All right. Hi, good morning, everybody. I'm Talia Ben-Jacob. I'm the Division Chief for Critical Care in the Department of Anesthesiology at Cooper Hospital. I'm also an Associate Professor of Anesthesiology at Cooper Medical School of Rowan University. Before, today I'm gonna talk to you guys about the epidemiology of fungal disease in the critically ill. Before I start, I just wanted to give a thank you to Raquel Nara, who's the Cooper Hospital Epidemiologist for collaborating with me on these slides. I have no disclosures. So we're gonna talk about today the epidemiology of invasive fungal disease. We're gonna talk about patient risk factors. We'll talk about clinical presentation. We're also gonna talk about the global trends in invasive candidiasis and invasive aspergillosis. We'll talk about the incidence and prevalence. We'll talk about some of the new emerging deadly fungal infections that are out there. We'll talk about morbidity and mortality outcomes. And we'll talk about a little bit of the emergence of resistance. The reason why my talk is gonna focus on invasive candidiasis and invasive aspergillosis is because those are the most common fungal infections that we see in critically ill patients. So the Prospective Antifungal Therapy Alliance was established in 2004, where it basically looked at invasive fungal infections in patients in tertiary care centers to improve the understanding of how invasive fungal infections work. Just to define patients at risk, to look at different kinds of patient groups and understand the different approaches to diagnosis and treatments in these patients. The reason why this task force was informed was because about 750,000 patients become infected with candidiasis during their hospital stays. And it's about 300,000 patients for invasive aspergillosis. And as you can see here, the percentages of the majority of these fungal infections are candidiasis and aspergillosis. So it's not just in critically ill patients, but it's all patients across the hospital board, which is why we're gonna focus on that today. So moving on to our ICU patients. So the patient factors. Next slide, thanks. So fungal infections affect about 13.2% of all critically ill patients. They infect our sicker patients. As you can see, the average SOFA score of a patient with a fungal infection is about 5.8. It infects our older patients, usually in patients greater than the age of 65. It's usually in patients with multiple medical comorbidities such as diabetes, COPD, and we'll talk about COPD a little bit later as well. It's usually in female patients. And as we can see, that usually fungal infections are a secondary infection on top of somebody who comes in with a bacterial infection in 72% of those patients. So unfortunately, a lot of times, we as healthcare providers and healthcare facilities are actually responsible for some of these fungal infections. Iatrogenic factors that can cause these are steroids, broad-spectrum antibiotics, and appropriate use of antibiotics, TPN, central venous catheters, mechanical ventilation, hemodialysis, GI surgery. And as we talked about before, with the majority of these patients already coming in with a bacterial infection such as sepsis and pneumonia, leads to higher risk for a patient developing a fungal infection. Other risk factors are patients with malignancies, solid tumors, organ transplants, immunosuppressive medications, HIV, COVID-19, aka immunocompromised patients. And the majority of the sources are either the respiratory tract, the urinary tract, sometimes the deep tissues if they're post-op surgical patients, the GI tract, and the bloodstream. So how do these infections present in the ICU? So usually with invasive candidiasis, the infections present somewhere between five to 12 days from admission. It's usually candidemia. It turns out that candidemia, depending on who you ask, is about the third or fourth most common nosocomial bloodstream infection. So it's something to really pay attention to. Or candida peritonitis, that's usually because, as we all know, yeast colonizes our gut, and then patients either have GI surgery or they have a perforation, which leads to candida peritonitis. You can get candida pneumonia, meningitis, endocarditis, or endophthalmitis, but they are actually much rarer. What's also interesting is sometimes there isn't really a specific presentation pattern of a fungal infection in the unit, and that's where we talk about what we call culture-negative sepsis. It's beyond the scope of my talk to talk about how you would treat culture-negative sepsis and when you would add the antifungals, but it's always something to keep in the back of our minds in an immunocompromised patient who clearly is presenting with SIRS criteria, and yet the culture data is negative, which leads us to invasive aspergillosis, because it actually is really hard to diagnose because there are no specific clinical features to invasive aspergillosis, and so patients who are presenting with culture-negative sepsis, this should be in the back of everyone's mind when they think about it, and these patients do not do well because most of these patients, as it commonly presents in patients who are neutropenic, as we talked about all our previous cancer patients in the solid organs, and it's also because it's usually presenting secondary to sepsis, as sepsis affects our neutrophils, and they're the gatekeepers to neutrophils, so it puts all those patients at higher risk for getting it. However, interestingly, when we mentioned COPD before, COPD also makes you very high risk for invasive aspergillosis. It's high risk as it affects the respiratory tract, but that is actually the mechanism for patients with COPD or influenza-like illness. It actually manifests differently as it affects the structure of the heart, making patients more susceptible. Patients with cirrhosis are also more