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Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 77

a herculean task. Various importantissues related to this major publichealth problem in India weredeliberated in this focused group

discussion. The practice patternsfrom across the country werecompared, and the best clinicalpractices were pinpointed.

Epidemiological Concerns

of Enteric Fever in the

Indian Scenario

T h e t e r m ‘ e n t e r i c f e v e r ’

( E F ) i n c l u d e s t y p h o i d a n dparatyphoid fevers . Typhoidf e v e r i s c a u s e d b y a G r a m -negative organism, Salmonel laenterica subspecies enterica serovar

Typhi (Salmonella typhi), whereasparatyphoid fever is caused by anyof the three serovars of Salmonellaenterica subspecies enterica, namelyS. paratyphi A, S. schottmuelleri (also

ca l led S. paratyphi B) , and S.

hirschfeldii (also called S. paratyphiC). Type A is the most commonpathogen worldwide, whereas

Type B predominates in Europe.Type C is rare, and is seen only inthe Far East. The overall ratio ofthe disease caused by S. typhi tothat caused by S. paratyphi is about

10 to 1.1

API Recommendations for the Management of

Typhoid FeverRajesh Upadhyay1, Milind Y Nadkar2, A Muruganathan3, Mangesh Tiwaskar4,

Deepak Amarapurkar5, NH Banka6, Ketan K Mehta7, BS Sathyaprakash8

T he p a ne l o f e x p e r t s whoparticipated in the meeting prefersto use the term ‘enteric fever’instead of ‘typhoid fever,’ as the

former covers both typhoid andparatyphoid. In adults, entericfever tends to cause constipation.Therefore, the presence of diarrheainstead in such a case should

raise suspicion of a co-infection.Long-term use of proton pumpinhibitors (PPIs) increases theincidence of EF because less orno acid in the stomach facilitates

the passage of bacteria withoutdestruction by the gastric acid.2

Definitions3

Confirmed enteric fever: Fever

≥38°C for at least three days, with

a laboratory-confirmed positiveculture (blood, bone marrow,

bowel flu id) of S. typhi.

Probable enteric fever: Fever ≥38°Cfor at least three days, with apositive serodiagnosis or antigendetection test but without S. typhi isolation.

Chronic carrier state: Excretionof S. typhi in stools or urine (orrepeated positive bile or duodenal

string cultures) for longer than one

year after the onset of acute entericfever; sometimes, S. typhi may be

Introduction

Enteric fever is a condition thatis taking its toll even now inIndia, where its prevalence doesn’t

seem to be decreasing in spite ofthe availability of antibiotics andvaccines in the market. With theemergence of antibiotic resistant

strains of the pathogenic organisms,the management of this diseaseis becoming more challenging.Further, there are no standardIndia-specific guidelines to treat

this scourge. In order to bridgethis need gap and for the benefi t ofprimary care doctors, the ‘EntericConclave,’ the first-of-its-kind, wasconducted. This meeting was a very

innovative initiative that facilitateda frank exchange of opinions

be twe e n g as t r o e n te r o l o g i s t s ,consulting physicians, and generalp ra c t i t i o ne rs , who ha d be e n

brought together under a commonroof to discuss the epidemiology,diagnosis, and management oftyphoid. While gastroenterologistsusually get to see only complicated

forms of the disease, and consultingphysicians mostly deal with casesthat are severe, majority of the

cases in India are taken care of byprimary care doctors. Thus, the

specialists barely see 15% of thesecases, whereas it is the primarycare doctor, who treats typhoid atthe grass-root level. Many of thesedoctors are forced to manage their

patients in the absence of diagnosticfacilities such as blood cultureand serological tests. Despitethe advances in medicine in thedeveloping countries, tackling a

disease like typhoid may seem like

Expert Panel

1. Director and Head, Dept. of Gastroenterology and Hepatology, Max Super-Specialty Hospital, New Delhi

2. Professor, Dept. of Medicine, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra

3. Adjunct Professor, Tamil Nadu Dr. MGR Medical University, Chennai, Tamil Nadu

4. Consultant Physician and Diabetologist, Asian Heart Institute, Mumbai, Maharashtra

5. Consultant Gastroenterologist, Bombay Hospital and Medical Research Center and Breach Candy Hospital,

Mumbai, Maharashtra

6. Chief Hepato-Gastroenterologist, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra

7. Consulting Physician, Asian Heart Institute and Health Harmony, Mumbai, Maharashtra

8. Professor of Gastroenterology, MS Ramaiah Medical College, Bengaluru, Karanataka

A P I R E C O M M E N D A T I O N S


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Journal of The Association of Physicians of India ■ Vol. 63 ■ November 201578

Fig. 1: Incidence of enteric fever in

India per 10,0000 per year6

Fig. 2: Prevalence of enteric fever

in India per 1,000 febrile

episodes with blood culture

taken6

Fig. 3: Incidence of antimicrobial

resistance in India6

*chloramphenicol,

ampicillin, cotrimoxazole

Fig. 4: Rise in the prevalence of

multidrug resistance in the

period 1999-2005

8

Fig. 5: Prevalence of seropositive titers in Indian patients with different age

groups

9

excreted without any history ofenteric fever.

Contamination and Transmission

Humans are the only naturalhost and reservoir. The infectionis transmitted by ingestion of

food or water contaminated withfeces. Contaminated water, andraw fruit and vegetables fertilized

with sewage water, have beensources of outbreaks. The highestincidence occurs where watersupplies serving large populationsare contaminated wi th feces .Cold foods such as Ice-cream is

recognized as a significant riskfactor for the transmission ofenteric fever.3

Global Prevalence of Enteric Fever

The world sees approximately22 million new typhoid cases occur

each year. The worst sufferers areyoung children in poor, resource-limited areas, who make up themajority of the new cases and

mortality figures (215,000 deathsannually). Most of these deathsare due to S. typhi infection. TheSouth-east Asian countries bear the

brunt of the disease, particularly

children and young adults. Other

areas of prevalence include Africaand South America. Outbreakshave been reported from Zambia,Zimbabwe, Fiji and the Philippines.There is evidence that enteric fever

is often under-reported, so the

actual figures might be even morethan those mentioned above.4

Prevalence of Enteric Fever in India

In disease-endemic areas, the

annual incidence of enteric feveris about 1%. Peak incidence is seenin children 5–15 years of age; but inregions where the disease is highlyendemic, as in India, chi ldren

younger than 5 years of age mayhave the highest infection rates.5

In 2008, Ochiai et al conducted

a prospective population-basedsurvey in five Asian countriesconsidered to be endemic for enteric,

using standardized surveillancetechniques, as well as standardizedc l i n i c a l a nd m i c ro bi o l o g i c a lmethods, to provide an updated

assessment of the burden of enteric

in Asia including India. Kolkatawas chosen as the study site. Resultsobtained in India are depicted in

Figures 1, 2 and 3.6

The resul ts showed a highincidence of enteric fever in India,

with the incidence in pre-schoolchildren (aged 2–5 years) being ofthe same order of magnitude as forschool-aged children (aged 5–15years). The high disease burden in

pre-school children underscores

the importance of vaccines anddelivery systems in this age group,as well as older chi ldren andadolescents.6


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Fifty-seven percent of isolateswere found resistant to nalidixic

acid, 1.6% to ciprofloxacin, and7 % we re m u l t i dru g - re s i s ta nt

(resistant to chloramphenicol ,ampicillin and cotrimoxazole).Nalidixic acid resistance being an

indirect marker of fluoroquinoloneresistance; indicates high resistancet o f l u o r o q u i n o l o n e . 6 S i n c efluoroquinolones are empirical

therapy of choice in enteric fever,7 increasing ra tes of ant ibiot icresistance may necessitate ther e p l a c e m e n t o f i n e x p e n s i v eantibiotics with newer, expensive

agents, which may be unavailable

and unaffordable to many poorpatients. This also highlightsthe need to monitor patterns ofresistance and to consider vaccines

as disease control tools.6

A prospective study that wasconducted in an Indian tertiary care

hospital found that the prevalenceo f m u l t i d r u g r e s i s t a n c e ( t ochloramphenicol, ampicillin, andco-trimoxazole) in the organisms

causing enteric fever had nearly

doubled between 1999 and 2005(Figure 4). While 80% of the patientswere infected by S. typhi , paratyphi

A was the pathogen in 9% of the

cases. The remaining 11% of thepatients were found to be infected

by other S. enterica and E. salmonella groups, typhimurium , and paratyphiC and senftenberg.8

The social and economic impactof enteric fever is also high becausepatients with acute disease and

complications may need to be

hospitalized. This results in lossof work days and, consequently,

income.3 In the study by Ochiai et al ,6 2% of Indian patients with enteric

fever required hospitalization.A study analyzed the trend ofantibody titers to O and H antigens

of S. typhi over a period of tenyears (1998-2002 and 2007-2011)in Indian patients of different agegroups, who had been diagnosedwith enteric fever. This study found

that the overall seropositivity ratesover the 10-year study period hadincreased significantly, as shownin Figure 5.9

Carrier State

On entering the human body,S a l m o n e l l a t y p h i c ro sse s theintestinal epithelial layer and iscarried by macrophages to theliver, pancreas, and spleen. From

the liver, the organisms can be shedinto the gallbladder, where, beingresistant to bile, they can stay forlong periods and give rise to eitheran active infection (cholecystitis) or

a chronic infection (carrier state).10

About 3 to 5% of infected people

become carriers, parti cularly thosewith gallbladder abnormalities,such as gallstones. These peopleare often asymptomatic and canremain in this state for many years

with little or no deleterious effect.However, they continue to excrete

bac ter ia for prolonged periods oftime, thus constituting a potentialsource of infection,10 particularly

in the setting of food preparation.The story of “Typhoid Mary,” a

cook in early 20th century New

York who infected approximately50 people (three fatally), highlightsthe role of asymptomatic carriers inmaintaining the cycle of person-to-person spread.11

Besides, the chronic carrier

state is the single most importantrisk factor for development of

hepatobi l iary carc inomas, assalmonella carriers with gallstoneshave been shown to carry an8.47-fold higher risk of developingcancer of the gallbladder.10

It is for these reasons that theeradication of carriage is of primeimportance.

