[CUHK Medical Grand Rounds] A lady with pulmonary mucormycosis
Presentation, history and investigations
Our patient was a 40-year-old lady who was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukaemia in October 2017. She was treated with chemotherapy (UKALL regimen; phase I induction: daunorubicin, vincristine, L asparaginase, prednisolone and intrathecal methotrexate; phase II induction: cyclophosphamide, cytarabine, 6-mercaptopurine and intrathecal methotrexate and methotrexate) and imatinib. Unfortunately, she was found to have disease relapse in May 2018, requiring a course of second-line chemotherapy (FLAG-IDA regimen consisting of fludarabine, cytarabine, idarubicin and granulocyte colony-stimulating factor) together with the second-generation tyrosine kinase inhibitor, dasatinib. Her treatment was complicated with recurrent episodes of bloodstream infection (by both Gram-positive and Gram-negative organisms). Eventually, she received chimeric antigen receptor T-cell therapy in mainland China in November 2018 and was then referred for haemopoietic stem cell transplantation (HSCT) in December 2018.
She presented to Prince of Wales Hospital in December 2018 with acute-onset fever and left pleuritic pain. Physical examination revealed high-grade fever, tachycardia, tachypnoea and reduced breath sounds over her left hemithorax. Chest radiograph showed opacity over the left middle zone. Pancytopenia with an absolute neutrophil count of <0.1 x 109 cells/L was noted.
The patient was started on empirical antibiotic therapy with piperacillin and tazobactam. However, neutropenic fever persisted and repeated chest radiographs showed no improvement either. Multiple broad-spectrum antibiotics and antifungals (meropenem, linezolid, cotrimoxazole, amikacin, amphotericin B, voriconazole, and micafungin) were given, without clinical response. CT of the thorax was arranged and revealed a gas-containing, rim-enhancing, cavitatory lesion over the left upper lobe, with surrounding consolidative changes. Bronchoalveolar lavage and aspiration of the lesion yielded old blood-stained fluid only, and culture was negative.
Left upper lobectomy was required for controlling the infection. Histology of the resected lung tissue showed consolidated lung with alveolar space filled with mixed inflammatory cells and cellular debris. Fungal elements that were angio-invasive with broad hyaline nonseptated hyphae which branched at right angles were also seen. Rapid-growing colonies resembling the appearance of cotton candy were noted on the culture medium, and were identified to be Mucor species. A course of liposomal amphotericin B was given, with satisfactory clinical response achieved. The patient subsequently underwent HSCT in March 2019 with posaconazole prophylaxis.
Mucormycosis, also known as zygomycosis, is a rare but potentially life-threatening fungal infection caused by a group of related molds (Mucorales), which include species in the genera of Mucor, Rhizopus, Rhizomucor, Absidia and Cunninghamella. It usually affects immunocompromised individuals such as those with poorly controlled diabetes mellitus (especially those with ketoacidosis) or haematological malignancy. Iron overload (eg, due to frequent blood transfusions in those with thalassaemia major or other haematological diseases) is another well recognized predisposing factor as Mucorales use free iron as a growth factor.1
Mucormycosis typically manifests as acute-onset, aggressive, angio-invasive infections with two common forms: rhino-orbito-cerebral or pulmonary. Dissemination through contiguous structures or haematogenous route may sometimes occur. Breakthrough mucormycosis can be seen in patients receiving antifungal prophylaxis, particularly with agents other than posaconazole. A high index of suspicion is of paramount importance for the diagnosis of mucormycosis as its clinical presentation is similar to that of Aspergillosis infection, which is more commonly seen.1
Of note, commonly used biomarkers such as 1,3-β-D-glucan and galactomannan are not useful for detecting antigen components of the Mucorales cell wall. Biopsy and culture of specimens from sites of involvement are frequently required for establishing the diagnosis. Characteristic broad, ribbon-like, thin-walled, aseptate hyphae with irregular branching can usually be seen in histopathologic examination, sometimes accompanied by surrounding tissue necrosis or evidence of fungal angio-invasion due to the strong tropism for blood vessels of Mucorales.2,3
The keys to successful treatment of mucormycosis include early diagnosis and early initiation of appropriate antifungal therapy, surgical debridement of involved tissue whenever possible, and reduction or reversal of immunosuppression if possible. Unlike Aspergillus, Mucorales are not susceptible to commonly used antifungal prophylaxis (eg, itraconazole, voriconazole) in patients with haematological malignancies. Amphotericin B (including lipid formulations) or posaconazole are the treatments of choice. The issue with amphotericin B, however, is its requirement of intravenous administration and side effects including infusion reactions and nephrotoxicity. The latter can be lessened by the use of lipid formulations (eg, liposomal amphotericin B). Posaconazole is available in oral formulations, which makes it an attractive option for step-down therapy or prophylaxis. However, its suspension formulation requires co-administration with a standard high-fat diet to enhance absorption. Its erratic absorption and, as a result, unpredictable serum drug levels necessitate therapeutic drug monitoring. In recent years, delayed-release tablets and intravenous formulations of posaconazole have been developed and are expected to solve the above problems. Isavuconazole is a newer azole antifungal approved by the US FDA for the treatment of mucormycosis. It is not registered in Hong Kong at the moment.2,3
Early initiation of appropriate antifungal therapy is of vital importance as treatment delays are associated with increased mortality. However, even with effective antifungal therapy, control of mucormycosis may remain suboptimal due to its angio-invasive nature and the susceptibility of the infected hosts. Surgical debridement of involved tissues is therefore frequently necessary and should always be considered whenever possible to achieve optimal therapeutic effect. Nevertheless, this may sometimes be challenging due to disease factors (eg, involvement of sinuses or cerebral cortex) or host factors (eg, bleeding tendency due to severe thrombocytopenia or coagulopathy). Similarly, reduction or reversal of immunosuppression is often difficult, if not impossible.2,3
The duration of antifungal treatment for mucormycosis is not well defined. In general, treatment should be continued till resolution of clinical and radiological changes of infection is achieved. Secondary prophylaxis may also be required for those who remain at risk of the infection (eg, HSCT recipients pending engraftment). 2,3