Herpesvirus Infections in Immunocompromised Patients (29 slides, 397KB)
Herpesvirus Infections
in Immunocompromised
Patients
An Overview
Immunocompromising
conditions
Congenital immunodeficiencies e.g.. Di George, WiskottAldrich syndrome.
AIDS
Haematological malignancies such as leukaemia.
Organ transplant recipients
Autoimmune diseases eg. SLE
Iatrogenically immunosuppressed patients e.g. cancer
patients receiving chemotherapy.
Herpesvirus
Enveloped DNA viruses.
Set up latent
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.
infection
following
primary
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.)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cytopathic Effect of CMV
(Courtesy of Linda Stannard, University of Cape Town, S.A.)
DEAFF test for CMV
(Virology Laboratory, Yale-New Haven Hospital)
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.
CMV pp65 antigenaemia
test
(Virology Laboratory, New-Yale Haven Hospital)
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 2 nd 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.
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.
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/ganciclovir 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.
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.
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.
Risk Groups
Ducan X-linked lymphoproliferative syndrome - this condition occurs
exclusively in males who had inherited a defective gene in the Xchromosome . 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 nonHodgekin’s lymphoma in AIDS patients. These include primary
lymphoma of the brain, Burkitt’s lymphoma, and immunoblastomas.
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.
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.
Human Herpes Virus 8
Now appears to be firmly associated with Kaposi’s sarcoma as well
as some lesser known malignancies such as Castleman’s disease
and primary effusion lymphomas.
HHV-8 DNA is found in almost 100% of cases of Kaposi’s
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.
in Immunocompromised
Patients
An Overview
Immunocompromising
conditions
Congenital immunodeficiencies e.g.. Di George, WiskottAldrich syndrome.
AIDS
Haematological malignancies such as leukaemia.
Organ transplant recipients
Autoimmune diseases eg. SLE
Iatrogenically immunosuppressed patients e.g. cancer
patients receiving chemotherapy.
Herpesvirus
Enveloped DNA viruses.
Set up latent
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.
infection
following
primary
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.)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cytopathic Effect of CMV
(Courtesy of Linda Stannard, University of Cape Town, S.A.)
DEAFF test for CMV
(Virology Laboratory, Yale-New Haven Hospital)
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.
CMV pp65 antigenaemia
test
(Virology Laboratory, New-Yale Haven Hospital)
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 2 nd 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.
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.
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/ganciclovir 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.
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.
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.
Risk Groups
Ducan X-linked lymphoproliferative syndrome - this condition occurs
exclusively in males who had inherited a defective gene in the Xchromosome . 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 nonHodgekin’s lymphoma in AIDS patients. These include primary
lymphoma of the brain, Burkitt’s lymphoma, and immunoblastomas.
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.
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.
Human Herpes Virus 8
Now appears to be firmly associated with Kaposi’s sarcoma as well
as some lesser known malignancies such as Castleman’s disease
and primary effusion lymphomas.
HHV-8 DNA is found in almost 100% of cases of Kaposi’s
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.