Hi, welcome to today's webinar, Managing Secondary Fungal Infections in Patients with COVID-19. My name is Dr. Ryan Mabes. I'm a professor of medicine and anesthesiology at Wake Forest School of Medicine in Winston-Salem, North Carolina. I also serve as a faculty intensivist and infectious disease specialist at Wake Forest Baptist Medical Center. I completed my internal medicine residency and fellowships in ID and critical care at the Naval Medical Center in San Diego. Following my fellowship, I served at the Naval Medical Research Unit Number 6 in Lima, Peru, working on studies in antimicrobial drug resistance and vaccine development. I am board-certified in internal medicine, infectious diseases, and critical care. And in SCCM, I have the privilege of serving on the Congress Program Committee, the FCCS Resource-Limited Committee, and I am the current vice chair of the Fundamental Disaster Management Committee. I have the privilege of moderating today's webcast. This webcast is being recorded. The recording will be available to registrants within 24 to 48 hours. To access, you'll be able to go to covid19.sccm.org slash webcast. This will be available later in the presentation as well. As a disclaimer, this educational activity was funded in part by a cooperative agreement with the Centers of Disease Control and Prevention. The CDC is an agency within the Department of Health and Human Services of the U.S. government. The contents of this resource center do not necessarily represent the policy of CDC or HHS and should not be considered an endorsement by the U.S. federal government. Also, this presentation is for educational purposes only. Material presented is intended to represent an approach, view, statement, or opinion of the presenter that may be helpful to others. These views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of the Society of Critical Care Medicine. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. So, a few housekeeping items before we get started. There will be a Q&A at the conclusion of both presentations. To submit questions throughout the presentation, go ahead and type into the question box located on your control panel. And now I have the privilege of introducing our speakers for today. Our first presenter today is Dr. Kieran Marr. She is the Medical Director of the Transplant and Oncology Infectious Diseases Program and a Professor of Medicine and Oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Marr is a member of several international and professional organizations, numerous scientific steering committees, and has authored over 200 peer-reviewed publications and textbook chapters and edited two books in the area of infectious diseases involving immunocompromised hosts. She is known worldwide for her translational and clinical research focused on diagnostics and the treatment of invasive fungal infections. I will tell you off-script here that as a former ID Fellowship Director, my fellows and I read Dr. Marr's articles as though they were prophecy. Her research led to the establishment of a JHU spinoff company, MycoMed Technologies, which was focused on the development of diagnostics to enable early treatment of fungal infections in medically immunosuppressed people. She has an active interest in healthcare innovation and entrepreneurship and serves as a Vice Chair in the Johns Hopkins Department of Medicine focusing on innovation in healthcare implementation. Our second presenter is Dr. Anne Coste. Dr. Coste is an infectious disease physician at Brest University Hospital in France. She trained in Montpellier University Hospital and at Brest University Hospital. She has a Master's Degree in Modeling and Clinical Pharmacology from the University of Rennes. Her areas of interest include pharmacokinetics, pharmacodynamics, antifungal agents, and invasive fungal infections in both immunosuppressed and ICU patients. Now I'll turn things over to our first presenter, Dr. Marr. Please take it away. Thank you, Dr. Mabes. It's a pleasure to be here, and thank you for the invitation, and thanks everyone for your attention. I'm going to address fungal infections associated with severe respiratory virus infections with a focus on epidemiology and risks. Here are some disclosures, and I'll start with a background not only about mold infections but about the relationship between invasive aspergillosis and influenza, something that's been appreciated for a long time, and then transition to discussion on COVID-associated pulmonary aspergillosis, or what we call CAPA, and COVID-associated mucormycosis, or what some people are terming CAM. Just in a way of context and to remind me to discuss some of the fundamental things about pulmonary mold infections, keep in mind that these are very robust environmental organisms that are inhaled constantly. I've seen data that suggests that actually we take in about 10 spores with every breath, and most of the time we're clearing these. The spore types and growth preferences can influence where they stay in the respiratory tract, with large spores getting large in the sinuses, and small spores, such as those that are given off by ascomycetes, such as aspergillus species, transitioning further down into the respiratory tract. Some molds can grow better in different environments and are hardier. These are really not attuned to being pathogenic per se, but they actually do prefer to be in the environment and composts, etc. There are also data that suggests quite a lot of epidemiologic and seasonal variability with exposure to airborne molds. The relationship between severe respiratory virus infections and fungal pneumonia is actually very well documented. If you look at immunosuppressed hosts, respiratory virus infections are one of the strongest predictors of subsequent invasive aspergillosis, and this is most commonly seen for influenza and respiratory syncytial virus infections. This dates back several decades. Invasive