Opportunistic Viral Infections Flashcards
What are opportunistic viral infections?
Those occurring in immunocompromised individuals with more severe presentations.
- Viral infection of a niche not available in the healthy
- ‘Endogenous’
- Latent viruses that reactivate in absence of immune system
- Acquired in past prior to immune suppression e.g. Varicella Zoster
- ‘Exogenous’
- Viruses acquired from environment
- increased severity in immunosuppressed e.g. Influenza, SARS-CoV-2
Which infections may occur more frequently or more severely in immunocompromised individuals?
Occur more frequently in immunocompromised
CMV, EBV, HSV
More severe presentation
VZV, Measles.
How may infection exist in immunocompromised individuals?
Absence or diminution in signs of infection
40% of infections post solid organ transplant were afebrile
Loss of localizing signs (peritonism and steroids)
Fever could be due to non-infectious causes
22% of fevers in solid organ transplant recipients
What problems does impaired ability to respond normally?
Metabolic/ Endocrine:
Alcohol Abuse
Diabetes Mellitus
Uraemia
Malnutrition
Impaired Barriers to Infection:
Burns
Haemodialysis
IVDU
Pregnancy, Extremes of Age
What are the types of immunodeficiency?
Primary immunodeficiency
UNC93B deficiency and TLR3 deficiency leading to predisposition to herpes simplex encephalitis, Epidermodysplasia verruciformis, SCID, haemophagoytic lymphohistiocytosis in perforin deficiency.
Acquired immunodeficiency
Solid organ transplantation
Bone marrow transplantation
Immunosuppressive drugs
Advanced HIV infection
Which virus and which genetic lesion?
EBV/perforin
HSV/UNC93B
HPV/EVER1 or EVER2
HHV8/STIM1
None of the above
HSV/UNC93B
How do we predict risk of opportunistic infections in HIV?
Risk of developing specific opportunistic infections can be predicted from CD4 count
AIDS defining illnesses (reference only)
Candidiasis of the esophagus, bronchi, trachea, or lungs
Cervical cancer, invasive
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (greater than one month’s duration)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy, HIV related
Herpes simplex: chronic ulcer(s) (more than 1 month in duration); or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (more than 1 month in duration)
Kaposi sarcoma
Lymphoma, Burkitt’s (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or M kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jiroveci pneumonia
Pneumonia, recurrent
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain
Wasting syndrome due to HIV
How does transplant affect immunocompromise?
Ongoing immunosuppression
What are major immunosuppressants?
From highest to lowest risk, what causes most risk of viral infection?
Allogeneic stem cell transplant
Advanced HIV infection (CD4 dep)
Solid organ transplant
Various monoclonal antibody therapies
Cytotoxic chemotherapy
DMARDs and steroids
What changes state of immunosuppression?
}Immunosuppressive Treatment
◦Type, Timing, Intensity
}Prior Treatment
◦Antimicrobial use, Chemotherapy
}Muco-cutaneous Integrity
◦Catheters, lines, drains
}Surgical Complications
◦collections
}Metabolic Conditions
◦Uraemia, alcoholism, DM, age
}Viral Infection
◦Herpesviruses, HBV, HCV, HIV, RSV,respiratory virus
What is the timeline of infection from a solid organ transplant?
How do post transplant infections happen?
What pre transplant serology is needed?
Pre-transplant serology
}HIV Ag/Ab
}HBV sAg
}HBV cTAb
}HBV sAb
}HVC Ab
}EBV IgG
}CMV IgG
}HSV IgG
}VZV IgG
}HTLV Ab
CMV monitoring or prophylaxis
EBV monitoring
Adeno monitoring (paeds BMT)
HSV prophylaxis if indicated
Which bugs can you test for in the CSF?
HSV
VZV
Enterovirus
EBV
CMV
Adenovirus
HHV6
JC virus
Which bugs can you test for in the blood?
CMV
EBV
Adeno
HHV6
Parvo
What bugs can you find in respiratory secretions?
