The pathophysiology of typhoid fever is complex and occurs through several stages.

Once, the bacteria(Salmonella typhi),survives the acidity of the stomach, it reaches the intestine and invades
the Payer`s patches of the intestinal wall.Payer`s patches are the clusters of cell primarily composed of
Macrophages are specialised cells that are essential to kill any bacteria.But, Salmonella Typhi is unaffected by
these macrophages but, start survive within the macrophage itself.
So , during this asymptomatic incubation period of 7-14 days, the bacteria spread throughout the
reticuloendothelial system of liver,spleen,gallbladder,and bone marrow.
The first week of symptomatic period is characterised by progressive elevation of temperature.
In the second week, the victim may experience abdominal pain, spleen enlargement and notice Rose spots on
his skin.
The third week is more intense as the bacteria start causing necrosis of the Payer`s patches of the intestine
which leads to perforation and bleeding.This is the terminal stage,if, left untreated, death is imminent.
That`s why,it is also called "enteric fever".Enteric which means, intestine.

PATHOPHYSIOLOGY
After ingestion by the host, Salmonella typhi invades through the gut and multiplies within the mononuclear
phagocytic cells in the liver, spleen, lymph nodes, and Peyer patches of the ileum.
After successfully passing through the stomach, any Salmonella subspecies may be phagocytized by the gut's
intraluminal dendritic cells, causing inflammation that leads to diarrhea. Its specialized fimbriae adhere to the
epithelium that overlies Peyer patches. Peyer patches are grossly visible aggregates of 5-100 lymphoid
follicles in the small bowel submucosa; these patches are larger and more numerous distally. They are the
primary mechanism for sampling antigens in the gut and initiating response. S enterica enters them via 1 of 3
pathways.
Intraluminal dendritic cells may infiltrate through the gut epithelium while carrying the bacterium. M cells may
transport it as well. Immobile and interspersed among regular enterocytes in Peyer patches, M cells are
epithelial cells that mature into professional phagocytes. They phagocytize bacteria such as S enterica and
present them to macrophages and T cells in the lamina propria. Most interestingly, S enterica may convert
normally nonphagocytic epithelial cells into bacterially-mediated endocytosis (BME).
In BME, Salmonella uses a type III secretion system—macromolecular channels those gram-negative bacteria
such as Salmonella insert into eukaryotic cells and intracellular membranes to inject virulence proteins—to
inject proteins SipA and SipC into the epithelial cell. These disrupt the normal brush border and force the cell to
form membrane ruffles. The ruffles engulf the bacilli and create vesicles that carry them across the epithelial
cell cytoplasm and the basolateral membrane. Salmonella pathogenicity island 1 (SPI-1) in the genome
encodes the elements of BME.
In the submucosa, Salmonella enters macrophages via bacteria-triggered pinocytosis or via macrophage
receptor–mediated phagocytosis. The intravacuolar environment activates the PhoP/PhoQ regulon, leading to
modification of protein and lipopolysaccharide elements of the bacterial inner and outer membranes. Thus,
Salmonella resists lysis and decreases host pro-inflammatory signaling. The bacterium also produces
homocysteine to inactivate nitric oxide and enzymes against other microbicides. Finally, with the VI antigen, a
polysaccharide capsule, S typhi and S paratyphi further protect themselves from lysis within the macrophage
and from neutrophils and complement without. The infected macrophage provides Salmonella a vehicle safe
from other elements of the immune system and in which it can multiply and travel. It passes through the
mesenteric lymph nodes into the thoracic duct and the lymphatics beyond to seed the reticuloendothelial
tissues—liver, spleen, bone marrow, and lymph nodes. In these havens, it multiplies until some critical density
is reached. It causes the apoptosis in the macrophages and enters the bloodstream to attack the rest of the
body. At this stage, the VI antigen comes into play. It forms a capsule to protect the bacterium from
complement and from phagocytic immune cells.
