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| ==Overview==
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| | {{CMG}}:{{AE}}{{DAMI}} |
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| ==Classification==
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| Cytomegalovirus infection can be classified based on the organ system involved into the following:
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| ===CMV retinitis===
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| *It is the most common clinical manifestation of [[cytomegalovirus]] infection.
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| *[[Retinitis]] is initially unilateral but progress to affect the contralateral side in the absence of therapy and [[immunosuppression]].
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| *In patients with [[CD4]] < 50cells/mm³ bilateral retinal involvement is high.
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| *Peripheral [[retinitis]] can be asymptomatic or present with floaters, scotomata, or peripheral [[Visual field defect|visual field defects]] whereas central retinal lesions or lesions impinging on the [[macula]] or [[optic nerve]] are result in decreased [[visual acuity]] and central [[Visual field defect|field defects]].
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| *On fundus examination the following findings can be demonstrated:
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| **Fluffy yellow-white retinal lesions, with or without intraretinal hemorrhage.
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| **[[Inflammation]] of the [[vitreous]] can be demonstrated in patients with severe [[immunosuppression]].
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| **Blood vessels appear sheathed.
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| **If left untreated, [[retinitis]] is a rapidly progressive condition and on fundus examination it demonstrates a characteristic brushfire pattern, with a granular, white leading edge advancing before an atrophic gliotic scar.
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| ===CMV [[colitis]]=== | | ==[[Roseola overview|Overview]]== |
| *[[Colitis]] is seen in 5 to 10% of patients with [[AIDS]] and [[cytomegalovirus]] end organ disease.
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| *[[Colitis]] presents with [[weight loss]], [[anorexia]], [[abdominal pain]], debilitating [[diarrhea]], [[fever]] and [[malaise]]. Patients with [[Gastrointestinal perforation|perforation]] of the [[bowel]] present with [[acute abdominal pain]].
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| *[[Computed tomography|CT]] abdomen in patients with [[cytomegalovirus]] colitis demonstrates colonic thickening.
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| *Complications of [[cytomegalovirus]] colitis include [[Gastrointestinal perforation|bowel perforation]] and hemorrhagic enteritis.
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| *[[Colonoscopy]] demonstrates mucosal lesions and the diagnosis is confirmed by the presence of characteristic intranuclear and intracytoplasmic [[inclusions]] on microscopic examination of the colonic [[biopsy]].
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| ===CMV esophagitis=== | | ==[[Roseola historical perspective|Historical Perspective]]== |
| *[[Cytomegalovirus]] [[esophagitis]] can be seen in few patients with [[AIDS]] and [[cytomegalovirus]] end organ disease.
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| *Patients present with symptoms of [[odynophagia]], [[Nausea and vomiting|nausea]], [[Abdominal pain|mid-epigastric or retrosternal discomfort]] and [[fever]].
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| *[[Endoscopy]] will reveal [[ulcers]] in the distal [[esophagus]] and diagnosis is confirmed by the demonstration of characteristic [[Inclusion bodies|intranuclear inclusion bodies]] in the [[endothelial cells]] of the [[biopsy]] specimen.
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| *Culture of [[cytomegalovirus]] from the [[esophageal]] [[biopsy]] is not sufficient to confirm the diagnosis in the absence of microscopic findings as majority of patients with low [[CD4]] counts have positive culture.
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| ===CMV pneumonitis=== | | ==[[Roseola classification|Classification]]== |
| *[[Cytomegalovirus]] [[pneumonitis]] is a uncommon condition and is usually asymptomatic.
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| *It is usually diagnosed on [[bronchoalveolar lavage]] and co-exists with an underlying pulmonary infection.
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| *[[Chest X-ray|Chest X-Ray]] demonstrates diffuse pulmonary interstitial infiltrates and diagnosis confirmation requires a correlation of the clinical features to imaging findings.
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| ===Neurologic disease=== | | ==[[Roseola pathophysiology|Pathophysiology]]== |
| [[Cytomegalovirus]] infection of the neurological system includes [[dementia]], [[Encephalitis|ventriculoencephalitis]] and [[Radiculopathy|polymyeloradiculopathies]]. Diagnosis of neurological disease requires correlation between the clinical symptoms and a positive [[Polymerase chain reaction|PCR]] for [[cytomegalovirus]] of the [[cerebrospinal fluid]].
