Case no.30

1. Case no.30 • A 10 y/o patient was admitted because of high fever associated with headache,malaise and chills.Based form the examinations and procedure done, patient was found to be having Typhoid fever.

2. Outline • Background • Mode of Transmission • Pathophysiology • Clinical manifestation • Diagnosis • Medical treatmant and related precautions • Prevention and vaccination • Case study and its legendary stories

3. Typhoid BY Chitchai Pumchandh

4. Background • Typhoid fever,also known as enteric fever,is a systemic infection by Samonella typhi or by the related but less virulent Samonella parathyphi. • Samonella parathyphi causes Parathyroid fever,a similarity in symptom but much milder disease. The case-fatality rate is also less lower.

5. Salmonella is a genus in the family Enterobacteriaceae that has more than 2300 serotypes, Of all Salmonella serotypes, only S typhi and S paratyphi are pathogenic exclusively in humans. Typhoid fever is a severe multisystemic illness characterized by the classic prolonged fever, sustained bacteremia without endothelial or endocardial involvement, and bacterial invasion of and multiplication within the mononuclear phagocytic cells of the liver, spleen, lymph nodes, and Peyer patches. Typhoid fever is potentially fatal if untreated.

6. More than 2,400years ago or around 430-426 B.C.,a devastating plague of these bacteria kill one third of the population of Athens during wartime and during the breakdown of sanitation, including their leader,Pericles. The balance of power shifted from Athens to Sparta,ending the Golden age of Pericles that marked Athenian dominance in the ancient world.

7. An ancient historian and General in the war ,Thucydides also contracted the disease,but he survived to write about the plague. His writing are the primary source on the outbreak, History Of The Peloponnesian War. • But he did not leave a precise enough description to decide definitively whether the disease was bubonic plague, smallpox or other ailments. • In 1994,DNA collected from teeth in an ancient mass grave was proved to be Typhoid fever by Manolis Papagrigokis and her colleagues at the University of Athens.

8. Mode of transmission • People are typically infected with S typhi and S paratyphi through food and beverages contaminated by a chronic stool carrier. Less commonly, carriers may shed the bacteria in urine. Individuals may also be infected by drinking sewage-contaminated water or by eating contaminated shellfish or faultily canned meat.

9. Salmonellae are gram-negative, flagellate, nonsporulating, facultative anaerobic bacilli that ferment glucose, reduce nitrate to nitrite, and synthesize peritrichous flagella when motile. All but S typhi produce gas upon sugar fermentation.

10. Pathophysiology • After ingestion by the host, S typhi invades through the gut and multiplies within the mononuclear phagocytic cells in the liver, spleen, lymph nodes, and Peyer patches of the ileum. • After successfully passing through the stomach, any Salmonella subspecies may be phagocytized by the gut's intraluminal dendritic cells, causing inflammation that leads to diarrhea.

11. Only the subspecies S enterica causes severe disease in the rest of the body. Its specialized fimbriae adhere to the epithelium that overlies Peyer patches. Peyer patches are grossly visible aggregates of 5-100 lymphoid follicles in the small bowel submucosa; these patches are larger and more numerous distally. They are the primary mechanism for sampling antigens in the gut and initiating response.

12. The infected macrophage provides Salmonella a vehicle safe from other elements of the immune system and in which it can multiply and travel. It passes through the mesenteric lymph nodes into the thoracic duct and the lymphatics beyond to seed the reticuloendothelial tissues—liver, spleen, bone marrow, and lymph nodes. In these havens, it multiplies until some critical density is reached.

13. It causes the apoptosis in the macrophages and enters the bloodstream to attack the rest of the body. At this stage, the Vi antigen comes into play. It forms a capsule to protect the bacterium from complement and from phagocytic immune cells. • From blood or from the liver via bile ducts, it infects the gallbladder and reenters the gastrointestinal tract in the bile, spreading to other hosts via stool. In addition, it occasionally invades the urinary tract and spreads via urine.

