Anti-viral policy (haematology/oncology)

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Objectives

This guidelines provides information for the use of anti-virals in children who have received a human stem cell transplant. 

Scope

This guideline has been developed to be used for children with haemato-oncology conditions.

1. INTRODUCTION

Viral infection in the immunocompromised patient can be life threatening despite the use of prophylaxis. Patients thought to be infected should be assessed rapidly and treatment initiated promptly. It must be remembered that immunocompromised patients can present atypically without pyrexia and without any localising features indicating the source of the infection. The possibility of infection with opportunistic organisms such as PCP and reactivation of previous infections e.g. CMV, VZV should always be considered. Viruses such as those responsible for the common cold can cause pneumonitis and death in recipients of allogeneic stem cell transplants. Small children may be particularly vulnerable to viral infection because of lack of previous exposure. Adenovirus is amongst the commonest causes of Haemopoietic Stem Cell Transplant (HSCT) procedure related mortality in children.

Viruses can cause many different symptoms and should always form part of a differential diagnosis for any immunocompromised patient. The viruses listed below are examples of the commonest identified in HSCT patients. For other viral infections see related documentation.

CLINICAL VIRUS
URTI CRV, Adenovirus
LRTI (pneumonia) CRV, CMV, Adenovirus
Sinusitis CRV
Mucositis HSV
Oesophagitis/Gastritis/Colitis   HSV, CMV, Adenovirus
Diarrhoea Rotavirus, Adenovirus, Norovirus, Sapovirus, Astrovirus, CMV
Haemorrhagic Cystitis Polyomavirus, Adenovirus
Hepatitis HAV,  HBV,  HCV,  CMV,  EBV,  Adeno (HSV,  VZV,  HHV6,  Enteroviruses)
PUO CMV, EBV, Adenovirus, HHV6
Meningitis HSV, VZV, Enteroviruses
Encephalitis HSV, CMV, EBV, HHV6, VZV
  • URTI – upper respiratory tract infection
  • LRTI – lower respiratory tract infection
  • CRV - Coryzal Respiratory Viruses (these include corona virus, influenza A/B/C including H1N1, parainfluenza 1-4, rhinovirus, respiratory syncitial virus, enteroviruses, Human metapneumovirus)
  • CMV – cytomegalovirus
  • HSV – herpes simplex virus
  • HAV – hepatitis A
  • HBV – hepatitis B virus
  • HCV - hepatitis C virus
  • EBV – Epstein Barr virus
  • HHV6 – human herpes virus 6
  • VZV – varicella Zoster virus
2. RELATED DOCUMENTATION

See 'related guidelines' section at the bottom of this guideline

3. AUTHORISED PERSONNEL/SPECIFIC STAFF COMPETENCIES

3.1 The diagnosis and management of viral disease will be directed by the Consultant/Associate Specialist or a senior member of the medical team.

3.2 The Medical/nursing team will be responsible for the monitoring & investigation of viruses. Microbiology/Virology staff will inform of recent virology results as they become positive.

4. EQUIPMENT/MATERIALS

4.1 IV/Oral Drug Kardex

4.2 IV Fluid Prescription Chart

5. PROCEDURE

5.1 VIRAL RESPIRATORY TRACT INFECTION:

For further information including clinical features see Pulmonary Complications Pre & Post HSCT SOP (YBMT-CLIN-0016)

At Risk Group

Patients with respiratory symptoms or signs within any of the listed risk groups should be discussed with the HSCT Consultant or HSCT Associate Specialist. The decision to start treatment will be based on the patient’s clinical condition, previous treatment etc:

  • Autografts within 30 days of HSCT
  • Sibling allograft recipients within 100 days of HSCT
  • Non-myeloablative allograft recipients within 6 months of HSCT
  • VUD transplants up to 6 months
  • Haplo-identical transplants until immune reconstitution
  • Patients receiving intensive immunosuppression post allograft
  • Patients with chronic GvHD
  • Allografts who have known chronic lung disease

This list is not exhaustive and other patients can develop pneumonitis although this is less common. It should be remembered that the presence of a virus may not be the cause of the patient’s symptoms.

