Typhoid Fever Dr. Dur Muhammad Khan (MRCP. FRCP)

A 20years old patient presents in the OPD with a history of fever for 10 days. He also complains of generalized weakness and headache. There is history of dry cough and abdominal pain but no diarrhoea. A 20years old patient presents in the OPD with a history of fever for 10 days. He also complains of generalized weakness and headache. There is history of dry cough and abdominal pain but no diarrhoea. Examination reveals Temp:102 F, Pulse : 70/m, BP: 110/70. Examination reveals Temp:102 F, Pulse : 70/m, BP: 110/70. There is mild splenomegaly. Rest of the examination is normal. What is the likely diagnosis? There is mild splenomegaly. Rest of the examination is normal. What is the likely diagnosis?

Typhoid Definition Definition Etiology Etiology Pathogenesis Pathogenesis Epidemiology Epidemiology Clinical manifestations Clinical manifestations The laboratory and other examinations The laboratory and other examinations Complications Diagnosis and differential diagnosis Prognosis Treatment

Definition of Typhoid fever Acute enteric infectious disease Acute enteric infectious disease caused by Salmonella typhi (S.Typhi). caused by Salmonella typhi (S.Typhi). prolonged fever, Relative bradycardia, apathetic facial expressions, roseola, splenomegaly, hepatomegaly, leukopenia. prolonged fever, Relative bradycardia, apathetic facial expressions, roseola, splenomegaly, hepatomegaly, leukopenia. intestinal perforation, intestinal hemorrhage intestinal perforation, intestinal hemorrhage

Etiology Serotype: D group of Salmonella Serotype: D group of Salmonella Gram-negative Gram-negative rod rod non-spore non-spore flagella flagella Culture characteristics Culture characteristics

Antigens: located in the cell capsule Antigens: located in the cell capsule H (flagellar antigen). H (flagellar antigen). O (Somatic or cell wall antigen). O (Somatic or cell wall antigen). Vi (polysaccharide virulence) Vi (polysaccharide virulence) “widel test” “widel test”

A schematic diagram of a single Salmonella typhi cell showing the locations of the H (flagellar), 0 (somatic), and Vi (K envelope) antigens.

Epidemiology continues to be a global health problem continues to be a global health problem areas with a high incidence include Asia, Africa and Latin America areas with a high incidence include Asia, Africa and Latin America affects about people with more than deaths a year. 80% in Asia. affects about people with more than deaths a year. 80% in Asia. sporadic occur usually, sometimes have epidemic outbreaks. sporadic occur usually, sometimes have epidemic outbreaks.

Source of infection Cases and chronic carriers Cases discharge from incubation, more in 2~4 weeks after onset, a few (about 2~5%) last longer than 3 months chronic carrier Typhoid Mary chronic carrier Typhoid Mary

Transmission fecal-oral route fecal-oral route close contact with patients or carriers close contact with patients or carriers contaminated water and food contaminated water and food flies and cockroaches. flies and cockroaches.

Pathogenesis gastrointestinal tract host- pathogen interactions gastrointestinal tract host- pathogen interactions The amount of bacilli infection (>10 5 baeteria). The amount of bacilli infection (>10 5 baeteria).

ingested orally  Stomach barrier (some Eliminated)  enters the small intestine  Penetrate the mucus layer  enter mononuclear phagocytes of ileal peyer's patches and mesenteric lymph nodes  proliferate in mononuclear phagocytes spread to blood. initial bacteremia (Incubation period). Pathogenesis

Pathogenesis  enter spleen, liver and bone marrow (reticulo-endothelial system) further proliferation occurs  A lot of bacteria enter blood again. (second bacteremia). (second bacteremia).  Recovery

Pathology Pathology essential lesion: essential lesion: proliferation of RES (reticuloendothelial system ) proliferation of RES (reticuloendothelial system ) specific changes in lymphoid tissues specific changes in lymphoid tissues and mesenteric lymph nodes. "typhoid nodules“ and mesenteric lymph nodes. "typhoid nodules“ Most characteristic lesion: Most characteristic lesion: ulceration of mucosa in the region of the Peyer’s patches of the small intestine ulceration of mucosa in the region of the Peyer’s patches of the small intestine

Major findings in lower ileum Hyperplasia stage(1st week): Hyperplasia stage(1st week): swelling of lymphoid tissue and proliferation of macrophages. swelling of lymphoid tissue and proliferation of macrophages. Necrosis stage(2nd week): Necrosis stage(2nd week): necrosis of swollen lymph nodes or solitary follicles. necrosis of swollen lymph nodes or solitary follicles.

