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Typhoid fever, also known as typhoid, is a disease caused by ''
Salmonella ''Salmonella'' is a genus Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruse ...
''
serotype A serotype or serovar is a distinct variation within a species of bacteria or virus or among immune cells of different individuals. These microorganisms, viruses, or Cell (biology), cells are classified together based on their surface antigens, al ...

serotype
Typhi bacteria. Symptoms may vary from mild to severe, and usually begin six to 30 days after exposure. Often there is a gradual onset of a high
fever Fever, also referred to as pyrexia, is defined as having a above the due to an increase in the body's temperature . There is not a single agreed-upon upper limit for normal temperature with sources using values between in humans. The increa ...

fever
over several days. This is commonly accompanied by weakness,
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than ...
,
constipation Constipation refers to bowel movements that are infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement. Complications f ...
,
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe headaches. Headaches can occur ...

headache
s, and mild vomiting. Some people develop a skin rash with rose colored spots. In severe cases, people may experience confusion. Without treatment, symptoms may last weeks or months.
Diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movement frame, Anatomy of the anus and rectum Defecation is the final act of digestion Digestion is the breakdown of large ins ...
is uncommon. Other people may carry the bacterium without being affected, but they are still able to spread the disease to others. Typhoid fever is a type of
enteric The gastrointestinal tract, (GI tract, GIT, digestive tract, digestion tract, alimentary canal) is the tract from the mouth to the anus which includes all the organs of the digestive system The human digestive system consists of the human ...
fever, along with
paratyphoid fever Paratyphoid fever, also known simply as paratyphoid, is a bacterial infection caused by one of the three serotype, types of ''Salmonella enterica subsp. enterica, Salmonella enterica''. Symptoms usually begin 6–30 days after exposure and are the ...
. So far, ''S. enterica'' Typhi is only known to infect and replicate within humans. The cause is the bacterium ''Salmonella enterica'' subsp. enterica
serovar A serotype or serovar is a distinct variation within a species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often de ...
Typhi growing in the
intestine The gastrointestinal tract, (GI tract, GIT, digestive tract, digestion tract, alimentary canal) is the tract from the mouth to the anus which includes all the organs of the digestive system The human digestive system consists of the human ...

intestine
s, ,
mesenteric lymph nodes The superior mesenteric lymph nodes may be divided into three principal groups: * mesenteric lymph nodes * ileocolic lymph nodes * mesocolic lymph nodes Structure Mesenteric lymph nodes The mesenteric lymph nodes or mesenteric glands are one of t ...
,
spleen The spleen is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's ...

spleen
,
liver The liver is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's t ...

liver
,
gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow Organ (anatomy), organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath ...

gallbladder
,
bone marrow Bone marrow is a semi-solid tissue Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a specific function * ''Triphosa haesitata'', a species of geometer moth found in North America * ''Triphos ...
and
blood Blood is a body fluid Body fluids, bodily fluids, or biofluids are liquid A liquid is a nearly incompressible In fluid mechanics or more generally continuum mechanics, incompressible flow (isochoric process, isochoric flow) refers t ...

blood
. Typhoid is spread by eating or drinking food or water contaminated with the
feces Feces ( faeces) is the solid or semi-solid remains of food that was not digested in the , and has been broken down by bacteria in the . Feces contains a relatively small amount of products such as bacterially altered , and dead epithelial cel ...

feces
from an infected person. Risk factors include limited access to clean drinking water, and poor
sanitation Sanitation refers to public health Public health has been defined as "the science and art of Preventive healthcare, preventing disease", prolonging life and improving quality of life through organized efforts and informed choices of society ...

sanitation
. Those who have not yet been exposed to the pathogen and ingest contaminated drinking water or food are most at risk for developing symptoms. As far as we currently know, only humans can be infected; there are no known animal reservoirs. Diagnosis is by from patient samples or detecting an immune response to the pathogen from blood samples. Recently, new advances in large-scale data collection and analysis are allowing researchers to develop better diagnostics - such as detecting changing abundances of small molecules in the blood that may specifically indicate typhoid fever. Diagnostic tools in regions where typhoid is most prevalent are quite limited in terms of accuracy and specificity; the time required for a proper diagnosis, increasing spread of antibiotic resistance, and the cost of testing is also a concern for under-resourced healthcare systems. A
typhoid vaccine Typhoid vaccines are vaccine A vaccine is a biological preparation that provides active to a particular . A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms ...
can prevent about 40 to 90% of cases during the first two years. The vaccine may have some effect for up to seven years. For those at high risk or people traveling to areas where the disease is common, vaccination is recommended. Other efforts to prevent the disease include providing clean
drinking water Drinking water, also known as potable water, is that is safe to or use for . The amount of drinking water required to maintain good health varies, and depends on physical activity level, age, health-related issues, and environmental conditions ...

drinking water
, good
sanitation Sanitation refers to public health Public health has been defined as "the science and art of Preventive healthcare, preventing disease", prolonging life and improving quality of life through organized efforts and informed choices of society ...

sanitation
, and
handwashing Hand washing (or handwashing), also known as hand hygiene, is the act of cleaning one's hand A hand is a prehensile, multi- fingered appendage located at the end of the forearm The forearm is the region of the upper limb between the Elbo ...

handwashing
. Until an individual's infection is confirmed as cleared, the individual should not prepare food for others. The disease is treated with
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy, ...
s such as
azithromycin Azithromycin is an antibiotic An antibiotic is a type of antimicrobial An antimicrobial is an agent that kills microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism In biology, an organism (from Anci ...

azithromycin
,
fluoroquinolones A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidal A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria Bacteria (; common noun bacteria, singular bacterium) ar ...
, or
third-generation cephalosporin The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as "''Cephalosporium''". Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...
s. Resistance to these antibiotics has been developing, which has made treatment of the disease more difficult. In 2015, 12.5 million new cases worldwide were reported. The disease is most common in India. Children are most commonly affected. Rates of disease decreased in the
developed world A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state A sovereign state is a political entity that is represented by one centralized governmen ...
in the 1940s as a result of improved sanitation and use of antibiotics to treat the disease. Each year in the United States, about 400 cases are reported and the disease occurs in an estimated 6,000 people. In 2015, it resulted in about 149,000 deaths worldwide – down from 181,000 in 1990 (about 0.3% of the global total). The risk of death may be as high as 20% without treatment. With treatment, it is between 1 and 4%.
Typhus Typhus, also known as typhus fever, is a group of infectious diseases An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to the infectious agents ...
is a different disease. Due to the similarity in symptoms, they were not recognized as distinct diseases until the 1800s. The name typhoid means "resembling typhus".