Flu A/B (Oseltamivir (oral drug) for 5 days, If resistance/severe/immunosuppressed → zanamivir (inhalation or IV))
Paraflu 1-4
Adenovirus
Enterovirus
RSV
HMPV
Rhinovirus
Coronaviruses
CMV in BAL
SARS CoV-2 (Tx with Sotrovimab or Casirivimab/imdevimab)
What bugs can you find on gut biopsy?
HSV
CMV
Adeno
What is the treatment?
}Opportunistic viral infections are often more difficult to treat
}Often requires
◦Early treatment
◦higher dose
◦longer course
◦sometimes drug combinations
}Increased risk of antiviral drug resistance
What are HHVs?
◦Herpes simplex virus (HSV) 1 & 2
◦Varicella zoster virus (VZV)
◦Cytomegalovirus (CMV)
◦HHV6 : Human herpes virus 6
◦Epstein Barr Virus (EBV)
◦HHV-8
What kind of viruses are the herpesviruses?
}DNA viruses
}Latent infection
◦Only a small subset of genes are expressed
◦Reactivation can occur leading to the expression of viral genes and production of progeny virus
Leads to destruction of the host cells
What do herpes viruses cause?
Most commonly
Cold sores, stomatitis, mouth ulcers
Recurrent genital disease (HIV and adult transplant
Serious complications
Cutaneous dissemination
Oesophagitis
Hepatitis
Viraemia
Treatment
Aciclovir or valaciclovir
Foscarnet
(Ganciclovir sensitive also)
When does HSV show up after transplant?
HSV reactivation in the pre-engraftment period
Aciclovir prophylaxis until CD4 count increases above a certain threshold or for specific time period
What is VZV?
}Varicella (primary infection)
Carries an Increased risk of complications:
◦Pneumonitis
◦Encephalitis
◦Hepatitis
◦Purpura fulminans in neonate
How does shingles reactivate post transplant?
- Shingles-often late complication post-transplant
- Shingles can be early sign of HIV infection-indication for HIV testing particularly in young person
- Multidermatomal or disseminated zoster is associated with high mortality
How may VZV in immunocomprised present?
Acute retinal necrosis (ARN)
Progressive outer retinal necrosis (PORN)
VZV-associated vasculopathy
What is VZV prevention?
Aciclovir prophylaxis provides some protection
Post-exposure prophylaxis of varicella with VZIg
What is VZV treatment?
}Aciclovir (first line)
}Valaciclovir
}Foscarnet sensitive
}Ganciclovir sensitive
What is the presentation of CMV?
When does CMV present post transplant?
In transplant the risk of CMV disease relates to pre-tx serostatus
solid organ transplant
D+/R- : carries the greatest risk of reactivation
bone marrow transplant: adoptive immunity
D-/R+ : carries the greatest risk of reactivation
What is CMV prevention strategies post-transplant?
CMV viral load twice weekly, treat if virus reactivates until suppressed (pre-emptive therapy)
Valganciclovir prophylaxis for 100 days
What is CMV treatment?
Prophylaxis (i.e. lung transplant)
Pre-emptive treatment (i.e. renal transplant / HSCT)
Treat if disease (HIV/AIDS)
Rx: Ganciclovir / Valganciclovir
Rx: Reduce immunosuppression
- Ganciclovir (IV): bone marrow suppression
- Valganciclovir: oral
- Foscarnet (IV) (nephrotoxicity)
- Cidofovir (nephrotoxicity)
- IVIg (with another drug for pneumonitis)
What are the phases of EBV?
Acute phase: febrile illness with lymphadenopathy & moderate hepatitis
After the acute phase: lifelong, latent, subclinical infection of B cells.
Intermittent attempts at viral replication kept in check by immunosurveillance
EBV stimulates host cells to divide – also kept in check.
In EBV/PTLD, illustrate immunosurveillance breakdown
Post-transplant lymphoproliferative disease (PTLD)
◦Latently infected B cells – polyclonal activation
◦Predisposes to lymphoma
◦suspicion on rising EBV viral load (> 105 c/ml) and CT scan
◦Confirmation with biopsy of lymph nodes
◦Management:
Reduce immunosuppression (regression in < 50%)
Anti-CD20 monoclonal Ab therapy (B cell marker) (“rituximab”)
What is Kaposi’s sarcoma and how do you investigate it?
