An Overview of the Management of the Most Important Invasive Fungal Infections in Patients with Blood Malignancies

Figures & data

Table 1 Different Clinical Manifestations, Treatment, and Outcome of Most Important Invasive Fungal Infections in Patients with Hematologic Malignancies

First Author and Published Time	Species	Clinical Sign	Underlying Disease	Treatment	Surgery	Method for Diagnosis	Outcome	Reference
Duque (2018)	Candida tropicalis	Renal micro abscesses	A child with lymphoblastic leukemia	LAMB, micafungin and fluconazole	No	PCR	Treated	^Citation88
Niles (2019)	Candida tropicalis	Thyroiditis	An adolescent male with ALL	Micafungin	No	MALDI-TOF MS	Treated Although infections of the thyroid gland are rare, thyroiditis should be suspected in immunocompromised patients.	^Citation114
Ma (2016)	Candida tropicalis	Osteomyelitis	A 52 year-old man with AML	Micafungin	Placing of two tubes for postoperative drainage	MRI and pus culture	Treated Combination treatment using antifungal agents, surgical debridement, and sufficient drainage is a better way to treat Candida osteomyelitis.	^Citation115
Vicari (2003)	Candida Tropicalis	Septic arthritis as sign of fungemia	A 24-year-old man with ALL	AMB	No	Blood and synovial fluid cultures	Died Fluconazole prophylaxis has resulted in a rise in the proportion of hematogenous candidiasis.	^Citation116
Harada (2019)	Fusarium solani	Pre-engraftment disseminated fusariosis	A 47-year-old man with AML	AMB for a total of 19 weeks	No	Blood culture, MALDI-TOF and DNA sequencing	Treated with immediate definitive diagnosis, sufficient and long-term administration of appropriate antifungal medication and avoidance of the systemic administration of steroids.	^Citation117
Ichikawa (2020)	Fusarium species	Fungal endophthalmitis and disseminated fusariosis	16-year-old male with AML	AMB, itraconazole and caspofungin	Surgical resection for Fusarium sinusitis	Vitreal culture	Treated Continuous administration of antifungal agents and vigorous surgical intervention may be necessary for the management of disseminated fusariosis.	^Citation118
Mardani (2019)	Fusarium species	Ecthyma, gangrenosum-like lesions, sinusitis endophthalmitis, and disseminated fusariosis	35-year-old man diagnosed with AML and prolonged febrile neutropenic	AMB, voriconazole and caspofungin	Endoscopic sinus surgery	BacT/alert Microbial Detection System, PCR sequencing	Died Probably due to the nonrecovery of neutrophil.	^Citation119
Delia (2016)	Fusarium solani	Skin nodules and pneumonia in spite of posaconazole prophylaxis	A 44-year-old male with AML	Voriconazole and AMB	No	Blood culture, skin biopsy and molecular methods	Died Drug-resistant fusariosis.	^Citation120
Fadhel (2019)	Mucorales species	Disseminated lung disease with muscular involvement	A 53-year-old female with AML	AMB and posaconazole	Surgical debridement	Lung and muscle biopsy, 16S sequencing	Treated Diagnosis depends on the analysis of the tissue samples collected from the affected system.	^Citation121
Miura (2019)	Mucorales species	Pulmonary mucormycosis	A 59-year-old woman with AML	AMB	Right upper lobectomy	HE	Treated Pulmonary mucormycosis undergoing leukemia treatment should be considered for rapid surgical therapy if the infected lesion is limited.	^Citation122
Biddeci (2019)	Mucorales species	Systemic fungal infection complicated by aortitis	A 6 years old girl with ALL	AMB and posaconazole	Urgent surgical intervention and pulmonary lobectomy	HE	Treated Correct diagnosis using a biopsy can significantly help the treatment process.	^Citation123
