ENTERIC FEVER

DR DARAKHSHAN TALAT SIDDIQUI HOUSE OFFICER

MEDICAL 4

ENTERIC FEVER
Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused primarily by Salmonella typhi and Salmonella paratyphi. The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within one month of onset. Survivors may be left with long-term or permanent neuropsychiatric complications.

 S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation, crowding, and social chaos.
The name S typhi is derived from the ancient Greek typhos, an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world, it remains endemic in developing countries.

A photomicrograph of Salmonella typhosus bacteria using a Gram stain technique.

Transmission
S typhi has no no human vectors. The following are modes of transmission: Oral transmission via food or beverages handled by an individual who chronically sheds the bacteria through stool or, less commonly, urine Hand-to-mouth transmission after using a contaminated toilet and neglecting hand hygiene Oral transmission via sewage-contaminated water or shellfish (especially in the developing world) An inoculum as small as 100,000 organisms causes infection in more than 50% of healthy volunteers.

RISK FACTORS
S typhi are able to survive at stomach pH as low as 1.5. Antacids, histamine-2 receptor antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria decrease stomach acidity and facilitate S typhi infection. HIV Travel to endemic area Developing world Contaminated water Contaminated foods Raw food

Epidemiology
Typhoid fever occurs worldwide, primarily in developing nations whose sanitary conditions are poor. Typhoid fever is endemic in Asia, Africa, Latin America, but 80% of cases come from Bangladesh, China, India, Indonesia,Nepal, Pakistan, or Vietnam. Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per 1,000 population) and kills an estimated 200,000 people every year .

RACE Typhoid fever has no racial predilection. Sex Fifty-four percent of typhoid fever cases in the United States reported between 1999 and 2006 involved males. Age Most documented typhoid fever cases involve schoolaged children and young adults. However, the true incidence among very young children and infants is thought to be higher. The presentations in these age groups may be atypical, ranging from a mild febrile illness to severe convulsions, and the S typhi infection may go unrecognized.

Pathophysiology

S typhi enters the host's system primarily through the distal ilium. S typhi has specialized fimbriae that adhere to the epithelium over clusters of lymphoid tissue in the ilium (Peyer patches), the main relay point for macrophages traveling from the gut into the lymphatic system. S typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil- based inflammation. The bacteria then induce their host macrophages to attract more macrophages. It co-opts the macrophages' cellular machinery for their own reproduction as it is carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes. Once there, the S typhi bacteria pause and continue to multiply until some critical density is reached. Afterward, the bacteria induce macrophage apoptosis, breaking out into the bloodstream to invade the rest of the body. The gallbladder is then infected via either bacteremia or direct extension of S typhi infected bile. The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer patches. Bacteria that do not reinfect the host are typically shed in the stool and are then available to infect other hosts.

Mortality/Morbidity
With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term febrile illness requiring a median of 6 days of hospitalization. Treated, it has few long-term sequelae and a 0.2% risk of mortality.Untreated typhoid fever is a life-threatening illness of several weeks' duration with long-term morbidity often involving the central nervous system. The case fatality rate in the United States in the preantibiotic era was 9%-13% .

CLINICAL PRESENTATION
Typhoid fever begins 7-14 days after ingestion of S typhi. The fever pattern is stepwise, characterized by a rising temperature over the course of each day that drops by the subsequent morning. The peaks and troughs rise progressively over time.

 Over the course of the first week of illness, the notorious gastrointestinal manifestations of the disease develop. These include diffuse abdominal pain and tenderness and, in some cases, fierce colicky right upper quadrant pain. Monocytic infiltration inflames Peyer patches and narrows the bowel lumen, causing constipation that lasts the duration of the illness. The individual then develops a dry cough, dull frontal headache, delirium, and an increasingly stuporous malaise. At approximately the end of the first week of illness, the fever plateaus at 103-104F (39-40C). The patient develops rose spots, which are salmon-colored, blanching, truncal, maculopapules usually 1-4 cm wide and fewer than 5 in number; these generally resolve within 2-5 days. These are bacterial emboli to the dermis.

