Prophylaxis of Fungal Infections in Transplant Patients: What has Changed in Recent Years?

ABSTRACT

Objective:  The present work aimed to review the invasive fungal infections (IFIs) and antifungal prophylaxis used in the last 20 years in transplant patients to identify the changes that occurred in this period and discuss the most current conducts.

Methods:  This is a systematic review in which the PubMed database was used, in which scientific articles from the last 20 years were selected, covering clinical trials, randomized controlled trials, systematic reviews of the literature and meta-analyses.

Results:  According to the present study, posaconazole and voriconazole are the antifungal drugs of choice for IFI prophylaxis in hematopoietic stem cell transplantation (HSCT). However, as posaconazole is not available in the public health system in Brazil, the most viable option remains voriconazole. Regarding IFI prophylaxis in solid organ transplantation (SOT), it was observed that there are variations depending on the transplanted target organ, and there is no evidence of its need in kidney transplantation. Although azoles are also the most used and bring clear benefits in liver and lung transplantation, some current studies have placed echinocandins on the same level, encouraging their use to prevent IFI in these patients.

Conclusion:  In the last five years, there has been a great shortage of clinical trials comparing different antifungal prophylaxis. New studies are needed to establish the most appropriate protocols for each condition and profile of the transplanted patient.

Descriptors
Hematopoietic Stem Cell Transplantation; Organ Transplantation; Post-Exposure Prophylaxis; Pre-Exposure Prophylaxis; Liver Transplantation; Lung Transplantation

RESUMO

Objetivo:  O presente trabalho objetivou revisar as infecções fúngicas invasivas (IFIs) e as profilaxias antifúngicas utilizadas nos últimos 20 anos em pacientes transplantados, de forma a identificar as mudanças ocorridas nesse período e discutir as condutas mais atuais.

Métodos:  Trata-se de uma revisão sistemática em que se utilizou a base de dados PubMed, na qual foram selecionados artigos científicos dos últimos 20 anos, abrangendo ensaios clínicos, ensaios controlados randomizados, revisões sistemáticas da literatura e metanálises.

Resultados:  De acordo com o presente estudo, o posaconazol e o voriconazol parecem ser as drogas antifúngicas de escolha na profilaxia de IFI em transplante de células-tronco hematopoiéticas (TCTH). Entretanto, como não há disponibilidade do posaconazol no sistema público de saúde do Brasil, a opção mais viável continua sendo o voriconazol. Com relação à profilaxia de IFI em transplante de órgãos sólidos (TOS), observou-se que existem variações em função do órgão-alvo transplantado, sendo que no transplante renal (TR) nem há evidência da sua necessidade. Apesar dos azóis também serem os mais utilizados e trazerem benefícios evidentes nos transplantes de fígado (TF) e de pulmão (TP), alguns estudos atuais têm colocado as equinocandinas no mesmo patamar, encorajando mais seu uso para prevenção de IFI nesses pacientes.

Conclusão:  Uma vez que nos últimos 5 anos existe grande escassez de ensaios clínicos comparando diferentes profilaxias antifúngicas, novos estudos são necessários a fim de estabelecerem os protocolos mais adequados para cada condição e perfil de paciente transplantado.

Descritores
Transplante de Células-Tronco Hematopoiéticas; Transplante de Órgãos; Profilaxia Pós-Exposição; Profilaxia Pré- Exposição; Transplante de Fígado; Transplante de Pulmão

INTRODUCTION

It is known that patients who have received solid organ transplantation (SOT), hematopoietic stem cell transplantation (HSCT), or bone marrow transplantation may develop invasive fungal infections (IFIs), with high mortality, prolonged hospitalization days and excessively increasing costs for healthcare facilities.¹ Most transplant recipients require lifelong treatment with potent immunosuppressive drugs. Excessive immunosuppression is associated with a higher incidence of these infections during the immediate postoperative period.²

