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Invasive Disease Due to Mucorales: a Case Report and Review of The REVIEW ARTICLE CK Yeung VCC Cheng Invasive disease due to Mucorales: AKW Lie a case report and review of the KY Yuen literature ○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○ !"#$#%&'()*+, Objective. To review the mycology, pathogenesis, clinical characteristics, investigations, and treatment modalities of mucormycosis. Data sources. A local case of mucormycosis; MEDLINE and non-MEDLINE search of the literature. Study selection. Key words for the literature search were ‘mucormycosis’ and ‘Mucorales’; all available years of study were reviewed. Data extraction. Original articles, review papers, meta-analyses, and relevant book chapters were reviewed. Data synthesis. Mucormycosis is a fungal infection that is rare but increas- ingly recognised in the growing population of immunocompromised patients. It is caused by saprophytic non-septate hyphae of the order Mucorales. The pulmonary and disseminated forms commonly occur in patients with haematological malignancy, especially acute leukaemia and lymphoma, and those receiving treatment with immunosuppressive effects. The rhinocerebral form is more prevalent in patients with diabetes mellitus, particularly those with the complication of diabetic ketoacidosis. The use of amphotericin B combined with surgery remains the mainstay of treatment. The prognosis largely depends on prompt correction of the underlying risk factors. New Key words: strategies to combat this life-threatening infection will result from better Amphotericin B; understanding of its pathogenesis. Diabetes mellitus; Conclusion. A high index of suspicion is needed, in appropriate clinical Immunosuppression; settings, to diagnose and aggressively treat this infection in view of the Leukemia; high mortality rate for susceptible patients. Mucormycosis !"#$%"&'(#)*'+,-.'/0123456 ! ! B ! !" !"#$%&%'(MEDLINE MEDLINE !" ! !" !"#$%& !"# !"#"$%&' ! !" !" #$%&'()*+ !" !"#$%& '(!)* +,-./0123 HKMJ 2001;7:180-8 !"#$%&'()*+,-./.0123456&789%+: The University of Hong Kong, Queen Mary !"#$%&'()*+,-./01234567,89:;0& Hospital, Pokfulam, Hong Kong: Division of Haematology, Department of !"( !"#$%&'()) !"#$ %&'()*+ Medicine !"#$%&'()"*+,-./01#2345672801# CK Yeung, MB, BS, MRCP AKW Lie, MRCP, FHKAM (Medicine) !"#$%&'()*+,-./B !"#$%&'()*+ Division of Infectious Diseases, Department !"#$%&'()*+,-./0123456789:;<=> of Microbiology VCC Cheng, MB, BS, MRCP !"#$%&'()*+,-./0%"1"234 KY Yuen, MRCPath, MD !"#$%&'()*+,-./012-3456&78 Correspondence to: Dr KY Yuen !"#$%&'()*+,-./01234567 180 HKMJ Vol 7 No 2 June 2001 Invasive disease due to Mucorales Introduction 150-450 x109 /L]. Bone marrow examination confirmed acute monoblastic leukaemia-M5. Blood culture grew Mucormycosis is an opportunistic fungal infection Salmonella enteritides (group D). caused by a filamentous fungus.1,2 The infection is relatively uncommon but cases are being recognised The patient was given intravenous cefoperazone- early and treated effectively with a combination of sulbactam 1 g twice daily for 14 days and ciprofloxacin antifungal agents and surgery, leading to improved 200 mg twice daily for 5 days. Induction chemotherapy survival.1,3 The increasing prevalence of mucormyco- including cytarabine 190 mg daily for 7 days and sis is due to wider use of cytotoxic chemotherapy and daunorubicin 95 mg daily for 3 days was started on immunosuppressive agents, resulting in a more severe day 9 of admission to hospital. Six days after chemo- and prolonged immunocompromised state.4 Risk factors therapy, he developed a neutropenic fever, with a for mucormycosis include haematological malignancy, temperature of 38.8°C, which did not respond to broad- namely leukaemia and lymphoma, diabetes mellitus, spectrum antimicrobial therapy. Examination for especially in poorly controlled patients and those sepsis, including blood culture, sputum, and urine with complications of diabetic ketoacidosis.2 The analysis was negative. Two days later, he was noted to use of steroids and immunosuppressive agents in have blood-tinged sputum, associated with increasing bone marrow and solid organ transplantation,5 broad- shortness of breath. Repeated chest X-rays showed spectrum antibiotics and cytotoxic chemotherapy, enlarging multiple round lesions in both lung fields. and dialysis for uraemic patients, particularly with Antimicrobial therapy was reviewed and imipenem, desferrioxamine therapy, are known predisposing amikacin, and amphotericin 0.7 mg/kg/d were com- causes.1,5-7 Malnutrition in children in developing menced on the same day. countries also carries a risk of mucormycosis with gastrointestinal involvement, and cerebral mucormy- The patient further deteriorated with acute respira- cosis has been reported in intravenous drug user via