COVID-19 digital pathology repository picking up steam

September 2021—When Stephen Hewitt, MD, PhD, went down the COVID-19 rabbit hole in early 2020, little did he know about the long-term value of a comprehensive COVID-19 digital pathology repository—and how such a project would come to fill his days and, occasionally, nights.

But fill his time it has. Since the early days of the pandemic, Dr. Hewitt has been working diligently on behalf of the National Institutes of Health to make the repository more than its original offering of a “flat file dump of cases with a little bit of metadata so you could find an individual patient or an individual organ.”

[dropcap]T[/dropcap]o understand the future of the NIH’s COVID-19 Digital Pathology Repository requires cognizance of its past. “We needed a better understanding of the pathophysiology of SARS-CoV-2 if we were to treat patients effectively,” recalls Dr. Hewitt, head of the Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, and captain, U.S. Public Health Service. To that end, he and collaborators from the NIH, in partnership with Indica Labs and Octo, launched the COVID-DPR—a centralized, cloud-based whole slide image library of tissue from those with SARS-CoV-2.

The repository, which went live in April 2020, is hosted by the NIH and underpinned by Indica Labs’ Halo Link platform, a Web-based collaborative slide-management and slide-sharing platform. The overarching goal for the COVID-DPR, says Dr. Hewitt, is to have it serve as a reference data set of COVID-19–related pathology for the greater biomedical community that, among other functions, helps inform immune response to SARS-CoV-2.

As of CAP TODAY press time, the COVID-DPR housed more than 2,300 whole slide images representing over 100 autopsies, as well as surgical specimens, cytology specimens, blood smears, and a comparator case of H1N1 influenza. The site also contains placental images because the placental pathology for pregnant women infected with SARS-CoV-2 is complex, Dr. Hewitt says. The autopsy images are arranged by organ and patient, with all patient information deidentified. But because the Halo platform is highly flexible, it easily could allow for other organizational schemas, Dr. Hewitt says, such as categorization by disease process “if we chose to break it down to patients with diffuse alveolar damage, thromboemboli, or pulmonary edema, with reference to lungs.”

Though many of the autopsy cases in the repository were donated by Dr. Hewitt’s pathologist colleagues at other institutions, the NIH has contributed 44 autopsies from its COVID-19 autopsy consortium, 15 of which had been uploaded by CAP TODAY press time. After uploading the NIH autopsies, which are comprehensive across organ systems, with multiple sections per site, Dr. Hewitt plans to add more autopsies from external collaborators. (Cases can be submitted via the COVID-DPR website, at covid19pathology.nih.gov.)

[dropcap]A[/dropcap]s they address a number of roadblocks—staffing and remote work issues chief among them, in addition to competing institutional goals—Dr. Hewitt and his colleagues are preparing to substantially expand and overhaul the repository. The project has obtained funding for the next four to five years, he says. “It doesn’t sound earth-shattering, but it’s important.”

Among the efforts underway are curating and annotating the whole slide images already in the repository to add metadata and simple histopathologic interpretations; uploading the remainder of the NIH consortium’s autopsies, along with associated immunohistochemical images, RNA in situ results, and EHR-derived data; and expanding the repository to support other NIH-funded COVID-19 studies.

Dr. Hewitt and his collaborators also hope to expand the site by adding more comparators, such as a nonhuman primate model of SARS-CoV-2 infection. Such comparators would allow investigators to contrast the pathophysiology of the virus among different organisms, thereby obtaining a better understanding of host response, Dr. Hewitt says. “We used to believe the pathophysiology and the spread of virus was more related to virus type than anything else.” But the study of Ebola and Zika precipitated a shift in thought, he says, leading pathologists who study virology to focus more on host response, such as how host response is inadequate or modified between the viral processes, than the virus itself. In addition, Dr. Hewitt and his team are working to obtain cases from the outbreak of SARS in the early 21st century, as well as historical images of the 1918 H1N1 influenza and examples of other strains of influenza, which too cause pulmonary damage.

Also in the works is a plan to host whole slide and associated images from SARS-CoV-2–related manuscripts. The manuscripts’ PubMed unique identifiers, or PMID, will be linked to the COVID-DPR, Dr. Hewitt says, allowing users to read a study and at the same time peruse the related whole slide images. The repository will only host images from NIH manuscripts initially but eventually will also display images from external studies.

