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Testing for H1N1 Flu during Surge Stresses Many U.S. Clinical Labs

 

H1N1, declared pandemic in June, continues to circulate, prompting planning for its anticipated resurgence in the months ahead

Jeffrey L. Fox
Jeffrey L. Fox is the Microbe Current Topics and Features Editor.

Summary

● The World Health Organization (WHO) designated H1N1 influenza a pandemic viral strain in June and, by early July, tabulated more than 94 thousand cases worldwide and 429 deaths, with cases unevenly distributed among more than 100 nations.

● The fast-developing H1N1 pandemic, although not uniformly virulent in its impact, is causing plenty of stress on public health and personal healthcare-delivery systems, including at clinical labs that faced a huge demand for viral testing.

● Officials at the U.S. Centers for Disease Control and Prevention tabulated nearly 34,000 U.S. cases of H1N1 flu and 170 deaths by early July, but they estimate that more than 1 million Americans were infected by the new strain.

● The impact of H1N1 varied widely as it moved across the country, and experiences among clinical laboratories also varied greatly from state to state and within similar communities.


The first two U.S. cases of H1N1 influenza in San Diego last April were barely noticed. Soon, however, a surge of such cases hit Mexico, mainly near Mexico City, quickly contributing via returning visitors to another surge in metropolitan New York. For the next several months, similarly unseasonable outbreaks of H1N1 were being reported throughout the United States, Mexico, Canada, and, soon, Europe and Asia, and then much of the rest of the world.

Thus, by mid-June, officials at the World Health Organization (WHO) designated H1N1 influenza a pandemic viral strain and, by early July, tabulated more than 98,000 cases worldwide and 429 deaths from this flu strain, with cases unevenly distributed among 137 countries and territories. Even as H1N1 was receding in the north, however, flu case numbers were on the rise in Argentina, Australia, Chile, and elsewhere in the Southern Hemisphere, where winter and the "regular" influenza season were beginning.

In July, WHO officials moved away from recommending comprehensive clinical testing and typing for H1N1. "For countries which are having cases, we will be recommending that they begin to move away from trying to laboratory test all individual cases and really move towards larger national indicators of disease-for example, following influenza- like illnesses, pneumonia cases, and so on," said Keiji Fukuda, Assistant Director- General of WHO during a press briefing. This change "will ease the burden on the laboratories and make testing much less of a chore than it has been. . . . In countries that do not have cases, however, we will be continuing to recommend that people who are suspected to have pandemic influenza be tested so that the presence of this virus can be confirmed."

Even as clinical microbiologists, physicians, and public health experts look back on their experiences in coping with sporadic but in some regions heavy and, often for the young and otherwise healthy, deadly outbreaks of this flu strain, many were left wondering what to expect when influenza season returns later this year to
the Northern Hemisphere. Amid other preparations for the anticipated resurgence, clinical microbiologists will be recalibrating guidelines for H1N1 testing, while other experts work through plans to develop and administer appropriate vaccines, while also building stockpiles of antiviral agents.

New York City and Mexico City Affected Early

This fast-developing H1N1 pandemic, even though not uniformly virulent in its impact, is causing plenty of stress on public health and personal health care delivery systems in many of the places it lands. Moreover, during early outbreaks where it hit hardest, it put some U.S. clinical microbiologists under virtual siege as they scrambled to keep up with ballooning numbers of tests and a huge demand on their time and energies, according to Christine Ginocchio, Director of Microbiology/Molecular Diagnostics at the North Shore Long Island Jewish Health System Laboratories in Great Neck, N.Y. She participated in a special late-breaking session focused on U.S. and Mexican responses to the recent H1N1 outbreak, convened during the 109th ASM General meeting, held last May in Philadelphia, Pa.

The first wave of H1N1 cases in Mexico had peaked by 26 April, a few days after the country instituted a nationwide "contingency" plan, severely restricting public activities with the aim of curtailing spread of the virus, according to special session participant Edmundo Calva of the Institute of Biotechnology in Cuernavaca, Mexico. Most of the cases involved young people in Mexico, and the greatest numbers of deaths fell among those between 20 and 29 years of age, he says. The apparent death rate was 2.7% of cases, and the transmissibility factor for this strain was 1.4.

foxfig1Although the fast-moving H1N1 outbreak in and near Mexico City gained worldwide attention in April, the first confirmed U.S. case also came in mid- April, according to Joseph Miller, chief laboratory preparedness officer for the influenza division at the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga., who participated in the ASM special session via telephone. By 5 June, CDC tallied 13,217 confirmed H1N1 cases and 27 deaths. By July, CDC officials had tabulated nearly 34 thousand U.S. cases of H1N1 flu and 170 deaths. However, officials estimated that more than 1 million Americans were infected with H1N1, with most of them not tested and only mildly affected.

