Abstract
Background:
In the United States, aspergillosis and mucormycosis are associated with substantial healthcare costs and mortality. Recent nationally representative data about hospitalisations for these infections are limited, though several reports specifically describe increases in COVID-19-associated aspergillosis and mucormycosis, likely because of critical illness-related immune dysregulation and treatments involving systemic corticosteroids.
Objectives:
To update disease burden estimates, we describe trends in aspergillosis-related and mucormycosis-related hospitalisations (A-RH and M-RH).
Methods:
We used the 2016–2021 Healthcare Cost and Utilisation Project National Inpatient Sample and U.S. Census Bureau data to calculate A-RH and M-RH rates, examining annual trends, overall and stratified by demographic characteristics. We examined A-RHs and M-RHs during 2020–2021, comparing features and in-hospital mortality for those with vs. without COVID-19.
Results:
During 2016–2021, an estimated 86,570 A-RHs occurred, with rates (per 1,000,000 population) stable from 2016 to 2019 (range: 42.3–44.5) and increasing from 40.1 (2020) to 51.5 (2021). An estimated 8565 M-RHs occurred, with rates increasing from 3.8 to 5.8. During 2020–2021, 6025/24,285 (24.8%) of A-RHs and 420/2920 (14.4%) of M-RHs were COVID-19-associated. A-RHs and M-RHs involving COVID-19 had mortality rates exceeding 50%, which was ≈3 to 4-fold higher than those for A-RHs and M-RHs without COVID-19.
Conclusion:
Rates of A-RHs and M-RHs in the United States peaked in 2021, likely reflecting the increased burden of COVID-19 in 2021 compared with 2020. Ongoing monitoring of risk factors and clinician awareness is essential for managing and preventing these infections.
Keywords: aspergillosis, COVID-19, epidemiology, hospitalisation, immunosuppression, International Classification of Diseases, invasive fungal infections, mucormycosis
1 ∣. Introduction
In the United States, aspergillosis and mucormycosis (previously zygomycosis) are associated with substantial healthcare costs (> $2 billion, 2019) and mortality (> 4300 deaths, 2018–2021) [1, 2]. Classic risk factors for these fungal infections include hematologic malignancy (HM), haematopoietic stem cell transplantation (HSCT), solid organ transplantation (SOT), uncontrolled diabetes (mucormycosis) and immunosuppressive medication receipt [3-5]. Severe COVID-19 emerged as an aspergillosis and mucormycosis risk factor, likely because of critical illness-related immune dysregulation and treatments involving systemic corticosteroids [2, 6].
During 2000–2013, rates of aspergillosis-related and mucormycosis-related hospitalizations (A-RH, M-RH) increased [5]. For M-RH, the percentage involving HM and SOT increased, while the percentage involving diabetes decreased. Rates of A-RH remained stable among HM-related hospitalizations, declined among HSCT-related hospitalizations and increased among SOT-related hospitalizations [5].
Since then, nationally representative trend data about these infections have been limited, though several reports specifically describe increases in COVID-19-associated aspergillosis and mucormycosis [2, 6]. We describe trends in A-RHs and M-RHs spanning the pre-pandemic and pandemic periods, allowing for an updated disease burden assessment.
2 ∣. Materials and Methods
We used the 2016–2021 Healthcare Cost and Utilisation Project National (HCUP) Inpatient Sample, a representative 20% stratified sample of U.S. community hospital discharges, excluding rehabilitation and long-term acute care facilities. Each year, this database includes ≈7 million hospitalizations, representing ≈35 million weighted hospitalizations (https://hcup-us.ahrq.gov/nisoverview.jsp).
A-RHs, M-RHs and selected concurrent conditions were defined using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes (Table S1). Hospitalisations were classified as COVID-19-associated if the ICD-10-CM code for COVID-19 was listed anywhere on the discharge summary, regardless of whether it was the primary diagnosis. We derived national A-RH and M-RH estimates using discharge weights. We calculated A-RH and M-RH rates separately and examined annual trends, overall and stratified by age, sex, region and race/ethnicity, using U.S. Census Bureau population estimates (https://www.census.gov/data/tables/time-series/demo/popest/2020s-national-detail.html) for denominators. We examined A-RHs and M-RHs during 2020–2021, comparing age, sex, Census region, payer, concurrent conditions and in-hospital mortality for those with vs. without COVID-19. We compared categorical variables using Rao–Scott χ2 tests and continuous variables using linear regression.