Factors Affecting Epidemiology12,13

Age

The incidence of enteric fever in

endemic areas is typically low inthe first few years of life, peakingin school-aged children and youngadults and then falling in middleage. Older adults are relatively

resistant, probably due to frequent boosting of immunity.

Season

In endemic areas, peaks oftransmission occur in dry weatheror at the onset of rains. This is

because warm and moist conditionsfavor the growth of the organism.Also, in summer, people are morelikely to drink water outside theirhomes which may be of quality.

In rainy season, the water may becontaminated.

Food habits

Eating food prepared outsidethe home, such as ice creams or

flavored iced drinks from streetvendors; drinking contaminated

water; and eating vegetables andsalads grown with human waste asfertilizer are major risks.

Other

A close contact or relative withrecent enteric fever

Poor socioeconomic status

High population density

Poor personal hygiene

Lack of sanitation

Lack of safe water supply

Low latrine use

Table 1: Antibiotic sensitivity pattern in vivo for Salmonella14

Antibiotic Patients(No.)

Responded(N%)

Resistant(N%)

Eervescencesperiod*

Ampicillin 32 7 (21.8%) 25 (78.12%) 7.5

Amoxycillin 40 9 (22.5%) 31 (77.5%) 8.0

Cotrimoxazole 19 3 (15.78%) 16 (84.2%) 7.2

Ciprooxacin 42 34 (80.5%) 8 (19.5%) 5.5Ooxacin 14 12 (85.71%) 2 (14.28%) 5.0

Amikacin 9 8 (88.8%) 1 (11.9%) 5.0

Cexime 6 6 (100%) - 6.5

Cefotaxime 5 4 (80%) 1 (20.0%) 6.5

Ceftriaxone 38 38 (100%) - 5.0

Chloramphenicol 2 - 2 (100%) -

*Mean in days


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Living near an open water body

R e c e n t c o n s u m p t i o n o fantimicrobials

Transmission of enteric feverhas also been attributed to flies,laboratory mishaps, unsteri leinstruments, and anal intercourse.

MDR Enteric Fever

I n 1 9 7 2 , c h l o ra m p he ni c o l -resistant S. typhi was first reported,and since then, chloramphenicol ormultidrug-resistant enteric fever(MDREF) has been reported during

outbreaks from many parts of theworld. MDREF is most commonlyseen in school-going children, butmay affect younger children aswell. MDREF is associated more

commonly with hepatomegalyand splenomegaly. Resistanceto ceftriaxone and cefixime has

been seen in many studies, as isresistance to quinolones, indicating

that Salmonella develops resistancerapidly against quinolones andh e n c e , e x i s t i n g q u i n o l o n e s ,like sparfloxacin, levofloxacin,gatifloxacin and moxifloxacin,

should be used very rationally(Table 1).14

Economic Implications of Enteric Fever

Management of enteric fever inIndia is a costly affair. According to

a prospective surveillance carriedout in an urban slum in Delhi,

the direct and indirect costs per

episode of blood culture-confirmed

enteric fever was INR 3,597 in anoutdoor setting. This cost increasedseveral fold (INR 18,131) in caseof hospitalization. Almost similarobservations have been made in

other studies from other parts ofthe country. The costs increasedseveral times due to increasedhospi ta l iza t ions and growingresistance to available antibiotics.

These costs also add to the annualloss of income to the affectedindividuals and their families.15

The Diagnostic Approach

in Enteric Fever

I s o l a t i o n o f S . t y p h i from blood, bone marrow, or a specif ic

anatomica l les ion i s the onlydef ini t ive way of diagnosingenteric fever.3 The presence ofcharacteristic clinical symptoms

or the demonstration of a specificantibody response is suggestive ofthe disease, but not definitive.

Clinical Features

The panelists were of the opinionthat a good clinical history and

physical examination are veryimportant for the diagnosis ofenteric fever. In fact, the presenceof fever with hepatosplenomegalyshould make one think of this

condition as one of the differentialdiagnoses. The participants were

completely in agreement about this

and felt that enteric fever can bediagnosed clinically by symptomssuch as fever with rigors, headache,toxemia, abdominal pain (early in

children), nausea, dry and coated

tongue, relative bradycardia (mostimportant clinical sign), and rosespots, which are rarely seen inclinical practice. First, the liver

becomes palpable . The spleenusually becomes palpable onlyafter a week.2

Typical Presentation16

7-14 days after ingestion of S.typhi

First Week

Fever

Exhibits a step-ladder pattern —i.e., the temperature rises over thecourse of each day and drops bythe subsequent morning. The peaksand troughs rise progressively overtime (Figure 6).

Gastrointestinal manifestations

Diffuse abdominal pain andtenderness ; sometimes, f iercec o l i c k y p a i n i n r i g ht u p p e rquadrant.

Monocytic infiltration in Peyer’s

patches, causing inflammationand narrowing of bowel lumen,resulting in constipation.

Other symptoms

Dry cough

Dull frontal headache

Delirium

Stupor

Malaise

Second week

Progression of above signs andsymptoms

Fever plateaus at 39-40°C

Rose spots

Sa lmon-colored, blanching ,m a c u l o p a p u l e s o n the c he s t ,abdomen, and back, may not bevisible in dark-skinned individuals

1-4 cm in width, less than 5 innumber, present in up to 25% ofpatients

They resolve within 2-5 days.

Fig. 6: Step-ladder pattern of fever

ENTERIC FEVER -

TYPICAL STEP-LADDER PATTERN

The fever goes up

a litle each day.

41°

40°

39°

38°

37°

36°

1 2 3 4 5 6 7 8

Days of illness


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Represent bacterial emboli tothe dermis

Abdominal distension

Soft splenomegaly

R e l a t i v e b r a d y c a r d i a —

t e m p e r a t u r e e l e v a t i o n s n o taccompanied by a physiologicalincrease in the pulse rate

Dicrotic pulse — double beat,

the second beat weaker than thefirst

Third week

Fever persists

Increase in toxemia

Anorexia

Weight loss

ConjunctivitisThready pulse

Tachypnea

Crackles over lung bases

Severe abdominal distension

Sometimes, foul, green-yellow,liquid diarrhea (pea-soup diarrhea)

Typhoid state — characterized by apathy, confusion, psychosis

Bowel perforation and peritonitis

due to necrosis in Peyer’s patches

Death may occur due to severetoxemia, myocarditis or intestinal

hemorrhage

Fourth week

Gradual improvement in fever,menta l s ta te , and abdominal

distension over a few days

Untreated patients may sufferfrom intestinal and neurological

complications

Weight loss and debilitatingweakness (may last for months)

Asymptomatic carrier state insome patients, who can transmitthe bacteria indefinitely

Atypical presentation16

I n s o m e p a t i e n t s , e n t e r i cfever may not present in thetypical manner described above.Presentation of the disease dependsupon the host response, geographic

region, race fac tors , and theinfecting bacterial strain.

F e v e r : T h e c h a r a c t e r i s t i c

stepladder fever pattern is seen

in just about 12% of cases, and thefever has a steady insidious onset.

GI symptoms: Diarrhea, and not

constipation, is common in youngchildren in AIDS and one-third

of immunocompetent adults withenteric fever

Other atypical manifestations:

Only fever

S e v e r e h e a d a c h e smimicking meningitis

Acute lobar pneumonia

Arthralgias

Urinary symptoms

Severe jaundice

Neurologica l symptoms insome patients, especially in Indiaand Africa, such as del irium,P a r k i n s o n i a n s y m p t o m s o rGuillain-Barré syndrome

Pancreatitis

Meningitis

Orchitis

Osteomyelitis

Abscesses

Laboratory Evaluation

The expert panelists opinedthat a very toxic-looking patientwith low counts should ra ise

suspicion of enteric fever or a viralinfection. Increased counts usuallysignify sepsis or perforation, witheosinopenia being an importantfinding. Monocytosis is also a

usual finding. The presence of botheosinopenia and thrombocytopeniais strongly suggestive of entericfever.2

Hematological tests17,18

Complete blood count

Hemoglobin: Mild anemia

Total leucocytic count (TLC):Low to normal

Eosinopenia

Platelets: Low to normal

Liver function tests:

Mildly abnormal

Serum transaminase levels 2 to3 times the upper limit of normal

Clinical jaundice is uncommon

Significant hepatic dysfunctionis rare

Cultures

Blood culture:

The specificity of a blood culture

is 100%. At least 25-30 ml of bloodshould be collected for a goodyield. The larger is the volume of

bl oo d, the bet te r th e yi el d. The

ideal time of doing a blood cultureis when the patient is havingchills (and not when the feverspikes, as is commonly thought).Blood for culture should be taken

before giving the first dose ofantibiotics. However, in clinicalpractice, antibiotic therapy isinitiated based on the diagnosis,

and a blood culture is advised. Itis always better to do an antibioticsensitivity test along with theculture, as this will help to selectthe most appropriate antibiotic.Culture should be repeated after

an hour and then after 24 hours.A single culture should not beencouraged. (The participants,on the other hand, revealed thatthey seldom did a blood culture

in a primary healthcare setup, asit was expensive for the patients.They usually depended on thefindings of the Widal test and thecomplete blood cell count, which

shows eosinopenia and relativelymphocytosis). The positivity ofthe blood culture is as follows:

1st week – 90%

2nd week – 75%

3rd week – 60%

4th week – 25%

The positivity of blood culture

decreases due to the administrationof antibiotics; however, the bloodcul ture wi l l cont inue to testpositive in resistant cases. Many atime, contaminants like coagulase-negative staphylococci in the blood

culture may cause a false-negativereport. Hence, the culture should

be done with due caution. A clotculture is also being done.2 The cost

of a blood culture in India rangesfrom ` 600 to ` 800.