5.1.1 Respiratory Syncytial Virus (RSV)

RSV has a 15-20% mortality from pneumonitis in the allograft population. Patients who are RSV positive pre-allogeneic transplant should not begin conditioning until symptoms have settled and viral shedding ceased.

Surveillance

Pre HSCT assessment, which includes nasopharyngeal aspirate (NPA) and throat swab for respiratory viruses.

Investigation

  • NPA – Direct Immunofluorescence if showing signs of respiratory symptoms
  • Throat swab – PCR if showing signs of respiratory symptoms
  • BAL if clinically indicated 

Infection Control

  • Inpatients should be nursed as a source patient in a closed single doored isolation cubicle without positive pressure.
  • Outpatients should be asked to sit away from other patients and to attend clinic/day ward later in the day.
  • Following contact, hand washing with soap and water and alcohol is essential.

Refer to Respiratory Syncytial Virus (RSV) NHSGG&C Control of Infection Committee Policy www.nhsggc.org.uk/infectioncontrol

Contact

If an allograft patient is in the same room as a known case, the patient must be screened.

Treatment

  • RSV - Patients with URTI who are <30 days post allograft or <60 days with severe lymphopenia

Ribavirin IV Dosing is not recommended for treatment of infants with RSV - SIGN guidelines 2006

Dose Duration
33mg/kg Loading dose, then
16mg/kg 6hrly for 4 days, then
8mg/kg 8hrly for 3 days, then review


5.1.2
 Parainfluenza 3 

Parainfluenza 3 has mortality from pneumonitis of about 5-10% in the allograft population.

Patients who are positive pre-allogeneic transplant should not begin conditioning until symptoms have settled and viral shedding ceased.

  • Symptomatic patients with URTI should receive supportive therapy as required with chest physiotherapy, adequate hydration and oxygen supplementation.
  • Intravenous Immunoglobulin may be considered.

LRTI should be discussed with HSCT consultant or HSCT associate specialist. IV Ribavirin is a treatment option which may be used (see above dosing table) for a maximum of 10 days, however there is little evidence to support its efficacy.

  • IV IgG 0.5g/kg
  • Methylprednisolone (if severe inflammation and no response)


5.1.3 Influenza A + B including H1N1

Flu A has a higher mortality than flu B from pneumonitis.

Prophylaxis

  • Vaccinate close household contacts in autumn
  • Consider vaccinating donor pre donation
  • Patients will receive a letter from the Schiehallion Unit for their GP to advise on appropriate action for vaccination for each Flu season.
  • Live attenuated influenza vaccines (Fluenz ®) nasal spray are contraindicated for children or adolescents who are severely immunocompromised and for close contacts of severely immunocompromised individuals. Appropriate alternative inactivated influenza vaccines should be considered.

Investigation

  • NPA – immunofluorescence, PCR
  • Nose /throat swab – PCR
  • BAL if clinically indicated
  • All patients with positive results should receive treatment even if it is beyond the 48 hour cut off recommended by the NICE guidelines and HPS 2013 – Guidance on the use of antiviral agents for the treatment of and prophylaxis of influenza, 2013-14 or refer to current HPS guideline updated annually

Infection Control

  • Inpatients should be nursed as a source patient in a closed single doored isolation cubicle without positive pressure and appropriate signage to control entry.
  • Out patients should be asked to sit away from other patients and to attend clinic/ day ward later in the day.
  • Following contact with the patient, hand washing with soap and water and alcohol is essential.
  • If the patient has H1N1 – the following precautions should be observed:
    • Protective Personal Equipment (PPE) must be used as follows - surgical face mask within one metre of patient, clean disposable plastic apron and gloves
    • For Aerosol Generating Procedures (AGPs) staff must have passed an FFP3 respirator fit test
    • Duration of isolation precautions for hospitalised patients should be continued for 7 days after onset of illness of 24hrs after the resolution of fever and respiratory symptoms, whichever is longer

Contact

If a patient on the HSCT Unit or a patient attending as an outpatient is Flu A/B positive consider giving HSCT patients who have been in prolonged contact prophylactic treatment. Current recommendations are that severely immunocompromised patients should receive Zanamivir as first line therapy, with Oseltamivir as second line therapy where Zanamivir is not a suitable option (see below for details).

