Effective prevention, treatment of rare invasive fungal infections requires ‘heightened awareness,’ research efforts

HemOnc Today and Infectious Disease News spoke with Thomas J. Walsh, MD, director of the Transplantation-Oncology Infectious Disease Program; chief of Infectious Diseases Translational Research Laboratory; professor of medicine, pediatrics, and microbiology and immunology; and the Henry Schueler Foundation Scholar in Mucormycosis at Weill Cornell Medicine of Cornell University, about the prevalence of rare infectious diseases in patients with cancer or HIV and how these diseases may complicate treatment. In this interview, Walsh discusses existing and emerging therapeutic options, and how the inherent nature of these infections makes research challenging.

Question: There are thousands of rare diseases. Which require the most urgent attention and why?

Answer: The question recognizes the extraordinary breadth of rare diseases, many of which overlap and can impact upon the same group of patients. Most importantly, one must recognize that collectively, rare diseases inflict suffering and often, unfortunately, death on numerous patients. Rather than prioritize one disease over another, I think that a broader sense is needed of the importance of these diseases, particularly as they pertain to individual specialty areas. For example, in the field of hematology/oncology and immunocompromised patients, we recognize rare infections, which, in that population, may not be so rare and can create terrible suffering and unfortunately death.

Thomas Walsh

Thomas J. Walsh, MD

Q: How prevalent are invasive fungal infections in patients with cancer, and why do they occur?

A: The prevalence and the incidence of invasive fungal infections in patients with cancer vary depending upon the net state of immune suppression. In days before we had developed effective antifungal prophylaxis, we were looking at frequencies of invasive fungal infections as high as 15% to 20%. That frequency has dropped substantially to approximately 5% to 10%. Yet, this is still a heavy burden of disease, with devastating life-threatening infections that often break through our current existing antifungal prophylactic therapy. Indeed, the more immunosuppressed the patient population is — such as those with hematological malignancies or undergoing allogeneic stem cell transplant, especially if it's complicated by graft-versus-host disease — then the greater the frequency of invasive mycoses. This is a very serious burden of disease for which there can be often minimal therapeutic options available.

Q: Why are invasive fungal infections especially difficult to diagnosis in patients with cancer? Are there specific signs and symptoms that could alert oncologists to the presence of these infections?

A: Unlike bacteria, such as Escherichia coli or Pseudomonas aeruginosa — which have endotoxin that elicit septic manifestations in femtomole concentrations — fungi, as eukaryotic organisms, do not necessarily have the biochemical signatures that may elicit a high degree of fever and sepsis features until the infections are more advanced. Pathogenic fungi tend to grow more slowly, more insidiously, and often are deeply invasive in tissues before they reach the bloodstream. They invade the lungs causing nonspecific pulmonary infiltrates, which could easily simulate a bacterial pneumonia. Thus, in many regards, the clinical manifestations of invasive mycoses in their early stages are often subtle or nonspecific in immunocompromised patients with hematological malignancies, thus thwarting a timely and definitive diagnosis.

We do, however, use some very practical clinical approaches toward early diagnosis of invasive fungal infections in patients with hematological malignancies. One is recognition of persistent fever without an apparent bacterial cause. In that situation, fungi may be emerging as an invasive fungal infection such as candidemia and disseminated candidiasis. Patients with persistent pulmonary infiltrates, such as pneumonia that is not responding to antibacterial antibiotics, is another common setting for invasive aspergillosis. Persistent sinus and lung opacities in a neutropenic patient may indicate the development of mucormycosis. Yet another example of a physical finding is the development of cutaneous lesions caused by disseminated fusariosis that emerge during antibacterial therapy.

All of these settings should prompt one to move quickly toward more deliberate diagnostic procedures such as blood cultures; bronchoalveolar lavage (BAL); sinus endoscopy; and CT scanning of the chest, sinuses or abdomen. We also have newer diagnostic assays for cell wall biomarkers, such as galactomannan in serum and BAL fluid for pulmonary aspergillosis, as well as (1—>3)- b-D-glucan in serum for invasive candidiasis, aspergillosis and several other mycoses.  Polymerase chain reaction technology for invasive fungal infections also is evolving with greater utility and availability. However, for many of the less common fungi, such as the Mucorales, Fusarium spp., and Scedosporium spp., we may not have diagnostic tools by which to recognize their infections at an early stage. Thus, clearly, much more work needs to be done in terms of early diagnosis and rapid detection.

