CMV

Question 1

Q. Conditions where T and B cell immunity is impaired
Q. Effects of impaired Tand B cell immunity

Answer 1

Diseases with impaired T cell immunity: HIV; Severe combined Immunodeficiency; Tcell lymphoma; Autoimmune diseases like Lupus; diabetes

=> Diseases with impaired B cell immunity:
X- linked Agammaglobulinemia; B cell Lymphoma- eg- NHL, HL, Burkitt’s lymphoma Autoimmune conditions eg- RA, Lupus, MS

Impaired T cell(cellular immunity) -> ⬆️susceptibility to:
Viral infections; Fungal (eg- candida) and Opportunistic infections(T cells kill infected cells)

Impaired B cell ( humoral immunity)->
Recurrent bacterial infections esp. with encapsulated bacteria eg- pneumonia

Activated B cells also secrete inflammatory cytokines - IL6, TNF alpha, INF gamma that participate in inflammatory cascade in autoimmune diseases

Question 2

CMV microbiology

Answer 2

• CMV is a β-herpesvirus
• Double-stranded DNA virus
• Replicates in the nucleus in multiple cell types
• May be present in:
  
  • Breast milk
  • Saliva
  • Faeces
  • Urine
• Not readily spread by casual contact–> Requires prolonged or intimate exposure
• Once infected → lifelong carriage
• Reactivation occurs with impaired T-cell immunity
• In organ transplant recipients, the transplanted organ is often the reservoir

=>The term “cytomegalovirus” reflects marked cellular enlargement
* Infected cells are 2–4× larger than normal
* Characteristic “owl’s eye” intranuclear inclusions

Question 3

Epidemiology
&
Risk Factors for reactivation

Answer 3

=>CMV infection is highly prevalent
* Detected in 50–80% of otherwise healthy adults

=>Risk factors for CMV disease:
* Transplant recipients
allogenic stem cell > lung > pancreatic > liver
-high risk of disease if seropositive donor and seronegative recipient (~70% overall)
* AIDS (CD4 count < 50/mL)
* Steroid use
* Mechanical ventilation, bacterial pneumonia and sepsis
* Red cell transfusion (via immunomodulation not transmission)
* Burns

=>Risk factorsfor reactivation:
critically ill patients with:
* Severe trauma
* Sepsis
* Shock
* Burns
* Cirrhosis
* Blood transfusion
* Mechanical ventilation

=>Reactivation in the critically ill-> The clinical significance of CMV reactivation in patients who are not classically immunosuppressed is controversial

Question 4

Clinical manifestations

Answer 4

=>General Systemic manifestations:
Fever ≥38°C, Malaise or fatigue

=>Organ specific manifestations in immunocompetent-
* Pneumonia
* Colitis
* LFT derrangement
* BM suppression

=>Immunocompromised:
* Pneumonitis
* Pericarditis, Myocarditis
* Oesophagitis
* Colitis, Toxic megacolon
* Meningoencephalitis
* GBS
* Thrombocytopenia
* TTP
* Retinitis, Uveitis present as u/l blurred vision, floaters, diagnosed on fundoscopy

Question 5

Indirect Consequences of CMV infection

Answer 5

=>Immunocompetent host

• Bacterial sepsis
• Fungal sepsis
• Cardiovascular disease
• Prolonged ventilation
• Prolonged ICU stay
• Increased mortality from all causes

=>Immunocompromised (transplant) host

• Chronic allograft nephropathy (renal transplant)
• Hepatic artery thrombosis (liver transplant)
• Accelerated Hep C recurrence (liver transplant)
• Bronchiolitis obliterans (lung transplant)
• New onset NIDDM
• Post-transplant lymphoproliferative disease

Question 6

Invx

Answer 6

1). Serology-> CMV antibodies (IgM or IgG)
* Sensitive for recent or acute infection
* Results invalidated by IVIg infusion, plasmapheresis, and similar interventions

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2). Antigen assay (pp65 antigenaemia)
* Detects CMV pp65 antigen in circulating leukocytes
* Cheap and previously the standard test
* Requires adequate neutrophil count–> Cannot be performed in severe neutropenia
* Requires fresh blood

3). PCR for CMV DNA

->Qualitative PCR
* Very sensitive for detecting CMV DNA
* Does not distinguish between latent and active infection

->Quantitative PCR
* IDEAL TEST
* Provides viral load
* Allows monitoring of response to therapy

4). Tissue histology
* Not always feasible
* Allows identification of:
* Cytomegalic cells
* Characteristic “owl’s eye” inclusion bodies

=>Immunohistochemistry for CMV = gold standard

=>Quantitative PCR = preferred diagnostic and monitoring tool

Question 7

CMV Management

Answer 7

=>First-line antiviral therapy

->Ganciclovir
* Selective inhibitor of CMV DNA polymerase-> backbone of therapy for serious active CMV infection
* Has much greater activity against CMV than aciclovir
* Cytotoxic handling and administration precautions required
* Dose adjustment required in renal impairment

->Valganciclovir
* Orally bioavailable pro-drug of ganciclovir
* Usually follows IV ganciclovir as step-down therapy

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=>Alternative agents (if ganciclovir contraindicated)

->Foscarnet->nephrotoxic and neurotoxic.
Toxicity often limits duration or feasibility of use

->Cidofovir->
* It is also nephrotoxic
The major approved indication is the management of CMV retinitis
* 5 mg/kg IV weekly for 2 weeks
* Must be administered with probenecid
* Avoid in renal disease

Question 8

Additional management considerations

Answer 8

=>CMV retinitis
* Intraocular implants or intravitreal injections may be used by ophthalmologists

=>Prophylaxis outside transplantation-
Not currently recommended