Use of Venovenous Extracorporeal Membrane Oxygenation in Patients With Acute Respiratory Distress Syndrome Caused by Fungal Pneumonia

Abstract

Background:

Patients with fungal pneumonias sometimes progress to acute respiratory distress syndrome (ARDS). Mortality has been reported as high as 60% to 90% in this group. Venovenous extracorporeal membrane oxygenation (VV-ECMO) can be used to support such patients, however, outcomes are not well understood.

Patients and Methods:

This was a retrospective study across the four adult ECMO centers in Minnesota for one decade (2012–2022). The outcomes of interest were duration of ECMO, survival rate, and complications. Data were extracted from the electronic medical record and analyzed using descriptive statistics.

Results:

Fungal pneumonia was the etiology of ARDS in 22 of 422 (5%) adults supported with VV-ECMO during the 10-year study period. Median patient age was 43 years (interquartile range [IQR], 35–56) and 68% were male. By type of fungal infection, 16 (72%) had blastomycosis, five (22%) had pneumocystis, and one (5%) had cryptococcus. Of the 16 patients with blastomycosis two were immunosuppressed whereas all five of the pneumocystis patients were immunosuppressed. The overall survival rate was 73%; most patients with blastomycosis (67%) and pneumocystis (80%) survived to hospital discharge. The duration of ECMO support was greater for the pneumocystis group (median, 30 days; IQR, 21–43) compared with blastomycosis (median, 10 days; IQR, 8–18).

Conclusions:

Our findings support the use of VV-ECMO for ARDS caused by fungal pneumonias in select immunocompetent and immunocompromised patients. Although survival was high, patients with pneumocystis required longer ECMO runs.

Infections caused by fungi such as Blastomyces dermatitidis and Pneumocystis jirovecii are an infrequent but serious cause of acute respiratory distress syndrome (ARDS).^1,2 According to the Minnesota Department of Health, there were an estimated 623 cases of blastomycosis from 2012 to 2022.³ Infections from Cryptococcus neoformans are also rare, and typically cause meningitis and at times, pneumonia.⁴ One study found that 15% of patients with blastomycosis developed ARDS and another study suggested that 25% of patients with acquired immune deficiency syndrome (AIDS) and pneumocystis pneumonia developed ARDS.^5,6 For patients with AIDS and Cryptococcus neoformans infections, the prevalence of acute respiratory failure was reported to be approximately 14%.⁷ Unfortunately, ARDS in general has been associated with mortality rates up to 30% to 40%, however, the mortality rate for blastomycosis-related ARDS has been reported to range from 50% to 90% and the mortality rate for pneumocystis pneumonia requiring mechanical ventilation has been estimated to be 62%.^8–12

The typical treatment for fungal ARDS includes support of oxygenation and ventilation and antifungal drugs. Blastomycosis and cryptococcus are treated with amphotericin B followed by azole therapy, whereas pneumocystis is usually treated with trimethoprim-sulfamethoxazole and high-dose corticosteroid therapy.^13–17 There is limited information on effective dosing of medications, such as amphotericin B, for patients being supported by extracorporeal membrane oxygenation (ECMO).¹⁸ Additionally, the role of ECMO in support of patients with ARDS caused by fungal pneumonia is less well defined, with some case reports suggesting improved survival.¹⁹

Several case reports have described ECMO support in patients with fungal ARDS, but larger case series are lacking.^19,20 Reporting increased numbers would facilitate further refinement of management.^13,19 In this study, we report the outcomes of patients with fungal ARDS supported with VV-ECMO at four adult ECMO centers in Minnesota over a 10-year period.

