Ventilator-Associated Pneumonia (VAP) is a common complication of mechanical ventilation. Overall, the percentage of VAP or cases of pneumonia associated with mechanical ventilation compared to the sum of nosocomial pneumonia cases is greater than 50%, with the highest incidence occurring in the ICU, where approximately 90% of pneumonia cases are ventilator-associated. Roughly 15% of people on mechanically-assisted breathing will develop the condition – although some estimates put that figure as high as 27% – and, of those, roughly half will die. That figure does include mortality from other conditions, but as many as 13% of VAP patients will die exclusively because of VAP.
“The approach to execution of the VAP trials, their issues, obstacles, and pitfalls, are similar to those seen in everyday ICU practice,” explains Slobodan Ilic, Executive Medical Director, Director of Infectious Disease
COVID-19 and Its Effects on the Body
The clinical features of COVID-19, the disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), vary widely among infected individuals. Otherwise, healthy children and younger adults are generally asymptomatic or develop only a mild illness (multisystem inflammatory syndrome of children, or MISC-C, excepted). However, older adults and those with underlying medical conditions such as obesity, diabetes, cardiovascular disease, and renal disease are at increased risk for developing much more severe clinical illness.
In up to 30-35% of these patients, respiratory compromise and other systemic manifestations may lead to hospitalization and the need for supplemental oxygen. It is precisely these patients – those with severe SARS-CoV-2 pneumonia accompanied by cytokine dysregulation, acute respiratory distress syndrome (ARDS), and systemic hyperinflammation – that are most likely to become critically ill and need mechanical ventilatory assistance. With compromised natural host defenses and exposure to bacterial pathogens (often multi-drug resistant) in the intensive care setting, the threat of VAP is significant. Secondary infections are prevalent amongst those with severe COVID, and they are ten times more likely to develop a bacterial or fungal infection than a viral one.
Connecting VAP and COVID-19
The diagnosis of VAP in the setting of severe COVID-19 can be challenging. Many of VAP’s clinical indicators, such as high fever or severe hypoxemia, are shared with COVID-19, and the same diagnostic criteria and bacterial colonization threshold values tend to be non-specific. The Clinical Pulmonary Infection Score (CPIS) (e.g., tracheal secretions, body temperature), often used as an indicator for VAP, is not valid in COVID patients because the symptoms overlap so much. In one study, more than 90% of COVID patients had a qualifying CPIS score by their second day in the ICU. To date, the only reliable means for diagnosing VAP in COVID-19 patients has been the direct observation of pulmonary fluids via endotracheal culture or BAL (bronchoalveolar lavage).
Effectively Managing Coinfection
The World Health Organization (WHO) has issued guidance to help clinicians manage this comorbidity. They advise oral, rather than nasal, intubation, especially in younger COVID-19 patients. Head elevation, frequent drainage of the intubation system, and other measures are also recommended. However, there is no substitution for experience in managing patients with VAP in the ICU.
“Patients who are initially hospitalized for COVID pneumonia spend some time in the ICU on mechanical ventilation, and then, at some point, they become resistant to multiple classes of antibiotics. This is a typical pathway for critically ill patients,” explains Ilic.
VAP and COVID: Understanding the Clinical Research Environment
Knowledge of, and experience with, the management of patients with VAP is invaluable to the successful design and execution of clinical trials in this challenging environment. Strategies for, and the ethical and legal considerations around, recruiting and enrolling compromised or unconscious patients, understanding of and strategies for dealing with the culture and stresses intrinsic to the ICU environment, and integrating clinical study requirements with ongoing patient management activities are critical to successful study execution.
The added complexities of addressing VAP in COVID-19 patients, from biosafety considerations to diagnostics, management, and investigational therapeutics integration, further amplify these issues. A trusted partner with experience addressing this environment’s challenges and the expertise to advise and guide both design and execution of clinical trials in affected patients can be a vital asset. Issues surrounding the consenting procedure and eligibility assessment are just some of the common problems that require knowledge and experience.
Clinical trials in the ICU environment, as previously mentioned, are especially challenging due to the specific environment that is highly pressured, overburdened, emotional, and immediate. If not carefully handled by an experienced CRO, COVID-19 clinical trials conducted in this challenging environment may lead to unwanted outcomes, distractions, deviations, disinterest, and sometimes even dishonesty, eventually resulting in potential safety issues, slow study progress, and low data quality. Pharm-Olam’s experience in conducting clinical trials in the ICU setting, especially in VAP patients, can translate into exceptional COVID-19 research. Clinical trials in the ICU environment, as previously mentioned, are especially challenging due to the specific environment that is highly pressured, overburdened, emotional, and immediate.
Work with a COVID & VAP Experienced CRO
At Pharm-Olam, we currently have several studies underway focusing on COVID-19 and VAP patients. Our team has extensive experience working in the ICU setting and navigating the array of issues surrounding this environment. As a CRO, we are equipped to handle COVID-19, VAP, and superinfection ventilator issues. If you are planning a COVID or pneumonia study that involves ICU subjects, contact us to learn more about our experience in this space and our CRO services, which could benefit your research.
René Wheat, Executive Director, Project Management
Slobodan Illic, Executive Medical Director/Director of ID-COE Medical Affairs & Pharmacovigilanc