Jeurkar (2019)	Mucorales species	Angioinvasive mucormycosis in frontal lobe that lead to cerebral edema, tonsillar herniation and brainstem infarction (source of infection was lung)	A 64-year-old female with AML	Prophylactic and treatment with voriconazole but AMB was not considered due to lack of consideration for mucormycosis.	No	HE	Died The combination of prolonged neutropenia, pulmonary nodules, and long-term voriconazole prophylaxis should have prompted further workup of mucormycosis prior to HSCT.	^Citation124
Ozhak-baysan (2010)	Aspergillus alliaceus and Aspergillus flavus	Pulmonary infection	A 64-year-old male with an AML	AMB and Voriconazole	No	Microscopic examination, BAL and fluid culture and PCR with sequences	Died Only voriconazole showed a low MIC against A. alliaceus, demonstrating that this drug is a better choice for the treatment of both strains.	^Citation125
Le (2020)	Aspergillus fumigatus	Central nervous system Aspergillosis infection	A 74-year-old male with CLL	Voriconazole	Craniotomy to evacuate the brain abscess	MRI and culture	Treated Early recognition and treatment of aspergillosis in CLL patients who present neurological symptoms can be lifesaving.	^Citation126
Rößler (2017)	Aspergillus fumigatus	Invasive pulmonary aspergillosis with multiple fungal abscesses	A patient in his early 70s with progressive AML	AMB and voriconazole	No	CT scan and BAL fluid culture	Died Azole resistance in A. fumigatus is an increasingly important phenomenon, leading to breakthrough infections despite prophylaxis.	^Citation127
Antonogiannaki (2019)	Aspergillus species	Invasive Aspergillus tracheobronchitis	A 50-year-old with hairy cell leukemia and previous Plasmodium falciparum infection	AMB	No	High resolution CT, BAL examination and direct smear	Died Previous P. falciparum infection was an additional predisposing factor for the manifestation of Aspergillus infection.	^Citation128
Turki (2017)	Aspergillus spp. and Aspergillus fumigatus	Cerebral aspergillosis and pneumonia	A 53 year old patient with LGL, Immune thrombocytopenia and combined antibody deficiency	AMB and voriconazole	No	MRI, chest radiography, CT and HE	Treated In cerebral involvement, prolonged treatment was recommended, and this patient showed no further relapse after 12 months of effective voriconazole treatment.	^Citation129
Inoue (2020)	Cryptococcus species	Cellulitis of the left mandible	31-year-old man with AML	LAMB, flucytosine and fluconazole	Surgical debridement	HE	Treated The surgical site healed after the operation.	^Citation130
Suleman (2019)	Cryptococcus neoformans	Cryptococcal meningitis and skin disease	60-year-old man with CLL	AMB, flucytosine and fluconazole	NO	Blood and CSF culture	Treated Physicians should be aware of possibility of disseminated cryptococcosis in patients with treatment-naïve CLL.	^Citation23
Ramirez 2019	Trichosporon asahii	Disseminated Infection	42-year-old male with AML	Caspofungin then LAMB and voriconazole.	NO	Culture, HE and MALDI-TOF	Died Invasive trichosporonosis is an acute fatal condition that occurs in immunosuppressed patients, usually under antifungal selective pressure.	^Citation131
Nguyen (2018)	Trichosporon asahii	Disseminated Infection	10-year-old boy with ALL	Micafungin, AMB and voriconazole	No	Culture	Died It is important to consider trichosporonosis in the evaluation of a critically ill individual with neutropenia and a rash, because the initial cutaneous presentation may appear benign and delayed therapy results in death.	^Citation132