Thinking Strategically about H1N1 and Anticipating Its Resurgence

Some experts are wondering whether H1N1 "will come back," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, National Institutes of Health in Bethesda, Md., who spoke at another forum on this strain of influenza, convened by the American Association for the Advancement of Science (AAAS), and held in Washington, D.C., early in July. However, he points out, "It hasn't left yet. We need to prepare for when children come back to school."

Some of that preparation entails development, testing, and scaled-up production of a vaccine, or vaccines, with which to protect the population against this new influenza strain along with other circulating strains. Another important component of getting ready for the autumn and winter flu season is to map a practical strategy for influenza strain testing and typing that addresses both public health and patient care needs, according to Anne Schuchat, U.S. Assistant Surgeon General and director of the National Center for Immunization and Respiratory Diseases at CDC, who also spoke during the July AAAS forum.

"The issue of testing is really relevant," Schuchat says. "There are balances to be struck [in terms of] what individuals need and what we have to do to meet public health needs. We're looking for a systematic sampling framework [because] we don't have a point-of-care test for H1N1." Many state and local public health laboratories and some hospitals are set up to do definitive PCR testing to type the H1N1 virus in specimens collected from patients. However, their aggregate capacity is nowhere near great enough to conduct universal testing, and coping with that shortfall is but one of several areas for which public health officials are being called on to develop strategies for flu outbreaks that could challenge available resources.

Coping with-Sometimes Triaging-Early Surge of Flu Tests

At least during the earliest stages of the 2009 H1N1 pandemic, information about viral spread depended on other than conventional circuitries, according to Ginocchio of the North Shore Long Island Jewish Health System Laboratories. "Facebook messages started flying." Thus, students in New York, many just back from spring breaks in Mexico, quickly notified friends electronically who was sick. That unfettered surge in e-mail traffic was an unusual early alert that came shortly before the more conventional surge hit nearby emergency rooms and clinical labs, which were faced with the task of doing more definitive testing of specimens from students, family members, and others with whom they had contact.

Thus, late in April, many clinical labs in metropolitan New York were hit with a surge of requests for flu tests, quickly pushing them into an emergency mode, according to Ginocchio. While students in the communities around them feverishly exchanged Facebook messages, the labs relied on stepped-up conference calls that included local and state public health officials as well as those at CDC, she says. The volume of flu tests per day shot up from dozens to 900 on one late-April day, while the lab was besieged with phone calls, sometimes 150 per day. Specimens were being triaged, supplies were ordered and reordered, and extra funding was authorized on a near-miraculous hurry-up basis. Meanwhile, extra lab space was carved from former office space that was gutted and then outfitted with benches, safety hoods, vacuum lines, and other necessities during the course of one very busy weekend. "It's amazing what an outbreak will do," she says.

By the middle of May, the lab group had done 10,000 tests in the space of about one month, Ginocchio continues. That testing placed "a huge burden on the lab," as did the collateral responsibilities, particularly fielding a surge in phone inquiries from many sources, including other labs, doctors, patients, families, and news media. Although a substantial fraction of testing was on specimens from the approximately 2,500 individual patients who came through the emergency department, the great bulk of testing was on specimens from the "worried well," she says. The main population group then testing positive consisted of 11- to 20-year-olds plus their younger siblings, a pattern that was consistent with these New York cases stemming mainly from young students returning infected with H1N1 flu from Mexico.

The respiratory virus panel (RVP) test provided the "best diagnostic option," according to Ginocchio and her collaborators. The RVP test showed "superior" sensitivity for all influenza strains, including H1N1, and "identified a significant number of additional respiratory pathogens." Meanwhile, rapid antigen testing had the lowest sensitivity, while the direct immunofluorescence assay (DFA) was intermediate.

A Glimpse at Varied H1N1 Clinical Testing Experiences within California

"We're not all blessed with the resources of that lab," says Ellen Jo Baron of Stanford University Medical Center in Palo Alto, Calif., referring to Ginocchio's experience in marshalling resources to deal quickly with the H1N1 surge in New York. For other reasons, Baron and her colleagues brought a different testing perspective in their initial dealings with H1N1. "We had stopped doing rapid antigen tests for respiratory viruses because of earlier difficulties, including high numbers of false-positive results," she says. "People said maybe we should bring it back when [H1N1] flu hit, but I said ‘no,' and that proved a lucky decision."

Because the Stanford clinical lab is not set up for routine PCR testing, "we were left with two options," Baron continues. "Send everything to the county or do our own DFA testing and send the positives for confirmation, which [the latter option] is what we did." Near the end of April, she says, "We were doing DFAs all day long. During the week of April 27, we did 250 samples, while the week before we did only 50."

