Background

In March 2020, the World Health Organization declared COVID-19, caused by the SARS-CoV-2 virus, a pandemic. Patients with severe cases resulting in hospitalization and mechanical ventilation are at risk for COVID-19–associated pulmonary aspergillosis, an invasive fungal infection, and should be screened for aspergillosis if they have persistent hemodynamic instability and fever. Early detection and treatment of this fungal infection can significantly reduce morbidity and mortality in this population.

Objective

To develop an evidence-based care step pathway tool to help intensive care unit clinicians assess, diagnose, and treat COVID-19–associated pulmonary aspergillosis.

Methods

A panel of 18 infectious disease experts, advanced practice registered nurses, pharmacists, and clinical researchers convened in a series of meetings to develop the Care Step Pathway tool, which was modeled on a tool developed by advanced practice nurses to evaluate and manage side effects of therapies for melanoma. The Care Step Pathway tool addresses various aspects of disease management, including assessment, screening, diagnosis, antifungal treatment, pharmacological considerations, and exclusion of other invasive fungal coinfections.

Results

The Care Step Pathway tool was applied in the care of a patient with COVID-19–associated aspergillosis. The patient was successfully treated.

Conclusion

The Care Step Pathway is an effective educational tool to help intensive care unit clinicians consider fungal infection when caring for COVID-19 patients receiving mechanical ventilation in the intensive care unit, especially when the clinical course is deteriorating and antibiotics are ineffective.

In December 2019, patients began presenting to hospitals in Wuhan, China, with severe respiratory disease. Shortly thereafter, researchers identified the novel coronavirus SARS-CoV-2, which resulted in a severe disease that was termed COVID-19. SARS-CoV-2 quickly swept through China and the world through respiratory transmission. In March 2020, the World Health Organization declared COVID-19 a pandemic; entire countries began to enter into national lockdowns to prevent the spread of disease as hospitals and intensive care units (ICUs) started to reach maximum patient capacity. Among patients admitted to the hospital for treatment, those most frequently requiring mechanical ventilation were male and of advanced age (older than 65 years) and had comorbidities such as hypertension, obesity, and diabetes.1 

Influenza-associated aspergillosis in patients receiving mechanical ventilation has been previously described.2,3  Patients with COVID-19 who were admitted to the ICU with the initiation of mechanical ventilation typically experienced prolonged and complicated hospitalizations. Among these patients, COVID-19–associated pulmonary aspergillosis (CAPA) was identified as a fungal disease that increased morbidity and mortality. The reported incidence of CAPA in this patient population varies, ranging from 3.8% to 35%.4  This variation is believed to be due to differing diagnostic capabilities, clinical presentations, reporting and screening practices, and provider knowledge of the association between the conditions across ICU facilities. Reported mortality rates associated with CAPA are as high as 51.2%.5  Common patient risk factors for CAPA include the presence of chronic lung disease, receipt of mechanical ventilation, and corticosteroid use.2,6  Thus, awareness of CAPA is especially critical given the recommendation for use of dexamethasone in patients with severe disease due to SARS-CoV-2 infection.7  Moreover, anti–interleukin-6 treatments such as tocilizumab are also attributed to increased patient susceptibility to invasive fungal infections, including CAPA.2 

Diagnosing CAPA can be challenging. Traditional diagnosis of invasive pulmonary aspergillosis involves radiography, culture and histologic evaluation, and assessment of serum fungal biomarker levels from bronchoscopies.8  Moreover, owing to aerosol production during the performance of bronchoscopies, these procedures are often limited to protect the health and safety of ICU staff members.2  Upper respiratory tract samples are less helpful in diagnosing CAPA because they do not distinguish between colonization and invasive disease. This distinction is often difficult to make and warrants the use of algorithms to better assess, diagnose, and treat disease. Additionally, systemic inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate are usually elevated in patients with severe COVID-19; therefore, these markers often cannot be used to determine the presence of other coinfections.9  Diagnostic imaging can also be challenging when assessing patients with suspected CAPA. Patients are often unfit for imaging studies because of their poor clinical status and prone positioning given associated severe acute respiratory distress syndrome (ARDS). Furthermore, chest radiographs and computed tomographic scans in COVID-19 patients often reveal diffuse pulmonary opacities consistent with ARDS, thus making it difficult to see distinct aspergillus crescent signs associated with CAPA.10,11  Finally, in the busy ICU setting, the activities of caring for the COVID-19 patient receiving mechanical ventilation leave little time for nurses to consider fungal diagnostic assessment and screening in a setting of persistent deterioration despite treatment for bacterial infections.