Major findings in lower ileum Ulceration stage(3rd week): Ulceration stage(3rd week): shedding of necrosis tissue and formation of ulcer intestinal hemorrhage, perforation. shedding of necrosis tissue and formation of ulcer intestinal hemorrhage, perforation. Stage of healing (from 4th week): Stage of healing (from 4th week): healing of ulcer, no cicatrices and no contraction healing of ulcer, no cicatrices and no contraction

Clinical manifestations Clinical manifestations Incubation period: 3 ～ 60 days(7 ～ 14). The initial period (early stage) First week. First week. Insidious onset. Insidious onset. Fever up to 39~40 0 C in 5~7 days Fever up to 39~40 0 C in 5~7 days chills 、 ailment 、 tired 、 sore throat 、 cough,abdominal discomfort and constipation et al. chills 、 ailment 、 tired 、 sore throat 、 cough,abdominal discomfort and constipation et al.

The fastigium satge second and third weeks. second and third weeks. Sustained high fever 、 partly remittent fever or irregular fever. Last 10 ～ 14 days. Sustained high fever 、 partly remittent fever or irregular fever. Last 10 ～ 14 days. Gastro-intestinal symptoms: anorexia 、 abdominal distension or pain 、 diarrhea or constipation Gastro-intestinal symptoms: anorexia 、 abdominal distension or pain 、 diarrhea or constipation Neuropsychiatric manifestations: confusion 、 blunt respond even delirium and coma or meningism Neuropsychiatric manifestations: confusion 、 blunt respond even delirium and coma or meningism

Circulation system: Circulation system: relative bradycardia. relative bradycardia. splenomegaly 、 hepatomegaly splenomegaly 、 hepatomegaly toxic hepatitis. toxic hepatitis. roseola :30%, maculopapular rash roseola :30%, maculopapular rash a faint pale color, slightly raised a faint pale color, slightly raised round or lenticular, fade on pressure round or lenticular, fade on pressure 2-4 mm in diameter, less than 10 in number on the trunk, disappear in 2-3 days. on the trunk, disappear in 2-3 days.

fatal complications: fatal complications: intestinal hemorrhage intestinal hemorrhage intestinal perforation intestinal perforation severe toxemia severe toxemia

defervescence stage fever and most symptoms resolve by the forth week of infection. fever and most symptoms resolve by the forth week of infection. Fever come down, gradual improvement in all symptoms and signs, but still danger. Fever come down, gradual improvement in all symptoms and signs, but still danger. convalescence stage the fifth week. disappearance of all symptoms, but can relapse the fifth week. disappearance of all symptoms, but can relapse

Special manifestations In children In children Often atypical Often atypical sudden onset with high fever. sudden onset with high fever. Respiratory symptoms and diarrhea, dominant. Respiratory symptoms and diarrhea, dominant. Convulsion common in below 3. Convulsion common in below 3. relative bradycardia rare. relative bradycardia rare. Splenomegaly, roseola and leucopenia less common. Splenomegaly, roseola and leucopenia less common.

In the aged In the aged temperature not high, weakness common. More complications.high mortality.

Laboratory findings Routine examinations: white blood cell count is normal or decreased. white blood cell count is normal or decreased. Leukocytopenia(specially eosinophilic leukocytopenia). Leukocytopenia(specially eosinophilic leukocytopenia). recovery with improvement of diseases recovery with improvement of diseases decreased in relapse decreased in relapse

Bacteriological examinations: Blood culture: Blood culture: the most common use 80~90% positive during the first 2 weeks of illness the most common use 80~90% positive during the first 2 weeks of illness 50% in 3rd week 50% in 3rd week not easy in 4th week re-positive when relapse and recrudesce not easy in 4th week re-positive when relapse and recrudesce attention to the use of antibiotics attention to the use of antibiotics

The bone marrow culture The bone marrow culture the most sensitive test specially in patients pretreated with antibiotics. the most sensitive test specially in patients pretreated with antibiotics. Urine and stool cultures increase the diagnostic yield positive less frequently stool culture better in 3~4 weeks Urine and stool cultures increase the diagnostic yield positive less frequently stool culture better in 3~4 weeks The duodenal string test to culture bile useful for the diagnosis of carriers. The duodenal string test to culture bile useful for the diagnosis of carriers. Rose spots: Not use routinely Rose spots: Not use routinely

Complications Intestinal hemorrhage Commonly appear during the second-third week of illness difference between mild and greater bleeding often caused by unsuitable food, diarrhea et al serious bleeding in about 2~8% a sudden drop in temperature 、 rise in pulse 、 and signs of shock followed by dark or fresh blood in the stool. serious bleeding in about 2~8% a sudden drop in temperature 、 rise in pulse 、 and signs of shock followed by dark or fresh blood in the stool.

