These days, invasive fungal pathogens are making medical news -- as well they should.
In Fall 2022, a World Health Organization (WHO) report named 19 key fungal threats, thus creating the agency's first-ever "fungal priority pathogens" list. WHO also called for better diagnostics and monitoring of antifungal drug resistance, as well as further research, innovation, and public health measures to control invasive fungal pathogens.
I believe the message was overdue. While some people equate "superbugs" solely with bacteria, specialists who care for immunocompromised patients have long dealt with life-threatening and drug-resistant fungi. Today, experts also worry that environmental factors, including climate change, will nurture scary new species.
For today let's consider Aspergillus -- a ubiquitous, sporulating fungus that has long inflicted myriad harms, from allergic airway disease in asthmatics to fatal, necrotizing pneumonia in people lacking white cells to tangled hyphal spheres (aka "fungus balls") in old, burnt-out pulmonary cavities.
Now we have yet another woe to add to the list: Aspergillus is invading lungs already damaged by SARS-CoV-2.
How Often -- and Why -- Does Aspergillosis Follow COVID?
No one has a definitive answer to the question of how often aspergillosis follows COVID-19, but consider data from a multinational study published in 2021 in which up to 15% of 823 intensive care unit (ICU) patients in Europe suffered coronavirus disease-associated pulmonary aspergillosis (CAPA). Not surprisingly, underlying conditions influenced individual outcomes. In this cohort, for example, the mortality of CAPA was 30% in patients with a solid organ transplant or neutropenia as opposed to 16% in patients without these additional risks.
Aspergillus is no stranger to Ashrit Multani, MD, my UCLA infectious diseases colleague who's an expert in pathogenic fungi, especially in patients with compromised immune systems. So, I recently asked whether he was surprised when he started seeing severely ill patients with COVID suffer aspergillosis.
"No, it didn't surprise me too much," Multani said. "I think it was just a matter of time before we started to see more and more cases. We've seen similar issues with viral infections...for example, there's been plenty reported in the literature about aspergillosis following flu."
Sure enough, I found a paper that outlined significant similarities between influenza and SARS-CoV-2. In particular, both viruses produce lymphopenia and lytic infections that, in turn, up the risk that Aspergillus sitting in the trachea of an already-sick person will later invade their lungs.
How exactly does this happen? Some patients experience severe COVID as a result of the life-threatening inflammation it can cause in the lungs of high-risk individuals. While clinicians have tried using different medications to tamp down this inflammation, they can often be a double edged-sword. For example, dexamethasone (a corticosteroid) and tocilizumab (Actemra; a monoclonal antibody that inhibits a pro-inflammatory receptor) have both been shown to save lives but carry significant risks for further infectious complications, including aspergillosis. For Multani, he sometimes uses a different, often life-saving agent called baricitinib (Olumiant) -- an immune modulator first developed for rheumatoid arthritis -- that is less likely to incite Aspergillus.
An Illustrative Case
When speaking with Multani, I asked for a sketch of a typical COVID-Aspergillus case. Here's what he shared:
During the Delta wave of 2021, a fully-vaccinated, immunosuppressed patient contracted COVID 6 years following a kidney transplant for diabetic nephropathy. She entered the ICU with an oxygen saturation of 78% but never needed intubation. Her treatment included 5 days of remdesivir (Veklury), 10 days of dexamethasone, and a single dose of tocilizumab. A few days after receiving the monoclonal antibody she was well enough to go home.
One week later, however, she returned to the emergency department. She was now saturating at 70% on 2 liters of oxygen. Her sputum grew Aspergillus fumigatus. After starting on isavuconazole (Cresemba) for the fungus, she slowly improved but still needed supplemental oxygen when discharged.
Then, except for an intercurrent illness due to human metapneumovirus, the patient steadily improved, both clinically and radiologically, while completing a 3-month course of antifungal therapy.
"So, this was a happy story, right?" I said to Multani.
"Absolutely. Today, she's doing fine," he replied, adding how grateful he was for newer, oral antifungals like the one that saved his patient.
That said, there are many others with the same double whammy of COVID plus Aspergillus who have not fared so well.
Take Note and Prepare
Fungi are all around us, and most of us never know. But for certain patients, the natural environment holds a genuine threat. And, quite possibly, so do more than a few healthcare settings.
"Aspergillus is a saprophytic, conidial mold isolated abundantly from soil, construction dust, and hospitals," reads the opening sentence of an excellent review published in August 2018, less than 2 years before the current pandemic began.
In light of this, I asked my colleague, how do we know that certain COVID patients aren't acquiring their Aspergillus infections in the ICU, either from equipment used in respiratory care, or even ventilators?
"Well, that's a very good question," Multani replied. "We have looked into this when we've seen similar bugs popping up in the hospital, like a cryptic species called Aspergillus lentulus [recently cultured] from a couple of non-COVID ICU patients. In that case, we asked the lab to check and learned they were not genomically related."
In short, that meant the two Aspergillus isolates did not originate from the same source.
For Multani and me, we're lucky to be able to obtain genomic profiles at our medical center, and to access certain types of antifungal drug susceptibility testing.
But, looking down the road -- with or without another pandemic -- this is exactly what every modern hospital may need in order to care for growing ranks of immunosuppressed patients in whom fungal infections and antifungal resistance will only rise over the next few years.
My final take-home? It's time for medical personnel to ramp up their knowledge of fungi. The WHO delivered an important wake-up call to clinicians and scientists alike. Now we must all take note and prepare for the coming storm.
Claire Panosian Dunavan, MD, is a professor of medicine and infectious diseases at the David Geffen School of Medicine at UCLA and a past-president of the American Society of Tropical Medicine and Hygiene. You can read more of her writing in the "Of Parasites and Plagues" column.