The document provides an overview of typhoid fever, primarily caused by Salmonella typhi, including its history, etiology, transmission, pathophysiology, clinical manifestations, and existing treatments and vaccinations. Typhoid fever remains a significant global public health issue, especially in developing nations, with millions of cases and deaths reported annually. Despite medical advancements, the incidence continues to rise, necessitating effective preventative measures and treatment strategies.

1. Saba Parvin Haque
MSc in Neuroscience
from “Sophia College For
Women”, Mumbai.
selfexplanatory.2022

3. Contents
 Introduction
 Etiology
 Transmission
 Pathophysiology
 Clinical manifestations
 Laboratory diagnosis
 Prophylaxis
 Treatments.

4.  In 1829, Pierre Louis was the first to coin the term “typhoid fever” after identifying lesions in the abdominal
lymph nodes of patients who had died from “gastric fever.”
 The term was derived from the Greek word “typhus” which meant “smoky” and was used to describe the delirium
that patients would exhibit with the disease.
 Although first described in the early 1800s, it was not until 1880 when the organism for typhoid fever was
discovered.
 In 1880, German pathologist Karl Eberth identified S. enterica. It was first cultured in 1884 by Georg Gaffky.
 Salmonella enterica serotype typhi is a gram-negative bacterium that is responsible for typhoid fever and has
been a burden on developing nations for generations.
 Several years later, Almroth Wright developed a vaccine for the disease.
 Despite significant efforts in research and medical advancements, typhoid fever is still a major, worldwide, public
health concern.
Introduction

5.  Typhoid fever is also called enteric fever.
 It is caused by Salmonella typhi and Salmonella paratyphi.
 Enteric fever is a cumulative term that illustrates both typhoid and paratyphoid fever.
 Paratyphoid is clinically indistinct from typhoid fever; thus, enteric and typhoid fever are used
mutually.
 Typhoid fever is one of the major causes of mortality and morbidity in overcrowded and unhygienic
areas though comprehensive research and public health interventions have decreased the occurrence.
 The disease course ranges from early gastrointestinal distress to nonspecific systemic illness but
ultimately may lead to multiple complications.
 Fever characteristically comes in a step-wise pattern (i.e., rises and falls alternatively) followed by
headache and abdominal pain.
Introduction

6. Etiology
 The main causative agent of typhoid fever
is Salmonella typhi and Salmonella paratyphi, both are
members of the Enterobacteriaceae family.
 Salmonella is a genus that has two
species Salmonella enterica serovar and enteritidis.
 Both Salmonella typhi and Salmonella paratyphi (A, B,
C) are Salmonella enterica serotypes.
 Nontyphoidal salmonella (NTS) is more typical in
children and is mostly limited to gastroenteritis.
 Gram negative
 Facultatively anaerobic bacilli

7.  Salmonella is said to spread by the ‘four Fs” (flies, fingers, feces, fomites).
 Maximum occurrence of typhoid happens in rainy season.
 Salmonella is transmitted by the fecal-oral route through contaminated water, undercooked foods, fomites of
infected patients, and is more common in areas with overcrowding, social chaos, and poor sanitation.
 It is only transmitted from an infected person to another person, as humans are its only host.
 House Flies do contaminated water, vegetables, foods, oysters, mussels.
 Chronic carrier- Typhoid marry (3-5%).
 Normal flora of the gut is protective against the infection.
 The use of antibiotics such as streptomycin destroys the normal flora, which heightens its invasion. Malnutrition
decreases normal gut flora and thus increases the susceptibility to this infection as well.
 Hence, the use of broad-spectrum antibiotics and poor nutrition amplify the incidence of typhoid fever.
Transmission

8.  Mary Mallon as “Typhoid
Mary” in the local newspaper
of the era
Mary Mallon in the
“Riverside Hospital”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959940/#!po=55.2632