Abbreviations: AMB, amphotericin B; LAMB, liposomal Amphotericin B; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; PCR, polymerase chain reaction; MALDI-TOF MS, matrix-assisted laser desorption/ionization mass spectrometry; MRI, magnetic resonance imaging; HSCT, hematopoietic stem cell transplant; BAL, bronchoalveolar lavage; CT, computed tomography; HE, histopathologic examination; CSF, cerebrospinal fluid; MIC, minimum inhibitory concentration.

Figure 1 Strategies for controlling invasive fungal infections in patients with hematologic malignancies.

Table 2 Other Invasive Fungal Infections Reported in Patients with Hematologic Malignancies

Fungal Infection	Species	Underlying Disease	Clinical Manifestation	Outcome	References
Coccidioidomycosis	Coccidioides species	ALL	Meningitis complicated by central nervous system vasculitis.	The patient was treated with AMB, intravenous fluconazole, Micafungin and prednisone.	^Citation250
Scopulariopsis	S. alboflavescens	AML	Pneumonia with large consolidation on the left side of the lung hilum.	AMB and voriconazole combination therapy was not successful and the patient died.	^Citation251
	S. brevicaulis	AML	Bronchial invasion that leads to mediastinal emphysema, bronchial bleeding, and bronchial obstruction before finally spreading to the entire lung.	The patient died because it was estimated that the patient had respiratory aspergillosis infection, and the optimal treatment was delayed.	^Citation252
	S. brevicaulis	AML	The patient with necrotic ulcers on his hard palate and his left tonsil.	Sinonasal infection was successfully treated with a combination of extensive surgical debridement and AMB.	^Citation253
	S. brevicaulis	AML	The patient with persistent fever that did not respond to wide spectrum antibiotics and AMB.	The fever subsided with itraconazole, and there was no recurrence of fungal infection with prolonged maintenance of oral itraconazole.	^Citation254
	S. brevicaulis	AML	Onychomycosis with local cutaneous invasion.	Unsuccessfully treated with high-dose micafungin, and the patient died from a cerebral hemorrhage in the context of chronic thrombocytopenia.	^Citation255
Geoterichosis	G. capitatum	ALL	The patient with fever and blood infection.	The patient died and fungal infection disseminated although caspofungin was used as prophylaxis.	^Citation256
	G. capitatum	Fanconi aplastic anemia	Neutropenic fever, multiple nodules were detected in liver and septic arthritis.	The patient treated with AMB and voriconazole but died due to sepsis and multiple organ failure.	^Citation257
	G. capitatum	AML with multilineage dysplasia	Blood infection and multiple nodular lesions in lung fields.	The patient treated with a combination of AMB, itraconazole, and voriconazole.	^Citation258
	G. capitatum	Plasma cell leukemia	Pneumonia	The patient treated successfully with an antifungal combination of voriconazole, caspofungin, and supportive therapy.	^Citation259
	G. capitatum	ALL	The infection involved lung, liver and skin	Caspofungin, AMB, and combination therapy with voriconazole improved patient condition, but the patient died due to heart and lung failure.	^Citation260
Ochroconis gallopavum	Ochroconis gallopavum	B-CLL	Disseminated Infection	AMB and itraconazole were used for treatment, but the patient died due to brain abscesses.	^Citation261
Scedosporium	S. prolificans	AML	Disseminated Infection	Combination of voriconazole and terbinafine in conjunction with central venous line removal and intravitreal voriconazole, contributed to the recovery of the patient.	^Citation262
	S. prolificans	ALL	Pneumonia	Successfully treated with liposomal AMB and who underwent autologous peripheral blood stem cells transplantation.	^Citation263
	S. prolificans	AML	Sepsis	Died AML and Fatal S. prolificans sepsis after Eculizumab treatment for paroxysmal nocturnal hemoglobinuria.	^Citation264
	S. prolificans	AML	Infective endocarditis	Died Multi-organ failure despite the combined use of voriconazole and terbinafine.	^Citation265

Abbreviations: AMB, amphotericin B; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia.

