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Pneumocystis Jirovecii (carinii) prophylaxis and pneumonia (PCP)

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Prophylaxis for Pneumocystis carinii/jirovecii

Pneumocystis jirovecii (formerly known as Pneumocystis carinii), is a yeast-like fungus of the genus Pneumocystis and is the causative organism of Pneumocystis pneumonia (PCP). PCP occurs in ~20% of patients with ALL who are not on prophylaxis. The infection is extremely unusual in patients who are compliant with Cotrimoxazole prophylaxis. The risk is also diminished in those receiving monthly IV Pentamidine or Dapsone, but is probably greater than those who take Cotrimoxazole. The risk of PCP is attributed to chronic immunosuppression and lymphocytopenia, not the severity of neutropenia.

Pneumocystis prophylaxis is recommended for all children on chemotherapy or immunosuppressive therapy for their cancer and children with severe aplastic anaemia.

Those at high risk include:

  • Heavily pretreated patients
  • Relapsed disease
  • Moderate to high dose steroids (often in combination with chemotherapy) for periods longer than 4 weeks
  • Post autologous stem cell transplant (Cotrimoxazole should start when neutrophils > 1.0 x109/L and platelets >50x109/L and continue for 6 months)
  • Post allogeneic stem cell transplant (Cotrimoxazole should start when neutrophils > 1.0 x109/L and platelets >50x109/L and continue for 12 months)
  • Patients with GvHD until they have been off immunosuppression for 3 months.
  • Regimens using lymphocyte depleting agents (alemtuzumab) or where CD4 count is <200 cells/uL and those receiving CNS irradiation.

Pneumocystis pneumonia (PCP) prophylaxis should start with the initiation of chemotherapy.

Prophylaxis with Cotrimoxazole

Cotrimoxazole (Trimethoprim (TMP) and Sulphamethoxazole (SMX) in 1:5 ratio) is the gold standard for prophylaxis and treatment of PCP.

The prophylactic dose of Cotrimoxazole, as the combined product, is 15mg/kg (or 2.5mg/kg of TMP) twice daily on two consecutive days i.e. Saturday and Sunday. For children who prefer tablets, round the dose up to the nearest ½ tablet. See Table 1 below.

(Note: The optimal dose schedule for TMP-SMX is not clear due to limited studies comparing regimens in patients with malignancy therefore in children, various regimens are acceptable including once- or twice-weekly prophylaxis or 3 non-consecutive days per week may be of equal efficacy, based on retrospective and observational studies.)

Starship Blood and Cancer, Auckland and CHOC, Christchurch have agreed to continue with twice weekly dosing. This is also in keeping with COG study recommendations. Whichever regimen is used, cotrimoxazole prophylaxis must not be stopped or missed (for example during C.difficile diarrhoea) and efforts to help compliance such as including into chemotherapy blister packs and on lists of medications should be used.

However Cotrimoxazole should not be administered with or close to the administration of intermediate or high dose Methotrexate. The combined use can increase the risk of Methotrexate toxicity.

Withhold Cotrimoxazole for at least 24 hours prior to the administration of intermediate or high dose Methotrexate infusions. Restart the Cotrimoxazole at least 72 hours after start of the Methotrexate infusion or the Methotrexate level is less than 0.4umol/L. If the child is a slow excretor of Methotrexate, restart Cotrimoxazole when Methotrexate levels are less than 0.1umol/L. What this means practically is that the oral cotrimoxazole will only be given to children receiving intermediate or high dose methotrexate when the child is at home.

Table 1 Cotrimoxazole

Alternative PCP Prophylaxis

If cotrimoxazole is not tolerated (neutropenia, drug reaction, patients with G6PD deficiency),or patient unable to tolerate oral medications then use pentamidine or dapsone. Close monitoring without PCP prophylaxis may be considered in low risk patients.

Pentamidine

Intravenous Petamidine is second line for PCP prophylaxis. Nebulised Pentamidine is not used due to occupational exposure of staff during administration.

Table 2 Alternative PCP prophylaxis

Pneumocystis Jirovecii (carinii) Pneumonia

Clinical features

  • fever
  • cough
  • tachypnoea (very characteristic rapid shallow breathing)
  • absence of signs on auscultation (unless patient is fluid-overloaded)
  • hypoxaemia
  • lymphopenia
  • CXR classically with diffuse bilateral shadowing (this may be normal in the early stages). CT scan chest is usually abnormal.