Patients and Methods

This was a retrospective, observational cohort study of patients supported with venovenous extracorporeal membrane oxygenation (VV-ECMO) at one of four adult Extracorporeal Life Support Organization (ELSO)-certified Centers of Excellence in Minnesota including University of Minnesota MHealth Fairview (n = 158; 2013–2022), Hennepin County Medical Center (n = 77; 2015–2022), Mayo Clinic (n = 74; 2019–2022), and Abbott Northwestern Hospital (n = 111; 2012–2022). Patients were included if they required VV-ECMO because of ARDS caused by fungal pneumonia. Patients requiring venoarterial or venoarteriovenous ECMO were excluded. Patients requiring left or right ventricular assist devices during their course were also excluded. The Institutional Review Boards at each site approved this study with a waiver of informed consent.

Data were extracted from the electronic medical record at each site by trained investigators as part of the construction of the Minnesota ECMO Consortium Database maintained with REDCap data.^21,22 Variables used for this study included patient demographics, comorbidities, indication for ECMO, hospital and intensive care unit (ICU) length of stay, length of ECMO run, in-hospital mortality, and complications. Summary descriptive statistics were calculated and used to describe characteristics and outcomes of this VV-ECMO cohort with fungal pneumonia, such as count and percentage for categorical variables and median and interquartile range for continuous variables, as appropriate. Microsoft Excel (Microsoft, Redmond, WA) was used for all data analysis.

Results

Of 422 patients in the Minnesota Consortium adult VV-ECMO database, 22 (5%) had fungal pneumonia identified as the cause of their ARDS. Four fungal pathogens were identified. Blastomycosis was found in 16 patients (73%), pneumocystis in five patients (22%), and one patient (5%) with cryptococcus. Of the patients with blastomycosis, one case occurred in 2014, one case in 2016, one case in 2017, and one case in 2018. Six of the blastomycosis cases occurred in 2019, three cases in 2020, and three cases in 2022. Baseline demographics, comorbidities, and pre-ECMO data are presented in Table 1. All patients received epoprostenol and high-dose steroid therapy prior to ECMO initiation. Patients with pneumocystis had the longest interval between intubation and ECMO initiation (median, 10 days; interquartile range [IQR], 5–13).

Table 1.

Demographics, Comorbidities, and Pre-ECMO Characteristics of Patients Supported With VV-ECMO Extracorporeal Membrane Oxygenation for Rare Fungal Pneumonias

Characteristic		Blastomycosis n = 16	Pneumocystis n = 5	Cryptococcus n = 1
Age in years, median (IQR)		50 (28–34)	41 (34–49)	35
Gender, n (%)	Male	13 (81%)	2 (40%)	0 (%)
Race/ethnicity, n (%)	White, non-Hispanic	12 (75%)	3 (60%)	1 (100%)
	Black/African American	0 (0%)	0 (0%)	0 (0%)
	Hispanic ethnicity	0 (0%)	0 (0%)	0 (0%)
	Asian	2 (12%)	0 (0%)	0 (0%)
	Unknown	1 (6%)	0 (0%)	0 (0%)
	Native American	1 (6%)	0 (0%)	0 (0%)
BMI, median (IQR)		31.2 (27.5–33.7)	29.4 (19.9–38.1)	41.01
Comorbidity, n (%)	Obesity (BMI >30)	10 (63%)	2 (40%)	1 (100%)
	Hypertension	4 (25%)	1 (20%)	0 (0%)
	Hyperlipidemia	2 (13%)	1 (20%)	0 (0%)
	Diabetes mellitus	2 (13%)	1 (20%)	0 (0%)
	Asthma	2 (13%)	1 (20%)	0 (0%)
	Pulmonary fibrosis	1 (6%)	0 (0%)	0 (0%)
	History of DVT or PE	2 (13%)	0 (0%)	0 (0%)
	Immunosuppressed state	2 (13%)	5 (100%)	0 (0%)
	Cirrhosis	1 (6%)	0 (%)	1 (100%)
PaO₂/FiO₂ prior to cannulation, median (IQR)		68 (57–77)^a	65 (55–77)	103
Proned prior to ECMO, n (%)		11 (77%)^a	3 (60%)	1 (100%)
Required vasopressors prior to ECMO, n (%)		12 (86%)^a	2 (40%)	0 (0%)
Aerosolized epoprostenol prior to ECMO, n (%)		14 (100%)^a	5 (100%)	1 (100%)
Paralyzed prior to ECMO, n (%)		12 (86%)^a	3 (60%)	1 (100%)
SOFA score prior to cannulation, median (IQR)		8 (7–11)^a	6 (5–7)	8
Days from intubation to ECMO cannulation, median (IQR)		3 (1.7–4.7)	10 (5–13)	6
Cannulated at outside facility, n (%)		8 (53%)	2 (40%)	0 (0%)
Corticosteroid therapy, n (%)		16 (100%)	5 (100%)	1 (100%)

