Infect Dis Clin N Am 18 (2004) 111125

Osler on typhoid fever: dierentiating

typhoid from typhus and malaria
Burke A. Cunha, MDa,b
a

Infectious Disease Division, Winthrop-University Hospital, Mineola, NY 11501, USA

b
State University of New York School of Medicine, Stony Brook, NY, USA

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

Typhoid fever is responsible for more than 30 million infections annually

worldwide and is associated with a 10% mortality rate. Salmonella typhi is
transmitted by fecally contaminated water or food products and always has
been associated with poor sanitation. Typhoid fever has been a major public
health problem since ancient times [1]. Greek and Roman writers refer to
acute febrile illnesses associated with diarrhea that were often fatal.
Although typhoid fever was not recognized as a distinct clinical entity per
se, there is little doubt that typhoid fever was prevalent in the ancient world
[2,3]. Hippocrates described approximately six cases in Book I and Book III
of Epidemics. The ancient Chinese physician Cheng Chung-Ching, in his
treatise of febrile and miscellaneous diseases, gives a good clinical description of typhoid fever [4,5].
Typhus fever is derived from the Greek word typhos, which refers to
smoke or pungent odor. Pungent smoke apparently referred to the malodors
associated with putrefaction and open sewers containing fetid material.
Initially, it was believed that there were two variants of typhus fever: one
called typhus, and the other called typhus-like (ie, typhoid because of its
resemblance to typhus). For centuries, clinicians had diculties in
dierentiating typhoid from typhus. Huxem in 1782 recognized two variants
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of typhus. He described typhus as the slow nervous fever and typhoid as

the putrid malignant fever [3,6]. Because of some overlap in the clinical
ndings of these infectious diseases, pathologic dierentiation did not occur
for nearly another century until 1837 when Gerhardt recognized that the
intestinal lesions of typhoid fever were not present in typhus [5,7].
The Dutch physician Van den Speighel (15781625), Professor of Surgery
at Padua, was the rst person to describe the ileal ulcers of typhoid fever.
Thomas Willis (16221675) at Oxford dierentiated typhoid fever from
typhus and other fevers by recognizing the characteristic appearance of
typhoid ulcers in the ileum. Willis used the term febris putrida to describe the
fever associated with ileal ulcers. He even suggested that the appearance of
the typhoidal ulcer resembled the lesions of smallpox. His observations were
important, because few infectious diseases aect the ileum besides typhoid
fever and tuberculosis [5,8].
In the beginning of the 19th century, autopsies increasingly were used to
correlate clinical and pathologic ndings. The French physician Bretonneau
rst noted that lymphoid tissue (ie, Peyers Patches of the ileum) was the
consistent site of typhoid ulcer. He referred to typhoid fever as dothienenterite, as did Sir William Osler (eg, dothienenteritis) [5]. Subsequently, the
French physician Pierre Charles Alexandre Louis (17871872) was the rst
person to use the term typhoid fever in his classic work on typhoid. Louis
preceded Osler in extensively correlating disease features with pathology.
From 1822 to 1827, Louis autopsied 83 controls dying from noninfectious
diseases and 50 patients dying from typhoid fever. Louis was concerned with
identifying the pathologic lesion in typhoid fever and not dierentiating it
from other fevers. He was unable to dierentiate typhus from typhoid fever,
which may be because typhus was rare in 19th century Paris, whereas typhoid
fever was fairly common. Louis was able to distinguish febris putrida (typhoid
fever) associated with ileal ulcers from febris pestilens (typhus fever) [5,9].
Osler expanded and improved Louis methods and was readily able to
clinically distinguish between typhus and typhoid fever.
William Gerhardt (18091902), an Edinburgh-trained American physician and student of Louis, saw typhus in Edinburgh and subsequently
typhoid fever in Paris and had no diculty in distinguishing between typhus
and typhoid fever in the Philadelphia outbreak of typhus fever in 1826 [7].
He appreciated that the clinical and pathologic features were distinctive,
reinforcing his clinical experience in Europe.
William Jenner (18151898) wrote a classic work on typhoid fever based
on his experience with typhus and typhoid fever in London. His most
important contribution was on the epidemiologic dierences between
typhus and typhoid fever. He noted that an outbreak of typhus fever had
no relationship to the incidence of typhoid fever and visa versa. He observed
that patients in the same household would have typhoid fever or typhus, but
not both diseases. In 1847, Jenner was infected with typhus, and 4 years
later he had typhoid fever. His previous clinical exposure and his own

