Finding The Zebra In The Haystack

Credit CDC

 

# 8637

 

According to ACEP (the American College of Emergency Physicians), hospital emergency rooms provided treatment to more than 136 million Americans in 2009. Which means that every day across the United States hundreds of thousands of people present at emergency rooms, with a wide variety of problems.

 

Some cases will be critically ill or injured, while others will have relatively simple complaints like URIs, fever, gastrointestinal complaints – all exceedingly common - yet all potentially early signs of MERS coronavirus infection.  

 

For doctors, nurses, and other medical personnel in the United States (and around the world) this adds the task of identifying and isolating what is currently  a needle-in-a-haystack – that one patient out of a million who might be carrying the MERS coronavirus – while simultaneously dealing with the urgent demands of a busy emergency room.

 

Today the likelihood that anyone presenting at an emergency room in the US with `flu-like’ symptoms has the MERS coronavirus is exceedingly, almost astronomically, low.  But that statistic is of little comfort to the staff and patients at the emergency rooms of Munster, Indiana or Orlando, Florida.  

 

The odds of being struck by lightning or winning the lottery are miniscule as well, but it still happens.

 

One of the tenets of emergency medicine is that you start with the most likely diagnosis, rule that out, and progressively work through next most likely scenarios before exploring more exotic illnesses.

 

It’s a variation of  Occam’s Razor, that the simplest explanation is often correct, and is often taught as an aphorism to medical students: `If you hear hoof beats, think horses, not zebras’.

 

While still literally a one-in-a-million shot that any given patient going to an North American ER today with `the flu’ has the MERS virus, if it continues to circulate unabated in the Middle East, the odds favor our seeing more `zebras’ showing up at local ERs over time.  

 

Which is why the CDC has updated their MERS Interim Guidance for Health Professionals, to help identify, isolate, and test potential MERS carriers before they can further spread the virus.  Some excerpts from this guidance follow:

 

Patients in the U.S. Who Should Be Evaluated for MERS-CoV Infection

Healthcare professionals should evaluate for MERS-CoV infection, patients in the U.S. who meet the following criteria:

1. Fever and pneumonia or acute respiratory distress syndrome (based on clinical or radiologic evidence) AND EITHER:
   • history of travel from countries in or near the Arabian Peninsula¹ within 14 days before symptom onset OR
   • close contact² with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula) OR
   • is a member of a cluster of patients with severe acute respiratory illness (e.g., fever and pneumonia requiring hospitalization) of unknown etiology in which MERS-CoV is being evaluated in consultation with state or local health department (more details below).
   OR
2. Close contact² of a confirmed or probable case of MERS (more details below).

See the Case Definitions for more information.

Patients with lower respiratory illness should also be evaluated for common causes of community-acquired pneumonia³, guided by clinical presentation and epidemiologic and surveillance information. For these patients, testing for MERS-CoV and other respiratory pathogens can be done simultaneously. Positive results for another respiratory pathogen (e.g., influenza) should not necessarily preclude testing for MERS-CoV because co-infection can occur.

For now, and for as long as the virus fails to transmit efficiently in the community, it makes sense to key in on those with some kind of link to recent travel from the the Middle East. Secondary transmission outside of the Arabian peninsula has - thus far - been rare, making this a reasonable criteria for greater scrutiny and MERS testing.

 

The big unknown right now is how well this virus spreads – either mildly or asymptomatically – among the contacts of active MERS cases.  And this is why there is so much focus on contact tracing, and testing of those who may have been exposed.

Right now we don’t know if Saturday’s revelation that a contact of the Indiana case has developed antibodies (see CDC: Contact Of Indiana MERS Case Tests Positive For The Virus) to the virus is a rare `exception to the rule’, or if it happens with some degree of regularity.

If anything `good’ can be said about the importation of the virus to the United States, it is that the CDC’s and local public health department’s investigations will probably tell us more about how this virus spreads to close contacts over the next couple of weeks than we’ve learned over the past two years.

 

The CDC’s guidelines for tracking and evaluating these contacts follows:

 

Evaluation and Management of Close Contacts

CLOSE CONTACTS OF A CONFIRMED OR PROBABLE CASE

Close contacts² of a confirmed or probable case of MERS while the case was ill should be evaluated in consultation with state and local health departments. Other contacts of the ill person, such as community contacts or contacts on conveyances (e.g., airplane, bus), should also be evaluated in consultation with state and local health departments.

Close contacts² of a confirmed or probable case, if not using recommended infection control precautions (e.g., appropriate use of personal protective equipment), are at increased risk and should be evaluated and monitored by healthcare professionals with a higher index of suspicion to detect MERS-CoV infection. The spectrum of illness due to MERS-CoV infection is incompletely defined. Although most reported cases have had severe acute lower respiratory illness, mild and asymptomatic infections have been reported and in some cases, diarrhea preceded respiratory symptoms. Testing nasopharyngeal and oropharygeal swabs by rRT-PCR to detect MERS-CoV should be considered on initial evaluation, regardless of the presence or nature of symptoms. Healthcare professionals should carefully monitor for the appearance of fever (T>100°F) or respiratory symptoms within 14 days following the close contact, as one of these signs would meet the criteria for a patient under investigation (PUI). Other early symptoms have included headache, chills, myalgia, nausea/vomiting and diarrhea. Symptomatic contacts should be evaluated and, depending on their clinical history and presentation, considered for more extensive MERS-CoV testing, including rRT-PCR testing of lower respiratory and serum specimens, and possibly MERS-CoV serology, especially if symptom onset was more than 14 days prior.