aspergillosis was actually reported as a complication of SARS in 2003. This came out in reports from China with necrotic pneumonia occurring in SARS patients receiving corticosteroids, and an interesting Canadian study actually showed that 10% of patients with SARS had pathologic findings that are suggestive of aspergillosis at autopsy. We also know that invasive aspergillosis is recognized as a complication of severe influenza, and there's been quite a lot of work that has gone into this subject, dating back to 1952, where Abbott wrote the first report of an autopsy that documented invasive aspergillosis as a complication of severe influenza virus infection. Subsequent to 2009 and recognition of the H1N1 virus, there were increasing reports of the association of aspergillosis occurring after severe influenza, and most of these studies have been done in the European Union, Taiwan, and Canada. I've summarized a table here that really puts together some of the larger findings and some of the larger studies. There's about a 16% to 19% incidence in ICU patients who are admitted there for severe influenza disease, and about a 45% to 61% mortality in these studies. Risks are a little bit difficult to discern because people are sick. What we can say is that lymphopenia associated with influenza may be associated with subsequent aspergillosis, and that it looks like it's more common in people with certain influenza virus types, such as H1N1. Important to also note that disease cannot only be invasive pneumonia, such as what we appreciate in immunosuppressed patients, but there's more tracheobronchial disease in these patients as well. Interestingly enough, this is poorly recognized by U.S. physicians. There have been two survey studies that have documented that only about 16% of critical care physicians and 26% of infectious disease specialists actually recognize the association. So we do have a lot of subsequent education to be done. But it's not surprising that in that context, when COVID emerged from China into Europe, that there were many different investigators that were looking for aspergillosis as a complication of severe COVID disease. And what happened, and I've summarized the timeline here, is that there were subsequently several different case series that emerged, first from France, and then from Germany, the Netherlands, Austria, Belgium, and then some better performed prospective studies that were estimating prevalence of disease in people with severe COVID-19 admitted to the ICU. This is a timeline that stops, actually, last summer. It has been gone on to be updated with several different important case series that I'm going to try and summarize here. One important one was this study from Bartoletti, an Italian prospective study that evaluated 108 ICU patients, and they reported a trend to lower mortality in people that had received boriconazole compared to no boriconazole. This is the survival probability shown here. Low numbers and a lot of risks for death, clearly, but treatment with boriconazole trending to better outcomes really suggested that this is not merely a colonization state, but there is some impact of the fungus in the airways or in the lungs, generating poor outcomes. Another study by White was published in Clinical Infectious Diseases last year in August. This was a UK multicenter study that reported an incidence of kappa of 26.7% in 135 ICU patients, and this was a combined incidence of both mold and yeast infections. Mortality was lower, again, with therapy, and risk was suggested to be recedive corticosteroids, dexamethasone, as well as underlying pulmonary disease. We did a study at Johns Hopkins led by Nate Perpelang, and we evaluated patients in the ICU in multiple different Johns Hopkins-affiliated centers and found that 39 out of 396 patients had what's met our criteria for kappa, and our multivariable models, this was most common in people with pulmonary vascular disease, liver disease, coagulopathies, solid tumors, multiple myeloma, lower BMIs, and corticosteroid receipt. We actually modeled the impact of the diagnosis according to multiple different variables and found that people that had COVID-associated pulmonary aspergillosis had worse ordinal severity of disease scores, longer time to improvement, twice as long intubation duration, and longer hospital stays. This has been a trend that has been consistent at Johns Hopkins, and we continue to monitor the diagnosis and therapy and outcomes, and we'll be publishing even larger studies soon. It's not to say that it's what other centers are seeing, and I'll just point to this one, a small study done in Michigan that reported only three of 256 patients were noted to have kappa. There is as well a whole lot of diagnostic variability and case reporting variability as well as potentially epidemiologic variability, and these are going to be some of the things that will be focused in the next talk. There's another French multicenter cohort that's been recently published, 366 patients in the ICU, in which 19.4% people had respiratory samples tested after decompensation, and quite a number of patients who had disease in that setting, 21. The risks in this study included recidivisithromycin and high-dose dexamethasone, and consistent with previous findings, mortality was higher in that cohort study as well. Several review of the literatures have been published now. This is one that was published relatively recently of 186 kappa cases that were reported between March and August of 2020. You can see the geographic variability in reports there with a lot of these reports coming out of Europe. They also summarized the diagnosis was a median of 10 days after a diagnosis of COVID using PCR. Older in age, and mainly men, I think these risks also overlapped the risks for having severe COVID, so do the risks reported here. I also wanted to note that there's a lot of variability in microbiology with some of the organisms that