Pneumocystis jiroveci infection in children and young people being treated for malignant disease, marrow failure or post-haemopoetic stem cell transplant - Prevention and management

Publication: 16/03/2015  
Last review: 18/04/2018  
Next review: 18/04/2021  
Clinical Guideline
CURRENT 
ID: 4138 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2018  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Prevention and management of Pneumocystis jiroveci infection in children and young people being treated for malignant disease, marrow failure or post-haemopoetic stem cell transplant

Background

Pneumocystis jirovecii, previously known as Pneumocystis carinii, is an opportunistic parasite that causes pneumonia (PCP) in immunocompromised hosts. P. jirovecii was originally thought to be a protozoa but more recent molecular studies have revealed a greater homology to fungi (1). Most immunocompetent children acquire asymptomatic infection with P. jirovecii by the age of 4 years (2,3), whilst symptomatic disease occurs almost exclusively in severely immunocompromised hosts.

The disease carries with it a high mortality rate of between 30-50%, in non-HIV (human inmmunodeficiency virus) infected immunocompromised patients (4)

This guideline describes the groups for which prophylactic therapy should be given and sets out suggestions for the investigation and management of cases with suspected infection.

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Prevention

Hughes et al defined an attack rate for PCP in children with acute lymphoblastic leukaemia (ALL) as 22-43%, depending on the stage of the disease, and in children treated for rhabdomyosarcoma (RMS) as 25% (5,6) without prophylaxis. A randomised controlled trial of PCP chemoprophylaxis with co-trimoxazole for children undergoing treatment for these 2 diseases showed the incidence of PCP over a 2-year period in the placebo group was 21%, whereas there were no cases of PCP in the daily co-trimoxazole group. (5).

On this basis of this work, and multiple observation studies and national and international treatment trial protocols, the following group of higher risk patients have been produced which should receive prophylactic treatment:

  • Acute Lymphoblastic Leukaemia (*)
  • T cell non-hodgkins lymphoma (NHL) (*)
  • Acute Myeloid Leukaemia treated with purine analogues (clofarabine, fludarabine, nelarabine)
  • Histiocytosis
  • HLH (haemophagocyctic lymphohistiocytosis)
  • Hodgkin’s disease
  • High risk Neuroblastoma
  • Ewings Sarcoma
  • Rhabdomyosarcoma
  • Wilms tumour receiving high-risk post-operative chemotherapy
  • Infant PNET (primative neuroectodermal tumour)
  • Intracranial Germ Cell Tumours
  • Recurrent PNET
  • Severe Aplastic Anaemia
  • Any patient receiving high dose chemotherapyn - see below for specific recommendations

(*) Co-Trimoxazole must always be stopped one week before and during high dose methotrexate therapy.

Additionally, any patient on temozolomide therapy should receive prophylaxis (7).

The first choice prophylactic treatment is co-trimoxazole (see Appendix for dosing schedule)

If a child must stop co-trimozaxole because of repeated cytopenias or other inability to tolerate it, Pneumocystis prophylaxis should continue with one of the alternative drugs.

Discuss drug of choice with a paediatric oncology pharmacist and the child’s haematology/oncology consultant. Of the second line agents, dapsone is the alternative of choice, as it is probably more effective than the others, although evidence is weak, and its action is systemic rather than limited to the lung. Pentamadine an option for those who do not tolerate dapsone, with atovaquone is also an alternative but fourth-line. (8,9,10)

Allogeneic transplants:
Daily co-trimoxazole prophylaxis should be commenced/continue on admission to the transplant unit.

Prophylaxis should continue until D+1. Treatment should then be reviewed and withheld (if applicable), and reinstated in accordance with the guidance below on the basis of the pre-transplant toxoplasmosis IgG result:

If BOTH the recipient AND donor are toxoplasmosis IgG NEGATIVE then daily co-trimoxazole should restart at D+28

If EITHER the recipient OR donor are toxoplasmosis IgG POSITIVE then daily co-trimoxazole should continue throughout transplant.