Culture involves inoculation of


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the specimen (blood, bone marrowor stool) into an enrichment broth,and when a growth appears ,making subcultures on solid agar.Biochemical testing is done to

identify the colonies obtained.

This is further confirmed by slideagglutination with appropriateantisera.19

Direct blood culture followed by microbiological identificationremains the gold s tandard inthe diagnosis of enteric fever.20

Blood culture shows growth ofthe organism in 80% to 100%of patients,17 particularly thosewith a history of fever for 7-10

days.3 However, patients who have

started antibiotics may not showany growth.17

The sensitivity range of bloodculture is estimated to be between40% and 80%. The sensitivity may

be low in endemic areas with highrates of antibiotic use, making

it difficult to estimate the truespecificity. 18

Failure to isolate the organisms

can be due to delay in diagnosis,limitations of laboratory media,widespread and irrational useof antibiotics, and low volumeof blood cultured, especial ly

in children.21 The probability ofrecovering the organisms is directlyproportional to the volume of

blood drawn; hence, it is essential

to have an adequate volume of blood taken for culture.20 Due tothe higher levels of bacteremia inchildren compared to that in adults,at least 10-15 ml of blood from

schoolchildren and adults, and 2-4

ml from toddlers and preschoolchildren should be taken to achieveoptimal isolation rates.3

Limitations in use

Less sensitive for diagnosis

of infection among children ascompared to adults22

Positive in only 40-60% of cases,

usually early in the course of thedisease18

Expensive and requires specialist

facilities and personnel20

S. typhi and S. paratyphi A arenot always culturable even i fgood microbiological facilities areavailable20

Bone marrow culture:

Culture of the bone marrow

aspirate is the gold standard forthe diagnosis of enteric fever,3 andcan yield positive results even ifthe patient has started antibiotics.23

It is of particular value in thepatients who have been treatedpreviously, have a long history ofillness and had a negative blood

culture with the recommendedvolume of blood.3

This test has a sensitivity of

55-67% and a specificity of 30%.18

The positivity rate can further beincreased to almost 100% if FANculture medium is used and growthis monitored in automated culture

systems.23

Speaking about bone marrowculture, the participants declared

that this investigation is neverc a r r i e d o u t a t t h e p r i m a r yhealthcare level. Even otherwise,it is avoided considering that it iscostly as well as painful. The expert

panelists informed that unlike blood culture, bone marrow cultureremains positive even after theadministration of antibiotics. Thus,

it is more suitable for hospitalizedand very sick patients.2

Limitations in use

Although the most sensitive, it isan invasive procedure, and cannot

be pe rf or me d ou ts id e sp ec ia li st

settings20

Has l imi ted c l inica l va lue ,

e s p e c i a l l y i n a m b u l a t o r ymanagement 18

The specimen is difficult toobtain

Stool culture:

S t o o l c u l t u r e c a n h e l p i n

detecting typhoid carriers. Stoolshould be collected from acutepatients in a sterile wide-mouthedplast ic conta iner and shouldpreferably be processed within

two hours of collection. The larger

is the quantity of stool collected,

the greater will be the likelihood

of getting a positive result. Rectalswabs can be obtained insteadof stool samples but they areless successful in isolating theorganism.3 A stool culture in India

costs about ` 350 to ` 450.A l l t h e p a n e l i s t s w e r e i n

agreement about the need to dorepeat stool cultures to detectcarriers, as they tend to shed the

bact eria spo rad ic al ly . Chefs, in

particular, should get their stoolculture done to rule out carrierstates, as they are likely to infecta large number of people whencooking.2

Limitations in use

S p o r a d i c s h e d d i n g o f t h eorganism in stools potential lycompromises the stool culturingapproach20

Becomes positive only after thefirst week of infection and has amuch lower sensitivity than blood

culture (30% vs. 40-90%)18

Sensitivity is low in developingcountries18

Not routinely used for follow-up18

Urine culture:

Urine culture, according tothe experts, is not usually done.P o s i t i v i t y o f u r i n e c u l t u r e

increases in carriers with urinaryobstruction.2

Urine culture for enteric fever

has variable sensitivity, the range being 0-58%. 18 In India, the cost ofa urine culture varies from ` 350to ` 450.

Rose spot culture:Punch-biopsy samples of rose

spots may be cultured to yielda sensitivity of 63% and may bepositive even in patients who havereviewed antibiotics.16

Serum culture:

To conduct serum culture, 1-3ml of blood is inoculated into atube without anticoagulant. Whenthe convalescent stage starts about5 days later, a second sample

is collected. After clotting, the


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serum is separated and testedimmediately or stored for a weekwithout affecting the antibodytitre.3

Duodenal aspirate culture:

S h a r i n g t h e i r e x p e r i e n c e s

with regard to duodenal aspirateculture, the panelists explained thatthis investigation may have goodsensitivity because bile directlyenters the duodenum. However,

they added that this test is notpractical and is more of academicinterest. A culture of the duodenalaspirate in chefs can help to detectcarriers amongst them. Other

materials which can be culturedinclude bile, rose spot discharge,

pus from a suppurative lesion, andCSF or sputum, if the patient hascomplications. At autopsy, culture

from the liver, spleen, gall bladder,and mesenteric lymph nodes is alsopositive.2

In a study24 of 36 patients with ba cter io lo gi ca ll y proven en te ri cfever, culture of duodenal contents(obtained with string capsules) was

found to be as sensitive in diagnosisas bone marrow culture and moreeffective than blood and stoolcultures in recovery of S. typhi.The sensitivity of duodenal content

culture was not affected by theduration of illness or antibiotictherapy. Even on the seventh day ofantibiotic treatment, the duodenalcontent culture was positive in

eight of 17 patients, whereas stoolculture was positive in only two ofthe same patients.

Apart from good sensitivity,duodenal content culture is simple,

economical and can be performedwith minimal facilities.24 However,

this method is not widely performeddue to poor tolerance of the stringdevice, particularly by children.25

According to a comparativestudy 25 of the various culturemethods, bone marrow culturesremain the most effective method

for the recovery of S. typhi. Stoolcultures appear to be more effectivein children than in adults, while

duodenal content cultures offer

little advantage in young (2 to 6years old) children.

Molecular diagnostics

P o l y m e ra se c ha i n re a c t i o n(PCR):

PCR is a promising test, whichis as sensitive as blood culture, butless specific.18 It has been found to

be >90% sens it ive and re latively

simple to perform. Moreover, itcan amplify DNA from dead orunculturable bacteria, providingan additional sensitivity benefit.However, it seems to have limited

potential for the diagnosis ofenteric fever. In the absence of anyvalidated PCR test, the in-housesystems current ly in use are

open to differing interpretationand do not meet the rigorousqual i ty control s tandards forworldwide acceptance.20 A PCR isquite expensive, costing anything

between ` 3800 and ` 4000 in India.

The experts felt that PCR maynot satisfy the criteria of a ‘gold

standard’ for the diagnosis ofenteric fever in terms of sensitivityand spec i f i c i ty , s ince i t doesnot cover all the antigens of the

disease. Only antigens 14, 15 and18 are picked up by one PCR test.Moreover, this test is not availablein remote and peripheral areas. Theparticipants also echoed the samesentiments, as they added that the

PCR is hardly ever used for thediagnosis of enteric fever in India.2

N e s t e d p o l y m e r a s e c h a i nreaction:

A nested polymerase chainreaction is more sensitive than PCR

and uses H1-d primers to amplifyspecific genes of S. typhi in the

blood of patients.18 It involves tworounds of PCR using two primers

with different sequences withinthe H1-d flagellin gene of S. typhi ,offering the best sensitivity andspecificity. 16

It is a promising rapid diagnosistest, with potential to replace bloodculture as the new gold standard.18

It is so sensitive that it can detect

even one bacterium in a given

sample within a few hours.26

Due to its high sensitivity andspecificity, nested PCR can serve asa useful tool to diagnose clinicallysuspected, culture negative casesof enteric fever.27

Benefits of nested PCR27

• S e n s i t i v i t y o f 1 0 0 % a n dspecificity of 76.9%

• Higher case detection comparedto blood culture even in the

later stages of the disease (53.8vs. 46.1%)

• Can be used as a diagnostic toolin any stage of the disease

• Not affect ed by empiri calantibiotic therapy unlike blood

culture. Hence, can serve as

an effective diagnostic testeven after the initiation ofantimicrobial therapy.