have been reported, including Aspergillus lenchilus and Cholitoeustes being ones that can be variably resistant to a lot of the antifungals that we use, including polyenes as well as mold-active azoles. So potentially keeping an eye out for azole resistance and antifungal susceptibilities in these organisms is important. This is an autopsy study of proven kappa cases that were diagnosed in 25 consecutive autopsies in Italy. This was 20% of the consecutive autopsies that were evaluated, 7 of 17 in the first wave and then fewer in the second wave of COVID in those institutions. Most of these were men and older in age, and you can see clearly necrotic and invasive disease occurring on autopsy in those patients. Another review of autopsies that have been reported in the literature summarized a much lower rate in 2% of cases that had pulmonary aspergillosis documented. Most of these cases of autopsies performed and summarized were in the U.S., so whether this reflects diagnostic variability, treatment variability or geographic epidemiologic variability I think at this point is unclear. This is for sure a variable pathobiology. Remember that these organisms are inhaled into the airway in a spore form and then germinate a more inflammatory hyphal form that can evoke a lot of creation of inflammation and potentially invasion into the lungs. There are a lot of COVID-associated risks that can mediate both the innate clearance in the airways as well as that secondary wave of immunity, both with regards to recruited phagocytic cells that are important to clearing the invasive infection as well as cellular immunity. I'll also end with a little summary on what has taken a lot of attention lately, and that's COVID-associated mucormycosis. In May, there were over 28,000 cases in India, and I've read that more recently the government is summarizing that there are now greater than 40,000 documented cases in India. There's very little in the literature, but I'll summarize some. This is a systematic review of the literature, only 99 cases that was reported early on after recognition of this syndrome. Most of them are occurring in India in men and in people that have diabetes. COVID-associated mucormycosis is largely diagnosed during severe COVID-19, a median of 15 days after diagnosis, 37% after resolution. So there is a long timeline of risks. Only 24% occur in people that have mild COVID-19. In this review, 85% of cases were associated with receipt of steroids, and most of them are disease that are apparent in the rhinoorbital and the rhinoorbital cerebral region. This is an epidemiologic study that was summarized by ophthalmologists in India during this dramatic surge during the second wave, during these dates, and these were over 2,000 patients that were managed by ophthalmologists during that period of time. Cases were highest in the region where most of the cases of severe COVID-19 were occurring in the southern region of India. Most cases I wanted to show this timeline occur at 10 to 15 days after diagnosis, but you can see this long tail in timing. So coming back with COVID-associated mucormycosis is not uncommon. Also I'd like to point out that the prevalence of this disease has been historically underestimated, however globally known to be highest in India. This is a really nice summary of global epidemiology pre-pandemic, and if you look at the rates of reported disease of mucormycosis, India has historically had the highest rates of mucormycosis globally, and it's probably a factor of underlying host risks as well as epidemiologic exposure. Diabetes as a risk is reported in 17 to 88 percent globally for this infection, but in the three case series that were performed pre-pandemic, it was reported that greater than 50 percent of people in India do have diabetes as a risk, and it's known to have a high nationwide prevalence at 7.3 percent, or about 77 million people with diabetes. In all of these studies, there's an element of seasonality that has been documented in other places around the world as well, and so it may not be consistent throughout the time of year and is really poorly understood, but you do see these variations according to weather and air humidity, for instance. So this is a nice review that summarizes the risks for COVID-associated mucormycosis with environmental factors coming into play, exposure indoors as well as in the outdoor environment, potentially with agriculture activities, as well as host factors. That can include steroid use, iron overload, as well as specific virus-associated exocrine damage to the beta cells in the pancreas, and potentially even specific viral risks in the lungs. In fact, this review, I think, is another good summary of the multiple risks that come into play, also suggesting that there's an element of viral-associated endothelitis that increases expression of the glucose-regulated protein, which is a heat shock protein, and interestingly enough, both the virus as well as mucor species, spore-binding proteins, actually utilize this receptor to be internalized into the endothelium. And so there may be true biologic pathogenicity that explains the increase in mucormycosis risks relative to other filamentous infections as well. I'll just end here in summarizing that filamentous fungal infections are increasingly recognized with severe viral infections. There's a complex pathogenesis. There is a documented association with both aspergillosis and mucormycosis, probably a multivariable risks associated with hosts, exposures, and treatments. There's a lot of differences in diagnosis and reporting. Definitions have been proposed and not validated, and we're going to hear a lot more about definitions, diagnosis, and management by Dr. Costa, and I will hand over to her. Thank you for your attention. Thank you, Dr. Marr. I will tell you about diagnosis and management of COPA. Here's a slide. First, we'll talk about clinical syndrome associated with invasive