Opportunistic Viral Infections Flashcards
What is a major cause of morbidity in autologous STC and mortality in allogenic STC?
Viral infections- 3 weeks patient engrafting, started on cyclosporin from chemo so immunosuppressed plus immunological conflict, not immediate.
Allogenic 1 year, autologous less of a problem.
graft from donor fight against host antigens, graft vs host immunosuppressive in itself.
What are the risk factors for virus associate morbidity and mortality?
Allogenic BMT Mismatched related, match unrelated Acute or chronic graft vs host disease Immunosuppressive therapy In vitro T cell depletion Delayed cd4 cell recovery
How can HIV infected hosts affect susceptibility to viral infection?
Risk of developing opportunistic infections can be predicted from cd4 count
CMV- below 50
HSV- higher
Anti retroviral- below 350 or earlier
What are the different routes of infection in the transplant recipient?
Virus acquired from graft- hep b, CMV
Virus reactivation from host- herpes
Novel infection from infected individual- measles, parvovirus, VZV
May primarily involve the grafted organ- CMV affect kidney
What are the different disease manifestations?
Increased severity of the disease
Wider range of systems involved
Disseminated disease
Each organism gives rise to different disease manifestations in different patient group eg CMV pneumonitis in HSCT, retinitis in AIDS
Novel syndromes- EBV associated post transplant lymphoproliferative disease
What is the basic principle of treatment for opportunistic viral infection?
Difficult, requires early treatment, higher dose, longer course, sometimes drug combinations
Increased risk of antiviral drug resistance
What is preferred between serology and virus detection?
Virus detection- nucleic acid, PCR etc, antigen detection
Serology- listed diagnostic value especially in immunosuppressed patients as they may not have developed antibodies, received blood products
How can be PCR be applied in a routine diagnostic lab?
Many types of samples- blood, resp secretions (predictive value low), vesicles swab, conjunctival swab, stools, biopsies, CSF, blood collected by EDTA bottle
Use of viral load in blood (quantitative assay)- CMV, EBV, adenovirus, can be used as guide to clinical significance of infection, monitor response to treatment.
What is PCR?
Exponential replication of DNA, RNA virus reverse transcription phase first.
Real time PCR, reporter probes
Ct- cycle threshold, after 17 cycle able to detect fluoresence. More cycle for fluoresce to be detected means, more virus
Using blood sample with known conc of CMV, serial dilution, and calibrate sample, quantification of sample.
What DNA viruses are included in the HHV group?
HSV 1 and 2 VZV CMV HHV 6 EBV HHV 8
How are HHV involved when immunosurveillance is broken up?
Latent infection, only small subset of genes are expressed
Reactivation can occur leading to expression of viral genes and production of progeny virus
Leads to destruction of the host cells
Where are the sites of latency for the HHV?
HSV 1,2 and VZV- sensory nerve ganglia CMV- b lymphocyte EBV- leukocyte and epithelial cells HHV 6 A and B- t lymphocytes, epithelial cells HHV 8- epithelial cells
When are HHV reactivated in allo stem cell recipients?
HSV- early before engraftment period HHV 6,7 CMV early EBV VZV Not so much now as patients are on acyclovir prophylaxis
What is the sequlae for HSV in the immunocompromised?
Transplant setting- viral reactivation in patients tested HSV igG positive pre transplant
Reactivation common in first month post treatment
What is e clinical course for HSV reactivation and the immunocompromised?
Cold sores, stomatitis, mouth ulcers
Recurrent genital disease (HIV)
Cutaneous dissemination and visceral involvement, oesophagitis, hepatitis
HSV encephalitis not increased in frequency
How is HSV diagnosed in the immunocompromised?
PCR on swab, biopsy, on blood.
if mouth ulcers differential diagnosis is enterovirus infection
What is the sequlae for VZV and the immunocompromised?