Signs and symptoms

Classically, the progression of untreated typhoid fever is divided into three distinct stages, each lasting about a week. Over the course of these stages, the patient becomes exhausted and emaciated. * In the first week, the body temperature rises slowly, and fever fluctuations are seen with relative
bradycardia Bradycardia is a condition typically defined wherein an individual has a resting heart rateHeart rate is the speed of the heartbeat measured by the number of contractions (beats) of the heart The heart is a muscle, muscular Organ (anatom ...
( Faget sign),
malaise As a medical term, malaise is a feeling of general suffering, discomfort, uneasiness, or pain, and often the first sign of an infection or other disease. The word has existed in French language, French since at least the 12th century. The term i ...
, headache, and cough. A bloody nose (
epistaxis A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can also flow down into the stomach and cause nausea and vomiting Vomiting (also known as puking, throwing up, barfing, emesis, among other names) is the involuntary ...
) is seen in a quarter of cases, and abdominal pain is also possible. A decrease in the number of circulating white blood cells (
leukopenia Leukopenia () is a decrease in the number of leukocytes. Found in the blood, they are the white blood cells, and are the body's primary defense against an infection An infection is the invasion of an organism's body Tissue (biology), tissues b ...
) occurs with eosinopenia and relative
lymphocytosis Lymphocytosis is an increase in the number or proportion of lymphocyte A lymphocyte is a type of white blood cell in the immune system The immune system is a network of biological processes that protects an organism In biology, an org ...
; blood cultures are positive for ''Salmonella enterica'' subsp. enterica serovar Typhi. The Widal test is usually negative in the first week. * In the second week, the person is often too tired to get up, with high fever in plateau around and bradycardia (sphygmothermic dissociation or Faget sign), classically with a dicrotic pulse wave.
Delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline mental functioning, that develops over a short period of time, typically hours to days. Delirium is a syndrome A syndrome is a set of medi ...
can occur, where the patient is often calm, but sometimes becomes agitated. This delirium has led to typhoid receiving the nickname "nervous fever".
Rose spots Rose spots are red macules 2-4 millimeters in diameter occurring in patients with enteric fever (which includes typhoid and paratyphoid). These fevers occur following infection by ''Salmonella typhi'' and ''Salmonella paratyphi'' respectively. Ros ...
appear on the lower chest and abdomen in around a third of patients.
Rhonchi Respiratory sounds, also known as lung sounds or breath sounds, refer to the specific sounds generated by the movement of air through the respiratory system. These may be easily audible or identified through auscultation of the respiratory system ...
(rattling breathing sounds) are heard in the base of the lungs. The abdomen is distended and painful in the right lower quadrant, where a rumbling sound can be heard. Diarrhea can occur in this stage, but constipation is also common. The spleen and liver are enlarged (
hepatosplenomegaly Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of both the liver The liver is an organ only found in vertebrates which detoxifies various metabolites, synthesizes proteins and produces biochemicals necessary f ...
) and tender, and liver
transaminases Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid cont ...
are elevated. The Widal test is strongly positive, with antiO and antiH antibodies. Blood cultures are sometimes still positive at this stage. * In the third week of typhoid fever, a number of complications can occur: ** The fever is still very high and oscillates very little over 24 hours.
Dehydration In physiology, dehydration is a lack of total body water In physiology Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology Biology is the natural science that studie ...

Dehydration
ensues along with malnutrition, and the patient is delirious (typhoid state). One-third of affected individuals develop a macular rash on the trunk. ** Intestinal haemorrhage due to bleeding in congested
Peyer's patches Peyer's patches (or aggregated lymphoid nodules) are organized lymph node, lymphoid follicles, named after the 17th-century Swiss people, Swiss anatomist Johann Conrad Peyer. They are an important part of gut associated lymphoid tissue usually foun ...
occurs; this can be very serious, but is usually not fatal. ** Intestinal perforation in the distal
ileum The ileum () is the final section of the small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from f ...
is a very serious complication and is frequently fatal. It may occur without alarming symptoms until
septicaemia Sepsis is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is followed by suppression of the immune system. Common signs and symptoms include fever, t ...
or diffuse
peritonitis Peritonitis is inflammation of the peritoneum, the lining of the inner wall of the abdomen and cover of the abdominal organs. Symptoms may include severe pain, swelling of the abdomen, fever, or weight loss. One part or the entire abdomen may be ...
sets in. ** Respiratory diseases such as
pneumonia Pneumonia is an inflammatory Inflammatory may refer to: * Inflammation, a biological response to harmful stimuli * The word ''inflammatory'' is also used to refer literally to fire and flammability, and figuratively in relation to comments t ...

pneumonia
and
acute bronchitis Acute bronchitis, also known as a chest cold, is short-term bronchitis – inflammation of the bronchus, bronchi (large and medium-sized airways) of the lungs. The most common symptom is a cough. Other symptoms include sputum, coughing up mucus, ...
**
Encephalitis Encephalitis is inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogen In biology Biology is the natural science that studies life and living ...
** Neuropsychiatric symptoms (described as "muttering delirium" or "coma vigil"), with picking at bedclothes or imaginary objects ** Metastatic abscesses,
cholecystitis Cholecystitis is inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a pr ...
,
endocarditis Endocarditis is an inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogen In biology Biology is the natural science that studies life and living ...

endocarditis
, and
osteitis Osteitis is inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogen In biology Biology is the natural science that studies life and living organ ...
** Low platelet count (
thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care units, intensive care patients and is seen in 20% of med ...

thrombocytopenia
) can sometimes be seen.


Causes


Bacteria

The
Gram-negative Gram-negative bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), do ...

Gram-negative
bacterium that causes typhoid fever is ''Salmonella enterica'' subsp. enterica serovar Typhi. Based on MLST subtyping scheme, the two main sequence types of the ''S.'' Typhi are ST1 and ST2, which are currently widespread globally. The global phylogeographical analysis showed dominance of a haplotype 58 (H58) which probably originated in India during the late 1980s and is now spreading through the world carrying multidrug resistance. A more detailed genotyping scheme was reported in 2016 and is now being used widely. This scheme re-classified the nomenclature of H58 to genotype 4.3.1.


Transmission

Unlike other strains of ''
Salmonella ''Salmonella'' is a genus Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruse ...
'', no animal carriers of typhoid are known. Humans are the only known carriers of the bacteria. ''S. enterica'' subsp. enterica serovar Typhi is spread through the fecal-oral route from individuals who are currently infected and from
asymptomatic carriers An asymptomatic carrier is a person or other organism that has become infection, infected with a pathogen, but that displays no signs or symptoms. Although unaffected by the pathogen, carriers can transmit it to others or develop symptoms in late ...
of the bacteria. An asymptomatic human carrier is an individual who is still excreting typhoid bacteria in their stool a year after the acute stage of the infection.


Pathogenesis and Pathology


Diagnosis

Diagnosis is made by any
blood Blood is a body fluid Body fluids, bodily fluids, or biofluids are liquid A liquid is a nearly incompressible In fluid mechanics or more generally continuum mechanics, incompressible flow (isochoric process, isochoric flow) refers t ...
,
bone marrow Bone marrow is a semi-solid tissue Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a specific function * ''Triphosa haesitata'', a species of geometer moth found in North America * ''Triphos ...
, or
culture Culture () is an umbrella term which encompasses the social behavior and Norm (social), norms found in human Society, societies, as well as the knowledge, beliefs, arts, laws, Social norm, customs, capabilities, and habits of the individuals i ...

culture
s and with the Widal test (demonstration of
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique mo ...

antibodies
against ''Salmonella''
antigens In immunology Immunology is a branch of biology and Medicine that covers the study of immune systems in all organisms. Immunology charts, measures, and contextualizes the Physiology, physiological functioning of the immune system in states of ...
O-somatic and H-flagellar). In epidemics and less wealthy countries, after excluding
malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign fo ...

malaria
,
dysentery Dysentery () is a type of gastroenteritis Gastroenteritis, also known as infectious diarrhea and gastro, is inflammation of the gastrointestinal tract The gastrointestinal tract, (GI tract, GIT, digestive tract, digestion tract, aliment ...
, or
pneumonia Pneumonia is an inflammatory Inflammatory may refer to: * Inflammation, a biological response to harmful stimuli * The word ''inflammatory'' is also used to refer literally to fire and flammability, and figuratively in relation to comments t ...

pneumonia
, a therapeutic trial time with
chloramphenicol Chloramphenicol is an antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medicat ...

chloramphenicol
is generally undertaken while awaiting the results of the Widal test and cultures of the blood and stool.