Serological tests

S e r o l o g i c a l t e s t s a r e t h emainstay of diagnosis of entericfever in developing countries. 21

S. typhi is known to express anumber of immunogenic structures

on its surface. Among them, O(liposaccharide), H (flagella), andthe somewhat less immunogenicVi capsule can be identified byserological tests. S. typhi expressing

O (O9, O12) , Vi , and H:d areabundantly present in most endemicareas.20 All the participating doctorsunanimously expressed the same

view that although the Typhidot,IgM Dipstick, and IDL Tubex testsare promising tests, they are stillnot being used routinely in India.

Widal test:

According to the World HealthOrganization, Widal, the most

widely available test in India,should not be done before oneweek of the onset of fever. Evenif it is positive before one week, itmight be a false-positive. With the

availability of other highly reliabletests, the importance of Widal hasdeclined. A single Widal has novalue. It may be obsolete; but inthe absence of any other reliable

modality, it may be done.2

Wi da l i s the m o st wi de l y

used test in many regions as it is


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relatively cheaper, easy to perform,and requires minimal training andequipment. The test is based onthe demonstration of a rising titerof antibodies in paired samples 10

to 14 days apart. It uses O and H

antigens of S. typhi, S. paratyphi A,S. paratyphi B and S. paratyphi C todetect antibodies in blood.28 At least

1 ml of blood should be collected toobtain a sufficient amount of serum.Usually O antibodies take 6-8 daysto appear and H antibodies 10-12days after the onset of disease.3

In acute enteric fever, therefore,the anti-O antibody titer is thefirst to rise, followed by a gradual

increase in anti-H antibody titer.

The anti-H antibody responsepersists longer than the anti-Oantibody.29

According to a study conductedin Nepal,29 a presumptive diagnosisof enteric fever can be made ifsignificant titers are greater than

1:80 for anti-O and greater than1:160 for anti-H.

However , i t i s di f f i cul t to

pinpoint a definite cut-off fora positive result since it varies

between areas and between timesin given areas.3 A fourfold rise in

antibody titer in a paired serum isconsidered more diagnostic.21

Widal has a sensitivity of 47-77%

and specificity of 50-92%.18 Whilea negative Widal test has a goodpredictive value for the absence ofthe disease, a positive result is seento have a low predictive value for

its presence.28

Advantages of Widal

Inexpensive

3

Good for screening a largenumber of patients in endemic

areas despite mixed results18

Use of slides instead of tubesgives results faster — in only a few

minutes19

Limitations in use

Standardization and qualityassurance of reagents may berequired18

M o d e r a t e s e n s i t i v i t y a n d

specificity3

The sensitivity, specificity, andpredictive values differ in differentgeographic areas26

Negative in 30% of cultureproven cases of enteric fever3

Prior antimicrobial treatment

may adversely affect the antibodyresponse3

F a l se - p o s i t i ve re su l t s m a y

be o bta ine d in othe r c l i n ica lconditions, such as malaria, typhus,

bacteremia and cirrhosis3

May lead to overdiagnosis ifrel ied upon solely in endemicareas28

Widal need not be performedif the diagnosis has already been

confirmed by the isolation of S.typhi from a sterile site.3 While atube Widal in India costs around

` 110 to ` 170, the slide Widal ispriced a bit higher between ` 150and ` 200.

Typhidot:

Typhidot is a rapid-dot enzymeimmunoassay (EIA) that takesabout three hours to perform.3 Itdetects IgG and IgM antibodies toa specific 50 kD outer membranep ro te i n ( O MP ) a nt i g e n o f S .typhi.21 Detection of IgM signifies

acute enteric in the early phase ofinfection while detection of bothIgG and IgM indicates acute entericin the middle phase of infection.3

The test becomes positive rightin the first week of fever and theresults are available within onehour. Thus, it is faster than bloodculture and Widal, in which results

take 48 and 18 hours, respectively.

In addition, this test is simpler and

more reliable than Widal.21

Its simplicity, speed, sensitivity(95%), specif ic i ty (75%), cost-effectiveness, abi l i ty to detectantigens early, and high negativeand positive predictive values make

Typhidot an efficient diagnostictool in resource-poor countries.3

Typhidot, the experts felt, is an

alternative to Widal, but is far morereliable. It is available even in tier 3cities, so it can be easily prescribed.

It becomes positive in the first week

itself. Typhidot-M is done in casesof acute infection.2 A Typhidot inIndia costs between ` 300 and ` 400.

Limitations in use3

IgG can persist for more thantwo years after typhoid infection.

Hence, detection of only IgG cannotdifferentiate between acute andconvalescent cases.

Previous infection may lead to

false positive results.

Typhidot- M:

Typhidot-M is a modi f ied,improved version of Typhidot,obtained by inactivating totalIgG in the serum sample, which

removes competitive binding and

allows access of the antigen to thespecific IgM, thereby enhancingdiagnostic accuracy. If specific

IgM is detected within three hours,it points towards acute typhoidinfection.3

Advantages

Superior to culture methodin terms of sensitivity (>93%),negative predictive value, and

speed3

Can replace Widal when used

along with culture method, forrapid and accurate diagnosis ofenteric fever3

High negative predictive valuemakes it useful in areas of highendemicity.3

Being rapid, easy to perform andreliable, it is suitable for entericendemic countries30

Latex agglutination test:

Studies on the efficacy of thelatex agglutination test (LAT) have

shown that:With a sensitivity of 100%,

specificity of 97.6%, and positiveand negative predictive values of

90.9% and 100%, respectively, LATcan be used for the presumptivediagnosis of enteric fever in remotehealth centers31

LAT could detect the antigen in100% of the sera of patients withnegative blood culture and positive

Widal, indicating better sensitivity

as compared to blood culture32


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LAT can be used for rapiddiagnosis of enteric fever thoughit cannot replace conventional

blood culture required for isolationof organism to report the antibioticsensitivity33

IDL Tubex test:

Tubex is an antibody-detectiontest that is user-friendly and can

be used at the point of care.19 Thissimple one-step rapid test can beperformed in just two minutes. 3 The test is as simple and fast asthe slide latex agglutination tests

but has been modified to improvethe sensitivity and specificity to75-85% and 75-90%, respectively.19 The O9 antigen used in the test is

extremely specific, and can detect

IgM O9 antibodies within minutes.A positive result is a definiteindicator of a Salmonella infection.3

As Tubex detects only IgMantibodies and not IgG, it is highlyuseful for the diagnosis of currentinfections, and performs better than

Widal, both in terms of sensitivityand specificity.3

Limitation in use

N e g a t i v e r e s u l t s m a y b eobtained in patients infected by

other serotypes, such as S. paratyphi A3

IgM dipstick test:

IgM dipstick test is based on thedetection of S. typhi-specific IgM

antibodies in serum or whole blood

samples.

Specific antibodies appeara week after onset of symptoms andsigns — this fact should be kept in

mind while interpret ing a negativeserological test.3

Advantages3

Requires no formal training,specialized equipment, electricityor cold storage facilities

Results are available the sameday, enabling prompt initiation oftreatment

Fast and simple to performIdeal for places with no culture

facilities

T a b l e 2 g i v e s t h e l i s t o ftests according to the week ofpresentat ion. The tests have been

categorized as feasible and non-feasible. The non-feasible testsinclude those that are expensive,no t e a s i l y a va i l a b l e , r e q u i re

specialized equipment, or are nottolerated.

It must be borne in mind that

tests are indicated after all theother febrile conditions have beenruled out.

Newer tests

Newer tests in the pipel ineinclude salivary IgM test, moleculari m m u no l o g y - ba se d te s t s a nd

nanotechnology-based tests.2

Screening for Carriers

Ente r i c f e ve r c o nt i nu e s tohave a high incidence due to thedissemination of the disease via

carriers.22 This calls for urgentmeasures to detect carriers asthey are a si lent threat to thecommunity.20 An ideal test forcarriers should be rapid, specific,

as well as sensitive.22 One such

measure is monitoring S. typhi in the stool. However, this may

be hamstrung by low level orsporadic shedding and the fact

that routine stool sampling may be expensive, t ime consumingand unpopular. Another optionis based on the observation that

enteric fever carriers may producehigher levels of Vi antibodies overextended periods compared toacutely infected patients. Hence,

development of simple, cheap, andnon-invasive Vi antibody assaysmay be of great help in identifyingcarriers.20

Current Approaches in the

Treatment of Enteric Fever

in India

With time, the treatment ofenteric fever is not only becoming

more complicated, but also costly, because of increased res istance to

the commonly used antibiotics inthe Salmonella enterica species.34

C h a r a c t e r i z e d b y a l e n g t h yincubation period, nonspecificsymptoms that are diverse innature, and complications thatcould threaten life, the disease

only adds to the financial burdenof individuals and maintains thepoverty cycle. It is estimated thatnearly 22 million new cases ofenteric fever develop every year,

the mortality rate being higher in

Table 2: Investigations according to week of presentation

Week of illness Feasible tests Non-feasible tests

1st week Hematological tests Eosinopenia17,18

Blood culture20

Typhidot/Typhidot-M 3

Widal (basal)28

Bone marrow culture3

PCR20

Duodenal aspirate culture25

Dipstick3

2nd week Hematological tests Leukocytosis17,18

Blood culture20

Stool culture18


Widal (basal or repeat – to see rising titer)28

Bone marrow culture3 Rose spot culture16

PCR20

Tubex3


Dipstick3

3rd week Hematological tests17,18

USG abdomen (hepatosplenomegaly)2

Blood culture20

Stool culture18

Widal (very high titer)28



PCR20

Tubex3


Dipstick3

4th week Hematological tests17,18

USG abdomen2

Blood culture20

Stool culture18

Widal (very high titer)28



PCR20

Tubex3


Dipstick3


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effectiveness. However, decreasedciprofloxacin susceptibility (DCS)

is now being seen. Since the 1990s,azithromycin has been showinggood results and is a promisingalternative to fluoroquinolones andcephalosporins.35