To address the diagnostic challenges surrounding CAPA as well as lack of awareness of the disease process, our team set out to develop an evidence-based care step pathway (CSP) to assist bedside nurses and health care providers in assessing, diagnosing, and treating CAPA. In developing this tool, we built on a CSP that was previously developed by the Melanoma Nursing Initiative.12  The purpose of the CAPA CSP was to improve early assessment, screening, diagnosis, and treatment of CAPA, as well as consideration of other invasive fungal infections. It also addresses a variety of pharmacological issues that affect treatment of these patients, who may be receiving multiple medications and supportive treatment modalities, including extracorporeal membrane oxygenation. The following case report illustrates the clinical complexity of CAPA in patients receiving mechanical ventilation in the ICU. The patient provided written consent to share his case for publication.

A 66-year-old Hispanic man was admitted to the hospital because of COVID-19 pneumonia after a 2-week history of worsening dyspnea, pyrexia, myalgia, anosmia (loss of smell), nausea, and anorexia. He received dexamethasone and tocilizumab (a monoclonal antibody directed against the interleukin-6 receptor). He spent 2 days in the hospital and was discharged to home in a stable condition. His medical history included obstructive sleep apnea with use of a continuous positive airway pressure machine, obesity (body mass index, calculated as weight in kilograms divided by height in meters squared, 35.1), hypertension, and hyperlipidemia, with outpatient medications consisting of lisinopril 40 mg daily, rosuvastatin 20 mg daily, and pantoprazole 40 mg daily.

Within 24 hours of discharge, the patient was readmitted with increasing shortness of breath and tachypnea, up to 36 breaths per minute. On admission, he was hypoxic with an oxygen saturation of approximately 80% on room air and required initiation of a high-flow nasal cannula (oxygenation rate, 60 L/min with 100% oxygen). His chest radiograph showed ground-glass opacities. Within 24 hours he required intubation and admission to the ICU owing to worsening hypoxia. He did not meet the requirements for administration of remdesivir but received convalescent plasma and was continued on dexamethasone for a total of 10 days. Figure 1 shows his hospital course from day –17 to day 34. During the hospital course, he experienced worsening hypoxia and leukocytosis and was found to have ventilator-associated pneumonia with Enterobacter aerogenes and methicillin-sensitive Staphylococcus aureus. However, by day 20 and with antimicrobial therapy, his fever returned, and he experienced leukocytosis along with increased ventilator and vasopressor requirements, including initiation of norepinephrine.

On day 24, bronchoscopy with bronchoalveolar lavage was performed owing to an increase in fever to 40 °C, leukocytosis with leukocyte count up to 22 400/μL, and hemodynamic worsening requiring the addition of vasopressin. Within 24 hours, the galactomannan index (Aspergillus antigen) from the bronchoalveolar lavage sample was found to be positive at 4.721 (negative: < 0.5 index), with a serum galactomannan of 0.156 and (1,3) β-D-glucan considered negative at less than 0.31 pg/mL. The patient had been receiving intravenous (IV) micafungin, 100 mg every 24 hours, as empiric therapy for fever and sepsis but was switched to IV isavuconazonium sulfate because of the positive galactomannan index and a new diagnosis of CAPA. The patient started to improve after a few days, and he eventually required a tracheostomy on day 28 owing to continued ventilator dependency. On day 30, repeat computed tomography angiography of the chest showed severe bilateral lower lobe consolidation with extensive ground-glass opacities (Figures 2 and 3).

