Fungal Infections

Corticosteroids and fungal infection

Corticosteroids (glucocorticoids) have been used in medicine since the end of the 1950’s. There are several related corticosteroids including prednisolone, prednisone, methylprednisolone, dexamethasone and hydrocortisone being the most frequently used oral agents. Parenteral (intravenous or intramuscular) steroids include hydrocortisone, methylprednisolone and dexamethasone. Inhaled or nasal corticosteroids include beclometasone, fluticasone, budesonide, mometasone and ciclesonide. Many different corticosteroids are used on the skin including hydrocortisone, betamethasone, clobetasol, clobetasone/clobetasol, diflucortolone, fluocinolone, flucononide, desoximetasone, fluocortolone, fluticasone, flurandrenolide, mometasone, halcinonide and triamcinolone. see review

The potency of steroids varies by compound. An approximation of potency is shown in this table.

Name

Glucocorticoid potency

Hydrocortisone (Cortisol)

1

Cortisone acetate

0.8

Prednisone

4

Prednisolone

4

Methylprednisolone

5 - 7.5

Dexamethasone

25 - 80

Fludrocortisone acetate

15

For corticosteroids applied to the skin the relative potency can been seen here  and also here.

Risks of invasive fungal infection with steroids

Invasive aspergillosis

Among 228 renal transplant recipients[1], a case control study revealed the impact of higher doses of prednisolone on acquisition of invasive aspergillosis.

Prednisolone dose

Invasive aspergillosis (%)

No invasive aspergillosis (%)

>1.25mg/Kg

8 (89)

8 (33)

<1.25mg/Kg

1 (11)

16 (67)

P = 0.0057

In 331 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)[2]. 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[3]. Cumulative prednisone receipt of >700 mg in the 3 months prior to admission was associated with the occurrence of invasive aspergillosis in COPD patients[4].  There are many other examples of increased risk of invasive aspergillosis after corticosteroids.

Candidaemia and invasive candidiasis

Corticosteroids are a risk factor for candidaemia and invasive candidiasis. Premature neonates treated for hypotension with corticosteroids developed invasive candidiasis 7.5-fold more often than those not receiving corticosteroids[5]. Breakthrough candidaemia was associated with corticosteroid therapy (53%) compared with non-breakthrough candidaemia (23%)[6]. Corticosteroids predispose patients undergoing surgery, including transplant surgery, those on haemodialysis for acute renal failure, HSCT and those with SLE to candidaemia. Some species differences are apparent for risk of infection.

Pneumocystis pneumonia (PCP)

Corticosteroids are a key risk factor in ~90% of patients with cancer who develop PCP, if not given co-trimoxazole (trimethoprim + sulphamethoxazole) prophylaxis. In particular, PCP often follows high dose dexamethasone given for brain tumours[7].  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[8].

Cryptococcal meningitis and infection

Cortisone acetate reduces the ability of alveolar macrophages to attach to and ingest C. neoformans, the chemotactic activity of cerebrospinal fluid 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

Disseminated histoplasmosis is associated with corticosteroid treatment, notably in SLE and cancer. Prednisone treatment >20 mg/day or prior therapy with corticosteroids are risk factors[9].

Mucormycosis

Cumulative prednisone dose of >600 mg prior to infection predisposes cancer patients to zygomycosis[10] and methylprednisone dose of 2–7 g was associated with mucormycosis after liver or pancreas-kidney transplantation[11]. 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%)[12]. Corticosteroids make these people susceptible by reducing the function of macrophages and neutrophils, and/or steroid induced diabetes.

Worse outcomes in patients with invasive fungal infection continuing on corticosteroids

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 similar patients who received a cumulative prednisolone dose of <7 mg/kg (12%)[13]. Among 94 patients with multiple underlying diseases with invasive aspergillosis, use of corticosteroid therapy increased the risk of dying 10.6-fold[14].

A daily prednisone-equivalent dose of 30 mg administered for 12 weeks (median) was clearly associated with a worse outcome from Pneumocystis pneumonia[15].