Drugs Recommended by the Expert

Panel for the Management of Enteric

Fever

After going through treatment

recommendations by the WorldHealth Organization (WHO), theAssociation of Physicians of India(API), and the Indian Associationof Pediatrics (IAP), the expert

advisory panel concluded thatthere was a need to s impl i fythe choice of the drugs in thetreatment of enteric fever. Theyunanimously declared that the

f luoroquinolones (espec ia l ly ,

ciprofloxacin and ofloxacin) and

cephalosporins (specifically thoseof the third and fourth generation)

are recommended for use as thefirst-line therapeutic agents.2

T a b l e 3 l i s t s t h e d r u g srecommended by the panelists forvarious patient populations, basedon the severity of their condition,r e s p o n s e t o t r e a t m e n t , a n dpossibility of antibiotic resistance

in them. They emphasized on theneed for doctors to titrate the doseof the antibiotics in every case,

base d on the pa tient’s ag e an d body weight. All of them agreed to

the fact that it is better to slightlyoverdose the patient rather thanunderdose the patient, when tryingto adjust the dose of the antibiotic

for the patient, bearing in mind thestrengths available in the market.Thus, i f the dose requirement

calculated for a patient amounts to

Table 3: Treatment of enteric fever2

Susceptibility Patient Antibiotic Dosage

Uncomplicated enteric fever

Quinolonesensitivity areas

Adult Responders: Fluoroquinolones, namely Ciprooxacin or Ooxacin 15 mg/kg body weight/day × 10 days

OR 3rd Generation Cephalosporin like Cexime 15-20 mg/kg body weight/day × 10 days

Nonresponders: Chloramphenicol OR 50-75 mg/kg body weight/day × 14 days

Amoxicillin 75-100 mg/kg body weight/day × 14 daysChild Responders: 3rd Generation Cephalosporin like Cexime 15-20 mg/kg body weight/day × 10 days

Nonresponders: Chloramphenicol OR 50-75 mg/kg body weight × 14-21 days

Amoxicillin 75-100 mg/kg body weight × 14 days

Quinoloneresistance areas

Adult Responders: Cexime 20 mg/kg body weight/day × 14 days

Nonresponders: Azithromycin 10-20 mg/kg body weight/day × 7 days

Child Responders: Azithromycin 10-20 mg/kg body weight/day × 7 days

Nonresponders: Cexime 15-20 mg/kg body weight/day × 14 days

Complicated enteric fever

Quinolonesensitivity areas

Adult Responders: 3rd and 4th Generation Cephalosporins like

Ceftriaxone 60 mg/kg body weight/day IV × 14 days

Cefotaxime 80 mg/kg body weight/day IV × 14 days

OR Fluoroquinolone like Ciprooxacin or Ooxacin 15 mg/kg body weight/day IV × 14 days

Nonresponders: Chloramphenicol 100 mg/kg body weight/day IV × 14-21 days

Ampicillin 100 mg/kg body weight/day IV × 14 days

Child Responders: Ceftriaxone or Cefotaxime 50-75 mg/kg body weight/day IV × 14 days

Nonresponders: Chloramphenicol 100 mg/kg body weight/day IV × 14-21 days

Amoxicillin 100 mg/kg body weight/day IV × 14 days

Quinoloneresistance areas

Adult Responders: Ceftriaxone or 60 mg/kg body weight/day IV × 14 days

Cefotaxime 80 mg/kg body weight/day IV × 14 days

Nonresponders: Fluoroquinolone 20 mg/kg body weight/day IV × 14 days

Child Ceftriaxone or Cefotaxime 50-75 mg/kg body weight/day IV × 14 days

bid: twice daily; qid: four times daily; tid: three times daily; IV: intravenously; PO: orally; TMP-SMX: trimethoprim-sulfamethoxazoleAdapted from1. Bhua ZA. Current concepts in the diagnosis and treatment of typhoid fever.BMJ 2006; 333:78-82.2. World Health Organization (WHO) Department of Vaccines and Biologicals. Background document: The diagnosis, prevention and treatment

of typhoid fever. Geneva: WHO; 2003:19-23. Available at: hp://www.who.int/vaccine_research/documents/en/typhoid_diagnosis.pdf; and3. Kundu R, Ganguly N, Ghosh TK, Yewale VN, Shah RC, Shah NK. IAP Task Force Report: Diagnosis of enteric fever in children. Indian Pediatr 2006; 43:884-7.

young children from low-resourceareas.4

History of Antibiotic Therapy in Enteric

Fever

C h l o r a m p h e n i c o l w a s t h edrug of choice for the treatment

of enteric fever since 1948, butplasmid-mediated resistance andits rare side-effect of bone marrow

aplasia put it behind on the shelf.This was followed by the use oftrimethoprim-sulfamethoxazole

a nd a m p i c i l l i n i n the 1 9 7 0 s ;however, their rampant use ledthe pathogen to get resistant tothem. In the 1980s, ceftriaxoneand ciprofloxacin proved to be

e f f e c t i ve a g a i ns t m u l t i dru g -resistant (MDR) strains of S. typhi ,and were therefore the drugs ofchoice. Ciprofloxacin and ofloxacinwere preferred to ceftriaxone

due to their oral use and cost-


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Table 4: List of red flag symptoms in

enteric fever36

Involvement Symptoms

Central nervoussystem

Headache, vomiting,seizures, altered states ofconsciousness, papilledema,and focal neurologicaldecits

Cardiovascularsystem

Chest pain, palpitations,new murmur or change incharacteristics of a previousmurmur, cardiacarrhythmias

Respiratorysystem

Chills, cough (with orwithout sputum), pleuriticpain, coarse crackles, and bronchial breathing

Musculoskeletalsystem

Local tenderness, rigidity,and pain giving rise toa loss of functionality inthe aected limb; acuteswelling and pain in jointswith or without an eusion

Gastrointestinalsystem

Jaundice, nausea, vomiting,and abdominal pain

Genitourinarysystem

Dysuria, frequency, andsuprapubic or pelvicdiscomfort

600 mg/day, it is advisable to givehim 750 mg instead of 500 mg. 2

When factors such as intoleranceto oral drugs, dehydration, extremesof age, and associated comorbid

conditions are present, parenteral

treatment should be instituted.Once the condition of the patientstabilizes, s/he should gradually

be de -e sc alated from pa re nt eral

therapy to oral drugs. With thedefervescence period usually beingabout 5 days, any patient who isnot responding adequately may beswitched to a different drug after

stopping the first, or the seconddrug may be added to the first one.2 However, at any point during thecourse of the illness, patients may

develop symptoms of developingcomplications, which should serveas red flags for the treating doctor.The important red flag symptomshave been listed in Table 4.36

Cephalosporins:

Cefixime, cefpodoxime proxetil,cef ipime, and ceftriaxone areexpanded-spectrum cephalosporinsthat have been very promisingin the management of enteric

fever. While the former two are

administered orally, the latter

two are given parenterally. Thefavorable pharmacokinetic profileof cefpodoxime proxetil allowsfor i ts twice dai ly dosing. In

past studies, all the 50 strainsresponsible for enteric fever werefound to be sensitive to ceftriaxone,cefixime, and cefpodoxime.37 The

minimum inhibitory concentration(MIC) of a drug can help to predictits efficacy. When a drug is given

in an appropriate dosage on the ba si s of so und ph armaco ki ne ti c

and pharmacodynamic principles,a clinical cure is facilitated byeradication of the pathogen’scarrier status and prevention of

resistance to the antimicrobialdrug.38 A study that tested theef f i cacy of cephalosporins inthe treatment of enteric feverfound that the MIC

50 and MIC

90

of cefotaxime, a parenteral third-generation cephalosporin, wasthe least in comparison to the oralthird-generation cephalosporin

c e f i x i m e a nd the p a re nte ra lfourth-generation cephalosporincefipime.37

Cefpodoxime and cefixime have be en used exte nsively in ente ricfever. Although cefpodoxime haswide applications in pediatricinfec t ious diseases , i t hasn’ t

b e e n u s e d m u c h i n e n t e r i cf e v e r ; t h o u g h i t i s s i m i l a r

pharmacological ly to cef iximeand cheaper than cefixime. In 140children assessed for suspected

e nte r i c f e ve r , a c o m p a ra t i vestudy showed that cefpodoximereduced treatment cost by 33%in comparison to cefixime, and isalso a safer oral option in children.

The two groups showed a similarclinical response with comparableperiods to defervescence in daysand clinical cure rates. The MIC for

cefpodoxime against all Salmonella

typhi isolated (n = 40) was


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than 7 days with azithromycin, beca us e this drug has stro nge rtissue penetration and accumulates

in the gall bladder. Thus, while a5-day course of azithromycin may

be considered to be an equivalentto a 10-day course of any other

antibiotic, a 7-day course of thesame is as good as another druggiven for 14 days.2

When compared to intravenousceftriaxone (75 mg/day; maximum2 . 5 g / da y ) da i l y f o r 5 da y s ,oral azithromycin (20 mg/kg/day;maximum 1000 mg/day) achieved

an almost similar cure rat (97%

vs. 94%) (Figure 7). No patienton azithromycin had a relapse,whereas few relapses were seenwith ceftriaxone.43

Azithromycin and ofloxacin werecompared for safety and efficacy in

40 patients with uncomplicatedenteric fever.