Intestinal perforation: The more serious.Incidence,1-4% The more serious.Incidence,1-4% Commonly appear during 2-3 weeks. Commonly appear during 2-3 weeks. Take place at the lower end of ileum. Take place at the lower end of ileum. Before perforation,abdominal pain or Before perforation,abdominal pain or diarrhea,intestinal bleeding. diarrhea,intestinal bleeding. When perforation, abdominal pain, sweating, drop in temperature, and increase in pulse rate, then, rebound tenderness when press abdomen, When perforation, abdominal pain, sweating, drop in temperature, and increase in pulse rate, then, rebound tenderness when press abdomen, abdomen muscle entasia, reduce or disappear in the sonant extent of liver, leukocytosis. abdomen muscle entasia, reduce or disappear in the sonant extent of liver, leukocytosis. Temperature rise.peritonitis appear. Temperature rise.peritonitis appear. celiac free air under x-ray. celiac free air under x-ray.

Toxic hepatitis: Toxic hepatitis: common,1-3 weeks common,1-3 weeks hepatomegaly, ALT elevated hepatomegaly, ALT elevated get better with improvement of diseases in 2~3 weeks get better with improvement of diseases in 2~3 weeks Toxic myocarditis. Toxic myocarditis. seen in 2-3 weeks, usually severe toxemia. seen in 2-3 weeks, usually severe toxemia. Bronchitis, bronchopneumonia. Bronchitis, bronchopneumonia. seen in early stage seen in early stage

Other complications: toxic encephalopathy. toxic encephalopathy. Hemolytic uremic syndrome. Hemolytic uremic syndrome. acute cholecystitis 、 acute cholecystitis 、 meningitis 、 meningitis 、 nephritis et al. nephritis et al.

Differential diagnosis Viral infections: Viral infections: such as upper respiratory tract infection. such as upper respiratory tract infection. abrupt onset with fever, headache, leucopenia, sore throat, cough, coryza. abrupt onset with fever, headache, leucopenia, sore throat, cough, coryza. no rose spots, no enlargement of liver & spleen. The course of illness no more than 2 wks. no rose spots, no enlargement of liver & spleen. The course of illness no more than 2 wks. differential diagnosis depends on typical manifestations and blood culture. differential diagnosis depends on typical manifestations and blood culture.

Malaria history of exposure to malaria. Paroxysms(often periodic) of sequential chill,high fever and sweating. Headache, anorexia, splenomegaly, anemia, leukopenia Characteristic parasites in erythrocytes,identified in thick or thin blood smears.

Leptospirosis Leptospirosis Endemic area,contacted with urine of mice. Abrupt fever,chills,severe headache,and myalgias, especially of the calf muscles. Leptospires can be isolated from blood,cerebrospinal fluid. Special agglutination titers develop after 7 days and may persist at high levels for many years.

Tuberculosis continuous high or low fever,fatigue,weight loss,night sweats. continuous high or low fever,fatigue,weight loss,night sweats. Mild cough Mild cough pulmonary infiltration on chest radiograph pulmonary infiltration on chest radiograph positive tuberculin skin test reaction(most cases) positive tuberculin skin test reaction(most cases) acid-fast bacilli on smear of sputum acid-fast bacilli on smear of sputum sputum culture positive for mycobacterium tuberculosis. sputum culture positive for mycobacterium tuberculosis.

Septicemia of Gram-negative bacilli abrupt onset,high fever,symptom of toxemia. abrupt onset,high fever,symptom of toxemia. Chill,sweats. Chill,sweats. Shock. Shock. Positive of gram-negative bacilli from blood culture. Positive of gram-negative bacilli from blood culture.