Duque JSR, To KK, Chiang AK, et al. Candida Tropicalis renal microabscesses in a child with leukemia confirmed using nucleic acid amplification and recovery after prolonged antifungal and corticosteroid treatment. Int J Infect Dis. 2019;81:110–113.30772467

 PubMed Web of Science ®Google Scholar

Niles D, Boguniewicz J, Shakeel O, et al. Candida tropicalis thyroiditis presenting with thyroid storm in a pediatric patient with acute lymphocytic leukemia. Pediatr Infect Dis J. 2019;38(10):1051–1053. doi:10.1097/INF.000000000000242431365478

 PubMedGoogle Scholar

Ma L, Tong H, Ruan L, Ling Z, Ren Y, Zhou X. Successful treatment of Candida tropicalis osteomyelitis with Micafungin in a leukemia patient. IDCases. 2016;6:109. doi:10.1016/j.idcr.2016.10.00227942462

 PubMed Web of Science ®Google Scholar

Vicari P, Pinheiro RF, MdLLF C, Yamamoto M, Figueiredo MS. Septic arthritis as the first sign of Candida tropicalis fungaemia in an acute lymphoid leukemia patient. Braz J Infect Dis. 2003;7(6):426–428. doi:10.1590/S1413-8670200300060001214636484

 PubMedGoogle Scholar

Harada Y, Murata M, Matsumoto A, et al. [Successful treatment of pre-engraftment disseminated fusariosis with high-dose liposomal amphotericin B in a cord blood transplant recipient]. Rinsho Ketsueki. 2019;60(12):1641–1646. Japanese. doi:10.11406/rinketsu.60.164131902814

 PubMedGoogle Scholar

Ichikawa S, Fukuhara N, Watanabe S, et al. Long-term survival after cord blood transplantation for acute myeloid leukemia complicated with disseminated fusariosis. J Infect Chemother. 2020;26(2):292–295. doi:10.1016/j.jiac.2019.08.02231570321

 PubMedGoogle Scholar

Mardani M, Khodashahi R, Lotfali E, Abolghasemi S, Hakemi-Vala M. Disseminated fusariosis with ecthyma gangrenosum-like lesions in a refractory acute myeloid leukemia patient. Curr Med Mycol. 2019;5(1):27–31. doi:10.18502/cmm.5.1.534

 Google Scholar

Delia M, Monno R, Giannelli G, et al. Fusariosis in a patient with acute myeloid leukemia: a case report and review of the literature. Mycopathologia. 2016;181(5–6):457–463. doi:10.1007/s11046-016-9987-527008433

 PubMed Web of Science ®Google Scholar

Fadhel M, Patel SV, Liu E, Fune L, Wasserman EJ, Asif A. Disseminated pulmonary with isolated muscular mucormycosis in an acute myeloid leukemia patient: a case report and literature review. Am J Case Rep. 2019;20:1210–1215. doi:10.12659/AJCR.91686431417073

 PubMed Web of Science ®Google Scholar

Miura K, Kobayashi N, Ito I, et al. Pulmonary mucormycosis developed during acute myelogenous leukemia and successfully treated by surgical resection before blood stem cell transplantation. AME Case Rep. 2019;3:48. doi:10.21037/acr.2019.11.0232030366

 PubMedGoogle Scholar

Biddeci G, Antonello M, Pizzi M, et al. Mucormycosis with peculiar aortic involvement in a child with acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2019;1–6.30821552

 PubMedGoogle Scholar

Jeurkar C, Margetich L, Sahin Z. Mucormycosis leading to cerebral edema and cerebellar tonsillar herniation after allogeneic bone marrow transplant: a case report. Case Rep Infect Dis. 2019;2019:5138198.31815025

 PubMed Web of Science ®Google Scholar

Ozhak-Baysan B, Alastruey-Izquierdo A, Saba R, et al. Aspergillus alliaceus and Aspergillus flavus co-infection in an acute myeloid leukemia patient. Med Mycol. 2010;48(7):995–999. doi:10.3109/1369378100374941820392148

 PubMed Web of Science ®Google Scholar

Le T-H, Kumar V, Gondal K, et al. Isolated central nervous system Aspergillosis infection in a chronic lymphocytic leukemia patient on Ibrutinib: A case report. BMC Infect Dis. 2020;20(1):1–3. doi:10.1186/s12879-020-4894-2

