Favourable outcome in a child with acute lymphoblastic leukaemia and pulmonary mucormycosis managed with combination antifungal therapy of liposomal amphotericin B and caspofungin

Abstract

Pulmonary mucormycosis (PM) accounts for more than half the cases of mucormycosis in paediatric haematological malignancies, with mortality reaching as high as 90%. Surgical debridement of lesion along with liposomal amphotericin B (L-AMB) constitutes the mainstay of management of mucormycosis and offers best chances of survival. There are no reliable data available in the literature justifying the use of combination antifungal therapy (CAfT). We describe a child with acute lymphoblastic leukaemia (ALL) who developed multiple localised PM during induction chemotherapy. He was managed with CAfT with L-AMB and caspofungin in view of progressive PM on high-dose L-AMB monotherapy. There was complete resolution of PM after 6 months of CAfT at the end of intensive chemotherapy of ALL. There were no significant side effects of CAfT. CAfT may be of value in cases of mucormycosis refractory to high doses of L-AMB, where surgical debridement is not feasible.

Background

Mucormycosis is an invasive fungal infection seen in around 2.2% of paediatric haematological malignancies, and the incidence seems to be rising in recent times.¹ Pulmonary mucormycosis (PM) comprises about half the total cases of mucormycosis in haematological malignancies. It is a dreadful disease associated with 50%–100% mortality depending on dissemination and underlying immunosuppression.^{2 3} Surgical debridement of lesion along with liposomal amphotericin B (L-AMB) constitutes the mainstay of management of mucormycosis. Posaconazole or isavuconazole is an add-on antifungal agent. There is no consensus on the use of combination antifungal therapy (CAfT) in mucormycosis.⁴ The role of CAfT, especially a rarely used combination of polyene and echinocandins, is controversial, with some studies favouring it while others refuting any significant impact on mortality.^{5 6} We describe a child with acute lymphoblastic leukaemia (ALL) who developed PM during induction phase chemotherapy. Due to progression of PM on L-AMB monotherapy and due to non-availability of posaconazole in market, he was offered combination therapy with L-AMB and caspofungin. He had complete resolution of PM after 6 months of CAfT.

Case presentation

A 6-year-old boy presented with fever, generalised lymphadenopathy and hepatosplenomegaly. He had bicytopenia (haemoglobin of 63 g/L, platelet count of 17 ×10⁹ /L) with a total leucocyte count of 19×10⁹ /L and peripheral blood film showing 58% blasts. He was diagnosed as having B-cell ALL on bone marrow examination. Cerebrospinal fluid examination did not show blasts. He was started on standard risk Berlin-Frankfurt-Munster (BFM) protocol with prednisolone of 60 mg/m². On day 7 of steroids, there was a recurrence of fever. He had a respiratory rate (RR) of 32/min and bilateral scattered crepitations in lung fields. The oxygen saturation (SpO₂) was maintained. Further chemotherapy was withheld and he was managed as febrile neutropenia with empirical parenteral antibiotics as per unit protocol.

Investigations and treatment

His chest X-ray was suggestive of bilateral non-homogeneous opacities in middle and lower zones. A contrast-enhanced CT scan of the chest revealed multiple (more than 10) soft tissue density nodules and cavitatory lesions with surrounding ground glass opacities suggestive of fungal pneumonia (figure 1A, B). Serum galactomannan index was 0.46 (<0.5 is normal). CT of the paranasal sinus, ultrasonography of the abdomen and two-dimensional echocardiography to look for disseminated fungal disease were normal. Blood culture was sterile. He was started on L-AMB at 3 mg/kg/day and escalated to 5 mg/kg/day once the CT-guided biopsy of lung lesion conformed morphology of mucormycosis. Culture of aspirate from the lesion was sterile. In view of persistent symptoms and high C reactive protein (CRP) of 13 mg/L (normal: 0.8–3 mg/L), the dose of L-AMB was further escalated to 8 mg/kg/day. During this time, definitive chemotherapy for ALL was withheld and he was managed with supportive therapy. A CT of the chest repeated after 4 weeks of L-AMB revealed a progression in the size and number of lung lesions (figure 1C, D). Tachypnoea was persistent (RR of 28), there was no hypoxia and repeat CRP was rising (15 mg/L). In view of progression and due to non-availability of posaconazole or isuvaconazole, caspofungin at a dose of 50 mg/m² was added to L-AMB. After 3 weeks of combination antifungal therapy, the tachypnoea settled and CRP decreased to 5 mg/L. There was significant resolution in size and number of fungal lesions (figure 1E, F). Meanwhile, due to recurrence of blasts on peripheral blood film, he was restarted on induction chemotherapy with two-thirds of doses of standard risk Indian Childhood Collaborative Leukemia Group protocol which has four doses of vincristine 1.5 mg/m², four doses of L-asparginase 10 000 units/m² and prednisolone 60 mg/m² for 4 weeks.⁷ Post-induction minimal residual disease (MRD) was high (0.03%). Subsequently, he was managed with BFM induction phase II with 75% of doses, high-dose methotrexate for four doses at 3 g/m² and 75% of doses of reinduction protocol. MRD at induction II was negative (<0.01%). He was monitored with CT of the chest at the beginning of each intensive protocol. Serial CT of the chest had shown regression of lung lesion and normalisation of CRP. At the start of maintenance cycle, CAfT was stopped and prophylactic oral posaconazole was started as it had become available in market by now. There were no significant side effects noticed for CAfT on periodic monitoring of renal and liver function tests.

Figure 1.