Neofytos et al. evidenced that Candida, Aspergillus, Cryptococcus, and other fungi caused most IFIs in SOT recipient patients. Invasive candidiasis was the most observed IFI, except in lung transplant recipients, in whom invasive aspergillosis was the most common. Organ damage, neutropenia, and corticosteroid administration were also observed to be predictors of death in these patients.³

The incidence of IFI in patients receiving HSCT transplantation is also significant, being reported in 5.4% to 16.0% of cases, with prolonged neutropenia and immunosuppression as contributing factors to the increased risk of fungal disease in these patients.⁴ The IFIs developed by HSCT transplant recipients also include aspergillosis and candidiasis, followed by a smaller number of scedosporiosis and zygomycosis.⁵

Treatment of an established IFI is often very difficult, and the most effective antifungal agents have toxicities that limit treatment. In this sense, antimicrobial prophylaxis could bring benefits such as reducing mortality and lowering healthcare costs.⁶ According to Evans et al., the chances of mortality due to IFIs are lower in patients who have received antifungal prophylaxis compared to those who have not.⁷ However, protocols for antimicrobial use vary widely among healthcare institutions, and the results of studies supporting specific practices also vary.⁸

Since the high rate of comorbidity in transplant patients raises the risk of developing IFI and may indicate the need for active antifungal prophylaxis in high-risk patients,⁹ this study proposes to review the IFIs and the different antifungal prophylaxes proposed in the last 20 years, both for patients undergoing HSCT and SOT, emphasizing the changes that have occurred in this period and the most up-to-date conducts.

METHODS

The PubMed database was used, in which scientific articles from the last 20 years were selected, covering clinical trials, randomized controlled trials, systematic literature reviews, and meta-analyses. The keywords used were: “Invasive Fungal Infections,” “Hematopoietic Stem Cell Transplantation,” “Organ Transplantation,” “Post-Exposure Prophylaxis,” “Pre-Exposure Prophylaxis,” “Liver Transplant,” and “Lung Transplantation.” Initially, 879 papers were found, of which 822 were excluded due to incompatibility with the aim of the study.

REVIEW AND RESULTS

Invasive Fungal Infections

IFIs are severe infections associated with high mortality rates, despite the availability of new classes of antifungal agents.¹⁰ The fungi most frequently presented as etiologic agents of IFIs include the genera Aspergillus and Candida.¹¹

Species of the genus Aspergillus are filamentous saprophytic fungi commonly found in the soil of subtropical climate regions. Inhalation of asexual spores produced by Aspergillus causes a group of diseases collectively called aspergillosis.¹²

Aspergillus fumigatus and other filamentous fungi grow as networks of filamentous hyphae that have characteristics of a classical microbial biofilm. Biofilm growth of A. fumigatus occurs in vivo at sites of infection, contributing to increased resistance to contemporary antifungal drugs.¹³ Although significant advances have been made in diagnosing this disease, obtaining mycological confirmation of infection is still difficult.¹⁴

On the other hand, the Candida genus is the cause of invasive candidiasis, much in evidence in the context of IFIs, and an important cause of complications and death in hospitalized patients.¹⁵ The most prominent species of this genus is Candida albicans. This dimorphic commensal fungus colonizes the vaginal and oral mucosa of healthy individuals and can become a pathogen when the balance between the fungus, mucosa, and host defense mechanisms is disrupted. The pathogenic potential of Candida depends on its ability to adhere and produce biofilms on abiotic and living surfaces. The cells in biofilms are much less susceptible to host defenses and the action of antimicrobials.¹⁶

IFIs are usually challenging to diagnose, especially in critically ill patients, and are responsible for considerable morbidity in immunocompromised individuals, including those with hematologic malignancies or recipients of solid organs or hematopoietic cell transplants.^17,18 Definitive diagnosis of fungal infection is possible only after histopathological examination or culture of the etiologic agent. Treatment is still challenging because one must assume that the agent isolated in culture is the actual pathogen of the infection.¹⁹