Q: What specific measures can patients with cancer and their clinicians take to prevent infections during cancer treatment?

A: There have been a number of very well-conducted randomized clinical trials showing the benefit of antifungal prophylaxis. These studies establish a foundation for the standard of care of our very high-risk patients with hematological malignancies for prevention of invasive fungal infections. However, we do see that there are fungi that will break through antifungal prophylaxis. These organisms, which are often are resistant to the prophylactic antifungal agent, include non-albicans Candida spp., Fusarium, Mucorales and Pseudallescheria spp. and pose a threat to our patients, thereby underscoring the need for more effective antifungal therapies and for better diagnostic tools.

Q: How does the occurrence of infections complicate cancer treatment?

A: Invasive fungal infections and other infection may complicate cancer treatment in several important ways. Independently, invasive fungal infections can contribute significantly to mortality. They can also result, once the infection has established, in increasing length of stay.   Invasive fungal infections also may delay in timeliness of antineoplastic therapy. If the infection is not under control, then potentially curative antineoplastic therapy may be delayed. If the invasive mycosis is still not under control and the patient is candidate for a stem cell transplantation, then the transplant may be delayed until the infection is controlled. If surgery is required for the management of a mould infection, then chemotherapy or transplantation may be delayed to allow for wound healing. Moreover, when antifungal agents are being used, some of them may interfere with metabolic clearance of the chemotherapeutic agents, resulting in severe adverse events. These include vincristine and triazole interaction, resulting in delayed CYP3A4-mediated clearance of the vinca alkaloid and potentially severe autonomic nervous system dysfunction.

Q: What challenges exist in the development of new drugs for rare invasive fungal infections? Have there been any recent strides in overcoming these challenges?

A: The challenges are such that organisms of the Kingdom fungi are eukaryotic, being that they have nuclei as well as cell membranes and organelles similar to those with mammalian cells.  Thus, discovering and developing new antimicrobial agents that are specific for fungi and will not also compromise mammalian cells is challenging.

Then, of course, there is always the risk–benefit for safety and toxicity whenever we do discover a new agent. The challenge is inherent in developing new compounds for uncommon or rare infections. Among the more recent developments that have occurred, isavuconazole (Cresemba, Astellas) was approved for treatment of invasive aspergillosis following a large noninferiority study compared it with voriconazole. Also very importantly, isavuconazole was approved as primary therapy for mucormycosis, a particularly devastating infection for which we only have one class of agents — the polyenes (amphotericin B). Isavuconazole is the first agent approved in more than a half a century for the primary treatment for mucormycosis. New agents for this infection are critically needed as they typically are resistant and they cause some of the most devastating destructive infections involving the lungs, sinuses and brain. The development of new agents for mucormycosis, such as isavuconazole, are a welcome advance.

Q: What are some effective strategies to protect transplant recipients from infections like aspergillosis?

A: Among the strategies for prevention, most commonly we use a prophylactic regimen. There are two phases, one of which occurs during the preparative regimen. During this phase, the main host defect is neutropenia, for which strategies have been developed for prevention of invasive fungal infections. Typically, one would use posaconazole (Noxafil, Merck), voriconazole, or fluconazole (Diflucan, Pfizer) for this indication. That can be backed up by empirical or preemptive antifungal therapy with liposomal amphotericin B during the neutropenic phase. During the post engraftment phase, in which patients are at risk for graft-versus-host disease, immunosuppression often with corticosteroids is needed. In that kind of situation, we will then also use an antifungal agent, such as posaconazole or voriconazole, where the risk of invasive aspergillosis and other mould infections is high. However, even then, those agents may not be fully able to prevent all invasive fungal infections. For example, when mucormycosis breaks through these antifungal triazoles, we would use liposomal amphotericin B to definitively treat such a breakthrough infection.