(A, B) Contrast-enhanced CT (CECT) of the chest showing multiple cavitating nodules in bilateral lung. These cavities show mural non-dependent contents within. (C, D) Follow-up CECT of the chest (after 4 weeks of above) showing increase in size of the nodules with increase in solid components inside the cavities. Some of the nodules have coalesced to form area of consolidation. (E, F) Follow-up CECT of the chest (after 3 weeks of above) showing decrease in size and number of soft tissue density nodules and cavitatory lesions. Significant resolution in consolidation is also seen.

Differential diagnosis

Diagnosis of mucormycosis is most frequently based on histopathological demonstration of aseptate to pauciseptated, non-pigmented, broad ribbon-like fungal hyphae with right angle branching in appropriate clinical setting. Aspergillus species are thinner and septate with acute angle branching. Mucorale hyphae are fragile and frequently get damaged during sample collection, leading to poor yield (one-third) in culture samples.⁸ Pulmonary lesions more than 10 in number on CT of the chest favour a diagnosis of mucormycosis over pulmonary aspergillosis.⁹ Biopsy of lung lesion in index child on H&E stain and Groccott stain revealed aseptate, non-pigmented, broad ribbon-like fungal hyphae conforming to morphology of mucormycosis (figure 2A–C). The index child thus had histological evidence of mucormycosis with negative fungal culture and supporting radiological findings. A negative galactomannan assay also favoured diagnosis of mucormycosis over aspergillosis.

Figure 2.

(A) Photomicrograph of lung biopsy showing linear core of lung parenchyma with marked interstitial expansion (H&E stain, 4×). (B) Photomicrograph of lung biopsy showing dense mixed inflammatory infiltrate with the presence of aseptate, non-pigmented, broad ribbon-like fungal hyphae conforming to morphology of mucormycosis (H&E stain, 40×). (C) Photomicrograph of lung biopsy showing dense mixed inflammatory infiltrate with the presence of aseptate, broad ribbon-like fungal hyphae (black coloured) conforming to morphology of mucormycosis (Groccott stain, 40×).

Outcome and follow-up

Presently the child is on maintenance chemotherapy with 6-mercaptopurine and methotrexate along with prophylactic posaconazole as per unit protocol.⁷ He is on monthly follow-up with clinical examination and complete blood count. He is being closely followed up for early signs of pneumonia or ALL relapse.

Discussion

Haematological malignancies including stem cell transplant, prolonged neutropenia, chronic steroid use and diabetes mellitus constitute the main risk factors for mucormycosis.¹⁰ PM accounts for more than half the cases of mucormycosis in paediatric haematological malignancies. It is subclassified into localised if confined to lungs, deep extension if mediastinal structures are involved and disseminated if other distant organs are affected.¹¹ The mortality in PM accounts for around 76% of cases in non-disseminated and more than 90% in disseminated cases.¹²

Surgical debridement of lesion along with L-AMB, which is a polyene group antifungal agent, constitutes the mainstay of management of mucormycosis and offers best chances of survival.¹³ L-AMB with a median dose of 5 mg/kg/day (range, 3–15 mg/kg/day) is the backbone of mucormycosis pharmacotherapy, especially if the lesion cannot be removed surgically. In refractory disease, higher doses of L-AMB along with the use of posaconazole or isuvaconazole, an azole group antifungal as add-on drug, are recommended.⁴ In the index child, due to multiple intraparenchymal nodules, surgical debridement was not feasible. Despite a higher dose of L-AMB, there was a progression in PM. Add-on drug posaconazole or isuvaconazole was not available in the market due to surge in mucormycosis cases in complicated patients with COVID-19. Therefore, a CAfT with L-AMB plus caspofungin was started.

CAfT with a differing mechanism of action probably increases the efficacy of individual antifungal agent by minimising resistance and thereby reducing the duration of treatment.¹⁴ The literature on the use of CAfT is limited and controversial. CAfT, mainly polyene plus azole, was found to be effective (response rate of 86% vs 41% after 30 days, p=0.04) compared with polyene therapy alone in seven paediatric and adult cases of rhino-orbital-cerebral mucormycosis in a diabetic cohort.⁵ A larger cohort of 106 adults with haematological malignancies did not find a significant difference in 6-week mortality on the use of CAfT, which was predominantly polyene plus azole (43% vs 41%, p=0.85).⁶ Similar results were seen in a historical cohort study comprising adult patients.¹⁵ In the above-mentioned studies, CAfT of L-AMB and caspofungin was rarely used. In 19 children of predominantly rhino-cerebral mucormycosis with haematological malignancies, CAfT (L-AMB plus echinocandins in 7 of 19 children) did not significantly reduce the mortality.¹ Because of limited sample size in varied subjects, non-uniform inclusion criteria, varying combination of antifungals, different end points, retrospective design and association with different risk factors, it is not possible to draw any meaningful and generalisable conclusion regarding the benefit of CAfT from the above studies. Therefore, the value of CAfT remains unclear, and latest guidelines on the management of mucormycosis do not recommend CAfT routinely.⁴ Index case highlights the utility of CAfT (polyene plus echinocandins) in cases of mucormycosis where surgical debridement is not feasible. Further studies are required to justify the use of CAfT in refractory mucormycosis.

Learning points.

• Pulmonary mucormycosis accounts for more than half the cases of mucormycosis in paediatric haematological malignancies, with mortality reaching as high as 90%.

• Surgical debridement of lesion along with a higher dose of liposomal amphotericin B (L-AMB) constitutes the mainstay of management of mucormycosis and offers best chances of survival.

• There are no robust data and recommendations favouring the use of combination antifungal therapy in mucormycosis.

• Combination antifungal therapy (L-AMB and caspofungin) may be of value in cases of mucormycosis refractory to high doses of L-AMB, where surgical debridement is not feasible.

Ethics statements

Patient consent for publication

Parents/Guardians consent obtained.