-Pre-HIV epidemic indolent tumour of
elderly men in Mediterranean
-Presents as a brownish/purplish vascular
lesion, can be cutaneous or visceral
-Characterised by
Spindle cell proliferation
Neo-angiogenesis
Inflammation and oedema
- Diagnosis made by biopsy
- Treated by chemotherapy and the initiation of antiretroviral therapy
What does HHV8 cause?
◦Primary effusion lymphoma (PEL)
◦
Multicentric Castleman disease
What is the proposed course of PML?
•Cognitive disturbance, personality change, motor deficits other focal neurological signs
•
- Demyelination of white matter
- → neurological deficits
- Diagnosis: MRI and PCR on CSF
What is Progressive multifocal leukoencephalopathy?
JC virus is a polyomavirus
Prior to the introduction of effective antiretroviral therapy, PML occurred in 5% of patients with AIDS with a high mortality, the incidence has now drastically declined
PML can be seen in other types of immunosupressed hosts:
i.e patients on humanised monoclonal antibodies such as Natalizumab (for treatment of multiple sclerosis)
What are th cognitive signs of PML?
}Cognitive disturbance, personality change, motor deficits other focal neurological signs
}
}The main pathological feature of PML
is a demyelination of white matter with
neurological deficits corresponding
to the area(s) of the brain affected
}Diagnosis: MRI and PCR on CSF
What are the Recommendations for patient monitoring when using Natalizumab?
What is BK cystitis?
- Polyomavirus
- Double stranded DNA
- BK cystitis post SCT -BK nephropathy post Renal Tx-Possibly other pathologies
An HIV infected patient presents with skin lesions resembling Kaposi Sarcoma, what is the causative virus?
HHV8
What is adenovirus?
}Particular problem post-BMT
}Exogenous infection or reactivation of persistent endogenous infection.
}Fever
}Encephalitis/Pneumonitis/Colitis
}
}High mortality with disseminated infection.
What are adenovirus symptoms?
Symptomatic screening in adults-urine, respiratory, stool and staging for disseminated disease to include blood if any of these are positive
Weekly blood monitoring (paeds)
What is adenovirus treatment?
A patient who received a stem cell transplant 2 weeks ago presents with mouth ulcers. Which of the following viral PCRs would you request on the mouth swab?
A. Enterovirus PCR
B. Adenovirus PCR
C. HSV PCR
D. HHV6 PCR
E. HHV8 PCR
HSV PCR
What virus causes progressive multifocal leukoencephalopathy?
JC Virus
How do Respiratory viruses in the immunocompromised present?
}Increased risk of complications (pneumonitis) and high mortality associated particularly with:
◦Influenza A and B
◦Parainfluenza 1, 2, 3 and 4
◦Respiratory Syncitial Virus (RSV) infection
◦Adenovirus
◦Novel coronavirus: MERS coronavirus
How do you diagnose Respiratory viruses in the immunocompromised?
Diagnosis:
–Specimens: Naso-pharynx aspirates (paeds), bronchio alveolar lavages, nose and throat swabs
–Investigations:
•Multiplex PCR is the method of choice:
Respiratory Syncitial Virus,
Human metapneumovirus,
Influenzae A and B
Parainfluenzae 1, 2, 3 , 4
Adenovirus, Rhinovirus…
- Solid phase EIA for: RSV and flu
- Direct Immunofluorescence and
cell culture(no longer in use in most laboratories)
What is the treatment of respiratory viruses?
}Influenza A and B
◦Oseltamivir (oral drug) for 5 days
◦If severely immunosupressed:
risk of oseltamivir resistance
zanamivir (inhalation or IV) is an alternative
◦
◦
}Other respiratory viruses do not have a standard treatment protocol
How do you prevent respiratory viruses?
}Prevention of influenza:
◦Life-long seasonal influenza vaccination of organ/BMT recipients
◦Influenza vaccination for close contacts
◦Oseltamivir prophylaxis if significant contact with case of influenza
◦
}Infection control!
◦Handwashing, protective clothing, limit visitors
◦Isolate immunocompromised patients (BMT)
◦Cohort nursing
What is Human parvovirus B19?