The case report illustrates the clinical complexity of COVID-19–associated pulmonary aspergillosis in patients receiving mechanical ventilation in the ICU.

One week after the initiation of antifungal therapy, the patient’s fever gradually lowered, and he began to show signs of clinical improvement and oxygenation by day 34. The patient remained ventilator dependent until day 68, when he was ultimately weaned to Trilogy (Phillips) bilevel positive airway pressure (BiPAP). Four days after he was transitioned to BiPAP, he was transferred from the ICU to a general medical ward (Figure 4). On day 75, he was weaned from BiPAP to a tracheostomy collar. He remained in the acute care hospital until day 87, when he was discharged to a rehabilitation hospital. Antifungal therapy was continued, and he was switched to oral antifungal treatment for another 10 days.

Challenges of this case included recognizing that there was an occult infectious process causing the poor outcomes. Moreover, once the team was considering fungal infection, the challenge became establishing the etiology using the diagnostic tools at hand. Finally, once the patient was started on antifungal therapy, it became a challenge to ensure that the course of therapy was continued and transitions occurred from IV to oral therapy across settings.

The CAPA CSP was developed as part of a collaborative agreement between the Centers for Disease Control and Prevention (CDC), the University of Alabama at Birmingham, the Mycoses Study Group Education and Research Consortium, and Terranova Medica, LLC. Given the morbidity and mortality associated with CAPA and the difficulty in traditional diagnosis of pulmonary aspergillosis, our collaboration was guided by the urgent educational need to raise awareness of CAPA and illustrate appropriate screening, diagnosis, and management of this infection.

The steering committee leadership consisted of 3 infectious diseases physicians, an advanced practice nurse, and a certified continuing education professional, all specializing in invasive fungal infections. The CSP content faculty consisted of 10 additional invasive fungal infection physician specialists, a critical care pulmonologist, an infectious diseases pharmacist, and an advanced practice ICU nurse. These content development faculty members worked in 6 targeted subgroups to create evidence-based recommendations. The groups focused on the following topics: (1) clinical assessment (including prescreening and awareness); (2) screening (conducting a series of diagnostic tests for aspergillosis); (3) evaluation (applying diagnostic criteria for proven or possible CAPA for treatment decision-making); (4) treatment with antifungal treatment regimens for probable and proven CAPA; (5) evaluation of other invasive fungal infections (including nonpulmonary aspergillosis, infection caused by molds, Pneumocystis jirovecii pneumonia, cryptococcal species infection, other endemic mycoses, and candidiasis); and (6) pharmacological considerations (including drug-drug interactions and toxicity management) (Figure 5).

Challenges of this case included recognizing that there was an occult infectious process causing the poor outcomes.

The 6 expert groups met by video conferencing and corresponded via email to review current CAPA research, case reports, and clinical experiences to inform evidence-based content. Multiple rounds of content were developed over a 6-month period to ensure full consensus of the groups for the CSP tool. A final editing round served to finalize the tool. On June 18, 2021, the content was released publicly on the Covid-19–Associated Fungal Infections Educational Initiative website (covidandfungus.org) in the form of a CSP poster and a companion document. After its internet launch, the CSP was made available in printed form to one of the authors’ COVID-19 ICUs for dissemination to the nurses and other health care team members as well as one of our faculty members who worked at an academic center and educated community affiliates.

We solicited feedback through an informal usability and user experience survey distributed using the Vertical-Response email marketing platform. We provided a direct link to the survey from the Covid-19–Associated Fungal Infections Educational Initiative website and distributed it directly to the centers who received printed forms. The survey included demographic questions for the responding health care team members (nurses, pharmacists, microbiologists, physicians). Also included were 4 objective questions about usability and experience: (1) How are you using the CSP? (2) What aspect of the CSP was most helpful? (3) What limited your ability to use the CSP? (4) What impact has the use of the CSP had for your patients?

The most helpful aspects of the Care Step Pathway are practical recommendations for CAPA screening, pharmacological considerations, treatment recommendations, and CAPA definitions.

Using a checklist approach, we illustrated the application of the assessment, evaluation, and treatment sections of the CSP to the CAPA case reported above (Figure 6).