Treatment for Influenza A and B and H1N1

Influenza A and B

NB: This MUST be initiated by the HSCT Consultant/Associate Specialist.

Severely immunocompromised patients should receive inhaled Zanamivir as first line therapy.

Zanamivir Dosing:

Inhalation of powder

Indications Age Dose
Prevention during an epidemic of Influenza (prophylaxis)  5-18 years  10mg once daily for up to 28 days 
Treatment of Influenza 5-18 years 10mg twice daily for 5 days
Post Exposure prophylaxis of Influenza 5-18 years 10mg once daily for 10 days


Zanamivir is not licensed for children under 5 years old. For these children, and for any child unable to use the diskhaler, prescribe Oseltamivir. However, severely immunocompromised patients are at increased risk of developing oseltamivir-resistant influenza, therefore need close monitoring.

Oseltamivir may also be appropriate for any HSCT patients no longer considered to be severely immunocompromised.

Oseltamivir (Tamiflu) Dosing: (give once daily for 10 days for prophylaxis and twice daily for 5 days for treatment):

Age/weight   Dose
<1 month   2mg/kg
1-3 months   2.5mg/kg
3mo - 1 year   3mg/kg
1-13 years <15kg 30mg
  15-23kg   45mg
  23-40kg 60mg
  >40kg 75mg
>13 years   75mg


*Follow up testing may also be indicated in outbreak situations. During an epidemic prophylaxis may be used up to 6 weeks.

NB: For severely immunocompromised patients who are unable to receive Zanamivir via diskhaler and/or in cases of suspected or confirmed oseltamivir resistance, an aqueous solution of Zanamivir is available for nebulisation or IV administration. This is an unlicensed preparation which is only available on a named patient basis direct from GSK. Contact details are available in HPS Guidance document (2013)


5.1.4 
H1N1

Severely immunocompromised patients should receive inhaled Zanamivir as first line therapy (see 5.1.3).

If the patient is not considered severely immunocomprimised treat initially with Oseltamivir (see 5.1.3). If no response to treatment with Oseltamivir consider the possibility of drug resistance. Zamanivir is an alternative viral neuraminidase inhibitor, which may be used following discussion with the virologist.

Post exposure PROPHYLAXIS: as per dosing guidelines in 5.1.3 at using prophylactic regimen.


5.1.5 
Human Metapneumovirus

This is a recognised cause of idiopathic pneumonia in immunocompromised children, putting them at risk of severe disease and hospitalisation. Patients develop rapidly spreading infiltrates and hypoxia. There are no large published studies to guide treatment. IVIgG has been used and Ribavirin demonstrates some in vitro activity.

5.2 OTHER VIRAL INFECTION:

5.2.1 HHV6

HHV6 is a ß herpes virus with similarities to CMV and HHV7. It is widespread in the human population, and persists in the lymphocytes and salivary glands. It can be reactivated during times of immunosuppression.

Clinical Features

  • Rash
  • Encephalitis
  • Convulsions
  • Short term memory loss
  • Graft failure

Investigation

  • Blood – HHV6 PCR
  • CSF – HHV6 PCR
  • MRI
  • EEG

Treatment

  • 1st line agent GANCICLOVIR - dose depends on renal function
  • 2nd line agent CIDOFOVIR

NB: This MUST be initiated by the HSCT Consultant/Associate Specialist

Duration: Until patient improves


5.2.2 
HSV

Clinical Features

  • Cold sores
  • Mouth ulcers
  • Genital lesions
  • Encephalitis
  • Meningitis Hepatitis
  • Oesophagitis
  • Generalised infection
  • Pneumonitis

Prophylaxis

Aciclovir Dosing:

Age Dose

1month-2yrs  

100-200mg four times daily orally
If IV 250mg/m2 three times daily

2yrs-18yrs

200-400mg four times daily orally
If IV 250mg/m2 three times daily


At Risk Group

  • Autografts to D30
  • Allografts to D100
  • Alemtuzumab (Campath) recipients CD4<0.4
  • Acute Leukaemia Neutrophil <1.0 x 109/L
  • Chemotherapy recipients with high incidence of previous cold sores/genital herpes

