Canterbury DHB

Viral infection in SCT

Hepatitis B

All patients undergoing chemotherapy or stem cell transplantation should be screened for past or current hepatitis. Test:

• All patients for HBsAg, anti-HBs, anti-HBc.
• HbeAg and anti-HBe if HBsAg-positive.
• HBV DNA if HBsAg-positive or anti-HBc-positive.

For a full review, see Liang, R. (2009). "How I treat and monitor viral hepatitis B infection in patients receiving intensive immunosuppressive therapies or undergoing hematopoietic stem cell transplantation." Blood 113(14): 3147-3153.

For the ECIL guideline, see Mallet, V., et al. (2016). "Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5)." Lancet Infect Dis 16(5): 606-617.

Risk factors for reactivation

The risk of reactivation is based on the serological profile and intensity of immunosuppression. Risk factors include:

• Patient risk factors
• Treatment risk factors
• Lymphoma
• HBsAg-positive
• HBV DNA-detectable
• ITP allogeneic stem cell transplant
• Autologous stem cell transplant
• R-CHOP or equivalent
• Fludarabine
• High dose steroids
• Alemtuzumab
• GVHD

Managing HBV-exposed patients undergoing chemotherapy and/or monoclonal antibodies (e.g. rituximab and obinutuzumab)

HBsAg-positive

Reactivation risk:

• Up to 85% after allogeneic transplantation
• Up to 70% risk after chemotherapy or anti-CD20
• Up to 40% risk after anti-TNF antibodies
• Up to 25% risk after corticosteroids
• 5% risk of fulminant hepatitic failure

1. Check baseline HBV DNA level.
2. Start entecavir immediately.
3. It is not necessary to delay chemotherapy in most patients but discuss with ID specialist first.
4. Monitor HBV DNA and LFTS 2-3 monthly initially. When undetectable, monitor 6-monthly.
5. Continue prophylaxis for 6 months after chemotherapy.
6. Continue for 12 months after MoAb, autologous SCT or high baseline HBV DNA.
7. Continue for 12 months after end of immunosuppression post-allogeneic SCT.
8. Treat as HBsAg-positive.
9. Discuss vaccination with ID specialist.
10. Risk continues for several years after transplant.

Occult infection

(HBsAg-negative, anti-HBc-positive, HBV DNA-positive)

Reactivation risk:

• Highest risk in patients from endemic areas, e.g. Taiwan, Korea
• Up to 10% risk after chemotherapy
• Up to 41% risk after anti-CD20
• Up to 40% after allogeneic transplantation

Resolved infection

(HBsAg-negative, HBcAb-positive, HBV DNA-negative)

Reports of reactivation in up to 10% in Asian patient populations.

1. Consider monitor HBV DNA and LFT.

HBV naïve

(HBsAg-negative, HBsAb-negative, HBcAb-negative)

1. Vaccinate.

Managing HBV-exposed patients undergoing allogeneic transplant

HBsAg-positive donor

Greater risk if HBV naïve recipient.

1. Avoid whenever possible.
2. Discuss with ID.
3. Start anti-HBV therapy immediately.
4. Harvest once HBV undetectable.
5. Monitor HBV DNA and serology.
6. Treat with anti-HBV therapy as for intensive chemotherapy.
7. Vaccinate donor and recipient.

HBsAg-positive recipient

HBV naïve donor or recipient

(HBsAg-negative, HBsAb-negative, HBcAb-negative)

In a study of 259 consecutive HBsAg-positive, HBV-DNA negative patients undergoing myeloablative allogeneic transplantation at a single Chinese institution, the rates of HBV reactivation after 6, 12, and 24 months in patients prophylaxed with lamivudine was 3%, 7%, and 24% compared to 0%, 0%, and 3% with entecavir.

Managing HBV reactivation after chemotherapy or transplant

1. Stop all chemotherapy and hepatotoxic drugs.
2. Discuss with ID specialist.
3. Delay in starting antiviral treatment increases the mortality of HBV reactivation.

CMV

See CMV Prevention.

EBV

Introduction

An abnormal EBV-specific T-cell response following stem cell transplantation leads to proliferation of EBV-infected B-cells which progresses to cause post-transplant lymphoproliferative disorder (PTLD) in up to 15% of patients. EBV DNA-aemia is more common after allogeneic SCT and PTLD is seen only after allogeneic SCT.

Risk factors for developing PTLD are:

• T-cell depletion (ATG, alemtuzumab)
• Recipient age >50
• Second allogeneic SCT
• GVHD
• Cord blood transplantation

Prevention of EBV-PTLD

Guidelines for managing EBV infections and PTLD after allogeneic SCT have been developed at the Sixth European Conference on Infections in Leukemia (ECIL-6).

For full details, see Styczynski, J., et al. (2016). "Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines." Haematologica 101(7): 803-811.

