Mucormycosis

Mucormycosis是由粘膜真菌引起的罕见感染。通常，人类免疫系统具有抵御我们身体的模具的能力。然而，在免疫功能低下的患者中，粘膜菌病非常危险，通常以高死亡率结束。一些国家最近看到这些mycoses的兴起，最常见于中性粒细胞减少症患有血液学疾病的患者，其死亡率很高。
mucormycosis

Mucormycosis causal agents

The order Mucorales holds 261 species, comprising 55 genera.Rhizopusspp。，，地衣spp。，，andMucorspp. account for two-thirds of medically important Mucorales genera. From these, around 38 Mucorales species are connected with human infections. The most frequent mucormycosis agents are地衣corymbifera, L. ornate, L. ramose, Mucor ardhlaengiktus, M. circinelloides, M. griseocyanus, M. irregularis, M. janssenii, M. lusitanicus, Rhizopus arrhizus,R. microsporus.The most commonly isolated species worldwide is根霉arrhizus(formerlyR. oryzae) (1–4).

诊断粘膜细胞增多

The most certain way to diagnose mucormycosis infection is to visualize the characteristic hyphae in tissue, sputum, exudates or scrapings, sampling, and cultivating the fungus in the laboratory. Sporangia are seldomly found, and the diagnosis is usually based on visual detection of hyphae. Mucorales fungi can be seen in infected tissues as erratically shaped, 6–25 mm in diameter (0.2–1.0 inches), non-septate, right-angle branching hyphae (Fig. 1）。Non-septate hyphae with characteristic branching are the most prominent traits which prevent the misidentification of infectious Mucorales fungi with other frequent mycosis-causing species such asAspergillusspp. orCandidaspp. Mucorales species are vasculotropic fungi (attacking blood vessels), and therefore hyphal infiltrations can often be found near blood vessels of the primary infected organs.

引起的皮肤Mucor irregularis
Figure 1. a) Cutaneous mucormycosis caused by Mucor irregularis; b) M. irregularis hyphae (Photo source: Ran Yuping et al. 2015,Wikipedia）。

As mucormycosis is a rare disease, premortal diagnosis can be difficult. For instance, in a review study on 116 leukemia cases with pulmonary filamentous fungal infections, the correct diagnosis was made before death in only 10% percent of the patients. Similarly, in a review study of 37 hematological cancer patients with histologically documented mucormycosis, the right diagnosis was made only 35% of patients before the fatal outcomes (4–6).

幸运的是，已经开发了专门的分子工具，可显着改善对该疾病的正确和及时诊断。内部转录的垫片（ITS）区域是真菌的最广泛测序的DNA区域。它在不同的物种中是高度保守的，可以用作遗传条形码。它是可靠的，快速的，并且通常被推荐为粘膜识别的一线方法（2,7）。

感染

The initial step of infection usually starts with the inhalation of fungal spores (Fig. 2）。粘膜菌病也可以从伤口感染开始，甚至有时与静脉滥用药物有关。吸入的真菌孢子可能会沉积在上呼吸道中，或者穿过肺肺泡。健康的生物可以抗击这些入侵者，因为肺泡巨噬细胞可以防止孢子发芽。然而，在免疫功能低下的生物体中，发生孢子发芽，菌丝开始生长。菌丝体（菌丝骨料）的形成标志着浸润性粘菌病的开始。在严重降低免疫能力的情况下，菌丝体可以侵入更深的组织层。

rhizopus sp. spores
Figure 2. Rhizopus sp. spores (Photo source: Curtis Clark,Wikipedia)

In patients suffering from pulmonary mucormycosis, symptoms often mimic clinical manifestations described for曲霉病. The main symptoms may include cough, fever, thoracic pain, difficulty breathing, and coughing up blood. Unfortunately, infections at the initial stage may often be asymptomatic (4).

Because Mucorales have a high tendency to invade blood vessels, this can often lead to the insufficient blood supply and thrombosis in the involved organ. The infections might start to spread through the bloodstream, and septic thromboembolism may appear in other organs. Because of the lacking of circulating neutrophils in the bloodstream, this often ends fatally (2,5,8).

Mucormycosis treatment

The treatment course usually stops the fungal reproduction and spreads with antifungal meds (Amphotericin B), unfortunately often with some side effects. Furthermore, Amphotericin B (either conventional or liposomal) is one of the few medications applied successfully in mucormycosis. However, if the fungus has already spread, an aggressive amputation of the infected body region must be done to stop its progress. Unfortunately, this sometimes means the removal of certain skin and bone segments, and sometimes even worse (1–3,9).

