Typhoid (Enteric) Fever and Typhoid conjugate vaccine (TCV)

Typhoid (Enteric) Fever and Typhoid conjugate vaccine (TCV)

Typhoid (Enteric) fever 

Typhoid fever is also called as enteric fever is very common illness leading morbidity and mortality and financial burden in developing countries. It is an infective illness caused by contaminated water or food. It is still cause of large number of hospital admissions and deaths in developing countries like India. It occurs throughout the year but very common during monsoon season. It is also found in developed countries mainly because of travelers visiting to endemic developing countries or the visitor coming from endemic regions for the typhoid. Let’s here discuss some facts about Typhoid (Enteric) fever and strategies available for its prevention and treatment with some focus on Typhoid vaccines especially the Typhoid conjugate vaccine.

Causative micro-organism for Typhoid fever:

Typhoid fever is caused by infectious bacterium Salmonella enteric serovar Typhi. It is also called as S. Typhi. It is a gram negative bacterium. The similar disease of less intensity is caused by S. paratyphi A and S. paratyphi B and S. paratyphi C. The Typhoid fever caused by S. typhi is 10 times more common than disease caused by S. paratyphi types all together. In some parts of the world incidences caused by S. paratyphi A are on rise. The capacity to cause disease is directly proportional to the infectious load. It can severely affect the hosts with low immunity. Additionally those hosts with diseased gastric acid contents are more prone to get affected.

Epidemiology of Typhoid fever:

Typhoid fever occurs worldwide especially in developing countries. Approximately 26 million people annually get affected by the typhoid fever. 1 percent of these affected may die. So considering the disease burden all over the world the mortality is high. The mortality proportion is higher in developing countries where no proper treatment is available. Additionally 5 million more cases are recorded annually all around the world caused by S. paratyphi. These are just estimates as actual number are not known because poor developing countries do not have the needed infrastructure for the testing and blood culture.

The disease burden is measured by total incidences per lakh population in any country. Most developed countries are recording incidences less than 15 per 1 lakh population. In South Asia these incidences range from 100-1000 per one lakh population annually. Unfortunately the incidences are highest in younger population and especially children less than 5 years old and infants. In this very young population the mortality and complications caused by the disease are highest even with treatment. Also this young age group needs most frequent hospitalizations because of Typhoid fever.

Typhoid causing bacterium S. Typhi and S. paratyphi are known to develop resistance to many commonly used antibiotics. Chloramphenicol was the antibiotic used for typhoid fever some decades ago now the S. typhi strains show resistance to the drug. Many times  S. typhi and S. paratyphi are resistant to all three first line antibiotics chloramphenicol, Fluoroquinolons and ampicillin. These drugs are no longer considered as first line for the treatment of Typhoid fever. There is also considerable proportion of typhoid fever incidences which are resistant to the nalidixic acid. These nalidixic acid strains originated from the parts of India and spreading to rest of the world.

How dose Typhoid fever spreads?

As we know Typhoid fever is infectious illness its spreads by infectious agent which is S. typhi or S. paratyphi. The person to person spread occurs. Person to person direct or indirect contact is mode of spread. The infection spreads by ingestion of contaminated food or water. The S. typhi and S. paratyphi is released in to the environment by infected person in feces and urine. When there is contamination of food or water by such S. typhi occurring in feces and the susceptible person consumes and gets infected. Salmonella Typhi and Salmonella paratyphi are especially adapted to human hosts to the point that they cannot infect other animals. Oyster and shellfish grown in water contaminated with human feces or using night soil as fertilizer are known to cause major out brakes in some parts of the world. This mode of spread is very conveniently found in developing countries of South Asia and African regions.

What is pathogenesis of Typhoid fever?

Enteric fever (Typhoid fever) occurs through ingestion of the contaminated water or food. Spread is mainly by fecal contamination of the food products and water. Street food and contaminated water reservoirs are main culprits usually detected. The infecting dose is 10 thousand to 10 crore S. typhi by ingestion. The incubation period ranges from 4-14 days and that usually depends upon initial number of inoculation. S. typhi is resistant to gastric acid to some extent. When it reaches to ileum the part of small intestine it invades the gut mucosa. This procedure typically takes place in the terminal regions of the ileum. Gut associated lymphoid cells carrying M receptors are invaded by the bacterium or it can also invade through the para-cellular route. Before invading the gut mucosa S. typhi attaches to the microvilli of the small intestine by an intricate mechanism. This intricate mechanism of membrane ruffling includes actin rearrangement and internalization of the intracellular vacuoles. S. typhi carries the virulence factors that decrease the pathogen recognition mechanism of the host. So host cannot initiate the inflammatory response at this stage. Ileum has lymph nodes. These are called as Peyer patches. Salmonella reaches to these patches.