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113

personal experience allowed him to clearly dierentiate these two acute

fevers [5,10].
William Budd (18111880) was the rst to determine that S typhi was
transmitted by way of the fecal oral route. His epidemiologic observations
are landmark studies in infectious disease epidemiology. In 1873, he
published a book on typhoid fever that emphasized his epidemiologic,
clinical, and pathologic observations on typhoid fever. Budds description of
the Thames stink of 1858 to 1859 attests to the foulness of fecal pollution
of the Thames River as a conduit for the transmission of typhoid fever in
greater London and in towns along the rivers route to the sea [11]. Budd
described the extent of water pollution at the time in his 1873 book [11]:
For the rst time in the history of man, the sewage of nearly three million
people had been brought to seethe and ferment under a burning sun, in one
vast open cloaca lying in their midst. The result we all know. Stench so foul,
we may well believe, had never before ascended to pollute this lower air.
Never before, at least, had a stink risen to the height of an historic event.
For many weeks the atmosphere of Parliamentary Committee-rooms was
only rendered barely tolerable by the suspension before every window, of
blinds saturated with chloride of lime, and by the lavish use of this and
other disinfectants. More than once, in spite of similar precautions, the lawcourts were suddenly broken up by an insupportable invasion of the
noxious vapours from the river. Meanwhile the hot weather passed away;
the returns of sickness and mortality were made up, and, strange to relate,
the result showed not only a death-rate below the average, but, as the
leading peculiarity of the season, a remarkable diminution in the prevalence
of fever, diarrhoea, and the other forms of disease commonly ascribed to
putrid emanations.

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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Kochs postulates to infect a chimpanzee with S typhi, which resulted in

typhoid fever [17]. Widal in 1896 and Wright in 1897 developed diagnostic agglutination tests for heat-killed S typhi [18,19].
In spite of the identication of the causative organism of typhoid fever
and diagnostic techniques to prove the diagnosis, physicians continued to
have diagnostic diculties in separating typhoid from typhus and even more
diculty in dierentiating typhoid fever from malaria. Osler had limited
experience with typhus but had extensive experience with typhoid and
malaria in Philadelphia, Baltimore, and Montreal. Because of the overlap in
some of the clinical features of typhoid fever and malaria, physicians at the
time introduced the term typho-malaria, which caused much diagnostic
confusion Typho-malaria was such a common diagnosis in the United States
that Osler extensively lectured and wrote to eliminate typho-malaria as
a diagnosis [5].
Typhoid fever was one of Oslers main clinical interests, and he wrote
extensively on the subject [2022]. His description of typhoid fever remains
a classic. In his book The Principles and Practices of Medicine, published in
1892, the rst and longest chapter is devoted to his description of typhoid
fever.
Oslers perspective
Typhoid fever
Osler (18491919) was a consummate clinician who was able to correlate
seemingly unrelated clinical ndings in cases to arrive at a diagnosis. He
related his clinical ndings to his pathologic ndings from autopsies of
patients with fatal infections. He devoted the rst part of his classic textbook
of medicine, which he wrote in Baltimore in 1892, to infectious diseases.
Infections were of considerable importance in Oslers era, which is reected
in the number of pages covering the major infectious diseases of the day.
Typhoid fever has pride of place in Oslers textbook and is not only listed
rst but is the subject of the longest single chapter. His clinical description of
typhoid fever with its protean manifestations and complications remains
unsurpassed [2326]. Osler appreciated the key diagnostic ndings of each
infectious disease and was able to realize the time course and sequence of
ndings as they evolved during the infection. Distinguishing laboratory
abnormalities also were used according to their diagnostic usefulness.
Because his classic treatise on typhoid fever is so descriptive and insightful,
part of it is reproduced from his 1872 textbook (authors italics) [20]:
The period of incubation lasts from a week to ten days, during which there
are feelings of lassitude and inaptitude for work. The onset is rarely abrupt.
There may be prodromal symptoms, either a rigor, which is rare, or chilly
feelings, headache, nausea, loss of appetite, pains in the back and legs, and
nose bleeding.

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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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of typhoid fever. When it occurs, it develops earlier and it subsides more

quickly.

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.

Typhoid fever versus malaria: key dierential points

Typhoid fever and malaria dier in incubation period, causative microorganism, epidemiology, contagiousness, and complications. The initial
clinical presentations of malaria and typhoid fever have many clinical
features in common, however. Both infections present as acute febrile
illnesses without localizing physical ndings. If rose spots are not present,
cannot be seen, or are faint or few, typhoid fever and malaria have no

