Corticosteroids

Corticosteroids have a complicated role as either a risk factor or a treatment for many fungal diseases. Patients taking high doses of corticosteroids on a long-term basis are particularly at risk – particularly HSCT recipients and patients with autoimmune disorders like SLE.

Particular care should be taken when prescibing corticosteroids for eye inflammation because it can worsen a fungal infection

Prednisone

Corticosteroid treatment as a risk factor for fungal infections

Lionakis and Kontoyiannis (2003) provide an in-depth review of the immunological changes caused by glucocorticoids and how they can predispose a patient to different fungal infections

Invasive aspergillosis

  • There are many examples of increased risk of invasive aspergillosis after corticosteroids.
  • A case-control study of 228 renal transplant recipients revealed the impact of higher doses of prednisolone on acquisition of invasive aspergillosis (Gustafson et al, 1983).
  • In 33 recipients of allogeneic stem cell (bone marrow) transplants (HSCT), use of high-dose prednisone (0.5–1.0 mg/kg per day) increased invasive aspergillosis and other fungal infections six-fold compared with regimens with low dose prednisone (0.25 mg/kg per day)(O’Donnell et al, 1984).
  • Prednisone doses of <1.9 mg/kg, 1.9–3.0 mg/kg and >3 mg/kg daily were associated with a risk of aspergillosis of 5%, 10%, and 14%, respectively in the late post-bone-marrow-transplant period (Marr et al, 2002).
  • Cumulative prednisone receipt of >700 mg in the 3 months prior to admission was associated with the occurrence of invasive aspergillosis in COPD patients (Guinea et al, 2010).  

Candidaemia and invasive candidiasis

  • Corticosteroids increase the risk of cutaneous and mucosal candidiasis by 5 times, particularly during the first few weeks of treatment (Fardet et al, 2016)
  • Premature neonates treated for hypotension with corticosteroids developed invasive candidiasis 7.5-fold more often than those not receiving corticosteroids (Botas et al, 1995).
  • Breakthrough candidaemia was associated with corticosteroid therapy (53%) compared with non-breakthrough candidaemia (23%) (Kontoyiannis et al, 2002).
  • The risking of dying of invasive candidiasis after surgery in increased by 50% in patients on corticosteroids (Klingspor et al, 2015)
  • Corticosteroids predispose patients undergoing surgery, including transplant surgery, those on haemodialysis for acute renal failure, HSCT and those with SLE to candidaemia.

Pneumocystis pneumonia (PCP)

  • Corticosteroids are a key risk factor in ~90% of patients with cancer who develop Pneumocystis pneumonia (PCP), if not given co-trimoxazole (trimethoprim + sulphamethoxazole) prophylaxis. In particular, PCP often follows high dose dexamethasone given for brain tumours (Slivka et al, 1993).
  •  Likewise corticosteroids with or without chemotherapy are a risk factor for PCP in patients with chronic lymphocytic leukaemia, with chronic graft-versus-host disease following HSCT, and nonmalignant conditions such as autoimmune disorders, especially SLE and Wegener’s granulomatosis. A median daily dose of 40 mg prednisone in patients with SLE is associated with development of PCP (Porges et al, 1992).

Cryptococcal meningitis and infection

  • Cryptococcal meningitis and infection. Cortisone acetate reduces the ability of alveolar macrophages to attach to and ingest C. neoformans, the chemotactic activity of CSF toward PMNs and monocytes and impairs microglial (brain macrophage) function. Corticosteroids predispose non-AIDS patients with cancer or sarcoidosis and HSCT and solid-organ transplant recipients to cryptococcosis. Corticosteroids are not helpful for raised intracranial pressure in patients with cryptococcal meningitis.

Histoplasmosis

Mucormycosis

  • Cumulative prednisone dose of >600 mg prior to infection predisposes cancer patients to zygomycosis (Kontoyiannis et al, 2000) and methylprednisone dose of 2–7 g was associated with mucormycosis after liver or pancreas-kidney transplantation (Jimenez et al, 2002). Patients with lupus erythematosus, auto-immune disease, Wegener granulomatosis, when treated with high-dose of steroid for a long time, are at increased risk of mucormycosis especially disseminated form and the mortality rate is very high (88%)(Petrikkos et al, 2012). Corticosteroids make these people susceptible by reducing the function of macrophages and neutrophils, and/or steroid induced diabetes.

Worse outcomes in HSCT recipients who continue on corticosteroids during invasive fungal infections

  • The risk of dying with or of invasive aspergillosis was higher (80%) in HSCT recipients who received a cumulative prednisolone dose of >7 mg/kg in the week before infection, compared with 12% of similar patients who received a cumulative prednisolone dose of <7 mg/kg (Ribaud et al, 1999).
  • Among 94 patients with multiple underlying diseases with invasive aspergillosis, use of corticosteroid therapy increased the risk of dying 10.6-fold (Kiertiburanakul et al, 2007).
  • A daily prednisone-equivalent dose of 30 mg administered for 12 weeks (median) was clearly associated with a worse outcome from Pneumocystis pneumonia (Yale & Limper, 1996).
  • Relapse of cryptococcal meningitis was intimately associated with continuing corticosteroid therapy (at least 20 mg prednisone-equivalent daily) after antifungal therapy has stopped (Diamond & Bennett, 1974).
  • Corticosteroids are associated with a worse outcome from disseminated Fusarium infection; 70% versus 33% mortality in haematological cancer patients receiving and not receiving glucocorticoids respectively (Nucci et al, 2003).
  • Dexamethasone in acute cryptococcal meningitis in AIDS produces slower sterilisation of the CSF and overall a worse outcome (Beardsley et al, 2016).

Benefits of corticosteroids as an adjunct to antifungals

  • Pneumocystis pneumonia (PCP) : several randomised studies have shown that adjunctive corticosteroids improve survival of patients with PCP in AIDS. The overall reduction in mortality was 46% at 1 month and 33% at 3-4 months of follow-up (Briel et al, 2005). The impact was greatest if antiretroviral therapy cannot be given. The need for mechanical ventilation is also reduced by adjunctive corticosteroids. This effect is not clearly seen in non-HIV patients who develop PCP, possibly because corticosteroids are the major risk factor for disease.
  • ABPA: exacerbations of allergic bronchopulmonary aspergillosis are typically treated with oral steroids. Inhaled corticosteroids are important for management of the underlying asthma, and may reduce the frequency of acute exacerbations. Inhaled corticosteroids reduce mortality from asthma.
  • Allergic fungal rhinosinusitis: patients are treated post-surgery with oral and/or local steroid, probably with benefit.
  • Dermatology: topical corticosteroids combined with topical antifungal therapy are valuable in reducing the inflammatory component of seborrhoeic dermatitis and kerion (tinea capitis).
  • Mulch pneumonitis: in chronic granulomatous disease appears to respond better to a combination of antifungal therapy (such as voriconazole) and adjunctive corticosteroids.

Choosing a corticosteroid

Read more about equivalent oral doses at the British National Formulary. Read more about equivalent topical strengths at the British National Formulary or Psoriasis.org

FORMULATIONAVAILABLE CORTICOSTEROIDS
Parenteral (IV or intramuscular) hydrocortisone, methylprednisolone, dexamethasone
Inhaled / intranasal beclomethasone, fluticasone, budesonide, mometasone, ciclesonide
Oral prednisolone, prednisone, methylprednisolone, dexamethasone, hydrocortisone
Topical hydrocortisone, betamethasone, clobetasol, diflucortolone, fluocinolone, fluocinonide, desoximetasone, fluocortolone, fluticasone, flurandrenolide, mometasone, halcinonide, triamcinolone
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