The COVID-DPR “is the first instance, of which we’re aware, where authors will be able to host whole slide images on servers unrelated to the publishers, as well as have a direct link to PubMed,” Dr. Hewitt says. In the past, he explains, efforts to host whole side images associated with manuscripts were undertaken by the journal publishers themselves. However, “they found this was a complicated process for which sustainability was problematic,” he adds, noting that most of those attempts have fallen by the wayside. “It’s still not in the mindset of investigators to post their images.”

[dropcap]P[/dropcap]erhaps because of its ambitious objectives, the repository project hasn’t been without technical challenges—among them, incorporating into the platform the clinical metadata from the NIH autopsies. This has posed difficulties “both in presenting the data and using it analytically,” Dr. Hewitt says. A potential solution to this problem involves building an interlinked search engine that would allow users to search for specific data and thereby access the related images. An alternative, he says, is to add new data fields and bring the clinical metadata directly into the site. How the data will be incorporated and the timeline are uncertain, he adds.

Integrating such data into the study of whole slide images is a challenge for the digital pathology space at large, Dr. Hewitt says, noting that data sets often are discontinuous and that the systems used to display whole slide images aren’t designed to handle quantitative data queries. Though image analysis and analytics are routinely performed on whole slide images, “only when we include the metadata in those analytics do we accomplish substantial gains,” he says. “I think the COVID-DPR will evolve so that in the future, researchers will be able to perform analyses on these images, but right now it’s very much ‘come and view.’” Furthermore, the version of Halo used for the repository doesn’t include the full analytics package offered by Indica Labs, though it may be added later. “That doesn’t mean we’re not taking the images—especially the NIH images—and running them through advanced analytics, but that’s happening on our internal platforms,” Dr. Hewitt says.

Using artificial intelligence to analyze images in the COVID-DPR too has been challenging, though the repository was conceived with an eye toward AI applications. Early in the pandemic, Dr. Hewitt says, researchers assumed that SARS-CoV-2 infection gave “a consistent and static histopathology. We didn’t know what it looked like, so everybody assumed it was unique and somewhat fixed.” But the autopsies that emerged in the initial weeks of the outbreak demonstrated an inconsistent histopathology, particularly pertaining to the lungs. For example, time of infection to time of death was a significant vector with regard to lung injury. Furthermore, several patterns of lung injury were observed, including thromboemboli, pulmonary edema, and progressive acute respiratory distress syndrome with diffuse alveolar damage.

Preanalytic variables involving the patient’s course of infection, as well as specimen handling, also complicated the potential for AI analysis. For instance, the CDC requires 72 hours of fixation for autopsy tissue specimens, Dr. Hewitt says, “which is a major preanalytic variable impacting quality.”

“Now, if you have a small or large fixed set of organs handled with a very tight protocol, such as a 24-hour postmortem protocol,” he explains, “AI may be more interesting to do. We’re pursuing that now, looking at hearts, kidneys, livers, and eventually lungs. One of the questions we’re more interested in today—compared to what people thought they were going to focus on at the beginning of the pandemic—is not, ‘Is this SARS or not?’ but ‘What is the contribution of comorbidities to the pathology that we see?’ We’re saying, ‘Is it COVID related, or is it hypertension, diabetes, or obesity?’ So we’re using AI to try to understand the intersection of the comorbidities with SARS-CoV-2.”

As Dr. Hewitt tackles these and other COVID-related issues, he acknowledges the irony that the subject of his investigation is the very thing that slows his efforts to enhance the repository. “If I had more hands in the laboratory,” he says, “I could better utilize my virtual collaborators.”
—Charna Albert

PathAI purchases Poplar Healthcare Management

The digital pathology and artificial intelligence firm PathAI has acquired Poplar Healthcare Management, the management service organization for the anatomic pathology laboratory services provider Poplar Healthcare PLLC.

Under terms of the transaction, Poplar’s facilities and approximately 350 employees now compose PathAI’s diagnostics division. Poplar Healthcare supports a nationwide client base of gastroenterologists, dermatologists, oncologists, urologists, and gynecologists, and their patients.

PathAI and Poplar will focus on further digitizing the Poplar laboratory workflow and leveraging PathAI’s image-analysis and algorithm-development capabilities to develop new clinical applications, according to a joint press release from the companies.

PathAI, 617-500-8457

LigoLab offers TestDirectly for at-home specimen collection

LigoLab Information Systems’ Test­Directly patient-engagement platform supports at-home specimen self-collection for diagnostic testing and preventative screening.

