A 45-year-old male with a history of a renal transplant 3 years ago, currently on tacrolimus, mycophenolate and prednisolone is admitted to your ICU with pulmonary infiltrates, hypoxia and worsening renal function.

a)    What are the potential infectious causes of the respiratory failure? Justify what empirical antimicrobial treatment you would commence.    (50% marks)

b)    Describe how you would manage his immunosuppressive therapy.    (50% marks)
 

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College answer

  1. Infectious causes: Most likely to be bacterial (e.g. Strep pneumo); however as is immunosuppressed patient consider and cover possible additional causative agents:
    • Bacteria most likely cause
      • Risk of bronchiectasis from mycophenolate → if this may be colonised with Pseudomonas aeruginosa needing cover
      • Early commencement of broad spectrum antibiotics with Pseudomonas coverage as per local sensitivity patterns (e.g. pip-taz, meropenem)
    • Viral pneumonia
      • Esp. influenza/RSV/adenovirus → oseltamivir
      • CMV pneumonia/pneumonitis – less common now with prophylaxis and at 3 years post-transplant; would not routinely investigate for unless other clinical suspicion or high risk (i.e. no prophylaxis immediately after transplant, prophylaxis recently stopped, donor +ve/recipient -ve). Treat with gancyclovir
    • Fungal – Pneumocystis jirovecii (PJP) very common if not on prophylaxis (trimethoprim- sulfamethozazole) –if clinical suspicion treats with Bactrim; otherwise ensure continue prophylaxis even if other cause identified
  1. Management of anti-rejection drugs & immunosuppression
    • Tacrolimus – needs levels monitored; many interactions with other agents including anti- microbials →; if tacrolimus continued dose will likely need to be reduced in renal failure
    • Consider ceasing all anti-rejection drugs and managing with steroids alone during septic period
    • May require stress-dose steroids if septic irrespective of other anti-rejection drug management (i.e. risk of adrenal insufficiency on prednisone)
    • Risk of neutropaenia with mycophenolate + tacrolimus – if present may need to be reduced or ceased during acute infection + G-CSF

Examiners Comments:

Some candidates answered only part of the question. The relevance of the immunosuppression was not appreciated in some answers and a generic list of infectious causes was given.

Discussion

The most likely infectious causes are:

Typical bacteria:

  • Classical community-acquired organisms eg. S.pneumoniae and Haemophilus
  • Gram-negatives, eg. Pseudomonas and Klebsiella

Atypical bacteria:

  • Mycoplasma species, including tuberculosis
  • All the usual community-acquired atypicals (eg. M.pneumoniae, the Chlamydias, Legionella, etc)

Viral

  • Influenza
  • "Common cold" viruses, eg. RSV, parainfluenza, etc
  • CMV

Fungal

  • Pneumocystis jirovecii
  • Aspergillus sp.

Is there any data regarding infectious causes of pulmonary infiltrates in the renal transplant recipient? Sure. Kalra et al (2005) lists multiple organisms, and in fact in most patients several species were simultaneously involved. Tuberculosis, PJP, Candida albicans and swarms of Enterobacteriacea were mentioned. However, these were patients from New Delhi, and so their microbial enemies may differ from those of the Norwegian transplant patients.

Justify your antibiotic choice? Well. 

  • Piperacillin/tazobactam would cover most Gram-positive and Gram-negative nasties
  • Azithromycin would take out any atypicals, apart from TB
  • Bactrim (trimethoprim/sulfamethoxazole) at a "treatment dose", as the risk of PJP is very high
  • The patient is on enough T-cell toxins to have a reasonable risk of viral pneumonitis, and if the suspicion was high enough, ganciclovir could be commenced to cover CMV. Oseltamivir probably has all the therapeutic benefits of coconut water, but the college wanted us to mention it as well. 

Now, how to manage the immunosuppressants. Three major issues are present:

  1. The patient is septic; and
  2. Renal function is impaired, but
  3. The graft is precious and must survive

The KDIGO Clinical practice guideline for the care of kidney transplant recipients and the Australian adaptation thereof are actually somewhat useless for this purpose. Fortunately, there are some good free articles out there (eg. Bafi et al, 2017), as well as paywalled ones (Kalil et al, 2007). In short:

  • Reduction in the immunosuppression is desirable. However:
    • Graft rejection can occur, particularly in renal transplant recipients (hearts and livers seem to be ok with a period of reduced dose immunosuppression)
    • An immune reconstitution syndrome may develop
    • Abrupt cessation of the steroids is obviously undesirable
  • Thus:
    • Continue the steroids, and consider increasing the dose, particularly if the patient is haemodynamically unstable
    • Cease the mycophenolate temporarily 
    • Omit the tacrolimus until the next serum tacrolimus level is available
    • Test levels regularly, as renal function influences clearance.

References

Kalra, Vikram, et al. "Spectrum of pulmonary infections in renal transplant recipients in the tropics: a single center study." International urology and nephrology 37.3 (2005): 551-559.

Bafi, Antônio Tonete, Daniere Yurie Vieira Tomotani, and Flávio Geraldo Rezende de Freitas. "Sepsis in solid-organ transplant patients." Shock 47.1S (2017): 12-16.

Kalil, Andre C., H. Dakroub, and Alison Gail Freifeld. "Sepsis and solid organ transplantation.Current drug targets 8.4 (2007): 533-541.