https://www.washingtonpost.com/investigations/lessons-unlearned-four-years-before-the-cdc-fumbled-coronavirus-testing-the-agency-made-some-of-the-same-mistakes-with-zika/2020/07/03/c32ca530-a8af-11ea-94d2-d7bc43b26bf9_story.html Lessons unlearned: Four years before the CDC fumbled coronavirus testing, the agency made some of the same mistakes with Zika [image: image.png] Robert S. Lanciotti, former CDC virologist and whistleblower, at his home in Fort Collins, Colo., on May 22. (Rachel Woolf for The Washington Post) By David Willman <https://www.washingtonpost.com/people/david-willman/> July 4, 2020 at 4:14 p.m. CDT Four years before the federal Centers for Disease Control and Prevention fumbled the nation’s chance to begin effective early testing for the novel coronavirus <https://www.washingtonpost.com/health/2020/02/28/what-you-need-know-about-coronavirus/?itid=lk_inline_manual_2>, the agency similarly mishandled its efforts to detect another dreaded pathogen. Amid a feared outbreak of the newly emerged Zika virus, senior CDC officials in 2016 sidelined an effective test for it — and instead directed public health laboratories nationwide to use a more complicated test that failed about one-third of the time. The agency’s response to Zika now stands as an unheeded prequel for how the CDC stumbled this year as it confronted the coronavirus pandemic, which has claimed more than 125,000 lives nationwide. Both Zika and the coronavirus originated overseas and became American health emergencies that have challenged the CDC’s ability to carry out its fundamental mission to rapidly identify and contain newly arrived pathogens. The parallels in how the CDC responded to the two health crises emerge from a Washington Post examination of federal investigative and regulatory records, congressional testimony, CDC emails and documents, and interviews with scientists and other technical experts. “It’s painful to watch the same challenges again and again,’’ said Timothy M. Persons, who has reviewed the efforts to counter Zika and the coronavirus as chief scientist of the U.S. Government Accountability Office. “As I think we saw with Zika, we need to apply lessons learned to definitely try and respond better.” An audit that Persons led <https://www.gao.gov/assets/690/684835.pdf>three years ago for the government faulted CDC leaders for not being more rigorous in evaluating the troubled test for Zika. Reliable early testing “is a critical piece of the overall preparedness and response system,” Persons said in an interview. President Trump and his appointees have generally praised the administration’s response to the coronavirus. But a review released on June 19 <https://www.washingtonpost.com/investigations/cdc-coronavirus-test-kits-were-likely-contaminated-federal-review-confirms/2020/06/20/1ceb4e16-b2ef-11ea-8f56-63f38c990077_story.html?itid=lk_inline_manual_20> by the Department of Health and Human Services said that CDC officials — despite seeing worrisome “anomalies” — skipped standard quality control checks before distributing the test kits for detecting the nation’s earliest cases of the virus. The review also confirmed that the kits were “likely” contaminated during the CDC’s manufacturing. CDC coronavirus test kits were likely contaminated, federal review confirms <https://www.washingtonpost.com/investigations/cdc-coronavirus-test-kits-were-likely-contaminated-federal-review-confirms/2020/06/20/1ceb4e16-b2ef-11ea-8f56-63f38c990077_story.html?itid=lk_interstitial_manual_21> Robert S. Lanciotti, a virologist who headed the CDC’s diagnostic efforts with Zika until May 2016 — when the agency stripped him of his leadership role after he warned against distributing the deficient test kits — said the decision-making with the coronavirus mirrored what he witnessed. “This is exactly the same mistake I saw during Zika,’’ Lanciotti said in interviews with The Post. Lanciotti said that by shelving effective tests in favor of less reliable approaches, CDC officials “slowed things down and screwed things up.’’ As reported in The Post in 2016 <https://www.washingtonpost.com/news/to-your-health/wp/2016/09/27/cdc-whistleblower-claims-agency-has-been-using-wrong-zika-test/?itid=lk_inline_manual_27>, Lanciotti had raised concerns then that the CDC’s preferred Zika test missed infections and that the agency withheld information about its deficiencies from local lab officials. CDC officials did not respond to questions for this article. On Saturday, an HHS spokeswoman, Caitlin Oakley, said the government at no point blocked the public health labs “from using any other” available test for the coronavirus. Representatives of the labs, however, have complained that then-existing regulations tethered them to the CDC’s troubled test. Former CDC Director Tom Frieden, who led the agency’s efforts against Zika in 2016, praised its overall performance with that virus and defended the decisions made with the Zika test. “Any test can get improved with time,” Frieden said. “And any action can be looked back on. . . . In the course of refining the test, you expect it to get better with time.” [image: image.png] Virologist Gilberto Santiago, left, and lab technicians Katia Matias, center, and Glenda Gonzalez work to process Zika tests at the CDC’s dengue virus lab in San Juan, Puerto Rico, in 2016. (Allison Shelley for The Washington Post) 'We weren't taken by surprise' Researchers discovered the virus that came to be called Zika in 1947 in the blood of a rhesus monkey in Uganda’s Zika Forest. Initially, the virus posed little threat to humans: Over the next three decades, fewer than 20 Zika infections would be diagnosed from Africa to Southeast Asia, and the reported symptoms were nonexistent or mild — occasional fever, headache and malaise. No deaths or other severe outcomes emerged. In June 2007, the CDC first dealt with Zika when the agency’s diagnostic lab in Fort Collins, Colo., received blood samples from physicians in Yap state, a cluster of tiny Pacific islands about 500 miles east of the Philippines in the Federated States of Micronesia. The island doctors suspected that an epidemic of rashes, eye redness and joint pain had been touched off by disease-carrying mosquitoes. At the time, Lanciotti was chief of the lab, which specialized in diseases spread by mosquitoes and ticks. Using a well-established molecular testing technique called polymerase chain reaction, or PCR, Lanciotti and his colleagues discovered that the epidemic in Yap was caused by the Zika virus. Lanciotti also developed a separate enzyme-based test, which showed whether a person’s blood carried Zika antibodies, another sign of infection. His lab continued to use those tests on Zika samples as small outbreaks emerged in the coming years elsewhere in the Pacific, still thousands of miles from the U.S. mainland. The CDC’s concern rose by late 2015, after Zika infections were detected widely along the northern coast of Brazil. This marked Zika’s first confirmed appearance in the Western Hemisphere — and the stakes were made more urgent by mysterious clusters of microcephaly, a birth defect that left newborns with tiny heads. In December 2015, Lanciotti began distributing instructions for how to conduct the molecular test, which his team was already using, to public health labs in 21 states and the District of Columbia, along with several counties, records show. A top priority, Lanciotti recalled during recent interviews, was to prevent Zika’s spread in the United States by likely hosts — including infected airline passengers returning from the 2016 Summer Olympics in Rio de Janeiro. If an infected person were bitten by a mosquito, Zika might spread to whomever the insect next found. Zika, he knew, could also be transmitted sexually. “When this hit in 2015, we weren’t taken by surprise,” Lanciotti recalled. “We had testing in place. . . . We knew there would be travelers returning, potentially infected with Zika.” Lanciotti’s approach was informed by his CDC experience with West Nile disease, another mosquito-spread virus: Using molecular and antibody testing, he and his colleagues had been the first to confirm that an outbreak in 1999 of human encephalitis in New York City was caused by West Nile. Lanciotti said the CDC did not manufacture the Zika test kits, but told others how to build them. The Zika molecular testing protocol that Lanciotti distributed instructed the local labs where to purchase chemical mixtures necessary for the tests and specified the temperatures and durations at which blood samples, along with the mixtures, should be heated, cooled and reheated during testing. Lanciotti also sent a “proficiency panel,” which each lab could use to verify whether it was generating reliable results with the test, called “Singleplex.” The panels included small tubes of inactivated Zika virus and a non-viral substance to verify accuracy. Within two weeks of receiving Lanciotti’s testing instructions, public labs in Florida, Texas, California, New York and Maryland were analyzing samples, interviews and CDC records show. “The approach that my lab took was, we want to develop a very rapid way for state public health partners detecting these viruses,” Lanciotti said. “We want to know right away if a traveler has Zika.’’ Rapid detection would enable health authorities to isolate an infected person and, if a cluster of cases emerged, the affected neighborhoods could be promptly sprayed with insecticide. If a pregnant woman were diagnosed with Zika, she would be informed immediately. [image: image.png] Rozilene Ferreira de Mesquita holds her son, Arthur Ferreira da Conceicao, as she visits Hospital das Clinicas da Universidade Federal de Pernambuco in Recife, Brazil, to see a doctor in 2016. Arthur was born with microcephaly, which the Zika virus has been linked to. (Matt McClain/The Washington Post) A more elaborate approach to testing By early 2016, CDC scientists based in Puerto Rico and at agency headquarters in Atlanta saw the emerging Zika crisis as an opportunity to deploy a new — and more elaborate — approach to detecting the virus. Instead of using the molecular test to look only for Zika, they would also target five additional pathogens: chikungunya virus and four strains of dengue fever. The new test, referred to by scientists as an “assay,” was called “Trioplex,” and was intended to provide convenience for labs that wanted to look simultaneously for Zika and the other pathogens. The portion of the Trioplex test targeting the four strains of dengue fever was known as the “pan-dengue” component. Four years later, the CDC would complicate its SARS-CoV-2 test with the “pan-coronavirus” component, designed to search for additional coronavirus strains. All of the viral strains targeted in the new test were transmitted by mosquitoes, but only Zika posed an imminent threat to the continental United States. Even if Trioplex detected a case of dengue or chikungunya, no effective medical treatments existed for their often mild symptoms, and neither dengue nor chikungunya was associated with birth defects. Unlike Lanciotti’s test, the CDC would manufacture and distribute the Trioplex test kits, each with 41 pages of instructions, versus two for Lanciotti’s concise protocol. The expanded diagnostic approach, however, introduced a challenge: Targeting multiple pathogens typically reduces a test’s sensitivity, according to scientific experts. “You always are careful about sacrificing sensitivity,” said Richard Meyer, a microbiologist who designed and conducted molecular tests before retiring as chief of the CDC’s rapid response lab for bioterrorism. Lanciotti said he worried about the change because he knew from his work during the Yap outbreak that, with Zika, only a relatively small amount of the virus could be detected in a person’s blood. Due to Zika’s low viral load, detecting it required a test with great sensitivity. “A small reduction in analytical sensitivity leads to a big problem, because most of the Zika cases had low levels of” virus in the blood, Lanciotti said. But Lanciotti did not oppose developing Trioplex — as long as it was not distributed until its sensitivity was upgraded, CDC records show. Lanciotti said he remained confident in the Zika test already in use, Singleplex. His work with Zika and other viruses drew accolades from the CDC. On Feb. 16, 2016, the CDC gave Lanciotti a “Director’s Recognition Award,” noting his “timely development of diagnostic tests that provided the first . . . evidence of a linkage between microcephaly and Zika virus.’’ By early that month, the testing had confirmed 50 cases of Zika infection among returned U.S. travelers, according to CDC documentation provided to the White House. President Barack Obama cited the cases in a letter on Feb. 22, 2016 <https://obamawhitehouse.archives.gov/the-press-office/2016/02/22/letter-president-zika-virus>, when he asked Congress for a $1.9 billion emergency appropriation to counter Zika. Nearly half, $828 million, was intended for the CDC’s efforts. At about the same time, the CDC began manufacturing the new Trioplex test kits in Atlanta. In a briefing with reporters on March 10, 2016, CDC Director Frieden said the “new PCR test [Trioplex] will be particularly helpful” in combating Zika. The emergency funding, he said, “is crucially important and urgently needed.” “The sooner we’re able to get a robust program up and running, the more we can reduce the risk to pregnant women,” Frieden said. On March 17, 2016, the Food and Drug Administration, which regulates some disease tests, granted the CDC an emergency use authorization for Trioplex, signifying it “may be effective.” The CDC then directed public health labs to use the test for Zika, records show. Six days later, Frieden told a House appropriations subcommittee that the agency had already “produced more than half a million” Zika test kits. At least 13 states, he said, were at “high risk” of Zika being spread by the *Aedes aegypti* mosquito. In Puerto Rico, alone, “we could see thousands of affected pregnancies,” he said. [image: image.png] Lab technician Ana Lucia Teixeira transfers pupa of Aedes aegypti, the type of mosquito that transmits the Zika virus, at