What Is New in Pulmonary Mucormycosis?

Abstract

Mucormycosis is a rare but life-threatening fungal infection due to molds of the order Mucorales. The incidence has been increasing over recent decades. Worldwide, pulmonary mucormycosis (PM) presents in the lungs, which are the third main location for the infection after the rhino-orbito-cerebral (ROC) areas and the skin. The main risk factors for PM include hematological malignancies and solid organ transplantation, whereas ROC infections classically are classically favored by diabetes mellitus. The differences between the ROC and pulmonary locations are possibly explained by the activation of different mammalian receptors-GRP78 in nasal epithelial cells and integrin β1 in alveolar epithelial cells-in response to Mucorales. Alveolar macrophages and neutrophils play a key role in the host defense against Mucorales. The diagnosis of PM relies on CT scans, cultures, PCR tests, and histology. The reversed halo sign is an early, but very suggestive, sign of PM in neutropenic patients. Recently, the serum PCR test showed a very encouraging performance for the diagnosis and follow-up of mucormycosis. Liposomal amphotericin B is the drug of choice for first-line therapy, together with correction of underlying disease and surgery when feasible. After a stable or partial response, the step-down treatment includes oral isavuconazole or posaconazole delayed release tablets until a complete response is achieved. Secondary prophylaxis should be discussed when there is any risk of relapse, such as the persistence of neutropenia or the prolonged use of high-dose immunosuppressive therapy. Despite these novelties, the mortality rate from PM remains higher than 50%. Therefore, future research must define the place for combination therapy and adjunctive treatments, while the development of new treatments is necessary.

Keywords: Epidemiology; Mucorales; pulmonary mucormycosis; review; treatment.

Figure 1

Summary of pulmonary mucormycosis: underlying diseases, sites of infection, physiological defenses against pulmonary invasion and diagnostic methods from the bedside. Physiological defenses in brief: alveolar macrophages can uptake Mucorales spores and restrict iron (Fe), which is essential for spore germination, resulting in spore persistence inside macrophages or their killing by defense mechanisms. On the other hand, integrin-β1 expressed on alveolar epithelial cells can recognize CotH7 on spores, facilitating spore internalization-germination. These germinating spores are recognized by neutrophils, which produce defensive molecules [cytokines, antimicrobial peptides (AMP), reactive oxygen species (ROS) or perforins] that result in hyphal damage. On the other hand, spores germinate in presence of Fe (both inside and outside macrophages) and invade endothelial cells resulting in invasion.

Figure 2

Images of pulmonary mucormycosis. (A) Reversed halo sign (indicated with an arrow) in a patient with hematological malignancy; (B) Reversed halo sign HS (arrow) in a patient with COVID-19; (C) Cavitation (arrow) in a condensation in a patient with COVID-19 and lung tumor.

Figure 3

Macroscopic aspect of Mucorales. Incubation at 30 °C on 2% malt extract (MEA) or potato dextrose agar (PDA). (A) Lichtheimia ramosa on MEA at day 2. (B) Rhizopus microsporus on PDA at day 6. (C) Lichtheimia corymbifera on PDA at day 6. (D) Mucor velutinosus on PDA at day 6.

Figure 4

Histological lesions in pulmonary Mucormycosis. (A) Focal well-delineated lesion, centred on arteries and veins of medium calibre (black arrows), characterized by vascular alterations associated with peripheral alveolar oedema, acute hemorrhages, ischemic necrosis, and minimal inflammation (pulmonary infarction) (HE staining). (B) Higher magnification of vascular lesions: thrombi and destruction of vascular wall (black arrowheads), associated with alveolar hemorrhages, oedema and minimal inflammation (mostly neutrophils) (HE staining). (C) Hyaline, pleomorphic hyphae are detected in the lesions; very often invading vascular spaces (pink arrowheads). Hyphae are irregular in size (from 3 to 25 µm in diameter), folded, rarely septate (pauciseptate), branching (at right angles) with a ribbon-like morphology, and could be highlighted using Grocott’s Methenamine Silver staining, or immunohistochemistry (inset; primary antibody: GeneTex GTX39191; WSSA-RA-1). Used with kind permission from G. Jouvion. Reproduced from New developments in Mucormycosis, Semin Respir Crit Care Med 2015; 36: 692–705 (Publisher Georg Thieme Verlag KG).

Figure 5

Legend Summary of PM management. * Reevaluation at week 1 should be done with caution. A paradox-ical worsening is possible after neutrophil recovery and should not be considered as a progression of the disease.