susceptible to invasive aspergillosis, as cirrhosis, whether compensated or decompensated, affects phagocytosis. So high-risk patients for invasive aspergillosis consist of, it usually affects the lungs or the sinuses. You can see acute invasive disease, which is usually seen in our neutropenic cancer patients and our bone marrow transplant patients, but the chronic lesions of COPD and then steroid use for all the immunosuppression and the change in the architecture of the lung, those patients are high risk. You can also see invasive aspergillosis manifesting as endocarditis, mediastinitis, vascular grafts, osteomyelitis, and CNS, but usually the endocarditis and the mediastinitis and the CNS are more so from a primary infection in the lung that has been spread by bloodstream down to the other locations. So what is the incidence and prevalence of these infections and how deadly are they? So what's interesting is invasive candidiasis was really found to like, started to be studied in the 1980s. And then they saw over the next bunch of years, they actually saw the rates of the incidence actually decrease. And they attributed this to the rates of decrease to the fact that empiric fluconazole was being started more frequently, as well as the fact that the central lines were being used less and less. However, shortly after that, somewhere in the early 2000s, they started seeing an increase again in these invasive candidiasis infections, but they attributed that to the fact that the population that was getting sick was older, they had more medical comorbidities, not so much the change in treatment plans or to lack of diagnosis, but it was more that older and sicker patients were living longer. However, then unfortunately, invasive candidiasis actually exploded during the COVID pandemic. And it was thought that that was related to the fact that we were giving so many people TNF-alpha, as well as the fact that patients were just more susceptible to change in the lung architecture, and then we were immunosuppressing everybody. About now, they think that the invasive candidiasis incidence is somewhere between three to 50%, but it's really hard to tell because most of the times these diagnoses go missed in the ICU, and they're really only determined post-mortem. So here's the rates of infective candidiasis during contemporary times. As you can see, they range somewhere between 0.9 to 8%, but it's really hard to tell because most of the time, the diagnoses of invasive candidiasis is only made by blood cultures, and either blood cultures take a long time to come back, or they never come back positive, and then there's other sources that are found on autopsy. So what's the significance of a patient getting a candidial infection in the ICU? So unfortunately, because these fungal infections mostly affect immunocompromised hosts, they contribute to the morbidity and the mortality, and they increase these rates. As we said before, they rank somewhere between the third to fourth most commonly isolated organisms in the blood, and the mortality rate of these infections is actually very high. Unfortunately, the incidence is often underestimated, and diagnosis is frequently made post-mortem. So invasive candidiasis infections, unfortunately, increase the average hospital length of stay, so they increase burdens on the hospital. They increase the ICU length of stay, and unfortunately, a lot of patients, despite adequate treatment, still die. So the rate of mortality prior to hospital discharge is 38%, and at one year, it's as high as 76.4%. So even if you do make it out of the hospital, you're still severely debilitated and sick post-hospital stay. Unfortunately, with everything going on, we've now developed new, more resistant bugs that are out there that are more deadly and more dangerous. So the most recently bug to come out would be Candida aureus, which debuted in 2009. No one's really sure where it came from, how it debuted, where it morphated from, but they did notice that it was easily transmitted and spread like wildfire. Since 2009, it's spread to over 25 countries on five different continents. The issue is it's not easily or readily identifiable. It's so easily transmitted that there was one point prevalence study that showed that a patient who came in who was simply colonized with Candida aureus, not even sick from it, managed to spread it to the rest of his ICU, despite the fact that they tried to decolonize him with chlorhexidine for close to 30 days. They thought that perhaps the Candida aureus was living on the reusable thermometers that they were using in their ICU. They also noticed that getting an antifungal as prophylaxis or to treat an unknown infection leads to more resistance and is a risk factor for actually getting Candida aureus. Other things they noted was admission in public hospitals. The longer you stayed in the ICU, the more likely you were to get it, and then getting fuconazole or having a central line. Unfortunately, Candida aureus is very deadly. The crude 30-day mortality rate is about 42%, and the attributable mortality directly to getting infected with Candida aureus is 27%. What's really scary is the fact that it's developing resistance really quickly, and it lives a really long time on dead things, like it can live as much as seven days on dry linen, which goes back to all the hand hygiene and the prevention. So our other deadly bug that we're going to talk about in this lecture is invasive aspergillosis. So invasive aspergillosis is actually the most common misdiagnosis in ICU patients. We're able to figure that out based on autopsies and post-mortem analysis of patients that have died in the hospital. The incidence ranges about from 0.2% to 17% of ICU patients. There's a tenfold increase in the Middle East and North Africa due to the inhaled spores. The reason why the incidence has such a large range is because there's different