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| *'''CMV Encephalitis'''
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| **Patients with [[cytomegalovirus]] [[encephalitis]] presents with [[fever]], [[lethargy]] and [[confusion]].
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| **[[Cerebrospinal fluid]] demonstrates lymphocytic pleocytosis, low-to-normal [[glucose]] levels, and normal-to-elevated [[protein]] levels.
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| *'''CMV Ventriculoencephalitis'''
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| **Patients have an acute onset of symptoms with focal neurological deficits, [[cranial nerve palsies]], [[nystagmus]] and rapid progression to death.
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| **Presence of periventricular enhancement on [[Computed tomography|CT]] or [[MRI]] is highly suggestive of [[CMV]] infection.
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| *'''CMV polyradiculomyelopathy'''
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| **Patients present with similar features of [[Guillain-Barre Syndrome|Guillian Barre Syndrome]].
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| **Patients with [[bladder incontinence]] and [[paraplegia]] with gradual worsening of symptoms over weeks.
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| **[[Cerebrospinal fluid|Cerebrospinal fluid analysis]] demonstrates neutrophilic pleocytosis, low [[glucose]] levels and elevated [[protein]] levels.
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| ==Pathogenesis== | | ==[[Roseola causes|Causes]]== |
| ===Transmission===
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| *[[CMV]] is transmitted through body fluids, including [[saliva]], [[urine]], human [[milk]], genital secretions, and [[blood]].
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| ===CMV Retinitis===
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| *Retinitis, caused by [[cytomegalovirus]] (CMV), involves the infection of all layers of the [[Retina|retinal tissue]].
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| *Spread of the the infection will occur at approximately 24 nanometers per day.
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| *Primarily infected areas include the [[Retinal pigment epithelium|retinal pigment epithelium]] and the subjacent [[choroid]].
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| *Infection will result in cellular [[necrosis]] across the [[retina]]; with the enlargement of infected cells, evidently hosting [[Inclusion|viral inclusions]].
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| *CMV retinitis, post-treatment, will commonly persist on the previously scarred, retinal tissue.
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| *Progression of infection may result in the development of small holes across previously [[Scarring|scarred]] and healed tissue.
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| *Formation of these tiny holes may result in rhegmatogenous, [[Retinal detachment|retinal detachments]]. <ref name="AAO">American Academy of Ophthalmology. Pathophysiology of CMV Retinitis. http://www.aao.org/focalpointssnippetdetail.aspx?id=bc891841-b847-4210-a66b-2bb28d1ef1bf. Accessed April 12, 2016. </ref>
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| ==Risk Factors== | | ==[[Roseola differential diagnosis|Differentiating Any Disease from other Diseases]]== |
| *Patients with the following conditions are at a higher risk for developing symptomatic cytomegalovirus infection:
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| **[[Organ transplant|Solid organ transplant]]
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| **[[Hematopoietic stem cell transplantation|Hematological stem cell transplant]]
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| **[[AIDS]]
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| **[[T-cell|T-cell deficiency]]
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| ==Epidemiology and Demographics== | | ==[[Roseola epidemiology and demographics|Epidemiology and Demographics]]== |
| *[[Cytomegalovirus]] ([[CMV]]) infects approximately 40-90% of the world population.<ref name="pmid27526428">{{cite journal| author=Pytka D, Czarkowska-Pączek B| title=[CMV infection in elderly]. | journal=Przegl Lek | year= 2016 | volume= 73 | issue= 4 | pages= 241-4 | pmid=27526428 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27526428 }} </ref>
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| *CMV seroprevalence in developing countries reaches more than 90% by [[adolescence]] and exceeds 95% by early adulthood.
| | ==[[Roseola risk factors|Risk Factors]]== |
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| | ==[[Roseola screening|Screening]]== |
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| | ==[[Roseola natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ==Diagnosis== | | ==Diagnosis== |
| ===Serological Tests===
| | [[Roseola history and symptoms|History and Symptoms]] | [[Roseola physical examination|Physical Examination]] | [[Roseola laboratory findings|Laboratory Findings]] | [[Roseola electrocardiogram|Electrocardiogram]] | [[Roseola chest x ray|Chest X Ray]] | [[Roseola CT|CT]] | [[Roseola MRI|MRI]] | [[Roseola echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Roseola other imaging findings|Other Imaging Findings]] | [[Roseola other diagnostic studies|Other Diagnostic Studies]] |
| *[[Serological testing|Serological]] tests are not useful for the diagnosis of [[cytomegalovirus]] infection, however absence of [[CMV]] [[IgG]] excludes the presence of infection.