14. After primary intestinal infection, further seeding of the Peyer patches occurs through infected bile. They may become hyperplastic and necrotic with infiltration of mononuclear cells and neutrophils, forming ulcers that may hemorrhage through eroded blood vessels or perforate the bowel wall, causing peritonitis. • The host recognizes the invader with toll-like receptors 2, 4, and 5. These induce cytokines such as interferon alpha, interleukin (IL)–12, and tumor necrosis factor-alpha, which recruit macrophages and cause the high fevers of the disease. Macrophages and neutrophils suppress the active infection. Later, humoral and CD4 T-cell–mediated immunity clears it.

15. Risk factor • Salmonella has mechanisms against acidic environments, but a pH level of 1.5 or less kills most of the bacilli. People who continually ingest antacids, histamine-2 receptor antagonists (H2 blockers), or proton pump inhibitors; who have undergone gastrectomy; or who have achlorhydria due to aging or other factors require fewer bacilli to produce clinical disease.

16. Acquired immune deficiencies or hereditary deficiencies in immune modulars such as IL-12 and IL-23 increase risk for infection, complications, and death

17. Clinical manifestration • The incubation period of typhoid fever varies with the size of the infecting dose and averages 7-14 (range, 3-60) days. In paratyphoid infection, the incubation period ranges from 1-10 days. During the incubation period, 10-20% of patients have transient diarrhea (enterocolitis) that usually resolves before the onset of the full-fledged disease.

18. As bacteremia develops, the incubation period ends. Patients often experience chills, diaphoresis, anorexia, dry cough, a dull frontal headache, and myalgias before the onset of a high fever. About 20-40% of patients present with abdominal pain. In immunocompetent adults, constipation is common and is most likely due to hypertrophy of Peyer patches.

19. The classic signs of enteric fever include fever, toxemia, delirium, abdominal pain, constipation, and hepatosplenomegaly. • The individual's temperature often rises to as high as 103-104°F (39-40°C) by the beginning of week 2. Constipation often develops early and is likely due to obstruction at the ileocecal valve by swollen Peyer patches. It may last for the entire duration of illness.

20. At approximately the end of the first week of illness, about a third of patients develop bacterial emboli to the skin known as rose spots. These are considered a classic symptom in typhoid fever, but they occasionally appear in shigellosis and nontyphoidal salmonellosis.

21. Rose spots constitute a subtle, extremely sparse (often <5 spots), salmon-colored, blanching, truncal, maculopapular rash with 1- to 4-cm lesions that generally resolve within 2-5 days. Relative bradycardia and a dicrotic pulse are also common during this stage of illness. • During the second week of illness, the patient is toxic-appearing and apathetic with sustained fever. The abdomen is slightly distended, and soft splenomegaly is common.

22. In the third week, the patient grows more toxic and anorexic with significant weight loss. The patient may have a thready pulse, tachypnea, conjunctivitis, and crackles over the lung bases. Pyrexia persists. The patient may enter into a typhoid state of apathy, confusion, and even psychosis. Patients may develop polyneuropathy. Abnormal cerebrospinal fluid should prompt a search for a different cause.

23. Meanwhile, the patient commonly has pronounced abdominal distension. Some individuals may produce liquid, foul, green-yellow diarrhea (pea soup diarrhea). At this stage, the patient may die from overwhelming toxemia, myocarditis, intestinal hemorrhage, or perforation due to necrotic Peyer patches. Rare complications of enteric fever include pancreatitis, meningitis, orchitis, and osteomyelitis.

24. During the fourth week, the fever, mental state, and abdominal distension slowly improve over a few days, but intestinal complications may still occur in surviving untreated individuals. Weight loss and debilitating weakness last months. Relapses occur in 10% of patients, mostly during the first 2-3 weeks of convalescence.

