Herpesvirus Infections in Immunocompromised Patients

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Herpesvirus Infections in Immunocompromised
Patients

• An Overview

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Immunocompromising conditions

• Congenital immunodeficiencies e.g.. Di George,
  Wiskott-Aldrich syndrome.
• AIDS
• Haematological malignancies such as leukaemia.
• Organ transplant recipients
• Autoimmune diseases eg. SLE
• Iatrogenically immunosuppressed patients e.g.
  cancer patients receiving chemotherapy.

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Herpesvirus

• Enveloped DNA viruses.
• Set up latent infection following primary
  infection.
• Reactivation are more likely to take place during
  periods of immunosuppression.
• Both primary infection and reactivation are
  likely to be more serious in immunocompromised
  patients.

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Herpesvirus Particle
HSV-2 virus particle. Note that all herpesviruses
have identical morphology and cannot be
distinguished from each other under electron
microscopy. (Courtesy of Linda Stannard,
University of Cape Town, S.A.)
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Herpes Simplex Virus

• Normal individuals
• Primary HSV infection usually occurs in
  childhood, the majority of infections are
  asymptomatic or present with a gingivostomatitis.
• The virus becomes latent in the craniospinal
  ganglia.
• The virus may then be reactivated from time to
  time by various triggers such as stress,
  infection, sunlight, immunosuppression.

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Herpes Simplex Virus

• Immunocompromised individuals
• Patients receiving cytotoxic therapy, organ graft
  recipients, and patients with AIDS are at risk of
  severe HSV disease.
• HSV disease are more frequent and severe in these
  patients.
• Severe local disease or disseminated infection
  may be seen.
• Acyclovir may be used to treat HSV infection, but
  resistance to acyclovir may emerge during long
  term therapy.
• Acyclovir is now routinely given as prophylaxis
  for those receiving organ graft transplant, and
  HSV has ceased to be a major problem in these
  patients.

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Varicella-Zoster Virus

• Normal individuals
• Primary infection (chickenpox) is one of the
  classical rash diseases of childhood.
• Following primary infection, the virus remains
  latent in the cranial-spinal ganglia.
• Reactivation leading to the appearance of
  shingles occurs in 10-20 of infected individuals
  and usually occurs after the fourth decade of
  life. Usually, only one episode of reactivation
  occurs.

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Immunocompromised individuals

• Primary infection
• Chickenpox is much more severe in children
  undergoing treatment for malignancies such as
  leukaemia and lymphoma.
• Life-threatening complications such as
  disseminated varicella, pneumonia, and
  encephalitis are much more likely to be seen.
• Reactivation
• Immunocompromised individuals are at risk of
  developing herpes zoster, herpes zoster may
  appear at an earlier age than usual in these
  individuals, furthermore, more than one episode
  may occur.
• Severe, disseminated disease may occur but
  fatality is rare.

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Treatment and Prevention

• Acyclovir may be used for the treatment of severe
  varicella or zoster infections.
• A live attenuated vaccine has now been licensed
  in many countries. Its use is still controversial
  in immunocompromised individuals because it is a
  live vaccine.
• Recent data suggests that it is safe in children
  with leukaemia provided that they are in
  remission.
• VZIG can be used to prevent primary infection in
  susceptible individuals.

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Cytomegalovirus

• Normal individuals
• Primary infection is usually asymptomatic,
  occasionally an infectious mononucleosis-like
  illness may be seen.
• Reactivations or re-infections are common
  throughout life and are usually asymptomatic.

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Immunocompromised individuals

• Both primary and recurrent infection may lead to
  symptomatic disease.
• Primary CMV infection is usually more severe than
  recurrent infection, with the exception of bone
  marrow transplant recipients, where primary and
  recurrent infections are just as severe.

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Clinical Manifestations

• Fever
• Pneumonitis
• Hepatitis
• Gastrointestinal manifestations eg. colitis
• Encephalopathy
• Retinitis
• Poor graft function
• Pneumonitis is the most severe manifestation,
  and carries a mortality rate of 85 in the
  absence of treatment.

