Enteric Fever – Part 1 – Typhoid Fever, Enteric Fever (Salmonella typhi), and Vaccination

Typhoid Fever definition
- Typhoid fever’s name is caused by Salmonella typhi; this is also called enteric fever.
- Enteric fever is an acute illness characterized by fever, headache, and abdominal discomfort.
- This is a clinical syndrome characterized by fever, GIT symptoms, and headache.
- Salmonella infections are divided into:
- Typhoidal infection caused by S.typhi.
- S.paratyphi generally has a less severe illness and is caused by S. Paratyphi A, B, or C.
- Non-typhoidal infection most common in the USA caused by:
- S. Typhimurium.
- S. Enteritidis.
- Salmonella is quite uncommon in the USA; 70% are acquired from abroad.
- Humans are the only source of this infection (S. Typhi and S. paratyphi), and the spread is from person to person or via contaminated foods or water.
Sample
- Widal test can be done on the serum of the patient.
- Feces can be used for the culture.
- A blood culture can be done and is positive in the early stage of the fever.
- Urine may also be needed for the culture.
- In a few cases, a bone marrow sample can be cultured.
Precautions
- Widal test will be positive after 7 to 10 days of the onset of fever.
- Culture gives the early result to detect the bacilli.
Pathophysiology
- Typhoid/Enteric fever is a syndrome that is characterized by:
- Fever.
- Headache.
- Cough.
- Splenomegaly.
- Leucopenia.
Epidemiology:
- Salmonella habitat is an animal gut. Predominantly animal pathogens can also cause disease in man.
- Foodstuffs from animal sources are important vehicles in the transmission of infection.
- Salmonella is found in humans as well as in chickens and eggs.
- It spreads by eating the chickens and uncooked eggs.
- It spreads only through close contact with an acutely infected person or chronic carrier.
- Most cases occur through contaminated foods or water.
- This is a global issue with 13 to 17 million cases per year and ∼60,000 deaths per year.
- Children under the age of one year are more prone to develop an infection, and the diseases are more severe.
- There is increasing antibiotics resistance to this disease.
- Enteric fever includes typhoid and paratyphoid fever.
- Paratyphoid fever is generally mild than typhoid fever.
- The Salmonella species cause typhoid fever.
- Salmonella typhi and S.paratyphi differs from the other species in that man is the only natural host.
Microbiology of Salmonella typhi:
- Salmonella typhi and S.paratyphi differ from the other species in that human is the only natural host.
- salmonella serologically divided into:
- Salmonella typhi.
- Salmonella cholerae-suis.
- Salmonella enteritidis.
- Salmonella different from the other types because it lives in the gastrointestinal tracts of animals and infects humans when there is the contamination of food or water with animal feces.
- S.Typhi can grow on ordinary media.
- From the feces, culture on the MacConkey agar (or Desoxycholate citrate agar) will see pale non-lactose fermenter colonies.
- Colonies on Xylose lysine desoxycholate agar show a red color colony with a central black area.
- Wilson’s and Blair’s Bismuth sulfite agar shows black metallic colonies due to H2S production.
- S.Typhi are motile due to flagella.
- Generally, salmonellae produce acid and gas from carbohydrates except for S.typhi, which does not produce gas.
- Summary of Salmonella typhi:
- Gram stain negative bacilli (rods). These are seen as single, pairs, and chains.
- These are motile.
- These are aerobic.
- Non-lactose fermenter.
- Produce H2S gas.
- Colonies are gray and can grow on ordinary media (blood agar).
- Selective media are:
- Culture may be taken from the feces.
- MacConkey agar = pale non-lactose fermenting coloies.
- Desoxycholate citrate agar = pale non-lactose fermenting colonies.
- Xylose-lysine desoxycholate agar = observe for red colonies with a black center.
- Wilson and Blair’s bismuth sulfite agar = observe black metallic colonies due to H2S production.
- Selenite F and tetrathionate broth for enrichment, then subculture to MacConkey agar.
- Their capsules consist of polysaccharides.
- These are motile with flagella.
- Gram stain negative bacilli (rods). These are seen as single, pairs, and chains.
Salmonella has three antigens (Virulence factors):
-
- O – antigen is present in the body of bacteria. It is endotoxin and provides antigenic variation.
- This resists alcohol extraction and is thermostable.
- H – An antigen is present in the flagella of the bacteria.
- It provides antigenic variation and motility.
- Flagella antigen undergoes variation by gene rearrangement.
- Vi – antigen is the most superficial of the somatic antigen of S. Typhi. Vi means for virulence.
