Abstract
Objectives:
The Laboratory Response Network (LRN) consists of US and international laboratories that respond to public health emergencies, such as biothreats. We used a qualitative approach to assess the successes and challenges of the LRN during the initial 10 weeks of the 2022 mpox outbreak (May 17–July 31, 2022).
Methods:
We conducted 9 unstructured interviews, which included 3 interviews with subject matter experts from the Centers for Disease Control and Prevention (CDC) and 6 interviews with state and local public health laboratories and epidemiologists and Association of Public Health Laboratories (APHL) staff. We asked guiding questions on investments in preparedness, successes, and challenges during the initial mpox response and asked for suggestions to improve future LRN responses to infectious disease outbreaks. We also reviewed data from 2 contemporaneous APHL surveys conducted in June and July 2022 in 84 LRN public health laboratories.
Results:
Notable successes included availability of an assay that had received clearance from the US Food and Drug Administration (FDA) for testing orthopoxviruses (non-variola Orthopoxvirus [NVO] assay) and a trained workforce; strong relationships among FDA, CDC, and the LRN; and strong communications between LRN laboratories and CDC. Challenges included variability among LRN laboratories in self-reported testing capacity, barriers to accessing the NVO assay for health care providers, and gaps in LRN function during surges of testing needs.
Conclusions:
The LRN system plays an essential role in the response to emerging infectious disease outbreaks in the United States. Lessons learned from the LRN’s initial response to the mpox outbreak can help guide improvements to better position the LRN for future responses, including continued engagement with health care providers, commercial laboratories, and laboratories in health care settings.
Mpox (formerly monkeypox 1 ) is caused by an infection with mpox virus, from the genus orthopoxvirus. Before the 2022 outbreak, most documented cases of mpox in people outside of Africa were linked to travel to mpox-endemic countries or contact with imported animals.2-4 On May 6, 2022, an mpox outbreak was confirmed in the United Kingdom.2,4 In the months that followed, mpox spread to 103 nonendemic countries. During the 2022 outbreak, most reported cases were among people who identified as gay, bisexual, or men who have sex with men. However, anyone who has been in close contact with someone who has mpox is at risk. 4
On May 17, 2022, the Massachusetts Department of Public Health notified the Centers for Disease Control and Prevention (CDC) of a suspected case of mpox, following testing by the Massachusetts State Public Health Laboratory, which used the non-variola Orthopoxvirus (NVO) assay, in collaboration with the CDC Laboratory Response Network (LRN). 5 CDC laboratories confirmed the mpox diagnosis. From May 17 through July 5, 2022, all mpox testing with the NVO assay (hereinafter “mpox testing”) for suspected mpox was performed through the LRN. On July 15, CDC published a report outlining the steps taken in the initial LRN response to scale up testing access. From May 17 through June 30, 2022, LRN laboratories tested 2009 specimens; the positivity rate was 36.3% (730 specimens for 395 patients). 5
To increase mpox testing capacity at the local and national level, CDC gathered data and worked with the US Food and Drug Administration (FDA) to submit an application for 510(k) clearance within 3 weeks of the first case, 6 allowing for the use of automated extraction methods and another real-time polymerase chain reaction (PCR) instrumentation with the NVO assay. An FDA 510(k) is a premarket submission to FDA that demonstrates that a test (or device) is safe, effective, and substantially equivalent to a test (or device) with an FDA premarket approval. 6 Within 6 weeks of the outbreak, 10 additional LRN laboratories validated the NVO assay to expand testing capability within 6 weeks of the outbreak. With CDC and FDA support, the NVO assay was deployed to 5 commercial laboratories; 1 commercial laboratory began offering the NVO assay for mpox testing on July 6, 2022, with the others offering the NVO assay later, increasing weekly US testing capacity to approximately 80 000 specimens (Figure 1).3,5 CDC also used its Health Alert Network to quickly disseminate information to health care providers and public health colleagues. 7
Timeline of mpox response activities by the Laboratory Response Network (LRN), United States, May 17–July 31, 2022.
