CDC Reports Potential Ebola Exposure At Lab

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

# 9485

 

In a late in the day Christmas Eve announcement to the media (as of this writing I’ve not found anything on the CDC website),  the CDC has reported a potential exposure of staff to the Ebola virus at one of their laboratories.  When a full statement becomes a available I’ll post it.  Until then we have this report from NBC News.

 

CDC Reports Possible Ebola Exposure at Containment Lab

A mistake at a CDC biocontainment lab may have exposed one technician, and possibly more, to the Ebola virus, federal health officials said Wednesday.

A sample of material that may have contained the virus was accidentally moved from a high-level containment lab to a lower-level lab this week at the Centers for Disease Control in Atlanta, according to a statement from Sherri Berger, the agency's chief operating officer.

Berger said only one lab technician at the second lab worked with the sample but other staff had contact with the laboratory room where it was processed. The mistake involving a fixed, sealed plate was discovered Tuesday, but by then the sample had been destroyed and the lab decontaminated in routine procedures, Berger said.

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This is unfortunately  the third high-profile mishandling of a select pathogen at a CDC lab this year, with two previous incidents involving anthrax and H5N1 avian flu.  Additionally, smallpox and other dangerous pathogens were found improperly stored at an FDA lab earlier this year (see FDA Statement On Additional 300 Vials Discovered At NIH Campus Lab).

 

Over the summer these incidents led to calls for stricter controls on laboratories, a Laboratory Bio-Safety Backlash, and house subcommittee hearings (see House Subcommittee Hearing on Biosafety). 

The CDC responded to these incidents by temporarily halting the transfer of select pathogens between labs, conducting an extensive internal review, and promising new, more stringent safety protocols (see CDC H5N1 Incident & Lab Safety Progress Reports).

 

CDC Director Dr. Thomas Frieden  is quoted today as saying he is troubled by this most recent incident, stating `"I have directed that there be a full review of every aspect of the incident and that CDC take all necessary measures"

 

CDC H5N1 Incident & Lab Safety Progress Reports

Transferring H7N9 Into Vials – Credit CDC

 

# 8959

 

In the wake of two serious lapses in biosecurity at CDC labs involving both anthrax and H5N1 avian flu CDC Director Dr. Thomas Frieden  promised a complete review of their safety procedures. One of his first actions was to halt the transfer of highly infectious agents from high containment labs until a safety review could be conducted.

 

In late July, the CDC issued a Statement On Formation Of An External Lab Safety Workgroup, and on the same day announced  New safety protocols in place, first CDC lab resumes transfer of inactivated materials out of high-containment laboratory.

 

Over the past month seen a good deal of editorializing on the problems of lab safety at the CDC and elsewhere, including in The Journal Nature Weighs In On Lab Accidents & Biosafety & The Laboratory Bio-Safety Backlash Continues, and in testimony before a House Subcommittee.

 

Today the  CDC has released a progress report on their efforts to get to the bottom of these incidents and improve laboratory safety, along with an internal review of the H5N1 cross-contamination.

 

For Immediate Release: Friday, August 15, 2014
Contact: Media Relations
(404) 639-3286

CDC Progress on Laboratory Safety

The Centers for Disease Control and Prevention today released a series of updates and actions taken showing its progress in laboratory safety. CDC reported on its response to the Animal and Plant Health Inspection Service’s (APHIS) Agricultural Select Agent Program’s (ASAP), part of the U.S. Department of Agriculture, summary of findings on the anthrax incident. CDC also reported findings of an internal CDC investigation on the H5N1 flu lab incident, and actions taken in response to findings of both the APHIS and CDC investigations into the H5N1 incident.

“CDC is working intensively to make our labs to be models not only of scientific rigor but also of safety," said CDC Director Tom Frieden, M.D., M.P.H.  “We will implement changes identified in these reviews – and more – so that we can continue the critical laboratory science needed to protect health in the US and around the world.”

Internal report on H5N1 flu lab incident

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This from the H5N1 lab incident executive summary.