If EITHER the recipient OR donor are toxoplasmosis IgG INDETERMINATE OR UNKNOWN then daily co-trimoxazole should restart at D+14.

BUT NOTE
Patients with a previous history (confirmed or suspected) of PJP should be reviewed individually by the consultant and treatment strategy may differ.

Autologous transplants:
Co-trimoxazole should be prescribed to all patients admitted for autologous transplant EXCEPT in the situation where a specific trial recommendation exists for an individual regime. The most frequently encountered trial is HRNBL-1, though each guideline/trial should be checked for every treatment episode.

Excluding schedules with specific trial recommendations, prophylaxis with daily co-trimoxazole should commence on admission and continue until lymphocyte count is above 1.

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Diagnosis

Symptoms of Pneumocystis infection are often non-specific, and include the following (11):

  • Progressive exertional dyspnea
  • Fever
  • Nonproductive cough
  • Chest discomfort
  • Weight loss
  • Chills

The physical examination findings are also highly nonspecific of any lower respiratory tract infection and include:

  • Tachypnoea
  • Fever
  • Tachycardia
  • Mild crackles and rhonchi but may be normal - especially in the presence of widespread infiltrates on chest x-ray
  • Cyanosis, nasal flaring, use of accessory muscles in severe disease

A feature which significantly raises concern of Pneumocystis infection is

  • Unexpectedly low oxygen saturations or
  • Rapid decrease in oxygen saturations after minimal exercise

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Investigation

All patients in whom Pneumocystis infection is suspected should be discussed with the patients haematology/oncology consultant, or the attending consultant out-of-hours.

Chest radiography should be requested. This may be normal or show a diffuse bilateral infiltrate, in keeping with a viral pneumonitis.

For patients in whom there is significant suspicion, a consultation with a respiratory physician may be sought for a bronchioalveolar lavage.

Computerised tomography of the chest may also be appropriate, in investigating the differential diagnosis, which includes pulmonary aspergillosis, viral pneumonitis or diffuse bacterial pneumonia.

While adult patients may reasonably have Pneumocystis infection excluded with serum beta d-glucan assays, their value in paediatric patients is as yet unclear and should only be assessed within a service evaluation or other clearly controlled context.

Induced sputum is of no diagnostic value in suspected Pneumocystis jirovecii infection in children

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Treatment / Management

Patients with strongly suspected Pneumocystis jirovecii infection may be treated with high dose Co-Trimoxazole during investigation

Patients with proven Pneumocystis jirovecii infection should be treated with high dose Co-Trimoxazole for 14 days (longer if clinically required).

This must be given intravenously (IV) at first but can be changed to oral once the patient is clinically stable.
 
In moderate to severe Pneumocystis jirovecii infections where supplemental oxygen is required adjuvant prednisolone (12,13) is given orally at a dose of 2mg/kg (max 80mg) for 5 days, the dose is then gradually reduced over the next 16 days and then stopped. Alternatively hydrocortisone can be given parenterally (see BNFc for more detail).

Corticosteroid treatment should ideally be started at the same time as the anti-pneumocystis therapy and certainly no later than 24 to 72 hours afterwards.

Alternative agents, when Co-Trimoxazole is contra-indicated, are listed in Appendix 2.

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Appendix 1: PCP Prophylaxis Dose Recommendations

Drug

Dose Calculation

Route

Frequency

Surface area

Dose

Co-trimoxazole

<0.5m2

24mg/kg

oral

Twice daily on 2 consecutive days per week

0.5-0.75m2

240mg

0.76-1m2

360mg

>1m2

480mg

Dapsone*

Children
>1month

2mg/kg daily (up to a maximum of 100mg daily)

 

oral

Once daily

4mg/kg weekly (up to a maximum of 200mg weekly)

oral

Once weekly

Pentamidine* +

Age
5 - 18years

300mg

nebulised

Once every 4 weeks

150mg

nebulised

Once every 2 weeks

Atovaquone

 

oral

 

NOTES: * = Does not cover S. Pneumonia and toxoplasma . + = Topical (lung) Rx. May lead to unusual or extra pulmonary PCP infection.

