Rose spots on the chest of a patient with typhoid fever due to the bacterium Salmonella Typhi
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Typhoid fever — also known simply as typhoid — is a common worldwide bacterial disease transmitted by the ingestion of food or water contaminated with the feces of an infected person, which contain the bacterium Salmonella enterica subsp. enterica, serovar Typhi.
The disease has received various names, such as gastric fever, enteric fever, abdominal typhus, infantile remittant fever, slow fever, nervous fever, and pythogenic fever. The name typhoid means "resembling typhus" and comes from the neuropsychiatric symptoms common to typhoid and typhus. Despite this similarity of their names, typhoid fever and typhus are distinct diseases and are caused by different species of bacteria.
Signs and symptoms
Classically, the course of untreated typhoid fever is divided into four individual 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 (Faget sign), malaise, headache, and cough. A bloody nose (epistaxis) is seen in a quarter of cases, and abdominal pain is also possible. A decrease in the number of circulating white blood cells (leukopenia) occurs with eosinopenia and relative lymphocytosis; blood cultures are positive for Salmonella typhi or S. paratyphi. The Widal test is negative in the first week.
- In the second week of the infection, the patient lies prostrate with high fever in plateau around 40 °C (104 °F) and bradycardia (sphygmothermic dissociation or Faget sign), classically with a dicrotic pulse wave. Delirium is frequent, often calm, but sometimes agitated. This delirium gives to typhoid the nickname of "nervous fever". Rose spots appear on the lower chest and abdomen in around a third of patients. Rhonchi are heard in lung bases.
- The abdomen is distended and painful in the right lower quadrant, where borborygmi can be heard. Diarrhea can occur in this stage: six to eight stools in a day, green, comparable to pea soup, with a characteristic smell. However, constipation is also frequent. The spleen and liver are enlarged (hepatosplenomegaly) and tender, and liver transaminases are elevated. The Widal test is strongly positive, with antiO and antiH antibodies. Blood cultures are sometimes still positive at this stage.
- (The major symptom of this fever is that the fever usually rises in the afternoon up to the first and second week.)
- In the third week of typhoid fever, a number of complications can occur:
- Intestinal haemorrhage due to bleeding in congested Peyer's patches; this can be very serious, but is usually not fatal.
- Intestinal perforation in the distal ileum: this is a very serious complication and is frequently fatal. It may occur without alarming symptoms until septicaemia or diffuse peritonitis sets in.
- Neuropsychiatric symptoms (described as "muttering delirium" or "coma vigil"), with picking at bedclothes or imaginary objects.
- Metastatic abscesses, cholecystitis, endocarditis, and osteitis
- The fever is still very high and oscillates very little over 24 hours. Dehydration ensues, and the patient is delirious (typhoid state). One-third of affected individuals develop a macular rash on the trunk.
- Platelet count goes down slowly and risk of bleeding rises.
- By the end of third week, the fever starts subsiding (defervescence). This carries on into the fourth and final week.
The bacterium that causes typhoid fever may be spread through poor hygiene habits and public sanitation conditions, and sometimes also by flying insects feeding on feces. Public education campaigns encouraging people to wash their hands after defecating and before handling food are an important component in controlling spread of the disease. According to statistics from the United States Centers for Disease Control and Prevention (CDC), the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid fever in the United States.
Diagnosis is made by any blood, bone marrow or stool cultures and with the Widal test (demonstration of Salmonella antibodies against antigens O-somatic and H-flagellar). In epidemics and less wealthy countries, after excluding malaria, dysentery, or pneumonia, a therapeutic trial time with chloramphenicol is generally undertaken while awaiting the results of the Widal test and cultures of the blood and stool.
The Widal test is time-consuming, and often, when a diagnosis is reached, it is too late to start an antibiotic regimen.
The term 'enteric fever' is a collective term that refers to severe typhoid and paratyphoid.
Sanitation and hygiene are the critical measures that can be taken to prevent typhoid. Typhoid does not affect animals, so transmission is only from human to human. Typhoid can only spread in environments where human feces or urine are able to come into contact with food or drinking water. Careful food preparation and washing of hands are crucial to prevent typhoid.
Two vaccines are licensed for use for the prevention of typhoid: the live, oral Ty21a 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 50 to 80% protective and are 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).
Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin. Otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice. Cefixime is a suitable oral alternative.