Patients can place orders online for test kits from pathology laboratories throughout the United States that are featured in TestDirectly’s platform. Via interfaces to national shipping services, TestDirectly provides laboratories with backend support for shipping test kits to patients and tracks the delivery of kits to patients and the resulting specimens to laboratories. The platform also tracks laboratory processing of specimens.

The TestDirectly portal uses email and SMS notifications for automated delivery of test results to patients. LigoLab most recently added functionality that allows patients to participate in videoconferencing and schedule consultations via the platform.

TestDirectly is an agnostic, cloud-based solution that can be integrated with laboratory information systems and revenue cycle management solutions to simplify the ordering, collection, and testing of specimen samples and provide patient reporting.

LigoLab Information Systems, 818-395-4659

Dr. Aller practices clinical informatics in Southern California. He can be reached at [email protected]. Dennis Winsten is founder of Dennis Winsten & Associates, Healthcare Systems Consultants. He can be reached at [email protected].

Study finds low CKD testing rates for at-risk adults

September 2021—Testing for chronic kidney disease in adults with hypertension and/or diabetes is low in routine clinical care, despite guideline recommendations, write the authors of a study published in Diabetes Care (Alfego D, et al. 2021;44[9]:2025–2032).

The authors looked at patients age 18 and older who had testing at a Labcorp facility between January 2013 and December 2019 and were defined as at risk for chronic kidney disease by ICD-9 or ICD-10 codes for type 1 or 2 diabetes or for hypertension.

Patients with only hypertension had the lowest rates (10.5 percent) of complete testing (estimated glomerular filtration rate and urine albumin-to-creatinine ratio), and patients with both conditions had the highest (41.4 percent). “Lack of complete testing was driven primarily by absence of albuminuria testing (79.0%),” the authors write, “rather than missing eGFR testing (10.4%).” They add, “These findings of low albuminuria testing are similar to other published studies, but on a larger scale.”

The findings support the utility of dedicated panels, the authors say, to simplify the testing process for primary care professionals and other clinicians who manage hypertension and diabetes.

The kidney profile, a test that combines eGFR and uACR in a single panel, is now widely available for use in clinical practice, says Jennifer Ennis, MD, a coauthor of the study and medical director of clinical and digital solutions at Labcorp. Development of the kidney profile was part of a “collaboration of the National Kidney Foundation, American Society for Clinical Pathology, leading laboratories, and clinical laboratory societies,” she says, “to advance CKD detection and promote awareness among providers and patients of this high-risk condition.”

FDA approves MMR RxDx as companion diagnostic

The FDA approved the Ventana MMR RxDx Panel to aid in identifying patients whose solid tumors are deficient in DNA mismatch repair and who may be eligible for Jemperli (dostarlimab-gxly) monotherapy, an anti-PD-1 immunotherapy from GSK.

“As the first companion diagnostic of its kind, this test can help qualify patients with solid tumors that are deficient in MMR who have progressed in their disease and who have no other suitable treatment options,” Roche Diagnostics CEO Thomas Schinecker said in a statement.

The Ventana MMR RxDx Panel is a label expansion of Roche’s current on-market Ventana MMR IHC Panel. MMR RxDx is intended for the assessment of expression of MMR proteins in formalin-fixed, paraffin-embedded tumor tissue stained with OptiView DAB IHC Detection Kit and ancillary reagents in the panel for Ventana anti-MLH1 (M1), Ventana anti-MSH2 (G219-1129), and Ventana anti-MSH6 (SP93), and OptiView DAB IHC Detection Kit with the OptiView Amplification Kit and ancillary reagents for Ventana anti-PMS2 (A16-4) on a BenchMark Ultra instrument.

Jemperli was approved by the FDA on Aug. 17 for the treatment of adult patients with dMMR recurrent or advanced solid tumors, as determined by an FDA-approved test, who have progressed on or following prior treatment and have no satisfactory alternative treatment options. This indication received accelerated approval based on tumor response rate and durability of response. Continued approval may depend on verification and description of clinical benefit in a confirmatory trial.

The MMR RxDx Panel and Jemperli were approved by the FDA for use in endometrial cancer in April.

FDA grants marketing authorization to Enhanced Liver Fibrosis Test

Siemens Healthineers’ Enhanced Liver Fibrosis Test was granted marketing authorization under the de novo review pathway.

