Case study: Lessons on managing invasive mould disease in the ICU
05 Aug 2023
byDr. Paula Ramirez, Prof. Gennaro De Pascale
In conjunction with the 42nd International Symposium on Intensive Care and Emergency Medicine (ISICEM), Pfizer sponsored a symposium addressing the complex challenges of managing invasive mould disease (IMD) in the intensive care unit (ICU), emphasizing the importance of a proactive mindset among intensivists. Using a real-life patient case study, Dr Paula Ramirez from La Fe University and Polytechnic Hospital, Valencia, Spain highlighted the significance of early suspicion, swift diagnosis, and timely treatment in critically ill patients with IMD. Professor Gennaro De Pascale from the Catholic University of the Sacred Heart, Rome, Italy discussed effective management strategies and the clinical evidence for various antifungals in treating IMD in critically ill patients.
Case presentation
• A 79-year-old woman presented with nephritic colicky abdominal pain, nausea, vomiting, and fever. Ultrasound revealed grade II right kidney ectasia. Her comorbidities include high blood pressure, hypercholesterolaemia, and nephrolithiasis. She was treated with meropenem and gentamicin. She developed septic shock, was treated with norepinephrine, and transferred to the ICU.
• The patient’s condition deteriorated, evolving to multiorgan failure requiring intubation and mechanical ventilation. Due to kidney failure, she had continuous extrarenal replacement treatment. A double-J catheter was placed to release kidney obstruction. She had refractory septic shock and cardiac failure, treated with norepinephrine, vasopressin, and dobutamine.
• Laboratory results showed that Klebsiella pneumoniae was present in her urine and blood samples. As her respiratory sample was H1N1 PCR positive, she was also treated with oseltamivir.
• The patient developed distal ischaemia in both forearms and hands due to complications of sepsis and high doses of vasopressors.
• In the following days, the patient improved, regaining cardiac and renal function, and was successfully weaned from vasopressors, mechanical ventilation, and renal replacement therapy. However, she had a new respiratory deterioration with fever. Chest x-ray showed complete atelectasis of the right lung. Bronchoscopy was performed, revealing whitish plaques on the bronchial mucosa. Cultures of the blood and bronchoalveolar lavage (BAL) were negative. Serum galactomannan (GM) was negative (0.338) but BAL GM was positive (3.5). Beta-D-glucan was negative.
• As the patient’s clinical presentation and test results showed the possibility of a fungal infection, isavuconazole was prescribed to the patient for 8 weeks, without adverse events. Aspergillus fumigatus was isolated; no other moulds were detected. Upon follow-up, the patient was tracheostomized, had spontaneous breathing, weaned off norepinephrine, and had good urinary output.
Lesson 1: Invasive fungal infections (IFI) are among the most frequently underdiagnosed conditions in the ICU.
A study evaluating discrepancies between clinical diagnoses and autopsy findings in critically ill patients found that invasive aspergillosis (IA) was the most frequently missed diagnosis (Table 1). [Hum Pathol 2018;76:85-90] “Notably, these were class I discrepancies, which have a direct impact on treatment. Death may have been avoided if IA was diagnosed and treated while the patient was alive,” explained Ramirez.
Lesson 2: Consider the possibility of IFI in critically ill patients, even if they are not typical patient hosts.
Critically ill patients display a decline in immune function due to immunoregulatory disturbances and immunoparalysis during multiorgan dysfunction. This could cause patients to be more susceptible to infections by opportunistic microorganisms. [Virulence 2014;5:80-97; N Eng J Med 2003;348:138-150]
Lesson 3: Actively suspect IFI when risk factors exist.
Viral infections are known to change nasal microbiota and epithelium gene expression, which may increase susceptibility to infection. [Microbiome 2015;3:74; Curr Top Microbiol Immunol 2014;385:327-356] Between 7–14 percent of immunocompetent patients admitted to the ICU for severe influenza have invasive pulmonary aspergillosis. [Lancet Respr Med 2018;6:782-792; Clin Infect Dis 2020;71:1760-1763] The incidence of COVID-19-associated IFI in ICUs was as high as 33.3 percent in France. [Lancet Respir Med 2020; 8:e48-e49]
In addition, chronic obstructive pulmonary disease, diabetes, liver cirrhosis or severe sepsis, and previous corticosteroid administration are frequently reported risk factors for IA in ICU patients. [Hum Pathol 2018;76:85-90]
Lesson 4: BAL GM is more useful than culture for the diagnosis of IA.