Widal test

Widal test is used to identify specific antibodies in serum of people with typhoid by using antigen-antibody interactions. In this test, the serum is mixed with a dead bacterial suspension of salmonella having specific antigens on it. If the patient's serum is carrying antibodies against those antigens then they get attached to them forming clumping which indicated the positivity of the test. If clumping does not occur then the test is negative. The Widal test is time-consuming and prone to significant false positive results. The test may also be falsely negative in the early course of illness. However, unlike the Typhidot test, the Widal test quantifies the specimen with .


Rapid diagnostic tests

Rapid diagnostic tests such as Tubex, Typhidot, and Test-It have shown moderate diagnostic accuracy.


Typhidot

The test is based on the presence of specific IgM and IgG antibodies to a specific 50 Kd OMP antigen. This test is carried out on a cellulose nitrate membrane where a specific ''S. typhi'' outer membrane protein is attached as fixed test lines. It separately identifies IgM and IgG antibodies. IgM shows recent infection whereas IgG signifies remote infection. The sample pad of this kit contains colloidal gold-anti-human IgG or gold-anti-human IgM. If the sample contains IgG and IgM antibodies against those antigens then they will react and get turned into red color. This complex will continue to move forward and the IgG and IgM antibodies will get attached to the first test line where IgG and IgM antigens are present giving a pink-purplish colored band. This complex will continue to move further and reach the control line which consists of rabbit anti-mouse antibody which bends the mouse anti-human IgG or IgM antibodies. The main purpose of the control line is to indicate a proper migration and reagent color. The typhidot test becomes positive within 2–3 days of infection. Two colored bands indicate a positive test. Single-band of control line indicates a negative test. Single-band of first fixed line or no bands at all indicates invalid tests. The most important limitation of this test is that it is not quantitative and the result is only positive or negative.


Tubex test

Tubex test contains two types of particles brown magnetic particles coated with antigen and blue indicator particles coated with O9 antibody. During the test, if antibodies are present in the serum then they will get attached to the brown magnetic particles and settle down at the base and the blue indicator particles remain up in the solution giving a blue color that indicates positivity of the test. If the serum does not have an antibody in it then the blue particle gets attached to the brown particles and settled down at the bottom giving no color to the solution which means the test is negative and they do not have typhoid.


Treatment


Oral rehydration therapy

The rediscovery of
oral rehydration therapy Oral rehydration therapy (ORT) is a type of fluid replacement used to prevent and treat dehydration, especially due to diarrhea. It involves drinking water with modest amounts of sugar and salts, specifically sodium and potassium. Oral rehydratio ...
in the 1960s provided a simple way to prevent many of the deaths of
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery defecation, bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration of ...
l diseases in general.


Antibiotics

Where resistance is uncommon, the treatment of choice is a
fluoroquinolone A quinolone antibiotic is a member of a large group of broad-spectrum antibiotic, broad-spectrum bacteriocidals that share a bicyclic molecule, bicyclic core structure related to the substance 4-Quinolone, 4-quinolone. They are used in human and ...
such as
ciprofloxacin Ciprofloxacin is an antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain type of infectious diarrhea, respiratory tract infections, skin infections, typhoid f ...

ciprofloxacin
. Otherwise, a third-generation cephalosporin such as
ceftriaxone Ceftriaxone, sold under the brand name Rocephin, is an antibiotic An antibiotic is a type of antimicrobial substance active against bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biologic ...

ceftriaxone
or is the first choice.
Cefixime Cefixime, sold under the brand name Suprax among others, is an antibiotic An antibiotic is a type of antimicrobial substance active against bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), ...

Cefixime
is a suitable oral alternative. Typhoid fever, when properly treated, is not fatal in most cases. Antibiotics, such as
ampicillin Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis Meningitis is an Acute (medical), acute inflammation of the protective me ...

ampicillin
, chloramphenicol, trimethoprim-sulfamethoxazole,
amoxicillin Amoxicillin is an antibiotic An antibiotic is a type of antimicrobial An antimicrobial is an agent that kills microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism In biology, an organism () is ...

amoxicillin
, and ciprofloxacin, have been commonly used to treat typhoid fever. Treatment of the disease with antibiotics reduces the case-fatality rate to about 1%. Without treatment, some patients develop sustained fever, bradycardia, hepatosplenomegaly, abdominal symptoms, and occasionally, pneumonia. In white-skinned patients, pink spots, which fade on pressure, appear on the skin of the trunk in up to 20% of cases. In the third week, untreated cases may develop gastrointestinal and cerebral complications, which may prove fatal in up to 10–20% of cases. The highest case fatality rates are reported in children under 4 years. Around 2–5% of those who contract typhoid fever become chronic carriers, as bacteria persist in the biliary tract after symptoms have resolved.


Surgery

Surgery is usually indicated if
intestinal perforation Gastrointestinal perforation, also known as ruptured bowel, is a hole in the wall of part of the gastrointestinal tract. The gastrointestinal tract includes the esophagus The esophagus (American English) or oesophagus (British English; Ameri ...
occurs. One study found a 30-day mortality rate of 9% (8/88), and surgical site infections at 67% (59/88), with the disease burden borne predominantly by low-resource countries. For surgical treatment, most surgeons prefer simple closure of the perforation with drainage of the
peritoneum The peritoneum is the serous membrane In anatomy Anatomy (Greek ''anatomē'', 'dissection') is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure ...

peritoneum
. Small-bowel resection is indicated for patients with multiple perforations. If antibiotic treatment fails to eradicate the hepatobiliary carriage, the
gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow Organ (anatomy), organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath ...

gallbladder
should be resected.
Cholecystectomy Cholecystectomy is the surgical removal of the gallbladder In vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular eukaryotic organisms that form the Kingdom (biology), biolo ...
is sometimes successful, especially in patients with
gallstone A gallstone is a stone A rock is any naturally occurring solid mass or aggregate of minerals or mineraloid matter. It is categorized by the minerals included, its chemical composition and the way in which it is formed. Rocks form the Ear ...

gallstone
s, but is not always successful in eradicating the carrier state because of persisting
hepatic The liver is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's t ...
infection.


Resistance

As resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and
streptomycin Streptomycin is an antibiotic medication used to treat a number of bacterial infections. This includes tuberculosis, Mycobacterium avium complex, ''Mycobacterium avium'' complex, endocarditis, brucellosis, Burkholderia infection, ''Burkholderia' ...

streptomycin
is now common, these agents are no longer used as first–line treatment of typhoid fever. Typhoid resistant to these agents is known as multidrug-resistant typhoid. Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and
Southeast Asia Southeast Asia, also spelled South East Asia and South-East Asia, and also known as Southeastern Asia or SEA, is the geographical United Nations geoscheme for Asia#South-eastern Asia, southeastern subregion of Asia, consisting of the regions ...

