Clinical Manifestations:

The clinical presentation of typhoid fever is variable, but a classic untreated course can be divided into four stages, each lasting approximately one week. However, with prompt antibiotic treatment, this progression is often altered.

• Week 1 (Initial Stage): Characterized by a gradually increasing fever (step-ladder pattern), reaching 39-40°C (102-104°F) by the end of the week. Patients often experience malaise, fatigue, headache (frequently frontal and severe), generalized myalgia, and anorexia. Abdominal discomfort may be present. Some individuals may have a dry cough. Epistaxis (nosebleeds) can occur in about 25% of cases. Relative bradycardia (a slower pulse rate than expected for the degree of fever) is a classic sign. Laboratory findings often reveal leukopenia, eosinopenia, and relative lymphocytosis. Blood cultures are usually positive during this stage, while the Widal test is typically negative.

• Week 2 (Progressive Stage): The patient becomes more severely ill with a sustained high fever. Delirium, characterized by confusion, disorientation, or agitation, may develop. Rose spots, which are transient, blanching, pink macules (1-3 mm in diameter), may appear on the trunk (abdomen and lower chest) in approximately one-third of patients. The abdomen may become distended and tender, particularly in the right lower quadrant. Diarrhea, with characteristic pea-soup colored stools, may occur, although constipation can also be frequent. Hepatosplenomegaly (enlargement of the liver and spleen) may be detectable and tender. The tongue may be coated with a brownish fur. Signs of dehydration may become apparent. The Widal test typically shows increasing titers of anti-O and anti-H antibodies. Blood cultures may remain positive.

• Week 3 (Complication Stage): The patient is often critically ill and toxic. The fever remains high and may be intermittent. The pulse may become feeble. Patients may lapse into a “typhoid state,” characterized by obtundation, muttering delirium, and picking at bedclothes (carphology). Intestinal complications are most likely during this week as the inflamed Peyer’s patches can ulcerate deeply. This can lead to intestinal hemorrhage (manifesting as melena or hematochezia) or intestinal perforation, resulting in peritonitis (severe abdominal pain, rigidity, and tenderness). Other complications, such as myocarditis, encephalitis, or cholecystitis, may also arise.

• Week 4 (Defervescence and Convalescence): In uncomplicated cases, the fever begins to subside, and other symptoms gradually improve as the patient’s temperature returns to normal (lysis). Recovery is often slow, and relapses of symptoms can occur. If left untreated, severe complications can lead to death.

Diagnosis:

The diagnosis of typhoid fever involves a combination of clinical suspicion and laboratory confirmation.

• Blood Culture: Considered the gold standard for diagnosing typhoid fever, particularly in the first week of illness when bacteremia is present. Multiple blood cultures may increase sensitivity.

• Stool Culture: Becomes more useful in the later stages of the illness and for identifying chronic carriers.

• Urine Culture: Can also be positive, especially after the first week.

• Bone Marrow Culture: The most sensitive method for detecting S. Typhi, but it is invasive and not routinely performed.

• Widal Test: A serological test that detects antibodies against the O and H antigens of S. Typhi. A significant rise in antibody titers between acute and convalescent serum samples is suggestive of recent infection. However, the Widal test has limitations due to low sensitivity and specificity, potential for false-positive results (due to past exposure or cross-reacting antibodies), and false-negative results (especially early in the illness). It is less reliable in areas where typhoid fever is endemic due to high background levels of antibodies.

• Typhidot (Tubex Test): A rapid serological test that detects IgM and IgG antibodies against a specific S. Typhi antigen. It offers faster results compared to the Widal test but also has limitations in sensitivity and specificity.

• Polymerase Chain Reaction (PCR): Can detect S. Typhi DNA in blood or stool samples, offering rapid and specific diagnosis. PCR is particularly useful in the early stages of the illness before antibody responses are detectable.

• Complete Blood Count (CBC): May show leukopenia (low white blood cell count), anemia, and thrombocytopenia (low platelet count).

• Liver Function Tests (LFTs): May reveal mild elevations in liver enzymes (transaminases).

Differential Diagnosis:

Typhoid fever shares symptoms with several other infectious diseases, necessitating careful differentiation:

• Malaria: Characterized by cyclical fever, chills, and sweating. Requires blood smear examination for diagnosis.

• Dengue Fever: Marked by high fever, severe headache, retro-orbital pain, muscle and joint pain (“breakbone fever”), and rash.

• Infectious Mononucleosis: Presents with fever, pharyngitis, lymphadenopathy, and fatigue.

• Tuberculosis (Disseminated): Can cause prolonged fever, weight loss, and organ involvement.

• Bacterial Endocarditis: Characterized by fever, heart murmur, and systemic embolization.

• Brucellosis: Presents with fever, sweats, joint pain, and fatigue.

• Leptospirosis: Caused by Leptospira bacteria, often associated with exposure to contaminated water.

• Amoebic Liver Abscess: Can cause fever, right upper quadrant pain, and hepatomegaly.

Complications:

If left untreated or inadequately treated, typhoid fever can lead to serious and life-threatening complications:

• Gastrointestinal Hemorrhage: Bleeding from eroded blood vessels in intestinal ulcers, ranging from mild to severe.

• Intestinal Perforation: A serious complication where the ulcerated intestinal wall ruptures, leading to peritonitis, a surgical emergency.

