Cytomegalovirus infection differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Overview

CMV infection can affect the eye, gastrointestinal tract and the central nervous system. Diagnosis of CMV requires differentiation of infections and diseases presenting with similar features. Majority of the patients with CMV end organ infection are immunosuppressed. Therefore CMV infection must be suspected in all the patients presenting with immunosuppression.

Differential Diagnosis of Cytomegalovirus infection

Cytomegalovirus Retinitis

Cytomegalovirus retinitis must be differentiated from tuberculosis, fungal infections, toxoplasmosis and syphilis:

Infectious Agent	Clinical Manifestations
Cytomegalovirus	Physical evidence of a cytomegalovirus presence in one of both eyes will generally clinical present in the form of lesions, adjacent retinal vessels. These lesions may impinge upon the fovea and the optic nerve. Furthermore they are usually discovered in close proximity to both. Further extending lesions may be present in close proximity to the vortex veins as well as the ora serrata.
Tuberculosis	Caseating granulomas Multiple choroidal tubercles- small grayish nodules located on the posterior pole of the eye Yellow necrotizing granulomas|
Fungal	Candida albicans Visibly hazy vitreous White circumscribed lesions Aspergillus fumigatus Yellow subretinal infiltrates Retinal infiltrates Fungal hyphae are located throughout the eye - suggestive of pulmonary involvement Cryptococcus neoformans Yellowish-white lesions located on the fundus of the eye Mutton-fat keratic precipitates
Toxoplasmosis	Localized areas of infiltrate Active lesions are adjacent to initial scarring
Syphilis	Hemorrhagic areas Flare visible in anterior and posterior portions

Cytomegalovirus Colitis

The symptoms of colitis such as bloody diarrhea and abdominal pain are seen are seen in all forms of colitis. The table below differentiates among the common causes of colitis. Cytomegalovirus colitis is diagnosed by demonstration of intranuclear inclusion bodies on colonic biopsy.

Diseases	History and Symptoms				Physical Examination				Laboratory findings
	Diarrhea	Rectal bleeding	Abdominal pain	Atopy	Dehydration	Fever	Hypotension	Malnutrition	Blood in stool (frank or occult)	Microorganism in stool	Pseudomembranes on endoscopy
Allergic Colitis	+	++	+	++					++
Chemical colitis	+	++	++		+	+			++		+
Infectious colitis	++	++	++		+++	+++	++	+	++	++	+
Radiation colitis	+	++	+		+			+	++
Ischemic colitis	+	+	++		+	+	+	+	++
Drug-induced colitis	+	+	++			+			++		+

Neurologic Infection

Cytomegalovirus infection presents with confusion and altered mental status. It must be differentiated from other disorders presenting with similar features. The following table is a list of disorders and their differentiating features:

Diseases	Symptoms				Physical Examination					Past medical history	Diagnostic tests			Other Findings
	Headache	↓LOC	Motor weakness	Abnormal sensory	Motor Deficit	Sensory deficit	Speech difficulty	Gait abnormality	Cranial nerves		CT /MRI	CSF Findings	Gold standard test
Meningitis	+	-	-	-	-	+	+	-	-	History of fever and malaise	-	↑ Leukocytes, ↑ Protein ↓ Glucose	CSF analysis	Fever, neck rigidity
Cytomegalovirus ventriculoencephalitis	+	+	+/-	+/-	-	-	+	+/-	+	History of fever and malaise	+	↑ Leukocytes, ↓ Glucose	CSF PCR	Fever, seizures, focal neurologic abnormalities
Brain tumor	+	-	-	-	+	+	+	-	+	Weight loss, fatigue	+	Cancer cells	MRI	Cachexia, gradual progression of symptoms
Hemorrhagic stroke	+	+	+	+	+	+	+	+	-	Hypertension	+	-	CT scan without contrast	Neck stiffness
Subdural hemorrhage	+	+	+	+	+	-	-	-	+	Trauma, fall	+	Xanthochromia	CT scan without contrast	Confusion, dizziness, nausea, vomiting
Neurosyphilis	+	-	+	+	+	+	-	+	-	STIs	+	↑ Leukocytes and protein	CSF VDRL-specifc CSF FTA-Ab -sensitive	Blindness, confusion, depression, Abnormal gait
Complex or atypical migraine	+	-	+	+	-	-	+	-	-	Family history of migraine	-	-	Clinical assesment	Presence of aura, nausea, vomiting
Hypertensive encephalopathy	+	+	-	-	-	-	+	+	-	Hypertension	+	-	Clinical assesment	Delirium, cortical blindness, cerebral edema, seizure
Wernicke’s encephalopathy	-	+	-	-	-	+	+	+	+	History of alcohal abuse	-	-	Clinical assesment and lab findings	Ophthalmoplegia, confusion
CNS abscess	+	+	-	-	+	+	+	-	-	History of drug abuse, endocarditis, immunosupression	+	↑ leukocytes, ↓ glucose and ↑ protien	MRI is more sensitive and specific	High grade fever, fatigue,nausea, vomiting
Drug toxicity	-	+	-	+	+	+	-	+	-	-	-	-	Drug screen test	Lithium, Sedatives, phenytoin, carbamazepine
Metabolic disturbances (electrolyte imbalance, hypoglycemia)	-	+	+	+	+	+	-	-	+	-	-	Hypoglycemia, hypo and hypernatremia, hypo and hyperkalemia	Depends on the cause	Confusion, seizure, palpitations, sweating, dizziness, hypoglycemia
Multiple sclerosis exacerbation	-	-	+	+	-	+	+	+	+	History of relapses and remissions	+	↑ CSF IgG levels (monoclonal bands)	Clinical assesment and MRI	Blurry vision, urinary incontinence, fatigue