Southeast Asia
. Many centres are shifting from using ciprofloxacin as the first line for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand, or Vietnam. For these people, the recommended first-line treatment is
ceftriaxone Ceftriaxone, sold under the brand name Rocephin, is an antibiotic An antibiotic is a type of antimicrobial substance active against bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biologic ...

ceftriaxone
. Also,
azithromycin Azithromycin is an antibiotic An antibiotic is a type of antimicrobial An antimicrobial is an agent that kills microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism In biology, an organism (from Anci ...

azithromycin
has been suggested to be better at treating resistant typhoid in populations than both fluoroquinolone drugs and ceftriaxone. Azithromycin can be taken by mouth and is less expensive than ceftriaxone which is given by injection. A separate problem exists with laboratory testing for reduced susceptibility to ciprofloxacin; current recommendations are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against
nalidixic acid Nalidixic acid (tradenames Nevigramon, Neggram, Wintomylon and WIN 18,320) is the first of the synthetic quinolone antibiotics. In a technical sense, it is a naphthyridone, not a quinolone: its ring structure is a 1,8-naphthyridine nucleus that c ...

nalidixic acid
(NAL), and that isolates that are sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", but that isolates testing sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin". However, an analysis of 271 isolates showed that around 18% of isolates with a reduced susceptibility to
fluoroquinolones A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidal A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria Bacteria (; common noun bacteria, singular bacterium) ar ...
, the class which CIP belongs, ( 0.125–1.0 mg/l) would not be picked up by this method.


Epidemiology

In 2000, typhoid fever caused an estimated 21.7 million illnesses and 217,000 deaths. It occurs most often in children and young adults between 5 and 19 years old. In 2013, it resulted in about 161,000 deaths – down from 181,000 in 1990. Infants, children, and adolescents in south-central and Southeast Asia experience the greatest burden of illness. Outbreaks of typhoid fever are also frequently reported from sub-Saharan Africa and countries in Southeast Asia. In 2000, more than 90% of morbidity and mortality due to typhoid fever occurred in Asia. In the United States, about 400 cases occur each year, and 75% of these are acquired while traveling internationally. Historically, before the antibiotic era, the
case fatality rate In epidemiology Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and risk factor, determinants of health and disease conditions in defined populations. It is a cornerstone of public health, and shapes ...
of typhoid fever was 10–20%. Today, with prompt treatment, it is less than 1%. However, about 3–5% of individuals who are infected develop a chronic infection in the gall bladder. Since ''S. enterica'' subsp. enterica serovar Typhi is human-restricted, these chronic carriers become the crucial reservoir, which can persist for decades for further spread of the disease, further complicating the identification and treatment of the disease. Lately, the study of ''S. enterica'' subsp. enterica serovar Typhi associated with a large outbreak and a carrier at the genome level provides new insights into the pathogenesis of the pathogen. In industrialized nations, water sanitation and food handling improvements have reduced the number of cases. Developing nations, such as those found in parts of Asia and Africa, have the highest rates of typhoid fever. These areas have a lack of access to clean water, proper sanitation systems, and proper health-care facilities. For these areas, such access to basic public-health needs is not in the near future. In 2004–2005 an outbreak in the
Democratic Republic of Congo The Democratic Republic of the Congo ( french: République démocratique du Congo (RDC) ), also known as Congo-Kinshasa, DR Congo, the DRC, the DROC, or the Congo, and formerly Zaire Zaire (, ), officially the Republic of Zaire (frenc ...

Democratic Republic of Congo
resulted in more than 42,000 cases and 214 deaths. Since November 2016,
Pakistan Pakistan, . Pronounced variably in English as , , , and . officially the Islamic Republic of Pakistan, is a country in South Asia. It is the world's List of countries and dependencies by population, fifth-most populous country, with a popul ...

Pakistan
has had an outbreak of extensively
drug-resistant Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial An antimicrobial is an agent that kills microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism In biology, an organis ...
(XDR) typhoid fever. In Europe, a report based on data for 2017 retrieved from The European Surveillance System (TESSy) on the distribution of confirmed typhoid and
paratyphoid fever Paratyphoid fever, also known simply as paratyphoid, is a bacterial infection caused by one of the three serotype, types of ''Salmonella enterica subsp. enterica, Salmonella enterica''. Symptoms usually begin 6–30 days after exposure and are the ...
cases found that 22 EU/EEA countries reported a total of 1,098 cases, 90.9% of which were travel-related, mainly acquired during travel to countries particularly in
South Asia South Asia is the southern region of Asia Asia () is 's largest and most populous , located primarily in the and . It shares the continental of with the continent of and the continental landmass of with both Europe and . Asia cov ...

South Asia
.


Prevention

Sanitation and hygiene are important to prevent typhoid. It can only spread in environments where human feces are able to come into contact with food or drinking water. Careful food preparation and washing of hands are crucial to prevent typhoid. Industrialization, and in particular, the invention of the automobile, contributed greatly to the elimination of typhoid fever, as it eliminated the public-health hazards associated with having horse manure in public streets, which led to large number of flies, which are known as
vectors Vector may refer to: Biology *Vector (epidemiology), an agent that carries and transmits an infectious pathogen into another living organism; a disease vector *Vector (molecular biology), a DNA molecule used as a vehicle to artificially carr ...
of many pathogens, including ''Salmonella'' spp. According to statistics from the United States
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services The United States Department of Heal ...
, the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid fever in the United States.


Vaccination

Two
typhoid vaccine Typhoid vaccines are vaccine A vaccine is a biological preparation that provides active to a particular . A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms ...
s are licensed for use for the prevention of typhoid: the live, oral
Ty21a Ty21a is a live attenuated bacterial vaccine that protects against typhoid Typhoid fever, also known as typhoid, is a disease caused by ''Salmonella'' serotype Typhi bacteria. Symptoms may vary from mild to severe, and usually begin six to 30 ...
vaccine (sold as Vivotif by Crucell Switzerland AG) and the injectable typhoid polysaccharide vaccine (sold as Typhim Vi by Sanofi Pasteur and Typherix by GlaxoSmithKline). Both are efficacious and recommended for travellers to areas where typhoid is endemic. Boosters are recommended every five years for the oral vaccine and every two years for the injectable form. An older, killed whole-cell vaccine is still used in countries where the newer preparations are not available, but this vaccine is no longer recommended for use because it has a higher rate of side effects (mainly pain and inflammation at the site of the injection). To help decrease rates of typhoid fever in developing nations, the World Health Organization (WHO) endorsed the use of a vaccination program starting in 1999. Vaccinations have proven to be a great way at controlling outbreaks in high incidence areas. Just as important, it is also very cost-effective. Vaccination prices are normally low, less than US$1 per dose. Because the price is low, poverty-stricken communities are more willing to take advantage of the vaccinations. Although vaccination programs for typhoid have proven to be effective, they alone cannot eliminate typhoid fever. Combining the use of vaccines with increasing public health efforts is the only proven way to control this disease. Since the 1990s, two typhoid fever vaccines have been recommended by the WHO. The ViPS vaccine is given via injection, while the Ty21a is taken through capsules. Only people 2 years or older are recommended to be vaccinated with the ViPS vaccine, and it requires a revaccination after 2–3 years with a 55–72% vaccine efficacy. The alternative Ty21a vaccine is recommended for people 5 years or older, and has a 5-7-year duration with a 51–67% vaccine efficacy. The two different vaccines have been proven as a safe and effective treatment for epidemic disease control in multiple regions. A version combined with
hepatitis A Hepatitis A is an infectious disease of the liver caused by ''Hepatovirus A'' (HAV); it is a type of viral hepatitis. Many cases have few or no symptoms, especially in the young. The time between infection and symptoms, in those who develop them ...
is also available. Results of a phase 3 trial of typhoid conjugate vaccine (TCV) in December 2019 reported 81% fewer cases among children.