After passing through blood mucosa these S. typhi goes to mucosal lymphoid tissues and then they are carried to blood. This is called as ‘first stage of bacteremia’ or ‘Primary bacteremia’. Most of the patients are asymptomatic in this phase and the blood culture is also found negative in this stage. During this phase of ‘Primary bacteremia’ these S. typhi are carried by blood and disseminated in various organs of reticulo-endothelial system. These S. typhi multiply extensively in macrophages in reticulo-endothelial system. After getting multiplied extensively in the reticulo-endothelial system these bacteria are released into the blood in very large number. This is called as stage of ‘Secondary bacteremia’. This stage of secondary bacteremia coincides with the symptoms of the disease. S. typhi are detectable in blood during this stage by blood culture. Onset of symptom essentially means the end of incubation period.

S. typhi when studied in-vitro shows deferent cytokine and chemokine response on epithelian cells than S. typhimurium. S. typhi initially down-regulates the inflammatory response on mucosa but initiates inflammatory response when invades deeper. Thus S. typhi penetrates deeper tissues. Peyer patches are enlarged. The bacterium may invade the muscularis and the serosa layer of the intestine. It may even cause the perforation of the intestine. The reticulo-endothelial system, Spleen and liver may be inflamed and enlarged. Mesenteric lymph nodes may be enlarged along with spleen. These organs may show focal necrosis. The lesions may bleed but usually heal without scar formation and stricture formation. Morphological changes are less prominent in infants than that seen in older children and adults.

Vi-polysaccharide antigen on S. typhi is very important in preventing the phagocytosis of the bacteria by host’s immune cells. After phagocytosis S. typhi resists the lysis and replicates inside the macrophages. S. typhi can occasionally produce diarrhea in hosts by cholera like toxin or E. coli heat labile enterotoxin. It also produces metabolic effects on hosts by Phop regulation. Fever and other systemic symptoms are caused by the cytokines the induce inflammations. These cytokines are IL6 and TNF alpha.

Patients own immunity level also decides the severity of the disease. Those infected with HIV have increased risk of sever disease and the complicated disease with increased mortality because of the disease. For spme reason people those are infected with H. pylori are more prone to S. typhi.

What are symptoms of Typhoid (Enteric) Fever?

Incubation period of Typhoid fever is usually 7-14 days but it depends on the initial inoculation dose and can vary from 4-30 days. The symptoms range from mild to severe. Low grade fever, malaise, slight dry cough constitute mild disease while severe symptoms with abdominal distention, abdominal discomfort with various complications constitute severe disease. Many factors like duration of illness before initiation of treatment, age, choice of anti microbial agents, previous exposure, vaccination history, virulence of the bacterial strain, quantity of inoculum ingested, and several other host factors like immunity plays important role in severity of the disease and complications and death.

In younger children the disease Typhoid fever can be very dramatic. The symptoms are usually very severe in children less than 5 year old and likely to lead to various complications and increased mortality. Diarrhea, toxicity and complications such as disseminated intravascular coagulation are common in children especially children younger than 5 year old with increased proportion of mortality. The other complications that occur in adults like relative bradycardia, neurologic manifestations and GI bleed are rare in children.

Typhoid fever usually manifest as high grade fever, anorexia, generalized malaise, muscular pain, abdominal discomfort, hepatosplenomegaly. In children diarrhea followed by constipation can be the manifestation of Typhoid fever. Initially the disease manifestation resembles with other diseases like dengue and malaria. Stepladder rise of pattern of fever classically described in literature is rare. The fever usually rises day by day. 7-10 days of illness macular or macula-papular rashes may appear in some patients. These lesions are difficult to get recognized in population of South Asia because of dark skin color. These lesions appear in number 10-15 on lower chest and abdomen. These rashes generally last for 2-3 days. Patients who are accepting feeds and medicines at home with less vomiting, diarrhea, hepatoslenomegaly, less toxic, less myalgia can be managed at home on oral medicines without admissions.