aspergillosis in COVID patients, clinical and radiological presentation of COPA, COPA diagnosis, and finally, COPA management. Dr. Marr introduced you to the pathophysiology of COPA. When infected with COVID-19, viruses cause airway epithelial damage. Epithelial cell death results in disrupted epithelial junction, imbalanced ciliary function, and release of all kinds of cytokines and chemokines. This triggers immune cell activation and releases more cytokines and chemokines, causing a vicious circle of hyperinflammation. Paradoxically, COVID-19 is characterized by suppression of type 1 and 3 interference and immunoparalysis. We inhale aspergillus spore permanently, but in COVID-19 patients, impaired clearance causes aspergillus spore proliferation and excess mucus production. This overgrowth worsens the hyperinflammation process and causes tissue damage. Eventually, aspergillus invades bronchial walls and penetrates lung parenchyma. Thus, clinical course of aspergillus is thought to begin with aspergillus colonization and progress to tissue invasion and then angioinvasion. Other types of lung aggression could help tissue invasion, such as vascular damage caused by COVID-19 or pulmonary embolism. You already know about this Italian study including nine autopsies of COVID-19 patients with proven CAVA. You can see several only hemorrhagic areas on the lung surface. However, CT scans showed only typical COVID-19 signs, such as bilateral pochi-ground-glass opacities with interstitial thickening. This zoological examination shows typical morphological features of aspergillus and angioinvasion in five cases. Angioinvasion is relatively rare in CAVA. This shows us that even when aspergillus invasion is severe enough to cause the patient's death, there is no suggestive clinical or radiological sign of fungal infection. There is little data on this other clinical form of invasive aspergillus. Aspergillus tracheobonchitis is caused by the bronchial and tracheal invasion. Bronchoscopic examination shows pseudomonogamous plaques or ulcers. When you see these lesions, you need to perform biopsy because it is hard to differentiate aspergillus from COVID-19 damage with the naked eye. On the size of 30 CAVA patients published by Bartoletti, six had evidence of aspergillus tracheobonchitis. All of them had a positive galactomannan antigen in bronchoalveolar leverage. Please note that tracheobonchitis can cohabitate with invasive pulmonary aspergillosis. The incidence of aspergillus tracheobonchitis is still unknown. Now, let's talk more about clinical presentation of CAVA. Dr. Moore told you about epidemiology and risk factors for CAVA. But when to suspect it? Studies report CAVA in patients on mechanical ventilation. Timing of CAVA diagnosis depends on when you search for it. In the international retrospective study published by Salmanton-Garcia, 186 CAVA patients were included. Most of them were from the fungiscope registry. 94% of patients were on mechanical ventilation. CAVA diagnosis was made at a median of 10 days after COVID-19 diagnosis and 7 days after beginning mechanical ventilation. In the prospective study conducted by White, an enhanced testing strategy was encouraged, but no systematic exam were performed. 86% of CAVA patients were on invasive ventilatory support. Median time to positivity was 7 days after ICU admission. Bartoletti and colleagues investigated in this prospective study 108 patients with systematic BAL on admission and at 7 days. 30 patients were diagnosed with CAVA. Cough, dyspnea, and fever at admission were not related to CAVA. Median time to positivity of an aspergillus test was 4 days after ICU admission. It is worth mentioning that 13% of patients had a positive galactomannan antigen, in bronchoalveolar leverage performed on admission. Conclusion is that there is no typical clinical sign of CAVA, and you can suspect it mainly in patients on mechanical ventilation for a few days. Dr. Ma already told you about risk factors for CAVA. Immunosuppression, defined with EURTC-MSG criteria, is the heaviest known risk factor, but is rarely observed. Steroid treatment, COPD, or other structural lung disease, liver disease, and pulmonary embolism have been associated with CAVA. I would like to share some yet unpublished results about two other risk factors. The ME-COVID study included 590 ICU patients. Patients were systematically screened once or twice a week, with three screenings performed before day 14. 24 patients were diagnosed with possible CAVA, and 76 with probable CAVA. ME-COVID investigators found by multivariate analysis that age was associated with CAVA. CAVA patients were older than non-CAVA. A combination therapy of dexamethasone and anti-IL-6 was also associated with critical risk of CAVA. You can also see that CAVA patients had higher SAPS-II score on admission. They beneficiated from mechanical ventilation for four more days than non-CAVA patients. Now, could radiological exams help us suspect CAVA? In influenza-associated pulmonary aspergiosis, reports of well-circumscribed nodules, twin bud, and bronchial wall thickening have been published. However, in CAVA patients, these lesions are rarely observed. Resin retrospectively compared CT scans from CAVA patients and influenza-associated aspergiosis patients. All presented with lung parenchyma abnormalities, but no aspect of twin bud and nodules were observed in CAVA patients. Only one presented with bronchial wall thickening. In the series of CAVA-proven autopsies, only one patient had pulmonary nodules out of four patients with a CT scan. Another reported feature of CAVA is cavitary lesions, which have been reported in nine out of 20 patients in the prospective study conducted by Papa Ballung, and five out of 16 CAVA patients in the wide study. But vascular injuries seen in COVID-19 patients can also cause the hallow sign of cavitary lesions and mimics other signs of pulmonary aspergiosis. To conclude with a