History


Early descriptions

The
plague of Athens The Plague of Athens ( grc, Λοιμὸς τῶν Ἀθηνῶν}, ) was an epidemic An epidemic (from Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially th ...
, during the
Peloponnesian War The Peloponnesian War (431–404 BC) was an ancient Greek Ancient Greek includes the forms of the Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to ...

Peloponnesian War
, was most likely an outbreak of typhoid fever. During the war,
Athenians , image_skyline = File:Athens Montage L.png, center, 275px, alt=Athens montage. Clicking on an image in the picture causes the browser to load the appropriate article. rect 15 15 985 460 Acropolis of Athens rect 15 475 485 ...
retreated into a walled-in city to escape attack from the
Sparta Sparta (Doric Greek Doric or Dorian ( grc, Δωρισμός, Dōrismós) was an . Its variants were spoken in the southern and eastern as well as in , , , , , some islands in the southern and some cities on the south east coast of ...

Sparta
ns. This massive influx of humans into a concentrated space overwhelmed the water supply and waste infrastructure, likely leading to unsanitary conditions as fresh water became harder to obtain and waste became more difficult to collect and remove beyond the city walls. In 2006, examining the remains for a mass burial site from Athens from around the time of the plague (~430 B.C.) revealed that fragments of DNA similar to modern day ''S.'' Typhi DNA were detected, whereas ''
Yersinia pestis ''Yersinia pestis'' (''Y. pestis'') (formerly ''Pasteurella __NOTOC__ ''Pasteurella'' is a genus Genus (plural genera) is a taxonomic rank Taxonomy (general) is the practice and science of classification of things or concepts, including th ...

Yersinia pestis
'' (plague), ''
Rickettsia prowazekii ''Rickettsia prowazekii'' is a species of gram-negative Gram-negative bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They constitute a large domain (biology), ...
'' (typhus), ''
Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria Pathogenic bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of biological cell The cell (from Latin ''cella'', mea ...

Mycobacterium tuberculosis
'',
cowpox virus Cowpox is an infectious disease caused by the cowpox virus (CPXV). The virus, part of the genus ''Orthopoxvirus'', is closely related to the ''vaccinia'' virus. The virus is Zoonosis, zoonotic, meaning that it is transferable between species, su ...
, and ''
Bartonella henselae ''Bartonella henselae'', formerly ''Rochalimæa'', is a proteobacterium that is the causative agent of cat-scratch disease (bartonellosis). ''Bartonella henselae'' is a member of the genus ''Bartonella'', one of the most common types of bacteri ...
'' were not detected in any of the remains tested. It is possible that the Roman emperor
Augustus Caesar Caesar Augustus (23 September 63 BC19 August AD 14) was the first Roman emperor The Roman emperor was the ruler of the Roman Empire during the History of the Roman Empire, imperial period (starting in 27 BC). The emperors used a variet ...

Augustus Caesar
suffered from either a liver abscess or typhoid fever, and survived by using ice baths and cold compresses as a means of treatment for his fever. There is a statue of the Greek physician,
Antonius Musa Antonius Musa (Greek language, Greek ) was a Greek botanist and the Roman Emperor Augustus (emperor), Augustus's physician; Antonius was a freedman who received freeborn status along with other honours. In the year 23 BC, when Augustus was seriou ...
, who treated his fever.


Definition and evidence of transmission

The French doctors Pierre-Fidele Bretonneau and Pierre-Charles-Alexandre Louis are credited with describing typhoid fever as a specific disease, unique from
typhus Typhus, also known as typhus fever, is a group of infectious diseases An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to the infectious agents ...
. Both doctors performed autopsies on individuals who died in Paris due to fever - and indicated that many had lesions on the
Peyer's patch Peyer's patches (or aggregated lymphoid nodules) are organized lymphoid follicles, named after the 17th-century Swiss Swiss may refer to: * the adjectival form of Switzerland *Swiss people Places *Swiss, Missouri *Swiss, North Carolina *Swiss, We ...

Peyer's patch
es which correlated with distinct symptoms before death. British medics were skeptical of the differentiation between typhoid and typhus because both were endemic to Britain at that time. However, in France only typhoid was present circulating in the population. Pierre-Charlles-Alexandre Louis also performed case studies and statistical analysis to demonstrate that typhoid was contagious - and that persons who already had the disease seemed to be protected. Afterward, several American doctors confirmed these findings, and then
Sir William Jenner Sir William Jenner, 1st Baronet, Order of the Bath, GCB, Physician Extraordinary to His Majesty, QHP, Royal College of Physicians, FRCP, Royal Society, FRS (30 January 181511 December 1898) was a significant English physician primarily known for h ...
convinced any remaining skeptics that typhoid is a specific disease recognizable by lesions in the Peyer's patches by examining sixty six autopsies from fever patients and concluding that the symptoms of headaches, diarrhea, rash spots, and abdominal pain were only present in patients which then had intestinal lesions after death; which solidified the association of the disease with the intestinal tract and gave the first clue to the route of transmission. In 1847 learned of an epidemic of typhoid fever in Clifton, and identified that all 13 of 34 residents who had contracted the disease drew their drinking water from the same well. Notably, this observation was two years prior to
John Snow John Snow (15 March 1813 – 16 June 1858) was an English physician and a leader in the development of anaesthesia and medical hygiene. He is considered one of the founders of modern epidemiology, in part because of his work in tracing the s ...

John Snow
discovering the route of contaminated water as the cause for a
cholera Cholera is an infection An infection is the invasion of an organism's body by , their multiplication, and the reaction of tissues to the infectious agents and the s they produce. An infectious disease, also known as a transmissible disea ...

cholera
outbreak. Budd later became health officer of
Bristol Bristol () is a city A city is a large human settlement.Goodall, B. (1987) ''The Penguin Dictionary of Human Geography''. London: Penguin.Kuper, A. and Kuper, J., eds (1996) ''The Social Science Encyclopedia''. 2nd edition. London: Routle ...

Bristol
and ensured a clean water supply, and documented further evidence of typhoid as a water-borne illness throughout his career.


Cause

Polish scientist Tadeusz Browicz described a short bacillus in the organs and feces of typhoid victims in 1874. Browicz was able to isolate and grow the bacilli but did not go as far as to insinuate or prove that they caused the disease. In April 1880, three months prior to Eberth's publication,
Edwin Klebs Theodor Albrecht Edwin Klebs (6 February 1834 – 23 October 1913) was a German-Swiss microbiologist A microbiologist (from Greek ) is a scientist A scientist is a person who conducts Scientific method, scientific research to advance knowl ...