The ELF Test, for use with the Advia Centaur XP Immunoassay System, provides a numeric score that is automatically generated via an algorithm and is used to assess the likelihood of progression to cirrhosis and liver-related clinical events in patients with advanced fibrosis (F3 or F4) due to nonalcoholic steatohepatitis.

This marketing authorization follows the breakthrough device designation granted by the FDA for the ELF Test in 2018.

Siemens Healthineers develops AI-based COVID severity algorithm

Siemens Healthineers collaborated with several health care institutions worldwide to develop the Atellica COVID-19 Severity Algorithm, a model designed to help predict the potential likelihood of progression to severe disease and life-threatening multiorgan dysfunction in COVID-19 patients.

Using deidentified COVID-19 patient data from more than 14,000 COVID-19 patients, nine clinically significant lab parameters were identified and selected for inclusion in the algorithm. D-dimer, lactate dehydrogenase, lymphocyte %, eosinophil %, creatinine, C-reactive protein, ferritin, PT-INR, and high-sensitivity cardiac troponin I are used, in addition to patient age, to help predict the likelihood of disease progression to severe disease endpoints.

The educational-use-only algorithm is available on the company’s website (https://bit.ly/COVID_severe-alg). By entering a patient’s lab values and age, the algorithm will generate a COVID-19 clinical severity score, including projected probability of progression to ventilator use, end-stage organ damage, and 30-day in-hospital mortality. The AI-based algorithm has been interfaced to the Atellica Data Manager software and is being evaluated as investigational use only to assess benefit to patient care. With integration into the existing physician order/sample processing/result reporting workflow, a later generation of the algorithm could provide clinical decision support capabilities to support standardized testing protocols for patients positive for COVID-19.

Illumina acquires Grail

Illumina has acquired Grail with the aim of making Grail’s Galleri test broadly available and affordable.

Galleri is a multi-cancer early detection blood test that is available now but not covered by insurance.

Illumina says there is no legal impediment to its acquiring Grail in the United States, but in the European Union, where regulators are reviewing the transaction, Illumina says it will hold Grail as a separate company during the regulatory review.

Illumina announced a year ago its intention to reunite with Grail four years after it was spun off. Its acquisition of Grail, Illumina says, will accelerate access to and adoption of the Galleri test.

Aug. 31, 2021—PreciseMDX introduced a cloud-based solution that enables labs to set up scalable, personalized, digital experiences. When a lab signs on with PreciseMDX, it receives step-by-step user onboarding, test orders management software, and online kit purchasing, all from the cloud. The solution supports any type of diagnostic test, the company says, including women’s and men’s health, sexual health, wellness and nutrition, COVID-19 testing, respiratory pathogens, nail fungal wound panels, and vaccines.

“The scramble to ramp up testing during COVID-19 exposed a need in the health care industry for an automated diagnostic testing experience so that labs can scale rapidly, patients can have control over the process and receive results quickly, and providers can treat patients quicker with a faster, more connected system,” Mark Dorner, co-founder and CEO of PreciseMDX, said in a press statement. “We saw this need and created a technology to completely transform the diagnostic testing experience to one that is automated, simple, and user friendly.”

PreciseMDX was designed and built following the National Institute for Standards and Technology security framework to support HIPAA, PIPEDA, GDPR, and other international standards. The software is multi-lingual and can integrate with multiple systems and third parties, including EPIC and other hospital EMRs, lab information systems, fulfillment companies, billing platforms, as well as airport, civil, and government systems.

Aug. 30, 2021—Visby Medical announced it has received FDA 510(k) clearance and was granted a CLIA waiver to market its single-use PCR diagnostic test for the multiplexed detection of sexually transmitted infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis using a self-collected vaginal swab.

“This FDA clearance and CLIA Waiver further validate our technology and allows us to start changing how infectious diseases are identified and treated to improve patient lives and public health monitoring,” Visby Medical founder and CEO, Adam de la Zerda, PhD, said in a press statement. “Accurate results can ensure the clinician is able to make informed decisions that can shorten infection duration, prevent transmission, and may lower the risk of complications, all while improving the patient and clinician experience.”

The Visby Medical Sexual Health Click Test offers a hands-on time of less than 15 seconds, results in 28 minutes, and an accuracy of about greater than 97 percent for all three pathogens. The device measures 3.3” (L) x 1.5” (W) x 4” (H), and no additional instruments are required to perform testing.

