Survival after Invasive Pulmonary Aspergillosis in a patient requiring sequential Veno- Arterial and Veno-Venous ECMO for refractory cardiorespiratory failure: a case report

Survival after Invasive Pulmonary Aspergillosis in a patient requiring sequential Veno- Arterial and Veno-Venous ECMO for refractory cardiorespiratory failure: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Survival after Invasive Pulmonary Aspergillosis in a patient requiring sequential Veno- Arterial and Veno-Venous ECMO for refractory cardiorespiratory failure: a case report Edgar G. Moglia Ordaz¹ This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7840777/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Invasive Pulmonary Aspergillosis (IPA) in critically ill patients on Extracorporeal Membrane Oxygenation (ECMO) is a highly lethal condition, with mortality reported over 80%. Diagnosing and managing this condition is complicated by underlying severe illness, non-specific findings, and profound acquired immune dysfunction. Case Presentation: We report the case of a 67-year-old female with no prior immunosuppression who survived a catastrophic 3-month ICU stay. She initially suffered an cardiac tamponade requiring surgical repair, which was complicated by a massive pulmonary embolism (PE) necessitating Veno-Arterial ECMO (VA-ECMO) and mechanical thrombectomy. After weaning from VA-ECMO, she developed severe ARDS from an E. coli ESBL pneumonia, requiring initiation of Veno-Venous ECMO (VV-ECMO). Her failure to improve led to a bronchoscopy, which was positive for Galactomannan antigen (index 0.7), prompting initiation of voriconazole for probable IPA. After 33 days, she was transferred to a referral center (Hospital Clínic), where VV-ECMO was weaned. However, she relapsed with severe respiratory failure. A new bronchoscopy confirmed invasive aspergillosis via culture of Aspergillus terreus and revealed high-load Cytomegalovirus (CMV) reactivation (240,000 copies/mL). She was successfully treated with a prolonged 7-week course of isavuconazole and ganciclovir. Her recovery was protracted, complicated by gastrointestinal bleeding and severe critical illness myopathy, but she was eventually weaned from all organ support and discharged to rehabilitation. Conclusions This case of survival highlights the extreme complexity of managing severe ARDS on ECMO. It underscores: (1) The importance of proactive investigation for fungal and viral superinfections, such as Aspergillus and CMV, in patients with ARDS who fail to improve, as this indicates profound acquired immunoparalysis. (2) The diagnostic utility of BAL galactomannan as an early marker, even when cultures are later positive for different species. (3) That survival, while rare, is possible with aggressive, multidisciplinary management and prolonged antifungal therapy. Case report Invasive Pulmonary Aspergillosis CAPA ECMO ARDS Galactomannan Aspergillus terreus CMV Reactivation Background Invasive Pulmonary Aspergillosis (IPA) has emerged as a significant threat in the intensive care unit (ICU), extending far beyond its classic association with severely immunocompromised hosts. The entity of Critically Ill-Associated Pulmonary Aspergillosis (CAPA) is now well-defined, with Acute Respiratory Distress Syndrome (ARDS) being a primary risk factor [ 1 ]. Extracorporeal Membrane Oxygenation (ECMO), while a life-saving therapy for refractory cardiorespiratory failure, paradoxically increases the risk for IPA by inducing a state of systemic inflammation and immune dysregulation [ 2 ]. This constellation of ARDS, ECMO, and IPA is exceptionally lethal, with mortality rates consistently reported to exceed 80% [ 3 ]. The diagnosis is notoriously difficult, as clinical and radiological signs are non-specific. Furthermore, these patients often develop multiple concurrent infections, including viral reactivations such as Cytomegalovirus (CMV), which are markers of a profound acquired immunoparalysis and further complicate management [ 4 ]. We present the exceptional case of a 67-year-old female who survived this exact constellation: sequential VA-ECMO and VV-ECMO support, complicated by confirmed Aspergillus terreus pneumonia and high-load CMV reactivation. This report, which includes the full 3-month ICU course across two institutions, has been prepared in accordance with the CARE guidelines [ 5 ] and provides critical insights into the diagnostic and therapeutic challenges of this complex syndrome. Case Presentation Patient Information A 67-year-old female with a history of hypertension, dyslipidemia, and atrial fibrillation (on Edoxaban) was admitted for an elective flutter ablation. She had no history of immunosuppression, neoplasia, or