Edwin Klebs
described short and
filamentous The word filament, which is descended from Latin ''filum'' meaning "Thread (yarn), thread", is used in English for a variety of thread-like structures, including: In commerce * Fiber or, more loosely, yarn * Filament (textiles) In physics and en ...
bacilli in the
Peyer's patch Peyer's patches (or aggregated lymphoid nodules) are organized lymphoid follicles, named after the 17th-century Swiss Swiss may refer to: * the adjectival form of Switzerland *Swiss people Places *Swiss, Missouri *Swiss, North Carolina *Swiss, We ...

Peyer's patch
es in typhoid victims. The bacterium's role in disease was speculated but not confirmed. In 1880, described a bacillus that he suspected was the cause of typhoid. Eberth is given credit for discovering the bacterium definitively by successfully isolating the same bacterium from 18 of 40 typhoid victims and failing to discover the bacterium present in any "control" victims of other diseases. In 1884, pathologist Georg Theodor August Gaffky (1850–1918) confirmed Eberth's findings. Gaffky isolated the same bacterium as Eberth from the spleen of a typhoid victim, and was able to grow the bacterium on solid media. The organism was given names such as Eberth's bacillus, ''Eberthella'' Typhi, and Gaffky-Eberth bacillus. Today, the bacillus that causes typhoid fever goes by the scientific name ''
Salmonella enterica ''Salmonella enterica'' (formerly ''Salmonella choleraesuis'') is a rod-headed, flagellate 's '' Artforms of Nature'', 1904 (''Giardia lamblia'') ('' Chlamydomonas'') A flagellate is a cell or organism with one or more whip-like Appendage, ap ...
'' serovar Typhi.


Chlorination of water

Most developed countries had declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. In 1893 attempts were made to chlorinate the water supply in
Hamburg en, Hamburgian(s) , timezone1 = Central (CET) , utc_offset1 = +1 , timezone1_DST = Central (CEST) , utc_offset1_DST = +2 , postal_code_type = Post ...

Hamburg
, Germany and in 1897
Maidstone Maidstone is the largest town A town is a human settlement. Towns are generally larger than villages and smaller than city, cities, though the criteria to distinguish between them vary considerably in different parts of the world. Origi ...
, England was the first town to have its entire water supply chlorinated. In 1905, following an outbreak of typhoid fever, the City of
Lincoln, England Lincoln () is a cathedral city, non-metropolitan district, and the county town of Lincolnshire, England. The Lincoln district had a 2012 population of 94,600. The 2011 census gave the Lincoln Urban Area, urban area of Lincoln, including North H ...
instituted permanent water chlorination. The first permanent disinfection of drinking water in the US was made in 1908 to the
Jersey City, New Jersey Jersey City is the second-most populous city in the U.S. state of New Jersey, after Newark, New Jersey, Newark.
, water supply. Credit for the decision to build the chlorination system has been given to John L. Leal. The chlorination facility was designed by George W. Fuller. Outbreaks in traveling military groups led to the creation of the Lyster bag in 1915; a bag with a faucet which can be hung from a tree or pole, filled with water, and comes with a chlorination tablet to drop into the water. The Lyster bag was essential for the survival of American soldiers in the
Vietnam War {{Infobox military conflict , conflict = Vietnam War , partof = the Indochina Wars The Indochina Wars ( vi, Chiến tranh Đông Dương) were a series of wars fought in Southeast Asia Southeast Asia, also spelled ...
.


Direct transmission and carriers

There were several occurrences of milk delivery men spreading typhoid fever throughout the communities they served. Although typhoid is not spread through milk itself, there were several examples of milk distributors in many locations watering their milk down with contaminated water, or cleaning the glass bottles the milk was placed in with contaminated water.
Boston Boston (, ), officially the City of Boston, is the capital city, capital and List of municipalities in Massachusetts, most populous city of the Commonwealth (U.S. state), Commonwealth of Massachusetts in the United States and 21st List of Unit ...

Boston
had two such cases around the turn of the 20th century. In 1899 there were 24 cases of typhoid traced to a single milkman, whose wife had died of typhoid fever a week before the outbreak. In 1908, J.J. Fallon, who was also a milkman, died of typhoid fever. Following his death and confirmation of the typhoid fever diagnosis, the city conducted an investigation of typhoid symptoms and cases along his route and found evidence of a significant outbreak. A month after the outbreak was first reported, the
Boston Globe ''The Boston Globe'' is an American daily newspaper A newspaper is a periodical Periodical literature (also called a periodical publication or simply a periodical) is a category of serial Serial may refer to: Arts, entertainment, and ...

Boston Globe
published a short statement declaring the outbreak over, stating "
Jamaica Plain Jamaica Plain is a neighborhood A neighbourhood (British English British English (BrE) is the standard dialect A standard language (also standard variety, standard dialect, and standard) is a language variety that has undergone s ...
there is a slight increase, the total being 272 cases. Throughout the city there is a total of 348 cases." There was at least one death reported during this outbreak: Mrs. Sophia S. Engstrom, aged 46. Typhoid continued to ravage the
Jamaica Plain Jamaica Plain is a neighborhood A neighbourhood (British English British English (BrE) is the standard dialect A standard language (also standard variety, standard dialect, and standard) is a language variety that has undergone s ...
neighborhood in particular throughout 1908, and several more people were reported dead due to typhoid fever, although these cases were not explicitly linked to the outbreak. The Jamaica Plain neighborhood at that time was home to many working-class and poor immigrants, mostly from
Ireland Ireland ( ; ga, Éire ; Ulster Scots dialect, Ulster-Scots: ) is an island in the Atlantic Ocean, North Atlantic. It is separated from Great Britain to its east by the North Channel (Great Britain and Ireland), North Channel, the Irish Sea ...

Ireland
. The most notorious carrier of typhoid fever, but by no means the most destructive, was
Mary Mallon Mary Mallon (September 23, 1869 – November 11, 1938), commonly known as Typhoid Mary, was an Irish Americans, Irish-born American cook believed to have infected 53 people with typhoid fever, three of whom died, and the first person in the ...
, known as Typhoid Mary. Although other cases of human-to-human spread of typhoid were known at the time, the concept of an asymptomatic carrier, who was able to transmit disease, had only been hypothesized and not yet identified or proven. Mary Mallon became the first known example of an
asymptomatic carrier An asymptomatic carrier is a person or other organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biology, properties of life. It is ...
of an infectious disease, making typhoid fever the first known disease being transmissible through asymptomatic hosts. The cases and deaths caused by Mary Mallon were mainly upper-class families in New York City. At the time of Mary's tenure as a personal cook for upper-class families, New York City reported 3,000 to 4,500 cases of typhoid fever annually. In the summer of 1906 two daughters of a wealthy family and maids working in their home became ill with typhoid fever. After investigating their home water sources and ruling out water contamination, the family hired civil engineer
George Soper George Albert Soper II (2 February 1870 – 17 June 1948) was an American Waste management, sanitation engineer. He was best known for discovering Mary Mallon, also known as Typhoid Mary, a carrier of typhoid fever who had no symptoms. Biography ...
to conduct an investigation of the possible source of typhoid fever in the home. Soper described himself as an "epidemic fighter". His investigation ruled out many sources of food, and led him to question if the cook the family hired just prior to their household outbreak, Mallon, was the source. Since she had already left and begun employment elsewhere, he proceeded to track her down in order to obtain a stool sample. When he was able to finally meet Ms. Mallon in person he described her by saying "Mary had a good figure and might have been called athletic had she not been a little too heavy." In recounts of Soper's pursuit of Mallon, his only remorse appears to be that he was not given enough credit for his relentless pursuit and publication of her personal identifying information, stating that the media "rob me of whatever credit belongs to the discovery of the first typhoid fever carrier to be found in America." Ultimately, 51 cases were suspected to be caused by Ms. Mallon and 3 deaths. In 1924 the city of
Portland, Oregon Portland (, ) is the list of cities in Oregon, largest and most populous city in the U.S. state of Oregon, and the county seat, seat of Multnomah County, Oregon, Multnomah County. It is a major port in the Willamette Valley region of the Pacif ...