Antifungal treatment options for most IFIs include formulations of amphotericin B, echinocandins, and triazole antifungal agents. However, each may be associated with limitations that have pathogen resistance and intolerability of the patient.¹⁸ Drugs such as amphotericin B, in its different formulations: lipidic complex, deoxycholate and liposomal, are available in the Brazilian Unified Health System (UHS), the first in suspension for injection and the following in powder for injection. Fluconazole is also available in capsules, oral suspension, and injectable solution; itraconazole, only in oral solution or capsule; and voriconazole, only for hospital use. Posaconazole, on the other hand, is not cited in the Ministry of Health’s National List of Essential Medicines (RENAME). Micafungin and caspofungin (both of the echinocandins group) are not mentioned in the RENAME; however, anidulafungin was recently incorporated into the UHS, and its use is reserved for patients with candidemia and other forms of invasive candidiasis.^20,21

IFI prophylaxis in HSCT

HSCT is one of the possible treatments established for patients with hematological malignancies and those with congenital and acquired disorders of the hematopoietic system.²² As for the patient profile, one study gathered patients from 3 to 64 years of age, and all had an indication for HSCT, i.e., the profile of patients undergoing this type of procedure is variable.²³

The development of severe and/or steroid-refractory graft-versus-host disease (GVHD) remains a significant limitation for the success of HSCT.²⁴ This condition results from complex and dynamic mechanisms that can start with early inflammation due to tissue injury.²⁵

GVHD is considered the main risk factor for invasive aspergillosis after HSCT,²⁶ with high mortality in immunocompromised hosts, as well as being the leading cause of late post-HSCT morbidity and mortality.²⁷

Ullmann et al., in a randomized, double-blind study on IFI prophylaxis in patients with GVHD, compared oral posaconazole with oral fluconazole. The incidence rate of invasive aspergillosis was 2.3% in patients using posaconazole versus 7.0% in those using fluconazole. In the posaconazole group, the overall mortality rate was 1%, and the adverse event rate was only 36%, while in the fluconazole group, the overall mortality was 3%, and adverse events occurred in 38%.²⁸ Still comparing these same two drugs, Shen et al., by analyzing 234 patients, observed that the incidence of proven, probable, or possible IFI was 9.4% and 22.2% in the posaconazole and fluconazole groups, respectively (p = 0.0114). In addition, the clinical failure rate was also lower in the posaconazole group but without statistical significance (p = 0.168).²⁹

In contrast, a study by Marks et al. presented a comparison between voriconazole and itraconazole, which concluded that prophylaxis success was significantly higher with voriconazole than with itraconazole (48.7% vs. 33.2%) and that tolerance to prophylaxis for 100 days was higher in patients receiving voriconazole (53.6% vs. 39.0%). Also, the need for other systemic antifungals was higher in patients who used itraconazole (41.9% vs. 29.9%), leading the authors to suggest voriconazole in preference.³⁰

Still, on voriconazole, a study by Wingard et al. compared it to fluconazole and obtained the following results: lower rate of IFIs (7.3% vs. 11.2%; p = 0.12), fewer Aspergillus infections (9 vs. 17; p = 0.09) and less frequent need for empirical antifungal therapy (24.1% vs. 30.2%, p = 0.11), although fungus-free survival rates were very similar between the two (75% vs. 78%; p = 0.49).³¹ A randomized clinical trial conducted by Hayashi et al., when selecting adult patients undergoing HSCT with acute grade II to IV GVHD or chronic GVHD requiring corticosteroid treatment, mentioned a higher 3-year overall survival rate with voriconazole prophylaxis than 3-year with itraconazole (67% vs. 49%).³²

The literature brings not only drugs for IFI prophylaxis in HSCT patients but also alternative measures: one research selected 206 patients to receive granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, or a combination of both, subcutaneously, five days after HSCT. A prophylactic granulocyte-macrophage colony-stimulating factor was associated with lower HSCT-related mortality at 100 days and lower IFI-related mortality at 600 days.⁴