Typhoid fever, when properly treated, is not fatal in most cases. Antibiotics, such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, amoxicillin, and ciprofloxacin, have been commonly used to treat typhoid fever in microbiology. Treatment of the disease with antibiotics reduces the case-fatality rate to about 1%.
When untreated, typhoid fever persists for three weeks to a month. Death occurs in 10% to 30% of untreated cases. In some communities, however, case-fatality rates may reach as high as 47%.
Surgery is usually indicated in cases of intestinal perforation. Most surgeons prefer simple closure of the perforation with drainage of the peritoneum. Small-bowel resection is indicated for patients with multiple perforations.
If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. Cholecystectomy is not always successful in eradicating the carrier state because of persisting hepatic infection.
Resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and streptomycin is now common, and these agents have not been used as first–line treatment for almost 20 years. Typhoid resistant to these agents is known as multidrug-resistant typhoid (MDR typhoid).
Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia. Many centres are therefore moving away from using ciprofloxacin as the first line for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand, or Vietnam. For these patients, the recommended first-line treatment is ceftriaxone. Also, azithromycin has been suggested to be better at treating typhoid in resistant populations than both fluoroquinolone drugs and ceftriaxone. Azithromycin significantly reduces relapse rates compared with ceftriaxone.
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 (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 ciprofloxacin (MIC 0.125–1.0 mg/l) would not be picked up by this method. How this problem can be solved is not certain, because most laboratories around the world (including the West) are dependent on disk testing and cannot test for MICs.
In 2000, typhoid fever caused an estimated 21.7 million illnesses and 217,000 deaths. Its incidence is highest in children and young adults between 5 and 19 years old. These cases as of 2010 caused about 190,000 deaths, up from 137,000 in 1990. Infants, children, and adolescents in south-central and Southeast Asia experience the greatest burden of illness. Nonetheless, outbreaks of typhoid fever are frequently reported from sub-Saharan Africa and countries in Southeast Asia. Historically, in the pre-antibiotic era, the case fatality rate of typhoid fever was 10–20%. Today, with prompt treatment, it is less than 1%. However, about 3-5% of individuals who are infected will develop a chronic infection in the gall bladder. Since S. 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 Typhi associated with a large outbreak and a carrier at the genome level provides new insights into the pathogenesis of the pathogen.
Around 430–424 BC, a devastating plague, which some believe to have been typhoid fever, killed one-third of the population of Athens, including their leader Pericles. The balance of power shifted from Athens to Sparta, ending the Golden Age of Pericles that had marked Athenian dominance in the Greek ancient world. The ancient historian Thucydides also contracted the disease, but he survived to write about the plague. His writings are the primary source on this outbreak and modern academics and medical scientists consider epidemic typhus the most likely cause. In 2006, a study detected DNA sequences similar to those of the bacterium responsible for typhoid fever in dental pulp extracted from a burial pit dated to the time of the outbreak.
The cause of the plague has long been disputed and other scientists have disputed the findings, citing serious methodologic flaws in the dental pulp-derived DNA study. The disease is most commonly transmitted through poor hygiene habits and public sanitation conditions; during the period in question, the whole population of Attica was besieged within the Long Walls and lived in tents.
During the American Civil War, 81,360 Union soldiers died of typhoid or dysentery. In the late 19th century, the typhoid fever mortality rate in Chicago averaged 65 per 100,000 people a year. The worst year was 1891, when the typhoid death rate was 174 per 100,000 people.
The Spanish-American War exposed American troops to typhoid fever overseas and also in stateside training camps. The Surgeon General of the Army, George Miller Sternberg, suggested that the War Department create a Typhoid Fever Board. Major Walter Reed, Edward O. Shakespeare, and Victor C. Vaughan were appointed August 18, 1898, with Reed being designated the President of the Board. The Typhoid Board determined that during the war, more soldiers died from this disease than from yellow fever or from battle wounds. The Board promoted sanitary measures including latrine policy, disinfection, camp relocation, and water sterilization, but by far the most successful antityphoid method was vaccination, which became compulsory in June 1911 for all federal troops.
The most notorious carrier of typhoid fever, but by no means the most destructive, was Mary Mallon, also known as Typhoid Mary. In 1907, she became the first carrier in the United States to be identified and traced. She was a cook in New York. She is closely associated with 53 cases and three deaths. Public health authorities told Mary to give up working as a cook or have her gall bladder removed. Mary quit her job, but returned later under a false name. She was detained and quarantined after another typhoid outbreak. She died of pneumonia after 26 years in quarantine.