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| ===Polymerase Chain Reaction===
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| *In patients with [[cytomegalovirus]] [[retinitis]] [[CMV]] [[DNA]] is detected in the vitreous in majority of patients.
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| *[[PCR]] for demonstration of [[CMV]] [[DNA]] is useful for the diagnosis of [[retinitis]] and neurologic disease.
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| *[[PCR]] of [[blood]] for demonstration of [[viremia]] is not useful for diagnosis of [[cytomegalovirus]] end organ disease as a negative result is not consistent with the absence of disease.
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| ===Microscopic Pathology===
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| *Demonstration of characteristic [[Inclusion bodies|intranuclear inclusion bodies]] in the [[biopsy]] from [[esophagus]] and [[colon]] confirms the diagnosis of [[esophagitis]] and [[colitis]].
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| ===CT Scan===
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| *In patients with [[cytomegalovirus]] [[Encephalitis|ventriculoencephalitis]] periventricular enhancement is suggestive of [[CMV]] infection.
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| *Colonic thickening can be demonstrated in patients with [[cytomegalovirus]] [[colitis]].
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| ==Treatment== | | ==Treatment== |
| [[Antiviral drugs|Antiviral therapy]] is the primary modality of treatment. Duration of therapy and the [[Antiviral Therapy|antiviral agents]] are selected based on the severity of the disease, location of the disease and the level of [[immunosuppression]]. | | [[Roseola medical therapy|Medical Therapy]] | [[Roseola surgery|Surgery]] | [[Roseola primary prevention|Primary Prevention]] | [[Roseola secondary prevention|Secondary Prevention]] | [[Roseola cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Roseola future or investigational therapies|Future or Investigational Therapies]] |
| ===CMV Retnitis===
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| The choice of therapy is based on the location of the lesions and level of [[immunosuppression]] of the patient. Systemic antiviral therapy is preferred as infection rate of the contralateral eye is reduced.
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| *'''Initial Therapy for patients with immediate sight-threatening lesions''' (Adjacent to the [[optic nerve]] or [[fovea]])
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| **Preferred Regimen(1): [[Ganciclovir]] intraocular implant + [[valganciclovir]] 900 mg PO (BID for 14–21 days, then once daily) {{and}} One dose of intravitreal [[ganciclovir]] may be administered immediately after diagnosis until [[ganciclovir]] implant can be placed
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| **Alternate Regimen (1): [[Ganciclovir]] 5 mg/kg IV q12h for 14–21 days, then 5 mg/kg IV daily {{or}}
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| **Alternate Regimen (2): [[Ganciclovir]] 5 mg/kg IV q12h for 14–21 days, then [[valganciclovir]] 900 mg PO daily {{or}}
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| **Alternate Regimen (3): [[Foscarnet]] 60 mg/kg IV q8h or 90 mg/kg IV q12h for 14–21 days, then 90–120 mg/kg IV q24h {{or}}
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| **Alternate Regimen (4): [[Cidofovir]] 5 mg/kg/week IV for 2 weeks, then 5 mg/kg every other week with saline hydration before and after therapy and [[probenecid]] 2 g PO 3 hours before the dose followed by 1 g PO 2 hours after the dose, and 1 g PO 8 hours after the dose (total of 4 g)
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| ***Note(1): This regimen should be avoided in patients with [[sulfa allergy]] because of cross [[hypersensitivity]] with [[probenecid]].
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| ***Note(2): If systemic anti-CMV treatment is not available, use sequential [[ganciclovir]] intravitreal injections until immune reconstitution in response to [[HIV AIDS medical therapy|anti retroviral viral therapy]] is achieved.
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| *'''For Small Peripheral Lesions'''
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| **Preferred Regimen: [[Valganciclovir]] 900 mg PO BID for 14–21 days, then 900 mg PO daily {{and}} One dose of intravitreal [[ganciclovir]] may be administered immediately after diagnosis to deliver high local concentration until systemic [[ganciclovir]] concentration is reached.