chronic lung disease. Clinical Findings and Timeline The patient's complex ICU course proceeded in distinct phases: Phase 1: Taponamiento and Multicomponent Shock (Day 0–1) On June 22nd, the ablation procedure was complicated by an laceration of the superior left pulmonary vein, leading to acute cardiac tamponade. Following an emergency pericardiocentesis (> 700 mL) and surgical repair under cardiopulmonary bypass (CPB), she was transferred to the ICU. She presented in multi-component shock: vasoplegic (norepinephrine 0.8 mcg/kg/min), hemorrhagic (requiring > 1000 mL blood loss replacement, 3 PRBCs, 1 platelet pool), and persistent hypoperfusion (Lactate > 4 mmol/L) with an echocardiogram showing a severely dilated right ventricle (RV). Phase 2: VA-ECMO, PE Diagnosis, and the "First Hit" (Day 1–8) A pulmonary artery catheter was placed, revealing obstructive shock (CI 1.85 L/min/m², mPAP 43 mmHg, PVRi 1082 dyn·s·cm⁻⁵). Based on these findings, Veno-Arterial ECMO was initiated emergently on June 23rd. A subsequent angio-CT scan confirmed a massive "saddle" pulmonary embolism, which was treated with mechanical thrombectomy. The patient received significant transfusions during this period (> 5 PRBCs, 3 platelet pools). Her RV function improved, and VA-ECMO was decannulated on June 29th. Notably, chest radiographs prior to decannulation already showed developing bilateral infiltrates. Phase 3: The "Second Hit" and Refractory ARDS (Day 8–15) On June 30th, 24 hours after weaning, she developed severe ARDS (PaO₂/FiO₂ < 100) and fever. A bronchial aspirate grew Escherichia coli ESBL. Despite Meropenem and prone positioning, her hypoxemia remained refractory, culminating in a cardiovascular collapse (desaturation to 30%) on July 6th. This necessitated urgent implantation of Veno-Venous ECMO. Phase 4: IPA Diagnosis and Management (Day 15 onwards) On VV-ECMO, the patient remained dependent on maximal support with persistent "white lung" imaging and poor lung compliance (< 15 ml/cmH₂O). This failure to improve prompted a search for a secondary pathology. Diagnostic Assessment A bronchoscopy with bronchoalveolar lavage (BAL) was performed on July 7th. Microbiology : Bacterial and fungal cultures were negative. Biomarkers : Serum GM was negative. However, the BAL fluid Galactomannan (GM) antigen test returned positive with an index of 0.7 (positive > 0.5), establishing a diagnosis of probable IPA per AspICU/EORTC-MSG criteria [ 4 ]. Imaging : A chest CT on July 18th showed diffuse bilateral infiltrates consistent with severe ARDS, but no classic nodules or halo signs. Follow-up (at Referral Center) : After transfer, a relapse of respiratory failure prompted a new bronchoscopy. This confirmed the diagnosis, with BAL culture growing Aspergillus terreus . Concurrently, BAL viral PCR revealed a high-load CMV reactivation (240,000 copies/mL). Therapeutic Intervention Therapeutic Intervention Treatment with voriconazole was started at our institution on July 11th. Due to a lack of clinical response, therapy was switched to isavuconazole on July 21st. Following the definitive diagnosis of A. terreus and CMV reactivation at the referral center, treatment with isavuconazole was continued for a total of 7 weeks, and ganciclovir was initiated. Follow-up and Outcomes After a 33-day ICU stay at our institution, the patient was transferred. At the referral center, she was weaned from VV-ECMO on August 2nd. Her recovery was protracted, complicated by a gastrointestinal bleed and severe critical illness myopathy. She was liberated from mechanical ventilation on September 1st and decannulated from her tracheostomy on October 1st. After a total of three months in two ICUs, she was discharged to a rehabilitation facility, hemodynamically stable and with good neurological condition, though with significant restrictive pulmonary sequelae. Discussion This case of survival from IPA on ECMO provides several critical learning points for intensivists. The Diagnostic Challenge: From CAPA Suspicion to Multi-Pathogen Confirmation This case perfectly illustrates the diagnostic algorithm for CAPA. The initial suspicion was rightly triggered by the "failure to improve" on ECMO, despite appropriate bacterial coverage. The positive BAL GM (0.7) was the pivotal early finding that justified antifungal therapy [ 4 , 9 ]. The subsequent isolation of A. terreus and high-load CMV reactivation reveals the profound state of acquired immunoparalysis. The CMV reactivation itself is a known independent risk factor for mortality and secondary infections, including IPA [ 10 ]. The initial BAL GM positivity, followed by a culture for A. terreus , highlights the utility of GM as a broad early