the Oswaldo Cruz Foundation, a federally funded research institution in Recife, in 2016. (Lianne Milton/Panos Pictures for The Washington Post) Missed infections Health officials had another concern: that Zika could be transmitted through blood transfusions involving an infected donor. Because of that, in early 2016, the nonprofit Blood Systems Research Institute began to assess the reliability of the Trioplex test. The work was performed under a long-standing contract with the National Institutes of Health. The blood organization, based in San Francisco, quickly found trouble with Trioplex. On April 13, 2016, Michael P. Busch, the institute’s director, sent an email to a senior CDC official: Testing over the previous two months had generated “disturbing’’ results. The data, Busch said, showed that Trioplex had missed 18 of 48, or 37.5 percent, of Zika infections it should have detected. Trioplex appeared to be “less sensitive than . . . Lanciotti’s assays,” Busch wrote in the email to Lyle R. Petersen, a division director at the CDC, along with three other officials at both the CDC and the FDA. Busch’s email asked the officials “to support rapid publication” of the test data that his institute had analyzed. One of the FDA officials, Jay Epstein, its director of blood research, responded to Busch on April 15: “I support publication,” and “Re lower sensitivity … it seems to me that users need to shift to better assays.” “There was a lot of controversy over the accuracy of that [Trioplex] test and performance,” Busch recently told The Post, adding that it reminded him of “the current situation with” the coronavirus. A senior CDC official who was involved with the Zika response from the outset said the agency did not take “enough time to evaluate” Trioplex before distributing it. “We made a bad decision with this Trioplex,” said the official, who spoke on the condition of anonymity because they were not authorized to comment publicly. “We already knew how to diagnose for Zika virus. We already had the tests, which were developed in Rob Lanciotti’s lab.” Lanciotti, meanwhile, was conducting his own studies in early 2016 on the reliability of Trioplex. In mid-April, Lanciotti sent emails to a handful of senior CDC colleagues, reporting that analyses performed on patient samples in his lab found that “Trio misses 30-39% of the Zika positives.” One of the email recipients, Ronald M. Rosenberg, CDC’s associate director of vector-borne diseases, suggested informing the state labs. “The simplest solution might be to convey this information to the states and let them decide” which test to use, Rosenberg wrote in an email on April 18 to Lanciotti and four other CDC scientists. “But whatever they decide . . . it might be unwise to abandon the singleplex.” As concerns mounted over the accuracy of Trioplex, its lead designer, Jorge L. Munoz, chief of the CDC’s dengue virus lab in Puerto Rico, told colleagues he saw no deficit in sensitivity, records show. Also on April 18, Frieden touted Trioplex to more than 1,500 health officials invited to a “Zika Action Plan Summit” at the agency’s headquarters. Frieden said CDC scientists had “done a phenomenal job” developing Trioplex and the antibody tests. He again called for the emergency funding from Congress. Two days later, Lanciotti voiced his growing concerns over Trioplex with Petersen, who had been detailed from Fort Collins to Atlanta to manage the CDC’s response to Zika. Lanciotti said the state labs “that have validated and are using the singleplex should be encouraged to make no changes until they hear from us about the revised trioplex.” Lanciotti also sent the email to 11 other senior CDC scientists. Petersen did not respond to Lanciotti, according to documents gathered by a subsequent CDC review. The next afternoon, on April 21, Lanciotti went a step further and emailed officials at 29 state labs that were using or had qualified to use Singleplex: “We want to inform you that in the Fort Collins laboratory we are continuing to use the Zika singleplex due to its greater relative sensitivity (that we have just established/become aware of through comparative analyses in several laboratories).” Another senior CDC official, virologist Ann Powers, admonished Lanciotti for his email. “While I certainly appreciate that you are wanting to make sure states are doing top quality testing, this email has created more trouble and confusion than it clarified,” Powers wrote on April 25. Two days later, CDC officials in Atlanta notified more than 100 public health labs that Trioplex was “recommended for use in the current Zika response.” The email made no mention of the Singleplex test or the data reflecting Trioplex’s inferior sensitivity. Some CDC officials