- This is a polysaccharide capsule that surrounds the O antigen, thus protecting the bacteria from an antibody attack on the O antigen.
- This aids in resistance to antibodies and complement.
- O – antigen is present in the body of bacteria. It is endotoxin and provides antigenic variation.
Mode of spread:
- Contaminated food (including meat).
- Contaminated water supply.
- The incubation period is 5 to 14 days and sometimes is longer (1 to 3 weeks after exposure and includes fever, headache, and abdominal pain).
- The incubation period for salmonella gastroenteritis is 6 to 72 hours.
Pathogenesis:
-
- There are three types of disease:
- Enteric fever.
- Gastroenteritis.
- Septicemia.
- This organism crosses the intestinal epithelium (invade the regional lymph nodes) multiply in the macrophagic cells of Peyer’s patches, mesenteric lymph nodes, and spleen.
- The Peyer’s patches inflamed and may ulcerate.
- Bacteremia occurs, and the infection spreads to the lungs, gallbladder, kidneys, and CNS.
- Finally, these bacteria settle in various organs.
- During this invasion, these bacteria are phagocytosed by the monocytes (mononuclear phagocytes) and can survive intracellularly, so these are called facultative intracellular parasites.
- Enteric fever is caused by the S.typhi and S. paratyphi A, B, C.
- These bacteria cause gastroenteritis, food poisoning, and few special species that may cause septicemia.
- Rarely salmonella may cause osteomyelitis, septic arthritis, and other purulent lesions.
- There are three types of disease:
Pathology of salmonella (Enteric fever):
The involvement by the salmonella bacteria is in stages.
- The first week there is bacteremia.
- There is splenomegaly in the second week, widespread reticuloendothelial system involvement, and foci of necrosis in the liver.
- In the third week, there is ulceration of peyer patches with intestinal ulcers and bleeding.
- Lastly, these bacteria colonize in the gallbladder leads to a chronic carrier state.
- Chronic infection may lead to infection of the joints, bones, meninges, and other sites.
Signs and Symptoms
- The onset of illness is insidious and non-specific, with intermittent fever, headache, and abdominal pain.
- Salmonella causes four types of diseases:
- Typhoid fever.
- Sepsis.
- Gastroenteritis (diarrhea).
- Carrier state.
- The incubation time is 7 to 14 days ( and the range is 3 to 60 days).
- The relapse occurs in 5 to 10% of the untreated cases.
- Salmonella infection is more common in children less than 10 years of age.
- Prodromal stage: Malaise, headache, cough, sore throat, abdominal pain, and constipation.
- Diarrhea is a late symptom and is usually in the third week of illness.
- Fever: It is constant and ascends in a stepwise pattern.
- 7 to 10 days: There is Paek and patients are sicker.
- Early diarrhea.
- Abdominal distension and cramps.
- Patients improve after 7 to 10 days.
- Untreated cases recover in about 4 weeks.
- Symptoms disappear with antibiotics within 3 to 4 days.
- Relapse may occur after 2 weeks.
- The gastroenteritis incubation period is 8 to 24 hours.
- There are nausea and vomiting.
- There is abdominal pain.
- There is diarrhea.
- Stools are typically loose, moderate volume, and do not contain blood.
- Diarrhea is self-limited and may last for 3 to 7 days.
- There may be a fever.
- Pregnant ladies if get an enteric fever then are more prone to abortion.
- This is a self-limiting disease, and recovery is usually within a week.
- Sometimes S/S may mimic appendicitis or inflammatory bowel disease.
- Physical findings are: In the early stage, there is abdominal tenderness, hepatosplenomegaly, and scanty maculopapular rash (rose spot).
- Complications are: There are complication without treatment or even after the treatment, usually after the third week of the disease, like:
- Meningitis.
- Lobar pneumonia.
- Osteomyelitis.
- Intesitinal hemorrage.
- Intestinal perforation.
- By the 4th week of the illness, the patients have gradual improvement, but in the developing countries, 30% of the patients will die.
- 10% of the untreated cases will have relapses.
- 1% to 2% of the cases in the USA have mortality.
Complications
- There may be:
- Relapse.
- Intestinal Perforation.
- Hemorrhage in the GIT.
- Myocarditis.
- The lungs may show pneumonia picture.
- Rarely periostitis.
- Most pregnancies end up in abortion.
- There may be bacteremia.
- Sepsis, when the salmonella enters the bloodstream, will infect the lungs, brain, and bone.
- Laboratory findings due to complications:
- Intestinal hemorrhage may be occult in 20% of the cases; it usually occurs during the 2nd or 3rd week.