Description of Program Being Evaluated
The LRN was established in 1999 to ensure a robust nationwide laboratory infrastructure that can respond quickly to biothreats (LRN-B) and chemical threats. This evaluation focused on LRN-B reference laboratories (referred to hereinafter as the LRN). The LRN is a collaboration among federal agencies, state and local public health partners, the US Department of Defense (DOD), and public health laboratories. The network includes partnerships with clinical and commercial laboratories to ensure connections at multiple laboratories within each LRN jurisdiction. The LRN network comprises approximately 120 state and local public health, military, veterinary, agriculture, food, and environmental laboratories. 8 The NVO real-time PCR primer and probe set (NVO assay) have been available to the LRN since 2005, when it was first granted 510(k) clearance by FDA. 6 Before the 2022 mpox outbreak, 68 LRN laboratories in 47 US states had established proficiency to perform the NVO assay. 5
CDC funds activities in the LRN that maintain public health laboratory capacity for responses to biothreats and emerging disease outbreaks. Eighty-four LRN laboratories maintain a biosafety level 3 (BSL-3) suite, allowing for laboratory scientists to safely test for biological threats.9,10 LRN laboratories consistently work with clinical laboratories within their jurisdictions to ensure relationships are established before outbreaks.
Purpose of the Evaluation
We aimed to identify the successes and challenges of the LRN during the initial 10 weeks of the public health response to the 2022 mpox outbreak (May 17–July 31, 2022) through a qualitative approach to understand the implications for future public health emergencies.
Methods
We conducted unstructured interviews with public health colleagues (interview participants) in August and September 2022 via Microsoft Teams. The interviews lasted 30 to 45 minutes and were facilitated by CDC staff. Interviewers used 4 broad questions as discussion guides, and notes were taken during each session:
What investments in preparedness supported the initial mpox response?
What were some of the main successes in the first 10 weeks of the mpox response?
What were some of the main challenges in the first 10 weeks of the mpox response?
How can the LRN improve its response to future infectious disease outbreaks?
For the interviews, we enlisted 7 CDC subject matter experts on poxviruses and emergency response, 15 staff from 5 state and local public health departments including epidemiologists and laboratory scientists, and 3 staff from the Association of Public Health Laboratories (APHL) who work closely with the LRN (Table 1). We invited epidemiologists, laboratory scientists, and other public health representatives and selected external participants with diverse viewpoints from public health departments that were heavily affected and directly involved in the mpox response.
Description of participants in unstructured interviews and respondents to surveys conducted by the APHL in a qualitative evaluation of the LRN during the initial mpox outbreak response, United States, May 17–July 31, 2022 a
Abbreviations: APHL, Association of Public Health Laboratories; CDC, Centers for Disease Control and Prevention; LRN, Laboratory Response Network.
Unstructured interviews were conducted in August and September 2022 by staff from CDC via Microsoft Teams. Surveys were conducted at APHL (by T.W.). Surveys were distributed via email to LRN laboratories, and survey responses were collated by APHL.
We also reviewed the results of 2 surveys conducted at APHL (by T.W.): the first on June 28, 2022, with 84 LRN laboratories and the second on July 25, 2022, with 83 LRN laboratories (Table 1). Surveys were distributed via email to LRN laboratories, and responses to surveys were collated by APHL. The surveys focused on laboratory capability and capacity to conduct mpox testing and challenges to testing capacity.
CDC, per the Paperwork Reduction Act of 1995 and the Office of Management and Budget, determined that ethical clearance was not required because fewer than 10 interviews with external partner organizations were included in the evaluation. 11
Results
Discussions with interview participants (n = 9), which included 3 interviews with subject matter experts from CDC and 6 interviews with state and local public health laboratories and epidemiologists and APHL staff, informed the most notable successes and challenges affecting the LRN’s initial 10-week response to the mpox outbreak in the United States (Table 2; Figure 2).