Group I : Pat ients receivedofloxacin 200 mg oral ly twice

daily for 7 days. Nineteen out of 20patients from group I were cured

with a mean fever clearance timeof 3.68 days

Group II : Patients receivedazithromycin orally 1 g on day 1and then 500 mg daily from day 2to day 6. All 20 patients from group

II were cured with a mean feverclearance time of 3.65 days.

Ofloxacin and azithromycin are

almost equally efficacious and safein enteric fever, and azithromycincould be used as an alternative

when ofloxacin is contraindicated,

as in children, pregnant women,

and quinolone-resistant cases ofenteric fever.44

Single vs. Multiple Drug Regimens

The expert panelists declared thatthere are no clear-cut guidelines for

the employment of monotherapyand combination therapy. Sinceit is not possible to tell whether apatient is going to respond to thetreatment or not on the very first

day, it is advisable for the clinicianto use his experiences with otherpatients in and around the area topresume resistance or sensitivity toa particular drug. Although culture

and antibiotic sensitivity would bedesirable in all cases, most doctors

depend on the clinical signs andsymptoms when treating patientsof enteric fever and refer them to

a tertiary care center, wheneverthe development of complicationsis suspected. If a patient doesnot seem to be responding tothe first-line drugs by day 5 of

treatment, an alternative treatmentopt ion should be considered.Combinat ion therapy may beconsidered when monotherapy

fails. Usually, a fluoroquinolone

is the first drug of choice. If theresponse is found to be inadequate,the oral cephalosporin, cefixime,is added. If the improvement in

the patient is still not satisfactory,the former drug is withdrawnand azithromycin is added. Anumber of doctors use f ixed-dose combinations these days;

however, the panel of experts didnot encourage their use, as theselack flexibility in dosing. 2 The

emergence of MDR S. typhi andconcerns about a delayed responseto quinolones has resulted in alot of anxiety among treatingp hy s i c i a ns . T he re ha ve be e n

several takes on the usage ofsingle versus multiple therapies.While some advocate it, othersrecommend their usage only inunresponsive cases. A comparative

Indian analysis was done in 62cases of enteric fever proven by

blood culture, out of which 59%

received a single drug (ei ther

a quinolone or cephalosporin);

and 40.3% cases received 2 drugssimultaneously. The duration offever from the beginning of theillness to the time of defervescence

was 13.54 days and 13.84 days in

the single-drug and multiple-druggroups, respectively. The meanduration for defervescence afterinitiation of antimicrobial therapyin the single-drug group was 5.24

days; and in the multidrug group,it was 4.32 days. There was nosignificant difference in the totalduration of fever or the time takenfor defervescence after initiation

of therapy in the single-drug andmultidrug groups. This reinforcesthe traditional recommendation

of treatment of enteric fever withone drug at a time. Treatmentwith a single drug is sufficient inenteric fever, and administration ofmultiple drugs should be restrictedto unresponsive cases.45

Role of Surgery

Enteric fever perforation isa common surgical emergencyin developing countr ies , but

optimal operative managementis debatable.46 Primary ileostomy

has been shown to be a bettersurgical option in comparisonwith others and can be a l i fe-

saver, particularly in patientswho present late in the course ofillness with rapidly deterioratinghealth.47 Enteric perforation should

always be treated surgically, andtimely surgery within 24 hours,with adequate and aggressiveresuscitation, decreases morbidityand mortality.48 The panelists also

addressed the issue of the typeof surgery that should ideally

be adopted to ope rate on sucha perforation. They concludedthat if CT imaging has helped to

detect the exact site of perforation,l a p a ro sc o p i c su rg e ry c a n beperformed; however, if the site hasnot been identified, then an opensurgery is advisable.2

Antibiotic Resistance

As seen earlier, the mainstay ofenteric fever management is the

use of antibiotics for empiric or

Fig. 7: Azithromycin vs.

ceftriaxone in enteric

fever43

Azithromycin Ceftriaxone

Antibiotic used

C

u r e r a t e ( % )

100

90

80

60

40

20

0


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directed therapy. Improper use

of antibiotics, especially broad-spectrum antibiotics can leadto emergence of resistance. Thecommonest factors that lead toantibiotic resistance are the misuse

and overuse of these drugs.49 Are-emergence of chloramphenicol

susceptibility in S. enterica serovartyphi isolates has been witnessedin some regions of India, where the

susceptibility has been found to beas high as 95%. Investigators havesuggested using chloramphenicol,along with the third-generationcephalosporins in enteric fever due

to ciprofloxacin-resistant S. enterica serovar typhi infection.50 Resistanceto fluoroquinolones has led to anincreased use of azithromycin and

third-generation cephalosporins.There are worldwide reports ofhigh level resistance to expanded-s p e c t r u m c e p h a l o s p o r i n s( e . g . c e f t r i a x o ne ) . Sp re a d o f

such resistance would furtherg r e a t l y l i m i t t h e a v a i l a b l etherapeutic options, with onlyr e s e r v e a n t i m i c r o b i a l s l i k ec a r b a p e n e m a n d t i g e c y c l i n e

be in g le ft as po ss ib le tre at me ntopt ions .50 It is suggested thatquinolones and third-generation

cephalosporins should be used asfirst-line antimicrobials in entericfever. The use of fourth-generationcephalosporins should be restrictedto complicated or resistant cases.51

Relapse of Enteric Fever

There are several factors, which

are associated with relapse ofculture-proven enteric fever asseen over 15 years in 1,650 childrenin MDR strains in South Asia.

Despite the drop in the morbidity

and mortal i ty associated with

enteric fever due to the adventof antibiotics, relapses continue

to occur in up to 10% of thepatients, even though they areimmunocompetent. Patients withdrug-resistant enteric fever whoreceived ineffective therapy have

a relapse rate, which is almost

twice that of those infected withpan-sensitive strains (Table 6).

Diarrhea is associated with lower

relapse rates in children infectedwith pan-sensitive enteric fever.Those infected with MDR strainshave a higher relapse rate whenpresenting with constipation or

starting specific therapy within14 days of fever onset. The useof quinolones or cephalosporinsas part of the treatment course

p r o t e c t s a g a i n s t s u b s e q u e n trelapse. In those areas where MDRenteric fever caused by S. typhi isprevalent, empirical treatment ofpatients with a cephalosporin or

quinolone should be considered,until infection is caused by a drug-sensitive strain.52

Role of Corticosteroids

The expert panelists emphatically

stated that steroids should beused strictly under supervision byqualified physician.2

When to Refer

Patients with fever that lastsfor more than 7 days should be

investigated for enteric fever,and their blood counts and renalfunction should be evaluated.Referral to a tertiary care centermust be done when there is any

evidence of complications such asencephalopathy, gastrointestinalhemorrhage, glomerulonephritis,m y o c a r d i t i s , p e r f o r a t i o n ,

peritonitis, pneumonitis, severe

dehydration, and shock. Other rarecomplications that serve as red flagsinclude apathy, presence of basalcrepitations, coma, endocarditis,Guillian-Barré syndrome, neuritis,

m e n i n g i t i s , o s t e o m y e l i t i s ,pancreatitis, pericarditis, psychosis,pyelonephritis, and unexplainedtachypnea. It is also advisable torefer the patient in case of any

diagnostic confusion or when s/hefails to respond to the primary orsecondary line of treatment withantibiotics.55

Treatment of Carriers

A person is said to be a chroniccarrier if s/he is asymptomatic,

but his or her stool or rectal swabcul tures test posi t ive for the

presence of S. typhi , a year afterrecovery.22 There are basicallythree types of carriers, namelyconvalescent carriers, who continueto shed bacilli in their feces for

3 weeks to 3 months; temporarycarriers, who sheds bacilli formore than 3 months up to a year;and chronic carriers, who shed

bacill i for more than a year.56 TheVi (virulence) antibody test is of

value when screening for carriers.The WHO recommends the use ofciprofloxacin 750 mg twice daily

for 4 months or 52 weeks. It is notrecommended for use in pregnantwomen. It may be used in childrenonly if the benefits outweigh therisks. If there is cholelithiasis,

cholecystec tomy is indicated.Schistosomiasis, if present, should

be treated.54

Management Guidelines

The IAP task force has made thefollowing statements:53

The timely and appropriatemanagement of enter ic fever

reduces morbidity and mortality.

General supportive measuressuch as the use of antipyretics,m a i n t e n a n c e o f h y d r a t i o n ,

appropriate nutrition, and promptrecogni t ion and treatment ofcomplications ensure a favorableoutcome.

In areas of endemic disease, 90%

Table 6: Relapse rate categorized by bacterial drug resistance and antimicrobials

used52

Initial therapy of exclusivelyampicillin, chloramphenicol,or TMP-SMX

Partial or full initial therapywith cephalosporins orquinolones

Resistance prole Cases of relapse/total number of cases (%) p value

Pan-sensitive 47/559 (8.4) 25/377 (6.6) 0.32Partial drug resistance 3/71 (4.2) 4/86 (4.7) 1a

Multidrug resistance 5/31 (16.1) 23/506 (4.5) 0.018a

All patients 55/661 (8.3) 52/969 (5.4) 0.018aFisher’s exact


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or more of enteric fever cases can be

managed at home with proper oralantibiotics and good care.