Laboratory investigations for suspected PCP

Investigations need to be specifically requested for Pneumocystis - bronchial washings are the best specimen.

  • Induced sputum (obtained after nebulised hypertonic saline) may be appropriate in older children particularly when BAL not possible. Occasionally sputum/tracheal aspirate can also be used 
  • Urgent Pneumocystis stain is performed (please specify and notify the laboratory of this sample being sent. Turn around time is 3 hours)
  • Pneumocystis PCR may be able to be performed on NPA/sputum (needs to be requested/discussed with laboratory)
  • Other investigations for an immunocompromised patient with respiratory illness will include:
    • Sputum/cough swab - microscopy, culture and sensitivities for bacteria, fungi, mycobacteria in older children.
    • Multiplex PCR of NPA/sputum for respiratory and other viruses including influenza, parainfluenza, adenovirus, RSV, herpes simplex, CMV, human metapneumovirus, bocavirus and enterovirus and atypical pathogens (legionella, pertussis, chlamydia, mycoplasma)
    • Urinary antigen  for Legionella +/- pneumococcal urinary antigen depending on age of child (much less specific in child aged < 5 years)

(Note Most of the legionella in New Zealand is L. longbeachae for which there is no urinary antigen test)  

Treatment

  • Commence high-dose IV cotrimoxazole
  • Dose 30mg/kg (combined) or TMP 5mg/kg every 6 hours as soon as BAL or specimens collected. ( doses as per NZFc)
  • Continue for 3 weeks with a minimum of 5 days intravenously if PCP is confirmed or without an alternative diagnosis.
  • Steroids should be used for those with moderate to severe disease such as hypoxia in room air <92% and/or requiring high dependency or intensive care respiratory support.
  • Should deterioration occur despite high-dose cotrimoxazole, carefully control fluid balance to avoid fluid overload and discuss with infectious disease for consideration of adding a second line therapy such as pentamidine intravenously (4mg/kg IV daily) or clindamycin and primaquine (Atovoquone often used, but not available in New Zealand as a single agent, only as a combined agent for malaria Atov-proguanil or Malarone).

Infection Control

Standard precautions although not with other immune compromised patients due to potential for person to person spread.

References

  • Levy E, Musick L, Zinter M et al. Safe and effective prophylaxis with biMonthly intravenous pentamidine in the pediatric hematopoietic stem cell transplant population. Ped Inf Dis J 25:2 135-141 2016
  • Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database of Systematic Reviews 2014, Issue 10 
  • Cooley L, Dendle C, Wolf J, The W, Chen S, Boutlis C, Thursky K. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies. Internal Medicine Journal 44 (2014) 
  • Terblanche AJ1, Green RJ, Rheeder P, Wittenberg DF Adjunctive corticosteroid treatment of clinical Pneumocystis jiroveci pneumonia in infants less than 18 months of age-a randomised controlled trial. S Afr Med J. 2008 Apr;98(4):287-90 
  • Smego et al : A Meta-Analysis of Salvage therapy for PCP. Arch Int Med 2001 161
  • Sleasman, J. W., Hemenway, C., Klein, A. S. & Barrett, D. J.Corticosteroids improve survival of children with AIDS and Pneumocystis carinii pneumonia. American Journal of Diseases of Children 1993 147, 30-4
  • New Zealand Formulary for children (NZFc) May 2016- release 47
  • British National Formulary for children (BNFc) 2009
  • Medsafe New Zealand Medicines and Medical Devices Safety Authority. Data Sheet Information for Health Professionals. www.medsafe.govt.nz/profs/datasheet
  • Royal Children's Hospital Melbourne. Paediatric Pharmacopeia. 13th Edition 2002
  • Ablin, Arthur; Supportive Care of Children with Cancer, 2nd Ed, 1997
  • Supportive Care Guidelines from current COG ALL Protocols

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Document Control

  • Date last published: 19 May 2016
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network, Paediatric Infectious Diseases, Paediatric Haematology/Oncology
  • Author(s): Jane Skeen, Radhika Sandilya
  • Owner: Jane Skeen
  • Review frequency: 2 years