Successes and challenges of the Laboratory Response Network (LRN) during the initial mpox outbreak, United States, May 17–July 31, 2022 a
Abbreviations: APHL, Association of Public Health Laboratories; BSL-3, biosafety level 3 suite; CDC, Centers for Disease Control and Prevention; FDA, US Food and Drug Administration; LIMS, laboratory information management system; PCR, polymerase chain reaction.
Interview participants included internal CDC subject matter experts on poxviruses and emergency response, staff from state and local public health departments including epidemiologists and laboratory scientists, and staff from APHL who work closely with the LRN (Table 1). Unstructured interviews were conducted in August and September 2022 by staff from CDC via Microsoft Teams.
Two surveys were conducted by APHL: the first on June 28, 2022, with 84 LRN laboratories, and the second on July 25, 2022, with 83 LRN laboratories. Surveys were conducted at APHL (by T.W.). Surveys were distributed via email to LRN laboratories, and survey responses were collated by APHL.
National testing volume and testing capacity for mpox using the non-variola Orthopoxvirus (NVO) test in public health laboratories in the Laboratory Response Network (LRN), United States, May 17–July 30, 2022.
Investments in Preparedness and Regulatory Environment
Successes
According to the APHL survey, 78 of 84 LRN laboratories (93%) had the capability to perform the NVO assay.
Survey respondents cited previously established relationships with the LRN and various hospital and clinical partners as a success. These hospital and clinical partners had experience with ordering mpox tests run by the LRN, public health consultations, and specimen shipping and handling with the LRN. Some LRN partners had already established electronic test ordering and reporting systems.
Challenges
Several interview participants noted that, despite prior preparedness investments, the LRN lacked adequate resources to simultaneously respond to multiple infectious disease threats. Interview participants described how the LRN program relied on supplemental funding provided during emergency responses to maintain readiness. Interview participants noted that the COVID-19 response had already taken a toll on the public health workforce when the demand occurred for mpox testing.
According to the APHL survey, 6 of 84 (7%) responding LRN laboratories did not have NVO testing capability at the onset of the outbreak. Survey respondents indicated that reasons included lack of trained, available staff and reagents.
Although CDC and FDA successfully updated the FDA-cleared NVO assay to expand capacity and improve processes, interview participants indicated that the effort to obtain FDA clearance took an extraordinary amount of staff time to complete amid an emergency response. Collecting additional validation data from CDC, the LRN, and commercial laboratories was required to secure enforcement discretion from FDA to allow for continued testing; subsequently, amendments to the assay were submitted to FDA for clearance.
Mpox Testing Capacity
As the pace of the outbreak increased during June and July 2022, the public, clinical community, and government leaders had concerns about mpox testing capacity and access. Efforts were made to expand testing capacity to ensure demand would not exceed supply.
Successes
Based on self-reported estimates of mpox testing capacity in LRN laboratories through the APHL surveys, testing capacity increased nationally from approximately 8000 tests per week early in the outbreak to 24 000 tests per week by June 30, 2022. Overall, the average self-reported in-laboratory turnaround time was 24 to 48 hours throughout the mpox response. The APHL surveys showed that the average turnaround time from sample collection to results reporting to health care providers was 34.5 hours during the week of June 20, 2022. Additional follow-up from APHL showed that the turnaround time in 5 LRN laboratories in jurisdictions heavily affected by the mpox outbreak ranged from 39 to 66 hours from June 30 through August 31, 2022. Interview participants shared that the increased turnaround time was likely because of inclusion of time from specimen collection, an increased volume of testing in jurisdictions with larger outbreaks, and possible shipping delays to public health laboratories.
APHL survey results showed that demand for mpox testing nationwide during the initial 10-week mpox response was <10% of available LRN testing capacity. However, the demand nearly met LRN capacity in some jurisdictions heavily affected by mpox. Five LRN laboratories in jurisdictions heavily affected by the mpox outbreak self-reported in the APHL surveys that their combined testing surge capacity was approximately 1500 specimens per week from June 30 through July 11, 2022, a period during which laboratories were receiving nearly 1000 specimens per week. Respondents to the APHL survey reported an average internal surge capacity of 315 specimens per week, with wide ranges in laboratory capacity of 15 to 3000 specimens per week.