had hoped that even if Trioplex failed to detect a Zika infection in pregnant women, those false negatives would be caught through later antibody tests. But because of Zika’s low viral load, that was not a reliable alternative: Antibodies in patients’ blood typically are not seen during the first few days of infection and are never present in samples of urine or amniotic fluid. Of 13 patients with Zika that Trioplex had failed to detect, four were also missed by the antibody test, according to analyses done by Lanciotti’s lab. If those samples had not been subjected to the Singleplex test, “4 confirmed cases would have gone undetected,’’ Lanciotti wrote in an April 28 email to CDC officials Petersen, Powers and Rosenberg. The scientists were usually based in Fort Collins, and Lanciotti reported to both Powers and her superiors, Rosenberg and Petersen. In a reply to the group titled, “trioplex sensitivity,” Rosenberg wrote: “Shouldn’t CDC officially communicate this limitation to users?” On May 2, Trioplex’s sensitivity was discussed during a conference call involving Lanciotti, Powers, Munoz and Julie M. Villanueva, a senior CDC scientist put in charge of the new Zika Emergency Operations Center. Villanueva this year co-developed the CDC’s test for the novel coronavirus, according to a scientific journal article she co-authored <https://wwwnc.cdc.gov/eid/article/26/8/20-1246_article>. Two days later, according to the CDC’s subsequent review, “potential enhancements to the Trioplex’’ were also discussed with Frieden during a “daily update call” that included Munoz. Frieden said he did not remember the call. Munoz, Petersen, Rosenberg, Powers and Villanueva did not answer written questions from The Post. “What bothered me the most was, we were telling our state public health lab partners to use a test that we weren’t fully convinced was ready for prime time,” Lanciotti recalled. “There was no question in my mind that we were going to be missing cases.” [image: image.png] Lab technicians in Puerto Rico process Zika tests at the CDC’s dengue virus lab in San Juan in 2016. (Allison Shelley for The Washington Post) Lab chief turned whistleblower On May 17, 2016, Rosenberg informed Lanciotti that the agency was stripping him of his duties as lab chief, but Rosenberg relayed no reason for the demotion, according to Lanciotti. Within days, Lanciotti filed a whistleblower complaint <https://www.washingtonpost.com/context/read-the-whistleblower-complaint-regarding-president-trump-s-communications-with-ukrainian-president-volodymyr-zelensky/4b9e0ca5-3824-467f-b1a3-77f2d4ee16aa/?itid=lk_inline_manual_114> with the U.S. Office of Special Counsel. In his complaint, Lanciotti alleged that the CDC had endangered public health by withholding the data about Trioplex’s sensitivity. He spoke recently about the issue <https://www.pogo.org/investigation/2020/06/cdc-whistleblower-identified-the-fatal-flaw-in-testing-years-ago/> with the Project on Government Oversight. On July 1, 2016, the special counsel’s office, which protects federal employees who reveal potential wrongdoing, determined there was a “substantial likelihood” that Lanciotti’s allegations were credible. Special Counsel Carolyn N. Lerner contacted the CDC to recommend Lanciotti’s reinstatement as lab chief, according to people familiar with the matter. The CDC promptly restored Lanciotti’s title — but continued to exclude him from the agency’s response to Zika. Lerner also referred Lanciotti’s allegations to Health and Human Services Secretary Sylvia M. Burwell for further investigation. That type of referral typically would have been assigned to the HHS Inspector General, experts said. Instead, Burwell sent the matter to Frieden, who assigned it to the CDC’s associate director for laboratory science and safety, Stephan Monroe. His review, released on Sept. 2, concluded that Trioplex had posed no danger and that agency officials acted prudently. Monroe’s review cited the favorable conclusion about sensitivity reached by Trioplex’s designer, Munoz, and described the available data for comparing the two tests as “inconclusive and contradictory.” His review also said, “It was reasonable to not share this information with external public health laboratories, as it did not provide any meaningful information for laboratories to act upon.” Lerner, the special counsel whose initial investigation won Lanciotti’s reinstatement, closed her office’s file on the case in a letter to the White House on Sept. 27, concluding that Monroe’s findings “appear reasonable.” A later Government Accountability Office report in May 2017 would find that Monroe’s review did not conduct “a comprehensive comparison of Trioplex and Singleplex.” Monroe did not respond