The presentation of typhoid fever may be tempered by coexisting morbidities and early diagnosis and administration of antibiotics. In malaria-endemic areas and in parts of the world where schistosomiasis is common, the presentation of typhoid may also be atypical. It is also recognized that multidrug-resistant S. Typhi infection is a more severe clinical illness with higher rates of toxicity, complications, and case fatality rates, which may be related to the greater virulence as well as higher numbers of circulating bacteria. The emergence of typhoid infections resistant to nalidixic acid and fluoroquinolones is associated with higher rates of morbidity and treatment failure. These findings may have implications for treatment algorithms, especially in endemic areas with high rates of multidrug-resistant and nalidixic acid– or fluoroquinolone-resistant typhoid.

If no complications occur, the symptoms and physical findings gradually resolve within 2-4 wk; however, the illness may be associated with malnutrition in a number of affected children. Although enteric fever caused by S. Paratyphi organisms has been classically regarded as a milder illness, there have been several outbreaks of infection with drug-resistant S. Paratyphi A, suggesting that paratyphoid fever may also be severe, with significant morbidity and complications.

What are complications of Typhoid fever?

Altered liver function on blood test is common finding in Typhoid fever but hepatitis, clinical jaundice and cholecystitis are rare but if occur they are severe and can be life threatening. Intestinal hemorrhage and intestinal perforation are possible complications in children. Intestinal perforation is usually preceded by the abdominal pain and abdominal tenderness usually in right lower quadrant of the abdomen. Vomiting can occur in this stage. Abdominal perforation leads to peritonitis too and usually characterized by rise in pulse rate, abdominal pain, tenderness, guarding rigidity. Rising WBC counts and free air can be detected on X-ray abdomen.

Some rare side effects include myocarditis leading to arrhythmia and sino-atrial block in extreme cases cardiogenic shock. In children although neurological complications are rare compared to adults but still known to occur in form of psychosis, chorea, increased intra cranial pressure, cerebellar ataxia, deafness and GBS. Fatality may be higher in neurological complications but if recovers it is usually recovery without sequelae.

Other serious complications include disseminated intravascular coagulopathy, acute bone marrow necrosis, HUS, nephritic and nephritic syndrome, meningitis, endocarditis, parotitis, orchitis and suppurative lymphadenitis.

With age increasing chances of becoming chronic carriers are increased too. Gallbladder involvement and antibiotic resistance leads to conversion to chronic carrier stage. Stage of chronic carrier is relatively rare in children than in adults. As carriers do not show any symptoms and can be detected only by tests, exact rate of chronic carriers in a population is largely unknown.

How the Typhoid fever is diagnosed?

Detection of bacteria by culturing blood or other anatomical site is good for confirmatory diagnosis. Blood culture is positive in nearly 40-60 percent patients with Typhoid fever in early symptomatic days of infection. Stool and urine becomes culture positive usually after 1st week. Blood culture is but less sensitive in many parts of the world as at many places facility and expertise needed for culture are usually not available. Many places antibiotics are used so rampantly and liberally that culture fails to grow the bacteria. Bone marrow culture is usually less affected by antibiotic use but collecting sample is invasive and relatively difficult.

Other findings on blood tests are non specific. WBC count is relatively low compared to disease severity and toxicity. In young children leukocytosis is rather common and WBC may reach to 20-25 thousand. Thrombocytopenia is feature of advanced disease. Liver function may be mildly deranged.

Widal test which is cheap and is widely used measures the antibodies to O and H antigens of the bacteria S. typhi. But it lacks sensitivity and specificity in endemic areas. Chances of getting false positive and false negative results are high. Diagnosis of Typhoid fever by Widal test alone may lead to error. Other newer tests that detect monoclonal antibodies to Vi polysaccharide antigen are developed but yet not with proven efficacy in large scale use in population. 

Nested polymerase chain reaction using H1-d primer is found to be reliable and gives results rapidly by amplifying the antigen load in blood sample. This test can even detect low level of bacteremia which may be undetectable by other tests. Because of difficulties in doing tests the mainstay of diagnosis remains clinical findings in most of the developing countries.

What is treatment of Typhoid fever?

Early diagnosis with appropriate treatment is essential. Majority of patients with Typhoid fever can be treated at home on oral medication with close medical follow up for complications and no response to treatment. Patient not able to take feed and medicines at home and/or is having vomiting, diarrhea and abdominal distension needs hospitalization and therapy with parenteral medicines. 

It is important to correct the electrolyte imbalance and hydration during the treatment so attention, resr and proper hydration is needed. 