Rose spots on abdomen of a patient with typhoid fever due to the bacterium Salmonella typhi

Rose spots on the chest of a patient with typhoid fever due to the bacterium Salmonella typhi

 During the second week of illness, the signs and symptoms listed above progress. The abdomen becomes distended, and soft splenomegaly is common. Relative bradycardia and dicrotic pulse (double beat, the second beat weaker than the first) may develop. In the third week, the still febrile individual grows more toxic and anorexic with significant weight loss. The conjunctivae are infected, and the patient is tachypneic with a thready pulse and crackles over the lung bases. Abdominal distension is severe. Some patients experience foul, green-yellow, liquid diarrhea (pea soup diarrhea). The individual may descend into the typhoid state, which is characterized by apathy, confusion, and even psychosis. Necrotic Peyer patches may cause bowel perforation and peritonitis. This complication is often unheralded and may be masked by corticosteroids. At this point, overwhelming toxemia, myocarditis, or intestinal hemorrhage may cause death.

 If the individual survives to the fourth week, the fever, mental state, and abdominal distension slowly improve over a few days. Intestinal and neurologic complications may still occur in surviving untreated individuals. Weight loss and debilitating weakness last months. Some survivors become asymptomatic S typhi carriers and have the potential to transmit the bacteria indefinitely.

ATYPICAL PRESENTATIONS
Atypical manifestations of typhoid fever include isolated severe headaches that may mimic meningitis, acute lobar pneumonia, isolated arthralgias, urinary symptoms, severe jaundice, or fever alone. Some patients, especially in India and Africa, present primarily with neurologic manifestations such as delirium or, in extremely rare cases, parkinsonian symptoms or Guillain-Barr syndrome. Other unusual complications include pancreatitis, meningitis,orchitis, osteomyelitis, and abscesses anywhere on the body.

Differentials
Abdominal Abscess Amebic Hepatic Abscesses Appendicitis Dengue Fever Influenza Leishmaniasis Malaria Rickettsial diseases Toxoplasmosis Tuberculosis Tularemia Typhus

WORKUP
Laboratory Studies The diagnosis of typhoid fever (enteric fever) is primarily clinical.

Culture
The criterion standard for diagnosis of typhoid fever has long been culture isolation of the organism. Cultures are widely considered 100% specific. Culture of bone marrow aspirate is 90% sensitive until at least 5 days after commencement of antibiotics. However, this technique is extremely painful, which may outweigh its benefit. Blood, intestinal secretions (vomitus or duodenal aspirate), and stool culture results are positive for S typhi in approximately 85%-90% of patients with typhoid fever who present within the first week of onset. They decline to 20%-30% later in the disease course. In particular, stool culture may be positive for S typhi several days after ingestion of the bacteria secondary to inflammation of the intraluminal dendritic cells. Later in the illness, stool culture results are positive because of bacteria shed through the gallbladder. Multiple blood cultures (>3) yield a sensitivity of 73%-97%. Largevolume (10-30 mL) blood culture and clot culture may increase the likelihood of detection.

Specific serologic tests

Assays that identify Salmonella antibodies or antigens support the diagnosis of typhoid fever, but these results should be confirmed with cultures or DNA evidence. The Widal test was the mainstay of typhoid fever diagnosis for decades. It is used to measure agglutinating antibodies against H and O antigens of S typhi. Neither sensitive nor specific, the Widal test is no longer an acceptable clinical method. Indirect hemagglutination, indirect fluorescent Vi antibody, and indirect enzyme-linked immunosorbent assay (ELISA) for immunoglobulin M (IgM) and IgG antibodies to S typhi polysaccharide, as well as monoclonal antibodies against S typhi flagellin, are promising, but the success rates of these assays vary greatly in the literature.

Other nonspecific laboratory studies

Most patients with typhoid fever are moderately anemic, have an elevated erythrocyte sedimentation rate (ESR), thrombocytopenia, and relative lymphopenia. Most also have a slightly elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT) and decreased fibrinogen levels. Circulating fibrin degradation products commonly rise to levels seen in subclinical disseminated intravascular coagulation (DIC). Liver transaminase and serum bilirubin values usually rise to twice the reference range. Mild hyponatremia and hypokalemia are common. A serum alanine amino transferase (ALT)tolactate dehydrogenase (LDH) ratio of more than 9:1 appears to be helpful in distinguishing typhoid from viral hepatitis. A ratio of greater than 9:1 supports a diagnosis of acute viral hepatitis, while ratio of less than 9:1 supports typhoid hepatitis.

