Consider, for sake of completeness, the superficial fungal infections which are often more nuisance value than sinister.
Superficial
- Tinea versicolor – Testing rarely indicated; MCS fungal (Malassezia furfur) of skin scrapings in doubtful cases.
- Dermatophytic
- Tinea (including ringworm) – MCS fungal of skin scrapings, hair, nail clippings as appropriate. Skin biopsy only occasionally indicated.
By contrast, deep fungal infections are invasive diseases that often present insidiously in the already unwell or immunocompromised and are notoriously difficult to eradicate.
Deep, disseminated (Invasive)
Investigations/specimens: May require any or all of Blood, Cerebrospinal fluid examination, urine, sputum, tissue biopsy or body fluid – MCS fungal. Histopathology. Cryptococcal Ag (serum and CSF) if indicated. Dimorphic fungal infections are geographically confined, but should be considered after travel history obtained.
- Predisposing factors include
- Neutropenia
- Neutrophil dysfunction
- Immunodeficiency
- Diabetes mellitus – If mucormycosis suspected: urgent lesion biopsy and sterile fluid, MCS fungal, consult pathologist.
- Malignancy
- Intravenous drug abuse
- Broad spectrum antibiotic therapy
- Indwelling catheter or prosthesis
Candida Infection
Although Candida albicans is the most common cause of invasive candidiasis, infections due to more frequently resistant non-albicans Candida species account for an increasing proportion of cases. A delay of more than 24 h before the commencement of systemic antifungals in the setting of candidemia and septic shock is associated with a near 100% mortality rate (Ben-Ami R., J Fungi 4(3); 2018, 97. doi:10.3390/jof4030097).
Treatment algorithm for patients with suspected or confirmed invasive candidiasis (incl. optional Candida scoring). Echinocandin indicates caspofungin, micafungin, or anidulafungin. BDG: (1,3)-β-d-glucan; LFAMB: lipid formulation of amphotericin B; CVC: central venous catheter.
CVC removal is associated with higher rates of treatment success, lower mortality rates.
Major issue with therapy is potential for renal impairment, minimised by reducing concomitant exposure to other potentially nephrotoxic drugs and pre-hydration with saline. Alternatively, Voriconazole is used for initial treatment of proven acute invasive aspergillosis in the immunocompromised patient. Fluconazole (400 mg/day) may be an alternative if mould infection remains clinically unlikely and the drug not previously administered for prophylaxis.
Amphotericin B nephrotoxicity or pre-existing renal impairment: allow serum creatinine to rise to 0.23 mmol/L before ceasing conventional amphotericin B except in patients where renal failure is expected to complicate management of underlying condition. Subsequent therapy will depend on clinical setting. Other settings prompting use of alternative agents include treatment for moulds less susceptible to amphotericin B, such as Scedosporium prolificans, S. apiospermum, Fusarium spp., Zygomycetes.
The real potential remains for early targeted treatments with novel antifungal agents based on molecular diagnostics.
Candidiasis – Pathological approach
Location/Site of Infection
- Local sites: If diagnosis is in doubt, send specimen from lesion for fungal microscopy and culture (MCS fungal).
- Mucous membranes: swab for microscopy and culture for fungi (yeasts)
- Oral
- Vaginal
- Skin: nail skin scrapings and nail clippings (MCS fungal); biopsy is rarely required.
- Cornea: corneal scraping or biopsy; prior arrangements must be made with the pathologist for direct inoculation into culture media (MCS fungal).
- Systemic Infections: Blood culture, MCS urine, Cerebrospinal fluid examination (as appropriate), MCS fungal tissue biopsy.
Associations
- Antibiotic therapy
- Diabetes mellitus
- Neutropenia
- Immunodeficiency – chronic candidiasis should always be confirmed by microscopy and culture (MCS fungal) and underlying causes of recurrent candidiasis excluded. The underlying immune deficits are variable and testing can include lymphocyte proliferative response, lymphocyte immunophenotyping, lymphokine production.