Prognosis: Case fatality 0.5 ～ 1%. Case fatality 0.5 ～ 1%. but high in old ages 、 infant 、 and serious complications but high in old ages 、 infant 、 and serious complications Have immunity for ever after diseases Have immunity for ever after diseases About 3% of patients become fecal carriers. About 3% of patients become fecal carriers.

TREATMENT General treatment isolation and rest isolation and rest good nursing care and supportive treatment good nursing care and supportive treatment close observation T,P,R,BP,abdominal condition and stool. close observation T,P,R,BP,abdominal condition and stool. suitable diet include easy digested food or half-liquid food.drink more water suitable diet include easy digested food or half-liquid food.drink more water intravenous injection to maintain water and acid-base and electrolyte balance intravenous injection to maintain water and acid-base and electrolyte balance

Symptomatic treatment: Symptomatic treatment: for high fever: for high fever: physical measures firstly physical measures firstly antipyretic drugs such as aspirin should be administrated with caution antipyretic drugs such as aspirin should be administrated with caution delirium,coma or shock,2-4mg dexamethasone in addition to antibiotics reduces mortality. delirium,coma or shock,2-4mg dexamethasone in addition to antibiotics reduces mortality.

Etiologic and special treatment 1.Quinolones: first choice first choice it’s highly against S.typhi it’s highly against S.typhi penetrate well into macrophages,and achieve high concentrations in the bowel and bile lumens penetrate well into macrophages,and achieve high concentrations in the bowel and bile lumens Norfloxacin (0.1 ～ 0.2 tid ～ qid/10 ～ 14 days). Norfloxacin (0.1 ～ 0.2 tid ～ qid/10 ～ 14 days). Ofloxacin (0.2 tid 10 ～ 14days). Ofloxacin (0.2 tid 10 ～ 14days). ciprofloxacin (0.25 tid) ciprofloxacin (0.25 tid) caution: not in children and pregnant

3.Cephalosporines: Only third generation effective Only third generation effective Cefoperazone and Ceftazidime. Cefoperazone and Ceftazidime. 2 ～ 4g/day.10~14 days. 2 ～ 4g/day.10~14 days. 4.Treatment of complication. Intestinal bleeding: Intestinal bleeding: bed rest, stop diet,close observation T,P,R,BP. bed rest, stop diet,close observation T,P,R,BP. intravenous saline and blood transfusion,and attention to acid-base balances. intravenous saline and blood transfusion,and attention to acid-base balances. sometimes,operative. sometimes,operative.

Perforation: Perforation: early diagnosis. early diagnosis. stop diet. stop diet. decrease down the stomach pressure. decrease down the stomach pressure. intravenous injection to maintain electrolyte and acid-base balances. intravenous injection to maintain electrolyte and acid-base balances. use of antibiotics. use of antibiotics. sometimes operative. sometimes operative.

Toxic myocarditis: Toxic myocarditis: bed rest, cardiac muscle protection drugs, bed rest, cardiac muscle protection drugs, dexamethasone, digoxin. dexamethasone, digoxin. 5.Chronic carrier: Ofloxacin 0.2 bid or ciprofloxacin 0.5 bid, 4 ～ 6 weeks. Ofloxacin 0.2 bid or ciprofloxacin 0.5 bid, 4 ～ 6 weeks. Ampicillin 3 ～ 6g/day tid plus probenecid 1 ～ 1.5g/day. 4 ～ 6 weeks. Ampicillin 3 ～ 6g/day tid plus probenecid 1 ～ 1.5g/day. 4 ～ 6 weeks. TMP+SMZ 2 tabs. Bid. 1 ～ 3 months. TMP+SMZ 2 tabs. Bid. 1 ～ 3 months. Cholecystitis may require cholecystectomy. Cholecystitis may require cholecystectomy.

MCQs Sahmonella is Sahmonella is a) Gram +ve rod b) Gram –ve cocci c) Gram –ve rod d) Gram +ve cocci e) Anaerob

Answer: C

Q2 In typhoid fever, splenomegaly In typhoid fever, splenomegaly a) Is present in the early first week b) Is present in the second week c) Present in early third week d) Is massive e) Carries a poor prognosis

Anwer: B

Q3 Which of the following is not a complication of typhoid fever Which of the following is not a complication of typhoid fever a) Intestenial haemorrhage b) Pneumonitis c) Dissemeinated intravascular coagulation d) Meningitis e) Pulmonary hypertension

Answer: E