Antipyretic therapy with paracetamol is provided as and when needed to control the fever. Soft and easily digestible diet is continued unless patient has abdominal distention. 

Antibiotic therapy is mainstay for the cure. Therapy with chloramphenical or amoxicillin causes relapse in significant number of patients and therapy with third generation cephalosporins and quinolons show good response in terms of cure rates. Antibiotic therapy is also guided by the resistance to antibiotics. As there is development of multidrug resistant strains causing resistance to fluoroquinolons and chloramphenicol, amoxicillins and cephalosporins, nalidixic acid, it brings big pressure on healthcare system as further choices for treatment are minimal. Fluoroquinolons are still not approved for use in children. 

In addition to antibiotics in complicated patients supportive treatment is very important. Patients with stupor, coma, obtundation, shock need dexamethasone injection. The corticosteroid injection in complicated disease is known to reduce the mortality and also serious abdominal complications.  

Azithromycin can be a better choice of drug for treatment of Typhoid fever in children with uncomplicated disease. 

For quinolon resistant infection cephalosporin third generation and azithromycin can be used alone or in combination. For multidrug resistant Typhoid fever that is sensitive to quinolons fluoroquinolon ofloxacin or ciprofloxacin can be used. Duration of antibiotic treatment is decided by the clinical response and usually between 7-14 days duration.

How to prevent Typhoid?

As we discussed above getting disease and suffering the disease and then getting treatment is difficult and many times not affordable. Prevention of Typhoid fever is that’s why important. Some strategies to prevent the Typhoid fever are following

· Washing hand before food and after use of toilets.

· Drinking safe water.

· Having food that is not contaminated with S. typhi. 

· Maintaining food hygiene.

· Proper disposal of fecal matter so that it does not contaminate the food and drinking water.

· Properly cooking fish and vegetables before consumption.

· Boiling water before using for drinking purpose if avoiding contamination is not possible.

· Effective Typhoid conjugated vaccine is available it should be used in routine immunization for those staying in endemic areas. Typhoid conjugated vaccine is also suggested to those who are going to visit the endemic areas and also people returning to developed countries from endemic areas.

What is Typhoid conjugated vaccine?

Typhoid conjugated vaccine is very effective vaccine to prevent Typhoid fever. It is injectable vaccine given by injection. The antigen Vi-polysaccharide is used in this vaccine. Vi-antigen is the one antigen that is carried on S. typhi capsule and when individual develops antibodies this polysaccharide antigen individual is protected from the Typhoid disease.

 When this polysaccharide antigen is injected it being the polysaccharide in nature induces the immunity in hosts but not strong and long lasting one. So this antigen is conjugated to the protein of Pseudomonas aeruginosa. After getting conjugated the protection rate after taking single dose is around 90 percent. After taking 2 doses of Typhoid conjugated vaccine, the hosts is protected with 98 percent people developing immunity lasting for lifelong.

What is schedule of Typhoid conjugated vaccine?

Typhoid conjugated vaccine first dose is given between 6-9 months and the second dose is suggested at age 2 years. Those who have missed dose can complete the vaccination even in adolescents. Currently typhoid conjugated vaccine is approved for use up to 45 years of age. This is safe vaccine and can be given with other vaccines including MMR vaccine. Co-administration with other vaccine does not seem to reduce efficacy neither increases the side effects of the vaccine.

Routine vaccination
Typhoid TCV is given at 6-9 months age then a booster at 2-5 years age.
Catch up vaccination
Single dose Typhoid TCV is recommended above age 2 years if not given previously.
Schedule of Typhoid TCV Vaccine

What are side effects of Typhoid conjugated vaccine? 

Compared to disease side effects are milder. In some patients local pain with mild redness and swelling can occur in 18 percent of those who received Typhoid conjugated vaccination. Fever can occur in 8-10 percent of patients who got Typhoid conjugated vaccine. Rarely abdominal discomfort and vomiting can occur. All side effects are usually milder and can be managed at home with oral symptomatic treatment when needed. Like all other vaccines this vaccine can lead to severe anaphylaxis reaction but that is exceedingly rare to occur.

<span class="has-inline-color has-luminous-vivid-orange-color">Dr Yatin Bhole MBBS DCh DNB</span>
Dr Yatin Bhole MBBS DCh DNB

This article was written by Dr Yatin Bhole who is practicing Pediatrician at Bhole Children Clinic, Ravet. This post is for general information and before applying it on yourself, you should meet your doctor or meet us in person.

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