Varicella as primary infection carries increased risk of complication
Secondary bacterial infection of rash, group a strep
Bullous or haemorrhagic skin lesions, purpura fulminans
Visceral involvement- pneumonitis and hepatitis
What happens if VZV reactivated from reactivation of endogenous virus in patients who are VZV igG positive pre transplant?
Shingles or herpes zoster, late complication more than 100 days post BMT
Dermatomal skin erruptions
Varicella like skin lesions with no dermatomal distribution, high risk of visceral involvement
VZV reactivation without skin lesions
What are the drugs most commonly used for HSV and VZV?
Acyclovir- nucleoside analogue, ACV triphosphate a potent inhibitor of HSV encoded DNA polymerase, oral or IV
Valaciclovir- valine ester prodrug of ACV, better availability
Both predominantly active against HSV and to lesser extent VZV
Risk of resistance
How can HSV VZV prevention occur?
ACV at prophylactic dose mainly to prevent HSV infection, started pre transplant, HIV patients on for years
Post exposure prophylaxis of severe varicella- VZIG
within 10 days of a significant contact with a case of chicken pox or shingles
What are the 3 sources of CMV infection after transplant?
Exogenous- primary infection, from graft, blood, persons excreting virus
Endogenous- reactivation
solid organ transplant, d+r-, carries greatest risk of reactivation
BMT, adoptive immunity, d-r+, carries greatest risk of reactivation
Exogenous re infection
What is the disease manifestation of CMV?
Fever Bone marrow suppression Interstitial pneumonitis, usual to have CMV secretions, so clinical decision Delayed engraftment, graft failure Hepatitis Oesophagitis, gastric, enterocolitis Immunosuppression Retinitis- HIV patients, when cd4 less than 50 (also caused by HSV, VZV)
How is CMV infection diagnosed?
PCR- EDTA blood, biopsy, CSF, vitreous fluid
Detection of viraemia does not guarantee CMV is the cause of clinical syndrome
Samples should be collected from target organ
Histo- owls eye inclusion, specific dx, insensitive
Tissue immunoflurosce- biopsy sample contain infected cells with CMV which can be visualised with antisera against antigens
What is the CMV treatment?
Ganciclovir IV- commonly used, nucleoside analogue, inhibited DNA viral polymerase, risk of bone marrow suppression
Valganciclovir- oral prodrug of ganciclovir
Foscarnet IV- pyrophosphate analogue, inhibits viral DNA polymerase, nephrotoxic
Combo
CMV hyperimmunoglobulin, used in pneumonitis
What is the management for CMV and HSCT, to prevent CMV disease?
Prophylaxis during high risk period, but bone marrow toxicity, emergence of resistant strains, late onset CMV disease OR
Pre emptive therapy- monitor viral load in a weekly basis, treat when rises above threshold (1000), most favourable for BMT
What are the 2 stages of EBV in normal host?
Acute- infectious mononucleosis, mainly infected B cells
Chronic- low grade replication in b lymphocytes with polyclonal activation, kept in check by cellular immune system
What happens with EBV if patient is immunosuppressed?
PTLD- predisposes to lymphoma, suspicion on rising EBV viral load and CT scan, confirmation with biopsy of lymph nodes
What is the management of EBV in immunosuppressed?
Antiviral not effective
Reduce immunosuppression, regression in less than 50%
Anti CD20 monoclonal antibody therapy eg rituximab B cell marker
What can EBV cause in HIV patients?
Oral hairy leukoplakia. Confused with candidiasis
Lymphomas, burkitts
How can HHV 8 present?
Problem in HIV patients
Kaposi sarcoma
Primary effusion lymphoma (pel) body cavity associated
Multi centric castlemans disease
What is kaposi sarcoma?
Angioproliferative disease Spindle cell proliferation Neo angiogenesis Inflammation and oedema Infection with HHV8 precedes the development of KS Involves lymphatic endothelium
How can diagnosis of kaposi sarcoma be made?
Clinical suspicion
Biopsy - presence of spindle cells, KSHV proteins are uniformly detected
What causes progressive multifocal leukoencephalopathy?
