Malaysian Journal of Medical Sciences, Vol. 7, No.

2, July 2000 (3-8)

BRIEF REVIEW

NEW ADVANCES IN THE DIAGNOSIS OF TYPHOID AND

DETECTION OF TYPHOID CARRIERS

Asma Ismail

Centre for Medical Innovations and Technology Development

and Department of Medical Microbiology and Parasitology
School of Medical Sciences, Universiti Sains Malaysia
16150 Kubang Kerian, Kelantan, Malaysia

For effective management of typhoid, diagnosis of the disease must be done with
speed and accuracy. Development of such a test would require antigens that are
specific for typhoid diagnosis. Attempts at finding the specific antigen have been
carried out throughout the years. The finding of such an antigen can lead to carrier
detection as well. Candidate antigens have been used in the development of antigen
or antibody detection tests with variation in sensitivity and specificity. Further
characterization and understanding of the candidate antigens combined with use
of innovative technologies will allow for the ideal test for typhoid and typhoid
carriers to be within reach.

Key words : New advances, typhoid diagnosis, typhoid carriers, typhoid antigent

Introduction of food by food handlers who are carriers, forms

the second commonest route of infection. Since
Typhoid fever remains a public health spread of the disease is via fecal-oral route, attempts
problem in most developing countries with an at breaking the transmission cycle would contribute
estimated incidence of 540 per 100,000 population toward the effective control of the disease. Control
(1) . Since typhoid may mimic the symptoms of other of typhoid outbreaks include screening of food and
fevers including dengue, malaria, hepatitis and scub water samples to trace the source of the aetiologic
typhus, in typhoid endemic regions, results obtained agent. The availability of diagnostic tests that are
from the laboratory are important in confirming the rapid, sensitive, specific, simple to perfom and cost
clinical diagnosis of typhoid and will contribute to effective to detect for the pathogen in contaminated
the effective management and treatment of typhoid food , water and healthy human carriers, would
cases. The conventional diagnosis for typhoid provide an effective tool in controlling and
include the culture method and antibody detection preventing typhoid.
tests. Although variations to the conventional In the quest of developing an accurate test
techniques have improved both tests, the search for for typhoid fever, there is a need to discover antigens
better and improved tests still prevails. specific for typhoid diagnosis. The finding of such
The continued high incidence of typhoid is an antigen can lead to diagnostics for carrier
due to the dissemination of the disease via typhoid detection as well. Studies have been done
carriers (2). Hence there is an urgent need to increase throughout the years to search for the specific
the chance of detecting the carriers so as to decrease antigen. Attempts at utilizing the antigens toward
the risk that they pose to the communities. In urban the development of a suitable diagnostic test have
areas where sewage disposal is lacking or been reported with variation in sensitivity and
inadequate, public water supplies are contaminated specificity. Our increasing understanding of the
and typhoid fever is common. The contamination candidate antigens and the use of innovative