Predisposing factors

The most important conditions that predispose to mucormycosis include (2):

  • Diabetes (both with and without ketoacidosis),
  • Hematological and other malignancies,
  • 器官移植，
  • Neutropenia (lower-than-normal levels of neutrophil white blood cells),
  • 皮质类固醇治疗（抑制免疫系统），
  • Iron overload (beneficial for fungal development),
  • Illicit intravenous drug use (potential direct inoculation of spores into the bloodstream),
  • Neonatal prematurity,
  • Malnourishment.
Mucormycosis - Black Fungus

Some studies suggest that the underlying disease can be connected to the site of infection. For example, pulmonary mucormycosis can be associated with hematological malignancies and neutropenia, diabetes with sinusitis, and rhinocerebral infections, while trauma frequently leads to dermal mucormycosis. Risk factors for the infection may vary considerably with the geographical area. In Mexico and India, the most frequent underlying disease was diabetes, while in Europe, it was hematological and other malignancies (9–11).

Video:The “Black Fungus” (Mucormycosis) is Hitting Hard in India and Why?

Sometimes, several factors can come together can greatly exacerbate Mucorales infections, as it happened in 2020 in India. During the COVID-19 epidemics, a peculiar rise in several serious types of infections was noticed in already clogged hospitals of India. Swellings and headaches quickly turned to black sores spreading on throats, cheeks, eyes, and sometimes the brain. It turned out that the causal agents were of the Mucorales fungi, and the COVID-19 situation worsened the infections. According to a review study, mucormycosis infections were spreading due to three elements: sugar, immunosuppressant drugs, and the pandemic. Or, as the researchers say with their own words: “An unholy trinity of diabetes, rampant use of corticosteroid in a background of COVID-19 appears to increase mucormycosis” (9).

References:

  1. Jeong, W., Keighley, C., Wolfe, R., Lee, W. L., Slavin, M. A., Kong, D. C. M., & Chen, S. A. (2019). The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports.Clinical Microbiology and Infection,25(1), 26-34.
  2. Skiada，A.，Pavleas，I。和Drogari-apiranthitou，M。（2020）。流行病学和粘膜病的诊断：更新。Journal of Fungi,6(4), 265.
  3. Walther，G.，Wagner，L。，＆Kurzai，O。（2019）。有关粘膜分类法的最新信息，重点是临床上重要的分类单元。Journal of Fungi,5(4), 106.
  4. Eucker, J., Sezer, O., Graf, B., & Possinger, K. (2001). Mucormycoses.Mycoses,44(7‐8), 253-260.
  5. Pagano, L., Ricci, P., Tonso, A., Nosari, A., Cudillo, L., Montillo, M., … & GIMEMA Infection Program. (1997). Mucormycosis in patients with haematological malignancies: a retrospective clinical study of 37 cases.英国血液学杂志,99(2), 331-336.
  6. Pagano，L.，Ricci，P.，Nosari，A.，Tonso，A.，Buelli，M.，Montillo，M.，…＆Gimema Incotection计划（Gruppo Italiano Malattie Ematogiche ematologiche dell’adulto）。（1995）。肺丝状霉菌病中的致命止血：血液学完全缓解的急性白血病患者的死亡原因不足。回顾性研究和文献综述。英国血液学杂志,89(3), 500-505.
  7. Cornely, O. A., Alastruey-Izquierdo, A., Arenz, D., Chen, S. C., Dannaoui, E., Hochhegger, B., … & Mucormycosis, E. C. M. M. (2019). Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium.The Lancet infectious diseases,19(12), e405-e421.
  8. Hopkins, R. J., Rothman, M., Fiore, A., & Goldblum, S. E. (1994). Cerebral mucormycosis associated with intravenous drug use: three case reports and review.Clinical infectious diseases,19(6), 1133-1137.
  9. Singh, A. K., Singh, R., Joshi, S. R., & Misra, A. (2021). Mucormycosis in COVID-19: a systematic review of cases reported worldwide and in India.Diabetes & Metabolic Syndrome: Clinical Research & Reviews.
  10. Corzo-León, D. E., Chora-Hernández, L. D., Rodríguez-Zulueta, A. P., & Walsh, T. J. (2018). Diabetes mellitus as the major risk factor for mucormycosis in Mexico: Epidemiology, diagnosis, and outcomes of reported cases.Medical mycology,56(1), 29-43.
  11. Skiada, A., Pagano, L. I. V. I. O., Groll, A., Zimmerli, S., Dupont, B., Lagrou, K., … & Petrikkos, G. (2011). Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007.Clinical Microbiology and Infection,17(12), 1859-1867.
  12. Yuping, R., Kaiwen, Z., Wenying, H., Jinghong, H., Xiaowei, F., Shuang, C., … & Chaoliang, Z. (2016). Observation of Fungi, Bacteria, and Parasites in Clinical Skin Samples Using Scanning Electron Microscopy. Modern Electron Microscopy in Physical and Life Sciences, 225.

Published:October 5, 2021Updated:October 28, 2021

杜桑·萨迪科维奇（Dusan Sadikovic）

Written by:

真菌学家- MSc,博士学位
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查尔斯·莱克（Charles Leduc）