On the use of echinocandins in HSCT, micafungin is a viable prophylactic option in patients with neutropenia. Huang et al. conducted a multicenter, randomized, open-label phase III study in which they compared the efficacy and safety of micafungin with itraconazole in patients with neutropenia undergoing HSCT and demonstrated that it achieved similar efficacy to itraconazole.³³ Another, more recent study retrospectively evaluated the effectiveness of oral prophylaxis with itraconazole/voriconazole in conjunction with intravenous micafungin at doses of 50, 100 or 150 mg. The result demonstrated that micafungin was effective and well tolerated in clinical practice for IFI prophylaxis in HSCT patients, and, furthermore that its combination with itraconazole/fluconazole was beneficial with no reported adverse effects. Furthermore, in a 2019 study, micafungin was also shown to be effective and safe for adult patients undergoing cord blood transplantation.^34,35

The use of amphotericin B lipid complex has also been studied in HSCT, but prophylactically in high doses, it was associated with nephrotoxicity, which could be aggravated by concomitant use of other nephrotoxic agents.³⁶

Some of the studies comparing prophylaxis options in patients undergoing HSCT can be seen in Table 1.

Table 1
Comparative studies on antifungal prophylaxes in patients receiving and/or candidates for hematopoietic stem cell transplantation.

Authors/year	Type of study	Sample	Prophylaxis	Best result	Comments
Ullmann et al. (2007)28	Randomized double blind	600 patients	Posaconazole versus fluconazole	Posaconazole	Incidence of invasive aspergillosis: 2.3% versus 7.0%, overall mortality 1% versus 3%, and adverse event rate: 36% versus 38%.
Wingard et. al. (2010)31	Randomized double blind	600 patients	Voriconazole versus fluconazole	Voriconazole	Although 6-month fungus-free survival and overall survival did not differ, voriconazole achieved a lower rate of IFIs (7.3% vs. 11.2%; P = 0.12) and fewer Aspergillus infections (9 vs. 17; P = 0.09).
Marks et al. (2011)30	Randomized prospective	489 patients	Voriconazole versus itraconazole	Voriconazole	Voriconazole can be administered for significantly longer periods, with less need for other systemic antifungals.
Huang et al. (2012)33	Randomized open phase III	287 patients	Micafungin versus itraconazole	Micafungin	Overall treatment success rate: 80% versus 73.5% and toxicity cases: 1 versus 29.
Chaftari et al. (2012)36	Randomized prospective	46 patients	Posaconazole versus amphotericin B	Posaconazole	Incidence of IFI: 0% versus 5% and mean number of patients with adverse effects: 7 versus 8.
Shen et al. (2013)29	Randomized multicentric	234 patients	Posaconazole versus fluconazole	Posaconazole	The incidence of proven, probable or possible IFI was 9.4% (11/117) and 22.2% (26/117) (p = 0.0114) in the posaconazole and fluconazole groups respectively.

• Source: Elaborated by the authors.

IFI prophylaxis in SOT

SOT has several purposes depending on the type of solid organ transplanted. SOT recipient patients often have several complex symptoms related to the underlying disease and chronic immunosuppression, and these factors certainly diminish their quality of life.³⁷

About the profile of the SOT recipient patient, the age range seems to vary between children and adults, and the presence of malignancies presents itself as a frequent pretransplant condition associated with increased mortality.³⁸

The most common agents of fungal infections in SOT-receiving patients include Candida, Aspergillus species, and Cryptococcus species, among others.³

Depending on the type of transplanted organ, the prevalence of these agents can change. In renal transplant (RT) recipient patients, the most common complications are from aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, and coccidioidomycosis consecutively.^39,40 Whereas in lung transplant (LgT), aspergillosis, more specifically that caused by A. fumigatus, is the predominantly most common infection,⁴¹ while in liver transplantation (LvT), infections by Candida have a higher prevalence.⁴²

