The Egyptian Journal of Haematology

: 2015  |  Volume : 40  |  Issue : 2  |  Page : 55--59

Risk and prognostic factors for invasive fungal diseases in paediatric patients with malignancy

Fatma S. E. Ebeid1, Rod Skinner2,  
1 Department of Paediatric Haematology and Oncology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Paediatric and Adolescent Haematology and Oncology, Children's BMT Unit, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

Correspondence Address:
Fatma S. E. Ebeid
Department of Paediatric Haematology and Oncology, Faculty of Medicine, Ain Shams University, Cairo 11566


Background Invasive fungal diseases (IFDs) remain a challenge in the treatment of patients with haematological malignancies. Aims The aim of the study was to evaluate factors that are thought to favour the onset of IFDs and identify prognostic factors that could predict the eventual outcome of these infections. Patients and methods A systematic review of the literature was conducted for an explicit identification of risk and prognostics factors for IFDs in immunocompromised children. We retrospectively reviewed two age-matched and sex-matched patients with refractory acute myeloid leukaemia who had undergone allogeneic bone marrow transplantation. Results Both patients were exposed to the same hospital conditions and had been admitted for the first time at nearly the same period. They had two different paths as regards the development and outcome of IFD. Conclusion Several factors may have an impact on the onset and outcome of IFDs, and identification of these factors is essential to the evaluation and management of IFD and for timely establishment of appropriate antifungal therapy. Egyptian J Haematol 40:-0 ͹ 2015 The Egyptian Society of Haematology.

How to cite this article:
Ebeid FS, Skinner R. Risk and prognostic factors for invasive fungal diseases in paediatric patients with malignancy.Egypt J Haematol 2015;40:55-59

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Ebeid FS, Skinner R. Risk and prognostic factors for invasive fungal diseases in paediatric patients with malignancy. Egypt J Haematol [serial online] 2015 [cited 2020 Apr 10 ];40:55-59
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Over the past years, the number of invasive fungal diseases (IFDs) has continued to persist, primarily because of the growing number of patients subjected to severe immunosuppression, patients undergoing treatment for haematological malignancies and patients undergoing haematopoietic stem cell transplantation (HSCT) [1] .

Fungi are opportunistic pathogens that can cause invasive infections as a result of the concurrence of multiple predisposing factors, an impaired immune system, and exposure to filaments or spores in the environment [2] . Until a few years ago, Candida spp. were held responsible for the majority of fungal infections, but over time a shift in the prevalent pathogens has been observed. At present, the majority of IFDs in severely immunocompromised patients are attributed to moulds [3],[4] . Invasive aspergillosis (IA) is the most common IFD of the respiratory tract, and affects ~20% of patients treated for acute myeloid leukaemia (AML) or myelodysplastic syndrome, and recipients of an HSCT [5] .

Current strategies for the management of IFDs include prophylaxis, empiric, pre-emptive and targeted therapy [6] . Considering the high mortality rate of IFDs [1] and the difficulties in its diagnosis, mould-active primary prophylaxis has been advocated [7] . This strategy implies the administration of broad-spectrum antifungal agents to patients who are at increased risk but who lack any indication of active infection at the time of administration [8] . Secondary prophylaxis or maintenance treatment, aiming at preventing relapse of a previous IFD during a new at-risk period, is generally recommended. The drug of choice in this particular setting should be based on the causative fungal pathogen and the prior response to antifungal therapy [9] . Empirical antifungal therapy is often initiated whenever a fever persists and IFD cannot be excluded as a cause [10] . Targeted therapy relies on treating microbiologically and histologically documented cases of invasive fungal infections (IFIs) [6] .


IFDs remain a challenge in the treatment of patients with haematological malignancies, especially in developing countries with limited resources. This work aims to analyse factors that are thought to favour the onset of IFDs and identify prognostic factors that could predict the eventual outcome of these infections. Consequently, we aim to provide a guide for the selection of candidates for antifungal therapy and the optimal time of administration.

 Patients and methods

A written concent from patients' guardian as well as approval of local ethical commitee was established.

A systematic review was conducted of the literature for an explicit identification of risk and prognostics factors for IFDs in immunocompromised children. The files of two age-matched and sex-matched patients with refractory AML who underwent allogeneic bone marrow transplantation were retrospectively reviewed. Both patients were exposed to the same hospital conditions at the Department of Paediatric and Adolescent Haematology and Oncology, and Children's BMT Unit, at Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne, UK, and had been admitted for the first time at almost the same period. They had two different paths as regards the development and outcome of IFD.

These two patients were selected on the basis of the findings of various studies that involved large numbers of patients and attempted to stratify immunocompromised patients into risk categories (low, intermediate and high risk) for IFD according to incidence and mortality rates. Patients with AML (above all in first induction) and those undergoing allogeneic HSCT were found to be at high risk for developing IFD [5],[11],[12],[13] . Consequently, these two patients were at the greatest risk for developing IFD. Further, some risk factors were thought to be specific to those undergoing allogeneic HSCT. Usually this procedure involves a prolonged period of immunosuppression to facilitate engraftment. Unfortunately, the drugs utilized for this purpose, as well as the transplant procedure itself, create environments that favour the development of IFD [12] .