- It is less common in treated cases.
- Intestinal perforation occurs in 3% of the untreated patients.
- Relapse occurs in one-fifth of the patients.
- Secondary suppurative lesions are seen in the lung (pneumonia), parotid gland (parotitis), and furunculosis.
Carrier state
- Roughly 30% of the patients become carriers due to persistent infection of the gallbladder.
- After the clinical recovery, 5% to 10% of the patients will continue to excrete S.typhi for several months, and these are the convalescent carrier.
- 1% to 4% of the patients continue to carry the organisms for >1 year; this is a chronic stage.
- These people have no active disease and are symptoms free.
- From the gallbladder, the bacterias are discharged into the intestine constantly and ultimately go out in the feces.
- The carrier may have cholecystitis and gallstones.
- This is difficult to eradicate the carrier of S. Typhi from the gall bladder.
- Antibiotics are effective in some of the carriers.
- While in most cases, bacteria persist and give rise to long-term permanent carriers.
- Some of the carriers require surgical removal of the gall bladder to cure them.
- Important: Everybody should wash their hands when they come out of the toilet/washroom.
- Pregnant ladies end up with abortions in enteric fever.
Lab Diagnosis
- CBC shows:
- Low TLC, leucopenia.
- Culture of blood, bone marrow, intestinal secretion, feces, and urine can be done.
- Blood culture, positive in the first week of infection in 80% of the cases. But blood culture may reach 90% of the cases, decreasing to 50% in the third week.
- For the culture, roughly 105 to 109 organisms are required, but this count may be low in infants and older adults.
- This count may be low in patients taking antacids and H2 receptor blockers.
- Blood culture is positive in 80% of the cases in the first week of infection.
- Blood culture is considered 100% specific.
- Buffy coat may decrease the time for isolation.
- This is subcultured on the MacConkey media.
- For the culture, roughly 105 to 109 organisms are required, but this count may be low in infants and older adults.
- Bone marrow culture is more sensitive than the blood culture but is usually not required.
- These bacteria are:
- Non-lactose fermentor.
- Motile.
- Produce H2S.
- If taken, bonemarrow culture will be positive and may have a high yield of up to 90% sensitivity.
- Stool examination show leucocytes and rarely RBCs.
- Stool culture will be a positive but not reliable test. This will be positive within the first 7 days of infection.
- This is negative in 60 to 70% of the cases during the first week if the patient is untreated, then positive in these patients in the third week.
- The chronic carrier may have stool culture positive even up to one year.
- Feces cultures on solid selective media:
- Desoxycholate citrate agar where there are non-lactose fermenting colonies.
- McConkey medium shows non-lactose fermenting colonies.
- There is no gas and no fermentation of the sugar.
- Xylose lysine desoxycholate agar shows red colonies with a black center.
- Laboratory culture findings of salmonella are:
Lab test Result Oxidase test Negative Indol Negative Lactose (nonlactose fermenter) Negative Urease Negative Voges-Proskauer Negative Simmon’s citrate Positive/Negative TSI (Produce H2S) Positive (except S.typhi is negative)
- Serologically salmonella has 5 serogroups: A, B, C, D, and E based on O somatic antigen.
- Based on H-antigen are 1200 serotypes.
- 7 to 10 days antibody to D-somatic antigen appears.
- These antibodies against O antigens reach their peak by 3 to 5 weeks.
- H-flagellar antibodies appear later on.
- 7 to 10 days antibody to D-somatic antigen appears.
- Based on H-antigen are 1200 serotypes.
- Widal test:
-
- The widal test was developed in 1896.
- Will be positive after 7 to 10 days of infection.
- The blood, bone marrow, bile, and stool culture is superior to the widal test for typhoid fever or carrier state diagnosis.
- If the culture’s facilities are not available, then the widal test is a valuable tool for the diagnosis.
- The titer of O-antibodies 1:80 is suspicious in unvaccinated patients.
- The titer of 1:160 is strongly suggestive of infection in unvaccinated individuals.
- The titer of 1:40 for Antibody to flagellar-antigen (H) are suspicious in unvaccinated individual.
- While 1:160 is strongly suggestive.
- Titers are much higher in the vaccinated individual.
- Vi antigen for S.typhi is used to screen the carrier. Antibodies to Vi-antigen are positive in only 70 % of the chronic carrier of S.typhi.
- Widal test reporting:
-
- Typhidot test claimed by the manufacturing companies that it would be positive after 2 to 3 days.