}Cause of chronic anaemia in the immunocompromised
}
}Diagnosis:
◦Serology (IgM) not useful in the immunocompromised
◦PCR on blood
◦
}Treatment: Human normal immunoglobulin. May require blood transfusion
What is Hep B?
The virus is one of the smallest enveloped animal viruses, but pleomorphic forms exist, including filamentous and spherical bodies lacking a core. These particles are not infectious and are composed of the lipid and protein that forms part of the surface of the virion, which is called the surface antigen and is produced in excess during the life cycle of the virus.
The core protein is the major component of the nucleocapsid. HBeAg may be generated from the core protein by proteolytic cleavage.
How do proteins change in Hep B?
What is the meaning of Hep B serology?
HBV sAg +
HBV core Ab + Current
HBV s Ab -
HBV s Ag -
HBV core Ab + Past
HBV s Ab +
HBV sAg -
HBV core Ab - Vaccination
HBV s Ab +
What happens in Hepatitis B in the immunocompromised?
Two things can happen:
◦Carriers may have flare of disease.
◦Those who have had past infection can reactivate
The risk of reactivation is particularly important with patients on B-cell depleting therapies (i.e Rituximab)
Prevention:
◦Nucleoside/nucleotide analogues (eg lamivudine, tenofovir, entecavir)
◦Prophylaxis
What is the risk of HBV reactivation?
What is Hep E?
}HEV is endemic in the UK (and in much of Europe)
}has now become the major cause of enterically transmitted viral hepatitis
}In developed countries:
◦HEV infection is a zoonosis caused by genotype 3 virus
}In developing countries:
◦HEV infection is mainly caused by genotype 1 virus
What is the modes of transmission of HEV?
}Modes of transmission of indigenous HEV in developed countries:
◦mainly through the consumption of undercooked meat such as pork
◦Other modes of transmission:
through blood transfusion, although uncommon
(In a recent study, a prevalence of HEV viraemia of 1:2848 blood donations (0.04%) was found in Southeast England, with a transmission rate of 42%)
Possibly through organ donation
}In the immunocompromised population, how does HEV progress?
Please examine the following hepatitis B serology results, which profile is consistent with past hepatitis B infection?
}
A. HBV sag (+), HBV core ab (+), HBV sab (-)
B. HBV sag (-), HBV core ab (-), HBV sab>100mIU/ml
C. HBV sag (-), HBV core ab (-), HBV sab (-)
D. HBV sag (-), HBV core ab (+), HBV sab of 15mIU/ml
(sag is surface antigen, sab is surface antibody)
D
A patient who received a stem cell transplant recently has a transaminitis. What investigations would you request on blood?
A. EBV serology
B. Hepatitis B surface antigen
C. Hepatitis C PCR
D. Hepatitis E PCR
E. CMV serology
B. Hepatitis B surface antigen
What is the baltimore classification?
How do we detect viruses?
- Viruses are challenging to grow- requiring human cells & dangerous
- Therefore we look for indirect or direct evidence of their presence
- Indirect detection: response of the immune system to the virus
- These tests are useful to see if you have ever had the infection
- Direct detection: fragments of the actual virus
- Viral proteins (lateral flow/antigen tests)
- Viral genetic material (the virus genetic material present with patient sample
- Polymerase chain reaction
- These tests are useful to see if you have the infection now
How may antibodies change over time?
- Measure levels of antibody in patients serum
- +++ IgM indicate Active or Resolving infection
- +++ IgG indicates past infection > 6 weeks ago
- Antibody levels ↓↓↓ reduced in Immunosuppressed
- Serological course may differ depending upon virus
What is the change in antibodies/ antigens in HAV and HBV?
How does PCR direct detection work?
How do we use diagnostic virology in the immunocompromised?
1.Screen prior to immunosuppression
- Identify previous viral exposure that may reactivate
- Guide the use of antiviral prophylaxis
2.Monitor using PCR
- Identify viral reactivation promptly → Rx
- Detect infection
- Approach is performed by protocol
What antigens do you screen for?
- HIV Ag/Ab
- HBV surface antigen
- HBV core antibody
- HBV surface antibody
- HCV antibody
- EBV antibody
- CMV antibody
- HSV antibody
- VZV antibody
- HTLV antibody
What do you monitor during immunosuppression?