From blood or from the liver via bile ducts, it infects the gallbladder and reenters the gastrointestinal tract in the
bile, spreading to other hosts via stool. In addition, it occasionally invades the urinary tract and spreads via
urine.
After primary intestinal infection, further seeding of the Peyer patches occurs through infected bile. They may
become hyperplastic and necrotic with infiltration of mononuclear cells and neutrophils, forming ulcers that may
hemorrhage through eroded blood vessels or perforate the bowel wall, causing peritonitis.
The host recognizes the invader with toll-like receptors 2, 4, and 5. These induce cytokines such as interferon
alpha, interleukin (IL)–12, and tumor necrosis factor-alpha, which recruit macrophages and cause the high
fevers of the disease. Macrophages and neutrophils suppress the active infection. Later, humoral and CD4 T-
cell–mediated immunity clears it.
Pathology and Pathogenesis of Enteric fever
 Caused by
S. typhi
S.paratyphi
The organisms penetrate ileal mucosa reach mesentric lymph nodes via Lymphatics , Multiply,
Invade Blood stream via thoracic duct
In 7 – 10 days through blood stream infect
Liver, Gall Bladder,, spleen, Kidney, Bone marrow.
After multiplication bacilli pass into blood causing secondary and heavier bactermia
Causes of Typhoid Fever
• Poor sanitation, contaminated water and infected milk is main factors responsible for developing
typhoid.
• Flies contaminate the food with germs and people carrying the germs can also spread the disease if
they prepare or serve food.
• Wrong dietary habits and faulty style of living lead to accumulation of toxic waste in the body and
promotes typhoid fever.
• It is common in people who eat more meat and fleshy foods.
Natural remedies for Typhoid Fever
• Complete bed rest is essential.
• Patient should be kept on a liquid diet of orange, barley juice and milk. Orange juice especially hastens
recovery as it increases energy, promotes body resistance and increases urinary output. Administer
warm water enema regularly.
• Apply cold compress to head if temperature rises above 103 degree Fahrenheit. Or wrap the body and
legs twice with a sheet wrung in cold water and then cover it with a warm material. The pack should be
kept for an hour and renewed after every 3 hours. Hot water bottles may be applied to the sides of the
body and feet.
• Fresh fruits and easily digestible foods can be given after temperature comes down to normal.
• Plain water or unsweetened lemon water can be used for drinking.
• Gradually start a well-balanced diet.
Treatment
Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin[5][6]
otherwise, a third-generation cephalosporin such as ceftriaxone Gramocef-Oor cefotaxime is the first
choice.[7][8][9] Cefixime is a suitable oral alternative.[10][11]
Typhoid fever in most cases is not fatal. Antibiotics, such as ampicillin, chloramphenicol, trimethoprim-
sulfamethoxazole, Amoxicillin and ciprofloxacin, have been commonly used to treat typhoid fever in developed
countries. Prompt treatment of the disease with antibiotics reduces the case-fatality rate to approximately 1%.
When untreated, typhoid fever persists for three weeks to a month. Death occurs in between 10% and 30% of
untreated cases. Though in some communities case-fatality rates may be as high as 47%.

Resistance
Resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole and streptomycin is now common,
and these agents have not been used as first line treatment now for almost 20 years. Typhoid that is resistant
to these agents is known as multidrug-resistant typhoid (MDR typhoid)
Third-generation cephalosporins and quinolones are drugs of choice for the treatment of typhoid fever
because they are less toxic and because many strains of Salmonella typhi often are resistant to
chloramphenicol

Treatment
Antibiotic therapy is the only effective treatment for typhoid and paratyphoid fevers. In the past, the drug of
choice was chloramphenicol (Chloromycetin). Doctors no longer commonly use it, however, because of severe
side effects, a high relapse rate and widespread bacterial resistance. In fact, the existence of antibiotic-
resistant bacteria is a serious and growing problem in the treatment of typhoid, especially in the developing
world.