Imaging Studies
Radiography: Radiography of the kidneys, ureters, and bladder (KUB) is useful if bowel perforation (symptomatic or asymptomatic) is suspected. CT scanning and MRI: These studies may be warranted to investigate for abscesses in the liver or bones,and other sites.

Histologic Findings
The hallmark histologic finding in typhoid fever is infiltration of tissues by macrophages (typhoid cells) that contain bacteria, erythrocytes, and degenerated lymphocytes. Aggregates of these macrophages are called typhoid nodules, which are found most commonly in the intestine, mesenteric lymph nodes, spleen, liver, and bone marrow but may be found in the kidneys, testes, and parotid glands. In the intestines, 4 classic pathologic stages occur in the course of infection: (1) hyperplastic changes, (2) necrosis of the intestinal mucosa, (3) sloughing of the mucosa, and (4) the development of ulcers. The ulcers may perforate into the peritoneal cavity.

 In the mesenteric lymph nodes, the sinusoids are enlarged and distended by large collections of macrophages and reticuloendothelial cells. The spleen is enlarged, red, soft, and congested; its serosal surface may have a fibrinous exudate. Microscopically, the red pulp is congested and contains typhoid nodules. The gallbladder is hyperemic and may show evidence of cholecystitis. Liver biopsy specimens from patients with typhoid fever often show cloudy swelling, balloon degeneration with vacuolation of hepatocytes, moderate fatty change, and focal typhoid nodules. Intact typhoid bacilli can be observed at these sites.

Histopathology of a lymph node in a case of Typhoid Fever.

Staging
The proper treatment approach to typhoid fever depends on whether the illness is complicated or uncomplicated. Complicated typhoid fever is characterized by melena (3% of all hospitalized patients with typhoid fever), serious abdominal discomfort, intestinal perforation, marked neuropsychiatric symptoms, or other severe manifestations. Depending on the adequacy of diagnosis and treatment, complicated disease may develop in up to 10% of treated patients. Delirium, obtundation, stupor, coma, or shock demands a particularly aggressive approach.

Treatment & Management

Supportive therapy Drinking fluids. This helps prevent the dehydration that results from a prolonged fever and diarrhea Diet. Fluids and electrolytes should be monitored and replaced diligently. Oral nutrition with a soft digestible diet is preferable in the absence of abdominal distension or ileus.

Antibiotics
Definitive treatment of typhoid fever (enteric fever) is based on susceptibility. Until susceptibilities are determined, antibiotics should be empiric, for which there are various recommendations. 2003 World Health Organization (WHO) guidelines recommend fluoroquinolone treatment for both complicated and uncomplicated cases of typhoid fever, but 38% of S typhi isolates taken in the United States in 2006 were fluoroquinolone resistant (nalidixic acidresistant S typhi [NARST]), and the rate of multidrug resistance was 13%. (Multidrug-resistant S typhi is, by definition, resistant to the original first-line agents, ampicillin, chloramphenicol, and trimethoprimsulfamethoxazole.)

Chloramphenicol (Chloromycetin)
Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. 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 typh strains with plasmidmediated 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. Produces rapid improvement in patient's general condition, followed by defervescence in 3-5 d. Reduced preantibiotic -era case-fatality rates from 10%-15% to 1%-4%. Cures approximately 90% of patients. Administered PO unless patient is nauseous or experiencing diarrhea; in such cases, IV route should be used initially.

Adult Dosing 50 mg/kg/day IV divided q6hr; in exceptional cases, patients with moderately resistant organisms or severe infections may require increased dosage up to 100 mg/kg/day; decrease these high doses as soon as possible.

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. Convalescence carriage occurs less commonly than with other agents when organisms are fully susceptible. Usually given PO with a daily dose of 75-100 mg/kg tid for 14 d.

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.