Regarding antifungal prophylaxis in RT recipients, there needs to be more literature or evidence on the topic; however, there is content on the use of immunosuppressive drugs in these patients and how to minimize immunosuppression to maintain efficacy in preventing rejection of the organ.⁴³ In a prospective, multicenter, open-label, randomized, controlled study on the treatment of invasive fungal infections and not prophylaxis in patients with RT, there needs to be more literature or evidence on the topic.⁴³ In a prospective, multicenter, open-label, randomized, controlled study on the treatment of invasive fungal infections and not prophylaxis, in patients with, the efficacy of micafungin was shown to be similar to that of voriconazole.⁴⁴

In cases of heart transplant (HT) recipients, although the literature reports fungal infection in these patients, there is a great scarcity of studies indicating options for prophylactic agents.⁴⁵

Concerning LvT, a 2015 open-label study showed that micafungin 100 mg was not inferior to standard treatment (fluconazole, liposomal amphotericin B or caspofungin) as antifungal prophylaxis in patients at high risk of IFI. The study patients had similar adverse event and liver function profiles, but the standard treatment showed, albeit in a very similar way, a higher clinical success rate: 99.3% versus 98.6%.⁴⁶

Winston et al. found that both anidulafungin and fluconazole are well tolerated in LvT recipients, reserving the use of anidulafungin in patients at high risk of invasive aspergillosis and in patients who received fluconazole before transplantation.⁴⁷

In addition, a more recent review work managed by Khalid et al. suggested that the efficacy of fluconazole was similar to that of liposomal amphotericin. Still, that fluconazole would be preferred due to its cost-effectiveness and safety profile.⁴⁸ Still on LvT, research by Kang et al. showed that micafungin could be used as an alternative to fluconazole, with no difference between the two in terms of IFI presence, time to IFI development, fungus-free survival, and adverse reactions. The research also found similar clinical success rates of 95.65% and 96.10% in the micafungin and fluconazole groups, respectively.⁴⁹

Concerning LgT, Al Jishi et al., in a single-center retrospective cohort study, investigated the use of echinocandin and concluded that it is an important second-line agent, still preempted by the azoles group, as LgT transplant recipient patients who received antifungal prophylaxis with azoles did not develop disseminated invasive aspergillosis, cryptococcal or endemic fungal infections.^50,51

The comparative studies mentioned in this subtopic on IFI prophylaxis in patients with SOT can be summarized and visualized in Table 2.

Table 2
Studies on invasive fungal infections in solid organ transplant patients undergoing different prophylaxis or treatment.

Population studied	Authors	Type of study	Sample	Prophylaxis	Result	Comments
RT	Shang et al. (2012)44	Randomized prospective	65 patients	Micafungin versus voriconazole (treatment)	Very similar results.	Incidence of fungal infection one to three months post-transplant: 83.6% (26/31) versus 85.3% (29/34).
LvT	Winston et al. (2014)47	Randomized double blind	200 patients	Anidulafungin versus fluconazole	Very similar results	Anidulafungin may be beneficial if the patient has an increased risk of Aspergillus infection or receives fluconazole before transplantation.
LvT	Saliba et al. (2015)46	Open-label, non-inferiority	344 patients	Micafungin versus standard treatment (fluconazole, liposomal amphotericin B or caspofungin)	Standard treatment	Clinical success rate: 99.3% versus 98.6%.
LvT	Kang et al. (2020)49	Randomized multicentric	172 patients	Micafungin versus fluconazole	Very similar results	The study groups did not differ significantly in terms of secondary efficacy outcomes.
LgT	Husain et al. (2006)52	Nonrandomized, retrospective, sequential	95 patients	Voriconazole versus targeted prophylaxis (itraconazole ± inhaled amphotericin)	Voriconazole	Better rate of invasive aspergillosis at 1 year. Mortality rate: 0.03/person-year versus 0.16/person-year.
LgT	Al Jishi et al. (2018)50	Retrospective cohort	777 patients	Echinocandin and azoles	Azoles	Despite having a lower adverse event profile, echinocandins are still considered second-line agents.

• Source: Elaborated by the authors.