BMI = body mass index; COPD = chronic obstructive pulmonary disease; DVT = deep vein thrombosis; ECMO = extracorporeal membrane oxygenation; FiO₂ = fraction of inspired oxygen; IQR = interquartile range; PaO₂₌ partial pressure of oxygen; PE = pulmonary embolism; SOFA = sequential organ failure assessment; VV-ECMO = venovenous extracorporeal membrane oxygenation.

Missing values for SOFA (2), PaO₂/FiO₂ (7), prone (2), vasopressor (2), epoprostenol (2), paralyzed (2).

Patients with blastomycosis were older and mostly male. Nearly one third (31%) of patients with blastomycosis had extrapulmonary manifestations, including neurologic, gastrointestinal, skin, bone, joint, blood, and genitourinary invasion. Two were immunocompromised; one was receiving chemotherapy and the other had common variable immunodeficiency. Diagnostic data that supported a diagnosis of pulmonary blastomycosis included sputum or bronchioalveolar lavage examination (100%), cytology (62%), antigen detection (25%), and antibody detection (25%). All patients with blastomycosis received liposomal amphotericin B while they were critically ill, then itraconazole (69%), voriconazole (18%), or fluconazole (6%) were prescribed. Doses of liposomal amphotericin ranged from 1 to 10 mg/kg per day. Of the five patients with pneumocystis pneumonia, three had human immunodeficiency virus (HIV) with an absolute CD4 T-cell counts on admission ranging from less than 10 to 314 cells/mm³. The other two patients were immunosuppressed because of medications. Patients with pneumocystis were diagnosed via respiratory culture of either sputum or bronchioalveolar lavage (20%), cytology (60%), and polymerase chain reaction (PCR; 60%). All patients with pneumocystis received trimethoprim-sulfamethoxazole and one received clindamycin and primaquine. The patient with cryptococcus was diagnosed via sputum culture and received amphotericin B and fluconazole.

Outcomes are presented in Table 2. Patients with blastomycosis had a high rate of acute kidney injury (AKI) requiring renal replacement therapy (RRT). Patients with pneumocystis had the longest ECMO runs and hospital length of stays. A total of 11 of 16 blastomycosis patients (69%), four of five pneumocystis patients (80%), and the single patient with cryptococcus survived to hospital discharge.

Table 2.

Outcomes of Patients Supported With Venovenous Extracorporeal Membrane Oxygenation for Rare Fungal Pneumonias