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AIDS Patients

• CMV disease is present in 7.4 to 30 of all AIDS
  patient.
• Sight-threatening retinitis, colitis, and
  encephalopathy are the most common manifestations
  of CMV disease in AIDS patients. Pneumonitis is
  extremely rare.

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Solid organ transplant recipients e.g. renal,
liver, heart

• Most common infection, leading cause of morbidity
  and mortality.
• Occurs 1 - 3 months following transplant.
• Primary infection more severe than recurrent
  infection.
• Patients may present with fever, pneumonitis, GI
  manifestations, hepatitis, and poor graft
  function.
• Does not appear to be associated with organ
  rejection.

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Bone marrow transplant recipient

• The host immune system is ablated before the
  transplant and thus every aspect of the immune
  system is deficient.
• CMV is the leading infection and the greatest
  cause of transplant failure.
• Both primary and recurrent infection may cause
  severe disease, pneumonitis is seen in 15 of
  patients.
• At special risk are seropositive recipients of
  graft from seronegative donors, and seronegative
  recipients of graft from seropositive donors.

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Laboratory Diagnosis (1)

• In general, the detection of CMV from blood
  specimens or bronchioalveolar lavage is more
  prognostic of clinical CMV disease than the
  detection of the virus from urine or saliva.
• 1. Virus isolation
• (a) Conventional cell culture - human embryo lung
  fibroblasts used, requires 1 to 3 weeks for
  characteristic CPE to appear, remains the gold
  standard for the diagnosis of CMV infection
• (b) Rapid culture methods - eg. DEAFF test -
  detects the expression of CMV early antigens
  within 24 to 48 hours of inoculation. Appears to
  be as sensitive and specific as conventional cell
  culture.

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Cytopathic Effect of CMV
(Courtesy of Linda Stannard, University of Cape
Town, S.A.)
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DEAFF test for CMV
(Virology Laboratory, Yale-New Haven Hospital)
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Laboratory Diagnosis (2)

• 1. CMV antigenaemia test - widely used in many
  European countries. CMV antigens at the surface
  of polymorphonuclear leukocytes are detected by
  immunoperoxidase or immunofluorescence
  techniques. A result can be obtained within 4 to
  6 hours but the technique is very tricky.
• 2. Polymerase chain reaction - becoming the
  method of choice in many centers, had been
  reported to carry a higher prognostic value for
  CMV disease than the DEAFF test. The use of
  real-time quantitative PCR has proven to be of
  great use in the management of bone marrow
  transplant recipients. However, the lack of
  standardization of real-time PCR protocols
  hindered the comparison of data between centers.
• 3. Serology - not reliable in general but
  occasionally, rises in IgG titre and the presence
  of IgM may be seen.

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CMV pp65 antigenaemia test
(Virology Laboratory, New-Yale Haven Hospital)
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Management (1)

• Ganciclovir - is the drug of choice. However, it
  is associated with neutropenia and
  thrombocytopenia.
• Valganciclovir - is now the drug of choice for
  prophylaxis against CMV in solid organ transplant
  recipients.
• Forscarnet - can be used as the 2nd line drug.
  Again it is very toxic and is associated with
  renal toxicity.
• Cifofovir (HPMCC) - approved for the treatment of
  CMV retinitis. It is also associated with renal
  toxicity. Like forscarnet, it is used as a 2nd
  line drug
• Drugs Under Investigation - Maribavir (UL97
  kinase inhibitor), brincidofovir (oral
  bioavailable form of cidofovir), and letermovir
  (viral terminase complex inhibitor).
• CMV hyperimmune globulin - found to be effective
  against CMV pneumonitis.

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Management (2)

• Transplant Recipients - once clinical disease is
  established, the patient should be treated
  vigorously with antiviral agents. Ganciclovir is
  the drug of choice. CMV hyperimmune globulin had
  been found to be useful in the treatment of CMV
  retinitis.
• AIDS patient with retinitis - vigorous antiviral
  therapy should be given. Both systemic and local
  (intravitreal implants) may be used.