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. Our analysis used a fully de-identified dataset, which ensured that no personally identifiable information was present. Therefore, Institutional Review Board (IRB) and Ethics Committee approvals were not required for this work. This activity was reviewed by CDC, deemed research not involving human subjects, and was conducted consistent with applicable federal law and CDC policy (see e.g., 45 C.F.R. part 46.102(l) [2], 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq).
3 ∣. Results
During 2016–2021, an estimated 86,570 A-RHs occurred, with rates (per 1,000,000 population) stable from 2016 to 2019 (range: 42.3–44.5) and increasing from 40.1 (2020) to 51.5 (2021) (Table 1). Rates across age groups, sexes, regions and races/ethnicities mostly remained stable during the pre-COVID-19 era (2016–2019) but increased during 2020–2021. From 2020 to 2021, the greatest rate increases involved patients ≥ 65 years (113.0–138.0), males (49.1–61.8), Western region (46.7–63.8) and patients who were non-Hispanic/Latino Black (39.5–50.8) or of another race/ethnicity (42.1–54.0). Among all A-RHs, aspergillosis subtypes included invasive pulmonary aspergillosis (10.4%), other pulmonary aspergillosis (38.4%), tonsillar aspergillosis (0.0%), disseminated aspergillosis (1.6%), allergic bronchopulmonary aspergillosis (15.8%), other forms of aspergillosis (5.4%) and aspergillosis (unspecified) (28.4%). Hospitalisations could involve more than one subtype.
TABLE 1 ∣.
Demographic characteristics and rates (per 1 million population) for aspergillosis-related hospitalizations, United States, 2016–2021.a
| 2016 | 2017 | 2018 | 2019 | 2020 | 2021 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|
|
|||||||
| Characteristics | No. (col. %) | Rate | No. (col. %) | Rate | No. (col. %) | Rate | No. (col. %) | Rate | No. (col. %) | Rate | No. (col. %) | Rate |
| Overall | 13,655 (100.0) | 42.3 | 14,010 (100.0) | 43.1 | 14,550 (100.0) | 44.5 | 14,045 (100.0) | 42.8 | 13,200 (100.0) | 40.1 | 17,110 (100.0) | 51.5 |
| Age group, years (n = 86,570) | ||||||||||||
| < 18 | 690 (5.1) | 9.4 | 865 (6.2) | 11.7 | 685 (4.7) | 9.3 | 550 (3.9) | 7.5 | 365 (2.8) | 5.0 | 570 (3.3) | 7.8 |
| 18–44 | 1855 (13.6) | 16.0 | 1860 (13.3) | 15.9 | 1965 (13.5) | 16.8 | 2010 (14.3) | 17.0 | 1600 (12.1) | 13.5 | 2125 (12.4) | 17.7 |
| 45–64 | 5210 (38.2) | 62.0 | 5165 (36.9) | 61.4 | 5575 (38.3) | 66.5 | 5125 (36.5) | 61.5 | 4945 (37.5) | 59.7 | 6655 (38.9) | 80.0 |
| ≥ 65 | 5900 (43.2) | 119.9 | 6120 (43.7) | 120.6 | 6325 (43.5) | 120.8 | 6360 (45.3) | 117.7 | 6290 (47.7) | 113.0 | 7760 (45.4) | 138.0 |
| Sex (n = 86,555) | ||||||||||||
| Male | 7675 (56.3) | 48.2 | 7765 (55.4) | 48.5 | 8075 (55.5) | 50.2 | 8150 (58.0) | 50.4 | 7965 (60.3) | 49.1 | 10,175 (59.5) | 61.8 |
| Female | 5965 (43.7) | 36.4 | 6245 (44.6) | 37.8 | 6475 (44.5) | 39.0 | 5895 (42.0) | 35.4 | 5235 (39.7) | 31.3 | 6935 (40.5) | 41.5 |
| Census region (n = 86,570) | ||||||||||||