 

What Happened

CDC’s Influenza Division (ID) laboratories had received the H9N2 and H5N1 virus samples as part of ongoing surveillance of human and animal influenza viruses. The virus samples were grown in cell culture and stored for future use. In response to a request from the U.S. Department of Agriculture (USDA), Southeast Poultry Research Laboratory (SEPRL), an aliquot of the H9N2 virus was sent from an ID laboratory to SEPRL on March 12, 2014. Since the H9N2 strain is not a select agent and the ID laboratory was unaware that it had been contaminated, select agent transfer procedures were not followed. On May 23, 2014, SEPRL notified CDC that it had identified an HPAI H5N1 virus (a select agent) in the H9N2 sample. The ID laboratory subsequently confirmed the contamination but did not notify the supervisory chain of command, including branch, division, center, and CDC leadership. The incident was reported to the CDC internal select agent program and to CDC management on July 9, 2014.

Why the Incident Happened

Contamination of the LPAI H9N2 virus culture with the HPAI H5N1 virus occurred at a CDC BSL3-E influenza laboratory. The contamination most likely happened due to the failure of a laboratory scientist to adhere to established best practices and the absence of an approved laboratory team-specific standard operating procedure (SOP) for the work being done. Although several factors contributed to the delay in reporting the incident, the primary factors were 1) a lack of sound professional judgment by those aware of the contamination; and 2) insufficient or ambiguous select agent and institutional reporting requirements. For example, guidance documents from the Federal Select Agent Program and from the CDC internal select agent program do not describe reporting of an unauthorized transfer of a select agent as required reporting of a release.

What Has CDC Done Since the Incident Occurred

In response to this specific incident, CDC has taken the following steps:

• Conducted an internal review (described in this report)
• Closed the laboratory involved until enhancements to safety and security can be implemented
• Included this laboratory in the CDC-wide moratorium on any biological material leaving any CDC BSL-3 or BSL-4 laboratory until adequate, additional approved safety measures are shown to be in place
• Notified USDA’s Animal and Plant Health Inspection Service (APHIS), which has since conducted an investigation and issued a report on the incident

These specific actions are in addition to broader actions recently undertaken by CDC to improve overall lab safety and security agency-wide. These broad actions include

• The appointment of a CDC Director of Laboratory Safety to serve as the single point of accountability to improve all laboratory safety protocols, practices, and procedures
• The establishment of an internal Biosafety Working Group under the direction of the CDC Director of Laboratory Safety
• The establishment of an external advisory group on biosafety comprising leading scientists and biosafety experts, which will serve as a work group of the Advisory Committee to the CDC Director
• A review of policies and procedures for laboratory safety and security in all CDC BSL-3 and BSL-4 laboratories
  

What Additional Steps Are Recommended Moving Forward

Additional recommendations include the following:

• Reassess all CDC laboratory procedures related to H5N1 and other HPAI viruses, including how and where this work is done at CDC and how it relates to CDC’s mission
• Develop written, approved policies and procedures to ensure that cross contamination of influenza viruses does not occur in the future
• Institute comprehensive quality control measures across all CDC laboratories through the performance of exclusivity testing of materials (i.e., testing to exclude the presence of other organisms) before transfer to internal and external laboratories. Materials should be accompanied by a written certificate of analysis that describes the tests and methods used.
• Broaden exclusivity testing of incoming samples to ensure the safety of laboratory scientists who work with the samples and their derivatives. For the near term, due to technologic constraints, such testing will likely be limited to agents of highest concern based on the likelihood or seriousness of their presence.
• Ensure that all ID staff are appropriately trained to understand when biosafety events are reportable and to whom they should be reported (both for select agents and non-select agents), and, more broadly, ensure that all CDC laboratory scientists receive such training. A site-specific SOP for event notification should be in place in each laboratory.
• Institute personnel actions as appropriate

Despite an impressively detailed `after-action’ review of the events leading up to biosafety lapse, due to a variety of factors, the exact point of cross-contamination has not been conclusively established.

The entire 16 page report is quite illuminating, shows just how complex the issues are when working in high containment facilities, and is well worth reading in its entirety.  