Q: How is the HIV population impacted by invasive fungal infections?

A: The HIV population is at particularly high risk for development of invasive mycoses before having immune constitution with antiretroviral agents. During that early phase, they are at risk for fungal diseases. These include cryptococcosis or cryptococcal meningitis, a particularly devastating infection with worldwide estimates of approximately 1.2 million incidents and mortality approaching 50% to 60%. It is a very serious infection. A second infection is Pneumocystis pneumonia, which can be a very debilitating infection of the lungs. These patients also may develop oropharyngeal and esophageal candidiasis. These are the three most common invasive fungal infections that will complicate HIV and can be very debilitating and potentially lethal. HIV-infected patients also are at increased risk for development of pulmonary and disseminated mycoses caused by dimorphic endemic fungi, including Histoplasma capsulatum, Coccidioides spp., and Telaromyces marneffei (formerly Penicillium marneffei).

Q: What is your take-home message for health care providers about rare diseases?

A: We need to underscore the global importance of the morbidity, mortality and human toll of suffering that occurs from rare diseases. For specific conditions that individual physicians may see within their own specialty, there should be a heightened awareness for rare diseases included within their differential diagnosis. There clearly needs to be accelerated research in the epidemiology, pathogenesis, host defenses, diagnosis, treatment and prevention of invasive fungal infections to improve prognosis and offer new hope for those patients afflicted with these often lethal diseases.

For more information:
 
Thomas J. Walsh, MD, can be reached at Weill Cornell Medicine, 1300 York Ave, New York, NY 10065.

Disclosure: Walsh reports support as an investigator of the Save Our Sick Kids Foundation, the Henry Schueler Foundation as a Scholar in Mucormycosis, and the Sharpe Family Foundation as Scholar in Emerging Infectious Diseases. Walsh also reports research grants for experimental and clinical antimicrobial pharmacotherapeutics from Astellas, Novartis, Merck/Cubist and Pfizer, as well as consultant roles with Astellas, Merck/Cubist, Novartis, Pfizer and Methylgene.

HemOnc Today and Infectious Disease News spoke with Thomas J. Walsh, MD, director of the Transplantation-Oncology Infectious Disease Program; chief of Infectious Diseases Translational Research Laboratory; professor of medicine, pediatrics, and microbiology and immunology; and the Henry Schueler Foundation Scholar in Mucormycosis at Weill Cornell Medicine of Cornell University, about the prevalence of rare infectious diseases in patients with cancer or HIV and how these diseases may complicate treatment. In this interview, Walsh discusses existing and emerging therapeutic options, and how the inherent nature of these infections makes research challenging.

Question: There are thousands of rare diseases. Which require the most urgent attention and why?

Answer: The question recognizes the extraordinary breadth of rare diseases, many of which overlap and can impact upon the same group of patients. Most importantly, one must recognize that collectively, rare diseases inflict suffering and often, unfortunately, death on numerous patients. Rather than prioritize one disease over another, I think that a broader sense is needed of the importance of these diseases, particularly as they pertain to individual specialty areas. For example, in the field of hematology/oncology and immunocompromised patients, we recognize rare infections, which, in that population, may not be so rare and can create terrible suffering and unfortunately death.

Thomas Walsh

Thomas J. Walsh, MD

Q: How prevalent are invasive fungal infections in patients with cancer, and why do they occur?

A: The prevalence and the incidence of invasive fungal infections in patients with cancer vary depending upon the net state of immune suppression. In days before we had developed effective antifungal prophylaxis, we were looking at frequencies of invasive fungal infections as high as 15% to 20%. That frequency has dropped substantially to approximately 5% to 10%. Yet, this is still a heavy burden of disease, with devastating life-threatening infections that often break through our current existing antifungal prophylactic therapy. Indeed, the more immunosuppressed the patient population is — such as those with hematological malignancies or undergoing allogeneic stem cell transplant, especially if it's complicated by graft-versus-host disease — then the greater the frequency of invasive mycoses. This is a very serious burden of disease for which there can be often minimal therapeutic options available.

