Typhoid fever differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2], Aysha Anwar, M.B.B.S[3]

Overview

Typhoid fever must be differentiated from other diseases that cause fever, diarrhea, and dehydration, such as Ebola, Shigellosis, malaria, and Lassa fever.

Differentiating Typhoid fever from other Diseases

The table below summarizes the findings that differentiate Typhoid fever from other conditions that cause fever, diarrhea, dehydration, and non-specific abdominal symptoms.

Disease	Findings
Typhoid fever-like syndrome	Caused by Salmonella Paratyphi A, B, C or Choleraesuis. Presents with fever, chills, vomiting, abdominal pain, generalized pain or malaise following an incubation period of 5-21 days.
Ebola	Presents with fever, chills, vomiting, diarrhea, generalized pain or malaise, and sometimes internal and external bleeding following an incubation period of 2-21 days.
Shigellosis & other bacterial enteric infections	Presents with diarrhea, possibly bloody, accompanied by fever, nausea, and sometimes toxemia, vomiting, cramps, and tenesmus. Stools contain blood and mucous in a typical case. A search for possible sites of bacterial infection, together with cultures and blood smears, should be made. Presence of leukocytosis distinguishes bacterial infections from viral infections.
Malaria	Presents with acute fever, headache, and sometimes diarrhea (in children). A blood smear must be examined for malaria parasites. The presence of parasites does not exclude concurrent viral infection. An antimalarial should be prescribed as an empiric therapy.
Lassa fever	Disease onset is usually gradual, with fever, sore throat, cough, pharyngitis, and facial edema in the later stages. Inflammation and exudation of the pharynx and conjunctiva are common.
Yellow fever and other Flaviviridae	Present with hemorrhagic complications. Epidemiological investigation may reveal a pattern of disease transmission by an insect vector. Virus isolation and serological investigation are helpful for distinguishing these viruses. Confirmed history of previous yellow fever vaccination will rule out yellow fever.
Abdominal abscess (e.g., ameobic hepatic abcess)	May present with abdominal pain, fever, loss of appetite, nausea, vomiting, diarrhea, constipation. H/o surgery, presence of a mass on physical examination, ultrasound or CT scan may help rule out abdominal abscess in such cases.
Brucellosis	Presents with recurrent fevers, acute abdominal pain, and other symptoms resembling typhoid fever. History of exposure to infected animals, including work in a slaughterhouse or as a veterinarian, may help differentiate brucellosis from typhoid fever.
Others	Viral hepatitis, leptospirosis, rheumatic fever, typhus, appendicitis, dengue fever,toxoplasmosis, rickettsial diseases, leishmaniasis, tuberculosis, and mononucleosis can produce signs and symptoms that may be confused with typhoid fever in the early stages of infection.

Differentiating diagnosis of Typhoid fever	Symptoms					Signs			Diagnosis	Additional Findings
	Fever	Rash	Diarrhea	Abdominal pain	Weight loss	Painful lymphadenopathy	Hepatosplenomegaly	Arthritis	Lab Findings
Brucellosis	✔	✔	✘	✔	✔	✔	✔	✔	Relative lymphocytosis	Night sweats, often with characteristic smell, likened to wet hay
Typhoid fever	✔	✔	✘	✔	✘	✘	✔	✔	Decreased hemoglobin	Incremental increase in temperature initially and than sustained fever as high as 40°C (104°F)
Malaria	✔	✘	✔	✔	✘	✘	✔	✔	Microcytosis, elevated LDH	"Tertian" fever: paroxysms occur every second day
Tuberculosis	✔	✔	✘	✔	✔	✔	✔	✔	Mild normocytic anemia, hyponatremia, and hypercalcemia	Night sweats, constant fatigue
Lymphoma	✔	✘	✘	✔	✔	✘	✔	✘	Increase ESR, increased LDH	Night sweats, constant fatigue
Mumps	✔	✘	✘	✘	✘	✔	✘	✘	Relative lymphocytosis, serum amylase elevated	Parotid swelling/tenderness
Rheumatoid arthritis	✘	✔	✘	✘	✘	✘	✘	✔	ESR and CRP elevated, positive rheumatoid factor	Morning stiffness
SLE	✘	✔	✘	✔	✔	✘	✘	✔	ESR and CRP elevated, positive ANA	Fatigue
HIV	✘	✘	✘	✔	✔	✔	✘	✔		Constant fatigue

Typhoid fever must be differentiated from other causes of diarrhea

Cause			Osmotic gap		History	Physical exam	Gold standard	Treatment
			< 50 mOsm per kg	> 50 mOsm per kg*
Watery	Secretory	Crohns	+	-	Abdominal pain followed by diarrhea	Abdominal tenderness when palpated in severe disease Blood seen on rectal exam Fever Tachycardia Hypotension	Colonoscopy with biopsy	Topical mucosamine and corticosteroids are preferred Mesalamine and sulfasalazine are used for remission
		Hyperthyroidism	+	-	Excessive sweating Heat intolerance Increased bowel movements	Lump in the neck Proptosis Tremors Increased DTR	TSH with T3 and T4	Carbimazole and methimazole Beta blockers like propylthiouracil Iodine-131
		VIPoma	+	-	Watery diarrhea Dehydration (thirst, dry skin, dry mouth, tiredness, headaches, and dizziness) Lethargy, muscle weakness Nausea, vomiting Crampy abdominal pain Weight loss Flushing	Tachycardia Rash Facial flushing Abdominal distention Abdominal tenderness in the right upper abdominal quadrant	Elevated VIP levels Followed by imaging	Sandostatin or chemotherapy for malignant tumors Surgical removal of the tumor
	Osmotic	Lactose intolerance	-	+	Abdominal pain Bloating Diarrhea Flatulence	Abdominal tenderness	Intestinal biopsy	Avoidance of dietary lactose Substitution to maintain nutrient intake Regulation of calcium intake Use of enzyme lactase
		Celiac disease	-	+	May be asymptomatic Vague abdominal pain Diarrhea Weight loss Malabsorption / steatorrhea Bloatedness	Abdominal pain and cramping Abdominal distention Tetany Mouth ulcers Dermatitis herpetiformis Signs of the fat-soluble vitamins A, D, E, and K deficiency	IgA tissue transglutaminase Ab	Gluten-free diet
	Functional	Irritable bowel syndrome	-	-	Abdominal pain or discomfort recurring at least 3 days per month in the past 3 months and associated with 2 or more of the following: Improves with defecation Onset associated with change in frequency of stool Onset associated with change in appearance of stool 25% of bowel movements are loose stools History of straining is also common	Abdominal tenderness Hard stool in the rectal vault	Clinical diagnosis ROME III criteria Pharmacologic studies based criteria	High dietary fiber Osmotic laxatives such as polyethylene glycol, sorbitol, and lactulose Antispasmodic drugs (e.g. anticholinergics such as hyoscyamine or dicyclomine)

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