The Journal Nature Weighs In On Lab Accidents & Biosafety

 

 

# 8890

 

In the wake of revelations regarding laboratory safety lapses both at the FDA and the CDC involving `select agents’ including anthrax, smallpox, and H5N1 avian influenza, and the ongoing Debate Over Gain Of Function research, we are seeing agencies, scientific journals, universities, politicians, consultants, newspaper editorial boards, scientific working groups, and individual scientists all publicly staking out their positions on these issues.

 

A little over two weeks ago, the Cambridge Working Group produced a consensus statement, which urges caution, and better regulation and oversight of laboratory research seeking to enhance the virulence, transmissibility, or host range of pathogens with pandemic potential (PPPs).

 

While just yesterday, the newly formed coalition Scientists for Science, posted a statement of their own, that called their work `essential’ and dismissed many of the concerns being raised over GOF research as being overstated.

 

Not everyone is convinced, however, as evidenced by last week’s ECDC Comment On Gain Of Function Research, which acknowledged the potential public health risks that these types of experiments can pose, and proposed that the overriding concern of researchers should be first, and foremost  `to do no harm.’

 

Today the Journal Nature has two articles on Laboratory safety standards (or the lack thereof).  First an article by Declan Butler, on the lack of universal, and consistent standards for laboratories conducting work on potentially dangerous pathogens.

 

Biosafety controls come under fire

Experts call for a stronger safety culture at secure sites after incidents involving anthrax and flu in a US laboratory.

Declan Butler

29 July 2014

Recent accidents involving deadly pathogens at a leading laboratory in the United States highlight the need for a major global rethink of biosafety controls, experts say.

The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, reported two accidents involving anthrax and the deadly H5N1 influenza virus. Biosafety professionals argue that such incidents show that without a strong culture of biosafety, even highly secure facilities are susceptible to errors that could place workers and the public at risk.

(Continue . . . )

 

A second report, this time an editorial, suggests that lab accidents such as the ones making headlines this summer happen far more often than are ever reported, and calls for full transparency.

 

Safety doesn’t happen by accident

To create a strong biosafety culture, information on mishaps involving deadly pathogens must be reported and shared fully and transparently.

(Continue . . .)

CDC Statement On Formation Of An External Lab Safety Workgroup

Credit CDC PHIL

 

# 8864

 

In the wake of two serious breaches in biosecurity at CDC labs involving anthrax and H5N1 avian flu, and a third incident involving long forgotten and improperly stored smallpox at an FDA lab  (see FDA Statement On Additional 300 Vials Discovered At NIH Campus Lab), the CDC has promised a complete review of their safety procedures. 

 

Earlier in the week CDC Director Thomas Frieden indicated an external committee of experts would be formed.  Today, the CDC has posted the following announcement, whereby eleven outside experts will provide advice and guidance to the CDC’s new Director of Laboratory Safety.

 

In a related story, the CDC also released an announcement on the lifting of the moratorium on shipping inactivated TB samples out of one of their CDC’s Clinical Tuberculosis Laboratory after completing  a safety review (see New safety protocols in place, first CDC lab resumes transfer of inactivated materials out of high-containment laboratory).

 

 

CDC announces the formation of an external laboratory safety workgroup

CDC announced today the formation of an external laboratory safety workgroup of the Advisory Committee to the Director of CDC. This group will provide advice and guidance to the CDC Director and CDC’s new Director of Laboratory Safety. The specific charge and functions of the workgroup include, but are not limited to:

• Reviewing and providing input into corrective actions for CDC’s laboratories. These include actions identified by the U.S. Department of Agriculture’s Animal and Plant Health Inspection Services and CDC’s Office of the Associate Director for Science following investigations conducted in response to the June 2014 transfer of potentially viable Bacillus anthracis from a CDC BSL-3 facility to CDC BSL-2 facilities; actions identified in follow up to an inadvertent shipment of an H5N1 influenza-containing laboratory specimen to an external BSL-3 laboratory; and other necessary actions identified through ongoing procedural reviews.
• Prioritizing implementation of additional safeguards across all CDC laboratories.
• Identifying potential weaknesses and necessary safeguards based on experiences of non-CDC (e.g., private and/or academic) laboratories.
• Identifying training and oversight needs to promote and sustain a culture of laboratory safety at CDC.
• Identifying ways to provide stronger safeguards for laboratories across the United States.
• Examining HHS lab protocols and reporting to the Secretary through the ACD on:
  • Whether current biosafety and biosecurity rules, processes, and procedures are appropriate.
  • Whether implementation or execution of the current protocols is adequate.
  • Recommendations for improving these protocols or their implementation.