Many patients with influenza-associated pulmonary aspergillosis (IAPA) or COVID-19-associated pulmonary aspergillosis (CAPA) have atypical clinical and radiological features that do not align with classic diagnostic algorithms (eg, EORTC/MSGERC). BAL GM assay is important for diagnosis, as serum GM can be negative and sputum/tracheal aspirate cultures can remain sterile. [Intensive Care Med 2020;46:1524-1535; Clin Infect Dis 2021;73:e3606-e3614]
Lesson 5: Guidelines recommend isavuconazole as the preferred treatment option for IA, CAPA.
The 2017 ESCMID-ECMM-ERS guidelines recommend isavuconazole for the treatment of Aspergillus disease (Figure 1). Likewise, the 2020 ECMM/ISHAM consensus criteria endorse isavuconazole as a treatment option for azole-sensitive CAPA, alongside voriconazole. [Clin Microbiol Infect 2018;24(Suppl 1):e1-e38; Lancet Infect Dis 2021;21:e149-e162]
Isavuconazole has distinct advantages over voriconazole. Unlike voriconazole, which is metabolized by multiple CYP450 enzymes (CYP2C19, CYP3A4, and CYP3A5) leading to various drug interactions, isavuconazole has more predictable pharmacokinetics and a simpler drug interaction profile. Additionally, isavuconazole offers improved tolerability, does not cause QTc interval prolongation, and does not require therapeutic drug monitoring. [Antimicrob Agents Chemother 2022;66:e0017722]
Clinical efficacy and safety of isavuconazole in IFI
Isavuconazole, a triazole antifungal, is the latest addition to the treatment strategies for IMD. It is indicated for the treatment of IA and mucormycosis in patients for whom amphotericin B is inappropriate. In the phase III SECURE trial, isavuconazole was as effective as voriconazole in treating IA, with comparable survival rates in both arms. Moreover, isavuconazole was better tolerated, leading to fewer treatment-emergent adverse events and drug discontinuations. [Lancet 2016;387:760-769]
Clinical evidence of isavuconazole activity against mucormycosis was shown in the VITAL trial, with patient survival rates similar to that of amphotericin B-treated matched controls. [Lancet Infect Dis 2016;16:828-837] “This data support isavuconazole as a first-line treatment option for mucormycosis, or in patients refractory or intolerant to amphotericin B," said De Pascale.
Case presentation
• A 79-year-old woman presented with nephritic colicky abdominal pain, nausea, vomiting, and fever. Ultrasound revealed grade II right kidney ectasia. Her comorbidities include high blood pressure, hypercholesterolaemia, and nephrolithiasis. She was treated with meropenem and gentamicin. She developed septic shock, was treated with norepinephrine, and transferred to the ICU.
• The patient’s condition deteriorated, evolving to multiorgan failure requiring intubation and mechanical ventilation. Due to kidney failure, she had continuous extrarenal replacement treatment. A double-J catheter was placed to release kidney obstruction. She had refractory septic shock and cardiac failure, treated with norepinephrine, vasopressin, and dobutamine.
• Laboratory results showed that Klebsiella pneumoniae was present in her urine and blood samples. As her respiratory sample was H1N1 PCR positive, she was also treated with oseltamivir.
• The patient developed distal ischaemia in both forearms and hands due to complications of sepsis and high doses of vasopressors.
• In the following days, the patient improved, regaining cardiac and renal function, and was successfully weaned from vasopressors, mechanical ventilation, and renal replacement therapy. However, she had a new respiratory deterioration with fever. Chest x-ray showed complete atelectasis of the right lung. Bronchoscopy was performed, revealing whitish plaques on the bronchial mucosa. Cultures of the blood and bronchoalveolar lavage (BAL) were negative. Serum galactomannan (GM) was negative (0.338) but BAL GM was positive (3.5). Beta-D-glucan was negative.
• As the patient’s clinical presentation and test results showed the possibility of a fungal infection, isavuconazole was prescribed to the patient for 8 weeks, without adverse events. Aspergillus fumigatus was isolated; no other moulds were detected. Upon follow-up, the patient was tracheostomized, had spontaneous breathing, weaned off norepinephrine, and had good urinary output.