Development of vaccination
During the course of treatment of a typhoid outbreak in a local village in 1838, English country doctor William Budd realised the "poisons" involved in infectious diseases multiplied in the intestines of the sick, were present in their excretions, and could then be transmitted to the healthy through their consumption of contaminated water. He proposed strict isolation as a method for containing such outbreaks in the future. The medical and scientific communities did not identify the role of microorganisms in infectious disease until the work of Louis Pasteur.
In 1880, Karl Joseph Eberth described a bacillus that he suspected was the cause of typhoid. In 1884, pathologist Georg Theodor August Gaffky (1850–1918) confirmed Eberth's findings, and 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 enterica, serovar Typhi.
The 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 during the Boer War. At that time, typhoid often killed more soldiers at war than were lost due to enemy combat. He further developed his vaccine at a newly opened research department at St Mary's Hospital Medical School in London from 1902, where he established a method for measuring protective substances (opsonin) in human blood.
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 vaccines should be produced for the troops being sent to the Western Front, thereby saving up to half a million lives during the War. The British Army was the only combatant at the outbreak of the war to be fully immunized against the bacterium, which meant that for the first time, 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 US 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.
Most developed countries saw declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. In 1908, the chlorination of drinking water was a significant step in the control of typhoid fever in the U.S. The first permanent disinfection of drinking water in the U.S. occurred on the Jersey City, New Jersey, 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. Antibiotics were introduced in clinical practice in 1942, greatly reducing mortality. Today, the incidence of typhoid fever in developed countries is around five cases per million people per year.
- Roger Sherman, one of the Founding Fathers of the United States, died of typhoid fever in 1793.
- In memory of Leland Stanford, Jr., who died of typhoid in 1884, his parents founded Stanford University.
- Gerard Manley Hopkins, English poet, died of typhoid fever in 1889.
- Prince Albert, husband of Queen Victoria, died of typhoid fever at the age of 42.
- Major Gonville Bromhead, who fought in the Battle of Rorke's Drift, depicted in the film Zulu, died of typhoid fever in India in 1891.
- Dr HJH 'Tup' Scott, captain of the 1886 Australian cricket team that toured England, died of typhoid in 1910.
- Wilbur Wright, the older of the two Wright Brothers, died of typhoid on May 30, 1912.
- Edith Claypole, a British scientist, died of typhoid in 1915. She acquired the disease while preparing vaccinations for WWI troops, despite the protection of having been vaccinated herself.
- 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.
- Huang Tzu, Chinese musician, died of typhoid fever in 1938.
- Mary Mallon, "Typhoid Mary", presumed to have infected 51 people over her career as a cook, died in 1938.
- Heath Bell, a relief pitcher for the San Diego Padres acquired typhoid on a 2010 trip to Fiji, but survived.
- Louisa May Alcott, author of Little Women, acquired typhoid while being a nurse at a hospital in Washington, D.C., but survived.
- Gen. Ignacio Zaragoza, general in the Mexican army in charge of the Battle of Puebla on May 5, 1862, died on September 8, 1862, shortly after his victory over the French army, of typhoid fever, at the age of 33.
- Abigail Adams, wife of Founding Father and President John Adams and mother of the sixth President John Quincy Adams, died of typhoid fever on October 28, 1818, at the age of 73.
- MedlinePlus Encyclopedia Typhoid fever
- Salmonella and Salmonellosis. Textbookofbacteriology.net. Retrieved on 2014-05-12.
- Oxford English Dictionary. typhoid, adj. and n. and typhus, n. Online version March 2011. Retrieved May 2011.
- Cunha BA (March 2004). "Osler on typhoid fever: differentiating typhoid from typhus and malaria". Infect. Dis. Clin. North Am. 18 (1): 111–25. doi:10.1016/S0891-5520(03)00094-1. PMID 15081508.
- "Controlling Endemic Typhoid Fever > Epidemiology of Microbial Diseases". Yale University. Retrieved 16 June 2014.
- Brusch et al. (1 April 2014). "Typhoid Fever". Medscape. Retrieved 16 June 2014.
- "Typhoid". Merriam Webster Dictionary. Retrieved 2013-06-24.
- Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.
- Parry CM, Beeching NJ (2009). "Treatment of enteric fever". BMJ 338: b1159–b1159. doi:10.1136/bmj.b1159. PMID 19493937.
- Fraser A, Goldberg E, Acosta CJ, Paul M, Leibovici L (2007). Fraser, Abigail, ed. "Vaccines for preventing typhoid fever". Cochrane Database Syst Rev (3): CD001261. doi:10.1002/14651858.CD001261.pub2. PMID 17636661.
- Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA (2011). Bhutta, Zulfiqar A, ed. "Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever)". Cochrane Database Syst Rev (10): CD004530. doi:10.1002/14651858.CD004530.pub4. PMID 21975746.
- Soe GB, Overturf GD (1987). "Treatment of typhoid fever and other systemic salmonelloses with cefotaxime, ceftriaxone, cefoperazone, and other newer cephalosporins". Rev Infect Dis (The University of Chicago Press) 9 (4): 719–36. doi:10.1093/clinids/9.4.719. JSTOR 4454162. PMID 3125577.
- Wallace MR, Yousif AA, Mahroos GA, Mapes T, Threlfall EJ, Rowe B, Hyams KC (1993). "Ciprofloxacin versus ceftriaxone in the treatment of multiresistant typhoid fever". Eur J Clin Microbiol Infect Dis 12 (12): 907–910. doi:10.1007/BF01992163. PMID 8187784.
- Dutta P, Mitra U, Dutta S, De A, Chatterjee MK, Bhattacharya SK (2001). "Ceftriaxone therapy in ciprofloxacin treatment failure typhoid fever in children". Indian J Med Res 113: 210–3. PMID 11816954.
- Коваленко А.Н. et al. (2011). "Особенности клиники, диагностики и лечения брюшного тифа у лиц молодого возраста". Voenno-meditsinskii zhurnal 332 (1): 33–39.
- Bhutta ZA, Khan IA, Molla AM (1994). "Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone". Pediatr Infect Dis J 13 (11): 990–993. doi:10.1097/00006454-199411000-00010. PMID 7845753.
- Cao XT, Kneen R, Nguyen TA, Truong DL, White NJ, Parry CM (1999). "A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group". Pediatr Infect Dis J 18 (3): 245–8. PMID 10093945.
- Baron S et al.
- Diarrhoeal Diseases (Updated February 2009) at the Wayback Machine (archived November 2, 2011). World Health Organization
- "Typhoid Fever". World Health Organization. Retrieved 2007-08-28.
- Cooke FJ, Wain J, Threlfall EJ (2006). "Fluoroquinolone resistance in Salmonella typhi (letter)". Brit Med J 333 (7563): 353–354. doi:10.1136/bmj.333.7563.353-b. PMC 1539082. PMID 16902221.
- Crump, J. A., & Mintz, E. D (2010). "Global trends in typhoid and paratyphoid fever.". Clinical Infectious Diseases 50 (2): 241–246. doi:10.1086/649541.
- Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al. (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
- Crump JA, Luby SP, Mintz ED (2004). "The global burden of typhoid fever.". Bull World Health Organ 82: 346–353.
- Muyembe-Tamfum JJ, Veyi J, Kaswa M, Lunguya O, Verhaegen J, Boelaert M (2009). "An outbreak of peritonitis caused by multidrug-resistant Salmonella Typhi in Kinshasa, Democratic Republic of Congo.". Travel Med Infect Dis 7 (40): 3. doi:10.1016/j.tmaid.2008.12.006.
- Baddam, Ramani, Narender Kumar, Kwai-Lin Thong, Soo-Tein Ngoi, Cindy Shuan Ju Teh, Kien-Pong Yap, Lay-Ching Chai, Tiruvayipati Suma Avasthi, and Niyaz Ahmed (2012). "Genetic fine structure of a Salmonella enterica serovar Typhi strain associated with the 2005 outbreak of typhoid fever in Kelantan, Malaysia.". Journal of Bacteriology 194 (13): 3565–3566. doi:10.1128/jb.00581-12.
- Yap, Kien-Pong, et al. (2012). "Insights from the genome sequence of a Salmonella enterica serovar Typhi strain associated with a sporadic case of typhoid fever in Malaysia". J. Bacteriol. 194 (18): 5124–5125.