clinical presentation, according to the task force report on the diagnosis and clinical management of Kappa, you should mainly consider Kappa in patients on mechanical ventilation for more than 5 days under corticosteroids therapy, especially in the presence of ERTC, MSG, prospector or structural lung disease. A systematic diagnostic workup is not yet recommended, but should be done in clinically deteriorating patients or patients with cavitary or nodular lesions on the CT scan. Now, how can we diagnose Kappa? We do have an old set of available tests and samples. I will not discuss each test specifically. However, any positive test in blood reflects angioinvasion and so invasive pulmonary aspergiosis. All other samples can reflect both colonization and infection. Tests performed on tracheal aspirates and sputum have a low specificity. However, the main problem is the lack of sensibility of all tests in all kinds of samples. Bassetti and colleagues conducted a systematic review for the FANDIQ project to summarize available evidence on the diagnostic performance for IPA in critically ill patients, not specifically in COVID-19 patients. When considering the three studies using histology as reference for IPA diagnosis, only galactomanin antigen in the bronchoalveolar lavage displays a good sensibility. All tests displayed good specificity and predictive positive values. However, prevalence of IPA in these studies was high and predictive positive values are much lower in less exposed populations. Kohler and colleagues proposed Kappa diagnosis criteria on behalf of the European Confederation of Medical Mycology and other societies. As the UFTC-MSG society criteria, three criteria are needed. One clinical criterion, one imaging criterion, and one microbiological criterion. The microbiological criterion determines whether you diagnose a probable Kappa or a possible Kappa. Both imaging and clinical criteria are often present in any COVID-19 patients admitted to in the ICU. However, the microbiological criteria for probable Kappa include either a positive direct examination culture or galactomanin antigen in bronchoalveolar lavage, either a positive galactomanin antigen or the two positive PCR in blood. A positive PCR in both blood and bronchoalveolar lavage meet also the probable Kappa definition. I remind you that you can also diagnose proven Kappa on bronchial biopsies performed during a bronchoscopic exam. In their review on laboratory tests performed in Kappa, the taskforce found a low sensitivity of galactomanin antigen in serum and beta-deglucan. Performance of both culture and galactomanin antigen in bronchoalveolar lavage were similar, around 50 to 60 percent. The low sensitivity of all laboratory tests justifies to multiply tests on bronchoalveolar lavage in order to increase the pool sensitivity. The ME-COVID study reported statistically different survival rates between patients diagnosed with possible Kappa, probable Kappa, and without Kappa. However, no laboratory tests can allow us to distinguish between aspergillus colonization and infection, and ones may fail to over-diagnose Kappa. Flickwirt published a series of six probable Kappa patients without any sign of invasive aspergillus on CT-guided post-mortem lung biopsies. Many patients diagnosed with Kappa survived with any antifungal treatment, and a recent meta-analysis didn't find any relationship between antifungal therapy and Kappa patients' mortality. The taskforce acknowledged the risk of misclassifying colonization for invasive aspergillus and concludes that Kappa is a complex disease involving a continuum of respiratory colonization, tissue invasion, and angioinvasive disease. The taskforce regarded the low or very low quality of evidence but made recommendations on Kappa management. So, when you consider Kappa, you should perform both a bronchoscopy and a bronchoalveolar lavage for diagnosis. In addition to direct examination and culture, a galactomannan antigen and a PCR should be performed on bronchoalveolar lavage. Both tests are useful. I didn't report this because PCR is not easily available in the US, but there are reports of patients with a negative galactomannan antigen but a positive PCR in bronchoalveolar lavage. The taskforce didn't make recommendations about lateral flow device-based assays for now. Due to the usual absence of suggestive signs of Kappa on imaging, standard CT is not recommended to refute or diagnose Kappa. Detection of aspergillosis in sputum and tracheal aspirite is considered insufficient evidence to support Kappa diagnosis because it can reflect early colonization. On the other hand, a positive galactomannan antigen in serum is in favor of angioinvasion and invasive aspergillosis. I insist that the biggest risk is underdiagnosis and not overdiagnosis. I remind you that only two patients out of nine proven Kappa received antifungal therapy in the autopsies theory published by Forte Rosa. So, management of Kappa implies antifungal therapy and the taskforce recommends to consider empirical therapy once bronchoalveolar lavage has been performed while waiting for test results. You can secondly stop antifungals if tests are negative. How should you treat Kappa? The taskforce recommends to follow guidance on invasive aspergillosis. Reference treatment is boriconazole for six weeks. In 2016, isabriconazole non-inferiority has been demonstrated and more recently, posacol non-inferiority as well. I want to talk about amphotericin B, which is at increased risk of nephrotoxicity in ICU patients and of caspofringin, which has a lower intrinsic activity. How to choose between those triazole agents? All ICU patients display high pharmacokinetic viability. All triazole agents are metabolized via and or inhibits cytochrome 3A4, which causes drug interaction. For example, with remdesivir, pantoprazole, immunosuppressants, but also fentanyl and benzodiazepine. Boriconazole does not have a good pharmacokinetic