Q: Why are invasive fungal infections especially difficult to diagnosis in patients with cancer? Are there specific signs and symptoms that could alert oncologists to the presence of these infections?

A: Unlike bacteria, such as Escherichia coli or Pseudomonas aeruginosa — which have endotoxin that elicit septic manifestations in femtomole concentrations — fungi, as eukaryotic organisms, do not necessarily have the biochemical signatures that may elicit a high degree of fever and sepsis features until the infections are more advanced. Pathogenic fungi tend to grow more slowly, more insidiously, and often are deeply invasive in tissues before they reach the bloodstream. They invade the lungs causing nonspecific pulmonary infiltrates, which could easily simulate a bacterial pneumonia. Thus, in many regards, the clinical manifestations of invasive mycoses in their early stages are often subtle or nonspecific in immunocompromised patients with hematological malignancies, thus thwarting a timely and definitive diagnosis.

We do, however, use some very practical clinical approaches toward early diagnosis of invasive fungal infections in patients with hematological malignancies. One is recognition of persistent fever without an apparent bacterial cause. In that situation, fungi may be emerging as an invasive fungal infection such as candidemia and disseminated candidiasis. Patients with persistent pulmonary infiltrates, such as pneumonia that is not responding to antibacterial antibiotics, is another common setting for invasive aspergillosis. Persistent sinus and lung opacities in a neutropenic patient may indicate the development of mucormycosis. Yet another example of a physical finding is the development of cutaneous lesions caused by disseminated fusariosis that emerge during antibacterial therapy.

All of these settings should prompt one to move quickly toward more deliberate diagnostic procedures such as blood cultures; bronchoalveolar lavage (BAL); sinus endoscopy; and CT scanning of the chest, sinuses or abdomen. We also have newer diagnostic assays for cell wall biomarkers, such as galactomannan in serum and BAL fluid for pulmonary aspergillosis, as well as (1—>3)- b-D-glucan in serum for invasive candidiasis, aspergillosis and several other mycoses.  Polymerase chain reaction technology for invasive fungal infections also is evolving with greater utility and availability. However, for many of the less common fungi, such as the Mucorales, Fusarium spp., and Scedosporium spp., we may not have diagnostic tools by which to recognize their infections at an early stage. Thus, clearly, much more work needs to be done in terms of early diagnosis and rapid detection.

Q: What specific measures can patients with cancer and their clinicians take to prevent infections during cancer treatment?

A: There have been a number of very well-conducted randomized clinical trials showing the benefit of antifungal prophylaxis. These studies establish a foundation for the standard of care of our very high-risk patients with hematological malignancies for prevention of invasive fungal infections. However, we do see that there are fungi that will break through antifungal prophylaxis. These organisms, which are often are resistant to the prophylactic antifungal agent, include non-albicans Candida spp., Fusarium, Mucorales and Pseudallescheria spp. and pose a threat to our patients, thereby underscoring the need for more effective antifungal therapies and for better diagnostic tools.

Q: How does the occurrence of infections complicate cancer treatment?

A: Invasive fungal infections and other infection may complicate cancer treatment in several important ways. Independently, invasive fungal infections can contribute significantly to mortality. They can also result, once the infection has established, in increasing length of stay.   Invasive fungal infections also may delay in timeliness of antineoplastic therapy. If the infection is not under control, then potentially curative antineoplastic therapy may be delayed. If the invasive mycosis is still not under control and the patient is candidate for a stem cell transplantation, then the transplant may be delayed until the infection is controlled. If surgery is required for the management of a mould infection, then chemotherapy or transplantation may be delayed to allow for wound healing. Moreover, when antifungal agents are being used, some of them may interfere with metabolic clearance of the chemotherapeutic agents, resulting in severe adverse events. These include vincristine and triazole interaction, resulting in delayed CYP3A4-mediated clearance of the vinca alkaloid and potentially severe autonomic nervous system dysfunction.

Q: What challenges exist in the development of new drugs for rare invasive fungal infections? Have there been any recent strides in overcoming these challenges?

