of other diseases important
in dierential diagnosis, but in which, on the contrary, a more or less
marked leukocytosis is the rule.
Epistaxis may also at times be considered indicative of existing typhoid
fever; at least, it is far less likely to occur in connection with a number of other
infectious diseases, which are, especially in the initial stage, to be taken into
consideration from the dierential diagnostic standpoint.
It is noteworthy, further, that the occurrence of profuse or persistent
sweating at the height of the fever is strongly opposed to the existence of
typhoid fever.
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Osler was at his best when he used the characteristics of the fever to
dierentiate between typhoid fever and malaria. He, like Hippocrates but
with greater precision, describes the malarial paroxysms and related this to
the various malarial species. He readily dierentiated tertian from quartan
malaria and recognized dual infections and their eect on fever curves. The
malarial paroxysms stood out in contrast to the slow, continuous rise in
fever found in typhoid fever. The characteristic fever of typhus was dierent
in that it initially rose abruptly but was not remittent. Chills were not
a feature of typhoid fever, but did occur with typhus and malaria. Similarly,
he recognized that sweating could occur with any febrile infectious disease,
but episodic profuse sweating occurred most often with malaria and was not
a clinical feature of typhoid fever. Osler was such a ne clinician, that he
could walk down a ward of patients with malaria or typhoid fever and
dierentiate them by their appearance. He noted that a sallow complexion
was characteristic of patients with malaria [5].
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North of Mason and Dixons line physicians are prone to diagnose malaria for
other diseases; south of the line they are more prone to diagnose other
diseases for malaria; in both regions it is a source of greater errors in vital
statistics than any other aection.
It is not my intention to bore you with any detailed account of the
hematozoon malariae, but I would remind you that there are three well
recognized varieties. (1) The tertian organism, which matures in forty-eight
hours and produces quotidian paroxysms if two groups are present,
tertian if there be only one. This is the common parasite of the simple
intermittents of the spring and early autumn. (2) The quartan parasite,
which has a cycle of development of seventy-two hours, and, if only on
group of organisms is present, causes the regular quartan intermittent; if
two or more groups are present, the paroxysms may be daily or every
other day. The quartan parasite is a rare form. There have been only
about fteen cases among 1000 examined at my clinic. (3) The parasite of
the irregular malarial fevers (estivo-autumnal form)the remittent,
continued, and pernicious types. This variety is small, less easily
recognized, is not so abundant in the peripheral circulation, and, in the
pernicious forms, may have curious seats of election, as in the brain or
intestines. It is further characterized by the development of the crescents,
a distinctive and characteristic form of great moment in diagnosis.
The character of the febrile paroxysms. Take any large series of carefully
recorded temperature charts, such as have been made in my wards during
the past seven years, and it is found that the duration of the pyrexia from
the rise above 99 F to the fall to normal is from eleven to twelve hours,
rarely shorter, still more rarely longer.
The blood shows the hematozoa in all stages of development. Practically
they are never absent in uncinchonized individuals. There is no leucocytosis.
With us it has been very much more common to mistake malaria for
typhoid fever than typhoid fever for malaria. The following are the important
points on dierentiation:
The mode of onset. In malarial remittent fever there is not the initial
period of malaise and ill-health; the onset is more sudden, chills are more
frequent. They are not, however, always present, as in the case of which I
have just spoken. On the other hand, chills at the onset of typhoid fever are
not very uncommon.
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Summary
One can only marvel at Oslers ability at the bedside to dierentiate the
causes of seemingly undierentiated fevers that were baing to most
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physicians [42]. Osler has much to teach the current generation of physicians
regarding identifying key clinical ndings that have important diagnostic
implications. Osler was careful to dierentiate between ndings that were
consistent with the diagnosis and ndings that were characteristic of the
diagnosis. He used this approach with great eectiveness and accuracy in
dierential diagnostic problems. His ability to distinguish typhoid fever
from typhus and malaria illustrates his clinical acumen and method [20
22,27]. As Osler said, the value of experience is not in seeing much, but in
seeing wisely cannot be overly stressed. Todays physicians are often too
laboratory-test-oriented and have the potential to overlook important
signicant clinical information by careful evaluation of the key physical and
laboratory ndings. Dierential diagnostic abilities can be improved. Using
an Oslerian approach, it is important to realize that some clinical ndings
have more diagnostic signicance than others. Clinical diagnostic problems
should be approached from an Oslerian perspective, because failure to do so
invites imprecise diagnosis.
Dierential diagnosis remains the hallmark of the master clinician.
Todays clinicians would benet greatly from reading Oslers description of
typhoid fever. As Osler himself suggested, But when you have seen, read.
And when you can, read the original descriptions of the masters who, with
crude methods of study, saw so clearly.
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