Surveillance

Pre HSCT assessment, which includes serological testing

Investigation

  • Viral Swab (in VTM) – PCR (please indicate patient symptoms on form)
  • If encephalitis – MRI, EEG, CSF for PCR, Hepatitis – biopsy sample to virology
  • Disseminated – EDTA blood for HSV PCR

Treatment

1st line: ACICLOVIR IV

Age Dose

Child 1 - 3 months 

20mg/kg three times daily for 14 days (21 days if CNS involvement) 

3months-12years

500mg/m2 three times daily for 5 days (21 days if CNS involvement) 

12years-18years

10mg/kg three times daily for 5 days (21 days if CNS involvement)


NB: 
Commence IV maintenance fluids during IV aciclovir administration. In renal impairment see dose adjustment table (Section 5.3).

If aciclovir resistance is suspected, a swab in viral transport medium

should be sent to virology.

2nd line GANCICLOVIR see dosing and administration in Diagnosis & Management of CMV SOP (YBMT-CLIN-0014)

3rd line: FOSCARNET IV infusion 40mg/kg three times a day for 2 - 3 weeks or until lesions heal (see dosing & administration).


5.2.3 
VZV

NB: VZV titres should be assessed for of all at risk patients prior to commencement of immunosuppressive treatment. See Chickenpox & Measles in the HSCT Setting SOP (YBMT-CLIN-0018)

5.3 DRUG DOSE REDUCTION IN RENAL IMPAIRMENT:

DRUG DOSE SCHEDULE
Aciclovir Oral prophylaxis:  Estimated GFR 10-20  HSV: normal dose 3-4 times/day
VZV: normal dose 8 hourly
Estimated GFR < 10ml/min give normal dose every 12 hours 
IV therapy: Estimated GFR 25-50ml/min give normal dose every 12 hours
Estimated GFR 10-25ml/min give normal dose every 24 hours
Estimated GFR <10 ml/min give 50% dose every 24 hours
Oseltamivir Reduce dose if: Estimated GFR <30 ml/min give 50% dose
Estimated GFR <10 ml/min - not recommended
Ganciclovir See Diagnosis and Management of CMV SOP
Foscarnet See Diagnosis and Management of CMV SOP

 

 

 

 

 

 

 

 

References
  1. Boeckh, M., The challenge of respiratory virus infections in hematopoietic cell transplant recipients. British Journal of Haematology, 2008. 143(4): p. 455-67.
  2. Boeckh, M., et al., Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clinical Infectious Diseases, 2007. 44(2): p. 245-9.
  3. Baldwin, A., et al., Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation. Bone Marrow Transplantation, 2000. 26: p. 1333-1338.
  4. Ljungman, P., et al., Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplantation, 2003. 31(6): p. 481-486.
  5. Neofytos, D., et al., Treatment of adenovirus disease in stem cell transplant recipients with cidofovir. Biology of Blood & Marrow Transplantation, 2007. 13(1): p. 74-81.
  6. Fanourgiakis, P., et al., Intravesical instillation of cidofovir in the treatment of hemorrhagic cystitis caused by adenovirus type 11 in a bone marrow transplant recipient. Clinical Infectious Diseases, 2005. 40(1): p. 199-201.
  7. Nagafuji, K., et al., Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients. Bone Marrow Transplantation, 2004. 34(10): p. 909-14.
  8. Englund, J.A., et al., Brief Communication: Fatal Human Metapneumovirus Infection in Stem-Cell Transplant Recipients. Ann Intern Med, 2006. 144(5): p. 344-349.
  9. www.medicines.org.uk
  10. BNF and BNFc
  11. Respiratory Syncytial Virus (RSV) NHSGG&C Control of Infection Committee Policy
  12. Bronchiolitis in children SIGN Guideline 91, Nov 2006 [WITHDRAWN] 
  13. Green Book Chapter 19 
  14. Guidance on the use of antiviral agents for the treatment and prophylaxis of Influenza 2013-14. 17th December 2013 version 1.0 1-19. Health Protection Scotland 2013
  15. Policy to prevent the Transmission Influenza (Adult). GGC Control of Infection Committee Policy April 2011 v3. 1-22
Editorial Information

Last reviewed: 01 March 2015

Next review: 01 March 2017

Author(s): Dr A M Ewins

Approved By: Clinical Effectiveness