However, this high-volume testing soon abated when county public health officials advised testing specimens only from those "most serious" cases. In general, the DFA "performed very well," she says. "We don't think we missed any. . . . DFAs are not done by a lot of labs, and you need experienced people to do them well. We'd do PCR if it were easier and less expensive and didn't demand a ton of labor."

During this period of intensified H1N1 testing, the "emerging infectious disease command center committee" at Stanford convened daily, set up a special website, and was poised to keep testing as well as other components of flu patient care operating in high gear, according to Baron. "We had a lot of surge materials on hand, and had a special emergency unit ready for ‘respiratory' patients," she says. "We were in good shape. We ran out of swabs but had other supplies ready, and our vendors had reagents in their warehouses ready to ship; it was amazing."

However, the situation at a nearby community hospital proved very different, even if the overall effects of the H1N1 outbreak were similar to those at Stanford, according to clinical microbiologist William Horbaly of O'Connor Hospital in San Jose, Calif. Of H1N1 itself, he says, "It's nasty, and we're seeing a lot of it." Late in June, he noted, "There are two people from the lab who are out with it." During a typical wintertime flu season, his hospital lab may do 160 rapid antigen tests per week. Although seasonal flu had subsided, the lab was doing close to that number late in June when H1N1 was causing outbreaks throughout California, with "quite a few positive," he says. "It's summertime, and it's not letting up."

Unlike Baron and her colleagues at Stanford, Horbaly and his colleagues "can't do DFAs," he says, adding: "I am extremely unhappy with the rapid tests, but we have no choice. Here, the emergency room (ER) doctors see every patient. There is no triage." When symptoms implicate flu, "every patient has a rapid flu test, and then we send the positives to the local public health lab for more testing. We were only getting about 20% positive, and I was worried we were missing a lot," he says.

When Horbaly heard about Ginocchio's comparative evaluation indicating that the rapid tests have very low sensitivity, "it blew me out of the water," he says. "I think it's unethical to offer those tests." One saving grace is that his group works closely with the hospital ER staff to make sure specimens are collected properly and tested very quickly. "Maybe that helps us get a higher rate of positives," he says.

Meanwhile, Rangaraj Selvarangan, who directs the Microbiology Laboratory at Children's Mercy Hospital in Kansas City, Mo., is conducting a survey via ClinMicroNet, asking microbiologists who are members of ASM Division C to provide information that he will use to develop a more comprehensive picture of how different viral tests performed during the recent H1N1 outbreak. "I have posted the survey . . . and received over 100 responses" as of mid-July, Selvarangan says. He expected to tabulate the survey and report its findings within a few months, possibly during the 49th ICAAC in San Francisco.

H1N1 Impact and also Clinical Testing Experiences Vary Greatly across U.S.

The rapid influenza antigen test misses "a considerable number of infected patients-less than half of our infected patients yielded a positive rapid test result," says Joseph M. Campos, who directs the microbiology and molecular diagnostics laboratory at Children's National Medical Center in Washington, D.C. "Accordingly we found it necessary to perform the much more sensitive and expensive PCR test . . . on higherrisk patients." He also points out that the surge in testing overwhelmed the ability of some state laboratories to do subtyping tests on a timely basis. "Thus there was a delay in distinguishing seasonal influenza A from novel H1N1, [which] caused our hospital to consider any PCR-confirmed influenza A result as a positive [H1N1] influenza result, which, in fact, was the case for us."

foxfig2"We saw our first positive [H1N1] on April 28, and it was followed by a substantial surge in testing," says clinical microbiologist Nathan Ledeboer of the Medical College of Wisconsin in Milwaukee. During the peak of that surge, the hospital lab was testing as many as 500 specimens per day-"substantially more than the ordinary." Initially, the tests were only about 10% positive, but that figure rose to near 50% soon after physicians got better at discerning what symptoms to heed in deciding which patients to test. By early July, Wisconsin reported 5,861 cases and 4 deaths fromH1N1flu infections, making it the state with the highest number of confirmed cases. For comparison: New York reports 44 deaths among 2,499 cases, the highest number of deaths attributed to this strain of influenza; California, had 21 deaths among 1,985 cases, and Texas 17 deaths among its 3,991 cases.