Differentiating cytomegalovirus infection in immunocompromised host

Cytomegalovirus infection is more common among immunocompromised patients who are at high risk for other fungal, bacterial, and viral infections. It should be differentiated from the following diseases:

Disease	Differentiating signs and symptoms	Differentiating tests
CNS lymphoma	Patient is immunocompetent Focal symptoms indicative of a mass lesion Seizure	Single solitary ring enhancing lesion on CT or MRI
Disseminated tuberculosis	Prior history of residence in an endemic area Chronic cough, weight loss, hemoptysis	PCR of CSF for tuberculosis Mycobacterial culture of CSF Brain biopsy for acid-fast bacilli staining Culture and acid stain positive for acid-fast bacilli CXR shows cavitations
Aspergillosis	Pulmonary lesions in addition to CNS lesions Symptoms may include cough, chest pain, and hemoptysis	CSF fungal culture, galactomannan
Cryptococcosis	Symptoms include cough, chest pain, and hemoptysis	Cryptococcal antigen from CSF and serum CSF fungal culture
Chagas disease	History of residence in Central or South America Acute infection is rarely symptomatic Encephalitis or focal brain lesions Myocarditis Chronic infections in immunocompromised patients develop into encephalitis with necrotic brain lesions causing a mass effect	Trypanosoma cruzi in blood, tissue, or CSF, PCR of tissue or body fluids, and serologic tests
CMV infection	Most common CNS opportunistic infection in AIDS patients Presents with encephalitis, retinitis, progressive myelitis, or polyradiculitis In disseminated disease, it involves both the liver and kidneys	Brain CT/MRI/biopsy: location of lesions is usually near the brain stem or periventricular areas PCR of CSF with detectable virus is diagnostic Brain biopsy with + staining for CMV or evidence of owl's eyes is also diagnostic, but it is rarely performed because of the location of brain lesions
HSV infection	Seizures, headache, confusion and/or urinary retention can be seen in disseminated disease, which usually affects only the immunocompromised or acute infections In pregnant women, it may be associated with concurrent genital/oral lesions; can be spread to the neonate during acute infection in the mother, or via viral shedding in the birth canal Neonatal HSV can range from localized skin infections to encephalitis, pneumonitis, and disseminated disease	Brain CT/MRI/biopsy: location of lesions is usually the medial temporal lobe or the orbital surface of the frontal lobe. PCR of CSF with detectable virus is diagnostic
Varicella Zoster infection	Multifocal involvement has subacute course, usually only in immunosuppressed, with headache, fever, focal deficits, and seizures. Unifocal involvement is more typically seen in immunocompetent hosts, occurring after contralateral cranial nerve herpes zoster, with mental status changes, TIAs, and stroke Disseminated varicella zoster virus can occur in adults during primary infection, presenting with pneumonitis and/or hepatitis Disease is a vasculopathy with hemorrhage and stroke	PCR of CSF with detectable virus is diagnostic
Brain abscess	Associated with sinusitis (abutting the sinuses) or with bacteremia Signs and symptoms includes fever and necrotizing brain lesions with mass effect	CSF culture or culture of brain abscess
Progressive multifocal leukoencephalopathy	Symptoms are often more insidious in onset and progress over months. Symptoms include progressive weakness, poor coordination, with gradual slowing of mental function. Only seen in the immunosuppressed. Rarely associated with fever or other systemic symptoms	PCR of CSF for JC virus Biopsy reveals white matter lesions and not well-circumscribed lesions.