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Child Health Guideline Identifier

Immunosuppression, Infection and Immunisation in Rheumatology

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As initiation of immune suppressive therapy is often (semi-) elective, it is essential to check the immune status of patients as early as possible so that routine and extra immunisations can be completed before immunosuppressive medication, without unnecessarily delaying treatment (see below).

Common Medications in Paediatric Rheumatology

  • Corticosteroids (Prednisone, Prednisolone, Methylprednisolone)
    Up to 1-2mg/kg/day (maximum 60mg daily)
    Pulsed IV methylprednisolone 10 - 30 mg/kg/dose (maximum 1g daily) for 3 days
  • Intravenous immunoglobulin (IVIG)
    Moderate (1g/kg/dose) or high (2g/kg/dose) dose for immunomodulation.
    Used in conditions like Kawasaki vasculitis, severe, resistant or steroid dependent Juvenile Dermatomyositis, SLE associated immune thrombocytopenia or auto-immune haemolytic anaemia
  • Immunosupressants
    The medications listed below have immunosuppressive effects. The potency of effects depends on the agent and dose used, whether used in combination and with or without corticosteroids.  
Class Half-life Action Immunosuppression
DMARDs I*
Methotrexate (dose < 25 mg/week)
Leflunomide (*Arava)
Sulphasalazine
Hydroxychloroquine (*Plaquenil)
 
0.9 - 2.3 hours
2-3 weeks
5-10 hours
30-50 days
 
Inhibits DNA synthesis
Inhibits DNA synthesis
Mainly T cells
Interferes with Ag
processing and possibly
Ag production
 
Uncertain, probably moderate at dose shown
Uncertain, probably moderate to severe
Mild
Mild
DMARDs II
Cyclosporine
Azathioprine (*Imuran) (dose < 3 mg/kg/day)
Mycophenolate mofetil
 
8.4 hours (5-18)
3-5 hours
11-24 hours
 
Mainly T cells
Mainly T cells
Mainly B and T cells
 
Severe
Moderate
Severe
Biologic DMARDs
Etanercept (*Enbrel)
Infliximab (*Remicaide)
Adalimumab (*Humira)
Tocilizumab (*Actemra)
  -  SoJIA 2 weekly IV
  -  PolyJIA 4 weekly IV
  -  RA 4 weekly IV
  -  RA 1-2 weekly SCT
Rituximab (*Mabthera)



Abatacept (*Orencia)
  -  Poly JIA
  -  RA (IV and SCT)
Anakinra (*Kineret) SCT
 
80 hours
7.7 - 9.5 days
14 days (10-20)

23 days
16 days
11-13 days
5-13 days
21 days (8-35)




11 days
14 days (8-25)
4-6 hours
 
Anti-TNF
Anti-TNF
Anti-TNF
Anti-IL6




B cells mainly, T cells,
and inhibits new ab
responses. Still present
3-6 months after infusion
Anti-CTLA4 (APC/T cell
interaction)

Anti-IL1
 
Severe
Severe
Severe
Severe




Severe



Severe


Severe but short half life
Cytotoxics
Cyclophosphamide 
 
3-12 hours
 
T and B cells
 
Severe

Patients are considered significantly immunosuppressed if they are on the following medication:

  1. Prednisone 2mg/kg/day for more than 1 week, or 1mg/kg/day for more than 1 month
    AND/OR
  2. Other medication with severe immunosupressive effects (as listed above), particularly:
    - if on combinations of DMARDs, biologic DMARDs or cytotoxics
    - If on steroids as well as single or multiple DMARDs
  3. Clinical indications eg severe autoimmune disease or unusual and/or persistent infections.

The value of additional immune testing on patients taking these medications is unknown.

Screening prior to immunosuppressive therapy

  1. All patients
    - Check routine immunisations are up to date, or serology if unclear.
    - Serology for VZV, Measles, Mumps, Rubella and Hepatitis A, B, C and HIV
  2. Tuberculosis
    - ALL patients before immunosuppressants 
    - Screening tests: Mantoux (particularly if < 5 years) or TB Quantiferon gold
    - If negative, repeat in 6 months for high risk patients and yearly for low risk patients
    - CXR within six months of starting biologics

Immunisations

Vaccination pre-immunosuppression:

  • Non-live vaccines, including HPV vaccine if applicable, should be given at least TWO WEEKS prior to immunosuppression (HPV vaccine currently licensed from 9 years of age) 
  • Live vaccines like MMR and Varicella should be given at least ONE MONTH prior to immunosuppression, if no history of varicella (or measles) or MMR and VZV IgG negative 
  • Pneumococcal vaccine in patients who are immunosuppressed or have functional asplenia (like SLE) 
    - <2yrs: PCV13 conjugate vaccine, as per high risk schedule (use of PCV13 rather than PCV10) 
    - >2yrs: If no prior pneumococcal vaccine, then 2 doses two months apart PCV13 conjugate vaccine (Prevenar), then PPV23 polysaccharide vaccine (Pneumovax) 2 months later. 
    - >2yrs: If prior conjugate vaccine given as per schedule, then single dose of PPV23. 
    - Repeat PPV23 once after 3-5 years if continued immunosuppression. 
  • Influenza vaccine should be given yearly for patient and household 

Vaccination if on immunosuppression:

  • Generally no live vaccines (eg. MMR, varicella, BCG) should be given, but other non-live vaccines should be given. However risks and benefits of infections vs immunisations need to be considered. Please discuss this with Infectious Diseases and Rheumatology. There is emerging evidence that varicella vaccines, for example, can be safely given to patients taking methotrexate and corticosteroids. 
  • All patients should receive HPV vaccine if age appropriate and yearly influenza vaccine (inactivated)
  • Meningococcal vaccines 
    - <2yrs: Consider conjugated monovalent Men C vaccine, TWO doses, 2 months apart, then when 
    - >2yrs: Conjugated quadrivalent meningococcal polysaccharide vaccine (A, C, Y, W135) 
    - Adolescents: Particularly when leaving school and in communal living - quadrivalent meningococcal vaccine (A, C, Y, W135) recommended.
      Repeat every 5 years if ongoing immunosuppression or in high risk areas.

After immunosuppression, routine vaccinations (see NCCN guidelines on immunisation)

As per Starship Haematology/Oncology Immunisation policy:

  • When off therapy for 4 months, check baseline serology (VZV/measles/mumps/rubella/Hep A, Hep B, diphtheria, tetanus, haemophilus influenzae b) 
  • Commence re-immunisation schedule, provided lymphocyte count > 1.0.
  • If serology shows preservation of other prior vaccine antibodies to all tested, polio/pertussis vaccines do not need to be re-administered
  • Immunoglobulin interferes with antibody responses to live vaccines (MMR/Varicella) only. Live vaccines should be delayed until at least:
      - 6 months after measles or VZ immunoglobulin
      - 9 months after IVIG 1g/kg/dose and
      - 11 months after IVIG 2g/kg/dose given

Antimicrobial & antifungal prophylaxis

  • Have high index of suspicion for opportunistic infections, other unusual infections eg. fungal, etc., or atypical presentations
  • Consider discussion with Infectious Diseases regarding appropriate investigations and treatment
  • While on immunosuppressives, patients may not show all the typical inflammatory signs of infection eg CRP is not a reliable marker of infection in patients on tocilizumab therapy
  • Evaluate on a case-by-case basis

Indications for Pneumocystis Jiroveci (PJP) Prophylaxis

  • Intravenous cyclophosphamide or mycophenolate mofetil
  • Consider prophylaxis if multiple immunosuppressants and/or corticosteroids
  • Consider prophylaxis depending on condition of patient eg. pulmonary pathology
  • ANCA-positive granulomatous vasculitis
  • Prophylaxis with co-trimoxazole
    - Recommended oral regimen: trimethoprim 150mg/m2/day with sulphamethoxazole 750mg/m2/day in divided doses twice a day, 2 - 3 times a week eg. co-trimoxazole 240mg BD Fri, Sat, Sun
    - If allergic to co-trimoxazole, give dapsone

Chickenpox

  • Check varicella zoster IgG prior to immunosuppression
  • If negative, immunise with chickenpox vaccine
    -  At least 1 month prior to immunosuppression and recheck VZV IgG in a month
    -  Two doses of varicella vaccine, 4-8 weeks apart, are recommended for children > 13 years
  • If  exposed to chickenpox and VZ IgG negative, give VZIG as soon as possible after exposure (up to 10 days after exposure) in a patient at high risk
     - If time of presentation >96 hours from exposure, also consider starting acyclovir from day 7, for 7 -14 days after initial contact (high dose oral or IV) after discussion with ID consultant in addition to VZIG
  • Dose oral acyclovir 80mg/kg/day in 4 divided doses from day 7 following exposure and for 7 -14 days
Age  Dose Acyclovir
1 mth to 2 years  200mg qid 
2-6 years  400mg qid 
>6 years  800mg qid 
  • If IgG positive before immunosuppression, this should be checked again on immunosuppression. If this is positive, VZIG will not provide any additional protections and should not be given. Acyclovir, as above, should be considered.
  • Active chickenpox should be treated with IV acyclovir (see ADHB pharmacy intranet site including medchart reference viewer)