Characteristic		Blastomycosis n = 16	Pneumocystis n = 5	Cryptococcus n = 1
Complications, n (%)	Gastrointestinal hemorrhage	1 (6%)	0 (0%)	1 (100%)
	Intracranial hemorrhage	3 (19%)	0 (0%)	0 (0%)
	Acute kidney injury	13 (81%)	0 (0%)	1 (100%)
	Arrhythmia	3 (19%)	1 (20%)	0 (0%)
	Pneumothorax	2 (13%)	0 (0%)	0 (0%)
	Pulmonary hemorrhage	0 (0%)	0 (0%)	1 (100%)
	Deep vein thrombosis	5 (33%)	1 (20%)	0 (0%)
	Required circuit change	3 (19%)	2 (40%)	0 (0%)
	Cannula bleeding	0 (0%)	1 (20%)	0 (0%)
	Cannula problems	6 (38%)	3 (60%)	0 (0%)
	Secondary pneumonia	4 (25%)	3 (60%)	0 (0%)
	Urinary tract infection	1 (6%)	0 (0%)	0 (0%)
	Bacteremia	6 (38%)	2 (40%)	0 (0%)
	C. difficile colitis	1 (6%)	0 (0%)	0 (0%)
CRRT required, n (%)		11 (69%)	0 (0%)	1 (100%)
Duration of mechanical ventilation in days, median (IQR)		18 (14–28)	30 (20–41)	^a
Tracheostomy, n (%)		7 (44%)	4 (80%)	1 (100%)
Days on ECMO, median (IQR)		10 (8–18)	30 (21–43)	15
Length of ICU stay in days, median (IQR)		26 (17–44)	47 (39–62)	34
Length of hospital stay in days, median (IQR)		32 (22–44)	47 (39–62)	39
Survived to discharge, n (%)		11 (69%)	4 (80%)	1 (100%)
Discharge disposition, n (%)	Home	3 (19%)	0 (0%)	0 (0%)
	LTACH or rehabilitation facility	7 (44%)	4 (80%)	1 (100%)
	Other hospital	1 (6%)	0 (0%)	0 (0%)

CRRT = continuous renal replacement therapy; ICU = intensive care unit; IQR = interquartile range; ECMO = extracorporeal membrane oxygenation; LTACH = long-term acute care hospital.

Patient not weaned from ventilator prior to discharge.

Discussion

Select patients with fungal pneumonia who developed severe ARDS and were not well supported by conventional management received VV-ECMO support. Although it appears that the number of cases of blastomycosis supported with VV-ECMO increased from 2012 to 2022, we hesitate to draw this conclusion because each institution contributed data from different date ranges. However, data from the Minnesota Department of Health do suggest an increasing incidence in blastomycosis cases.³

Patients supported with VV-ECMO for severe fungal-related ARDS had a 73% survival to discharge. This is consistent with a retrospective study investigating the management and outcomes of 43 patients with blastomycosis-related ARDS.¹³ They found that there was a 40% mortality rate for patients with blastomycosis-related ARDS, and all three patients who received ECMO survived.¹³ In patients with pneumocystis-related ARDS treated with VV-ECMO we found a mortality rate of 20%, compared with a previous study reporting a 58% mortality rate for patients admitted to the ICU for pneumocystis pneumonia and 81.8% mortality for patients supported with ECMO.²³ Last, in our study the patient with cryptococcosis-related ARDS survived with support from ECMO. This is in contrast to a case report by Orsini et al.,¹⁵ which reported a patient with untreated AIDS and cryptococcus-related ARDS who did not survive. Unfortunately, there is a lack of additional published data or case reports of patients being treated with ECMO for cryptococcus-related ARDS, and outcomes remain largely undescribed.

Additionally, we found that patients with pneumocystis-related ARDS had the longest runs on ECMO and longest hospital stays. Interestingly, these patients also had an increased interval between intubation and cannulation for ECMO. A case series by Benarczyk et al.¹⁹ attributes the success of using VV-ECMO to support patients with fungal-related ARDS to prompt diagnosis and treatment with antifungals, as well as initiation of VV-ECMO within 72 hours. Additionally, three of the 16 (69%) patients with blastomycosis received increased dosages of liposomal amphotericin B in part because of concerns regarding pharmacokinetics with the ECMO circuit. Although the standard dosing for liposomal amphotericin B is 5 mg/kg per day, two case reports have describe treating patients with blastomycosis supported by ECMO with increased doses of liposomal amphotericin B (7.5 mg/kg per day and 10 mg/kg per day).^18,24 Last, although co-infection with coronavirus disease 2019 (COVID-19) and fungal pneumonia has been described in the literature, none of the patients that we treated were positive for COVID.²⁵

Conclusions

Our case series represents data collected from four very distinct hospitals, including two academic medical centers, a quaternary community hospital, and a county hospital. This strengthens the generalizability of our findings to other ECMO centers and states. Additionally, these data were pulled from our ECMO consortium in which our catchment area represents the entire state of Minnesota and portions of surrounding states. Many of the patients were retrieved by our ECMO teams after they were originally cannulated elsewhere. Nonetheless, we still found favorable survival among patients with fungal-related ARDS supported by VV-ECMO.