Clinical Assessment

Specific clinical issues for the ICU bedside registered nurse and other health care providers to consider in ICU patients infected with SARS-CoV-2 and receiving mechanical ventilation are shown in the checklist in Table 1. In this case, the patient showed pulmonary or clinical deterioration that was unexplained or unresponsive to antimicrobial therapies targeting bacterial sources. Moreover, the patient met clinical criteria for a COVID-19–associated invasive fungal infection. He required mechanical ventilation and remained in the ICU for more than 48 hours. Additionally, his imaging was consistent with ARDS or pulmonary invasive fungal infection, he showed clinical and hemodynamic deterioration, and he had recent corticosteroid and tocilizumab use.

With those clinical criteria met, the next step, evaluation, was undertaken (Table 2). Evaluation for probable CAPA was supported by an abnormal chest radiograph and a positive galactomannan airway specimen result.

Hospital formularies may determine available anti-fungal options at local hospitals. The patient in our study was initially treated with micafungin; however, owing to the presumptive CAPA diagnosis, he was switched to isavuconazonium sulfate in accordance with the CSP treatment checklist (Table 3).

The patient did not have evidence of other invasive fungal infections or travel to an endemic area. Criteria for the evaluation of other invasive fungal infections in the CSP include ruling out nonaspergillus pulmonary or rhinofacial/orbital molds such as mucormycosis or fusariosis, Pneumocystis jirovecii, Cryptococcus species, histoplasmosis, blastomycosis, coccidioidomycosis, or candidiasis. A diagnostic commentary is provided for each of these infections in the CSP.

Awareness of pharmacological factors is important in the rapidly changing ICU setting. Medication levels can be affected by extracorporeal membrane oxygenation and the presence of renal and liver failure. In a patient with COVID-19, QTc prolongation can affect the myocardium and the potential for drug-drug interactions; thus, serial electrocardiograms are warranted during treatment. Indeed, many antifungal drugs can alter pharmacodynamic pathways, leading to drug-drug interactions and pharmacokinetic issues such as increasing or decreasing drug levels. Monitoring for therapeutic drug levels may be indicated. Moreover, transition of antifungal therapy from an IV to an oral route of administration requires planning. Koehler et al2  recommended 6 to 12 weeks of azole therapy, although the optimal duration of treatment for CAPA is still unknown. Continuity of care is an important factor in improving patient outcomes. The course of treatment should be clearly communicated during the transition of care to step-down units and outside facilities. Owing to the high bioavailability of voriconazole and isavuconazonium sulfate oral formulations, the need for IV access should be reassessed on transfer or discharge to avoid additional complications and high costs associated with IV drug formulations and home health care.13,14 

Finally, the length of ventilation, including ventilator weaning, highlights the severe nature of CAPA. In our case, the patient survived his CAPA and was able to describe his case publicly in video interviews. The full CSP poster, CSP companion document with references, and patient case interview are available at the Covid-19–Associated Fungal Infections Educational Initiative website (covidandfungus.org).

Care Step Pathway Usability and Experience Survey

Eleven individuals evaluated the CSP via survey. Of those individuals, 55% evaluated hard copies of the CSP that were directly distributed to specific institutions, and 44% downloaded the CSP directly from the website. In terms of specialties, 44% of respondents were from critical care and pulmonary medicine, 33% were from infectious diseases, and the remainder were from other specialties (laboratory medicine). Regarding the most common uses of the CSP, 24% of respondents were using it for clinical assessment, 24% for CAPA treatment guidance, 19% for screening, 15% for diagnosis of CAPA, 10% to evaluate for non-CAPA invasive fungal infections, and 10% to assess pharmacological factors. Respondents indicated that the most helpful aspects of the CSP were practical recommendations for CAPA screening, pharmacological considerations, treatment recommendations, and CAPA definitions. Respondents indicated the following limitations of CSP use: inadequate time to implement the CSP (18%), lack of institutional support for recommended testing (27%), and colleagues’ lack of understanding of fungal diseases (55%). At this early stage of use, 70% of respondents reported that they did not know what impact use of the CSP has had on patient outcomes; nevertheless, 20% reported that its use could be associated with decreased mortality, and 10% reported that its use could be associated with decreased length of stay.