to written questions from The Post. Frieden, to whom Monroe had reported directly, said he viewed the report as an independent review. It established to his satisfaction, Frieden said, that the CDC acted correctly with Trioplex, including the decision to withhold the test data from the public health labs and other users. “I think it’s very important in public health to share more rather than less,” Frieden said in an interview. “But that doesn’t necessarily mean that you share the results of evaluations that have not been done in a systematic way, that may not be accurate.” [image: image.png] President Trump speaks during a tour of the Centers for Disease Control and Prevention in Atlanta on March 6, flanked by Health and Human Services Secretary Alex Azar, left, CDC Director Robert Redfield, second from right, and Stephan Monroe, the CDC’s associate director for laboratory science and safety. Monroe reviewed the CDC’s handling of a test for the Zika virus and concluded in September 2016 that the agency had acted prudently and that “it was reasonable” not to share data with public health labs that raised questions about the test’s accuracy. (Jim Watson/AFP/Getty Images) At least seven state and local public labs defied the CDC’s original directive and continued to use Singleplex, according to scientists familiar with the matter and CDC records. Among them were the central labs for the states of New York, Maryland, Florida, Massachusetts and New Jersey. Burwell, now the president of American University, declined through a spokeswoman to be interviewed. The CDC eventually tried to improve Trioplex’s sensitivity. On Sept. 21, 2016, the FDA approved a CDC-requested change to Trioplex, telling lab officials nationwide that they could try to boost its sensitivity by first extracting higher volumes of genetic material from samples of blood or urine. The samples would then be analyzed in the PCR machines. But few of the labs had the specialized instruments necessary for the larger extractions, according to scientists familiar with the matter, including Busch, who had warned in April about Trioplex’s sensitivity. The CDC’s modification of Trioplex, Busch said, “didn’t really fix the problem.” Within days of the change to Trioplex, the CDC’s request for emergency funding to counter Zika was granted: On Sept. 28, 2016, Congress passed a spending measure that included $1.1 billion of the $1.9 billion that Frieden had for months sought on the Obama administration’s behalf. A total of $394 million wound up going to the CDC. Meanwhile, in a dynamic that would be repeated this year with the coronavirus, many state lab officials privately fumed over the CDC’s handling of Trioplex, afraid to speak out because their operations depended on funding from the agency. [image: image.png] Tom Frieden, then director of the Centers for Disease Control and Prevention, walks through the agency’s Emergency Operations Response center in Atlanta in 2014. Frieden led the CDC’s response to Zika in 2016 and defended the agency’s testing for the virus. (Michel du Cille/The Washington Post) But in an extraordinary plea on Oct. 14, 2016, the presidents of three organizations representing government and commercial scientists urged the CDC to release data that would illuminate Trioplex’s “performance characteristics.” The presidents, PhD scientists Susan E. Sharp, Charles E. Hill and Alexandra Valsamakis, represented the American Society for Microbiology, the Association for Molecular Pathology and the Pan American Society for Clinical Virology, respectively. Their letter <https://www.amp.org/AMP/assets/File/position-statements/2016/CDC_Zika_testing_letter.pdf?pass=80>noted that “comparative studies of the Trioplex and Singleplex . . . suggest that Trioplex is significantly less sensitive than the Singleplex assay.” “The lack of access to all data regarding test performance of these assays prevents laboratory professionals from making informed decisions about which test to adopt or recommend. Access to these data would provide transparency and allow for optimal patient care.” On Jan. 12, 2017, 10 months after the rollout of Trioplex, the CDC informed users of the test that they could discard the non-Zika components of Trioplex. This essentially reduced Trioplex to the original Singleplex test. In the end, Zika did not inflict widespread harm within the United States. Reported Zika infections — mostly among returned travelers — totaled 5,168 in 2016 before declining to 452 in 2017, 74 in 2018 and just 22 last year, according to CDC records and interviews. Lanciotti retired in December 2018, after 29 years with the CDC. *This story has been updated to include comment from HHS.* Alice Crites contributed to this report.