- Heymann, David L., ed. (2008), Control of Communicable Diseases Manual, Washington, D.C.: American Public Health Association, pg 665. ISBN 978-0-87553-189-2.
- Levine et al (1982). "Precise estimation of the numbers of chronic carriers of Salmonella Typhi in Santiago, Chile, an endemic area.". J. Infect. Dis 146: 724–726. doi:10.1093/infdis/146.6.724.
- G Gonzalez-Escobedo, JM Marshall, JS Gunn (2010). "Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state.". Nature Reviews 9 (1): 9–14. doi:10.1038/nrmicro2490.
- Yap, Kien-Pong, et al. (2014). "Comparative genomics of closely related Salmonella enterica serovar Typhi strains reveals genome dynamics and the acquisition of novel pathogenic elements.". BMC Genomics. 15 (1): 1007.
- Papagrigorakis MJ, Yapijakis C, Synodinos PN, Baziotopoulou-Valavani E (2006). "DNA examination of ancient dental pulp incriminates typhoid fever as a probable cause of the Plague of Athens". Int J Infect Dis 10 (3): 206–214. doi:10.1016/j.ijid.2005.09.001. PMID 16412683.
- Shapiro B, Rambaut A, Gilbert MT (2006). "No proof that typhoid caused the Plague of Athens (a reply to Papagrigorakis et al.)". Int J Infect Dis 10 (4): 334–335. doi:10.1016/j.ijid.2006.02.006. PMID 16730469.
- Byrne, Joseph Patrick (2008). Encyclopedia of Pestilence, Pandemics, and Plagues: A-M. ABC-CLIO. p. 190. ISBN 0-313-34102-8.
- "Armies of pestilence: the effects of pandemics on history". James Clarke & Co. (2004). p.191. ISBN 0-227-17240-X
- "1900 Flow of Chicago River Reversed". Chicago Timeline. Chicago Public Library. Archived from the original on 2007-03-07. Retrieved 2007-02-08.
- Walter Reed Typhoid Fever, 1897-1911, http://exhibits.hsl.virginia.edu/typhoid/, Claude Moore Health Sciences Library. University of Virginia.
- "Nova: The Most Dangerous Woman in America".
- Asimov, Asimov's Biographical Encyclopedia of Science and Technology 2nd Revised edition
- Aronson SM (1995). "William Budd and typhoid fever". Rhode Island medicine 78 (11): 310. PMC 1279260. PMID 8547718.
- "Sir Almroth Edward Wright". Encyclopaedia Britannica.
- "Library and Archive Catalogue". Royal Society. Retrieved 1 November 2010.
- USAMRMC: 50 Years of Dedication to the Warfighter 1958 – 2008. U.S. Army Medical Research & Material Command (2008). 2008. p. 5. ASIN B003WYKJNY.
- Leal, John L. (1909). "The Sterilization Plant of the Jersey City Water Supply Company at Boonton, N.J." Proceedings American Water Works Association. pp. 100–9.
- Fuller, George W. (1909). "Description of the Process and Plant of the Jersey City Water Supply Company for the Sterilization of the Water of the Boonton Reservoir." Proceedings American Water Works Association. 110-34.
- Ruggles, Eleanor (1944) Gerard Manley Hopkins: a life. Norton.
- Scott, Belinda F.. (1910-09-23) Biography – Henry James Herbert Scott – Australian Dictionary of Biography. Adbonline.anu.edu.au. Retrieved on 2014-05-12.
- "Straw for Silence". The Spectator (F.C. Westley) 203. 1959. ISSN 0038-6952. OCLC 1766325. Retrieved March 16, 2011.
- Hakaru Hashimoto#Biography
- "Heath Bell Recovering After Bout With Typhoid Fever on Vacation". aolnews.com. 2011. Retrieved 17 October 2011.
- Easmon C (2005-04-01). "Typhoid fever and paratyphoid fever". Travel Health. Retrieved 2008-10-05.
- Harrison NG. "Walter Reed and Typhoid Fever, 1897–1911". Univ of Virginia. Retrieved 2008-10-05.
- Nicolson, Stuart (2008-06-26). "Typhoid left city (Aberdeen) 'under siege'". BBC News. Retrieved 2008-10-05.
- O'Hara C (2006-01-26). "Typhoid Fever Led To The Fall Of Athens". Elsevier. Retrieved 2008-10-05.
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