- HIV infection – Chronic mucocutaneous candidiasis
- Autoimmune polyendocrinopathy
- Polyglandular autoimmune syndrome (type 1)
- particular association with hypoparathyroidism
- Polyglandular autoimmune syndrome (type 1)
- Iron deficiency (severe)
- Vitamin B12 deficiency
- Folate deficiency
Aspergillosis
Invasive aspergillosis is the most common mould infection in immunocompromised hosts.
Spectrum of aspergillosis disease as a function of immunosuppression. With decreasing cell-mediated immunity, the likelihood of invasive disease increases.
Risk factors for invasive aspergillosis include (Patterson, TF, UpToDate Apr 5, 2021.):
• neutropenia
• glucocorticoids
• hematopoietic cell transplantation
• solid organ transplantation (particularly lung transplantation)
• biologic agents
• pulmonary diseases
• critical illness
Amphotericin B remains the empiric treatment of choice for invasive fungal infections. Dose of amphotericin B: for a
- yeast infection (e.g. candidiasis) – 0.7 mg/kg/day
- except C. krusei and C. glabrata: 1 mg/kg/day
- mould infection (e.g. aspergillosis) – 1 mg/kg/day
Histoplasmosis
Histoplasmosis is caused by a fungus, Histoplasma capsulatum, found in soil with high organic content and undisturbed bird and bat droppings, like that about old chicken houses, bat caves, and pigeon roosts. People become infected with after breathing in the microscopic fungal spores from the air. Yet over 90% of infected people remain asymptomatic; a few develop only a mild lung infection; while in others it can spread (disseminated histoplasmosis) and cause severe, life threatening illness. Immunocompromised people, such as those with HIV or those who have had an organ transplant, are at risk of these severe complications.
Investigations: MCS sputum, MCS bronchoalveolar lavage, bronchial brush, wash. Lung biopsy. Blood culture. Bone marrow biopsy (aspiration with culture). Tissue biopsy, but the organism is seldom grown from fibrotic lesions in the mediastinum or from histoplasmomas. HIV serology (with consent and counselling), as the length of treatment and the prognosis will be different in patients with AIDS. See also AIDS.
Pathological classification:
- Acute primary pulmonary/mediastinal granulomatosis
- Histoplasmomas
- Chronic pulmonary infection
- Progressive disseminated infection
- Acute
- Subacute
- Chronic
- Histoplasma capsulatum var duboisii
- African histoplasmosis – Biopsy, with microscopy and culture, of skin lesion, subcutaneous nodule, bone abscess, lymph node, as appropriate.
African histoplasmosis caused by Histoplasma capsulatum var. duboisii is an important deep mycosis endemic in Central and West Africa and Madagascar characterized by granulomatous skin and subcutaneous tissue lesions and in bones. Lungs and other internal organs are rarely involved. The natural reservoir of the etiological agent has only been recently discovered in a bat cave in Nigeria, with local skin and serum reactivity suggestive of frequent prevalence of asymptomatic infections due to H. capsulatum var. duboisii among the residents in the vicinity of the cave micro-focus of the fungus. The exact portal of entry into the body is not known, but inhalation into the lungs and direct inoculation in the skin have been incriminated (Gugnani and Muotoe-Okafor, Rev Iberoam Micol 14(4); 1997, 155).
Melioidosis
Endemic in SE Asia and northern Australia. The clinical illness may be acute, sub-acute or chronic; reactivation of latent infection may occur. Localised infection may progress rapidly to septicaemia. Blood culture, MCS sputum, Wound swab, Throat swab, Rectal swab, urine (males) or tissue biopsy; Burkholderia pseudomallei Ab are of only limited clinical utility.
Acute
- Wound infection
- Pneumonia
- Septicaemia
Chronic
- Abscess – common sites include skin, lymph node, bone, brain, lung, myocardium and liver
- Lung infection – chronic cavitating infection, which may be difficult to distinguish clinically from tuberculosis.
Mucormycosis
Most mucormycosis infections occur as severe sinus and facial infections associated with diabetic ketoacidosis and neutropenia occasioning life-threatening rhino-cerebral extension and pulmonary infection. A ketone reductase of Rhizopus organisms allows them to thrive in high glucose, acidic conditions. Genera most commonly found in human infections are Rhizopus, Mucor, and Rhizomucor; Cunninghamella, Absidia (now Lichtheimia), Saksenaea, and Apophysomyces are genera less commonly implicated in infection. Lack of regular septations contributes to hyphal fragility and difficulty growing the fungal agents of mucormycosis from clinical specimens (Cox, Gary M., “Mucormycosis (zygomycosis),” UpToDate Jan 4, 2021).