Key points

• Primary prophylaxis is not recommended.
• Monitor EBV DNA-aemia by Q-PCR weekly in high risk patients from day 10 to 100.
• The EBV DNA doubling time may be 2-3 days so more frequent testing for rising levels.
• Thresholds for pre-emptive treatment based on EBV DNA-aemia are not established and should be discussed on a case-by-case basis.
• Rituximab is recommended for pre-emptive therapy in patients at high risk of EBV-PTLD.
• Rituximab should be combined with reduction in immunosuppression if possible.
• Features of EBV-PTLD are fever, lymphadenopathy, organomegaly, and rising LDH. If not treated, these are associated with high mortality.
• Diagnosis of EBV-PTLD should be based on biopsy of involved tissue with EBER-immunostain.

Treatment of EBV-PTLD

Fever and lymphadenopathy are the most common features. If not treated, these are associated with a high mortality. LN biopsy is the gold standard with PET-CT and EBV DNA-aemia an alternative if this is not possible. Pre-emptive treatment with rituximab is successful in 90% compared to 65% with EBV-PTLD. Reduction in IST used pre-emptively is effective in 68% alone and >80% in combination with rituximab. EBV-CTL are effective in >90% pre-emptively and 75% in therapy.

No recommendation was made for the threshold value for starting pre-emptive therapy and values between 1000 and 40,000 copies/ml have been proposed. The rate of EBV replication is likely to be clinically significant. In a study of patients receiving alemtuzumab, the median viral load at diagnosis of PTLD was 49 300 copies/mL (50-65 200 000 copies/mL). Notably, 23% and 45% of cases, respectively, had </=10 000 and </=40 000 copies/mL.

Since rituximab is associated with an increased risk of infection, its use is recommended in patients at high risk of EBV-PTLD accompanied monitoring for hypogammaglobulinaemia. The standard dose is rituximab 375 mg/m² weekly until EBV DNA-aemia negative. Give 1 dose of rituximab and recheck EBV DNA. Consider withholding subsequent doses if there has been a significant fall and no prior evidence of PTLD. Routine administration of 4 doses of rituximab is usually not necessary.

Toxoplasma

Introduction

Toxoplasma is a protozoal intracellular parasite that can infect any nucleated cell in the human body. The most commonly infected tissues are eyes, brain, lymph nodes, heart, and lungs. In immunocompetent hosts, the infection is asymptomatic or causes mild fever and/or lymphadenopathy. Reactivation is rare after standard chemotherapy although cases have been reported (about 1 in 10,000 cases). During immunosuppression, after HSCT, reactivation of latent zoites can occur, resulting in multi-organ failure.

Epidemiology

Prevalence of seropositive individuals varies around the world from 10-20% in North America to >90% in parts of South America. Primary infection is from ingestion of bradyzoites in undercooked pork/lamb/goat, tachyzoites in raw milk, or ingestion of soil/water contaminated by oocytes from cat faeces.

Reactivation is the primary mechanism of disease. It occurs in 10-15% of seropositive HSCT recipients. The overall incidence of the disease reported in European centres is 3-6%. Toxoplasma disease in seronegative recipients has been reported but is uncommon. Mortality is very high (up to 80%) despite treatment due to the non-specific initial presentation and delay in diagnosis.

Clinical features

Transplant patients with toxoplasmosis can present with fever, lymphadenopathy, hepatosplenomegaly, meningitis, brain abscess, chorioretinitis, pneumonitis, myocarditis, hepatitis, pancytopenia, or disseminated disease. Symptoms often present within 3 months post-transplant but later presentations can be seen, particularly after discontinuation of chemoprophylaxis, or even interruption of the anti-pneumocystis prophylaxis with cotrimoxazole, which may exert a protective role.

Diagnosis

• A high degree of suspicion is required to make the diagnosis in time to treat it effectively.
• Mental abnormalities, fatigue, fever, and pneumonitis that is unresponsive to broad-spectrum antibiotics should lead to specific investigations.
• The CRP is usually only mildly elevated.
• LDH and ferritin are non-specific but markedly elevated in the majority of patients. Haemophagocytosis is evident in one third.
• CT chest frequently shows bilateral, diffuse ground glass opacities.
• MRI is more sensitive than CT but typical features are only present in 60%.

Screening

Screening using PCR has been studied. Blood samples usually become positive before invasive tissue disease. Even amongst a selected population, around 600 tests were required to pre-emptively detect one positive case. Screening patients at highest risk has been suggested, e.g. seropositive recipients, particularly within the first 100 days after transplant, after starting high-dose corticosteroids, and in those not receiving cotrimoxazole prophylaxis.

Prophylaxis and treatment

Cotrimoxazole (which is usually being given simultaneously for PCP prophylaxis) has a prophylactic effect but reactivation can occur when cotrimoxazole is stopped. Treatment is with pyrimethamine (with folinic acid prophylaxis) and sulphadiazine for six weeks followed by 3 month maintenance.

• Pyrimethamine PO 100-200 mg loading then 50-75 mg daily plus sulphadiazine PO 1 g if <60 kg or 1.5 g if >60 kg 6-hourly for 6 weeks at full dose, then at half dose for 3 months (grade A).
• Pyrimethamine PO 100-200 mg loading then 50 mg daily plus clindamycin PO or IV 600 mg 6-hourly (grade B).
• Pyrimethamine should be combined with folinic acid 10-25 mg daily.

Topic Code: 336290