profile with a narrow therapeutic index, non-linear pharmacokinetics and strong interactions. However, therapeutic drug monitoring is available in most centers and its profile has been and is still being studied in the ICU and other special populations. Oral boriconazole is safe to use in patients with renal impairment, but you should be aware of the solvent vehicle SBCD accumulation in those patients. The clinical significance of the SBCD accumulation is still being investigated. There is no dose adaptation needed in patients on renal replacement therapy, and you can use both oral and IV formulations of boriconazole because of SBCD clearance with hemofiltration. However, monitor closely boriconazole serum levels in ECMO patients. To date, only five cases of azole-resistant kappa have been described. In patients with azole-resistance exceeding 10%, a combination therapy should be started while waiting for resistance tests. If confirmed, switch to liposomal amphotericin B. What should we do with immunomodulating agents? To date, there are proven benefits of dexamethasone therapy. No data supporting stopping or continuing immunomodulating agents are available. So, the taskforce recommends not to stop concomitant corticosteroids therapy in kappa patients. Here are my take-home messages. Kappa is rare but real. There is no typical clinical or radiological sign of kappa, and you should consider kappa in deteriorating patients, especially those on mechanical ventilation. When suspected, you should perform a bronchoscopy and a bronchoalveolar lavage to diagnose kappa. Colonization is hard to distinguish from infection, even when using microbiological tests. However, as we say in France, the doctor should benefit the patient. So, my opinion is that you should treat all patients with probable kappa. Treatment includes triazoline therapy and continuing standard of care including corticosteroids therapy. I turn it back to Dr. Mavis. Well, thank you very much, Dr. Costa and Dr. Marr as well. Those were both fantastic presentations. And I know I certainly learned a lot, and I've had the pleasure of speaking with both of you a great deal over the last couple of weeks. So, we do have a number of questions from the audience. And I think what I would like to do is start with a question from Andrea Tully. Andrea Tully, this question was directed at Dr. Marr, but I think it is broadly applicable to both of you. And Dr. Marr, you addressed a little bit of this in your presentation already. So, the question is about the link between kappa and COVID-associated mucormycosis and dexamethasone as being, I think we all think, relatively clear. The question is about tocilizumab. Dr. Costa addressed the risk of combination therapy with dexamethasone and IL-6 inhibitors as being potentially additive to the risk of aspergillosis in patients with COVID-19. Do you think there's anything distinct, though, about IL-6 inhibition specifically, about that particular pathway? Or is it perhaps just the result of additive immunosuppression? It's a great question. And I'm not sure anyone knows the answer precisely. The IL-6 pathway is certainly involved in potentially mediating secondary responses to subsequent infection and clearance of the inflammatory impact of having aspergillus germinating in the airways and recruiting so many different pro-inflammatory cells. But I think that actual risks for invasive disease are additive. We haven't seen in large studies of the tocilizumab studies, for instance, that there's a huge signal of subsequent secondary fungal infections. Albeit, I have a lot of doubts about the quality of those data, because these are not studies with thousands of people that have undergone a real complete microbiologic evaluation for this complication. But in general, my sense is that these are additive. Thank you very much. Dr. Costa, any thoughts? No more thoughts. Understood. Thank you so much. Actually, for you, Dr. Costa, this is on a similar thread here. You also cited evidence that the combined use of dexamethasone and IL-6 inhibitors may increase the risk of CAPA. In the meantime, though, we have to balance this, just as you said, with this data from these large platform trials, recovery, remap, CAP, and so forth, that have shown decreased mortality benefit when we use these agents in combinations with patients with severe hypoxemia and other features like elevated C-reactive protein, for example, a certain limited duration of illness. How do we, in managing the critically ill patient or the potentially critically ill patient, how do we balance those risks? We have this very real risk of secondary infection, either bacterial superinfection or fungal superinfection, but also this pretty reproducible mortality benefit when we use these drugs. How should our colleagues manage or balance this risk at the bedside? Is there any particular thing that would tip you one direction or another? As Dr. Marth said, there was no strong signal about superinfection with fungal agents in the biggest trial about tocilizumab. So I think when a patient should benefit from tocilizumab, you should use it. However, in the studies conducted, only a few selected patients beneficiated from tocilizumab. The two biggest studies included only patients at the very first stage of clinical deterioration and one of them in patients admitted in the ICU for less than 24 hours. So I don't really know what you do in the US, but in France, we give tocilizumab only to patients which are on high flow nasal oxygen and not in those who beneficiate from invasive mechanical ventilation. Then when you gave tocilizumab to a patient and he's on invasive mechanical ventilation, you should, I don't know if you should screen him automatically, but you should definitely screen him for any fungal infection in case of clinical deterioration. I think that's broadly similar to our practice here in the United States. Dr. Marth, any thoughts about