Interviewees noted that CDC immediately invested in the manufacturing and procurement of reagents to support mpox testing in LRN laboratories. CDC procured required reagents for mpox testing and made them available in its International Reagent Resource distribution system, eliminating private sector procurement demands from LRN laboratories.
Challenges
Interviewees noted that, with the initial LRN protocol for the NVO assay relying on a manual, time-consuming extraction process performed in BSL-3 facilities at the beginning of the public health response, capacity was stretched in heavily affected jurisdictions, limiting initial mpox testing capacity. Interview participants also noted a lack of clarity on biosafety requirements. In response to 2 questions on biosafety practices in the July APHL survey, 63 of 79 laboratories responded that the inactivation of specimens was performed in BSL-3 spaces. Of the 63 respondents, 38 not only inactivated but also performed mpox testing in BSL-3 spaces. Despite the updated NVO assay and guidance for inactivation and testing, which allowed for automated extraction to be safely conducted in BSL-2 spaces, several laboratories continued to perform mpox testing using BSL-3 practices. Performing testing with BSL-3 practices is more time and resource intensive, as additional safety precautions need to be met. 10
Mpox Testing Accessibility
Interview participants noted that a robust response to the mpox outbreak required assessing and improving accessibility to the NVO assay for mpox testing for health care providers and patients.
Successes
Interview participants noted that implementation of the NVO assay in commercial laboratories, as facilitated by CDC and FDA, offered a convenient and familiar path for health care providers to access this test. However, interview participants had conflicting comments about commercial laboratory support for mpox testing with the NVO assay. One interview participant shared that their laboratory was backlogged because of manual extraction procedures and that having commercial laboratories was extremely helpful. Other interview participants noted that they did not think it was necessary to add commercial laboratories and that their public health laboratory maintained sufficient capacity to meet mpox testing needs in their jurisdictions. We noted considerable variability among interview participants in perceived need to increase accessibility to the NVO assay.
Challenges
Despite availability of the NVO assay and increases in LRN capacity, interview participants perceived inadequate capacity for mpox testing and barriers to accessing the NVO assay, such as gaps in familiarity with the LRN. Responses to the APHL surveys showed that investments in data modernization to implement and improve data systems that are connected, adaptable, and sustainable, thereby improving efficiency and timeliness for public health, were underway; however, some LRN laboratories did not yet have electronic ordering and reporting systems available to health care providers during the initial mpox outbreak. The lack of electronic ordering and reporting processes in LRN laboratories resulted in time-consuming processes to manually transfer data for reporting to public health departments and CDC. The reporting of mpox test results was also affected by the limited number of LRN laboratories with electronic laboratory reporting (ELR); only 17 LRN laboratories could report results directly from their laboratory information management system (LIMS) by ELR for mpox at the start of the outbreak, with 12 laboratories implementing this capacity during the outbreak. Survey respondents reported using 3 methods to report results to CDC, with some using multiple methods. Survey respondents also listed fragmented data systems as a challenge in this response.
Because health care providers do not typically work with the LRN, interview participants who were health care providers stated that they were unfamiliar with the processes to access testing. The LRN requires health care providers to work with public health epidemiologists to evaluate unusual cases, complete forms, and submit specimens for testing. Mpox cases presented and transmitted in a novel way, with patients not only accessing care through primary care providers and emergency departments but also sexual health clinics; therefore, test requests were often from clinicians who were not familiar with the LRN or public health processes for test requests, which caused confusion in how to request testing. Interview participants noted that, while they were learning about mpox, they were also learning the process to work with the LRN, creating frustration on both sides. The APHL survey showed that LRN laboratories used various methods to report results to health care providers and public health departments, including by telephone, fax, LIMS/ELR, and postal mail.