| Northeast | 2385 (17.5) | 42.5 | 2570 (18.3) | 45.8 | 2520 (17.3) | 44.9 | 2380 (16.9) | 42.5 | 2085 (15.8) | 37.3 | 2590 (15.1) | 45.2 |
| Midwest | 2930 (21.5) | 43.1 | 2885 (20.6) | 42.3 | 3090 (21.2) | 45.3 | 2915 (20.8) | 42.7 | 2940 (22.3) | 43.0 | 3735 (21.8) | 54.3 |
| South | 4675 (34.2) | 38.2 | 4770 (34.0) | 38.6 | 4955 (34.1) | 39.8 | 5060 (36.0) | 40.3 | 4500 (34.1) | 35.5 | 5770 (33.7) | 45.3 |
| West | 3665 (26.8) | 47.9 | 3785 (27.0) | 49.0 | 3985 (27.4) | 51.2 | 3690 (26.3) | 47.1 | 3675 (27.8) | 46.7 | 5015 (29.3) | 63.8 |
| Race/ethnicity (n = 84,115) | ||||||||||||
| White | 9055 (69.6) | 36.5 | 9090 (67.0) | 36.5 | 9745 (68.6) | 39.0 | 9160 (66.5) | 36.6 | 8195 (63.7) | 33.2 | 10,570 (63.4) | 42.0 |
| Black | 1645 (12.6) | 38.2 | 1965 (14.5) | 45.2 | 1900 (13.4) | 43.3 | 1910 (13.9) | 43.2 | 1760 (13.7) | 39.5 | 2290 (13.7) | 50.8 |
| Hispanic | 1345 (10.3) | 23.5 | 1465 (10.8) | 25.1 | 1495 (10.5) | 25.1 | 1605 (11.6) | 26.6 | 1710 (13.3) | 27.9 | 2275 (13.6) | 36.3 |
| Asian or Pacific Islander | 560 (4.3) | 29.1 | 570 (4.2) | 28.9 | 555 (3.9) | 27.5 | 640 (4.6) | 31.2 | 740 (5.8) | 35.5 | 915 (5.5) | 42.9 |
| Native American | 55 (0.4) | 13.5 | 75 (0.6) | 18.1 | 105 (0.7) | 25.0 | 90 (0.7) | 21.2 | 55 (0.4) | 12.8 | 100 (0.6) | 23.1 |
| Other race/ethnicity | 355 (2.7) | 41.6 | 405 (3.0) | 46.1 | 410 (2.9) | 45.4 | 375 (2.7) | 40.5 | 400 (3.1) | 42.1 | 530 (3.2) | 54.0 |
Among all aspergillosis-related hospitalisations, aspergillosis subtypes included invasive pulmonary aspergillosis (10.4%), other pulmonary aspergillosis (38.4%), tonsillar aspergillosis (0.0%), disseminated aspergillosis (1.6%), allergic bronchopulmonary aspergillosis (15.8%), other forms of aspergillosis (5.4%) and aspergillosis (unspecified) (28.4%). Hospitalisations could involve more than one subtype. SAS 9.4 survey procedures were used for analyses.
Among A-RHs, the percentage distribution of most underlying conditions fluctuated somewhat during 2016–2021 (Figure 1A). In particular, from 2020 to 2021, the percentage involving HM declined from 22.5% to 16.6% and the percentage involving COVID-19 increased from 10.9% to 26.8%. In 2021, 31.6% involved diabetes, 28.2% chronic obstructive pulmonary disease (COPD), 9.7% SOM and 7.8% asthma.
FIGURE 1 ∣.
Underlying conditions for hospitalisations associated with aspergillosis* (A) and mucormycosis† (B), United States, 2016–2021. COPD = chronic obstructive pulmonary disease; ESRD = end-stage renal disease; HM = hematologic malignancy; SOM = solid organ malignancy; SOT = solid organ transplant. *Fewer than 10% of aspergillosis-related hospitalizations involved cirrhosis, end-stage renal disease, haematopoietic stem cell transplant, HIV infection, or immune-mediated inflammatory diseases, or solid organ transplant. †Fewer than 10% of mucormycosis-related hospitalizations each year involved asthma, cirrhosis, haematopoietic stem cell transplant, HIV infection, or immune-mediated inflammatory diseases.