25. One to four percent of untreated patients become chronic carriers, defined as individuals who excrete Salmonella for more than 1 year. Some individuals may continue to excrete the bacterium for decades. Bladder infection with Schistosoma haematobium predisposes to urinary carriage. The parasite itself becomes a carrier.

26. Stool carriage is more frequent in people with preexisting biliary abnormalities, perhaps because S enterica survives in gallstones, and these people have a greater incidence of cholecystitis. Chronic carriers have a greater risk for carcinoma of the gallbladder and other gastrointestinal malignancies; chronic carriers had a 6-fold increase in the risk of death due to hepatobiliary cancer.

27. Diagnosis • The diagnosis is suggested by assays that identify Salmonella antibodies and antigens and is then confirmed by isolation of the organism. • If patients present within the first week of the disease, blood, intestinal secretions, and stool culture results are usually positive in approximately 85-90% of patients with typhoid fever. They decline to 20-30% later in the course of the disease.

28. Medical treatment • Antibiotics should be started empirically while the results of confirmatory tests are pending. • Antibiotics -- Chloramphenicol was introduced in 1948 and was once the mainstay of treatment. By the 1970s, widespread resistance to the drug developed. Ampicillin and co-trimoxazole became treatments of choice. However, in the late 1980s, some S typhi strains developed simultaneous plasmid-mediated resistance to all 3 drugs. Fluoroquinolones and third-generation cephalosporins have filled the breach, but some resistance exists to both.

29. Resistance to ciprofloxacin is increasing. • Southeast Asia has reduced susceptibility to ciprofloxacin. • Ciprofloxacin is no longer a good first-line treatment for S typhi infection that arises in Southeast Asia. • Uncomplicated typhoid fever from the western hemisphere should be treated empirically with ciprofloxacin for 7 days. The treatment for cases from Southeast Asia is controversial. Some authorities recommend high-dose ciprofloxacin.

30. Some consider this inadequate, as reports of treatment failure under those conditions have increased. Then it is recommended empiric first-line therapy with trimethoprim/sulfamethoxazole and second-line therapy with ampicillin or chloramphenicol. • Resistance to ceftriaxone is only sporadic in Southeast Asia and elsewhere. Ceftriaxone should be the first-line empiric treatment for severe typhoid fever, and the course should last 10-14 days

31. Clinicians should consider a 48-hour course of dexamethasone if the patient has shock or altered mental status. This may reduce the mortality risk from 56% to 10%. Corticosteroids are reserved for the only the most ill patients because they may increase the risk of relapse.

32. Drugs • Chloramphenicol (Chloromycetin) -- Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria. Since its introduction in 1948, has proven to be remarkably effective for enteric fever worldwide. For sensitive strains, still most widely used antibiotic to treat typhoid fever. In the 1960s, S typhi strains with plasmid-mediated resistance to chloramphenicol began to appear and later became widespread in many endemic countries of the Americas and Southeast Asia, highlighting need for alternative agents. • Contraindications Documented hypersensitivity

33. Trimethoprim and sulfamethoxazole (Bactrim DS, Septra) -- Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa. As effective as chloramphenicol in defervescence and relapse rate. Trimethoprim alone has been effective in small groups of patients. • Contraindications Documented hypersensitivity; megaloblastic anemia due to folate deficiency

34. Ciprofloxacin (Cipro) -- Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared. Proven to be highly effective for typhoid and paratyphoid fevers. Defervescence occurs in 3-5 d, and convalescent carriage and relapses are rare. Other quinolones (eg, ofloxacin, norfloxacin, pefloxacin) usually are effective. If vomiting or diarrhea is present, should be given IV. Fluoroquinolones are highly effective against multiresistant strains and have intracellular antibacterial activity. • Contraindications Documented hypersensitivity

35. Amoxicillin (Trimox, Amoxil, Biomox) -- Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. At least as effective as chloramphenicol in rapidity of defervescence and relapse rate. • Contraindications Documented hypersensitivity