CMV monitoring PCR or prophylaxis
EBV monitoring PCR
BK monitoring PCR (Renal & BMT)
Adenovirus monitoring PCR (Paediatric BMT)
HSV prophylaxis if indicated
A 51-year-old with a recent HSCT is unwell. Which is the most appropriate test?
ALT = 800 IU/mL
A.EBV IgG/IgM
B.HBV sAb
C.Parvovirus PCR
D.HEV PCR
E.CMV IgG/IgM
D.HEV PCR
What is the chronology of HSCT?
Which type of immunosuppression carries the greatest relative risk of developing a viral infection ?
A.Steroids
B.Solid organ transplant
C.Allogeneic stem cell transplant
D.Monoclonal antibody therapies
E.Cytotoxic chemotherapy
Allogeneic stem cell transplant
What issues do you get for Herpes?
Increased frequency
Increased severity /risk of dissemination
More organs can be involved (pneumonitis, eosophagitis, hepatitis); NB: not enceph!
Increased risk of acyclovir resistance
What is the management for HSV 1 and 2?
HIV/AIDS
-CD4 <200
-
Prophylaxis
- Test for HSV IgG
- Bone marrow
- 1 month (until engraftment)
- Solid organ
- 3-6 months
- And if treated for rejection
A patient who received a stem cell transplant 2 weeks ago presents with mouth ulcers.
Which of the following viruses would you test for on the mouth swab?
- A.Enterovirus
- B.Adenovirus
- C. Herpes simplex type 1
- D. Human herpesvirus 6
- E. Human gammaherpesvirus 8,
C. Herpes simplex type 1
What is PTLD?
◦Latently infected B cells – polyclonal activation
◦Predisposes to lymphoma
◦suspicion on rising EBV viral load (> 105 c/ml) and CT scan
◦Confirmation with biopsy of lymph nodes
What are the issues of EBV?
Oncogenesis
- B cell latency, high turn-over
- T-cells monitor/control this
B-cell lymphomas
PTLD (post-transplant lympho-proliferative disorder
What is the management of EBV?
Monitor EBV levels
Ix for lymphoma as needed
Rx: ?Rituximab
Rx: reduce immunosuppression
What is SOT vs HSCT in CMV?
Renal Transplant:
- Donor + / Recipient –
- Immunosuppressed patient gets given some CMV for the first time
Bone Marrow Transplant:
- Donor - / Recipient +
- Patient with CMV has immune system replaced with one that hasn’t seen CMV
Which of these is NOT an antiviral?
●
A.Sotrovimab
●
B.Valganciclovir
●
C.Foscarnet
●
D.Rituximab
●
E.Tenofovir
A.Rituximab
What is JC virus?
- JC virus is a polyomavirus
- Progressive multifocal leukoencephalopathy
- Effective antiretroviral therapy has drastically reduced PML incidence in HIV+ve patient
- PML can be seen in other types of immunosuppressed
- humanised monoclonal antibodies
- Natalizumab (for treatment of multiple sclerosis)
What are the hepadnaviridae?
- Hep A: more severe, vaccinate
- Hep B: re-activation, vaccinate/prophylaxis
- Hep C: ?increased fibrosis, Rx direct-acting antiviral
- Hep E: chronic infection, reduce immunosuppression
What are the markers of Hep B?
- sAg+
- Circulating virus
- cAb+ (IgM)
- Acute immune response
- eAg+
- Circulating virus
- sAb+
- Generated from:
- sAg (virus)
- sAg (vaccine)
- cAb+ (IgG/total)
- Generated from cAg (virus)
- Prior infection
- eAb+
- Generated from eAg (virus)
Which patient has previously had Hepatitis B Infection?
sAg= Surface antigen cAb = core antibody sAb= Surface antibody
A.sAg+, cAb+, sAb-
B.sAg-, cAb-, sAb+ (100mIU/ml)
C.sAg-, cAb+, sAb-
D.sAg-, cAb-, sAb-
E.sAg+, cAb-, sAb-
C. sAg-, cAb+, sAb-
