Viral infections in immunocompromised patients: recent developments

1
Viral infections in immunocompromised
patientsrecent developments

• Dr Andrew Turner
• Clinical Virology
• Manchester Royal Infirmary
• UK

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Introduction

• Virus infections are important causes of
  morbidity and mortality in immunocompromised
  patients, including
• Patients with primary immunodeficiency, including
  Severe combined immunodeficiency (SCID)
• Solid organ transplant (SOT) recipients
• Haematopoietic stem cell transplant (HSCT)
  recipients
• HIV-infected patients

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Introduction

• Infections caused by CMV, HSV, VZV and EBV, and
  by respiratory viruses such as RSV,
  parainfluenzaviruses and influenzaviruses are
  familiar
• The significance of adenovirus infections is
  increasingly recognised
• Other viruses are of emerging significance, such
  as BK virus, human herpesvirus 6 (HHV6) and human
  metapneumovirus (hMPV)

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Background

• In addition to the direct consequences of virus
  infection there are also indirect effects, which
  may include
• GvHD
• Delayed engraftment in BMT
• Graft failure
• Predisposition to bacterial and fungal infections
• association with malignancy, e.g. post-transplant
  lymphoproliferative disease (PTLD)

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Background

• Immunocompromised patients are
• more susceptible to infection and disease
• More likely to develop persistent infection
• More likely to develop multiple infections,
  especially patients with SCID
• may develop unusual clinical manifestations, i.e.
  which are not seen in immunocompetent patients

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Background

• The spectrum of viruses and the clinical
  presentation may vary between different patient
  groups, for example
• CMV retinitis in HIV
• CMV pneumonitis in transplantation
• BK nephropathy in renal transplantation
• BK-associated haemorrhagic cystitis in HSCT

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Virus infections in HSCT

• Increased significance of virus infections
• Changes in conditioning regimes
• Increasing number of transplants
• Improved diagnostics
• Availability of additional antivirals
• Developments in T cell immunotherapy
• Will be discssed in relation to BK virus, human
  herpesvirus 6 (HHV6), human metapneumovirus
  (hMPV) and adenoviruses

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UK Bone marrow transplants 1996 - 2004
Data source British Society of Blood and Bone
Marrow Transplantation
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Human herpesvirus 6 (HHV6)

• HHV6 is lymphotropic
• 2 major variants, A and B
• Ubiquitous infects most people by 2 years of age
• persists in lymphocytes
• and salivary glands

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Human herpesvirus 6 (HHV6)

• HHV6 reactivates after HSCT, detectable in blood
  at a median of 20 days post-Tx
• HHV6 type B is commoner than type A
• HHV6 associated with encephalitis and impaired
  memory, and with delayed platelet engraftment
• Recent study found that plasma viraemia was
  associated with
• All-cause mortality
• Grade 3-4 GvHD
• Lower probability of monocyte and of platelet
  engraftment
• High viral load associated with risk of CNS
  dysfuntion
• Zerr DM et al. Clin Infect Dis 2005 40932-940

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Human herpesvirus 6 (HHV6)

• Predictive value of HHV6 viral load testing not
  yet established
• Asymptomatic reactivation appears to be common so
  interpretation of positive results can be
  problematic
• Foscarnet, ganciclovir and cidofovir all have in
  vitro activity and have been used for treating
  patients but no controlled trial data exist

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BK virus

• A human polyomavirus
• non-enveloped, DNA virus
• Seroprevalence in adults is between 60 80
• primary infection in childhood
• latent infection in renal tubules and urothelial
  cells
• Reactivation, mostly asymptomatic viruria, with
  decoy cells in urine

BK virus
Decoy cells
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BK virus

• BK reactivation in immunocompromised, e.g.,
  pregnancy, AIDS, transplantation
• BK viruria in up to 95 HSCT recipients
• BK virus causes nephropathy in renal transplant
  recipients, which may be complicated by graft
  loss
• Associated with haemorrhagic cystitis in HSCT