Lesson 1: Invasive fungal infections (IFI) are among the most frequently underdiagnosed conditions in the ICU.
A study evaluating discrepancies between clinical diagnoses and autopsy findings in critically ill patients found that invasive aspergillosis (IA) was the most frequently missed diagnosis (Table 1). [Hum Pathol 2018;76:85-90] “Notably, these were class I discrepancies, which have a direct impact on treatment. Death may have been avoided if IA was diagnosed and treated while the patient was alive,” explained Ramirez.
Lesson 2: Consider the possibility of IFI in critically ill patients, even if they are not typical patient hosts.
Critically ill patients display a decline in immune function due to immunoregulatory disturbances and immunoparalysis during multiorgan dysfunction. This could cause patients to be more susceptible to infections by opportunistic microorganisms. [Virulence 2014;5:80-97; N Eng J Med 2003;348:138-150]
Lesson 3: Actively suspect IFI when risk factors exist.
Viral infections are known to change nasal microbiota and epithelium gene expression, which may increase susceptibility to infection. [Microbiome 2015;3:74; Curr Top Microbiol Immunol 2014;385:327-356] Between 7–14 percent of immunocompetent patients admitted to the ICU for severe influenza have invasive pulmonary aspergillosis. [Lancet Respr Med 2018;6:782-792; Clin Infect Dis 2020;71:1760-1763] The incidence of COVID-19-associated IFI in ICUs was as high as 33.3 percent in France. [Lancet Respir Med 2020; 8:e48-e49]
In addition, chronic obstructive pulmonary disease, diabetes, liver cirrhosis or severe sepsis, and previous corticosteroid administration are frequently reported risk factors for IA in ICU patients. [Hum Pathol 2018;76:85-90]
Lesson 4: BAL GM is more useful than culture for the diagnosis of IA.
Many patients with influenza-associated pulmonary aspergillosis (IAPA) or COVID-19-associated pulmonary aspergillosis (CAPA) have atypical clinical and radiological features that do not align with classic diagnostic algorithms (eg, EORTC/MSGERC). BAL GM assay is important for diagnosis, as serum GM can be negative and sputum/tracheal aspirate cultures can remain sterile. [Intensive Care Med 2020;46:1524-1535; Clin Infect Dis 2021;73:e3606-e3614]
Lesson 5: Guidelines recommend isavuconazole as the preferred treatment option for IA, CAPA.
The 2017 ESCMID-ECMM-ERS guidelines recommend isavuconazole for the treatment of Aspergillus disease (Figure 1). Likewise, the 2020 ECMM/ISHAM consensus criteria endorse isavuconazole as a treatment option for azole-sensitive CAPA, alongside voriconazole. [Clin Microbiol Infect 2018;24(Suppl 1):e1-e38; Lancet Infect Dis 2021;21:e149-e162]
Isavuconazole has distinct advantages over voriconazole. Unlike voriconazole, which is metabolized by multiple CYP450 enzymes (CYP2C19, CYP3A4, and CYP3A5) leading to various drug interactions, isavuconazole has more predictable pharmacokinetics and a simpler drug interaction profile. Additionally, isavuconazole offers improved tolerability, does not cause QTc interval prolongation, and does not require therapeutic drug monitoring. [Antimicrob Agents Chemother 2022;66:e0017722]
Clinical efficacy and safety of isavuconazole in IFI
Isavuconazole, a triazole antifungal, is the latest addition to the treatment strategies for IMD. It is indicated for the treatment of IA and mucormycosis in patients for whom amphotericin B is inappropriate. In the phase III SECURE trial, isavuconazole was as effective as voriconazole in treating IA, with comparable survival rates in both arms. Moreover, isavuconazole was better tolerated, leading to fewer treatment-emergent adverse events and drug discontinuations. [Lancet 2016;387:760-769]
Clinical evidence of isavuconazole activity against mucormycosis was shown in the VITAL trial, with patient survival rates similar to that of amphotericin B-treated matched controls. [Lancet Infect Dis 2016;16:828-837] “This data support isavuconazole as a first-line treatment option for mucormycosis, or in patients refractory or intolerant to amphotericin B," said De Pascale.