Portland, Oregon
experienced an outbreak of typhoid fever, consisting of 26 cases and 5 deaths, all deaths due to intestinal
hemorrhage Bleeding, also known as a hemorrhage, haemorrhage, or simply blood loss, is blood Blood is a body fluid in humans and other animals that delivers necessary substances such as nutrients and oxygen to the Cell (biology), cells and transports ...
. All cases were concluded to be due to a single milk farm worker, who was shedding large amounts of the typhoid pathogen in his urine. Misidentification of the disease, due to inaccurate Widal test results, delayed identification of the carrier and proper treatment. Ultimately, it took four samplings of different secretions from all of the dairy workers in order to successfully identify the carrier. Upon discovery, the dairy worker was forcibly quarantined for seven weeks, and regular samples were taken, most of the time the stool samples yielding no typhoid and often the urine yielding the pathogen. The carrier was reported as being 72 years old and appearing in excellent health with no symptoms. Pharmaceutical treatment decreased the amount of bacteria secreted, however, the infection was never fully cleared from the urine, and the carrier was released "under orders never again to engage in the handling of foods for human consumption." At the time of release, the authors noted "for more than fifty years he has earned his living chiefly by milking cows and knows little of other forms of labor, it must be expected that the closest surveillance will be necessary to make certain that he does not again engage in this occupation." Overall, in the early 20th century the medical profession began to identify carriers of the disease, and evidence of transmission independent of water contamination. In a 1933
American Medical Association The American Medical Association (AMA), founded in 1847 and incorporated in 1897, is the largest association and lobby group Advocacy groups, also known as special interest groups, use various forms of advocacy Advocacy is an activity by ...
publication, physicians' treatment of asymptomatic carriers is best summarized by the opening line "Carriers of typhoid bacilli are a menace". Within the same publication, the first official estimate of typhoid carriers is given: 2 to 5% of all typhoid patients, and distinguished between temporary carriers and chronic carriers. The authors further estimate that there are 4 to 5 chronic female carriers to every one male carrier, although offered no data to explain this assertion of a gender difference in the rate of typhoid carriers. As far as treatment, the authors suggest: "When recognized, carriers must be instructed as to the disposal of excreta as well as to the importance of personal cleanliness. They should be forbidden to handle food or drink intended for others, and their movements and whereabouts must be reported to the public health officers". Today, Typhoid carriers exist all over the world, but the highest incidence of asymptomatic infection is likely to occur in South/Southeast Asian and Sub-Saharan countries. The
Los Angeles County department of public health The Los Angeles County Department of Public Health (DPH) provides public health services to Los Angeles County residents. Barbara Ferrer is the Director for the Los Angeles County Department of Public Health. Muntu Davis, MD, MPH is the Los Angel ...
tracks typhoid carriers and reports the number of carriers identified within the county yearly; between 2006 and 2016 0-4 new cases of typhoid carriers were identified per year. Cases of typhoid fever must be reported within one working day from identification. As of 2018, chronic typhoid carriers must sign a "Carrier Agreement" and are required to test for typhoid shedding twice yearly, ideally every 6 months. Carriers may be released from their agreements upon fulfilling "release" requirements, based on completion of a personalized treatment plan designed with medical professionals. Fecal or gallbladder carrier release requirements: 6 consecutive negative feces and urine specimens submitted at 1-month or greater intervals beginning at least 7 days after completion of therapy. Urinary or kidney carrier release requirements: 6 consecutive negative urine specimens submitted at 1-month or greater intervals beginning at least 7 days after completion of therapy. As of 2016 the male:female ratio of carriers in Los Angeles county was 3:1. Due to the nature of asymptomatic cases, many questions remain about how individuals are able to tolerate infection for long periods of time, how to identify such cases, and efficient options for treatment. Researchers are currently working to understand asymptomatic infection with ''
Salmonella ''Salmonella'' is a genus Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruse ...
'' species by studying infections in laboratory animals, which will ultimately lead to improved prevention and treatment options for typhoid carriers. In 2002, Dr
John Gunn
described the ability of ''
Salmonella ''Salmonella'' is a genus Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruse ...
'' sp. to form Biofilm, biofilms on Gallstone, gallstones in mice, providing a model for studying carriage in the gallbladder. Dr. Denise Monack and Dr. Stanley Falkow described a mouse model of asymptomatic intestinal and systemic infection in 2004, and Dr. Denise monack, Monack went on to demonstrate that a sub-population of superspreaders are responsible for the majority of transmission to new hosts, following the Pareto principle, 80/20 rule of disease transmission, and that the intestinal microbiota likely plays a role in transmission. Dr. Denise monack, Monack's mouse model allows long-term carriage of salmonella in mesenteric lymph nodes,
spleen The spleen is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's ...

spleen
and
liver The liver is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's t ...

liver
.


Vaccine development

British bacteriologist Almroth Edward Wright first developed an effective typhoid vaccine at the Army Medical School in Netley, Hampshire. It was introduced in 1896 and used successfully by the British during the Second Boer War in South Africa. At that time, typhoid often killed more soldiers at war than were lost due to enemy combat. Wright further developed his vaccine at a newly opened research department at St Mary's Hospital (London), St Mary's Hospital Medical School in London from 1902, where he established a method for measuring protective substances (opsonin) in human blood. Wright's version of the typhoid vaccine was produced by growing the bacterium at Thermoregulation, body temperature in broth, then heating the bacteria to 60 °C to "heat inactivate" the pathogen, killing it, while keeping the surface Antigen, antigens intact. The heat-killed bacteria was then injected into a patient. To show evidence of the vaccine's efficacy, Wright then collected serum samples from patients several weeks post-vaccination, and tested their serum's ability to Agglutination (biology), agglutinate live typhoid bacteria. A "positive" result was represented by clumping of bacteria, indicating that the body was producing anti-serum (now called Antibody, antibodies) against the pathogen. Citing the example of the Second Boer War, during which many soldiers died from easily preventable diseases, Wright convinced the British Army that 10 million vaccine doses should be produced for the troops being sent to the Western Front (World War I), Western Front, thereby saving up to half a million lives during World War I. The British Army was the only combatant at the outbreak of the war to have its troops fully immunized against the bacterium. For the first time, their casualties due to combat exceeded those from disease. In 1909, Frederick F. Russell, a U.S. Army physician, adopted Wright's typhoid vaccine for use with the Army, and two years later, his vaccination program became the first in which an entire army was immunized. It eliminated typhoid as a significant cause of morbidity and mortality in the U.S. military. Typhoid vaccination for members of the American military became mandatory in 1911. Before the vaccine, the rate of typhoid fever in the military was 14,000 or greater per 100,000 soldiers. By World War I, the rate of typhoid in American soldiers was 37 per 100,000. During the second world war, the United States army authorized the use of a trivalent vaccine - containing heat-inactivated Typhoid, Paratyphoid fever, Paratyphi A and Paratyphoid fever, Paratyphi B pathogens. In 1934, discovery of the Vi capsular polysaccharide vaccine, Vi capsular antigen by Arthur Felix and Miss S. R. Margaret Pitt enabled development of the safer Vi Antigen vaccine - which is widely in use today. Arthur Felix and Margaret Pitt also isolated the strain Ty2, which became the parent strain of
Ty21a Ty21a is a live attenuated bacterial vaccine that protects against typhoid Typhoid fever, also known as typhoid, is a disease caused by ''Salmonella'' serotype Typhi bacteria. Symptoms may vary from mild to severe, and usually begin six to 30 ...
, the strain used as a live-attenuated vaccine for typhoid fever today.