marker for Aspergillus invasion. The "Three-Hit" Pathophysiology and Immune Paralysis The patient's lung was subjected to a "first hit" (CPB, massive transfusion, TEP), followed by a "second hit" ( E. coli VAP), leading to refractory ARDS. The subsequent relapse after ECMO decannulation, with confirmed A. terreus and CMV pneumonitis, constituted a "third hit". This sequence is a textbook example of the progressive host immune dysregulation seen in prolonged critical illness [ 6 ]. The isolation of A. terreus is particularly noteworthy, as this species is known to be intrinsically resistant to Amphotericin B, making the azole-based therapy (isavuconazole) the correct choice [ 11 ]. The Therapeutic Conundrum: Pharmacokinetics on ECMO The lack of response to voriconazole is a crucial teaching point. Azoles are lipophilic and are known to be sequestered by the ECMO circuit, leading to subtherapeutic drug levels in up to 60% of patients [ 7 ]. The switch to isavuconazole, a non-inferior alternative per the SECURE trial [ 8 ], was a logical step. Self-Critical Analysis and Limitations A critical review of our management reveals two potential areas for improvement, which serve as key limitations and learning points. First, the time to suspect IPA. While the initial focus on the E. coli VAP was appropriate, the failure to improve after 5–7 days of targeted antibiotic therapy could have, in retrospect, triggered an earlier search for fungal superinfection. Our pro-active bronchoscopy on day 8 of this phase (day 15 of initial ICU stay) was timely, but this case argues for including API in the differential diagnosis even earlier. Second, the absence of Therapeutic Drug Monitoring (TDM) for voriconazole represents a significant limitation. Given the well-documented pharmacokinetic variability on ECMO, relying on standard dosing may have contributed to the initial lack of clinical response. This case strongly supports the argument to incorporate TDM as a standard of care when using azoles in this population. Survival Against the Odds The survival of this patient starkly contrasts with the > 80% mortality reported in the literature for IPA on ECMO [ 3 ]. We hypothesize that the successful outcome was multifactorial, stemming from: (a) early and accurate characterization of the initial obstructive shock; (b) a high index of suspicion leading to a timely diagnosis of IPA; (c) aggressive, multidisciplinary organ support; and (d) specific, guideline-directed antimicrobial therapy for both the fungal and viral pathogens. Conclusions This case demonstrates that survival from IPA in the setting of severe ARDS requiring ECMO, while rare, is achievable. It underscores the paramount importance of maintaining a high index of suspicion for fungal and viral superinfections in any ECMO patient with a torpid evolution, as this may signal a state of profound acquired immunoparalysis. Proactive diagnostic strategies centered on BAL galactomannan are critical and should not be delayed. Finally, clinicians must be acutely aware of the pharmacokinetic challenges posed by the ECMO circuit and strive to optimize antifungal dosing, ideally guided by TDM, to improve the chances of a favorable outcome in these critically ill patients. Declarations ● The Institutional Ethics Committee of Centro Médico Teknon granted an exemption from requiring ethics approval for this case report. ● Clinical trial number : not applicable. Consent for publication: ● Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests: ● The authors declare that they have no competing interests. Funding: No funding was received for this report. Author Contribution E.G.M.O. was the primary physician involved in the patient's care, conceived of the case report, and drafted the manuscript Acknowledgement To the family and the patient for allowing this case report to be written. To the entire ICU and cardiac surgery team at the Teknon Medical Center for the teamwork they performed. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. References Bassetti M, Giacobbe DR, Vena A, et al. Diagnosis and treatment of invasive aspergillosis in the critically ill patient. Expert Rev Anti Infect Ther. 2019;17(9):685–97. Böll B, Rilinger J, Zotzmann V, Fichtner F. Appraisal of fungal infections during ECMO therapy. Crit Care. 2018;22(1):159. Rilinger J, Zotzmann V, Fichtner F, et al. Outcomes of severe aspergillosis in patients undergoing extracorporeal membrane oxygenation: A systematic review. Acta Anaesthesiol Scand. 2024;68(1):15–24. 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. Clin Infect Dis. 2020;71(6):1367–76. Riley DS, Barber MS, Kienle GS, et al. CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol. 2017;89:218–35. Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019;5(1):18. Shekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care. 2012;27(6):e7419–18. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised, double-blind, non-inferiority trial. Lancet. 2016;387(10020):760–9. Meersseman W, Lagrou K, Maertens J, et al. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med. 2008;177(1):27–34. Papazian L, Hraiech S, Lehingue S, et al. Cytomegalovirus reactivation in ICU patients. Intensive Care Med. 2016;42(1):28–37. Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of. Additional Declarations No competing interests reported. Supplementary Files CAREcheck.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7840777","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":550423724,"identity":"2a6ef5ab-3011-44c7-b768-e21c7f221910","order_by":0,"name":"Edgar G. 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The entity of Critically Ill-Associated Pulmonary Aspergillosis (CAPA) is now well-defined, with Acute Respiratory Distress Syndrome (ARDS) being a primary risk factor [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Extracorporeal Membrane Oxygenation (ECMO), while a life-saving therapy for refractory cardiorespiratory failure, paradoxically increases the risk for IPA by inducing a state of systemic inflammation and immune dysregulation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis constellation of ARDS, ECMO, and IPA is exceptionally lethal, with mortality rates consistently reported to exceed 80% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The diagnosis is notoriously difficult, as clinical and radiological signs are non-specific. Furthermore, these patients often develop multiple concurrent infections, including viral reactivations such as Cytomegalovirus (CMV), which are markers of a profound acquired immunoparalysis and further complicate management [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe present the exceptional case of a 67-year-old female who survived this exact constellation: sequential VA-ECMO and VV-ECMO support, complicated by confirmed \u003cem\u003eAspergillus terreus\u003c/em\u003e pneumonia and high-load CMV reactivation. This report, which includes the full 3-month ICU course across two institutions, has been prepared in accordance with the CARE guidelines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and provides critical insights into the diagnostic and therapeutic challenges of this complex syndrome.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatient Information\u003c/h2\u003e\u003cp\u003eA 67-year-old female with a history of hypertension, dyslipidemia, and atrial fibrillation (on Edoxaban) was admitted for an elective flutter ablation. She had no history of immunosuppression, neoplasia, or chronic lung disease.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical Findings and Timeline\u003c/h3\u003e\n\u003cp\u003eThe patient's complex ICU course proceeded in distinct phases:\u003c/p\u003e\u003cp\u003ePhase 1: Taponamiento and Multicomponent Shock (Day 0\u0026ndash;1)\u003c/p\u003e\u003cp\u003eOn June 22nd, the ablation procedure was complicated by an laceration of the superior left pulmonary vein, leading to acute cardiac tamponade. Following an emergency pericardiocentesis (\u0026gt;\u0026thinsp;700 mL) and surgical repair under cardiopulmonary bypass (CPB), she was transferred to the ICU. She presented in multi-component shock: vasoplegic (norepinephrine 0.8 mcg/kg/min), hemorrhagic (requiring\u0026thinsp;\u0026gt;\u0026thinsp;1000 mL blood loss replacement, 3 PRBCs, 1 platelet pool), and persistent hypoperfusion (Lactate\u0026thinsp;\u0026gt;\u0026thinsp;4 mmol/L) with an echocardiogram showing a severely dilated right ventricle (RV).\u003c/p\u003e\u003cp\u003ePhase 2: VA-ECMO, PE Diagnosis, and the \"First Hit\" (Day 1\u0026ndash;8)\u003c/p\u003e\u003cp\u003eA pulmonary artery catheter was placed, revealing obstructive shock (CI 1.85 L/min/m\u0026sup2;, mPAP 43 mmHg, PVRi 1082 dyn\u0026middot;s\u0026middot;cm⁻⁵). Based on these findings, Veno-Arterial ECMO was initiated emergently on June 23rd. A subsequent angio-CT scan confirmed a massive \"saddle\" pulmonary embolism, which was treated with mechanical thrombectomy. The patient received significant transfusions during this period (\u0026gt;\u0026thinsp;5 PRBCs, 3 platelet pools). Her RV function improved, and VA-ECMO was decannulated on June 29th. Notably, chest radiographs prior to decannulation already showed developing bilateral infiltrates.