 Patients' characteristics

The first patient, a 16-year-old male patient, had refractory AML to ADE1 (cytarabine 100 mg/m 2 /12 h day 1-10, daunorubicin 50 mg/m 2 /d day 1, 3, 5, etoposide 100 mg/m 2 /d day 1-5), FLA-ID (fludarabine 30 mg/m 2 /d day 1-5, cytarabine 2 g/m 2 /d day 1-5, idarubicin 10 mg/m 2 /d day 1-3) and also to an investigational drug (aurora kinase AT9283). He responded to intravenous methotrexate and intramuscular PEG-asparaginase course [14] , therfore, another three courses were given. He underwent allogeneic matched unrelated HSCT 8 months after his initial diagnosis, with a conditional regimen consisting of busulfan, cyclophosphamide, melphalan and alemtuzumab (CD52 monoclonal antibodies). As a result, he experienced deep long-lasting neutropenia due to the malignancy, the chemotherapy given and the HSCT process, and he had a central venous line (CVL) inserted for about 18 months.

He developed a few complications in the form of short-lasting grade 2 skin graft-versus-host disease (GVHD), short-lasting mucositis and mild infectious complications. As a consequence, he did not receive multiple courses of antibiotics, and had a low hospital admission rate, having been admitted only for chemotherapy and during the transplant period. He did not receive total parenteral nutrition and tested negative for cytomegalovirus. The patient was on prophylactic antifungal therapy according to the hospital protocol and did not develop any evidence of IFD.

The second patient, a 16-year-old male patient, had refractory AML to ADE1 and FLA-ID. Three months after his initial diagnosis, he had not achieved remission and underwent allogeneic matched-sibling HSCT [15] . His conditioning regimen comprised busulfan, cyclophosphamide and melphalan. Therefore, he experienced deep long-lasting neutropenia from diagnosis until engraftment.

He presented at his initial AML diagnosis with possible widespread pulmonary aspergillosis and initially complained of fever and cough. High-resolution computed tomography demonstrated widespread infiltration in all lung zones, pictures suggestive of fungal infection. Investigations to detect fungal infection, in the form of bronchoalveolar lavage, pleural aspirate, galactomannan and Aspergillus PCR, were negative. This could be explained by the fact that prior administration of antifungals interfere with the accuracy of fungal-specific diagnostic assays, thereby inducing false-negative results [16],[17] . On the basis of the clinical and radiological profiles, he was treated with empirical antifungal therapy in the form of intravenous voriconazole and liposomal amphotericin B for 5 weeks. Follow-up high-resolution computed tomography, 3 months later, demonstrated significant improvement in fungal infection. Besides the probably pulmonary aspergillosis, he developed recurrent infections during the pretransplant period in form of perianal abscess, central line infection and multiresistant Klebsiella spp. blood infection.

His main problem was uncontrolled chronic grade 2 GVHD (skin, oral, liver) for nearly 16 months, which required administration of steroids and other immunosuppressant agents. Consequently, he developed recurrent viral infection after transplant in the form of norovirus, respiratory syncytial virus, metapneumvirus and influenza A. He tested negative for cytomegalovirus. Owing to infections and GVHG complications, he had a long duration of hospital admission: for nearly most of the pretransplant period, the transplant period, and for about 30 days after transplant; in addition he had twice weekly clinic visits. He received many courses of intravenous antibiotics, and the course lasted from 5 to 21 days. A CVL was inserted at diagnosis but was replaced because of line infection; the patient has had a CVL for nearly 2 years now. He developed a short period of mucositis, needed total parenteral nutrition administration because of weight loss, and developed renal impairment.

The patient was initially treated with empirical antifungal therapy, and then received prophylactic antifungal therapy, caspofungin, during the transplant period. Liposomal amphotericin B as a secondary prophylactic antifungal therapy post-transplant was administered because of continuing use of immunosuppressive treatment. The patient did not develop any evidence of flaring or recurrence of IFD.


Over the past two decades, the number of patients at risk of developing IFDs has increased because of the wider use of intensive myelosuppressive and/or immunosuppressive agents in the treatment of haematological cancers [18] . Risk factors that determine proneness to IFDs are discussed below.

Genetic variation within key innate or adaptive immune response genes may influence the susceptibility to, as well as the outcome of, IFD [19] especially when immune defences fail (e.g. interleukin-10 production, toll-like receptor polymorphism and polymorphism in the plasminogen gene) [20],[21],[22] .

Moulds are ubiquitous saprophytes present in air, soil and water; therefore, exposure to these agents is almost universal. The primary mode of acquiring a mould infection is inhalation of fungal spores [2] . In the majority of environment-related cases, IFDs constitute a nosocomial infection, and this may be the result of contamination of the air due to building activities in the hospital [23] , malfunction or contamination of hospital ventilation systems without high-efficiency particulate air filters [24] or disseminated spores originating from potted plants, flowers and carpets [25] , as well as water supplies [26] .