While Wisconsin was recovering from an early surge of H1N1 flu testing in mid-June, North Carolina was anticipating one, according to clinical microbiologist Melissa Miller of the University of North Carolina (UNC) School of Medicine in Chapel Hill. "We're on the upswing, and now getting about 50% positive tests," she said last June. "We're very prepared, and we have had the luxury of time . . . to beef up our capacity." That anticipated H1N1 surge proved "very mild" in North Carolina, says Peter Gilligan, also at UNC, who spoke with Microbe several weeks later. "We are bracing for the fall, when [H1N1] is likely to be worse than it was this spring. Everyone should get their flu shots this fall." Another concern, he points out, is that circulating methicillin-resistant Staphylococcus aureus, which is an "infrequent cause of an aggressive pneumonia in young people," could coincide with H1N1 outbreaks during the fallwinter flu season to cause a "perfect storm, with lots of deaths. This is a ‘worst-case' scenario, but not unreasonable."

Iowa was also affected only mildly by H1N1, according to Michael Pentella of the University Hygienic Laboratory at the University of Iowa in Iowa City, Iowa. Thus, Iowa had fewer than 100 H1N1 cases as of early July, according to CDC data. Earlier in-state discussions held soon after the first cases of H1N1 were detected in Mexico and California led to an agreement setting strict criteria for collecting specimens, he says. Clinical labs thus served as "gate keepers" for the state lab, and patients had to "meet the criteria for having flu-like symptoms" before confirmatory testing was done. "We avoided [testing for] the ‘worried well' by working closely with our colleagues," he says.

Even with relatively light demands on H1N1 testing compared to other regions of the country, the Iowa lab dealt with supply shortages, including challenges in procuring viral transport media and reagents for PCR tests, Pentella says. "Sometimes we couldn't get enough, but we did get what we needed in a difficult time." At an even more practical level, lab personnel visited local discount superstores when necessary to buy cold packs, and they also sometimes "reused packing materials" for specimens, he says.

In Michigan, clinical microbiologists quickly adopted CDC-recommended testing protocols but also adjusted as needed to the rapidly changing pattern of in-state H1N1 outbreaks, according to Patricia Somsel of the Michigan Department of Community Health in Lansing, whose lab is responsible for doing viral subtype analyses. For instance, one early criterion for subtyping flu specimens-only from individuals who had traveled, particularly to Mexico or New York-was dropped when local outbreaks occurred among individuals who had never left Michigan and had little or no contact with travelers, thus making that stipulation untenable.

Even so, the surge of H1N1 testing in Michigan lasted only about one month, although the lab continued to test for flu subtypes to gather surveillance data, Somsel says. Because its role was to type and confirm other testing, the "high positivity" rate was "skewed, and not terribly representative of the disease burden," she says. Nonetheless, the overall exercise proved valuable, and "there was an intensity not seen since West Nile virus first hit," she adds. "The epidemiologists were poised like dogs at the gate."

Extracting Insights from H1N1 Experiences, Anticipating Next Steps

"There is a near consensus that H1N1 will come back in the fall, and we might see a substantial surge," says Ledeboer of the Medical College of Wisconsin in Milwaukee. The recent scramble to track H1N1 could prove a "game changer" for future efforts to monitor influenza and other human respiratory viruses. Further, he adds, "The public health and clinical ‘world' need to collaborate and communicate. They have different goals, but in these situations, we can get a whole lot more done if we collaborate."

"The spring or ‘herald wave,' has usually been mild when compared to the fall return of a new virus that causes influenza," says Mary Gilchrist, former director of the William A. Hinton Massachusetts State Laboratory Institute in Jamaica Plain. "Are we ready and can we be ready? Does the performance this spring make us complacent when we should be the opposite?"

Clinical labs help to provide "accurate scientific information to guide decision making," Gilchrist continues. For instance, flu testing and typing can help officials when allocating limited resources during a pandemic in situations where residents of one town have seasonal flu, while those in another are infected mainly with the more virulent pandemic strain. Although currently limited antiviral treatment options tend to offset some of the usefulness of clinical testing results, even unreliable tests provide some sense during a full-blown epidemic of where a virus is circulating, other clinical microbiologists point out.

In terms of testing capacity to prepare for the coming flu season, "we have no good idea how much testing might be needed, particularly to address public health versus clinical needs," says Gilligan of UNC. "They are not the same thing." On the public health level, early testing for purposes of surveillance provides a useful picture of how the virus is spreading. However, on the local level in hospitals and physicians' offices, "we don't have a good handle on how much testing doctors and parents will want," he says. "We're also getting [specimens] from places we hadn't imagined, such as prisons. How will such testing be done?"
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"We are sometimes too wedded to our outbreak plan," says Gilchrist. But it is not the plan so much as the "planning" that is important, and there is great value in recognizing when to scrap plans to better deal with changing circumstances. "Strategies to manage the surge are likely to change quickly," says Schuchat of CDC. "Our experiences from the spring are helping to develop guidance for the fall." And, adds Gilligan, "It's an exciting time intellectually. Many people are depending on us to provide the best diagnostic services."

 

 

 

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