During 2020–2021, 6025/24,285 (24.8%) A-RHs were COVID-19-associated (Table 2). COVID-19–associated A-RHs (vs. non-COVID-19-associated) differed significantly by age group (p < 0.001), with more involving 45–64-year-olds (46.1% vs. 36.3%); region (p = 0.003), with more involving the West (33.0% vs. 27.6%); race/ethnicity (p < 0.001), with more involving Hispanic/Latino patients (24.2% vs. 10.9%); payer (p = 0.013), with more involving Medicaid (19.2% vs. 15.8%); and diabetes (42.2% vs. 27.2%, p < 0.001). COVID-19-associated A-RHs less frequently involved COPD (21.0% vs. 31.4%, p < 0.001), HM (6.2% vs. 22.4%, p < 0.001), HSCT (1.0% vs. 3.7%, p < 0.001), HIV infection (0.8% vs. 2.2%, p = 0.002), SOT (3.7% vs. 6.8%, p < 0.001) and solid organ malignancy (4.6% vs. 11.7%, p < 0.001). In-hospital mortality was higher for COVID-19-associated A-RHs (55.7%) vs. non-COVID-19-associated (15.5%) (p < 0.001).
TABLE 2 ∣.
COVID-19 vs. non-COVID–associated aspergillosis and mucormycosis-related hospitalizations, United States, 2020 to 2021.a
| Aspergillosis | Mucormycosis | |||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| Characteristic | With COVID-19 (n = 6025) |
Without COVID-19 (n = 24,285) |
p | With COVID-19 (n = 420) |
Without COVID-19 (n = 2920) |
p |
| Age group, years (n = 30,310 , A-RH; n = 3340, M-RH) | ||||||
| < 18 | 45 (0.7) | 890 (3.7) | < 0.001 | b | 240 (8.2) | 0.019 |
| 18–44 | 520 (8.6) | 3205 (13.2) | 155 (36.9) | 715 (24.5) | ||
| 45–64 | 2780 (46.1) | 8820 (36.3) | 160 (38.1) | 1295 (44.3) | ||
| ≥ 65 | 2680 (44.5) | 11,370 (46.8) | 100 (23.8) | 670 (22.9) | ||
| Sex (n = 30,310, A-RH; n = 3340, M-RH) | ||||||
| Male | 3660 (60.7) | 14,480 (59.6) | 0.483 | 310 (73.8) | 1760 (60.3) | 0.016 |
| Female | 2365 (39.3) | 9805 (40.4) | 110 (26.2) | 1160 (39.7) | ||
| Census region (n = 30,310, A-RH; n = 3340, M-RH) | ||||||
| Northeast | 735 (12.2) | 3940 (16.2) | 0.003 | 60 (14.3) | 330 (11.3) | 0.282 |
| Midwest | 1330 (22.1) | 5345 (22.0) | 45 (10.7) | 435 (14.9) | ||
| South | 1970 (32.7) | 8300 (34.2) | 180 (42.9) | 1010 (34.6) | ||
| West | 1990 (33.0) | 6700 (27.6) | 135 (32.1) | 1145 (39.2) | ||
| Race/ethnicity (n = 29,540, A-RH; n = 3025, M-RH) | ||||||
| White | 3050 (52.8) | 15,715 (66.1) | < 0.001 | 185 (46.2) | 1480 (52.8) | 0.245 |
| Black | 815 (14.1) | 3235 (13.6) | 85 (21.3) | 410 (14.6) | ||
| Hispanic | 1400 (24.2) | 2585 (10.9) | 100 (25.0) | 625 (22.3) | ||
| Asian or Pacific Islander | 270 (4.7) | 1385 (5.8) | b | 135 (4.8) | ||
| Native American | 45 (0.8) | 110 (0.5) | 15 (3.7) | 50 (1.8) | ||
| Other race/ethnicity | 195 (3.4) | 735 (3.1) | b | 105 (3.7) | ||