DISCUSSION AND CONCLUSION

According to the present study, posaconazole and voriconazole are the antifungal drugs of choice in IFI prophylaxis in HSCT. Similarly, Wang et al., in a recent systematic review and meta-analysis of 69 randomized clinical trials that reported comparisons of 12 treatments with a total of 14,789 patients, concluded that voriconazole would be the best choice for patients undergoing HSCT, thus contrasting with some past studies that gave preference to posaconazole.⁵³ In any case, as posaconazole is not available in UHS, voriconazole (available for hospital use) is the viable option in Brazil’s public health system.^{20,28,30–33,54} Micafungin may also be a beneficial option for prophylaxis of IFIs in HSCT patients. It may be used in combination with itraconazole or fluconazole, and this consensus has not changed at present. However, since micafungin is not yet available in UHS, its use is restricted to the private healthcare system.^33–35

Regarding IFI prophylaxis in SOT, it has been observed that variations depend on the transplanted target organ. There is not enough literature in RT highlighting the need for antifungal prophylaxis.⁴³ The literature addresses antifungals in RT when discussing the treatment of IFI in patients who develop the disease. In these cases, it is possible to use both micafungin and voriconazole, since they have similar clinical results.⁴⁶

In LvT, azoles were a better option in past studies, while more current studies show similar efficacy of echinocandins. A systematic review and meta-analysis also concluded no difference between echinocandins and other antifungals in advancement against IFIs. Anidulafungin, micafungin and fluconazole stand out here as agents of choice. Still, micafungin is not available on the UHS and anidulafungin is restricted to those with candidemia and other forms of invasive candidiasis. Thus, fluconazole is still the most viable option in the public system.^46–49,55

In LgT, recent and past studies suggest using azoles as the prophylactic agents. Similarly, a recent study places azoles as first-line antifungal agents in 80% of cases, echinocandins in approximately 18.3%, and amphotericin B in only 1.5%.^50,51 However, a recent systematic review and meta-analysis demonstrated that patients undergoing LgT using voriconazole had an increased risk of developing squamous cell carcinoma, suggesting caution with this particular agent. Furthermore, there is a clear need to choose specific drugs according to the patient, and the various comparative clinical trials demonstrate different strategies.^52,55,56

Past studies were more wary of the echinocandins (the group in which micafungin, anidulafungin, and caspofungin are included), due to the need for daily parenteral administration and the increasing reports of disruptive infections, thus dampening enthusiasm for the use of these agents. Giannella et al. reported that although echinocandins have a low rate of drug interactions, the need for daily parenteral administration was indeed a problem.⁵⁷ However, current studies place echinocandins and azoles on the same level regarding benefits, further encouraging their use for IFI prevention in transplant patients. As for liposomal amphotericin, although this drug does not alter the cytochrome P450 system, its nephrotoxicity has been and continues to be a major concern.^46–50,52

It is also important to note that there is still no consensus on the need for antifungal prophylaxis in all transplant patients. Several programs do not routinely use antifungals perioperatively in these patients, and one study showed a similar incidence of IFI in the absence of prophylaxis.⁵² Thus, new studies, specifically clinical trials and randomized controlled trials, are needed to establish the most appropriate protocols for each condition and patient profile. There needs to be more current data (considering the last five years) on the subject of this study.

ACKNOWLEDGEMENTS

We thank librarian Denise Serrano for helping us technically with the preparation of the references and tables.

• Como citar: Silva MAM, Callera F, Leão MVP. Profilaxia de Infecções Fúngicas em Pacientes Transplantados: O que Mudou nos Últimos Anos? BJT. 2023.26 (01):e0523. https://doi.org/10.53855/bjt.v26i1.475_PORT
• FUNDING
  Not applicable.

DATA AVAILABILITY STATEMENT

All dataset were generated or analyzed in the current study.

References

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Edited by

• Section editor: Ilka de Fátima Santana F Boin https://orcid.org/0000-0002-1165-2149

Publication Dates

• Publication in this collection
  13 Sept 2024
• Date of issue
  2023

History

• Received
  29 June 2022
• Accepted
  03 Jan 2023