Ciprofloxacin (Cipro)
Inhibits bacterial DNA synthesis and, consequently, growth. Continue treatment for at least 2 wks (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.

Ciprofloxacin (Cipro)
Not currently recommended for use in children and pregnant women because of observed potential for causing cartilage damage in growing animals. However, arthropathy has not been reported in children following use of nalidixic acid (an earlier quinolone known to produce similar joint damage in young animals) or in children with cystic fibrosis, despite highdose.

Antibiotics of Choice

Endemic area Uncomplicated enteric fever Severe typhoid

Ofloxacin or ciprofloxacin orally 7.5mg/kg b.i.d or levofloxacin orally 500mg daily for 3-5 days*
Ofloxacin or ciprofloxacin 7.5mg/kg infused over 30-60 minutes every 12 hours or levofloxacin 500mg infused every 24 hours until oral treatment can be substituted. Continue same dose for 10-14 days.

Non-immune
Ofloxacin or ciprofloxacin orally 7.5mg/kg b.i.d or levofloxacin orally 500mg daily for 5-7 days*
Ofloxacin or ciprofloxacin 7.5mg/kg infused over 30-60 minutes every 12 hours or levofloxacin 500mg infused every 24 hours until oral treatment can be substituted. Continue same dose for 10-14 days. Immunocompromised patients should receive at least three weeks treatment

Cefotaxime (Claforan)
Arrests bacterial cell wall synthesis, which inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Excellent in vitro activity against S typhi and other salmonellae and has acceptable efficacy in typhoid fever. Only IV formulations are available. Recently, emergence of domestically acquired ceftriaxone-resistant Salmonella infections has been described.

Azithromycin (Zithromax)
Treats mild to moderate microbial infections. Administered PO at 10 mg/kg/d (not exceeding 500 mg), appears to be effective to treat uncomplicated typhoid fever in children 4-17 years.

Ceftriaxone (Rocephin)
Third-generation cephalosporin with broad-spectrum activity. Excellent in vitro activity against S typhi and other salmonellae.

Ofloxacin (Floxin)
A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.

Levofloxacin (Levaquin)
For pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

Corticosteroids
Dexamethasone may decrease the likelihood of mortality in severe typhoid fever cases complicated by delirium, obtundation, stupor, coma, or shock if bacterial meningitis has been definitively ruled out by cerebrospinal fluid studies. To date, the most systematic trial of this has been a randomized controlled study in patients aged 3-56 years with severe typhoid fever who were receiving chloramphenicol therapy. This study compared outcomes in 18 patients given placebo with outcomes in 20 patients given dexamethasone 3 mg/kg IV over 30 minutes followed by dexamethasone 1 mg/kg every 6 hours for 8 doses. The fatality rate in the dexamethasone arm was 10% versus 55.6% in the placebo arm (P =.003). A 2003 WHO statement endorsed the use of steroids as described above.

Surgical Care
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.

Deterrence/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. In endemic countries, the most cost-effective strategy for reducing the incidence of typhoid fever is the institution of public health measures to ensure safe drinking water and sanitary disposal of excreta. The effects of these measures are long-term and reduce the incidence of other enteric infections, which are a major cause of morbidity and mortality in those areas.

Vaccines
In endemic areas, mass immunization with typhoid vaccines at regular intervals considerably reduces the incidence of infections. Travelers should be vaccinated at least one week prior to departing for an endemic area. Vaccines are not approved for use children younger than 2 years. Currently, the 3 typhoid fever vaccines include injected Vi capsular polysaccharide (ViCPS; Typhim Vi, Pasteur Merieux) antigen, enteric Ty21a (Vivotif Berna, Swiss Serum and Vaccine Institute) live-attenuated vaccine, and an acetone-inactivated parenteral vaccine (used only in members of the armed forces). The efficacy of both vaccines available to the general public approaches 50%.

 Vi capsular polysaccharide antigen vaccine is composed of purified Vi antigen, the capsular polysaccharide elaborated by S typhi isolated from blood cultures. Primary vaccination with ViCPS consists of a single parenteral dose of 0.5 mL (25 g IM) one week before travel. The vaccine manufacturer does not recommend the vaccine for children younger than 2 years. Booster doses are needed every 2 years to maintain protection if continued or renewed exposure is expected.