Close follow-up is necessary to

detect complications or failure totherapy.

Na l i d i x i c a c i d- re s i s ta nt S .typhi (NARST) species usuallydemonstrate reduced susceptibilityto fluoroquinolones.

Third-generation cephalosporins

a r e r e c o m m e n d e d f o r f i r s t -line treatment. While cefiximeand cefpodoxime proxeti l areadministered orally, ceftriaxone,

cefotaxime, and cefoperazone

are given parenterally. Of these,

ceftriaxone is the most convenientto use . Ora l thi rd-generat ion

cephalosporins need to be given inhigher doses to treat enteric fever.

Azithromycin is a preferredalternative agent in uncomplicatedenteric fever.

Aztreonam and imepenem are

potential second-line drugs.

For life-threatening infectionsresistant to all other recommendedantibiotics, fluoroquinolones may

be used.

Following are recommendations by the WHO:54

Culture and sensitivity tests

should be used to guide the choiceof antibiotics.

F l u o r o q u i n o l o n e s a r e t h e

optimal choice for the treatmentof enteric fever in all age groups.

In areas where the bacterialspecies is still sensitive to traditional

first-line drugs (chloramphenicol,a m p i c i l l i n , a m o x i c i l l i n , o rtrimethoprim-sulfamethoxazole),and f luoroquinolones are notavailable or affordable, these drugs

remain appropriate for treatingenteric fever.

S u p p o r t i v e m e a s u r e s l i k e

oral or intravenous hydration,antipyretics, appropriate nutrition,and blood transfusions are also

important. Electrolyte imbalances,anemia, and thrombocytopenia also

need to be corrected.

People infected with entericfever, or exposed to someone

infected with enteric fever, MUSTNOT be permitted to work if theirwork involves food handling orcaring for children, patients or theelderly, and should not prepare

food for others.

As enteric fever can be carried

on the hands it is very important towash hands thoroughly after usingthe toilet and before handling food.Hands should be washed with soapand water for at least 15 seconds,rinsed and dried well.

Prevention of Enteric Fever

Primary as well as secondarystrategies need to be adopted inthe prevention of enteric fever and

its complications. While secondary

prevention stratagems attempt toreduce the morbidity and mortalityassociated with the disease, theprimary prevention approaches

entail measures that help to avoidgetting infected completely orat least prevent overt c l inicalmanifestations of the disease.57

Secondary Prevention

The aim of secondary preventionis to decrease the clinical severity ofenteric fever and its complications,

so that it doesn’t prove to be fatal.

Table 7: Five key steps to safer food54

Key step Explanation

Keep clean Why? Dangerous microorganisms are widely found in soil, water,animals, and people. These are carried on the hands, cloth usedfor wiping, utensils, and cuing boards; and the slightest contactcan transfer them to food and cause foodborne diseases.

How? Hands should be washed before handling food, during foodpreparation, and after using the toilet. All surfaces and equipmentused for food preparation should be washed and sanitized.Kitchen areas and food should be protected from insects, pests,and other animals.

Separate rawand cookedfood

Why? Raw food, especially meat, poultry, and seafood, and their juices,can contain dangerous microorganisms that might be transferredonto other foods during food preparation and storage.

How? Raw meat, poultry, and seafood should be separated from otherfoods. Equipment and utensils such as knives and cuing boardsshould be kept separate for handling raw foods. Food should bestored in containers to avoid contact between raw and preparedfoods.

Cookthoroughly

Why? Cooking food to a temperature of 70°C kills almost all dangerousmicroorganisms and ensures that it is safe for consumption. Foodsthat require special aention include minced meats, rolled roasts,large joints of meat, and whole poultry.

How? Food should be cooked thoroughly, especially meat, poultry, eggs,and seafood. Soups and stews should be boiled till 70°C. Meat andpoultry should not be pink. Ideally, the use of a thermometer isadvocated.

Keep at safetemperatures

Why? Microorganisms can multiply very quickly if food is stored atroom temperature. By keeping the temperature below 5°C orabove 60°C, the growth of microorganisms is slowed down orstopped. Some dangerous microorganisms still grow below 5°C.

How? Cooked food should not be kept at room temperature for morethan 2 hours, and should be refrigerated promptly. Cookedand perishable food should be preserved preferably below 5°C.Cooked food should be kept piping hot (more than 60°C) prior toserving. Food should not be refrigerated for too long and frozenfood should not be thawed at room temperature.

Safe waterand rawmaterials

Why? Safe water should be used or it should be treated to make it safe.Fresh and wholesome foods and pasteurized milk should beconsumed. Fruits and vegetables should be washed properly,especially if eaten raw. Do not use food beyond its expiry date.

How? Raw materials, including water and ice, may be contaminatedwith dangerous microorganisms and chemicals. Toxic chemicalsmay be formed in damaged and moldy foods. Care in theselection of raw materials and simple measures such as washingand peeling may reduce the risk.


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The judicious use of efficacious

antimicrobials early in the diseaseis the most important component

of secondary prevention. Whenprescribing antibiotics for patientswho have acquired the infectionfrom regions where S. typhi speciesare mul t idrug res is tant , i t i s

advisable to select the drug, basedon the most current reviews.57

Primary Prevention

Environmental measures toensure the supply of treated water

along with proper sanitation,

identification of chronic carriersof enteric fever to break the chainof transmission of the disease, andvaccination of susceptible hosts

in order to make them immuneto the organism, constitute thethree main approaches for primaryprevention. Unfortunately, owingto cost implications, many parts of

developing countries continue tohave poor sanitation facilities anddrink water that is not potable.57

Need for adequate sanitation

and uncontaminated consumables:

Chlorination of drinking waterat home should be advocated. Thetreated water should preferably

be st or ed in a na rr ow -m ou the dvessel and drawn out by tilting the

container or using a tap to avoidcontamination. People should beencouraged to use latrines at homeand the disposal of wastes must bedone in closed sewerage systems.

Raw fruits and vegetables should be washe d thor ou gh ly , an d th elatter should preferably be cooked

before consumption. Hygienicpractices should be adopted in the

storage of milk and the preparationo f m i l k p r o d u c t s . S t u d i e sshould be done by the publichealth department to ascertainthe quali ty of drinking water

being supplied to the community.Surveillance by hospitals can helpto evaluate the effectiveness of suchinterventions.58

The World Health Organization

(WHO) has suggested some tips for

safer food, which have been listedin Table 7.54

Identifying and treating chronic

carriers:

Chronic carriers of the pathogenresponsible for the development ofenteric fever can cause localized

or sporadic cases of the disease,particularly if they handle foodthat is consumed by others. Onceidentified, they should be taken

away from these situations. Sincenearly 90% of chronic carriersdemonstrate high titers of serumVi antibodies, serological tests todetect the same can be useful for

screening. Doing stool culturesrepeatedly after inducing strong

purgation can also serve thispurpose. Several weeks of oralc i p ro f l o x a c i n o r no r f l o x a c i n

t h e r a p y h a s b e e n s h o w n t oeradicate the carrier state in up to90% of the cases, without the needfor cholecystectomy, which used to

be advocated in the past.57

Vaccination:

The use of affordable vaccinesseems to be the most lucrativeprophylactic intervention. In spite

of the fact that the first vaccine fortyphoid was introduced by Wrightway back in 1896, its effectivenesswas established through controlledfield trials nearly seven decadeslater. Vaccination against typhoid

as a routine is not required incountries where high sanitationstandards are in place. However,its administration is recommendedfor individuals travelling to areas

of the world where typhoid isendemic, people who are in close

contact with a chronic carrier oftyphoid, and laboratory staff thathandle samples containing S. typhi

bacteria . The standard old typhoidvaccines included a monovalentvaccine (containing only S. typhi),a bivalent vaccine (containing S.typhi and S. paratyphi A) and the

traditional typhoid paratyphoid Aand B (TAB) vaccine (containing S.typhi , S. paratyphi A , and S. paratyphiB). As of now, only two types of

typhoid vaccines are available in

Table 8: Comparison of the Vi-PS and Ty21a vaccines59

Parameter Vi-PS Ty21a

Type of vaccine Polysaccharide Live aenuated

Route ofadministration

Parenteral Oral

Formulations Liquid for injection Enteric-coated tablets and suspension

Content per dose 25 µg of the antigen 2 × 109 bacteriaNumber of doses Single dose 3 doses every other day

Protective ecacy 60% to 70% within 3 yearsand around 50% after 3 yearsof vaccination

62% and 70% after 7 years of vaccinationwith the enteric-coated tablets and liquidsuspension, respectively

Storage 2-8°C 2-8°C

Thermostability 6 months at 37°C2 years at 22°C

14 days at 25°C

Clinical tolerability Well tolerated; other thanlocal swelling, no majorside-eects such as fever anderythema

Side-eects include fever, rash, headache,abdominal pain, nausea, diarrhea, vomiting,myalgia, sepsis, pain, urticaria, anaphylacticreaction, weakness, and demyelinatingdisease

Safety Safe even in HIV patients Best avoided in HIV patients

Contraindications Children under 2 years ofage Children under 6 years of age, pregnantwomen, and immunocompromised state.

Cost Cheaper Costlier

Interactions None reported Reduced ecacy on concurrent use withantibiotics or IgG and increased ecacywhen given to a patient being treatedwith meoquine; interferes with thediagnostic eect of tuberculin test; alcoholconsumption to be avoided within 2 hoursof taking the vaccine.