Interview participants who were health care providers noted that they sometimes sent patients with mpox to local emergency departments, urgent care clinics, or infectious disease specialists because of concern or confusion about CDC guidance on specimen collection. This practice of sending patients elsewhere resulted in delays in testing.
LRN and Partner Relationships
Successes
Interview participants noted that partnerships among CDC, APHL, state and local public health departments, DOD, and health care providers have strengthened the LRN and were an asset to the mpox response. CDC also leveraged relationships with FDA, commercial laboratories, and manufacturers to rapidly expand mpox testing capacity and accessibility. APHL provided support by managing questionnaires with the LRN and providing timely data to CDC to answer questions and support the response. In addition, CDC established weekly calls to disseminate information, answer questions, and allow laboratories to exchange knowledge. Partners also pointed to the gatekeeping function of state and local public health epidemiologists as critical components of the early mpox response. Because LRN laboratories were testing for a rare infection and because testing among people with a low likelihood of infection results in an elevated risk of false-positive results, communication about testing criteria from CDC and public health departments, including the public health laboratory, was vital to ensuring that mpox testing capacity in the LRN was used for those patients who urgently needed testing. Interview participants also cited updates provided through CDC’s Health Alert Network as critical to the response.
Challenges
During the initial 10-week mpox response, some LRN laboratories noted that they worked well with other LRN laboratories in their state or between states to share testing demands, but some interview participants noted challenges in providing testing support to other LRN laboratories. Challenges occurred because of differing state, local, and jurisdictional policies that govern how laboratories can accept specimens from other jurisdictions. In addition, some LRN laboratories did not have electronic reporting processes for specimens sent to or tested by other jurisdictions, creating challenges in reporting results. Staff burnout from other outbreak responses such as the COVID-19 pandemic made some LRN laboratories hesitant to offer support when a previous relationship did not exist.
As noted in interviews, communication challenges frustrated health care providers and public health colleagues during the initial response to the mpox outbreak. Because cases of mpox in the United States were rare before this outbreak, guidance on mpox specimen collection and testing needed to be revised as additional information became available. Although CDC distributed information to LRN laboratories and through clinician communication channels, interview participants indicated that health care providers and patients were confused about access to mpox testing.
Interview participants noted that CDC guidance was often unclear early in the response. Some interview participants received conflicting guidance from different CDC subject matter experts. Interview participants emphasized the importance of having clear information and tools available online.
Lessons Learned
The past few years have demonstrated the need to strengthen the US public health system, including public health laboratories. 12 Given that the mpox response was the first outbreak response after the onset of the COVID-19 pandemic, we incorporated lessons learned from the COVID-19 pandemic to improve the mpox response. One facilitator of the swift response from LRN laboratories was the availability of an FDA-cleared assay and a trained workforce to conduct mpox testing. In addition, many of the actions during the initial mpox response were based on the COVID-19 response. At the onset of the mpox outbreak, CDC worked with vendors to ensure the availability of necessary equipment, reagents, and consumables. To alleviate procurement demands for each LRN laboratory, CDC collaborated with the International Reagent Resource to ensure that a consistent inventory of reagents was available for the LRN to carry out testing. Staff also worked to increase testing capacity by partnering with commercial laboratories. Finally, CDC LRN program staff held weekly meetings with LRN laboratories to share information, discuss challenges, and answer questions.
The LRN is an integral part of the national preparedness and response infrastructure. Based on the successes and challenges discussed with public health colleagues, we propose the following recommendations for the LRN’s continued engagement in future outbreaks.
• Sustain infrastructure support: Increase and sustain public health laboratory infrastructure, including ensuring redundancies in equipment necessary during the testing processes, ensuring adequate reagent supplies, and having up-to-date training.