 Ty21a is an oral vaccine that contains live attenuated S typhi Ty21a strains in an entericcoated capsule. The vaccine elicits both serum and intestinal antibodies and cell-mediated immune responses. In the United States, primary vaccination with Ty21a consists of one enteric-coated capsule taken on alternate days to a total of 4 capsules. The manufacturer recommends revaccination with the entire 4-dose series every 5 years if continued or renewed exposure to S typhi is expected.

 Acetone-inactivated parenteral vaccine is currently available only to members of the US Armed Forces. Efficacy rates for this vaccine range from 75%-94%. Booster doses should be administered every 3 years if continued or renewed exposure is expected.

Complications
Neuropsychiatric manifestations:
A toxic confusional state, characterized by disorientation, delirium, and restlessness, is characteristic of late-stage typhoid fever. Facial twitching or convulsions multiple brain abscesses Meningismus and Encephalomyelitis

 Respiratory
Cough Ulceration of posterior pharynx Occasional presentation as acute lobar pneumonia (pneumotyphoid)

Cardiovascular
Nonspecific electrocardiographic changes occur in 10%-15% of patients with typhoid fever. Toxic myocarditis occurs in 1%-5% of persons with typhoid fever and is a significant cause of death in endemic countries. Toxic myocarditis occurs in patients who are severely ill and toxemic and is characterized by tachycardia, weak pulse and heart sounds, hypotension, and electrocardiographic abnormalities. Pericarditis is rare, but peripheral vascular collapse without other cardiac findings is increasingly described.

Hepatobiliary
Mild elevation of transaminases without symptoms is common in persons with typhoid fever. Jaundice may occur in persons with typhoid fever and may be due to hepatitis, cholangitis, cholecystitis, or hemolysis. Pancreatitis and accompanying acute renal failure and hepatitis with hepatomegaly have been reported.

Intestinal manifestations
The 2 most common complications of typhoid fever include intestinal hemorrhage (12% in one British series) and perforation (3%-4.6% of hospitalized patients). From 1884-1909 (ie, preantibiotic era), the mortality rate in patients with intestinal perforation due to typhoid fever was 66%-90% but is now significantly lower. Approximately 75% of patients have guarding, rebound tenderness, and rigidity, particularly in the right lower quadrant.

Typhoid fever Typhoid fever cholecystitis with an ulceration and perforation of the gallbladder into the jejunum.

The air bubble below the right hemidiaphragm (on the left of the image) is a pneumoperitoneum.

 Genitourinary manifestations
Immune complex glomerulitis and proteinuria have been reported, and IgM, C3 antigen, and S typhi antigen can be demonstrated in the glomerular capillary wall. Nephritic syndrome may complicate chronic S typhi bacteremia associated with urinary schistosomiasis. Nephrotic syndrome may occur transiently in patients with glucose-6-phosphate dehydrogenase deficiency.

Hematologic manifestations
Subclinical disseminated intravascular coagulation is common in persons with typhoid fever. Hemolytic- uremic syndrome is rare. Hemolysis may also be associated with glucose-6-phosphate dehydrogenase deficiency.

Musculoskeletal and joint manifestations

Skeletal muscle characteristically shows Zenker degeneration, particularly affecting the abdominal wall and thigh muscles. Clinically evident polymyositis may occur. Arthritis is very rare and most often affects the hip, knee, or ankle.

Prognosis
The prognosis among persons with typhoid fever depends primarily on the speed of diagnosis and initiation of correct treatment. Generally, untreated typhoid fever carries a mortality rate of 10%-20%. In properly treated disease, the mortality rate is less than 1%.

Patient Education
Because vigilant hand hygiene, vaccination, and the avoidance of risky foods and beverages are mainstays of prevention, educating travelers before they enter a disease-endemic region is important. Because the protection offered by vaccination is at best partial, close attention to personal, food, and water hygiene should be maintained. The US Centers for Disease Control and Prevention dictum to "boil it, cook it, peel it, or forget it" is a good rule in any circumstance.