\u003c/p\u003e\u003cp\u003ePhase 3: The \"Second Hit\" and Refractory ARDS (Day 8\u0026ndash;15)\u003c/p\u003e\u003cp\u003eOn June 30th, 24 hours after weaning, she developed severe ARDS (PaO₂/FiO₂ \u0026lt; 100) and fever. A bronchial aspirate grew Escherichia coli ESBL. Despite Meropenem and prone positioning, her hypoxemia remained refractory, culminating in a cardiovascular collapse (desaturation to 30%) on July 6th. This necessitated urgent implantation of Veno-Venous ECMO.\u003c/p\u003e\u003cp\u003ePhase 4: IPA Diagnosis and Management (Day 15 onwards)\u003c/p\u003e\u003cp\u003eOn VV-ECMO, the patient remained dependent on maximal support with persistent \"white lung\" imaging and poor lung compliance (\u0026lt;\u0026thinsp;15 ml/cmH₂O). This failure to improve prompted a search for a secondary pathology.\u003c/p\u003e\n\u003ch3\u003eDiagnostic Assessment\u003c/h3\u003e\n\u003cp\u003eA bronchoscopy with bronchoalveolar lavage (BAL) was performed on July 7th.\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eMicrobiology\u003c/b\u003e: Bacterial and fungal cultures were negative.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eBiomarkers\u003c/b\u003e: Serum GM was negative. However, the BAL fluid Galactomannan (GM) antigen test returned positive with an index of 0.7 (positive\u0026thinsp;\u0026gt;\u0026thinsp;0.5), establishing a diagnosis of probable IPA per AspICU/EORTC-MSG criteria [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eImaging\u003c/b\u003e: A chest CT on July 18th showed diffuse bilateral infiltrates consistent with severe ARDS, but no classic nodules or halo signs.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eFollow-up (at Referral Center)\u003c/b\u003e: After transfer, a relapse of respiratory failure prompted a new bronchoscopy. This confirmed the diagnosis, with BAL culture growing \u003cb\u003eAspergillus terreus\u003c/b\u003e. Concurrently, BAL viral PCR revealed a high-load CMV reactivation (240,000 copies/mL).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\n\u003ch3\u003eTherapeutic Intervention\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eTherapeutic Intervention\u003c/div\u003e\u003cp\u003eTreatment with voriconazole was started at our institution on July 11th. Due to a lack of clinical response, therapy was switched to isavuconazole on July 21st. Following the definitive diagnosis of \u003cem\u003eA. terreus\u003c/em\u003e and CMV reactivation at the referral center, treatment with isavuconazole was continued for a total of 7 weeks, and ganciclovir was initiated.\u003c/p\u003e\n\u003ch3\u003eFollow-up and Outcomes\u003c/h3\u003e\n\u003cp\u003eAfter a 33-day ICU stay at our institution, the patient was transferred. At the referral center, she was weaned from VV-ECMO on August 2nd. Her recovery was protracted, complicated by a gastrointestinal bleed and severe critical illness myopathy. She was liberated from mechanical ventilation on September 1st and decannulated from her tracheostomy on October 1st. After a total of three months in two ICUs, she was discharged to a rehabilitation facility, hemodynamically stable and with good neurological condition, though with significant restrictive pulmonary sequelae.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case of survival from IPA on ECMO provides several critical learning points for intensivists.\u003c/p\u003e\n\u003ch3\u003eThe Diagnostic Challenge: From CAPA Suspicion to Multi-Pathogen Confirmation\u003c/h3\u003e\n\u003cp\u003eThis case perfectly illustrates the diagnostic algorithm for CAPA. The initial suspicion was rightly triggered by the \"failure to improve\" on ECMO, despite appropriate bacterial coverage. The positive BAL GM (0.7) was the pivotal early finding that justified antifungal therapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The subsequent isolation of \u003cem\u003eA. terreus\u003c/em\u003e and high-load CMV reactivation reveals the profound state of acquired immunoparalysis. The CMV reactivation itself is a known independent risk factor for mortality and secondary infections, including IPA [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The initial BAL GM positivity, followed by a culture for \u003cem\u003eA. terreus\u003c/em\u003e, highlights the utility of GM as a broad early marker for \u003cem\u003eAspergillus\u003c/em\u003e invasion.