9.  Typhoid fever continues to be a serious public health problem throughout the world.
 It has been estimated that typhoid fever caused about 21 million cases and 200 000–
600 000 deaths annually, 90% of which occurred in Asia.
 Until the twentieth century, the disease had a worldwide distribution.
 Afterward, the number of typhoid cases in developed countries greatly decreased, as
a result of changes in sanitation and hygiene.
 According to the World Health Organization (WHO), from the beginning of 2021
through December 12, 1,380,955 suspected cases of typhoid fever have been
reported including 502 deaths (CFR 0.03%), including 30,934 confirmed cases
Epidemiology

10. https://images.app.goo.gl/9r4hv6aJf4Qux67R7
Epidemiology

11.  Countries with a high endemicity, classified as high-risk regions (incidence >100 cases
per 100 000 population per year), include south–central Asia, southeast Asia, and
southern Africa.
 Medium risk areas (10–100 cases per 100 000) are the rest of Asia, Africa, Latin America,
and Oceania, except for Australia and New Zealand.
 In the other parts of the world, the incidence of typhoid fever is low (<10 per 100 000).
 Most cases in developed countries are carried by travelers returning from endemic
areas and travelers visiting relatives and friends that are at heightened risk due to their
likelihood to be less cautious with sources of food and water. Those less likely to seek
vaccination and pretravel consultation are also at heightened risk.
 In developed countries, epidemics are less common than sporadic cases.
 In the United States, they account for 7% of total cases.
Epidemiology

12.  Salmonella typhi is more common than Salmonella paratyphi, and Salmonella
paratyphi A is more prevalent than Salmonella paratyphi B infections.
 The number of new cases of typhoid fever has been increasing worldwide due to rapid
increases in population, pollution, and shortages of pure drinking water.
 Still, death rates have decreased due to extensive research, changes in treatment
modalities, and the invention of new drugs despite growing multidrug-resistance.
 Up to 4% of patients with typhoid fever go on to become chronic carriers.
 These patients remain asymptomatic after their acute treatment, but they may excrete
Salmonella for up to 1 year in their stool, or less frequently their urine.
Epidemiology

13.  The pathogenesis of typhoid fever depends upon a number of factors, including infectious species,
virulence, host's immunity, and infectious dose.
 The larger the infectious dose, the shorter the incubation period, and the higher the attack rate.
 Typhoid fever is more severe in debilitated and immunocompromised patients such as those with HIV
(mainly paratyphi), those on glucocorticoid therapy, and those with altered phagocyte function (i.e.,
patients with malaria and sickle cell anemia).
 Salmonella is an acid-sensitive bacteria except for a few resistant strains, so typically it is destroyed in
the stomach by gastric acid unless a large dose is ingested.
 In patients with achlorhydria, intake of antacids and antihistamines, colonization of Salmonella occurs
even with smaller doses.
 Food and beverages also act as buffers against gastric acid that facilitates bacteria reaching the small gut.
Pathophysiology

14.  The virulence of Salmonella is determined by typhoid toxin, Vi antigen (polysaccharide capsule), liposaccharide O
antigen, and flagellar H antigen.
 Strains positive for Vi antigen have an attack rate twice that of Vi negative strains, even for the same dose of micro-organisms.
 One of the main differences between Salmonella typhi and non-typhoidal salmonella (NTS) is the presence of Vi antigen
in Salmonella typhi but absent in NTS.
 The main role of the Vi antigen is to act as an antiphagocytic agent preventing the action of macrophages, thus shielding the O
antigen from antibodies that confer the serum resistance.
 The flagellar H antigen provides bacterial mobility and adherence upon the gut wall mucosa.
 Invasion of the gut wall is assisted by flagella, and the type III secretion system is capable of transferring bacterial protein into
enterocytes and M cells (specialized epithelial cells that serve as antigen-presenting cells in gut mucosa or lymphoid tissue) or by
direct penetration of mucosa.
 Bacteria attached to M cells are absorbed by pinched off cytoplasm containing bacteria and extruded into the luminal space.
 In this process, M cells are damaged, and the basal lamina is exposed.
 It provides easy access to pathogens for the invasion, which worsens the condition.
Pathophysiology