Aug. 27, 2021—The FDA has granted premarket approval to Thermo Fisher Scientific‘s Oncomine Dx Target test as a companion diagnostic to identify patients with isocitrate dehydrogenase-1 mutated cholangiocarcinoma who may be candidates for Tibsovo (ivosidenib tablets). Tibsovo is an IDH1 inhibitor that is approved for the treatment of adult patients with previously treated, locally advanced or metastatic CCA with an IDH1 mutation as detected by an FDA-approved test.

Tibsovo (Servier Pharmaceuticals) is also approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutated relapsed or refractory acute myeloid leukemia and for adults with newly diagnosed IDH1-mutated AML who are 75 years old or older or who have comorbidities that preclude the use of intensive induction chemotherapy.

The Oncomine Dx Target test is a next-generation-sequencing­–based test that delivers robust and reproducible results in the IDH1 gene clinically associated with CCA. The test is approved and reimbursed by government and commercial insurers in more than 15 countries.

Aug. 26, 2021—BD has launched its FDA-approved BD COR PX/GX system, a fully automated, high-throughput diagnostic platform that integrates robotics and sample management software algorithms to automate the complete molecular laboratory workflow from sample processing to diagnostic test result.

The BD COR system offers two instruments: the BD COR PX integrates and automates the sample workflow for diagnostic specimens and assays, and the BD COR GX automates specifically the BD Onclarity HPV assay with extended genotyping. The PX instrument will prepare samples by performing preanalytical processing steps and automatically deliver the samples to the GX instrument for analysis. The GX instrument will perform the analytical steps of the BD Onclarity HPV assay, including extraction, amplification and, detection.

The system is modular and scalable and has onboard capacity for reagents and samples that provide six to eight hours of walkaway time.

Aug. 25, 2021—Siemens Healthineers announced that its Enhanced Liver Fibrosis test was granted marketing authorization under the de novo review pathway. The ELF test, for use with the Advia Centaur XP immunoassay system, provides a simple numeric score that is generated automatically via an algorithm and is used to improve patient care by assessing the likelihood of progression to cirrhosis and liver-related clinical events in patients with advanced fibrosis (F3 or F4) due to nonalcoholic steatohepatitis.

“Our ELF Test, the only IVD assay granted marketing authorization by FDA, measures biomarkers directly involved in the active process of scarring,” Deepak Nath, PhD, president of laboratory diagnostics for Siemens, said in a press statement. “Available worldwide for more than 10 years, including in the European Union, this test combines three serum biomarkers to assess the likelihood of progression to cirrhosis and liver-related clinical events in patients with advanced fibrosis due to NASH. Clinicians in the U.S. now have access to a convenient and minimally invasive tool that can enhance their prognostic patient management.”

The FDA granted breakthrough device designation to the test in November 2018.

Aug. 24, 2021—Hardy Diagnostics has released its HardyChrom Group A Strep agar, a chromogenic medium recommended for the selective cultivation and differentiation of group A streptococcus from clinical specimens. Identification can be made based on colony color: The medium will display red-brown or red-orange colonies on the HardyChrom Group A Strep agar when Streptococcus pyogenes is present; non-group A streptococcus isolates appear as blue, clear, or white colonies.

August 2021—Euroimmun launched its SARS-CoV-2 NeutraLISA assay, a surrogate neutralization test intended for the detection of neutralizing antibodies against SARS-CoV-2.

The CE-marked assay is based on ELISA technology and uses nonpathogenic viral proteins and can be processed in common laboratory settings, the company says, either manually or automatically.

The SARS-CoV-2 NeutraLISA assay supplements the company’s CE-marked QuantiVac ELISA and SARS-CoV-2 Interferon-gamma Release assay, which is expected to be available with the CE mark soon. Used in combination, the assays help evaluate the immune response to SARS-CoV-2 induced through natural infection or vaccination with S1/RBD-based vaccines from multiple angles.

Euroimmun, 973-656-1000

August 2021—Roche’s Cobas SARS-CoV-2 has received FDA emergency use authorization for testing individuals without symptoms or reasons to suspect COVID-19. This authorization supports the guidance update from the CDC to expand SARS-CoV-2 testing to include people without symptoms and applies to pooled samples containing up to and including six individual samples. Asymptomatic testing with the Cobas SARS-CoV-2 test is also available in countries accepting the CE mark.

The test, for use on Cobas 6800/8800 systems, is a real-time RT-PCR test intended for the qualitative detection of nucleic acids from SARS-CoV-2.

Roche, 317-521-2000