\u003c/p\u003e\n\u003ch3\u003eThe \"Three-Hit\" Pathophysiology and Immune Paralysis\u003c/h3\u003e\n\u003cp\u003eThe patient's lung was subjected to a \"first hit\" (CPB, massive transfusion, TEP), followed by a \"second hit\" (\u003cem\u003eE. coli\u003c/em\u003e VAP), leading to refractory ARDS. The subsequent relapse after ECMO decannulation, with confirmed \u003cem\u003eA. terreus\u003c/em\u003e and CMV pneumonitis, constituted a \"third hit\". This sequence is a textbook example of the progressive host immune dysregulation seen in prolonged critical illness [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The isolation of \u003cem\u003eA. terreus\u003c/em\u003e is particularly noteworthy, as this species is known to be intrinsically resistant to Amphotericin B, making the azole-based therapy (isavuconazole) the correct choice [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eThe Therapeutic Conundrum: Pharmacokinetics on ECMO\u003c/h2\u003e\u003cp\u003eThe lack of response to voriconazole is a crucial teaching point. Azoles are lipophilic and are known to be sequestered by the ECMO circuit, leading to subtherapeutic drug levels in up to 60% of patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The switch to isavuconazole, a non-inferior alternative per the SECURE trial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], was a logical step.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSelf-Critical Analysis and Limitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA critical review of our management reveals two potential areas for improvement, which serve as key limitations and learning points. First, the time to suspect IPA. While the initial focus on the \u003cem\u003eE. coli\u003c/em\u003e VAP was appropriate, the failure to improve after 5\u0026ndash;7 days of targeted antibiotic therapy could have, in retrospect, triggered an earlier search for fungal superinfection. Our pro-active bronchoscopy on day 8 of this phase (day 15 of initial ICU stay) was timely, but this case argues for including API in the differential diagnosis even earlier. Second, the absence of Therapeutic Drug Monitoring (TDM) for voriconazole represents a significant limitation. Given the well-documented pharmacokinetic variability on ECMO, relying on standard dosing may have contributed to the initial lack of clinical response. This case strongly supports the argument to incorporate TDM as a standard of care when using azoles in this population.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eSurvival Against the Odds\u003c/h2\u003e\u003cp\u003eThe survival of this patient starkly contrasts with the \u0026gt;\u0026thinsp;80% mortality reported in the literature for IPA on ECMO [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. We hypothesize that the successful outcome was multifactorial, stemming from: (a) early and accurate characterization of the initial obstructive shock; (b) a high index of suspicion leading to a timely diagnosis of IPA; (c) aggressive, multidisciplinary organ support; and (d) specific, guideline-directed antimicrobial therapy for both the fungal and viral pathogens.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case demonstrates that survival from IPA in the setting of severe ARDS requiring ECMO, while rare, is achievable. It underscores the paramount importance of maintaining a high index of suspicion for fungal and viral superinfections in any ECMO patient with a torpid evolution, as this may signal a state of profound acquired immunoparalysis. Proactive diagnostic strategies centered on BAL galactomannan are critical and should not be delayed. Finally, clinicians must be acutely aware of the pharmacokinetic challenges posed by the ECMO circuit and strive to optimize antifungal dosing, ideally guided by TDM, to improve the chances of a favorable outcome in these critically ill patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e● The Institutional Ethics Committee of Centro M\u0026eacute;dico Teknon granted an exemption from requiring ethics approval for this case report.\u003c/p\u003e\u003cp\u003e● \u003cb\u003eClinical trial number\u003c/b\u003e: not applicable.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003cp\u003e ● Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e\u003ch2\u003eCompeting interests:\u003c/h2\u003e\u003cp\u003e● The authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eNo funding was received for this report.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eE.G.M.O. was the primary physician involved in the patient's care, conceived of the case report, and drafted the manuscript\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eTo the family and the patient for allowing this case report to be written. To the entire ICU and cardiac surgery team at the Teknon Medical Center for the teamwork they performed.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBassetti M, Giacobbe DR, Vena A, et al. Diagnosis and treatment of invasive aspergillosis in the critically ill patient. Expert Rev Anti Infect Ther. 2019;17(9):685\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eB\u0026ouml;ll B, Rilinger J, Zotzmann V, Fichtner F. Appraisal of fungal infections during ECMO therapy. Crit Care. 2018;22(1):159.