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Prevention

• Pre-transplant donor-recipient matching - shown
  to be effective in reducing CMV disease but will
  be very difficult to implement in Hong Kong
  because of the high seropositive rate.
• Prophylaxis - prophylaxis with acyclovir/ganciclov
  ir for all transplant recipients and CMV
  immunoglobulin for seronegative recipients of
  graft from seropositive donors should be
  considered.
• Vaccination - an experimental live attenuated
  vaccine known as the Towne strain is available
  but there is great reluctance to give it to
  immunocompromised individuals. Subunit vaccines
  are being developed.

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Post-transplant surveillance

• Weekly surveillance blood, urine or saliva
  cultures are now routinely carried out for bone
  marrow transplant recipients and other organ
  transplant recipients if clinically indicated.
  Bronchioalveolar lavages are performed routinely
  at 1 month post-transplant in some centres.
• In general, a positive result from urine or
  saliva warrants extra vigilance and relaxation of
  immunosuppression should be considered. A
  positive result from the blood or BAL warrants
  the commencement of antiviral therapy with
  ganciclovir.

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Epstein-Barr Virus

• After primary infection, EBV maintains a steady
  low grade latent infection in the body.
• During periods of immunosuppression, the virus
  may reactivate to cause clinical disease.
• In a few cases, lymphoproliferative lesions and
  lymphoma may develop. These lesions tend to be
  extranodal and in unusual sites such as the GI
  tract or the CNS.
• Three groups of immunocompromised patients are
  particularly susceptible to severe EBV associated
  diseases X-linked lymphoproliferative syndrome,
  transplant recipients, and AIDS.

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Risk Groups

• Ducan X-linked lymphoproliferative syndrome -
  this condition occurs exclusively in males who
  had inherited a defective gene in the
  X-chromosome . This condition accounts for half
  of the fatal cases of IM.
• Transplant Recipients - solid organ tranplant
  recipients encountering primary EBV infection in
  the post transplant period may develop Post
  Transplant Lymphoproliferative Disorder.
  Transplant recipients are also prone to develop
  lymphoproliferative disorders and lymphomas
  several years after the transplant.
• AIDS - EBV is associated to varying degrees with
  certain types of non-Hodgekins lymphoma in AIDS
  patients. These include primary lymphoma of the
  brain, Burkitts lymphoma, and immunoblastomas.

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Post Transplant Lymphoproliferative Disorder

• PTLD is thought to be a lymphoproliferation of
  EBV infected B-cells arising in the setting of
  over immunosuppression.
• The patients at risk are those who encounter EBV
  as a primary infection during the post-transplant
  course.
• The proliferation may be seen anywhere lymphoid
  tissue presides, although in lung transplant
  recipients, presentation in the allograft is
  relatively common.
• Histopathological manifestation appears as
  nodular sheets of atypical lymphoid cell which
  are not dissimilar to Non-Hodgkins lymphomas.
• Some cases are similar to lymphomatoid
  granulomatosis or T-cell rich B-cell lymphomas
  with a large subset of reactive T-cells.
  Reduction in immunosuppression often results in
  regression of PTLD.

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HHV-6 and HHV-7

• Like other herpesviruses, HHV-6 and HHV-7 become
  latent following primary infection and are
  reactivated from time to time, especially during
  periods of immunosuppression.
• HHV-6 infection is firmly associated with roseala
  infantum. It had also been associated with
  neurological manifestations such as febrile
  convulsions, meningitis, and encephalitis.
• It had also been associated with a variety of
  symptoms in transplant recipients such as fever,
  graft vs host disease, liver and CNS
  manifestations. However such associations are
  very difficult to prove since CMV is almost
  always concomitantly reactivated.
• Likewise the role of HHV-6 reactivation in HIV
  infection remains unclear.
• HHV-7 is not associated conclusively with any
  human disease.

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Human Herpes Virus 8

• Now appears to be firmly associated with Kaposis
  sarcoma as well as some lesser known malignancies
  such as Castlemans disease and primary effusion
  lymphomas.
• HHV-8 DNA is found in almost 100 of cases of
  Kaposis sarcoma.
• Most patients with KS have antibodies against
  HHV-8.
• The seroprevalence of HHV-8 is low among the
  general population but is high in groups of
  individuals susceptible to KS, such as
  homosexuals.
• Unlike other herpesviruses, HHV-8 does not have a
  ubiquitous distribution.