The group is set to meet for the first time in early August and will meet as frequently as needed.

 

(Continue . . . . )

 

APHL Statement Regarding Biosafety Incidents At Federal Labs

Credit CDC PHIL

 

# 8840

 

 

The Association of Public Health Laboratories (APHL) is a non-profit organization of long standing that represents local, territorial, county and state public health laboratories of all types, including medical, environmental, agricultural and veterinary with the goal of promoting the safety, training, and excellence of public health laboratories across the United States.

 

With the recent revelations of hundreds of improperly stored vials of potentially deadly pathogens (see FDA Statement On Additional 300 Vials Discovered At NIH Campus Lab) – including smallpox – and reports of serious lab mishaps involving anthrax and bird flu (H5N1) at a CDC lab (see Subcommittee Hearing On CDC Lab Incidents), there are understandably concerns over what other bad biosafety news might be in the offing.

 

Yesterday in his testimony, CDC Director Dr. Thomas Frieden indicated that all CDC, FDA, and NIH labs were conducting (or about to conduct) full inventories to ensure there were no more improperly stored pathogens in government labs, and said it was possible that additional lapses could be discovered.

 

But these federal labs are far from the only research or testing facilities where lapses in protocol, or judgment, could produce potentially serious consequences.  During yesterday’s hearing, the GAO’s managing director for applied research and methods, Dr. Nancy Kingsbury, admitted the government didn’t have a good feel for how many high containment bio labs were were in the United States. 

 

Other panel members suggested that - between Federal, State, academic, and corporate labs - that number could reach as high as 1,000 labs.  And that there is no single regulatory agency in charge of creating safety protocols, and inspecting labs for compliance, across the nation.

 

 

Which brings us to a statement (my thanks to Marion Koopmans for tweeting the link), posted by the APHL that commends the CDC on their quick response to the recent lab incidents, and urges that all labs take immediate steps to `review their protocols and procedures immediately and thoroughly’ and work to `instill a culture of quality and safety’ in labs around the nation.

 

APHL Response to Biosafety Incidents at CDC and Other Federal Laboratories

The recent series of incidents in federal laboratories serves as a wake-up call for all laboratories--governmental, academic and those in the private sector.

APHL commends the CDC for its swift and assertive response to the biosafety incidents discussed in its conference call and report of July 11. We believe that the agency has taken the appropriate steps to improve the culture of safety and quality across CDC laboratories. APHL will work closely with the agency as it hones its biosafety processes and procedures and strengthens its quality management systems to assure that all aspects of laboratory management are administered effectively.

These changes will require sustained effort on the part of CDC leadership, staff, funders and partners. Enhanced federal support may also be needed to bolster oversight systems.

Because CDC is the sole provider of many materials used by public health laboratories to monitor and detect diseases and other health hazards, the moratorium on movement of all biological materials from BSL-3 and BSL-4 laboratories will have an impact on their operations. In the coming week, APHL will be in contact with CDC to determine how and when these materials – which are essential to public health services at the state and local level – can be delivered.

Lastly, the recent series of incidents in federal laboratories serves as a wake-up call for all laboratories--governmental, academic and those in the private sector. APHL urges its members and partner laboratories to review their protocols and procedures immediately and thoroughly. Having strong quality management systems in place, and a culture of quality and safety, is essential to retaining the public’s longstanding trust in laboratory results. The public deserves, and rightly expects, laboratory systerms that merit this confidence.