| Payer (n = 30,285, A-RH; n = 3340, M-RH) | ||||||
| Medicare | 2880 (47.9) | 12,600 (51.9) | 0.013 | 120 (28.6) | 855 (29.3) | 0.961 |
| Medicaid | 1155 (19.2) | 3845 (15.8) | 120 (28.6) | 850 (29.1) | ||
| Private | 1760 (29.3) | 7140 (29.4) | 165 (39.3) | 1080 (37.0) | ||
| Other | 215 (3.6) | 690 (2.8) | 15 (3.6) | 135 (4.6) | ||
| Concurrent conditions | ||||||
| Asthma | 465 (7.7) | 1895 (7.8) | 0.922 | 25 (6.0) | 110 (3.8) | 0.347 |
| Cirrhosis | 80 (1.3) | 430 (1.8) | 0.290 | b | 55 (1.9) | n/a |
| COPD | 1265 (21.0) | 7620 (31.4) | < 0.001 | 60 (14.3) | 340 (11.6) | 0.491 |
| Diabetes | 2540 (42.2) | 6595 (27.2) | < 0.001 | 265 (63.1) | 1340 (45.9) | 0.005 |
| End stage renal disease | 375 (6.2) | 1245 (5.1) | 0.143 | 20 (4.8) | 215 (7.4) | 0.385 |
| Hematologic malignancy | 375 (6.2) | 5440 (22.4) | < 0.001 | 30 (7.1) | 825 (28.3) | < 0.001 |
| Haematopoietic stem cell transplant | 60 (1.0) | 910 (3.7) | < 0.001 | b | 150 (5.1) | n/a |
| HIV infection | 50 (0.8) | 530 (2.2) | 0.002 | b | 20 (0.7) | n/a |
| Immune-mediated inflammatory diseases | 350 (5.8) | 1650 (6.8) | 0.218 | b | 110 (3.8) | n/a |
| Solid organ transplant | 225 (3.7) | 1645 (6.8) | < 0.001 | 25 (6.0) | 255 (8.7) | 0.397 |
| Solid organ malignancy | 280 (4.6) | 2845 (11.7) | < 0.001 | b | 160 (5.5) | n/a |
| Mean length of stay, days (SE) | 30 (0.8) | 16 (0.2) | < 0.001 | 19 (1.6) | 22 (0.7) | < 0.001 |
| In-hospital death (n = 30,295, A-RH; n = 3340, M-RH) | 3355 (55.7) | 3765 (15.5) | < 0.001 | 220 (52.4) | 525 (18.0) | < 0.001 |
Abbreviations: A-RH = aspergillosis-related hospitalizations; COPD = chronic obstructive pulmonary disease; M-RH = mucormycosis-related hospitalizations.
Data are shown as no. (col. %), unless otherwise indicated. SAS 9.4 survey procedures were used for analyses.
Cells with ≤ 10 hospitalizations are not shown.
From 2016 to 2021, an estimated 8565 M-RHs occurred, with rates increasing from 3.8 to 5.8 (Table 3). Rates across age groups, sexes, regions and races/ethnicities mostly remained stable during 2016–2019. From 2020 to 2021, these rates generally remained stable or increased, with the greatest increases for M-RHs involving 45–64-year-olds (6.8–10.7), males (5.2–7.4), Southern region (3.8–5.6) and Hispanic/Latino (4.9–6.8) patients. Among all M-RHs, mucormycosis subtypes included pulmonary mucormycosis (25.3%), rhinocerebral mucormycosis (11.4%), gastrointestinal mucormycosis (2.2%), cutaneous mucormycosis (10.6%), disseminated mucormycosis (5.7%), mucormycosis unspecified (39.9%), other zygomycoses (1.7%) and zygomycosis unspecified (3.1%).
TABLE 3 ∣.