ways to diagnose, different ways to teach, and there's different ways for determining whether or not a patient actually has the disease, and these practices range across the different hospitals and the different patients. It does affect about 300,000 patients a year, but what's really scary is there's about 30 million people who are at risk for developing invasive aspergillosis because it's an opportunistic infection caused by inhaling spores. The mortality is really high. So it turns out that the overall mortality of invasive aspergillosis is actually very similar to invasive candidiasis. The difference is that patients with invasive aspergillosis will die sooner, meaning that 52% die prior to discharge versus the 30% that die with invasive candidiasis. But once again, as you can see, at one year, it's about the same 75% of patients. It is the major cause of death after allogenic bone marrow transplantation, so we do need to be careful with those patients. And of course, with the COVID pandemic, again, as we talked about, the blossoming invasive candidiasis, we also developed a new version of pulmonary aspergillosis known as COVID-associated pulmonary aspergillosis. The incidence is really hard to determine because there's no gold standard at this point. This disease is relatively new, so the diagnostic testing is very different. Across the board, there's no gold standard for diagnostic testing. There's no gold standard for clinical presentation or imaging. However, they estimate that the incidence is probably about 8% in all COVID patients that are mechanically ventilated. With regards to the prevalence, the prevalence ranges anywhere from like zero to 30%, and that's also because there's different ways to diagnose the data. And the overall average after doing a cohort study in 480 patients was that it was about 10% of COVID patients will have Kappa at any given time and 11% in those that were mechanically ventilated. As you can see here, here are some of the characteristics of Kappa, of the patients they affect. It's more likely to affect older patients of ages greater than 75. It's more likely to affect men. It's more likely to affect patients that have immune compromise. And that's either because of the secondary effects of the hyper-inflammatory rate of sepsis. They feel that COVID-associated pulmonary aspergillosis is very different than regular invasive aspergillosis. You don't need to be neutropenic in order to get it, but it's more related to the fact that sepsis, that the first part of COVID, and it's more like the influenza-like illness, that the first part of COVID depletes all the body's immune response. And then you get the hyper-inflammatory state, which makes you more prone in combination with the fact that we give patients things like anakinra, steroids. 62% of patients who receive steroids are likely got Kappa. Sorry, 62% of patients with Kappa receive steroids, anakinra, tocilizumab. So a lot of this could be atrodianic by the fact that we knock out patients' immune systems when they present us with COVID. Kappa mortality is pretty high. It's 59.2%. If patients received mold-active fungals, such as like mycofungin or boriconazole, their survival rate improved to 46.8%, but the mortality rate was still 30% if they were untreated. And once again, it's hard to, and once again, a lot of patients do go untreated because it's very hard to diagnose. So emergence of antifungal resistance. So there's two ways that the fungi can be resistant. One is intrinsic, which is primary. It's either naturally present in the fungus, kind of the way that Candida auris is mutating, or there's secondary, which is basically driven by inappropriate antifungal drug use and prolonged exposure to an antifungal. As we mentioned that receiving fluconazole is a risk factor for developing some of these diseases. So 90% of invasive candidiasis strains are now resistant to fluconazole. 35% are resistant to amphotericin B, and 40% are resistant to two or more antifungal classes. As we can see that Candida albicans, which is the most common, is not highly resistant, but then looking down at Candida auris, which is the new emerging fungi that we're worried about, it's now showing resistance to, 95% are resistant to fluconazole, 6% to fluconazole and amphotericin, and then there's multiple other resistances that are out there. So it's very important to be judicious about the antifungals that we use, how and when, but that will be in a later talk. So how do we prevent resistance? So one, the number thing is to send cultures. So if you're concerned that someone has an antifungal infection, you wanna send all the isolates you possibly can from sterile body sites, and then initiate an appropriate antibiotic, sorry, antifungal therapy. But like we talked about before, the best way to really prevent resistance is to prevent infections. So ways to do that are surveillance cultures for patient being admitted to the ICU, practicing excellent hand hygiene, making sure that we clean all our equipment, especially the reusable equipment that could potentially be shared between patients, like we talked about the thermometers or the blood pressure cuffs, isolating patients, making sure they stay isolated, decolonizing them with like appropriate chlorhexidine baths and doing these processes for like 30 days or greater to ensure the eradication of the colonization. So in summary, we reviewed the incidence and prevalence of invasive candidiasis and invasive aspergillosis. We discussed our new emerging infections. We reviewed our clinical presentation and our risk factors and the mortality rates, and we discussed prevention of resistance. Up next, my partners up here are gonna discuss about diagnostic methods and current treatment. And we will take questions at the end. Thank you.

fungal diseases

invasive candidiasis

aspergillosis

Candida auris

antifungal stewardship