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| *'''Chronic Maintenance Therapy (Secondary Prophylaxis) for CMV Retinitis'''
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| **The drug of choice for chronic maintenance therapy and the preferred route (i.e., [[implant]], [[Intravitreal administration|intravitreal]] injection, [[Intravenous therapy|IV]], oral, or combination; and which [[drug]]) should be made in consultation with an ophthalmologist. Considerations should include the anatomic location of the retinal lesion, vision in the contralateral eye, the patient’s immunologic and virologic status and response to [[HIV AIDS medical therapy|antiretroviral therapy]].
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| **Patients with sight-threatening [[retinitis]] will most benefit from [[ganciclovir]] implant to control [[retinitis]] progression, due to the delivery of high concentration of [[ganciclovir]] at the site of infection.
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| ***Preferred Regimen (1): [[Valganciclovir hydrochloride|Valganciclovir]] 900 mg PO daily + [[ganciclovir]] intraocular implant (for sight-threatening retinitis) {{or}}
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| ***Preferred Regimen (2): [[Valganciclovir]] 900 mg PO daily (for small peripheral lesions) {{and}}
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| ***Note(1): [[Ganciclovir]] intraocular implant should be replaced every 6–8 months until sustained immune recovery is documented.
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| ***Alternate Regimen (1): [[Ganciclovir]] 5 mg/kg IV 5–7 times weekly {{or}}
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| ***Alternate Regimen (2): [[Foscarnet]] 90–120 mg/kg IV once daily {{or}}
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| ***Alternate Regimen (3): [[Cidofovir]] 5 mg/kg IV every other week with [[saline]] hydration and [[probenecid]] as above.
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| *'''Immune Restoration Uveitis (IRU)'''
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| **Preferred Regimen (1): Periocular [[corticosteroid]] or a short course of systemic steroid
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| *'''Stopping Chronic Maintenance Therapy for CMV Retinitis'''
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| **[[CMV]] treatment for at least 3–6 months, with [[CD4]] count >100 cells/mm3 for >3 to 6 months in response to [[AIDS antiretroviral drugs|ART]].
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| **Therapy should be discontinued only after consultation with an ophthalmologist, taking into account magnitude and duration of [[CD4]] count increase, anatomic location of the lesions, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring.
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| **Routine (i.e., every 3 months) ophthalmologic follow-up is recommended for early detection of relapse or immune restoration uveitis, and then annually after [[Immune reconstitution syndrome|immune reconstitution]].
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| *'''Reinstituting Chronic Maintenance/Secondary Prophylaxis for CMV Retinitis'''
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| **CD4 + count <100 cells/mm³
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| ===CMV Colitis and Esophagitis===
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| Duration of therapy: 21–42 days or until signs and symptoms have resolved
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| *Preferred Regimen (1): Ganciclovir 5 mg/kg IV q12h, may switch to valganciclovir 900 mg PO q12h once the patient can absorb and tolerate PO therapy.
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| *Alternate Regimen (1): Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for patients with treatment limiting toxicities to ganciclovir or with ganciclovir resistance {{or}}
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| *Alternate Regimen (2): Oral valganciclovir may be used if symptoms are not severe enough to interfere with oral absorption {{or}}
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| *Alternate Regimen (3): For mild cases: If ART can be initiated or optimized without delay, withholding CMV therapy may be considered.
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| **Note (1): Maintenance therapy is usually not necessary, but should be considered after relapses.
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| ===CMV Pneumonitis===
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| *Doses are the same as for CMV retinitis.
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| *Treatment experience for CMV pneumonitis in HIV patients is limited. Use of IV ganciclovir or IV foscarnet is reasonable.
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| *The role of oral valganciclovir has not been established.
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| *The duration of therapy has not been established.
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| ===Neurologic Disease===
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| *Doses are the same as for CMV retinitis.
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| *Treatment should be initiated promptly.
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| *Combination of ganciclovir IV + foscarnet IV to stabilize disease and maximize response; continue until symptomatic improvement
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| *Continue therapy until resolution of neurologic symptoms
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| *Optimize ART to achieve viral suppression and immune reconstitution
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| ==References== | | ==Case Studies== |
| {{Reflist|2}}
| | [[Roseola case study one|Case #1]] |