3
Asma Ismail

technologies for laboratory procedures are addressed observed when comparing the convalescent titer to
in this review. It is the intention of this review to the acute titer. This could be due to the fact that most
elucidate the use and effectiveness of the various patients attended the hospital during the
diagnostic tests available for the diagnosis of typhoid convalescent phase, after initial pretreatment by the
fever and for the detection of typhoid carriers. general practioners failed.
When interpreting the Widal test it is of
utmost importance that the test be interpreted against
Conventional methods of typhoid diagnosis
the background normal titer of the population in
Current diagnosis for typhoid is still via the question. It is not uncommon to find what is
method of culture and antibody detection by means considered positive in a non-endemic area may be
of the Widal test. Isolation of Salmonella typhi has considered normal in an endemic area. The
remained as the gold standard, with culture the bone interpretation of the tests may also vary among the
marrow aspirate or a combination of specimens from endemic areas.
blood, stool or urine. However, it is well recognised Despite problems of accurate diagnosis
that facilities for culture are not readily available or associated with the Widal test, studies have shown
are limited in many areas. Although the culture that the test may be useful among febrile paediatric
method may show specificity, it however lacks patients in endemic areas (14).
sensitivity and speed. If positive, culture produces
results within 2-7 days, but culture negative typhoid
Advances in typhoid diagnosis
is well recognised ( 3). Culture is also less sensitive
for diagnosis of infection among children compared
to adults ( 4,5,6). The culture method despite its An ideal diagnostic test for typhoid and
shortcomings in speed and sensitivity is still useful typhoid carriers should be rapid, specific as well as
for antibiotic sensitivity testing. sensitive. The development of a rapid and specific
The value of the Widal test, which uses the test combined with sensitive diagnosis would
bacterial agglutination technique for the diagnosis provide for prompt, effective management and
of typhoid and paratyphoid fevers, has been assessed control of typhoid fever. The existing conventional
by several investigators. In endemic areas where tests lack speed, sensitivity and specificity. To
culture facilities are lacking or limited, the Widal overcome the limitations of the existing tests, new
test remains among the few tests available to specific antigens and new diagnostic techniques
differentiate enteric infection from other illnesses have been employed. Some of the antigenic
due to bacteria, viruses or animal parasites (7). candidates include outer membrane proteins (15),
However, it is also recognised that agglutination tests lipopolysaccharides (16) and heat shock proteins
have serious shortcomings (8). Discrepancies in (17) . The need for an alternative, low cost test for
results between laboratories or even within the same typhoid has also spurred the development of other
laboratory have been reported especially when serological’assays’including
preparations of the antigens had come from different counterimmunoelectrophoresis (18), ELISA (19) ,
sources (9,10). There is also evidence that among RIA (20) and the haemagglutination assay (21).
patients who have been proven as typhoid cases, Coagglutination tests have also been used for the
detection of antibody against the O and H antigens detection of antigens in urine and serum (22,23).
has not been demonstrated by the Widal test (11). and DNA probes have been suggested for the
On the other hand, antibodies against Salmonella detection of S.typhi in blood (24). However, none
typhi have been detected among nontyphoid of the tests have so far obtained widespread
Salmonella infections (12) and sometimes even in acceptance in microbiological laboratories. Since
diseases not caused by Salmonella (13). For typhoid fever is common in developing and
meaningful interpretation of the test, demonstration underdeveloped countries, the race toward
of a 4 fold rise in antibody titers between acute and development of the ultimate ideal test still continues.
convalescent sera, at least 10-14 days later, is This is because the development of such a test will
essential. In the clinical settings, it is common have a huge economic significance as well as impact
practice to make an interpretation based on a single on public health management for all endemic
serum specimen which may not reflect the diagnostic countries in the region.
value of the test. More often even when paired sera Outer membrane proteins (OMP) due to their
are obtained, a decrease in titer is commonly location have been primed as important candidates