Dapsone
From Paediatric Formulary 8th Edition - Dapsone PCP prophylaxis orally >1month - 1mg/kg/day up to 100mg
From BNFC 1month -18years 2mg/kg once daily (max 100mg)
From Martindale - In children from 1 month of age the recommended dose of dapsone is 2 mg/kg daily (to a maximum of 100 mg daily) or 4 mg/kg weekly (to a maximum of 200 mg weekly).6

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Appendix 2: PCP Treatment Dose Recommendations

Drug

Dose Calculation

Route

Frequency

Additional Information

Co-trimoxazole

Child
1 month -
18 years

60mg/kg every
12 hours for 14 - 21 days

Oral
or
IV infusion

Twice daily (every 12 hours)

Give every 12 hours for a total of 14 to 21 days
(total daily dose may alternatively be given in 3 - 4 divided doses

 

Dapsone

Children
1 month -
12 years

2mg/kg daily (up to a maximum of 100mg daily)

 

oral

Once daily

 

Child
13 - 18 years

100mg

oral

Once daily

Pentamidine

Age
1 month -
18 years

4mg/kg

Intravenous infusion

Once daily

 

Pneumocystis species demonstrate a high degree of host species specificity. Those infecting humans have been named P. jirovecii, whilst P. carinii refers to those infecting rats.

Provenance

Record: 4138
Objective:

Aims

To improve the diagnosis and management of Pneumocystis jiroveci infection in children and young people immunosuppressed through malignant disease or marrow failure

Objectives

To provide evidence-based recommendations for appropriate diagnosis, investigation and management of Pneumocystis jiroveci infection

Clinical condition:

Pneumocystis jirovecii infection

Target patient group: Children and young people with cancer and related conditions at risk of infection
Target professional group(s): Secondary Care Doctors
Adapted from:

Evidence base

  1. Edman JC, Kovacs JA, Masur H, Santi D V, Elwood HJ, Sogin ML. Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. Nature. 1988 Aug 11;334(6182):519–22.
  2. Vargas SL, Hughes WT, Santolaya ME, Ulloa A V, Ponce CA, Cabrera CE, et al. Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2001 Mar 15;32(6):855–61.
  3. Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics. 1978 Jan;61(1):35–41.
  4. Su YS, Lu JJ, Perng CL, Chang FY. Pneumocystis jirovecii pneumonia in patients with and without human immunodeficiency virus infection. J Microbiol Immunol Infect. Dec 2008;41(6):478-82.
  5. Hughes WT, Kuhn S, Chaudhary S, Feldman S, Verzosa M, Aur RJ, et al. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. The New England journal of medicine. 1977 Dec 29;297(26):1419–26.
  6. Hughes WT, Feldman S, Aur RJ, Verzosa MS, Hustu HO, Simone J V. Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis. Cancer. 1975 Dec;36(6):2004–9.
  7. Temozolomide. Summary of Product Characteristics
  8. El-Sadr WM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med 1998; 339: 1889–95. PubMed
  9. Chan C, et al. Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides. J Infect Dis 1999; 180: 369–76. PubMed
  10. Hughes WT, et al. Comparison of atovaquone and azithromycin with trimethoprim-sulfamethoxazole for the prevention of serious bacterial infections in children with HIV infection. Clin Infect Dis 2005; 40: 136–45. PubMed
  11. Bennett, NJ. Overview of Pneumocystis jirovecii Pneumonia . Medscape 225976, Dec 2013.
  12. Briel M, Bucher H, Boscacci R, Furrer H. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD006150.
  13. BNFc (Jan 2015) 5.4.8 Drugs for pneumocystis pneumonia https://www.medicinescomplete.com/mc/bnfc/current/PHP13133-treatment.htm

References and Evidence levels:
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

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