15.  The cystic fibrosis transmembrane conductance regulator (CFTR) is said to be important in the
uptake of Salmonella; so, patients with abnormal CFTR protein are resistant to typhoid.
 The transferred proteins activate the host cell Rho GTPases, which trigger the actin rearrangement so
that bacterial protein uptake takes place in the phagosomes where the bacteria can grow.
 This special characteristic of the bacteria helps them to remain viable in a pool of host immunity.
 Salmonella also produces a molecule that stimulates the epithelial release of chemoattractant
eicosanoid, which sequesters neutrophils into the lumen and potentiates mucosal damage.
 Bacteria induce proliferation of Payer patches via recruitment of lymphocytes and mononuclear cells
and induce necrosis and eventually, ulceration that complicates the symptoms.
 Pathogens reach the reticuloendothelial system via both lymphatic system and bloodstream, including
other multiple organs, most commonly gallbladder in almost all cases.
Pathophysiology

16.  The early bacteremic phase (24 hours to 72 hours) is asymptomatic and transient as these
bacteria are phagocytosed by macrophages and monocytes in the reticuloendothelial system
called primary bacteremia.
 The capacity of pathogens to grow in these immune cells makes them characteristic, and
intracellular multiplication of bacteria in the reticuloendothelial system enforces them to re-
enter the bloodstream causing continuous bacteremia for several days and weeks known as
secondary bacteremia.
 Secondary bacteremia is the phase in which disease symptoms manifest.
 Like in other gram-negative bacteria, an endotoxin has an important role in the pathogenesis.
 The lipopolysaccharide induces the shock-like reaction, and endotoxemia leads to vascular
hyperactivity and catecholamine release, which causes focal necrosis and hemorrhage.
Pathophysiology

17. Pathophysiology
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18. Pathophysiology
https://www.ncbi.nlm.nih.gov/books/NBK8435/bin/ch21f1.jpg

19.  The early symptoms of typhoid appear:
headache, malaise, generalized aching,
fever, and restlessness that may interfere
with sleep.
 There may be loss of appetite,
nosebleeds, cough, and diarrhea or
constipation.
 Persistent fever develops and gradually
rises, usually in a stepwise fashion,
reaching a peak of 39 or 40 °C (103 or
104 °F).
Clinical Manifestations/Symptoms

20.  During about the second week of fever, typhoid bacilli are present in great numbers in the
bloodstream. At that point, some patients develop a rash of small rose-coloured spots on the
trunk, which lasts four or five days and then fades away.
 The lymph follicle along the intestinal wall in which the typhoid bacilli have multiplied become
inflamed and necrotic and may slough off, leaving ulcers in the walls of the intestine. The dead
fragments of intestinal tissue may erode blood vessels, causing hemorrhage, or they may
perforate the intestinal wall, allowing the intestine’s contents to enter the peritoneal cavity
(peritonitis).
 Other complications can include acute inflammation of the gallbladder, heart
failure, pneumonia, osteomyelitis, encephalitis, and meningitis. With a continued high fever,
the symptoms usually increase in intensity, and mental confusion and delirium may appear.
Clinical Manifestations

21.  By the end of the third week, the patient is emaciated, abdominal
symptoms are marked, and mental disturbance is prominent.
 In favourable cases, about the beginning of the fourth week, the fever
begins to decline, the symptoms begin to abate, and the temperature gradually
returns to normal.
 If untreated, typhoid fever proves fatal in about 10 to 30 percent of all cases;
with treatment, as few as 1 percent of patients die from the disease.
 Patients with diseases such as cancer or sickle cell anemia are
particularly prone to develop serious and prolonged infection with S. Typhi.
Clinical Manifestations