Our study has several limitations. First, our relatively small case series does not reflect all fungi that are capable of causing ARDS or may require ECMO support. Additionally, the fungi reported in this study, such as blastomycosis, illustrate the fungi that are endemic to our area. Another limitation is the retrospective nature of our study, however, given the rare nature of fungal ARDS, a prospective study would be exceedingly logistically difficult. Furthermore, selection bias is a possible confounder of the outcomes reported in this case series. We are unable to report how many patients with fungal ARDS at our sites were not selected for ECMO support and their associated outcomes. Additionally, we did not perform any adjustments for confounders in our analysis, and therefore we cannot draw conclusions about associations of ECMO, other treatments, or pathogen with survival. Finally, although our data are from four distinct centers, it is geographically limited to Minnesota and may not reflect national or international trends in the management of fungal ARDS.

There is a paucity in information on supporting patients with fungal-related ARDS using ECMO. Our study helps address this data shortage and supports the use of VV-ECMO in the treatment of 22 patients with fungal-related ARDS from four adult ECMO centers in Minnesota over a 10-year period, with survival rates ranging from 69% to 100% depending on the fungus. These findings can help direct management of patients with fungal-ARDS and may inform eligibility of similar patients at other institutions considering ECMO use. Future studies should investigate survival on the national and international scale and determine which clinical characteristics are most predictive of successful use of ECMO in patients with fungal ARDS.

Footnotes

Funding Information

The National Library of Medicine Award Number R01LM012982 of the National Institutes of Health. RedCap access was supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences.

Author Disclosure Statement

The authors have no conflicts of interest or financial ties to disclose.

References

McBride

, Gauthier

, Klein

. Clinical manifestations and treatment of blastomycosis. Clin Chest Med, 2017; 38(3):435–435; doi: 10.1016/J.CCM.2017.04.006

Truong

, Ashurst

. Pneumocystis jirovecii pneumonia. StatPearls; 2022.

Minnesota Department of Health. Blastomycosis (Blastomyces dermatitidis and Blastomyces gilchristii). 2022. Available from: https://www.health.state.mn.us/diseases/blastomycosis [Last accessed: May 23, 2023].

Gushiken

, Saharia

, Baddley

. Cryptococcosis. Infect Dis Clin North Am, 2021; 35(2):493–514; doi: 10.1016/j.idc.2021.03.012

Azar

, Assi

, Relich

, et al. Blastomycosis in Indiana clinical and epidemiologic patterns of disease gleaned from a multicenter retrospective study. Chest, 2015; 148(5):1276–1284; doi: 10.1378/chest.15-0289

Baumann

, Jung

, Koss

, et al. Incidence and mortality of adult respiratory distress syndrome: A prospective analysis from a large metropolitan hospital. Crit Care Med, 1986; 14(1):1–4; doi: 10.1097/00003246-198601000-00001

Visnegarwala

, Graviss

, Lacke

, et al. Acute respiratory failure associated with cryptococcosis in patients with AIDS: Analysis of predictive factors. Clin Infect Dis, 1998; 27(5):1231–1237; doi: 10.1086/514984

Schuerer

DJE

, Kolovos

, Boyd

, et al. Extracorporeal membrane oxygenation: Current clinical practice, coding, and reimbursement. Chest, 2008; 134(1):179–184; doi: 10.1378/chest.07-2512

Lemos

, Baliga

, Guo

. Acute respiratory distress syndrome and blastomycosis: Presentation of nine cases and review of the literature. Ann Diagn Pathol, 2001; 5(1):1–9; doi: 10.1053/adpa.2001.21473

10.