 

 

 

The sobering revelations from the CDC and FDA regarding biosecurity – while undeniably bad – are at least known problems that have been (quite commendably) publicly identified, and are being dealt with. More troubling are those hidden biosafety lapses – large and small - that are likely lurking in hundreds of other labs in the Untied States (and around the world).

 

One hopes that every lab in the country will heed the APHL’s advice and will go over their procedures and inventories  with a fine toothed comb looking to prevent incidents such as we’ve just witnessed at the CDC and FDA. 

 

Whether we will hear about all of the lapses uncovered, or whether some (perhaps, many) of them will be handled `discreetly’, is something I suspect we will never truly know.  

 

But either way, this summer is a wake up call for labs – both public and private - across the country.  

They need to either find that much vaunted `culture of safety’  within themselves, or some group of politicians and bureaucrats will surely do for – or to -  them. 

 

And that’s a `fix’ that I doubt many of these researchers would want to see arbitrarily imposed. . 

FDA Statement On Additional 300 Vials Discovered At NIH Campus Lab

Transferring H7N9 Into Vials – Credit CDC

 

# 8839

 

Just hours after the House subcommittee hearing on lapses at the CDC labs involving anthrax and avian H5N1 influenza, the FDA has announced details on roughly 300 vials of improperly stored pathogens that were recovered from the same cold storage room on the NIH campus where 6 vials of smallpox were discovered a couple of weeks ago (see CDC Media Statement on Newly Discovered Smallpox Specimens).

 

Among these latest discoveries are vials marked as containing such diverse pathogens as dengue, influenza, Q fever, and rickettsia, and are believed to date back 50 years or more.  

 

While we were aware that additional vials were discovered at the time of the announcement regarding the smallpox discovery, today’s announcement from the FDA provides additional details.

 

Update on findings in the FDA cold storage area on the NIH campus

For Immediate Release

July 16, 2014

Statement

As previously reported, on July 1, 2014, biological samples were found in the cold storage area of U.S. Food and Drug Administration laboratories on the National Institutes of Health campus. The FDA has since acquired additional information from the federal investigative agencies regarding inventories of the materials.

The investigation found 12 boxes containing a total of 327 carefully packaged vials labeled with names of various biological agents such as dengue, influenza, Q fever, and rickettsia. Upon the discovery of these vials on July 1, 2014, FDA employees followed standard protocol and turned them all over to the appropriate NIH safety program officials, who in turn transferred them to the appropriate investigative agencies, as per standard protocols.

As announced on July 8, 2014, six vials labeled “variola” (the causative agent of smallpox) along with ten other samples with unclear labeling were transported safely and securely with the assistance of federal and local law enforcement agencies in a government aircraft to CDC’s high-containment facility in Atlanta. In addition, 32 samples were destroyed following inventory at the NIH facility, including 28 labeled as normal tissue and four labeled as “vaccinia,” the virus used to make the smallpox vaccine. To be clear, vaccinia does not cause smallpox. These vials represented no value to forensic sciences and were destroyed according to standard protocols.

The remaining 279 biological samples were then transferred by the investigating agencies to the U.S. Department of Homeland Security’s National Bioforensic Analysis Center for safeguarding. There were no smallpox samples included in this transfer. The FDA received confirmatory information about the samples yesterday, thus permitting public disclosure of this additional information.

While an investigation continues regarding the origin of these samples, this collection was most likely assembled between 1946 and 1964 when standards for work with and storage of biological specimens were very different from those used today. All of the items labeled as infectious agents found in the collection of samples were stored in glass, heat-sealed vials that were well-packed, intact, and free of any leakage, and there is no evidence that anyone was exposed to these agents.

Overlooking such a sample collection is clearly unacceptable. The FDA has already taken steps to ensure that similar material is not present in its other cold storage areas by initiating a thorough review of all common cold storage spaces. The agency is in the process of reviewing its policies and procedures in order to implement a corrective action plan so that potentially hazardous samples are never overlooked in the future.

