INVASIVE MOLD INFECTIONS: ON THE RISE IN CHILDREN

George R Thompson, III, MD: Antonio, invasive mold infections are becoming more prevalent in children. Can you give us some big-picture thoughts on that?

Risk Factors

Antonio Arrieta, MD: Yes, of course. Our oncologists are increasingly successful in treating more cancers in children, particularly hematological malignancies. To do that, they are utilizing significantly more immunosuppressive agents and stretching the limits of available donors for hematopoietic stem-cell transplant (HSCT) treatments. This has resulted in a larger population at risk for fungal infections with improved survival who remain at risk for longer periods of time. The result is a substantially increased incidence of invasive mold infections.1

George R Thompson, III, MD: Yes, it’s been amazing to see these newer oncologic agents and how they’ve improved outcomes for hematologic malignancies. The downside, though, is that they provide longer periods of immunosuppression and seem to accumulate risk for infection over time. We are certainly seeing more cases of Aspergillus spp. and Mucorales infections.1 Are any other fungi increasing in frequency in your patients over the last few years?

Antonio Arrieta, MD: We’ve seen some modest increases in the incidence of Lomentospora prolificans, which is an extremely difficult fungus to treat.2 But in other parts of the world, the incidence of L prolificans is increasing significantly as the climate changes, particularly in areas such as Australia.3 The incidence of Fusarium spp. has also been increasing somewhat, but again there is a geographic distribution. For example, in Brazil, they have reported a significant problem with infections caused by Fusarium spp.4

George R Thompson, III, MD: Those examples point to the need to know your local epidemiology. So, some hospitals have a lot more Aspergillus spp., some have a lot more Mucorales, particularly if construction projects are ongoing. Then, some hospitals are struggling through very resistant infections such as those caused by Fusarium, Lomentospora, and Scedosporium spp. It can be a real challenge.

As we look at these increased risks for mold infections, you mentioned that it’s cumulative—the patients are receiving more potent immunosuppression, and the duration of immunosuppression is also longer. What are other risk factors for invasive mold infections?

Antonio Arrieta, MD: Table 1 provides an overview of risk factors. As I mentioned previously, some of the cancer therapies that are currently being used, particularly in AML, which otherwise has a very low survival rate, are now resulting in prolonged periods of neutropenia. The incidence of fungal infections has increased significantly for these patients. Then, of course, some regimens are utilized to expand the donor pool in HSCT. We are using T-cell depletion and T-cell suppression with medications to try to prevent graft-versus-host disease (GVHD) as a consequence of mismatch between donor and recipient.1,7 Then, of course, when GVHD happens, there are multiple agents that are being utilized, some of them very novel and for which we don’t yet fully understand the risk for infection that may apply. But we know very well that steroids are a significant risk for fungal infections in patients with GVHD.7

Table 1: Risk factors for invasive mold infections in pediatrics.1-17


AML = acute myeloid leukemia; ALL = acute lymphocytic leukemia; CNS = central nervous system; GI = gastrointestinal.

George R Thompson, III, MD: That’s a really good point. For some of these new agents, we think we understand the mechanism of the drug, but they have off-target effects that are not described until the clinical trials. Ibrutinib may be a good example of that. We thought of it as a breakthrough for treatment of hematologic malignancies, chronic lymphocytic leukemia, etc. But we saw those terrible cases of disseminated Aspergillus with the drug, including cases in the central nervous system.13 It’s tough. To me, it’s a reminder that these new drugs are tremendous advances, but that we really need to pay attention and look for some of these off-target effects that might predispose [patients] to infections or other adverse events. What are some other host factors?

Antonio Arrieta, MD: Some of the pediatric primary immunodeficiencies, specifically chronic granulomatous disease (CGD), carry a substantial risk for invasive aspergillosis, primarily pulmonary aspergillosis.14 Typically, these cases do not have the same microbiology that you see in many patients. We see some less common (cryptic) species such as Aspergillus nidulans that could impact diagnosis and management.

George R Thompson, III, MD: And one of the things we saw a lot were these patients who were severely ill with coronavirus disease (COVID-19) in the intensive care unit (ICU) who would develop aspergillosis or mucormycosis. Did you see much of that in the pediatric population?

Antonio Arrieta, MD: Fortunately, we didn’t. We had fewer patients hospitalized, and they were less severely ill. We did have some children in the ICU. We had one kid who ended up in the ICU for almost 3 months, but I can remember only that one kid. So we did not experience what you in the adult world experienced. There have not been many reports of pediatric SARS-CoV-2 infection associated with mold infections,11 but we also do not see as many influenza-associated invasive fungal infections in the ICU. We don’t see that as much in pediatrics.

George R Thompson, III, MD: That’s great to hear. It’s fantastic that the pediatric patients are not having to deal with that as much. What about environmental factors? Lots of hospitals are under construction. Some of our hospitals are fairly old, and they’re added onto. It seems like those are risks for mold infections for our patients.12 And then, also, I don’t think this is as big a deal in the pediatric population, but cannabis has become a big issue for us with the adult population at a risk for mold infections.8

Antonio Arrieta, MD: Well, George, in pediatrics we have expanded our age group and typically, most oncology services now include adolescents and young adults. We typically go up to 26 years of age. So, we do have some cannabis-smoking patients.

Regarding construction, everything changes when there is construction going on: we reroute patients, we have valet parkers to park them away from the area in construction, everybody’s wearing N-95 masks, etc. We use very close surveillance to see if there’s an increased incidence in molds in the area.

TABLE OF CONTENTS

Faculty

George R. Thompson, III, MD

Professor of Medicine
University of California, Davis, School of Medicine
Sacramento, California

Antonio C. Arrieta, MD

Division Chief
Pediatric Infectious Diseases
Children’s Hospital of Orange County (CHOC)
Orange, California

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