Meyer

, McManus

, Maki

. Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med, 1993; 329(17):1231–1236; doi: 10.1056/NEJM199310213291704

11.

Vasquez

, Mehta

, Agrawal

, et al. Blastomycosis in northeast Tennessee. Chest, 1998; 114(2):436–443; doi: 10.1378/chest.114.2.436

12.

RandallCurtis

, Yarnold

, Schwartz

, et al. Improvements in outcomes of acute respiratory failure for patients with human immunodeficiency virus-related Pneumocystis carinii pneumonia. Am J Respir Crit Care Med, 2000; 162(2):393–398; doi: 10.1164/ajrccm.162.2.9909014

13.

Schwartz

, Embil

, Sharma

, et al. Management and outcomes of acute respiratory distress syndrome caused by blastomycosis: A retrospective case series. Medicine (Baltimore), 2016; 95(18):e3538; doi: 10.1097/MD.0000000000003538

14.

Limper

, Knox

, Sarosi

, et al. An official American Thoracic Society Statement: Treatment of Fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med, 2011; 183(1):96–128; doi: 10.1164/rccm.2008-740ST

15.

Orsini

, Blaak

, Tam

, et al. Disseminated cryptococcal infection resulting in acute respiratory distress syndrome (ARDS) as the initial clinical presentation of AIDS. Intern Med, 2016; 55(8):995–998; doi: 10.2169/internalmedicine.55.5768

16.

Lahm

, Neese

, Thomburg

, et al. Corticosteroids for blastomycosis-induced ARDS: A report of two patients and review of the literature. Chest, 2008; 133(6):1478–1480; doi: 10.1378/chest.07-2778

17.

Ewald

, Raatz

, Boscacci

, et al. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection. Cochrane Database Syst Rev, 2015; 2015(4):CD006150; doi: 10.1002/14651858.CD006150.PUB2

18.

Zhao

, Seelhammer

, Barreto

, et al. Altered pharmacokinetics and dosing of liposomal amphotericin b and isavuconazole during extracorporeal membrane oxygenation. Pharmacotherapy, 2020; 40(1):89–95; doi: 10.1002/phar.2348

19.

Bednarczyk

, Kethireddy

, White

, et al. Extracorporeal membrane oxygenation for blastomycosis-related acute respiratory distress syndrome: A case series. Can J Anaesth, 2015; 62(7):807–807; doi: 10.1007/S12630-015-0378-Z

20.

Wanta

, Tyner

, Bohman

, et al. Successful treatment of refractory hypoxemia secondary to disseminated histoplasmosis using extracorporeal membrane oxygenation support. A A Case Rep, 2016; 7(8):161–164; doi: 10.1213/XAA.0000000000000374

21.

Harris

, Taylor

, Minor

, et al. The REDCap consortium: Building an international community of software platform partners. J Biomed Inform, 2019; 95:103208; doi: 10.1016/j.jbi.2019.103208

22.

Harris

, Taylor

, Thielke

, et al. Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform, 2009; 42(2):377–381; doi: https://doi.org/10.1016/j.jbi.2008.08.010

23.

Schmidt

, Lueck

, Ziesing

, et al. Clinical course, treatment and outcome of Pneumocystis pneumonia in immunocompromised adults: A retrospective analysis over 17 years. Crit Care, 2018; 22(1):1–9; doi: 10.1186/S13054-018-2221-8

24.

Servais

, Ammar

, Gurnani

. Treatment of pulmonary blastomycosis with high-dose liposomal amphotericin B in a patient receiving extracorporeal membrane oxygenation. BMJ Case Rep, 2019; 12(6):e229612; doi: 10.1136/bcr-2019-229612

25.

Raffaelli

, Tanzarella

, De Pascale

, et al. Invasive respiratory fungal infections in COVID-19 critically ill patients. J Fungi (Basel), 2022; 8(4):415; doi: 10.3390/jof8040415