CDC: Press Conference Transcript, Audio & Timelines For Lab Incidents

H5N1 Photo Credit – CDC PHIL

 

 

# 8827

 

For those who missed yesterday’s bombshell press conference on recent government lab biosafety incidents involving anthrax, smallpox and  avian H5N1, the CDC has posted the audio file, transcript, and some timeline graphics. 

 

While there has been a great deal of excellent media coverage over the past 18 hours (including Helen Branswell’s  What happened at the CDC’s flu lab? & Lisa Schnirring’s More problems shutter CDC labs, prompt review for CIDRAP News), many will still want to hear this press conference in its entirety.

 

Press Briefing Transcript

CDC Press Conference on laboratory quality and safety after recent lab incidents

Friday, July 11, 2014 11:30 a.m. ET

• Audio recording  [MP3, 10.3 MB]

 

 

These incidents are still under investigation, and so there are still large gaps in our understanding of how they occurred.  The H5N1 cross-contamination incident in particular has two large and critical holes in the timeline (see below) that will require filling in. 

 

The first is what transpired between March 12, when the (presumed H9N2) samples are shipped from the CDC to the USDA lab in Athens, Ga and May 23rd, when the USDA determined they were working not with H9N2, but with the highly pathogenic H5N1 virus.  

 

How the virus sample became cross contaminated, and how that went undetected for 40 days, remain open questions.

Even more troubling is how the discovery of this mistake could have been made on May 23rd - and shared between two major government agencies (USDA & CDC) - and yet senior management at the CDC were not informed until July 7th, a gap of more than six weeks.

 

March 12

• CDC Influenza Division (ID) shipped low pathogenic avian influenza H9N2 to USDA SEPRL in Athens, Ga
  Genetic analysis confirmed identity of H9N2
• Shipment delivered on March 13 to USDA Southeast Poultry Research Laboratories (SEPRL) (Athens GA)
  SEPRL observed pathogenicity in chickens inconsistent with H9N2 virus
  SEPRL performed molecular analyses on SEPRL virus stock and material sent by CDC
  SEPRL confirmed highly pathogenic H5N1 contamination and destroyed all SEPRL virus stocks in biosafety level 3
  (BSL-3) enhanced

May 23

• SEPRL notified CDC ID that SEPRL virus stock was contaminated and destroyed

May 23

• CDC ID confirmed H9N2 virus was contaminated by H5N1 virus

July 9

• CDC Responsible Official was notified; investigation is ongoing

 

The H5N1 flu incident, while apparently contained, could have been an economic disaster had the virus escaped the USDA lab and entered the poultry and/or wild bird population of the United States. 

 

Regarding the Anthrax investigation, you’ll also find a graphic timeline available at this link.

 

Although none of these incidents resulted in the infection of lab personnel, or the release of a pathogen outside of the lab, they all had the potential to do so – and in the words of the CDC’s Director, `These events should never have happened.’  

An obviously anguished Dr. Frieden went on to say:

`Together, these events I’m sure have many people asking and questioning government labs.  They may be wondering whether we're doing what we need to do to keep our workers and our communities safe.  And I think it's fair to raise those questions.  I’m disappointed by what happened, and frankly, I’m angry about it.'

 

The post mortem on all of this is likely to be long and messy, and the fallout is likely to extend well beyond the CDC and USDA labs. These incidents show that no matter how sophisticated the laboratory, no matter how detailed the safety protocols, there is always the risk of human error.

 

Something which is sure to re-ignite the debate over the wisdom and safety of GOF (`Gain of Function’) and DURC (`Dual Use of Concern’) research has been simmering for several years.  While I’ll have more on that in future blogs, for now you may wish to revisit:

 

The Call For Urgent Talks On `GOF’ Research Projects

U.S. Issues New DURC Oversight Rules

Nature: H5N1 viral-engineering dangers will not go away

Referral: Dr. Mackay On MERS-CoV Testing

Coronavirus – Credit CDC PHIL

 

# 7921

 

 

Dr. Ian Mackay has a informative post this morning on his Virology Down Under blog on the recently announced rapid blood test for MERS-CoV.   As readers who follow this blog already know, lab tests are not always definitive.   First  a link to Ian’s piece, then I’ll be back with a bit more.