Demographic characteristics and rates (per 1 million population) for mucormycosis-related hospitalisations, United States, 2016–2021.a
| 2016 | 2017 | 2018 | 2019 | 2020 | 2021 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|
|
|||||||
| Characteristics | No. (col. %) | Rate | No. (col. %) | Rate | No. (col. %) | Rate | No. (col. %) | Rate | No. (col. %) | Rate | No. (col. %) | Rate |
| Overall | 1240 (100.0) | 3.8 | 1220 (100.0) | 3.8 | 1370 (100.0) | 4.2 | 1395 (100.0) | 4.2 | 1420 (100.0) | 4.3 | 1920 (100.0) | 5.8 |
| Age group, years (n = 8565) | ||||||||||||
| < 18 | 145 (11.7) | 2.0 | 140 (11.5) | 1.9 | 160 (11.7) | 2.2 | 100 (7.2) | 1.4 | 100 (7.0) | 1.4 | 145 (7.6) | 2.0 |
| 18–44 | 265 (21.4) | 2.3 | 220 (18.0) | 1.9 | 280 (20.4) | 2.4 | 255 (18.3) | 2.2 | 390 (27.5) | 3.3 | 480 (25.0) | 4.0 |
| 45–64 | 460 (37.1) | 5.5 | 490 (40.2) | 5.8 | 575 (42.0) | 6.9 | 635 (45.5) | 7.6 | 565 (39.8) | 6.8 | 890 (46.4) | 10.7 |
| ≥ 65 | 370 (29.8) | 7.5 | 370 (30.3) | 7.3 | 355 (25.9) | 6.8 | 405 (29.0) | 7.5 | 365 (25.7) | 6.6 | 405 (21.1) | 7.2 |
| Sex (n = 8565) | ||||||||||||
| Male | 845 (68.1) | 5.3 | 715 (58.6) | 4.5 | 795 (58.0) | 4.9 | 785 (56.3) | 4.9 | 845 (59.5) | 5.2 | 1225 (63.8) | 7.4 |
| Female | 395 (31.9) | 2.4 | 505 (41.4) | 3.1 | 575 (42.0) | 3.5 | 610 (43.7) | 3.7 | 575 (40.5) | 3.4 | 695 (36.2) | 4.2 |
| Census region (n = 8565) | ||||||||||||
| Northeast | 215 (17.3) | 3.8 | 135 (11.1) | 2.4 | 165 (12.0) | 2.9 | 165 (11.8) | 2.9 | 175 (12.3) | 3.1 | 215 (11.2) | 3.8 |
| Midwest | 235 (19.0) | 3.5 | 235 (19.3) | 3.4 | 230 (16.8) | 3.4 | 255 (18.3) | 3.7 | 190 (13.4) | 2.8 | 290 (15.1) | 4.2 |
| South | 370 (29.8) | 3.0 | 380 (31.1) | 3.1 | 465 (33.9) | 3.7 | 490 (35.1) | 3.9 | 475 (33.5) | 3.8 | 715 (37.2) | 5.6 |
| West | 420 (33.9) | 5.5 | 470 (38.5) | 6.1 | 510 (37.2) | 6.6 | 485 (34.8) | 6.2 | 580 (40.8) | 7.4 | 700 (36.5) | 8.9 |
| Race/ethnicity (n = 8155) | ||||||||||||
| White | 615 (53.2) | 2.5 | 615 (54.2) | 2.5 | 700 (53.2) | 2.8 | 755 (56.1) | 3.0 | 680 (49.8) | 2.8 | 985 (53.5) | 3.9 |
| Black | 115 (10.0) | 2.7 | 140 (12.3) | 3.2 | 195 (14.8) | 4.4 | 195 (14.5) | 4.4 | 230 (16.8) | 5.2 | 265 (14.4) | 5.9 |
| Hispanic | 285 (24.7) | 5.0 | 295 (26.0) | 5.1 | 335 (25.5) | 5.6 | 265 (19.7) | 4.4 | 300 (22.0) | 4.9 | 425 (23.1) | 6.8 |
| Asian or Pacific Islander | 75 (6.5) | 3.9 | 25 (2.2) | 1.3 | 35 (2.7) | 1.7 | 70 (5.2) | 3.4 | 50 (3.7) | 2.4 | 90 (4.9) | 4.2 |
| Native American | 15 (1.3) | 3.7 | b | b | b | b | b | b | 45 (3.3) | 10.5 | 20 (1.1) | 4.6 |
| Other race/ethnicity | 50 (4.3) | 5.9 | 60 (5.3) | 6.8 | 40 (3.0) | 4.4 | 55 (4.1) | 5.9 | 60 (4.4) | 6.3 | 55 (3.0) | 5.6 |
Among all mucormycosis-related hospitalizations, mucormycosis subtypes included pulmonary mucormycosis (25.3%), rhinocerebral mucormycosis (11.4%), gastrointestinal mucormycosis (2.2%), cutaneous mucormycosis (10.6%), disseminated mucormycosis (5.7%), mucormycosis unspecified (39.9%), other zygomycoses (1.7%) and zygomycosis unspecified (3.1%). Hospitalizations could involve more than one subtype. SAS 9.4 survey procedures were used for analyses.