4
 NEW ADVANCES IN THE DIAGNOSIS OF TYPHOID AND DETECTION OF TYPHOID CARRIERS

to elicit host immune response (16,25). Although the method used as the gold standard should
several possible antigenic candidates have been approach 100% in terms of its sensitivity, specificity,
elucidated from studies on the OMPs, only the 50 positive and negative predictive values. Evaluation
kDa protein has undergone a full scale multinational studies have shown that TYPHIDOT-M was superior
clinical trial in order to evaluate its diagnostic value to the culture method (35,36). Although culture
( 26,27,28,29 ). The 50 kD outer membrane protein remained as the gold standard, it could not compete
was determined to be antigenic as well as specific with TYPHIDOT-M in terms of sensitivity (>93%),
for Salmonella typhi since it only reacted negative predictive value as well as speed ( 35,36
immunologically with typhoid sera (30). Further ). TYPHIDOT-M could also be used to replace the
evaluation of the antigen using the dot enzyme Widal test when used in conjunction with the culture
immunosorbent assay (EIA) method revealed that method for the rapid and accurate diagnosis of
the 50 kD antigen could detect for the presence of typhoid fever. The high negative predictive value
specific IgM and IgG in sera from patients with acute of the test suggested the usefulness of TYPHIDOT-
typhoid (31,32,33,34). M in a highly endemic area.
Evaluation of the tests in clinical settings,
showed that the dot EIA test (TYPHIDOT) offers Finding the typhoid carrier
simplicity, speed ( 1-3 hours), specificity (75%),
economy, early diagnosis, sensitivity (95%) and with The human population is a reservoir as well
high negative and postive predictive values ( 31 ). as natural host for several enteric pathogens . These
When interpreting the test, detection of IgM would asymptomatic carriers represent an important
reveal acute typhoid (early phase of infection) while reservoir that helps to perpetuate the disease and is
detection of both IgG and IgM would also suggest responsible for the outbreaks of enteric diseases
acute typhoid (middle-phase of infection). In highly including typhoid fever. Approximately, 2-5% of
endemic areas where the rate of typhoid transmission typhoid cases become chronic biliary carriers and
is high, the detection of specific IgG will increase. hence perpetuate the endemicity of the disease (37).
Since IgG could persist for more than 2 years after The chances of becoming a carrier increases with
typhoid infection (34) the detection of specific IgG age and is evidently greater among women (38). The
could not differentiate between acute and detection of these carriers thus is an important aspect
convalescent cases. Furthermore, cases of false of disease control. The current gold standard to
positive results due to previous infection may also detect for carriers is by means of stool culture . This
occur. On the other hand, IgG positive may also is not only tedious and costly, it also has a low
occur in the event of current re-infection. In cases sensitivity (39). Multiple bacteriological
of re-infection, there will be a secondary immune examination of stools are also necessary to make a
response with a significant “boosting” effect of IgG reliable diagnosis due to intermittent or light fecal
over IgM such that the latter could not be detected excreters among carriers. There have been studies
hence “masking the effect” of IgM (35). One on carriers that showed positive fecal culture only
possible strategy to resolve the problems mentioned after 196 negative culture results (40). Hence there
is to detect for the presence of IgM by making sure is a need to have an alternative serological carrier
that its presence is “unmasked” (35,36). To increase detection system that is not only specific, sensitive
diagnostic accuracy in these situations, a and cost-effective but is also easy to use in the field.
modification to the original TYPHIDOT test was When developing a serodiagnostic test it is
done by inactivating total IgG in the serum sample. important to determine the antibody that would be
Studies with the modified test called TYPHIDOT- an indicator for carrier diagnosis. Studies with Vi
M have shown that inactivation of IgG would antigens (41) have shown that IgG is the primary
remove competitive binding and allow accessibility indicator for carriers and IgM does not play a role.
of the antigen to the specific IgM, when present. IgA can be found in both the acute and carrier state
The detection of specific IgM (within 3 hours) . When further tested, IgA and secretory IgA were
would suggest acute typhoid infection. Evaluations found most frequently in the sera of dysentery and
on the TYPHIDOT and TYPHIDOT - M tests in typhoid carriers. No secretory IgA was detected
clinical settings showed that both tests performed among vaccinated individuals (42). When
better than the Widal test and even the culture quantifying the content of immunoglobulins in
method ( 35,36 ). different forms of typhoid fever, the carrier state
In the laboratory diagnosis for typhoid fever, showed high IgA and IgG content which began as

5
Asma Ismail

early as the acute period (43). Other studies have Multi-tests developed for the detection of the
also shown that IgA among carriers seemed to be organism in environmental samples would also
elevated 2.4 times compared to non carriers (but with enhance typhoid control since it would allow for
a previous typhoid history) while IgM is only tracing of the source of contamination.
elevated among acute typhoid cases (44 ). IgG was While carrier detection is important for public
found to be high among typhoid and typhoid carriers. health, reports have also shown a close relationship
The high IgA content among carriers may reflect between biliary disease and chronic carriers (51) .
prolonged immunological stimulation since IgA Recent developments have shown that the risk of
when formed does not last long in the body (in cases gallbladder carcinoma has increased among typhoid
of acute typhoid). It has been suggested that the carriers (52,53,54). Hence a test to detect for typhoid
continuous presence of IgA among typhoid carriers carriers that is cheap, sensitive, specific and user
may be due to S.typhi being the primary occupant friendly for field work would promote not only
of the biliary system during chronic infection (41). effective management but also reduce gallbladder
Hence IgA detection among healthy individuals may carcinoma and dysfunction.
also indicate typhoid carrier state.
Among the antigens used in the serological Correspondence :
screening for carriers ( 45,46) none equaled the Vi
antigen in terms of widespread acceptance as an
Profesor Dr. Asma Ismail, PHD,
indicator of typhoid carriers (47). Various techniques
Centre for Medical Innovations and Technology,
have been used in the development of a diagnostic
Development and Department of Medical
test which uses the Vi antigen from Citrobacter
Microbiology and Parasitology,
freundii. Passive heamagglutination assay has been
School of Medical Sciences, Universiti Sains
used and was found to show high specificity and
Malaysia
sensitivity especially when used in highly endemic
16150 Kubang Kerian, Kelantan, Malaysia
areas (47,48). However, the sera needed to be
preabsorbed with sheep erythrocytes before being
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