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119

distinguishing exanthem which may be useful for diagnostic purposes. Both

infections are characterized at onset by a prominent generalized headache.
Splenomegaly occurs in typhoid and malaria. Most cases of typhoid fever
present with constipation. In the absence of diarrhea, the gastrointestinal
origin of typhoid may be missed. Diarrhea when present, is an important
clue to dierentiate typhoid from malaria [20,33].
In his usual and careful clinical analysis, Osler emphasized characteristic
clinical features. Epistaxis is common in typhoid fever and, if present,
dierentiates typhoid fever from malaria. In laboratory tests, Osler pointed
out that leukopenia usually occurred in typhoid fever, and the presence of
leukocytosis was associated with malaria [6,20,33]. Knowing the key clinical
ndings for these infectious diseases, Osler was able to distinguish between
these infections at the bedside without specialized tests.
Osler paid a great deal of attention to fever patterns and appreciated the
relationship between pulse and temperature [2022,27,33]. He used the
character of the pulse (eg, whether it was dicrotic or not) as a diagnostic aid.
Using his powers of observation and clinical correlation at the bedside, he
was able to use fever curves and pulse relationships to distinguish typhoid
fever, typhus fever, and malaria [3436]. Oslers (authors italics) keen
clinical observations on the fever characteristics in typhoid are best
expressed in his own words [21].
The most important features, especially with regard to typhoid fever, to be
taken into consideration is this connection are the character of the febrile
course, particularly the character of the temperature-and pulse-curves and their
relations to each other, the acute enlargement of the spleen, the appearance
of a peculiar roseolous eruption, and the character of the stools. Next in
importance are bronchitis and pulmonary hypostasis, the state of the blood,
especially of the leukocytes, and the demonstration of the diazo-reaction.
With regard to the course of the temperature, the character of its ascent, in
the well-known step-like manner, at most ve, days, may be of great weight
in the dierential diagnosis. Scarcely any other infectious disease to be
taken into consideration exhibits this mode of onset.
Its remarkable slowness in comparison to the height of the temperature
does not occur anywhere nearly so often in any other disease to be taken into
consideration from the standpoint of dierential diagnosis.
The dicrotism of the pulse is also of diagnostic signicance. It is much more
common in cases of typhoid fever than in all the other infectious diseases
taken together. If both phenomena, slowing and dicrotism, are observed
together, this fact may materially strengthen the diagnosis.
In no other acute infectious disease is the occurrence of enlargement of the
spleen, especially at the time stated, even approximately so frequent; and in
one does this condition persist so longinto the third or the fourth week of
the disease, and perhaps longer.
This distinguishes typhoid fever from typhus fever, and from the acute
exanthemata, to which typhus is closely related, if these diseases should
ever be attended with any enlargement of the spleen.

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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.

Osler appreciated the seasonal and geographic relationships with these

three infections. Typhoid fever occurred in the fall, whereas typhus was
a disease of winter, and malaria occurred in the summer months. Osler
described important physical ndings that are helpful in dierentiating
malaria from typhoid fever. He was able to appreciate that herpes labialis
commonly is associated with malaria and is rare in typhoid fever. Epistaxis,
which frequently occurs in typhoid fever, is not a clinical feature of malaria.
A dry bronchitic cough is common to typhoid and malaria. Osler described
in detail the dierences in the faces of patients with typhus and typhoid
fever. He appreciated that early in the disease, the apathetic faces of typhoid
fever were not uncommon in severe forms of malaria. He associated early
enlargement of the spleen with typhoid fever and appreciated that
splenomegaly occurred later in the course of malarial infection. He also
realized that splenomegaly was not a feature of typhus fever. Abdominal
tenderness early in the infection pointed to typhoid fever rather than
malaria, because abdominal pain was not a feature of typhus [2022,
27,33,35,37].
Because of the absence of eective antimicrobial therapy for typhoid
fever, many patients died of the infection. Osler had the opportunity to do
autopsies on many fatal cases of typhoid fever. He was struck by the absence
of intestinal ndings in the areas of Pyers patches in typhus fever and
malaria, because these ndings were constant in typhoid fever. He clearly
dierentiated the characteristics of the rash of typhoid fever (eg, rose spots)
from the exanthem of typhus fever [20,22]. In his examination of the blood,
he noted the presence a mononuclear cell response in typhoid fever, which
occurred in association with the early relative leukopenia seen in typhoid
fever. Using observations by Manson, Marchiafava, and Bignami, Osler
examined blood smears to conrm the diagnosis of malaria and to
determine its species [38,39]. Osler appreciated that crescents in the blood
of patients with malaria indicated the presence of Plasmodium falciparum,
with its more severe course and complications [33]. Osler (authors italics)
had two general principles to guide practitioners in dierentiating typhoid
from malaria, which he phrased aphoristically in his 1899 article [21]:

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Two clinical rules should guide practitioners:

1. An intermittent fever which resists quinine is not of malarial origin.
Infection with the tertian organism, producing quotidian or tertian
paroxysms, is the only variety of malarial fever prevalent in the Northern
and Middle States. This form of the parasite is peculiarly susceptible to the
action of quinine, and even a grain or two daily may suce to clear the
blood within forty-eight hours. The constancy, the infallibility of the action
of this drug is one of the most remarkable phenomena in medicine. Our
clinical charts of simple intermittents, now numbering many hundreds, may
be searched through and through without nding an instance in which the
paroxysms were not checked by the use of quinine, and usually within
thirty-six or forty-eight hours.
2. In these localities a continued fever is not due to malarial infection. I am
speaking now, remember, of the regions named, in which the aestivoautumnal organism and the graver forms of the disease caused by it are
very rare. For remarkable complexity in the clinical manifestations, for
variability in mode of onset, in the course, and in the symptoms, the aestivoautumnal infection takes precedence even of typhoid fever. With a vigilance
quickened by repeated surprises, we are yearly made to feel the subtleness of
this protozoan.
The fever in malaria from the outset is marked by remissionhence the term
remittent feverof a grade rarely seen in typhoid until the late stages. Once the
fastigium is reached, the fever in the latter presents a remarkable steadiness;
the two-hour record may show several days of variation of not more than
a degree. The chart has a Pennsylvania-Railway-like directness, in marked
distinction to the zig-zag Baltimore-and-Ohio-Railway chart of aestivoautumnal fever. The early anemia, with sallow complexion, often suggests the
diagnosis, even when other symptoms are like those of typhoid fever.
Learn to suspect typhoid fever, and not malaria, in every case of fever of
six or seven days duration, particularly if it resists the action of quinine.
It is hoped that the pernicious term typho-malarial fever has been forever
banished from our nomenclature.

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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In cases in which typhoid fever and malaria could not be dierentiated

because of the absence of associated ndings, Osler was quick to settle the
issue by examination of the blood or an empiric trial of quinine, as earlier
suggested by Lavaran. In patients with non-P falciparum malaria, quinine
would result in a rapid clinical response, defervescence of fever, and clearing
of the parasites from the blood within 2 to 3 days. P falciparum would
respond more slowly. Osler recommended examination of the blood on
a therapeutic trial of quinine in dicult cases that could not be dierentiated
on clinical grounds alone [33,40]. Oslers dierential diagnostic approach
(authors italics) is apparent in the following 1897 article [41]:

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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123

The fever, which presents three points of great importance in the

dierentiation.
The slow, step-like ascent to the fastigium is not met with in malaria. The
rise is abrupt, and on the rst or second day the temperature may reach
104 F or 105 F. You will see in the chart passing around that the
temperature on the third day in that patient reached nearly 106 F, is in itself
almost enough to exclude typhoid fever.
The malarial remittents never have the remarkable continuous type of fever
which we see in typhoid after the fastigium is reached. No other disease,
except pneumonia, presents the same persistent pyrexia, with perhaps not
more than a degree or a degree and a half of diurnal variation. This is
characteristic particularly of the second week of the disease, or from the fth
to the twelfth day. In the estivo-autumnal infections the remissions are, as
a rule, marked-two, three, and even four degrees.
In the later stages, say in the third week, when in typhoid fever there are
wider excursions and marked remissions, the pyrexia in the remittent fever
becomes much more broken, is apt to be more intermittent in character, and
the temperature may even be subnormal for several hours of each day.
Third. The general appearance of the patient. Walking through a ward
containing malarial intermittent cases and typhoid fever patients once can
usually pick out readily those with the former disease. The early anemia and
the sallowness are very characteristic. This is not the case with malarial
remittent fever. During the rst week the aspect may be typically typhoidal,
the expression dull and heavy, and the cheeks ushed. Marked anemia and
the sallow tint may not develop until the patient has been under
observation for a week or more.
Fourth. The gastro-intestinal, bronchitic, and nervous features oer less
valuable criteria of dierentiation. Herpes on the lips, when present, is
important because of the great rarity in typhoid fever and the great frequency
in malaria. The tongue in remittent fever is usually more coated, pasty, and
white early in the disease. Bronchitis is common in both. Mental hebitude
and delirium, while more common in typhoid fever, are not at all infrequent in
the severer types of the estivo-autumnal fever.
Fifth. The examination of the bloodIn any estivo-autumnal form is sure
to be rewarded by the detection of perfectly distinctive forms, if not of the
intracellular, of the characteristic crescents.
Sixth. Quinin has not inuence on typhoid fever. Properly administered, it
checks the malarial remittent fever in from two to four days.
In paludal (malarial) regions, does typhoid fever present malarial
aspects? It is the rooted and grounded belief of a very large section of the
physicians of this country that typhoid fever very often presents malarial
features. The phrase is on their lips constantly. Failure to recognize the
extraordinary protean character of the disease is in the main responsible
for this delusion.

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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