36. Cefotaxime (Claforan) -- Arrests bacterial cell wall synthesis, which inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms. Excellent in vitro activity against S typhi and other salmonellae and has acceptable efficacy in typhoid fever. Only IV formulations are available. • Contraindications Documented hypersensitivity

37. Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum gram-negative activity against gram-positive organisms; Excellent in vitro activity against S typhi and other salmonellae. • Contraindications Documented hypersensitivity

38. Other drugs • Azithromycin (Zithromax) • Cefoperazone (Cefobid) • Levofloxacin (Levaquin)

39. Corticosteroids -- These agents reduce mortality in severely ill patients with depressed levels of consciousness or shock. • Dexamethasone (Decadron) -- Prompt administration of high-dose dexamethasone reduces mortality in patients with severe typhoid fever without increasing incidence of complications, carrier states, or relapse among survivors.

40. Prevention • Travelers to endemic countries should avoid raw unpeeled fruits or vegetables since they may have been prepared with contaminated water; in addition, they should drink only boiled water. • Routine typhoid vaccination is not recommended in the United States. Vaccination is indicated for travelers to endemic areas, persons with intimate exposure

41. Vaccines • The following 3 typhoid vaccines are used: • Vi capsular polysaccharide (ViCPS) antigen vaccine (Typhim Vi, Pasteur Merieux) • Ty21a (Vivotif Berna, Swiss Serum and Vaccine Institute) • Acetone-inactivated parenteral vaccine

42. Case study and its legends • A wealthy middle-aged man presented to his physician a few days after the onset of flulike symptoms, including fever, myalgias, chills, severe abdominal pain, and a cough, in addition to severe abdominal pain. Over the next 2 weeks, he lost a great deal of weight. He had intermittent but ever-increasing fevers. About 3 weeks after the onset of symptoms, he developed a few pale, salmon-colored macules on his trunk.

43. His cough became much more frequent and severe. He became delirious, listlessly wandering around the house fiddling with doorknobs. During the fourth week of his illness, he rapidly declined with increasing somnolence. After nearly 4 weeks of illness, he died surrounded by his loving family.

44. The patient was Prince Albert, the Consort to Queen Victoria. He was diagnosed with typhoid fever. His personal physician, Sir William Jenner, a leading expert on the disease, made the diagnosis of typhoid fever. Prince Albert received the best therapy of the day.

45. Typhoid Mary • 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 American carrier to be identified and traced. She was a cook in New York; some believe she was the source of infection for several hundred people.

46. She is closely associated with forty seven cases and three deaths.[7] 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.

47. Part of the problems Mary had stemmed from her vehement denial of the situation. She maintained that she was healthy and had never had typhoid fever. Historians say it also stemmed from the prejudice that existed against working-class Irish immigrants at the time.

48. Today, a Typhoid Mary is a generic term for a carrier of a dangerous disease who is a danger to the public because they refuse to take appropriate precautions.

49. Famous typhoid victims • Famous people who have succumbed to the disease include: • Anurag Goel of India • Alexander the Great (Typhoid is one of many possibilities of his cause of death, including malaria, West Nile virus, pancreatitis, and poisoning.) • Pericles • Archduke Karl Ludwig of Austria • Franz Schubert (disputed) • Charles Trenet

50. Margaret Breckenridge, highest-ranking Army nurse under Ulysses S. Grant • Evangelista Torricelli • Benjamin Harrison's wife Caroline • Robert E. Lee's daughter Annie • Mary Henrietta Kingsley • Herbert Hoover's father and mother • Mark Hanna • William McKinley's daughter Katherine • Wilbur Wright • Leland Stanford, Jr. • William T. Sherman's father • Albert of Saxe-Coburg-Gotha, British prince consort, Queen Victoria's husband • Ann Rutledge, alleged fiancée of Abraham Lincoln