 Web of Science ®Google Scholar

Rößler S, Bader O, Stölzel F, et al. Progressive dispersion of azole resistance in Aspergillus fumigatus: fatal invasive Aspergillosis in a patient with acute myeloid leukemia infected with an A. fumigatus strain with a cyp51A TR46 Y121F M172I T289A Allele. Antimicrob Agents Chemother. 2017;61(8):e00270–00217. doi:10.1128/AAC.00270-1728743702

 PubMed Web of Science ®Google Scholar

Antonogiannaki E-M, Proklou A, Tamiolakis D, Vassalou E, Kondili E. Invasive Aspergillus tracheobronchitis in a patient with hairy cell leukemia and previous Plasmodium falciparum infection. Monaldi Arch Chest Dis. 2019;89:2. doi:10.4081/monaldi.2019.1055

 Web of Science ®Google Scholar

Turki AT, Rashidi-Alavijeh J, Dürig J, Gerken G, Rath P-M WO. Successful treatment of cerebral aspergillosis: case report of a patient with T-cell large granular lymphocytic leukemia (T-LGL). BMC Infect Dis. 2017;17(1):797. doi:10.1186/s12879-017-2877-829281994

 PubMed Web of Science ®Google Scholar

Inoue H, Motohashi T, Ioku Y, Watanabe M, Nakajima M, Sugitatsu M. The detection of Cryptococcus in skeletal infection after tooth extraction in an acute myeloid leukemia patient. IDCases. 2020;19:e00700. doi:10.1016/j.idcr.2020.e0070031993323

 PubMed Web of Science ®Google Scholar

Suleman A, Padmore R, Faught C, Cowan J. Disseminated cryptococcal infection in a patient with treatment-naïve chronic lymphocytic leukemia (CLL). IDCases. 2019;17:e00566. doi:10.1016/j.idcr.2019.e0056631194156

 PubMed Web of Science ®Google Scholar

Ramírez I, Moncada D. Fatal disseminated infection by trichosporon asahii under voriconazole therapy in a patient with acute myeloid leukemia: a review of breakthrough infections by trichosporon spp. Mycopathologia. 2019;1–12.30600418

 PubMed Web of Science ®Google Scholar

Nguyen JK, Schlichte MJ, Schady D, Pourciau CY. Fatal disseminated Trichosporon asahii fungemia in a child with acute lymphoblastic leukemia and a morbilliform eruption. Pediatr Dermatol. 2018;35(1):e86–e87. doi:10.1111/pde.1335929266471

 PubMed Web of Science ®Google Scholar

Tager D, Hatch A, Segar J, Roller B, Al Mohajer M, Zangeneh TT. Coccidioidal meningitis complicated by central nervous system vasculitis in a patient with leukemia. Med Mycol Case Rep. 2017;16:8–11. doi:10.1016/j.mmcr.2017.03.00328386527

 PubMedGoogle Scholar

Kurata K, Nishimura S, Ichikawa H, et al. Invasive Scopulariopsis alboflavescens infection in patient with acute myeloid leukemia. Int J Hematol. 2018;108(6):658–664. doi:10.1007/s12185-018-2496-129987744

 PubMed Web of Science ®Google Scholar

Yang Q, Wei J, Chen Z. Fatal bronchial invasion of Scopulariopsis brevicaulis in an acute monocytic leukemia patient. Diagn Microbiol Infect Dis. 2012;73(4):369–371. doi:10.1016/j.diagmicrobio.2012.04.01022633337

 PubMed Web of Science ®Google Scholar

Gluck O, Segal N, Yariv F, et al. Pediatric invasive sinonasal Scopulariopsis brevicaulis–a case report and literature review. Int J Pediatr Otorhinolaryngol. 2011;75(7):891–893. doi:10.1016/j.ijporl.2011.03.02621543124