- The urine culture may be done and is positive in the case of enteric fever but is less sensitive.
- This is positive in the third or fourth week of the infection.
- This is done on the MacConkey media.
- Bacteriophage typing is done to identify the different strains of S.typhi and also Paratyphi.
- This is useful for the epidemiological investigation in case of the source of the outbreak.
- Summary of diagnosis:
- Samonella is non-motile.
- Biochemical tests show acid and gas formation from the carbohydrate.
- S.typhi does not produce gas formation.
- Serologically can identify antigens.
- O somatic antigen.
- H flagellar antigen.
- Vi surface antigen
Summary of the available lab tests for the diagnosis of Typhoid fever:
Summary of typhoid fever diagnostic tests:
- White blood cell count: It is low during the first two weeks.
- It is decreased from 4000 to 6000/cmm.
- 3000 to 5000/cmm during the next two weeks.
- 10,000/cmm or more/cmm may suggest perforation or sepsis (suppuration).
- There may be anemia, and this may be due to bleeding and is hypochromic and microcytic.
- Blood cultures are positive during the first 10 days, in 90% of the patients and relapse.
- <30% are positive after the third week.
- Stool culture is positive after the 10th day with increasing frequency up to the 4th or 5th week.
- Stool culture-positive after 4 months indicates a carrier.
- Urine culture is positive during the 2nd to 3rd week in 25% of the patients; even the blood culture is negative.
- Widal test: H and O agglutinins appear in the serum after 7 to 10 days, increase to the peak in 3rd to 5th week, then gradually fall for several weeks; there is no increase during the relapse.
- O Antibody appears before the H appears and is usually higher at the beginning.
- During convalescence, the H titer becomes higher than the O antibody.
- Widal test may be positive in case of vaccination or previous infection.
- Early treatment with antibiotics may cause titer to remain low or negative.
Treatment
- The drug of choice is Ciprofloxacin.
- Chloramphenicol is also effective, but this may have a serious side effect.
- Co-trimoxazole is also used and has less serious side effects than Chloramphenicol.
Treatment of the carrier
- The carriers are asymptomatic.
- It is documented that the carrier shed S.tryphi in the stool for one year, and is observed in 1 to 3% of these patients.
- The gallbladder is the site for persistent infection.
- It is difficult to eradicate S.Typhi from the gallbladder. Mostly these are permanent carriers.
- To eradicate carrier infection, prolonged use, and a high dose of the antibiotics are needed.
- Ampicillin is the drug of choice, but it has to be given in higher doses and prolonged.
- Chloramphenicol is not good for carriers.
- Ciprofloxacin has good results.
Control of the disease
- The Hygenic measure like:
- Clean water supply.
- Adequate disposal of the sewage material.
- Washing of the hands after the defecation. The best is to wash your hands with soap at least three times.
- Take care of food handling and processing.
- For the carriers, give them treatment and advise them to wash their hands after the defection.
- Vaccination should be advised in the family where there is a history of enteric fever.
- Injectable vaccine.
- The oral vaccine is replacing the injectable vaccines. These are Vi capsular polysaccharides.
Vaccines types used:
Type of vaccine Dose of vaccine Remarks Vi capsular polysaccharide (ViCPS) Typhim Vi - 25 µg in 0.5 mL I/M given once
- Booster dose every 2 years
- Side effect fever = 1%
- The headache = 1.5 to 3%
- Local erythema or induration = 7%
- Not recommended for children <2 years
Heat killed the whole organism (S.typhi) - 0.5 mL I/M = two doses
- 4 weeks apart
- Booster 0.1 mL every three years
- Dose for children 6 months to 10 years = 0.25 mL I/M
- Fever = 17 to 29%
- Headache severe = 10%
- Pain at the site of injection = 35 to 60%
Ty21a (Vivotif Berna)
This is live oral, attenuated live bacteria
- One capsule one hour before a meal
- Gien for 4 days
- Booster every 5 years
- There are a few sides effects
- Not given in the immunocompromised patients.
- Not given in children <6 years of age.
For the layman:
- Widal test will be positive after 7 to 10 days of typhoid fever.
- O antigen indicates an acute infection and early to rise.
- H antigen appears late than O antigen and indicates past infection or vaccination.
- The titer of O antigen 1:40 is negative.
- The titer of 1:80 is borderline; repeat the widal test after 5 to 7 days.
- Rising titer will indicate typhoid fever.
- If the level is the same, then less likely for typhoid fever.
- Widal test will be negative in the first 3 to 7 days of typhoid fever.
- In the first few days, advise blood culture.