that? No, and I agree with this. I'd just also like to add that there's a tremendous impact on survival bias here, right? Because the people who don't survive this infection are not at risk for these secondary infections and even our incidence calculations are not really made relative to number of days at risk. And so it makes sense to me that the people who have the severest disease that require multiple different immunosuppressive agents in order to control the pulmonary inflammation and ARDS, that they're going to be at highest risk for secondary infections afterwards. And I think that our commitment has to be towards treating their inflammatory lung disease first and then keeping our minds open for what may come next. Absolutely. Well, thank you so much. And I think that's a great way for us to all balance that at the bedside, that these large trials, some of that mortality risk is kind of baked in. And just as Dr. Marr and Dr. Koster both were saying, you know, it's patients who die very rapidly of COVID are not at risk for invasive fungal infections. The fact that they live long enough puts them at risk. This is not necessarily a bad thing. Dr. Marr, one question that I had, and this actually relates to Dr. Koster's presentation as well, is on, and this is not necessarily a guideline discussion, it's sort of a, what are you folks doing today? And I'll tell you that empirically, for a lot of the same reasons that Dr. Koster described, I'm using relatively little boriconazole in the ICU. I have personally in my own practice, I may be confessing a sin, but I've been leaning relatively heavily on nisabuconazole myself, in part because of data from, including from one of your own studies, showing efficacy for nisabuconazole comparable to boriconazole for the treatment of invasive aspergillosis. Now, this is relatively easy for me in the ICU because I'm an ID doctor and the stewardship committee lets me do that. But as a practical matter, I find myself using that agent quite a bit more, boriconazole quite a bit less. Is this getting too far ahead of the data, or is this a defensible approach? Well, I'll point out that the study that was done that showed non-inferiority between nisabuconazole and boriconazole, yes, I was one of the authors and looked at a lot of the data, but this is a relatively small study, right? And really, in my opinion, pretty underpowered for a non-inferiority study, as 50% of those people actually had documented invasive aspergillosis. And so my experience in subsequent use of the drug is that it is more tolerable. I definitely believe that to be true, both with regards to drug interactions and hepatotoxicities and some of the more rare but concerning issues with worry, but we do see a lot of breakthrough infections when the drug is used in the prophylactic agent, and that's been published by a number of different groups. And I don't have as comfortable a sense with the use of that drug in treating severe and disseminated invasive aspergillosis, quite frankly. The problem with kappa is a lot of these folks also have inflammatory liver disease. And so, you know, what you're doing is also measuring the combined hepatotoxicities of giving a pretty robust and hepatotoxic azole. We don't have a lot of good options. I think that the centers that are using posaconazole, because they also have IV formulations more frequently in Europe than here, also see good outcomes. There is variability of how much of that gets into the airways as well. So there's a lot of choices. I don't think that there's one drug that fits as the best, but we need to understand the products and individualize quite a lot. Wonderful. Thank you very much. That's very informative. Dr. Kostek, any additional thought? I think I totally agree with Dr. Marr. I just want to remind people that the toxicity of voriconazole is correlated with voriconazole levels. So most of the toxicity is reversible once you adjust voriconazole dosage. In special groups such as ECMO patients and patients undergoing renal replacement therapy, I definitely think you should use voriconazole because other azole agents have not been studied in these populations. So voriconazole is appealing and we want to know more about those drugs. But for now, I think we know much about voriconazole in the special groups. That's very wise. Thank you very much to both of you for that. So this is a question from the audience. One question has to do with dose and type of steroids used to correlate with the risk of these invasive fungal infections. My impression, and I think this is broadly true in the literature, is obviously the risk goes up with the higher doses of steroid. Now, 6 milligrams of dexamethasone for 10 days is not a massive dose of glucocorticoids. But shortly before the pandemic, a Spanish group did the DEXA-ARDS trial, which was an all-cause ARDS trial, using 20 milligrams of dexamethasone for five days, followed by 10 milligrams for five days. Not specifically a COVID trial, but I am aware of some centers using essentially that higher dose of steroid in patients with COVID-associated ARDS. I don't think we have a lot of data on increasing risk of kappa specifically with different steroid doses, but I think that that is a reasonable supposition. Any thoughts or any specific data about that? I'm not aware of any large studies that have actually been able to model risks for these secondary infections by steroid dose. I would agree with you. I'll also note that, I mean, even the tinnitus association with mucormycosis, these are people also who have come in the door with probably a good amount of these fungi in their airways, and we're suppressing secondary responses. We have seen dose-dependent risks in other immunosuppressed populations, such as alloBMT patients, and so you could probably project that to be in place here, but I'm not sure that we've got the data to demonstrate it. Anne, do you have a... I'm not aware of any large studies