In the initial phases of the COVID-19 pandemic, many patients experienced prolonged hospitalizations, and those who received mechanical ventilation had increased morbidity and mortality. Despite the use of evidence-based practice with ventilation involving prone positioning and lung protection,15  many patients did not recover as would be expected with ARDS from another viral illness. Given the recommendation to use glucocorticosteroids for the treatment of severe COVID-19, fungal infections should be considered as the cause of pyrexia and leukocytosis in patients with severe illness despite adequate and appropriate antimicrobial therapy. Observation of these clinical scenarios led to the search for and identification of atypical types of pneumonia in COVID-19 patients, including CAPA in ICU patients receiving mechanical ventilation.

The CSP for CAPA constitutes a vital educational tool for health care providers, including bedside nurses, who care for patients infected with SARS-CoV-2, particularly in the ICU. This tool’s ability to promote early identification of CAPA among ICU patients has the potential to raise awareness of CAPA among clinical nursing staff members and medical providers, shorten ICU stays, reduce ventilator days, and improve mortality. As discussed in the case report, prompt recognition and anti-fungal treatment of CAPA resulted in both improvement in clinical condition and reduced ventilator needs.

Our usability and experience survey regarding the CSP was limited by the informal nature of the survey and the small number of respondents. Although the results are informative, the responses could be biased by an increased willingness to complete the survey among those with interest in the topic.

The CSP described in this article was developed to increase awareness of the potential association of SARS-CoV-2 infection with invasive fungal infections, particularly pulmonary aspergillosis. The case study demonstrates the utility of application of the CSP for diagnosing and treating CAPA in the ICU setting. This educational tool can improve understanding of potential invasive fungal infections in COVID-19 patients receiving mechanical ventilation and facilitate an evidence-based approach to assessment, diagnosis, and treatment, leading to earlier intervention and fewer missed opportunities for improved patient outcomes.

The authors acknowledge the input of the COVID and Fungus Steering and Content Development Committee in developing the evidence-based Care Step Pathway. Members of this committee who are not authors of the article are George R. Thompson III, MD, John W. Baddley, MD, Andrej Spec, MD, Dimitrios Kontoyiannis, MD, Ilan Schwartz, MD, Kimberly Hanson, MD, Latesha Elopre, MD, P. Lewis White, PhD, Luis Ostrosky-Zeichner, MD, Melissa D. Johnson, PharmD, Minh-Hong Thi Nguyen, MD, Sharon Chen, MD, and Thomas F. Patterson, MD. We also acknowledge Tom Davis for his work as a graphic artist and website designer for the covidandfungus.org website and images in this article.

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Footnotes

 

To purchase electronic or print reprints, contact the American Association of Critical-Care Nurses, 27071 Aliso Creek Rd, Aliso Viejo, CA 92656. Phone, (800) 899-1712 or (949) 362-2050 (ext 532); fax, (949) 362-2049; email, reprints@aacn.org.

 

Financial Disclosures

This project was funded in part by a cooperative agreement between the Centers for Disease Control and Prevention (CDC; CFD-RFA-CK20-2003) and the University of Alabama at Birmingham. The University of Alabama at Birmingham is collaborating with the Mycoses Study Group Education and Research Consortium and Terranova Medica, LLC, on this initiative. The CDC is an agency within the Department of Health and Human Services. The contents of this article do not necessarily represent the policy of the CDC or the Department of Health and Human Services and should not be considered an endorsement by the federal government. In addition, Carolynn T. Jones is supported, in part, by the National Center for Advancing Translational Sciences–funded Ohio State University Center for Clinical Translational Science (grant UL1TR002733).

 

See Also

To learn more about caring for patients with COVID-19, read “Cutaneous Manifestations of COVID-19 in Critical Care” by Swoboda in AACN Advanced Critical Care, 2022;33(2):186-195. Available at www.aacnacconline.org.