 

New MERS-CoV laboratory test: takes 10-minutes but what can it tell you?

 

The two main measures of the accuracy of any diagnostic test are sensitivity and specificity.

• Sensitivity is defined as the ability of a test to correctly identify individuals who have a given disease or condition.

• Specificity is defined as the ability of a test to exclude someone from having a disease or illness.

 

While a rapid MERS-CoV test would be a great boon to surveillance, our experience with Rapid Influenza test kits (see MMWR: Evaluating RIDTs) has not been all that encouraging.

 

According to the CDC:

The rapid tests vary in terms of sensitivity and specificity when compared with viral culture or RT-PCR. Product insert information and research publications indicate that:

• Sensitivities are approximately 50-70%
• Specificities are approximately 90-95%

 

But of course, this is a different test, a different collection method, and a different virus.  As Dr. Mackay points out, we need to see some real-world data on how well this new test works in the field.

 

We also know a lab test can have excellent sensitivity and specificity under laboratory conditions – but if the sample collected from the patient doesn’t contain enough virus (or is improperly stored or transported) – then the best test in the world won’t be accurate.

Testing for MERS has often relied on taking throat swabs - which can be sub-optimal when trying to detect deep lung infections. As we’ve seen with H5N1, H7N9, and MERS-CoV -  false negatives can result.

 

The World Health Organization issued the following testing recommendations for MERS last summer (see WHO: Revised MERS-CoV Case Definitions), for precisely this reason.

 

Inconclusive testing: Patients with an inconclusive initial testing should undergo additional virologic and serologic testing to determine if the patient can be classified as a confirmed MERS-CoV case. It is strongly advised that lower respiratory specimens such as sputum, endotracheal aspirate, or bronchoalveolar lavage fluid be used when possible. If patients do not have signs or symptoms of lower respiratory tract infection and lower track specimens are not available or clinically indicated, both nasopharyngeal and oropharyngeal swab specimens should be collected.

If initial testing of a nasopharyngeal swab is negative in a patient who is strongly suspected to have MERS-CoV infection, patients should be retested using a lower respiratory specimen tract or a repeat nasopharyngeal specimen with additional oropharyngeal specimen if lower respiratory tract specimens are not possible, and paired acute and convalescent sera.

 

A reminder, that at least with lab tests,  `No’ doesn’t always mean `no’.

Study: Hematological & Biochemical Abnormalities In H7N9 Patients

Credit CDC

 

# 7853

 

 

Since H7N9’s emergence last spring in China, researchers have been frantically trying to determine just how much of a threat this virus poses, and how best to treat patients who have been infected.  Last May in EID Journal: Clinical Course & Treatment Of Four Early H7N9 Cases we began to see details on the severity of hospitalized H7N9 cases, and since that time roughly 1/3rd of all hospitalized cases have died.

While this fatality rate is less than what we’ve seen with the H5N1 virus, it remains an extraordinarily high for any influenza virus.  Unknown, of course, are how many `mild’ cases that never sought hospital care and recovered on their own.

 

Researchers writing in The Lancet last June (see Clinical Severity Of Human H7N9 Infection) estimated that between 1500 and 27,000 symptomatic infections with avian influenza A H7N9 virus might have occurred as of the end of May, 2013.  But unless and until comprehensive seroprevalence studies can be conducted, this remains unproven.

 

All we really know is that among the 136 cases that were identified and hospitalized, 44 died and many of those that recovered did so only after many weeks of intensive care.  Those who were ill enough to be hospitalized were very ill, indeed.

 

Which brings us to a new study, published yesterday in the Journal of Medical Virology, that describes the laboratory findings of 39 H7N9 patients hospitalized at the First Affiliated Hospital, Zhejiang University between March and April of this year. 

 

The full report is behind a pay wall, but their basic findings are available in their abstract. 

 

 

Laboratory findings in patients with avian-origin influenza A (H7N9) virus infections

Juanwen Zhang, Ying Zhao, Yu Chen^*

 

 

Briefly, these researchers found:

Hematological abnormalities

• leukopenia
• lymphopenia
• thrombocytopenia with prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT)
• elevation of D-dimer levels.