Cells with ≤ 10 hospitalizations are not shown.
Among M-RHs, the percentage distribution for underlying conditions was mostly stable from 2016 to 2019, except for a decline in HM (37.1%–32.6%). This percentage further declined to 25.4% in 2020 and was 25.8% in 2021. Other notable changes from 2020 to 2021 were a decline in the percentage involving end-stage renal disease (9.2%–5.5%) or SOT (10.2%–7.0%) and an increase in those involving diabetes (46.5%–49.2%) or COVID-19, which increased from 10.6%–14.1% (Figure 1B). In 2021, 12.2% involved COPD and 7.0% SOT.
During 2020–2021, 420/2920 (14.4%) M-RHs were COVID-19-associated (Table 2). COVID-19-associated M-RHs (vs. non-COVID-19-associated) were significantly different by age group (p = 0.019), with more involving 18–44-year-olds (36.9% vs. 24.5%); males (73.8% vs. 60.3%, p = 0.016) and diabetes (63.1% vs. 45.9%, p = 0.005), and fewer involving HM (7.1% vs., 28.3%, p < 0.001). In-hospital mortality was higher for COVID-19-associated MR-H (52.4%) vs. non-COVID-19-associated MR-H (18.0%) (p < 0.001).
4 ∣. Discussion
Our analysis revealed that the rates of A-RHs and M-RHs in the United States peaked in 2021. This finding likely reflects the increased burden of COVID-19 in 2021 compared with 2020 (https://gis.cdc.gov/grasp/covidnet/covid19_5.html), along with increased clinician awareness and testing for these COVID-19-associated infections and more use of corticosteroids for treating severe COVID-19 [7, 8]. A-RHs and M-RHs involving COVID-19 had mortality rates exceeding 50%, which was ≈3 to 4-fold higher than those for A-RHs and M-RHs without COVID-19. This aligns with mortality rates reported in a smaller study that included all types of fungal infections (48.5% [COVID-19-associated] vs. 12.3% [non-COVID-19-associated]) [6]. Our findings also mirror prior reports highlighting racial/ethnic disparities in COVID-19-associated fungal infections, as well as the higher rate of hospitalisations for A-RH and M-RH in the Western United States [2, 6] (Table 3).
Direct comparisons with the 2000–2013 HCUP analysis are challenging because of the potential misalignment between ICD-9-CM (used for the earlier study) and ICD-10-CM coding [9] and COVID-19 pandemic-related changes during 2020–2021. However, we observed notable differences in trends in hospitalisation rates and for certain underlying medical conditions. While the earlier analysis indicated an increase in A-RH and M-RH rates [5], our findings for the pre-COVID-19 period (2016–2019) showed that these rates remained relatively stable or increased only slightly. During 2000–2013, the percentage of M-RH involving HM and SOT increased, whereas during 2016–2019, these percentages remained stable (SOT) or slightly declined (HM) [5]. Additionally, the previous study reported a rise in M-RH involving hematologic malignancies (HM) and solid organ transplants (SOT), whereas our analysis revealed stable percentages for SOT and a slight decline for HM [5]. The reasons for these discrepancies are not entirely clear but might reflect changes in antifungal prophylactic strategies aimed at preventing aspergillosis and mucormycosis, as well as advancements in the treatment of cancers and other conditions that result in less severe immunosuppression, thereby reducing the risk of these fungal infections [10, 11].
This study's primary limitation is the lack of clinical and laboratory data and reliance on ICD-10-CM codes, which might fail to detect ≈25%–50% of aspergillosis, mucormycosis and other mould infections [12]. An important limitation in diagnosing aspergillosis and mucormycosis is the challenge of meeting the microscopic or microbiological criteria necessary to classify cases as probable or proven, as delineated in the updated criteria from the European Organisation for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) [13]. Medical record documentation might not always align with these criteria, which could have led to disease misclassification in the HCUP data-base. Finally, the most recent year of available data were 2021, which limits the timeliness of our findings, particularly in assessing trends following the peak of the COVID-19 pandemic. Nonetheless, our analysis underscores the need for continued monitoring of risk factors and clinician awareness of aspergillosis and mucormycosis, particularly among at-risk patients including those with severe COVID-19.