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BK virus

• Detection of BK viruria has a low predictive
  value for BK disease
• BK viral load testing in blood may be better for
  diagnosis and monitoring
• BK viraemia occurs in about 1/3 HCST recipients,
  typically about 40 days post-Tx
• Viral load of more than 10,000 copies/ml
• associated with haemorrhagic cystitis
• Erard V, et al. Blood 2005 106 1130-1132

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BK virus

• Treatment of haemorrhagic cystitis is largely
  supportive
• Avoidance of cyclophosphamide toxicity
• Diuresis and bladder irrigation
• Platelet replacement
• Surgical intervention may be necessary
• Cidofovir active against BK virus in vitro and
  accumulates in renal tissue and urine
• Case series suggest cidofovir can lead to
  clearance of viraemia and stabilisation of graft
  in BK nephropathy but role not established in HSCT

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Human metapneumovirus (hMPV)

• Discovered in 2001
• Paramyxovirus first member of metapneumovirus
  genus
• Related to RSV 4 genotypes A1, A2, B1, B2 A2
  is the commonest
• Occurs world-wide, most individuals infected by
  age 5
• Causes upper and lower respiratory tract
  infections
• Seasonal incidence late winter/early spring
• different genotypes may co-circulate

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Human metapneumovirus (hMPV)

• Lower respiratory tract infections mainly in very
  young and the elderly
• Conflicting data on significance of dual
  infection with RSV
• More serious infections reported in
  immunocompromised patients
• may be an important cause of idiopathic pneumonia
  in HSCT detected in 3.8 BAL samples from HSCT
  patients 4 patients died
• Englund P, et al. Blood 2004 104 58a (abstract
  189)

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Human metapneumovirus (hMPV)

• Originally identified in cell culture but
  difficult to isolate
• Value of serology limited by early acquisition of
  infection
• Detection of hMPV by immunofluoresence in
  respiratory secretions may be useful depending on
  availability of commercial reagents
• Real time RT-PCR is the method of choice but not
  widely available
• Most published assays based on prototype strain
• Need to be able to detect all 4 genotypes
• No established treatment although ribavirin has
  similar in vitro activity against hMPV and RSV

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Adenoviruses

• Non-enveloped, DNA viruses capsid formed by
  hexons and pentons, fibres project from penton
  bases
• 51 serotypes grouped into 6 species (formerly
  sub-groups), A to F
• Primary infection with one or serotype in
  childhood site of latency uncertain
• Many serotypes cause disease in immunocompromised
  patients
• commonest are 1, 2 and 5 (species C) and 34 and
  35 (species B)

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Adenoviruses

• Species Tissue tropism Serotypes
• A Gastrointestinal tract 12, 18, 31
• B Urinary tract, lung 3, 7, 11, 14, 16, 21, 34,
• 35, 50
• C Respiratory tract 1, 2, 5, 6
• D Eye, gastrointestinal 8-10, 13, 15, 17, 19,
  20
• tract 22-30, 32, 33, 36-39,
• 42-49, 51
• E Respiratory tract 4
• F Gastrointestinal tract 40,41
• Leen AM, Rooney CM, Br J Haematol 2005 128
  135-144

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Adenoviruses

• Adenovirus infections are common in HSCT with
  reported rates of 5 29
• Incidence higher in children and time of
  diagnosis is earlier than in adults (less than 30
  days cf. more than 90 days)
• Variation in reported rates may be due to
• Differences in patient groups (adults/children)
• Conditioning regimes
• Diagnostic tests used
• Testing protocols
• Lack of accepted case definitions for
  infection/disease

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Adenoviruses

• Clinical features include
• Pneumonia
• Gastrointetsinal disease
• Hepatitis
• Haemorrhagic cystitis
• Nephritis
• Encephalitis
• Reported mortality varies from 30 50