Relapse of cryptococcal meningitis was intimately associated with continuing corticosteroid therapy (at least 20mg prednisone-equivalent daily) after antifungal therapy has stopped[16].

Corticosteroids are associated with a worse outcome from disseminate Fusarium infection; 70% versus 33% mortality in haematological cancer patients receiving and not receiving glucocorticoids respectively[17].

Dexamethasone in acute cryptococcal meningitis in AIDS produces slower sterilisation of the CSF and overall a worse outcome Beardsley J et al, NEJM 2016;374:542-54

Better outcomes with adjunctive corticosteroids in treatment with antifungal therapy

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[18]. 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.

Corticosteroids are also important in the management of several other fungal infections.

  • Exacerbations of allergic bronchopulmonary aspergillosis (ABPA) 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.
  • Topical corticosteroids combined with topical antifungal therapy are valuable in reducing the inflammatory component of seborrheic 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.


[1] Gustafson TL, Schaffner W, Lavely GB, Stratton CW, Johnson HK, Hutcheson RH Jr. Invasive aspergillosis in renal transplant recipients: correlation with corticosteroid therapy. J Infect Dis 1983;148:230-8.

[2] O’Donnell MR, Schmidt GM, Tegtmeier BR, et al. Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin prophylaxis in high-risk patients. J Clin Oncol 1994;12:827–34.

[3] Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002;100:4358–66.

[4] Guinea J, Torres-Narbona M, Gijón P, Muñoz P, Pozo F, Peláez T, de Miguel J, Bouza E. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect. 2010;16:870-7.

[5] Botas CM, Kurlat I, Young SM, Sola A. Disseminated candidal infections and intravenous hydrocortisone in preterm infants. Pediatrics 1995;95:883–87.

[6] Kontoyiannis DP, Reddy BT, Hanna H, Bodey GP, Tarrand J, Raad II. Breakthrough candidemia in patients with cancer differs from de novo candidemia in host factors and Candida species but not intensity. Infect Control Hosp Epidemiol 2002;23:542–45.

[7] Slivka A, Wen PY, Shea WM, Loeffler JS. Pneumocystis carinii pneumonia during steroid taper in patients with primary brain tumors. Am J Med 1993; 94: 216–19.

[8] Porges AJ, Beattie SL, Ritchlin C, Kimberly RP, Christian CL Patients with systemic lupus erythematosus at risk for Pneumocystis carinii pneumonia. J Rheumatol 1992; 19: 1191–14.

[9] Hansen KE, St Clair EW. Disseminated histoplasmosis in systemic lupus erythematosus: case report and review of the literature. Semin Arthritis Rheum 1998;28:193–99.

[10] Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KV. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis 2000;30:851–56.

[11] Jimenez C, Lumbreras C, Aguado JM, et al. Successful treatment of Mucor infection after liver or pancreas-kidney transplantation. Transplant 2002;73: 476–80.

[12] Petrikkos G, Skiada A, Lortholary O, et al. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 2012 ; 54 (S1) : S23-34.

[13] Ribaud P, Chastang C, Latge JP, et al. Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis 1999;28:322–30.

[14] Kiertiburanakul S, Thibbadee C, Santanirand P. Invasive aspergillosis in a tertiary-care hospital in Thailand. J Med Assoc Thai 2007;90:895-902.

[15] Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clinic Proceedings 1996;71:5–13.

[16] Diamond RD, Bennett JE. Prognostic factors in cryptococcal meningitis. A study in 111 cases. Ann Intern Med 1974;80:176–81.

[17] Nucci M, Anaissie E, Queiroz-Telles, et al. Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer 2003;98:315–19.

[18] Briel M, Boscacci R, Furrer H, Bucher HC. Adjunctive corticosteroids for Pneumocystis jirovecii pneumonia in patients with HIV infection: a meta-analysis of randomised controlled trials. BMC Infect Dis 2005;5:101.

 

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