Supplementary Material
Additional supporting information can be found online in the Supporting Information section. Table S1: International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) for conditions of interest for aspergillosis- and mucormycosis-related hospitalizations, 2016–2021.
Acknowledgements
This text was edited for grammar and style with the assistance of OpenAI's ChatGPT (GPT-3.5). All content has been reviewed for accuracy by the authors.
Funding:
The authors received no specific funding for this work.
Disclosure
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Footnotes
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are openly available in the National (Nationwide) Inpatient Sample (NIS) Database at http://hcup-us.ahrq.gov/db/nation/nis/nisdbdocumentation.jsp.
References
- 1.Benedict K, Whitham HK, and Jackson BR, “Economic Burden of Fungal Diseases in the United States,” Open Forum Infectious Diseases 9, no. 4 (2022): ofac097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gold JA, Ahmad FB, Cisewski JA, et al. , “Increased Deaths From Fungal Infections During the Coronavirus Disease 2019 Pandemic—National Vital Statistics System, United States, January 2020–December 2021,” Clinical Infectious Diseases 76, no. 3 (2023): e255–e262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Baddley JW, “Clinical Risk Factors for Invasive Aspergillosis,” Medical Mycology 49, no. Suppl 1 (2011): S7–s12. [DOI] [PubMed] [Google Scholar]
- 4.Lanternier F, Sun H-Y, Ribaud P, Singh N, Kontoyiannis DP, and Lortholary O, “Mucormycosis in Organ and Stem Cell Transplant Recipients,” Clinical Infectious Diseases 54, no. 11 (2012): 1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Vallabhaneni S, Benedict K, Derado G, and Mody RK, “Trends in Hospitalizations Related to Invasive Aspergillosis and Mucormycosis in the United States, 2000–2013,” Open Forum Infectious Diseases 4, no. 1 (2017): ofw268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gold JA, Adjei S, Gundlapalli AV, et al. , “Increased Hospitalizations Involving Fungal Infections During COVID-19 Pandemic, United States, January 2020–December 2021,” Emerging Infectious Diseases 29, no. 7 (2023): 1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Egger M, Bussini L, Hoenigl M, and Bartoletti M, “Prevalence of COVID-19-Associated Pulmonary Aspergillosis: Critical Review and Conclusions,” Journal of Fungi (Basel, Switzerland) 8, no. 4 (2022): 390. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Hoenigl M, Arastehfar A, Arendrup MC, et al. , “Novel Antifungals and Treatment Approaches to Tackle Resistance and Improve Outcomes of Invasive Fungal Disease,” Clinical Microbiology Reviews 37 (2024): e00074–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Khera R, Dorsey KB, and Krumholz HM, “Transition to the ICD-10 in the United States: An Emerging Data Chasm,” JAMA 320, no. 2 (2018): 133–134. [DOI] [PubMed] [Google Scholar]
- 10.Patterson TF, Thompson GR III, Denning DW, et al. , “Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America,” Clinical Infectious Diseases 63, no. 4 (2016): e1–e60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. , “Global Guideline for the Diagnosis and Management of Mucormycosis: An Initiative of the European Confederation of Medical Mycology in Cooperation With the Mycoses Study Group Education and Research Consortium,” Lancet Infectious Diseases 19, no. 12 (2019): e405–e421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Gold JA, Revis A, Thomas S, et al. , “Clinical Characteristics, Health Care Utilization, and Outcomes Among Patients in a Pilot Surveillance System for Invasive Mold Disease—Georgia, United States, 2017–2019,” Open Forum Infectious Diseases 9 (2022): ofac215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Donnelly JP, Chen SC, Kauffman CA, et al. , “Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium,” Clinical Infectious Diseases 71, no. 6 (2019): 1367–1376. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are openly available in the National (Nationwide) Inpatient Sample (NIS) Database at http://hcup-us.ahrq.gov/db/nation/nis/nisdbdocumentation.jsp.