CAPA not a surprise
CAPA is “not an unfamiliar story” in the world of fungal disease, given a history of influenza-associated pulmonary aspergillosis (IAPA), said Kieren A. Marr, MD, MBA, adjunct professor of medicine and past director of the transplant and oncology infectious diseases program at Johns Hopkins University, Baltimore, who has long researched invasive fungal disease.
Dr. Kieren A. Marr
European researchers, she said, have led the way in describing a high incidence of IAPA in patients admitted to ICUs with influenza. In a retrospective multicenter cohort study reported in 2018 by the Dutch-Belgian Mycosis Study group, for instance, almost 20% of 432 influenza patients admitted to the ICU, including patients who were otherwise healthy and not immunocompromised, had the diagnosis a median of 3 days after ICU admission. (Across other cohort studies, rates of IAPA have ranged from 7% to 30%.)
Mortality was significant: 51% of patients with influenza and invasive pulmonary aspergillosis died within 90 days, compared with 28% of patients with influenza and no invasive pulmonary aspergillosis.
Reports from Europe early in the pandemic indicated that CAPA was a similarly serious problem, prompting establishment at Johns Hopkins University of an aggressive screening program utilizing biomarker-based testing of blood and bronchoalveolar lavage (BAL) fluid. Of 396 mechanically ventilated COVID-19 patients admitted to Johns Hopkins University hospitals between March and August 2020, 39 met the institution’s criteria for CAPA, Dr. Marr and her colleagues reported this year in what might be the largest U.S. cohort study of CAPA published to date.
“We now know definitively that people with severe influenza and with severe COVID also have high risks for both invasive and airway disease caused by airborne fungi, most commonly aspergilliosis,” Dr. Marr said.
More recent unpublished analyses of patients from the start of the pandemic to June 2021 show persistent risk, said Nitipong Permpalung, MD, MPH, assistant professor in transplant and oncology infectious diseases at Johns Hopkins University and lead author of the cohort study. Among 832 patients with COVID-19 who were mechanically ventilated in Johns Hopkins University hospitals, 11.8% had CAPA, he said. (Also, 3.2% had invasive candidiasis, and 1.1% had other invasive fungal infections.)
Other sources said in interviews that these CAPA prevalence rates generally mirror reports from Europe, though some investigators in Europe have reported CAPA rates more toward 15%.
(The Mycoses Study Group recently collected data from its consortium of U.S. medical centers on the prevalence of CAPA, with funding support from the CDC, but at press time the data had not yet been released. Dr. Thompson said he suspected the prevalence will be lower than earlier papers have suggested, “but still will reflect a significant burden of disease.”)
Patients in the published Johns Hopkins University study who had CAPA were more likely than those with COVID-19 but no CAPA to have underlying pulmonary disease, liver disease, coagulopathy, solid tumors, multiple myeloma, and COVID-19–directed corticosteroids. And they had uniformly worse outcomes with regards to severity of illness and length of intubation.
How much of CAPA is driven by the SARS-CoV-2 virus itself and how much is a consequence of COVID-19 treatments is a topic of active discussion and research. Martin Hoenigl, MD, of the University of Graz, Austria, a leading researcher in medical mycology, said research shows corticosteroids and anti–IL-6 treatments, such as tocilizumab, used to treat COVID-19–driven acute respiratory failure clearly have contributed to CAPA. But he contends that “a number of other mechanisms” are involved as well.
Dr. Martin Hoenigl
“The immunologic mechanisms are definitely different in these patients with viral illness than in other ICU patients [who develop aspergilliosis]. It’s not just the corticosteroids. The more we learn, we see the virus plays a role as well, suppressing the interferon pathway,” for example, said Dr. Hoenigl, associate professor in the division of infectious diseases and the European Confederation of Medical Mycology (ECMM) Center of Excellence at the university. The earliest reports of CAPA came “when ICUs weren’t using dexamethasone or tocilizumab,” he noted.
In a paper published recently in Lancet Respiratory Medicine that Dr. Hoenigl and others point to, Belgian researchers reported a “three-level breach” in innate antifungal immunity in both IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytose and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils.
The researchers ran a host of genetic and protein analyses on lung samples (most collected via BAL) of 169 patients with influenza or COVID-19, with and without aspergillosis. They found that patients with CAPA had significantly lower neutrophil cell fractions than patients with COVID-19 only, and patients with IAPA or CAPA had reduced type II IFN signaling and increased concentrations of fibrosis-associated growth factors in the lower respiratory tracts (Lancet Respir Med. 2022 Aug 24).
Dr. Tom Chiller
Tom Chiller, MD, MPH, chief of the Center for Disease Control and Prevention’s Mycotic Disease Branch, said he’s watching such research with interest. For now, he said, it’s important to also consider that “data on COVID show that almost all patients going into the ICUs with pneumonia and COVID are getting broad-spectrum antibiotics” in addition to corticosteroids.
By wiping out good bacteria, the antibiotics could be “creating a perfect niche for fungi to grow,” he said.