Investigations: Lesion biopsy, with fungal microscopy and culture to identify causative organism. To grow mucor species a cube of tissue of at least 1 cm on all sides is required to grow these rarely septate fungi. In addition to Rhizopus, Mucor, and Absidia, human diseases due to Rhizomucor, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum sp. have all been confirmed. Fusarium spp. can cause a similar clinical syndrome. Early lesion biopsy for definitive diagnosis is essential: the pathologist must be consulted urgently. See also Infection (increased susceptibility).
Janelle Trees, in August’s Diabetes Management Journal, reports that:
CoVid-19 infection, in combination with diabetes and corticosteroids is now essentially considered a triple-whammy for Mucormycosis, rhinoorbital-cerebral and pulmonary mucormycosis cases sharply increased during India’s second wave of COVID mid-year. Mucormycosis is angioinvasive, providing a pathophysiological link with CoVid-19, with
infarction of infected tissue a hallmark of the disease. CoVid-19 has also been associated with opportunistic
fungal infections, including Candida and Aspergillus. The hypoxic, hyperglycaemic, and acidic environment created by SARS-CoV-2, with associated high ferritin and low white-cell count, promotes the growth of mucormycosis. Without prompt treatment, dissemination of the fungus is fast and potentially devastating within 12 hours- historically, around half of diagnoses are post-mortem.
- Diabetes mellitus – Mucormycosis may occur in Type 1 DM with ketoacidosis
- Post-renal transplantation
- Cytotoxic therapy, especially acute leukaemia
Treatment involves early and aggressive surgical debridement combined with intravenous amphotericin-B.
References
Ben-Ami, Ronen. “Treatment of Invasive Candidiasis: A Narrative Review.” Journal of fungi (Basel, Switzerland) vol. 4,3 97. 16 Aug. 2018, doi:10.3390/jof4030097.
Cox, Gary M., “Mucormycosis (zygomycosis),” UpToDate. Jan 4, 2021. https://www.uptodate.com/contents/mucormycosis-zygomycosis.
“Fact sheet: Histoplasmosis.” Version 1. Queensland Health. Nov 11, 2015. http://disease-control.health.qld.gov.au/condition/770/histoplasmosis.
Gugnani HC, Muotoe-Okafor F. African histoplasmosis: a review. Rev Iberoam Micol 14(4); 1997: 155-9. PMID: 15538817.
Panackal, Anil A., Bennett, John E., and Williamson, Peter R. “Treatment options in Invasive Aspergillosis.” Curr Treat Options Infect Dis 6(3); 2014: 309-325. doi:10.1007/s40506-014-0016-2.
Patterson, Thomas F. “Treatment and prevention of invasive aspergillosis.” UpToDate. Apr 5, 2021. https://www.uptodate.com/contents/treatment-and-prevention-of-invasive-aspergillosis.
RCPA Manual. “Candidiasis.” The Royal College of Pathologists of Australasia. Oct 31, 2014. Available at http://www.rcpa.edu.au/Library/Practising-Pathology/RCPA-Manual/Items/Clinical-Problems/C/Candidiasis.
Slavin, Monica A., Szer, Jeff; Grigg, Andrew P., Roberts, Andrew W., Seymour, John F., Sasadeusz, Joseph; Thursky, Karin; Chen, Sharon C., Morrissey, C. Orla; Heath, Christopher H., Sorrell, Tania and the Mycoses Interest Group of Australasian Society for Infectious Diseases. :Guidelines for the use of antifungal agents in the treatment of invasive Candida and mould infections.” Intern Med J. 2004 Apr;34(4):192-200. doi: 10.1111/j.1444-0903.2004.00541.x. Erratum in: Intern Med J. 2004 Nov;34(11):657.
Trees, Janelle. “Lethal Mucormycosis Upsurge in India.” Diabetes Management Journal. Aug 2021.