Antibiotics and resistance

Chloramphenicol was isolated from ''Streptomyces'' by Dr. David Gottlieb (biologist), David Gotlieb during the 1940s. In 1948 American army doctors tested its efficacy in treating typhoid patients in Kuala Lumpur, Malaysia. Individuals who received a full course of treatment cleared the infection, whereas patients given a lower dose suffered a relapse. Importantly, asymptomatic carriers continued to shed bacilli despite chloramphenicol treatment - only ill patients were improved with chloramphenicol. Resistance to chloramphenicol became frequent in Southeast Asia by the 1950s, and today chloramphenicol is only used as a last resort due to the high prevalence of resistance.


Terminology

The disease has been referred to by various names, often associated with symptoms, such as gastric fever, enteric fever, abdominal typhus, infantile remittant fever, slow fever, nervous fever, pythogenic fever, drain fever and low fever.


Notable people

* Augustus, Emperor Augustus of Rome (suspected based on historical record but not confirmed), survived. *Albert, Prince Consort, husband of Queen Victoria of the United Kingdom, died in 24 days after first record of "feeling horribly ill". Died 14 December 1861 after suffering loss of appetite, insomnia, fever, chills, profuse sweating, vomiting, rash spots, delusions, inability to recognize family members, worsening rash on abdomen, a change in tongue color, then finally a state of extreme fatigue. Attending physician Sir William Jenner, 1st Baronet, William Jenner, an expert on Typhoid fever at the time, diagnosed him. *Edward VII of the UK, son of Queen Victoria, while still Prince of Wales, had a near fatal case of typhoid fever. *Nicholas II of Russia, Tsar Nicholas II of Russia, survived, illness was circa 1900-1901. *William Henry Harrison, the 9th President of the United States, President of the United States, United States of America, died 32 days into his term, in 1841. This is the shortest term served by a United States President. * Stephen A. Douglas, political opponent of Abraham Lincoln in 1858 and 1860, died of typhoid on June 3, 1861. * Ignacio Zaragoza, Mexican general and politician, died at the age of 33 of typhoid fever on September 8, 1862. * William Wallace Lincoln, the son of US president Abraham Lincoln, Abraham and Mary Todd Lincoln, Mary Todd Lincoln, died of typhoid in 1862. * Martha Bulloch Roosevelt, mother of president Theodore Roosevelt and paternal grandmother of Eleanor Roosevelt, died of typhoid fever in 1884. *
Mary Mallon Mary Mallon (September 23, 1869 – November 11, 1938), commonly known as Typhoid Mary, was an Irish Americans, Irish-born American cook believed to have infected 53 people with typhoid fever, three of whom died, and the first person in the ...
, "Typhoid Mary" - see history section, "carriers" for further details * Leland Stanford Jr., son of American tycoon and politician A. Leland Stanford and eponym of Stanford University, Leland Stanford Junior University, died of typhoid fever in 1884 at the age of 15. *Three of Louis Pasteur's five children died of typhoid fever. * Gerard Manley Hopkins, English poet, died of typhoid fever in 1889. * Lizzie van Zyl, South African child inmate of the Bloemfontein concentration camp during the Second Boer War, died of typhoid fever in 1901. * Tup Scott, Dr HJH 'Tup' Scott, captain of the 1886 Australian cricket team that toured England, died of typhoid in 1910. * Arnold Bennett, English novelist, died in 1932 of typhoid, two months after drinking a glass of water in a Paris hotel to prove it was safe. * Hakaru Hashimoto, Japanese medical scientist, died of typhoid fever in 1934.


Outbreaks

* Plague of Athens (suspected) * "Burning Fever" outbreak among Native Americans in the United States, indigenous Americans. Between 1607-1624, 85% of the population at the James River died from a typhoid epidemic. The World Health Organization estimates the death toll was over 6,000 during this time. *
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, Kent outbreak in 1897-1898: 1,847 patients were recorded to have typhoid fever. This outbreak is notable because it was the first time a typhoid vaccine was deployed during a civilian outbreak. Almroth WAlmoth Edward Wright's vaccine was offered to 200 healthcare providers, and of the 84 individuals who received the vaccine none developed typhoid whereas 4 who had not been vaccinated became ill. *American army in the Spanish–American War, Spanish-American war: government records estimate over 21,000 troops suffered from typhoid, resulting in 2,200 deaths. * In 1902, guests at mayoral banquets in Southampton and Winchester, England, became ill and four died, including William Stephens (Dean of Winchester), the Dean of Winchester, after consuming oysters. The infection was due to oysters sourced from Emsworth, where the oyster beds had been contaminated with raw sewage. *
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in 1908 - linked to milk delivery. See history section, "carriers" for further details. * Outbreak in upperclass New Yorkers who employed
Mary Mallon Mary Mallon (September 23, 1869 – November 11, 1938), commonly known as Typhoid Mary, was an Irish Americans, Irish-born American cook believed to have infected 53 people with typhoid fever, three of whom died, and the first person in the ...
- 51 cases and 3 deaths from 1907 to 1915. * Aberdeen, Scotland in summer 1964 - traced back to contaminated canned beef sourced from Argentina sold in markets. More than 500 patients were quarantined in the hospital for a minimum of four weeks, and the outbreak was contained without any deaths. *Dushanbe, Tajikstan in 1996 - 1997: 10,677 cases reported, 108 deaths *Kinshasa, Democratic Republic of the Congo in 2004: 43,000 cases and over 200 deaths. A prospective study of specimens collected in the same region between 2007 and 2011 revealed about one third of samples obtained from patient samples were resistant to multiple antibiotics. *Kampala, Uganda in 2015: 10,230 cases reported


References


Further reading

* * * * * * {{Authority control Typhoid fever, Intestinal infectious diseases Conditions diagnosed by stool test Waterborne diseases Wikipedia medicine articles ready to translate Wikipedia emergency medicine articles ready to translate Vaccine-preventable diseases