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Adenoviruses

• Virus can be detected from numerous sites
  including
• Throat
• Nasopharynx and respiratory secretions
• Blood
• Stool
• Urine
• CSF
• Tissue biopsies
• Conventional culture methods are slow and have
  largely been replaced by PCR (with EIA for
  detection of serotype 40/41 infections)

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Adenoviruses risk factors for infection and
disease

• Chakrabarti et al (2002) studied 76 adult HSCT
  recipients
• Adenovirus isolated from 19.7 patients only
  those receiving a T-cell depleted graft
• 40 infected patients developed disease risk
  factors identified were
• Severe lymphopenia (ALC less than 0.3 x 109)
• Failure to reduce immunosuppression
• Positive blood PCR at diagnosis
• Chakrabarti S et al. Blood 20021001619-27.

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Adenoviruses risk factors for infection and
disease

• Lion et al. (2003) studied 132 paediatric HSCT
  recipients using RT-PCR for detection of all 51
  serotypes
• Incidence of infection was 27
• Adenovirus DNA detectable in blood at median of
  16 days post-transplant, a median of 29 days
  before death in fatal cases
• Subsequently studied 80 paediatric patients and
  found rising viral load in faeces also predictive
  of adenovirus disease
• Lion et al. Blood 2003 102 1114-1120 and 2003
  102 (suppl. 1) 196a (abstract)

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Adenoviruses

• Risk factors for infection
• younger age
• matched unrelated donor or mismatched donor
• total body irradiation
• adenovirus positive donor
• use of Campath or ATG

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Adenoviruses

• Risk factors for disease
• Detection of virus at multiple sites
• Moderate to severe GvHD
• Immunosuppressive therapy
• Lymphocytopenia
• Viraemia
• Rising blood viral load
• Rising faecal viral load

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Adenoviruses

• Pre-emptive treatment based on post-transplant
• surveillance
• Reduction of immunosuppression if possible
• Antiviral therapy
• Ribavirin
• Cidofovir
• Donor leucocyte infusion (DLI)

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Antiviral therapy for adenovirus infection/disease

• Ribavirin
• guanosine analogue with broad antiviral activity
• Used for treating adenovirus infection and
  disease with variable results
• Cidofovir
• Nucleotide analogue with potent in vitro activity
  against several DNA viruses
• Appears to be more efficacious in vivo than
  ribavirin
• Low dose regime used to avoid nephrotoxicity
• Neither agent is particularly effective for
  established disease
• No controlled clinical trial data exist
• may be important to determine species in case of
  differences in antiviral sensitivity (Morfin F et
  al. Antivir Ther 2005 10 225-229)

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Invasive adenovirus infections in paediatric HSCT
patients

• Study of 71 HSCT recipients at Royal Manchester
  Childrens Hospital
• Used RT-PCR based on consensus primers for the
  hexon gene
• Monitored blood and faeces samples weekly and
  other sites as indicated
• In total, 9 patients developed invasive
  adenovirus infection, 3 of whom died

31
Invasive adenovirus infection illustrative case
32
T cell therapy for adenovirus infection/disease

• Adoptive immunotherapy with in vitro using
  expanded cytotoxic T lymphocytes (CTLs) shown to
  be effective for prevention and treatment of
  disease due to CMV and EBV
• Adenovirus-specific immune responses are less
  well understood but several groups a re working
  on different approaches to adenovirus-adoptive
  immunotherapy

33
Adenovirus-adoptive immunotherapy
Leen AM, Rooney, CM, British Journal of
Haematology 2004 128 135-144
34
Recent diagnostic developments

• Real-time PCR is replacing conventional methods
  of virus detection, such as shell vial culture or
  CMV antigenaemia testing
• Rapid (e.g. Fast TaqMan)
• Sensitive
• Accurate quantitation
• Wider use of sequencing for genotyping and
  anti-viral resistance testing
• Future developments include use of
• Luminex technology
• Microarrays

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Kinderscout, Derbyshire, January 2006