    Significant exposure (for which VZIG indicated in susceptible patients as described above) includes the following:
    - Same household
    - Playmate with face to face indoor play(>5 mins) or same room or classroom (> 1 hour)
    - Same hospital room or visitors

Chickenpox and IVIG

  • Protection from IVIG and VZIG last for about 4 weeks after last infusion
  • Immunoglobulin interferes with antibody responses to live vaccines (MMR/Varicella) only. To ensure response, live vaccines should be delayed until at least:
    - 6 months after measles or VZ immunoglobulin
    - 9 months after IVIG 1g/kg/dose and
    - 11 months after IVIG 2g/kg/dose given

Measles

  • Check Measles IgG prior to immunosuppression. If negative, immunise with MMR vaccine 1 month prior to immunosuppression
  • If IgG negative, patient should receive immunoglobulin within 6 days of exposure (see Measles guideline)
  • If IgG positive before immunosuppression, this should be checked again on immunosuppression. If this is positive, immunoglobulin will not provide any additional protection and should not be given.

Measles and IVIG

  • Protection from IVIG and measles immunoglobulin last for about 4 weeks after last infusion
  • Immunoglobulin interferes with antibody response to live vaccines (MMR/varicella) only. To ensure response, live vaccines should be delayed until at least:
      - 6 months after measles or VZ immunoglobulin
      - 9 months after IVIG 1g/kg/dose and
      - 11 months after IVIG 2g/kg dose given

Approach to infection in patients on immunosuppressive therapy 

  • Please discuss ALL proposed changes with Rheumatology consultant
  • If serious infection suspected, treat infection, postpone next dose of immunosuppressant and request Rheumatology review
  • If on biologic therapy eg. etanercept, adalimumab etc., stop until infection is under control. 
  • If on combinations of immunosuppressants, consider stopping one and/or increasing intervals between doses
    - If on leflunomide and severe infection, consider using cholestyramine to enhance clearance from body
  • If on chronic steroids
    - Consider reducing steroid dose if possible, but also
    - Consider HPA-axis suppression and risk of adrenal crisis. Do not discontinue steroids abruptly and ensure that patient receives stress doses, especially if fever >38°C or has operative procedure (see below)
    - Patients will need IV fluids and IV hydrocortisone if not tolerating oral fluids

Corticosteroid Stress Doses

See also Stress Steroid Management Clinical Guideline

Corticosteroid Stress doses = 5 -10 times maintenance

i.e. Cortisone 50 mg/m2/day PO, or, if severe 100mg/m2/day IV

Note:
Prednisone potency = 5 x cortisone potency
Continuous IV infusion of hydrocortisone is preferable to IV boluses 

Suggested doses:
Prednisone/Prednisolone/Methylprednisolone 10 mg/m2/day PO/IV (equivalent to Cortisone 50mg/m2/day) or
Hydrocortisone 100mg/m2/24hr by continuous IV infusion 

Further Reading

  1. Pileggi GS et al. Safety and Immunogenicity of Varicella Vaccine in Patients with Juvenile Rheumatic Diseases Receiving Methotrexate and Corticosteroids. Arthritis Care and Research. Vol.62 (7) Jul 2010:1034-1039
  2. Buhler S et al. Vaccination recommendations for adult patients with autoimmune inflammatory rheumatic diseases. Swiss Medical Weekly. 2015;145:w14159
  3. Heijstek MW et al. EULAR recommendations for vaccination in paediatric patients with rheumatic diseases. Ann Rheum Dis (2011). Doi:10.1136/ard.2011.150193
  4. Rubin LG et al. 2013 IDSA Clinical practice guideline for vaccination of the immunocompromised host. Clinical Infectious Diseases 2013.
  5. NZ MOH Immunisation Handbook 2014

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Document Control

  • Date last published: 18 July 2017
  • Document type: Clinical Guideline
  • Services responsible: Paediatric Rheumatology
  • Author(s): Elizabeth Wilson, Emma Best, Jackie Yan, Rebecca Dean
  • Editor: Greg Williams
  • Review frequency: 2 years

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