Neutropenia and impaired cell-mediated immunity are the most prominent defects predisposing individuals to mould infections. Neutrophils are essential in the control of fungal infections and in the initiation and execution of the acute inflammatory response; together with monocytes/macrophages, they internalize resting or swollen conidia, and through respiratory burst combat the growth of fungal elements. It is generally accepted that the longer and deeper the neutropenia, the higher the incidence [2] and fatality rate of IFDs [27] . Prolonged neutropenia caused by the lack of recovery of granulocytopoiesis, due to progression of the underlying malignancy that is unresponsive to chemotherapy with increasing burden of leukaemic cells in the bone marrow, is strongly correlated with a poor prognosis [28],[29] and is a predictor of mortality in patients with IA [30] .

AML patients are considered to be at the highest risk of developing IFDs. These patients develop neutropenia as a result of invasion of their bone marrow by leukaemic cells, as well as through the use of myeloablative cytotoxic therapy. Moreover, the function of the few remaining cells is usually debilitated, with dysplastic neutrophils that display a lower fungicidal activity against yeasts and, presumably, moulds [31] . Those patients may also be heavily transfused as a result of full-blown AML after a long episode of pre-existing myelodysplasia, or after an allogeneic HSCT in whom erythropoiesis was slow to recover [32],[33] . The role of iron overload in the emergence of IFD has been highlighted, as iron is essential for the growth and virulence of moulds, and high levels of free iron may enhance mucosal damage and may impair cellular antimicrobial systems [33] .

Drugs used to treat the underlying disease or its complications enhance the risk of IFDs in immunocompromised patients. Steroids are a well-known major risk factor for the development of IFD. They suppress the ability of monocytes/macrophages to kill conidia [34] and inhibit polymorphonuclear cell activity against hyphae [35] . Consequently, its use is correlated with a significant negative impact on the prognosis of IA [36] . Cytotoxic chemotherapy decreases neutrophil numbers as well as their function. The dose and duration of treatment are both essential risk factors [37] . Treatment regimens that involve new antineoplastic or immunosuppressive agents, particularly purine analogues (e.g. fludarabine) and antibodies targeted against T lymphocytes, are thought to enhance the risk of IFD. These agents may also induce prolonged lymphocytopenia with an impairment of cell-mediated immunity [38],[39] .

The incidence of IFDs in HSCT recipients varies according to the type of transplant (autologous or allogeneic), HLA matching (matched or mismatched), relatedness of the donor (related or unrelated), conditioning regimen (myeloablative or nonmyeloablative) and source of stem cells (bone marrow, peripheral blood or cord blood) [40] . The increased use of unrelated and HLA-mismatched donors [41],[42] and the use of alternative stem cell sources such as umbilical cord blood have led to increased risk for IFD [43],[44] . Time after a transplant procedure is also important: the early phase, within the first 30 days of the allogeneic HSCT, is characterized by neutropenia, lymphocytopenia and mucosal damage, which can be aggravated by acute GVHD. During the late phase, after 100 days of the procedure, impairment of cellular and humoral immunity is usually overcome, supplemented by other risk factors such as chronic GVHD, relapsing underlying malignancy, cytomegalovirus infection and administration of steroids or immunosuppressant agents (e.g. sirolimus, cyclosporine and infliximab) [45],[46] .

It is noteworthy that in a patient who acquires IA during pretransplant conventional chemotherapy the risk of recrudescence when he or she subsequently undergoes HSCT is extremely high [47] . In allogeneic HSCT recipients, both acute and chronic GVHD are instrumental in the onset of IFD, although they do not seem to have an impact on the outcome of IFD [28],[30],[36] . However, when uncontrolled GVHD coincides with IA, the prognosis will be dismal, as suppression of the host defence mechanisms to control GVHD will be inevitable and devastating [48] .

The overall prognosis of IFD depends on several factors, including the site of infection, the rapidity of diagnosis and the type and severity of immunosuppression [49] . A crucial factor in optimizing therapy in any patient with IA is the decrease or elimination of the immunosuppressant whenever possible [6] . As a general rule, allogeneic HSCT recipients, patients not in remission of their malignancy and individuals with an uncontrolled disseminated disease will have the worst outcome if they have to be treated for IA [2] . Other well-established negative prognostic factors are proven IFD [28],[50] and renal and liver insufficiency [36],[48] .

Various studies have demonstrated that clinical practice can also influence the outcome of IFD as an appropriate therapeutic approach, early diagnosis and early initiation of appropriate antifungal therapy [49] are correlated with a better prognosis [28],[30],[36],[48],[50] . The literature suggests that if patients are diagnosed and treated early with appropriate antifungal therapy the response rates may reach 50% or greater [6] .


Several factors may have an impact on the onset and outcome of IFDs, and identification of these factors is essential in the evaluation and management of IFD and for timely establishment of appropriate antifungal therapy.


Conflicts of interest

There are no conflicts of interest.


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