Booster dose Every 2 years for people whoremain at risk

Every 3 years for people living in endemicareas; yearly for people traveling toendemic regions


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the Indian market for use clinically,namely the Vi polysaccharide(Vi-PS) vaccine and the Ty21a oralvaccine. A comparison of the two

vaccines has been done in Table 8.59

Since both these vaccines are

safe and do not produce majorside-effects, they are good for

public health and school-basedimmunizat ion programs. Theemployment of these vaccineshas been recommended by theWHO for chi ldren residing in

areas where typhoid is endemicand antibiotic-resistant strains ofS. typhi are present. In 2013, theVi-PS vaccine was licensed forclinical use in lndia by the Drug

Controller General of India (DCGI).The seroconversion rate reportedwith this vaccine has been 98.05%,

but a significant fall in the antibody

titers has been observed after 18months, indicating the need for a

booster dose. The exact t ime framefor administration of the boosterdose can be established only onfollowing-up for a long period.59

A l t h o u g h e n t e r i c f e v e r i scommon in lndia, and there are

concerns about the prevalence

of multidrug resistant strains,the typhoid vacc ine i s beinggrossly underutilized. The use of

vaccines appears to be very cost-effective, considering the financialimplications of diagnosing typhoid

by blood culture, the expenditureson hospitalization and medicines,

and the loss of daily productiveworking hours, as a result of theillness. Therefore, the expert grouprecommends the use of these two

typhoid vaccines routinely inunvaccinated adults, especiallythose who are at high risk.59

The Vi-TT conjugate vaccineis a fourth generation typhoidvaccine that has been indigenouslyd e v e l o p e d b y a n I n d i a n

biotechnological company. Af ter

being tested and analyzed forefficacy and safety in more than athousand individuals belonging todifferent age groups, this vaccinewas launched in Hyderabad in

2013. As evident from the fourfold

increase in the serum IgA responsesof patients, the vaccine evoked aseroconversion of 98% in infants

between 6 and 24 months of age ,99% in children aged 2 to 15 years,

and 92% in individuals belonging

to the 15-45 year age group. It has been shown to be superior to theVi-PS typhoid vaccines and alsohas a good safety profile, being

tolerated by people of all the testedage groups.59

Complications of Enteric

Fever

When patients of enteric feverare left untreated, its complicationsmostly tend to occur in the third

and fourth weeks of infection,the complication rate being ashigh as 15%. The most importantcomplications met with in clinicalpractice include gastrointestinal

bl ee di ng , in te st inal pe rf orat io n, bronchit is , encephalopathy wi thconfusion as a result of toxemia,a nd to x i c m y o c a rdi t i s . 60 The

panelists felt that it is important forthe treating physician to recognizethe various complications of entericfever early and plan his or herline of management accordingly,

because a number of complicationsneed to be managed in a tertiarymedical care center and hencecall for timely referral followed

by the medical management with

appropriate antibiotics along withany surgical interventions, if foundto be necessary.2

They were of the opinion that thecomplications of enteric fever arenot very commonly seen in primary

care setups and at the familyphysician level . Some doctorssee only one or two complicatedcases in a year at t imes, withchi ldren and e lder ly pat ients

being the ones who are more

likely to develop complicationsin comparison with individualsfrom other age groups. They feltthat there is a need for doctors toidentify red flag symptoms like

dehydration, toxemia, al teredsensorium, and abdominal rigidity

and guarding in these patients

early, so that the development ofmajor complications can be averted,and the associated mortality can

be decreased. Physicians alsoneed to look for certain age or

gender specific complications;for example, bronchitis is seenmore often in children, whereasintestinal perforations are morecommon in males.2

Intestinal Complications

T h e g a s t r o i n t e s t i n a lcomplications of enteric fever canrange from something as benign

as glossitis or an esophageal ulcerto a problem that can prove fatalsuch as intestinal perforation or

bleeding. Gastrointestinal bleeding,seen in 10% of the patients, is the

commonest complication; and in 2%of these cases, there may be a needfor blood transfusions.60 Severeuntreated cases of enteric fever areassociated with the development of

intestinal as well as extraintestinalc o m p l i c a t i o n s . S u r g i c a linterventions may be requiredto manage certain complications

involving the small gut, acalculouscholecystitis, perforation of the

g a l l b l a d d e r , o r g a n g r e n e . 61Salmonella cholecystitis, a rarecomplication of Salmonella typhi

infection, presents with high-grade fever, jaundice and right-sided abdominal pain (Charcot’striad). Tender hepatomegaly and adistended gallbladder are the usual

examination findings.62

Intestinal Perforation

The most serious complicationo f e nte r i c f e ve r i s i n te s t i na l

perforation, as the morbidity andmortality rates associated withit are high. An indicator of theendemicity of enteric fever, theincidence of intestinal perforationv a r i e s g e o g r a p h i c a l l y , t h e

perforation rate ranging between0.6% and 4.9% worldwide. Therate of enteric perforation in Indiais higher, owing to factors such asdrought, illiteracy, poverty, and

proliferation of bacterial strainsthat are mul t idrug res is tant .

Youngsters in their second or third


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decade of life are more likely to

develop this complication, as theytend to eat street food more often,practice poor hand hygiene, andneglect their health.63

Ileal perforation is witnessedmore frequently in remote areas

due to a lack of good medicalfacilities. Factors associated with

an increased risk of perforationinclude male gender, leukopenia,short disease duration, presence of

bacterial strains that are multidrugresistant, and incomplete antibiotic

therapy. The treating surgeonusually finds it difficult to managesuch cases, as the patients presentthemselves or are diagnosed lateafter being initially treated by

quacks.63

T he i ndi sc r i m i na te u se o f

glucocorticoids, lack of awareness,poverty, and poor medical andtransportation facilities complicatematters further. While the mortalityassociated with enteric fever-

related perforation ranges from 0to 2% in the developed nations,it is much higher (9 to 22%) inthe developing countries, dueto reasons such as the want of

intensive care, poor resuscitation

facilities, antibiotic resistance,regional taboos, delay in surgery,more perforations, fecal peritonitis,and increased disease duration.63

The clinical features of entericperforation and their incidence

ra te s , a s wa s re p o r te d by aretrospective study of 155 patientswho were operated for intestinalperforation due to enteric fever ina Central Indian district hospital,

have been listed in Table 9. It is

advisable to manage such cases with

timely and appropriate surgical

interventions, safe anesthesia ,

proper operative care, and the useof wide-spectrum antibiotics withlow resistance.63

Gastrointestinal Bleeding

G a s t r o i n t e s t i n a l b l e e d i n g

generally occurs in the third weekas a result of ulceration, whichoccurs due to necrosis in the small

bowels . About 20% of the patients

with enteric fever test positivefor the presence of occult bloodin their stool. Massive bleeding is

very rarely seen, although gross bleeding may be observed in 10%

of the patients. The first signs of bl ee di ng are a su dde n dec re asein the blood pressure and bodytemperature, the former dropping

to 80-90 mmHg or even lower andthe patient going into a state ofshock. Before chloramphenicolwas discovered and used for thetreatment of enteric fever, theincidence rate of perforations was

higher. While perforations usually

occur in the third week of infection,with the distal part of the ileum

being involved most of the times,they can occur even in the first 2

weeks in fulminant cases.60

Bleeding in the gastrointestinal

tract can occur in the form of eitheroccult blood in stool or melena. Inenteric fever, this happens due toerosion of Peyer’s patches into anintestinal vessel. On colonoscopy,

it is seen that the terminal ileum

is the most commonly involved

site, followed by the ileocecal

valve, the ascending colon, and the

transverse colon. The ulcers seenin such cases are usually multipleand punched out in appearance,and their margins are slightly

elevated.64

Extraintestinal Complications

S. typhi infection may at timesmani fest wi th extra intest ina linfectious complications, which can

involve various systems and organsof the body, as shown in Table10. It is important to recognize

these complications, specifical ly inpatients who have just been to an

endemic region and are returninghome. This can help to prevent adelay in the diagnosis of entericfever.36

Hematological Complications

V a r i o u s h e m a t o l o g i c a l

complications have been witnessedin patients suffering from entericfever, such as hemolytic anemia,he m o l y t i c u re m i c sy ndro m e ,and disseminated intravascular

coagulation (DIC). In these patients,the hemoglobin level and plateletcount may be normal or low, buttheir leukocytic count can be low,

normal, or high. Generally, thereis evidence of eosinopenia, andprolongation of the prothrombintime is also detected.60

Neurological Complications

The neurological complication

rates in enteric fever vary (5-35%)in accordance with the extent of

Table 9: Clinical features of enteric

perforation63

Symptom Frequency

Fever 100%

Abdominal pain 100%

Distention 78.06%

Dehydration 76.12%Constipation 73.54%

Vomiting 30.96%

Shock 28.38%

Chest infection 22.58%

Table 10: Extraintestinal complications of enteric fever36

Organ system Prevalence Complications

CNS 3-35% Encephalopathy, cerebral edema, subdural empyema, cerebralabscess, meningitis, ventriculitis, transient Parkinsonism, motorneuron disorders, ataxia seizures, Guillain–Barré syndrome,psychosis

Cardiovascular 1-5% Endocarditis, myocarditis, pericarditis, arteritis, congestiveheart failure

Pulmonary 1-6% Pneumonia, empyema, bronchopleural stula

Bone and joint < 1% Osteomyelitis, septic arthritis

Hepatobiliary 1-26% Cholecystitis, hepatitis, hepatic abscesses, splenic abscess,peritonitis, paralytic ileus

Genitourinary <

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