• Update and exercise LRN surge plans: Ensure that a scalable surge plan for the LRN is in place for response. Updated surge plans outline the course of action when a new disease arises, with standardized processes and systems. It is important for the LRN to preidentify laboratories that can provide surge support in the event of the outbreak. Updated plans should outline the role of the LRN and metrics to indicate when a surge to commercial or academic laboratories is needed. This effort should include actions to strengthen the connections with clinical and commercial laboratories.
• Update approved protocols: LRN protocols should be reviewed and updated to include automated extraction methods when appropriate. Updating protocols to use automated extraction can include expanding capability to detect a range of emerging infectious diseases with specific assays.
• Modernize data systems: As part of data modernization of public health laboratories, electronic test ordering and reporting should be implemented across the LRN to facilitate accessibility of testing and avoid errors through manual processes.
• Increase training for laboratory staff, health care providers, and public health colleagues: Proactive steps to provide training on working with the LRN could help to build relationships with public health agencies and health care providers before the occurrence of another outbreak and improve test accessibility.
• Improve communication and relationships: Improving communication among CDC, LRN member laboratories, and health care providers could reduce misperceptions and provide critical testing guidance during outbreak responses. As one component of this effort, the LRN secure website can be improved to better support communication. Additional relationships are needed to help the LRN operate optimally. The LRN is meant to operate as a network. In theory, member laboratories can reach out to nearby member laboratories for testing support when their testing capacity is exceeded.
Limitations
This study had several limitations. First, in interviews conducted by CDC, the number of interview participants included (n = 9) and time for each interview (30-45 minutes) were limited. The sample size was intentionally small to produce a timely report, and the time for each interview was intentionally limited to accommodate schedules and multiple competing demands on our public health colleagues. Second, although the interviews captured key themes similar to the larger APHL survey, results could have been strengthened by including perspectives from others, including clinical and hospital partners. Because of limited time to gather timely data for the time frame of the initial mpox response (May 17–July 31, 2022), we were not able to interview non–public health partners. Third, this evaluation focused on only the first 10 weeks of the outbreak and did not capture information on improvements made or challenges faced later in the outbreak.
Conclusion
The LRN serves as a national system for biothreat preparedness and response. Although preparedness investments allowed the LRN to detect the first mpox case in the United States and to serve as the sole source of mpox testing for the first approximately 7 weeks of the 2022 outbreak, the response highlighted opportunities to improve the LRN to meet the needs of emerging infectious disease outbreaks.
Discussions with public health colleagues highlighted several ways for the LRN to improve and evolve, including strengthening the ability to conduct surge testing within the network. Although some lessons learned from the COVID-19 pandemic response were applied to the mpox response, challenges remain to avoid shortcomings in future outbreak responses. Testing readiness for future responses will require a systematic approach that expands engagement with health care providers, commercial laboratories, emergency departments, and health clinics as well as with the LRN and public health departments and laboratories. Although the LRN has been expected to quickly identify a single case or small cluster caused by a rare pathogen, pressure is increasing for other partner laboratories to provide access to diagnostic testing services and to rapidly report results for every public health disease outbreak. Challenges identified during the mpox outbreak response provide a roadmap for modernizing the LRN to advance its position and expand response preparedness to future infectious disease threats.
Footnotes
Acknowledgements
We express our gratitude to several CDC colleagues for their contribution to this article, namely, John Brooks, MD, Jasmine Chaitram, MPH, Bruce Furness, MD, MPH, Christina Hutson, PhD, MS, CAPT Jennifer McQuiston, DVM, MS, Victoria Olson, PhD, and Reynolds Salerno, PhD. Their expertise and insights were invaluable in the completion of this work. We also thank our partners from various LRN jurisdictions, including the New York City Department of Health and Mental Hygiene, the Illinois Department of Public Health, the Los Angeles County Department of Public Health, the Texas Department of State Health Services, and the DC Department of Health. Finally, many thanks to Scott Becker, MS, Ewa King, PhD, and Chris Mangal, MPH, from APHL and all participating LRN laboratories and staff who responded to the APHL surveys for their contribution to this project and years of collaboration with CDC on the LRN.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Disclaimer
The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of CDC.