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRilinger J, Zotzmann V, Fichtner F, et al. Outcomes of severe aspergillosis in patients undergoing extracorporeal membrane oxygenation: A systematic review. Acta Anaesthesiol Scand. 2024;68(1):15\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDonnelly 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. Clin Infect Dis. 2020;71(6):1367\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRiley DS, Barber MS, Kienle GS, et al. CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol. 2017;89:218\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMatthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019;5(1):18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care. 2012;27(6):e7419\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised, double-blind, non-inferiority trial. Lancet. 2016;387(10020):760\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeersseman W, Lagrou K, Maertens J, et al. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med. 2008;177(1):27\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePapazian L, Hraiech S, Lehingue S, et al. Cytomegalovirus reactivation in ICU patients. Intensive Care Med. 2016;42(1):28\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWalsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Case report, Invasive Pulmonary Aspergillosis, CAPA, ECMO, ARDS, Galactomannan, Aspergillus terreus, CMV Reactivation","lastPublishedDoi":"10.21203/rs.3.rs-7840777/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7840777/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eInvasive Pulmonary Aspergillosis (IPA) in critically ill patients on Extracorporeal Membrane Oxygenation (ECMO) is a highly lethal condition, with mortality reported over 80%. Diagnosing and managing this condition is complicated by underlying severe illness, non-specific findings, and profound acquired immune dysfunction.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e\u003cp\u003eWe report the case of a 67-year-old female with no prior immunosuppression who survived a catastrophic 3-month ICU stay. She initially suffered an cardiac tamponade requiring surgical repair, which was complicated by a massive pulmonary embolism (PE) necessitating Veno-Arterial ECMO (VA-ECMO) and mechanical thrombectomy. After weaning from VA-ECMO, she developed severe ARDS from an \u003cem\u003eE. coli\u003c/em\u003e ESBL pneumonia, requiring initiation of Veno-Venous ECMO (VV-ECMO). Her failure to improve led to a bronchoscopy, which was positive for Galactomannan antigen (index 0.7), prompting initiation of voriconazole for probable IPA. After 33 days, she was transferred to a referral center (Hospital Cl\u0026iacute;nic), where VV-ECMO was weaned. However, she relapsed with severe respiratory failure. A new bronchoscopy confirmed invasive aspergillosis via culture of \u003cem\u003eAspergillus terreus\u003c/em\u003e and revealed high-load Cytomegalovirus (CMV) reactivation (240,000 copies/mL). She was successfully treated with a prolonged 7-week course of isavuconazole and ganciclovir. Her recovery was protracted, complicated by gastrointestinal bleeding and severe critical illness myopathy, but she was eventually weaned from all organ support and discharged to rehabilitation.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis case of survival highlights the extreme complexity of managing severe ARDS on ECMO. It underscores: (1) The importance of proactive investigation for fungal and viral superinfections, such as \u003cem\u003eAspergillus\u003c/em\u003e and CMV, in patients with ARDS who fail to improve, as this indicates profound acquired immunoparalysis. (2) The diagnostic utility of BAL galactomannan as an early marker, even when cultures are later positive for different species. (3) That survival, while rare, is possible with aggressive, multidisciplinary management and prolonged antifungal therapy.\u003c/p\u003e","manuscriptTitle":"Survival after Invasive Pulmonary Aspergillosis in a patient requiring sequential Veno- Arterial and Veno-Venous ECMO for refractory cardiorespiratory failure: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-28 10:56:05","doi":"10.21203/rs.3.rs-7840777/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"63f7fc0e-dd52-4d5a-91d1-f331eba81313","owner":[],"postedDate":"November 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-14T12:09:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-28 10:56:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7840777","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7840777","identity":"rs-7840777","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}