JC virus is a polyomavirus
Prior to introduction of effective antiretroviral therapy, PML was common in AIDS patients, now declined
PML can be seen in other hosts- high dose steroids, on humanised monoclonal antibodies such as Natalizumab for Tx of MS
What is the main pathological feature of PML?
Demyelination of white matter with focal neurological deficits corresponding to area of brain
May also occur after intro of cART, known as immune reconstitution PML
Dx- MRI and PCR on CSF
How adenovirus affected in immunocompromised ?
Problem post BMT (Paeds)
Exogenous infection or reactivation of persistent endogenous infection
Prognosis- high mortality with disseminated infection
How can adenvirus present in the immunocompromised host?
Fever Bone marrow suppression Haemorrhagic cystitis Necrotising pneumonitis Hepatitis Colitis
How are resp viruses affected in the immunocompromised?
Increased risk of complications- pneumonitis High mortality associated with: Influenza A and B Parainfluenza 1,2,3,4 RSV Adenovirus MERS coronavirus
How is resp virus diagnosed in immunocompromised?
Specimens- naso pharynx aspirates, bro chip alveolar lavages, nose and throat swabs
Ix- multiple PCR
Solid phase for EIA for RSV and flu
Direct immunoflurescence and cell culture
What is the treatment for resp virus?
Influenza A and B oseltamivir for 5 days
Severely immunosuppressed- risk of oseltamivir resistance
Zanamivir inhalation of IV is an alternative
Ribavarin attempted for RSV and parainfkuenzae, must be started early before progression to LRTI has occurred
What is involved in prevention of resp virus?
Prevention of influenza- vaccination of organ or BMT recipients, for close contacts
oseltamivir prophylaxis if significant contact with case of influenza
Infection control
How can measles present?
Fatal disease in immunocompromised Giant cell pneumonia Subacute measles encephalitis No treatment Post exposure prophylaxis- human normal immunoglobulin
What is dx and Tx of human parvovirus b19?
Cause of chronic anaemia in the immunocompromised
Serology not useful in immunocompromised, use PCR on blood
Treat with human normal immunoglobulin,may require blood transfusion
What is the definition of chronic hep b?
Hepatitis surface b antigen detected for more than 6 months
What will be there if there has been cleared acute or chronic hep b?
Core antibody
What is hep core igM a marker of?
Acute infection and reactivation
What are the hep b markers for vaccinated?
Surface antibody
Core antibody negative
If surface antibody less than 10 non responder
More than 10- protective
How is hep b affected in the immunocompromised?
Carriers may have flare of disease
Those who had last infection ie core antibody positive and surface antigen negative may revert to positive surface antigen
Risk of reactivation important in patients on B cell depleting therapy
How can hep b be prevented in immunocompromised?
Nucleoside/nucleotide analogues- lamivudine, tenofovir, entecavir
Hep b immunoglobulin in liver transplant
What is the major cause of enteric ally transmitted viral hepatitis?
Hep E, now endemic in UK
Developed countries- HEV infection is a zoonosis caused by genotype 3 virus
Developing countries- mainly caused by genotype 1 virus
What is the mode of transmission of hep e in developed countries?
Consumption of undercooked meat such as pork, wild boar, deer and rabbits
Blood transfusion, organ donation
How is hep E affected in the immunocompromised patient?
Cause significant morbidity and can establish chronic infection
Treatment- dose reduction of immunosuppressants and or addition of ribavarin
No recommendation of routine screening of blood,organ and tissue donors atm
What should be included in the basic screen in virological investigation of transamintis?
Hep A igM Hep B surface antigen Hep C viral PCR Hep E viral PCR EBV and CMV PCR Adenvirus PCR for paeds
What are the different types of immune deficiency in the host?
Innate- SCID
Acquired- malignancy (lymphoma), viral infections (flare up of HIV with HSV), iatrogenic, allograft stem cell transplant particularly bad
