COVID-19: increase in deaths from fungal infections during the pandemic

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Startling study findings based on a new research conducted by scientists from the Mycotic Diseases Branch at the U.S. Centers for Disease Control and Prevention-Georgia and the U.S NIH’s National Center for Health Statistics-Maryland are showing that more Americans have died from a variety of fungal infections during the ongoing SARS-CoV-2 pandemic.

The study findings were published in the peer reviewed journal: Clinical Infectious Diseases. 

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac489/6611491?login=false

Our analysis of US death certificate data found that >13,000 persons died from fungal infections during 2020–2021, representing an increase in the numbers and age-adjusted rates of death from fungal infections compared with previous years.

This increase was primarily driven by COVID-19–associated fungal deaths, particularly those involving Aspergillus and Candida, and highlights the importance of considering fungal infections in patients with COVID-19.

We also found striking racial/ethnic disparities and geographic differences in rates of death from fungal infections.

In our analysis, fungal death counts rose in tandem with COVID-19 surges during January and October 2021 but not during the first COVID-19 surge in April 2020. Recent analyses of testing practices have documented a precipitous decrease in testing for pathogens other than SARS-CoV-2 (the virus that causes COVID-19) during April 2020, a finding that authors have attributed to strained healthcare resources during the early COVID-19 pandemic [17, 18].

We suspect that the absence of a peak in fungal deaths during April 2020 might reflect a lack of disease detection and reporting rather than a truly low number of COVID-19–associated fungal deaths. Conversely, the peaks in fungal deaths that occurred during January and October 2021 might reflect increased clinician awareness and testing for COVID-19–associated fungal infections, and possibly, the increased use of corticosteroids and tocilizumab (both known risk factors for invasive mold infections and candidiasis) [6] to treat patients with severe COVID-19.

Our finding that Candida and Aspergillus were the most commonly identified fungal pathogens causing death is consistent with previous literature describing fungal disease epidemiology both before and during the COVID-19 pandemic [6, 9, 12, 19]. In our analysis, a higher percentage of COVID-19 – associated fungal deaths involved Candida and Aspergillus compared with non-COVID-19–associated fungal deaths, a finding that aligns with reports identifying COVID-19 as a risk factor for invasive aspergillosis and candidiasis [6, 12].

Although US data on the incidence of COVID-19–associated fungal infections are sparse, a multicenter study from Europe found that >10% of critically ill COVID-19 patients might develop invasive aspergillosis, with mortality rates exceeding 40% [12]. Limited reports also suggest that the incidence of invasive candidiasis might have increased during the COVID-19 pandemic [6, 20].

In contrast, research has not identified a clear link between the COVID-19 pandemic and the incidence of other types of fungal infections in the United States, although US cases of COVID-19–associated fungal infections with Pneumocystis, Cryptococcus, endemic fungi (i.e., Coccidioides, Histoplasma), and Mucorales spp. have all been reported [6, 10, 21-23].

Although we identified an increase in the number of deaths from Mucorales spp. during 2020–2021 compared with previous years, yearly rates of death for this pathogen remained low throughout the study period (<0.1 per 100,000 population). This finding is consistent with reports highlighting the rarity of mucormycosis in the United States [4, 24, 25]. Nonetheless, previous reports suggest that mucormycosis can cause severe illness, disfiguration, and death in COVID-19 patients, including among those who lack severe immunocompromising conditions [10, 13].
Compared with the White and Asian populations, other groups had higher rates of fungal death, particularly when examining fungal deaths associated with COVID-19. This finding is consistent with previous literature describing the disproportionate burdens of both COVID-19 and fungal diseases on certain communities of color [26].

Racial/ethnic disparities in the rates of infection and mortality from COVID-19 are well documented and may stem from inequities in the social determinants of health; for example, persons from certain racial/ethnic groups might be more likely to live in crowded settings, hold jobs requiring in-person work, or have limited healthcare access [27, 28]. The impact of these inequities might extend to fungal diseases, many of which are environmentally acquired and associated with certain occupational exposures [29-31].

Other factors linked to inequities in the social determinants of health, particularly differences in underlying conditions that increase fungal disease risk (e.g., diabetes) and pre-COVID-19 health status, likely contributed to the observed racial/ethnic disparities in fungal burden.

Fungal death rates varied widely among US census divisions, a finding largely accounted for by differences in rates of death from Coccidioides and Aspergillus infections. Coccidioides is primarily endemic to the southwestern United States; that this pathogen contributed so markedly to the fungal death rates in the Mountain and Pacific divisions underscores the threat it poses to public health in the region [32].

To our knowledge, the finding that death rates from Aspergillus were twice as high in the Pacific division compared with other divisions has not previously been documented, although research suggests that airborne Aspergillus spore counts and rates of invasive aspergillosis might vary depending on factors such as temperature, precipitation, geography, and season [33].

The geographic distribution of aspergillosis has not been well described, in part because aspergillosis is only reportable in one US state [34].
Greater public health surveillance for fungal infections, involving geographically and demographically diverse populations, might provide critical information to guide the prevention, diagnosis, and treatment of fungal diseases.

Because US census divisions have differing racial/ethnic compositions and because fungal death rates varied substantially by both US census division and race/ethnicity, we assessed potential confounding or interactions between race/ethnicity and census division by examining division-stratified racial/ethnic fungal death rates and race/ethnicity-stratified division fungal death rates.
A complete analysis of these stratified death rates was not possible because of NVSS privacy restrictions on small data cells involving geographically stratified data. However, we found that racial/ethnic disparities generally persisted within each US census division and that rates of fungal deaths generally differed by race/ethnicity when stratified by census division (data not shown). Further research may help to describe the intersection of demographic and geographic factors associated with severe fungal diseases.
Our findings have several notable limitations.

First, provisional mortality data from 2021 are incomplete and subject to change, particularly during recent months, as delayed reports might later increase death counts. Our use of broad single race categories limited the level of detail with which we could assess racial/ethnic disparities, particularly among multiracial persons. Another limitation was that we could not assess underlying medical conditions among patients with COVID-19–associated fungal deaths; this is because the CDC-WONDER platform does not allow for the tabulation of more than two sets of conditions in combination. Further, data based on ICD-10 codes for fungal infections, particularly those for mold infections such as invasive aspergillosis, are subject to imprecision in reporting and underreporting [35].

In our analysis, more than one-third of deaths involved an unspecified fungal pathogen, limiting our ability to precisely describe each fungal pathogen’s contribution to overall fungal mortality. Also, our analysis likely underestimates the impact of fungal diseases during the COVID-19 pandemic. Current fungal diagnostic tests generally lack sensitivity and might not be widely available or utilized if healthcare providers do not suspect a fungal infection [36, 37].
Deaths from invasive mold infections including aspergillosis might be particularly undercounted because this diagnosis is frequently missed. Studies of autopsies, a procedure performed for <5% of COVID-19 decedents during 2020–2021 [8], have identified mold infections as one of the most commonly missed diseases among ICU and hematologic malignancy patients [38, 39]. Finally, in focusing only on deaths from fungal infections, our analysis did not address the considerable long-term morbidity faced by certain survivors of severe fungal infection [40].

Despite its limitations, our analysis demonstrates the substantial burden of fungal infections in the United States and highlights an increase in fungal deaths during the first two years of COVID-19 pandemic. These data might help increase clinician awareness and support public health planning, with the ultimate goals of decreasing morbidity and mortality from fungal infections. Detailed public health surveillance for fungal infections, involving geographically and demographically diverse patient populations, might help better characterize disease epidemiology and guide ongoing efforts to prevent fungal infections among disproportionately affected populations.

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