• Peritonitis: Inflammation of the peritoneum due to intestinal perforation, causing severe abdominal pain, rigidity, and sepsis.

• Myocarditis: Inflammation of the heart muscle, potentially leading to heart failure.

• Encephalitis: Inflammation of the brain, resulting in neurological symptoms such as confusion, seizures, and coma.

• Meningitis: Inflammation of the meninges (membranes surrounding the brain and spinal cord).

• Cholecystitis: Inflammation of the gallbladder, which can occur due to S. Typhi colonization.

• Pneumonia: Lung infection that can develop as a secondary complication.

• Osteomyelitis: Bone infection, a rare complication.

• Septic Arthritis: Joint infection, also a rare complication.

• Renal Complications: Including glomerulonephritis or acute kidney injury.

• Psychiatric Disturbances: Delirium, psychosis, and other mental health issues can occur during the acute phase.

• Relapse: Recurrence of symptoms after initial improvement, occurring in about 10-20% of untreated cases.

Treatment:

The primary goal of treatment is to eradicate the S. Typhi infection and prevent complications.

• Antibiotic Therapy: Antibiotics are the mainstay of treatment. The choice of antibiotic depends on local resistance patterns.

  • Fluoroquinolones (e.g., Ciprofloxacin, Ofloxacin): Highly effective and often used as first-line agents in areas with low resistance. Oral or intravenous administration is possible.

  • Third-Generation Cephalosporins (e.g., Ceftriaxone, Cefotaxime): Also effective and commonly used, particularly for severe cases or in areas with fluoroquinolone resistance. Administered intravenously or intramuscularly.

  • Azithromycin: A macrolide antibiotic that is also effective against S. Typhi and can be administered orally.

  • Older Antibiotics (e.g., Chloramphenicol, Trimethoprim-Sulfamethoxazole [Cotrimoxazole], Ampicillin, Amoxicillin): While historically used, resistance to these antibiotics is now widespread in many parts of the world, limiting their current utility.

• Dosage and Duration: The specific antibiotic, dosage, and duration of treatment are determined by the severity of the illness and local antimicrobial susceptibility data. Treatment typically lasts for 7-14 days, although shorter courses may be used with some antibiotics.

• Supportive Care:

  • Fluid and Electrolyte Management: Maintaining adequate hydration is crucial, especially if the patient has fever and diarrhea. Oral rehydration solutions or intravenous fluids may be necessary.

  • Nutritional Support: A balanced and easily digestible diet is recommended.

  • Antipyretics: Paracetamol (acetaminophen) can be used to manage fever and discomfort.

  • Hygiene Measures: Strict attention to hygiene is important to prevent the spread of infection.

• Corticosteroids: In severe cases of typhoid fever with complications like encephalopathy or myocarditis, corticosteroids (e.g., dexamethasone) may be used as adjunctive therapy to reduce inflammation.

• Management of Complications: Specific interventions are required for complications such as intestinal hemorrhage (blood transfusion, endoscopy), intestinal perforation (surgical repair), and neurological involvement (supportive care, anticonvulsants if needed).

• Management of Chronic Carriers:

  • Antibiotics: Prolonged courses of antibiotics, such as ciprofloxacin or amoxicillin, are used to attempt to eradicate S. Typhi from the gallbladder.

  • Cholecystectomy: Surgical removal of the gallbladder may be considered for chronic carriers, particularly if antibiotic therapy fails or if the individual has gallstones.

Prognosis:

The prognosis of typhoid fever is generally good with early diagnosis and appropriate antibiotic treatment. The case fatality rate in treated patients is typically less than 1%. However, without treatment, the mortality rate can be as high as 10-20%. The development of complications significantly worsens the prognosis. Relapses can occur in a small percentage of treated patients.

Prevention:

Prevention strategies for typhoid fever focus on improving sanitation, hygiene, and vaccination.

• Public Health Measures:

  • Improved Sanitation: Ensuring access to safe drinking water and proper sewage disposal is the most effective way to prevent typhoid fever.

  • Food Safety: Implementing and enforcing regulations for food handling, preparation, and storage.

  • Health Education: Educating the public about the importance of handwashing, safe food and water practices.

  • Surveillance and Outbreak Response: Monitoring for cases of typhoid fever and implementing rapid public health interventions to control outbreaks.

• Individual Measures:

  • Handwashing: Frequent and thorough handwashing with soap and water, especially after using the toilet and before preparing or eating food.

  • Safe Water: Drinking safe water, which may involve boiling, chlorination, or using water filters.

  • Safe Food: Consuming thoroughly cooked food and avoiding raw or undercooked foods, especially in endemic areas. Avoiding ice from unknown sources.

  • Travel Precautions: Travelers to endemic areas should be particularly vigilant about food and water safety.

• Vaccination: Two types of typhoid vaccines are available:

  • Ty21a (Oral, Live Attenuated Vaccine): Administered in a series of capsules taken over several days. Provides protection for approximately 5 years.

  • Vi Polysaccharide Vaccine (Injectable, Inactivated Subunit Vaccine): Administered as a single injection. Provides protection for approximately 2 years.

  • Recommendations: Vaccination is recommended for travelers to endemic areas, individuals in close contact with known carriers, and in response to outbreaks.