A: The challenges are such that organisms of the Kingdom fungi are eukaryotic, being that they have nuclei as well as cell membranes and organelles similar to those with mammalian cells.  Thus, discovering and developing new antimicrobial agents that are specific for fungi and will not also compromise mammalian cells is challenging.

Then, of course, there is always the risk–benefit for safety and toxicity whenever we do discover a new agent. The challenge is inherent in developing new compounds for uncommon or rare infections. Among the more recent developments that have occurred, isavuconazole (Cresemba, Astellas) was approved for treatment of invasive aspergillosis following a large noninferiority study compared it with voriconazole. Also very importantly, isavuconazole was approved as primary therapy for mucormycosis, a particularly devastating infection for which we only have one class of agents — the polyenes (amphotericin B). Isavuconazole is the first agent approved in more than a half a century for the primary treatment for mucormycosis. New agents for this infection are critically needed as they typically are resistant and they cause some of the most devastating destructive infections involving the lungs, sinuses and brain. The development of new agents for mucormycosis, such as isavuconazole, are a welcome advance.

Q: What are some effective strategies to protect transplant recipients from infections like aspergillosis?

A: Among the strategies for prevention, most commonly we use a prophylactic regimen. There are two phases, one of which occurs during the preparative regimen. During this phase, the main host defect is neutropenia, for which strategies have been developed for prevention of invasive fungal infections. Typically, one would use posaconazole (Noxafil, Merck), voriconazole, or fluconazole (Diflucan, Pfizer) for this indication. That can be backed up by empirical or preemptive antifungal therapy with liposomal amphotericin B during the neutropenic phase. During the post engraftment phase, in which patients are at risk for graft-versus-host disease, immunosuppression often with corticosteroids is needed. In that kind of situation, we will then also use an antifungal agent, such as posaconazole or voriconazole, where the risk of invasive aspergillosis and other mould infections is high. However, even then, those agents may not be fully able to prevent all invasive fungal infections. For example, when mucormycosis breaks through these antifungal triazoles, we would use liposomal amphotericin B to definitively treat such a breakthrough infection.

Q: How is the HIV population impacted by invasive fungal infections?

A: The HIV population is at particularly high risk for development of invasive mycoses before having immune constitution with antiretroviral agents. During that early phase, they are at risk for fungal diseases. These include cryptococcosis or cryptococcal meningitis, a particularly devastating infection with worldwide estimates of approximately 1.2 million incidents and mortality approaching 50% to 60%. It is a very serious infection. A second infection is Pneumocystis pneumonia, which can be a very debilitating infection of the lungs. These patients also may develop oropharyngeal and esophageal candidiasis. These are the three most common invasive fungal infections that will complicate HIV and can be very debilitating and potentially lethal. HIV-infected patients also are at increased risk for development of pulmonary and disseminated mycoses caused by dimorphic endemic fungi, including Histoplasma capsulatum, Coccidioides spp., and Telaromyces marneffei (formerly Penicillium marneffei).

Q: What is your take-home message for health care providers about rare diseases?

A: We need to underscore the global importance of the morbidity, mortality and human toll of suffering that occurs from rare diseases. For specific conditions that individual physicians may see within their own specialty, there should be a heightened awareness for rare diseases included within their differential diagnosis. There clearly needs to be accelerated research in the epidemiology, pathogenesis, host defenses, diagnosis, treatment and prevention of invasive fungal infections to improve prognosis and offer new hope for those patients afflicted with these often lethal diseases.

For more information:
 
Thomas J. Walsh, MD, can be reached at Weill Cornell Medicine, 1300 York Ave, New York, NY 10065.

Disclosure: Walsh reports support as an investigator of the Save Our Sick Kids Foundation, the Henry Schueler Foundation as a Scholar in Mucormycosis, and the Sharpe Family Foundation as Scholar in Emerging Infectious Diseases. Walsh also reports research grants for experimental and clinical antimicrobial pharmacotherapeutics from Astellas, Novartis, Merck/Cubist and Pfizer, as well as consultant roles with Astellas, Merck/Cubist, Novartis, Pfizer and Methylgene.