tory distress, arterial hypoxaemia, and systemic hypo- the haematogenous route.7 Thus, the infection is tension requiring mechanical ventilation and intensive often an indication of a serious predisposing condition. care. Bronchoscopy was performed, which showed This review focuses on the epidemiology, present- diffuse inflammation of the bronchial mucosa. Apart ing signs and symptoms, diagnosis, treatment, and from scanty enterococci recovered from bronchoal- new directions in the approach to management of veolar lavage (BAL), the concentrated BAL smear mucormycosis. showed numerous broad, non-septated hyphae with wide-angled branching, suggestive of mucormycosis, Case report and fungal culture of the specimen later yielded Cunninghamella bertholletiae. The diagnosis was A 57-year-old HIV-negative Filipino presented with pneumonia due to Cunninghamella spp. Despite fever and prostration. He had a known history of poorly increasing the dose of liposomal amphotericin to controlled non–insulin-dependent diabetes mellitus, 3 mg/kg/d, he developed multiorgan failure and managed with self-administered oral hypoglycaemic finally died 24 hours later. Tissue invasion by fungal agents for 18 months. On admission, his fasting blood hyphae and the presence of disseminated infection glucose and glycosylated haemoglobin (HbA1c) were could not be confirmed by histology, as his relatives 10.3 mmol/L (normal range, 3.9-6.1 mmol/L) and did not consent to autopsy. 11.4% of total haemoglobin (normal range, 4-7% of total haemoglobin), respectively. On admission, he Discussion had a fever (temperature, 39.2°C), chills, and rigor. Examination showed a grossly overweight patient with Mycology fever, sternal tenderness, and borderline hypotension. Mucormycosis is an infection caused by ubiquitous Chest radiography was unremarkable. Peripheral fungal agents of the order Mucorales.2 The fungi blood smear revealed blasts and a leucoerythroblastic occur in air, soil, and food and are filamentous con- picture (white blood cell count, 4.9 x 109 /L [normal sisting of broad irregular hyphae of 15 to 20 mm in range, 3.2-9.8 x 109 /L]; neutrophil count, 0.83 x 109 /L diameter, mostly non-septated with right-angled [normal range, 1.8-7.8 x 109 /L]; lymphocyte count, branching (Fig). The infection is commonly due to 2.16 x 109 /L [normal range, 1.0-4.8 x 109 /L]; blast Rhizopus, Rhizomucor, Absidia, and Mucor from the count, 1.67 x 109 /L [normal range, 0 x 109 /L]; haemo- family of Mucoraceae and, rarely, C bertholletiae globin level, 115 g/L [normal range, 140-175 g/L]; caused by Cunninghamellaceae (Table 1). Differen- and a platelet count of 61 x 109 /L [normal range, tiation among these genera is based on the morphology HKMJ Vol 7 No 2 June 2001 181 Yeung et al neutrophils. A study has shown that the combined effects of diabetes, ketosis, and low pH negated the in- hibitory property of serum towards spore germination.10 Investigators have demonstrated that the fungistatic activity of serum is caused by the presence of trans- ferrin in the serum, which reduces the free iron avail- able to the fungus for growth.10 Acidosis temporarily disrupts the capacity of transferrin to bind iron in the serum, thereby reducing the host inhibition of fungal growth. The presence of a ketoreductase in the fungi may allow them to utilise ketone bodies in their me- tabolism, accounting for the increased susceptibility in diabetic ketoacidosis. Waldorf,11 however, could not Fig. Microscopic view of fungal hyphae detect any significant differences in germination of Rhizopus oryzae between normal and diabetic sera of the asexual cycle, physiologic characteristics, and with the addition of iron that saturated the total iron- zygospore production.2 The fungi are aerobic organ- binding capacity, nor with the addition of sufficient isms that grow in most culture media after 2 to 5 days transferrin to bind all free serum iron. Reduced neu- of incubation at temperatures of 25°C to 55°C, pro- trophil chemotaxis and adhesion to hyphae in diabetes ducing fluffy white, grey, or brownish colonies.2 Posi- mellitus have been demonstrated.12 Alveolar macro- tive growth is highly suggestive of infection in relevant phages in diabetes are also defective in inhibition of clinical settings, although it is not diagnostic owing to spore germination and hyphae damage.11,13 Desferri- occasional colonisation.8 Histological examination oxamine therapy for patients undergoing dialysis is showing tissue invasion by this fungus is diagnostic. associated with mucormycosis.7 The fungus can accu- mulate iron to stimulate growth by utilising desferri- Pathogenesis oxamine as a siderophore.7,14 These combined effects Rhinocerebral and pulmonary mucormycosis is an air- of acidosis and desferrioxamine accumulation in borne
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