Immunocompromised patients are generally at high risk of Invasive Fungal Infections (IFI), potentially leading to diseases like pneumonia, an infection in the lungs which can be caused by a fungus, bacteria, or viral infection.

Pneumonia is a major cause of morbidity and mortality in these individuals and this may especially be the case in patients with hematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic hematopoietic stem cell transplants (HSCT).[1]

Although new treatment options have become available to treat patients with cancer and hematological malignancies, Invasive Fungal Infections remain a major concern due to the increased potential of morbidity and mortality in these patient populations.

The effects of novel anti-cancer agents Although a growing number of new immune-modulating drugs has shown to advance the treatment of patients with cancer, some of these agents have also attribute to the increase of risk for Invasive Fungal Infections. This increased risk may especially be seen in patients treated with tyrosine kinase inhibitors (TKI), in particular inhibitors of Bruton tyrosine kinase (BTK) mammalian target of rapamycin (mTOR) Janus kinase (JAK) and phosphatidylinositol 3 kinases (PI3K) delta.[1]

Inhibition of immune checkpoints, such as programmed cell death protein 1 (PD1) or cytotoxic T lymphocyte-associated protein 4 (CTLA4) may show a wide-ranging of mostly immune-related adverse events. Subsequent immunosuppression, primarily including corticosteroids, may, in turn, result in the development of opportunistic infections including fungi, requiring optimizing the management of immune-related adverse events.[1]

Diagnostic failure Immunocompromised patients can be infected by a broad range of potential pathogens. However, in many cases, diagnostic testing fails to identify a microbial etiology for lower respiratory illness even with bronchoalveolar lavage (BAL).

Studies have shown that culture methods, PCR, and antigen testing on BAL samples only yields a positive result of 30-67% of the time. In addition, Idiopathic Pulmonary Syndrome (IPS), a non-infectious pulmonary complication of transplants, can have many overlapping symptoms with infectious pneumonia. Treatment for IPS is the administration of steroids which can exacerbate infections. As a result, there is a major unmet medical need for better diagnostics to aid in the management of immunocompromised patients with pneumonia.

Clinical evaluation Karius, a life sciences company focused on generating genomic insights for infectious diseases, has developed a microbial cell-free plasma next-generation sequencing test for pathogen detection capable of detecting >1,000 organisms. The test is performed in a CLIA-certified/CAP-accredited laboratory with results typically provided within one day from sample receipt.

To understand the increased risk and to improve the timely diagnosis of pneumonia in immunocompromised adult patients, including those with hematological cancers, Karius, in collaboration withDuke Clinical Research Institute, has launched a multicenter, prospective study designed to evaluate the diagnostic value of the Karius Test.

The test developed by Karius is a non-invasive liquid biopsy, based on next-generation sequencing of microbial cell-free DNA that can rapidly detect over 1,000 bacteria, DNA viruses, fungi, and parasites. The test helps clinicians make rapid, treatment decisions and is currently being used by over 100 hospitals nationwide by mapping each patients microbial landscape from a single blood draw.

Diagnostic yield Given the medical need, the clinical evaluation will compare the diagnostic yield of the Karius Test to standard testing methods used to diagnose infectious causes of pneumonia in immunocompromised patients including those with hematological cancers.

Patients with suppressed immune systems are especially vulnerable to life-threatening pneumonia due to their decreased ability to fight infections. Standard methods to diagnose pneumonia can be invasive, time-consuming, often requiring weeks to months for a result, and in some cases inconclusive, failing to identify the pathogen causing the infection.

The PICKUP study (NCT04047719) will investigate the additive diagnostic value of the Karius Test in the diagnosis of pneumonia in these patients and its impact on clinical decision-making in this specific population. In addition, the Karius Test will be used to serially monitor pathogen levels during treatment to examine the association between microbial load and pneumonia progression.

The ability to diagnose invasive life-threatening infections in immunocompromised patients has been one of the most challenging areas in clinical infectious disease practice, noted Mickey Kertesz, Chief Executive Office of Karius.

We are enthusiastic to be collaborating with a number of leading cancer centers for this study and anticipate that the Karius Test will demonstrate a higher diagnostic yield than traditional invasive testing methods, Kertesz added

Unknown causative pathogen Often in pneumonia, the causative pathogen is unknown or can be challenging to diagnose despite extensive diagnostic testing, explained Stephen P. Bergin, M.D., Assistant Professor of Pulmonary and Critical Care Medicine at Duke University Health System and lead investigator for the PICKUP study.

Accurate and timely pathogen identification is particularly critical for immunocompromised patients who are susceptible to life-threatening infections from a much broader array of pathogens. We look forward to exploring the potential value of a non-invasive tool capable of rapidly diagnosing respiratory infections in this vulnerable population, Bergin concluded.

Overcoming limitations Previous studies have demonstrated the ability of the Karius Test to overcome many of these limitations to diagnose the cause of pneumonia and enable targeted treatment.

The PICKUP study will include approximately 200 patients from up to 10 centers in the United States, including Duke University Health, University of Pittsburgh Medical Center, Fred Hutchinson Cancer Research Center, The University of Texas MD Anderson Cancer Center, City of Hope, Tulane Cancer Center and Tulane Medical Center and The University of California, San Francisco Medical Center.

Clinical trials Pneumonia in the ImmunoCompromised Use of the Karius Test for the Detection of Undiagnosed Pathogens (PICKUP) NCT04047719

Reference [1] Mellinghoff SC, Panse J, Alakel N, et al. Primary prophylaxis of invasive fungal infections in patients with hematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Ann Hematol. 2018;97(2):197-207. doi:10.1007/s00277-017-3196-2

Featured image: Karius laboratory. Photo courtesy: 2020 Karius. Used with permission.

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Study Evaluates Diagnostic Value of the Karius Test for Pneumonia in Immunocompromised Patients - OncoZine