 PubMed Web of Science ®Google Scholar

Ng KP, Soo-Hoo TS, Na SL, Gan GG, Sangkar JV, Teh AK. Scopulariopsis brevicaulis infection in a patient with acute myeloid leukemia. Med J Malaysia. 2003;58(4):608–612.15190640

 PubMedGoogle Scholar

Gavril D, Woerther PL, Ben Lakhdar A, et al. Invasive cutaneous infection due to Scopulariopsis brevicaulis unsuccessfully treated with high-dose micafungin in a neutropenic patient. Infection. 2017;45(3):361–363. doi:10.1007/s15010-016-0971-227909895

 PubMed Web of Science ®Google Scholar

Oya S, Muta T. Breakthrough infection of Geotrichum capitatum during empirical caspofungin therapy after umbilical cord blood transplantation. Int J Hematol. 2018;108(5):558–563. doi:10.1007/s12185-018-2481-829926359

 PubMed Web of Science ®Google Scholar

Parkan OM, Atalay MA, Koc AN, Pala C, Aydemir G, Kaynar L. [Fungemia and septic arthritis caused by Saprochaete capitata in a patient with fanconi aplastic anemia: a case report]. Mikrobiyol Bul. 2017;51(1):87–93. Turkish. doi:10.5578/mb.3317628283014

 PubMed Web of Science ®Google Scholar

Ikuta K, Torimoto Y, Yamamoto M, et al. Successful treatment of systemic Geotrichum capitatum infection by liposomal amphotericin-B, itraconazole, and voriconazole in a Japanese man. Intern Med. 2010;49(22):2499–2503. doi:10.2169/internalmedicine.49.388721088357

 PubMed Web of Science ®Google Scholar

Fianchi L, Montini L, Caira M, et al. Combined voriconazole plus caspofungin therapy for the treatment of probable Geotrichum pneumonia in a leukemia patient. Infection. 2008;36(1):65–67. doi:10.1007/s15010-007-6235-417926005

 PubMed Web of Science ®Google Scholar

Gao GX, Tang HL, Zhang X, Xin XL, Feng J, Chen XQ. Invasive fungal infection caused by geotrichum capitatum in patients with acute lymphoblastic leukemia: a case study and literature review. Int J Clin Exp Med. 2015;8(8):14228–14235.26550401

 PubMed Web of Science ®Google Scholar

Fukushima N, Mannen K, Okamoto S, Shinogi T, Nishimoto K, Sueoka E. Disseminated Ochroconis gallopavum infection in a chronic lymphocytic leukemia: a case report and review of the literature on hematological malignancies. Intern Med. 2005;44(8):879–882. doi:10.2169/internalmedicine.44.87916157992

 PubMed Web of Science ®Google Scholar

Tong SY, Peleg AY, Yoong J, Handke R, Szer J, Slavin M. Breakthrough Scedosporium prolificans infection while receiving voriconazole prophylaxis in an allogeneic stem cell transplant recipient. Transpl Infect Dis. 2007;9(3):241–243. doi:10.1111/j.1399-3062.2007.00203.x17605752

 PubMedGoogle Scholar

García-Ruiz JC, Amutio E, Hernández I, et al. Clinical resolution of Scedosporium prolificans pneumonia associated with treatment with liposomal amphotericin B in a patient with acute leukemia. Rev Iberoam Micol. 1998;15(3):158–159.18473538

 PubMedGoogle Scholar

Hanmantgad M, Nog R, Seiter K. Acute myeloid leukemia and fatal Scedosporium prolificans sepsis after eculizumab treatment for paroxysmal nocturnal hemoglobinuria: a case report. Stem Cell Investig. 2017;4:100. doi:10.21037/sci.2017.12.04

 Google Scholar

Ochi Y, Hiramoto N, Takegawa H, et al. Infective endocarditis caused by Scedosporium prolificans infection in a patient with acute myeloid leukemia undergoing induction chemotherapy. Int J Hematol. 2015;101(6):620–625. doi:10.1007/s12185-015-1752-x25630434

 PubMed Web of Science ®Google Scholar