22. Laboratory Diagnosis
 Blood Culture
 Stool Culture
 Bone marrow
 Widal Test
 Skin snip test (punch biopsy)
 Polymerase chain reaction (PCR) Assay
 Enzyme-Linked Immunosorbent Assay (ELISA)
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https://images.app.goo.gl/3rEk1TprzJDuPkqM8
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23. Vaccination prophylaxis
 Oral vaccine
 Live attenuated vaccine: (Ty21a) (Vivotif TM, Berna Biotech, Crucell; Zerotyph caps,
Boryung). This vaccine was developed in the early 1970s, requires at least three doses
for optimal protection, and is supplied as gelatin capsules coated with phthalate or
sachets containing lyophilised Ty21a, a mutant strain of Salmonella enterica serovar
Typhi (S. Typhi).
 Parenteral vaccines
 Monovalent typhoid vaccines: Vi polysaccharide is a well-standardized antigen that is
effective in a single parenteral dose, is safer than whole-cell vaccine, and may be
used in children 2 years of age or older.

24.  Capsular polysaccharide vaccines: (ViCPS) (TypherixTM, GSK; Typhim ViTM, Sanofi Pasteur;
TypBar, Bharat Biotech; Shantyph, Shanta Biotech; Typho-Vi, BioMed; Zerotyph inj, Boryung, South
Korea; Typhevac-inj, Shanghai Institute of Biological Products) is a one-dose injectable solution
consisting 25 µg Vi antigen prepared from the surface polysaccharide of S. Typhi strain Ty2.
surface polysaccharide of S. Typhi strain Ty2.
 Conjugate vaccine: (Vi-TT), where the Vi antigen is coupled to a carrier protein. At the time of
review there is only one licensed conjugate vaccine (Peda-typhTM, BioMed). It consists of Vi
coupled to tetanus toxoid (TT). This vaccine has been licensed only in India and only limited
clinical data are available to document its safety and immunogenicity. Multiple other
conjugates are in development consisting of Vi linked to tetanus toxoid or to other carrier
proteins.
 Multivalent combination vaccines: Combined ViCPS and hepatitis A vaccines (HepatyrixTM,
GSK; ViatimTM, Aventis Pasteur) contain 25µg Vi polysaccharide antigen of S. Typhi combined
with either 1440 EL.U. or 160 AU of inactivated hepatitis A virus grownin human diploid cells and
adsorbed onto aluminium hydroxide.
Vaccination prophylaxis

25. Treatment
• cholecystectomy

26. Prevention
 Wash your hands
 Avoid drinking untreated water
 Avoid raw fruits and
vegetables
 Choose hot foods
 Avoid eating at street food
stands, and only eat food that
is still hot.
https://images.app.goo.gl/Y6SL3Zhcxmwnm2ro8

27. References
 https://www.google.co.in/url?sa=t&source=web&rct=j&url=https://www.cdc.gov/mm
wr/preview/mmwrhtml/mm6411a4.htm&ved=2ahUKEwiN6rGFyJ7vAhVI83MBHTUuAOk
QFjAGegQIHRAF&usg=AOvVaw1d_OG2t2D55uVXA3V9NFdV
 https://www.frontiersin.org/articles/10.3389/fimmu.2014.00516/full
 NCBI - WWW Error Blocked Diagnostic. (n.d.). https://www.ncbi.nlm.nih.gov/books/NBK8435/
 https://www.researchgate.net/publication/221975580_Typhoid_fever_vaccine_develo
pment_A_partially_answered_question
 NCBI - WWW Error Blocked Diagnostic. (n.d.). https://www.ncbi.nlm.nih.gov/books/NBK8435/
 News Desk. (2022, January 8). Typhoid fever in the DRC: More than 500 deaths in 2021. Outbreak
News Today. http://outbreaknewstoday.com/typhoid-fever-in-the-drc-more-than-500-deaths-in-2021/

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