 

Biochemical abnormalities

• elevated serum lactate dehydrogenase (LDH)
• elevated aspartate aminotransferase (AST)
• elevated creatine kinase (CK)
• elevated alanine aminotransferase (ALT) activities,
• increased C-reactive protein (CRP) concentration,
• as well as hyponatremia, hypokalemia, hypocalcemia, hypoproteinemia, and hypoalbuminemia.

 

Arterial blood gas analysis

• reduced arterial oxygen (PaO₂)
• reduced carbon dioxide pressures (PaCO₂).

 

While these laboratory findings were commonly observed in the early stages of H7N9 infection, they are not pathognomonic – that is, diagnostically specific – to H7N9 infection. 

 

Given that some of my readers may be unfamiliar with all of these lab tests, I’ve provided a few general descriptions of these tests below:

The reduced arterial blood gases (PaO₂ & PaCO₂) are consistent with hypoxia that would be associated with any pneumonia.

 

In the biochemical analysis, elevated ALT & AST are usually associated with liver damage, while LDH is an enzyme released when certain cells (typically liver, kidney, heart, or muscle) die.  An elevated CPK level  usually means there has been damage or stress to muscle tissue, the heart, or the brain.

 

Increased PT, APPT, and elevated D-dimer levels are often associated with DIC (Disseminated intravascular coagulation),a clotting disorder that can lead to serious internal and external bleeding. While sepsis is the primary cause of DIC, it can also be triggered by systemic fungal, bacterial, parasitic (malarial) or viral infections (including influenza).

 

Hyponatremia, hypokalemia and hypocalcemia refer to low levels of sodium, potassium, and calcium in the blood serum. Hypoproteinemia and hypoalbuminemia refer to low levels of protein and albumin in the blood.

 

Although a good deal depends upon the degree of deviation from the norm in these blood tests, the picture painted by this study is that these patients experienced profound systemic challenges due to their H7N9 infection, which probably helps to explain the high mortality rate. 

 

In 2008, we looked at an analysis (see Clinical Case Review Of 26 Chinese H5N1 Patients) published in PLoS One that revealed remarkably similar laboratory findings.  Of the 26 cases studied, 17 (65%) died.  

 

Some excerpts from that study:

 

The prevalence of patients with abnormal haematological findings at admission [leukopenia (46%), lymphopenia (62%), and moderate thrombocytopenia (50%)] increased to 92%, 89% and 73%, respectively, during hospitalization.

<snip>

Elevated ALT, AST, creatine kinase (CK), creatine phosphokinase isoenzymes (CPK), lactic dehydrogenase (LDH), and plasma glucose concentration, and decreased albumin levels were observed in more than half of cases at admission, and developed in nearly all cases during hospitalization. Elevated creatine level was observed in 25% of cases during hospitalization. Seventeen (77%) cases developed proteinuria at a median of 9.0 days (IQR 7.0–11) after illness onset.

<snip>

All 17 fatal cases had multi-organ failure, including respiratory failure (94%), cardiac failure (71%), renal failure (27%) and 24% had disseminated intravenous coagulation.

 

It should be noted that late hospital treatment was the norm among these Chinese H5N1 patients, with some never receiving antivirals, even once hospitalized. The abstract of today’s H7N9 study does not provide comparable details on admissions, treatment, or outcomes.

 

While the recovery rate with H7N9 last spring was double that which we’ve seen over the years with H5N1, today’s study  suggests that both viruses are capable of producing similar pathogenesis in humans. At least among those experiencing the most severe presentation of the illness.

 

We don’t currently have a vaccine against the H7N9 virus, but early treatment with antiviral medications has been associated with fewer symptoms, more rapid recovery, and a lower mortality rate. The CDC recently released antiviral guidance documentation in the event that the H7N9 manages to spread beyond China.

 

H7N9: CDC Guidance On Antiviral Chemoprophylaxis

H7N9: Updated CDC Guidance For Antiviral Treatment