about modeling fungal risk according to corticosteroid dosage, but yes, I think you can project from immunosuppressed patients. For now, we just know about one dosage of corticosteroid efficacy, so we should definitely stick to it for now, but... No, no, and I agree completely. I agree. Very helpful. Thank you both very much. Actually, since we're on the topic then, and I'm going to direct this at Dr. Kost, as we learn more about Kappa, do you think there might be a role for antifungal prophylaxis in selected patients, purely hypothetically, and recognizing that our evidence is very limited right now? I really hope that one day we will be able to predict which patients will develop Kappa. For now, we don't really know which one is going to develop a fungal invasive disease. So, for now, there is no known benefits of antifungal prophylaxis, and giving it to all ICU patients would be, I think, not a good idea for ecological purpose, and because of the toxicity as well. To my knowledge, there are no published data on antifungal prophylaxis in COVID-19 patients. There has been one published in influenza-associated aspergillosis patients, but regrettably, only a few patients were included, and about 20 patients with Kappa were included in the study. So, patients received posaconazole or standard of care, and there was no difference in either mortality, but neither aspergillosis incidence in both groups. So, for now, I can't recommend it. I know some Belgium critically ill ICU doctors have tried aerosolization of amphotericin B, but they didn't publish their results. I don't think they conducted, until now, a good study, a good design study about it. So, that was actually a question from one of our colleagues in the audience about aerosolized antifungal therapy, and I think that ties it together very nicely. That would be interesting, but it doesn't sound like we're anywhere close to being there yet. Maybe Dr. Ma know about a study about this? Well, I agree with what you said on prophylaxis. I've had several decades of work doing prophylaxis studies, and the one thing that you need to do is to be able to find the population where you can measure a difference, and we don't know that. And we failed to identify that population, even for influenza-associated aspergillosis that led to the inadequacy of that randomized trial effort. So, I don't think that we're quite there yet. I completely agree. You know, some centers have said that they've been giving prophylaxis and they haven't seen any infections subsequent, whether that be voriconazole or posiconazole or inhaled AMFO, but those analyses are fraught with problems. I do believe that the inhaled products, this is a setting where this is going to be very important because a lot of our agents don't get backed up into the epithelial lining fluid, and this is where all the action is really in this kind of disease. Now, Dr. Marr, this was a thought I had when I was listening to your presentation, specifically about mucormycosis, which is, is there something about India specifically? It's interesting that in Western Europe, in Southeast Asia, in North America, you know, you hear reports of individual cases of mucormycosis, but as a, on the scale reported in India, that seems like, like that's been something new. Do you think there is perhaps an environmental feature or host factors presence that may be predisposing Indian patients suffering from COVID-19 to mucor specifically? Or is it perhaps a function of availability of diagnostics that perhaps other developing countries also are seeing mucor, but the local capacity for diagnosis is absent? Just curious about any thoughts. I think it's definitely exposure, environments, and the host. I don't think that it has to do with therapy, quite honestly. We use steroids in a lot of other places. Agree. What is poorly understood is the variability and environmental exposure of these organisms. All filamentous fungi are endemic. They like to grow in certain types of environments. And even if you look at India, there are certain species that are, you know, increase in representation in different parts of the country. Apophizomyses, for instance, is not common in Europe or in the US, but it's common in the South of India. And so it is, this is reflective of our geographic and seasonal variability. We've shown that in Seattle and we've shown it in other places. Even the Indian data show it. This, as well as potentially even exposures that lead to more airway exposure of these organisms. We know that these organisms are really common in tobacco and smoking is a risk. And we also have a lot of people who inherently have a risk because of either poorly controlled diabetes or undiagnosed diabetes. And so all of that together has led to, you know, a horrible, horrible epidemic. I don't think it's diagnosis at all. Thank you. Thank you very much. Well, that brings us to actually the conclusion of our time. So thank you all very much. That brings us to our complete hour. I first of all, just really want to thank both Dr. Costa and Dr. Marr for taking all of this time today to answer these questions and to thank you for the wonderful presentation. I'd also like to thank our audience for attending. Once again, this webcast is being recorded. The recording will be available to registrants within 24 to 48 hours. To access, go to covid19.secm.org slash webcast. To register for additional COVID-19 webcasts, you can also visit secm.org slash disaster. For more resources, you can visit secm.org slash COVID-19 rapid resources. That will conclude our presentation today. Once again, my name is Dr. Ryan Maves. Thank you once again to Dr. Costa, to Dr. Marr, and to the SECM staff for putting this all together. Have a wonderful rest of your day and stay safe.

webinar

secondary fungal infections

COVID-19

COVID-associated pulmonary aspergillosis

COVID-associated mucormycosis

CAPA

CAM

Aspergillus fungi

diagnosis

management