Close contacts² who are ill and being evaluated for MERS-CoV infection and do not require hospitalization for medical reasons may be cared for and isolated in their home. (Isolation is defined as the separation or restriction of activities of an ill person with a contagious disease from those who are well). For asymptomatic close contacts² who are being evaluated for MERS-CoV, the possible benefit of home quarantine or other measures, such as wearing masks, is uncertain due to lack of information about transmissibility from persons with asymptomatic infection. Asymptomatic contacts who test positive by PCR, especially in respiratory specimens or serum, likely pose a risk of transmission, although the magnitude and contributing factors are unknown. Providers should contact their state or local health department to discuss home isolation, home quarantine or other measures for close contacts, especially for patients who test positive, and to discuss criteria for discontinuing any such measures. Recommendations may be modified as more data become available. For more information, see CDC’s Interim Home Care and Isolation Guidance for MERS-CoV.

CLOSE CONTACTS OF A PUI

Evaluation and management of close contacts² of a PUI should be discussed with state and local health departments. Close contacts of a PUI should monitor themselves for fever and respiratory illness and seek medical attention if they become ill within 14 days after contact. Healthcare providers should consider the possibility of MERS.

 

Clusters of Respiratory Illness in Which MERS-CoV Infection Should Be Considered

Clusters⁴ of patients with severe acute respiratory illness (e.g., fever and pneumonia requiring hospitalization) without recognized links to a case of MERS-CoV infection or to travelers from countries in or near the Arabian Peninsula should be evaluated for common respiratory pathogens.³ If the illnesses remain unexplained, providers should consider testing for MERS-CoV, in consultation with state and local health departments.

(Continue . . . )

 

The reality is (in the near term) that hundreds of people will probably be evaluated for, and cleared of, MERS for every case that proves positive.  We know that so far, most contacts of known cases never develop illness.  And that is likely to remain the case unless the virus changes in some way.  

 

The current risk to the general community is very low. Outside of the Arabian Peninsula, MERS remains a very rare virus.

 

Our best hope of keeping it rare is to remain vigilant and exercise an abundance of caution when it comes to isolating suspected cases. But no matter how vigilant we remain - mild, asymptomatic, or atypical presentations of the virus – could easily thwart even the best of surveillance and containment plans. 

 

Which means that until this virus can be contained and controlled at its source (the Arabian Peninsula), it is likely to pose a serious challenge to the entire world’s public health systems for some time to come.

WHO: Seroepidemiological Investigation Of Contacts Of MERS Cases

Released by WHO Nov 19th, 2013

 

# 7990

 

We’ve a detailed set of guidelines –published yesterday (Nov 19th) by the World Health Organization – that outlines the steps recommended for health officials to take when investigating contacts of known or suspected MERS cases.

 

While designed primarily as a reference text for public health officials doing contact investigation, this 24-page PDF file  also provides us a much better idea of what is (or at least, should be) involved in these types of investigations.

 

Some highlights follow, but you’ll want to download and read the entire document.  After which, I’ll return with a little more.

 

Seroepidemiological Investigation of Contacts of  Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Patients

(Selected Excerpts)

1.1  OBJECTIVES

The data collected from this study will be used to characterize the key epidemiological transmission features of MERS-CoV virus, to help understand spread, severity, spectrum of disease, and impact on the community and to inform operational models for implementation of countermeasures such as case isolation, contact tracing and quarantine.

The primary objectives of this study are to:

• Estimate frequency of MERS-CoV infections (as measured by virologic and serologic tests) in
  relation to human and other exposures (i.e. evaluate determinants/risk factors [including
  sources] for infection) among contacts of confirmed MERS-CoV cases
• Evaluate (modifiable) risk factors (e.g. exposures, behaviours, practices) for human MERS-
  CoV infection
• Evaluate the extent of MERS-CoV transmission among contacts of confirmed and probable
  MERS-CoV patients
• Describe the presentation and clinical course of disease with MERS-CoV infection
• Quantify the proportion of asymptomatic/sub-clinical MERS-CoV infections

 
COMMENT: Comprehensive study investigations such as the one described below can provide rich data to assess a number of secondary outcomes. Many other secondary objectives can be investigated in terms of epidemiological, immunological, clinical, virological, economic, genetic, behavioural, environmental, and animal factors associated with risk of MERS-CoV infection or outcome of infection. These are not discussed in detail in this protocol. 

<SNIP>

2.3.2  CONTACTS OF A  CONFIRMED HUMAN MERS-COV CASE

The first stage of this investigation will be to identify all contacts of confirmed and probable MERS-CoV patients. 

For the purposes of this study, contacts of a confirmed or probable human MERS-CoV case are defined as all individuals who are associated with some sphere of activity of the case and who may have similar environmental or other exposures as the case. Contacts can include household members, other  family contacts, visitors, neighbours, colleagues, teachers, classmates, co-workers, servants, members of a social group, or others, and do not have to have had close personal contact with the case. Each group of contacts will form a separate, though sometimes overlapping, cohort of contacts. For example, one cohort may include all of the schoolmates who sit in the same classroom as the case if the case is a student, or office colleague of an office worker, even if they have not had recent close contact with the case. Alternatively, if the case owns a farm, or works on a farm, all of the workers on that farm could be included as contacts regardless of whether or not they had close physical contact with the case. The goal is to include a broad range of people with different types of exposures who have been part of the same environments as the case in order to be able to link type of exposure to evidence of infection. 

<SNIP>

2.4.3  DATA COLLECTION

 

After enrolment and informed consent, a standardized baseline data set will be collected with any specimens for MERS-CoV testing (and date of specimen collection). Baseline data to be collected include: age, gender, location, relationship to confirmed case-patient, occupation, signs and symptoms, and underlying conditions.  In addition, detailed questions will be asked to evaluate risk factors for human infection with MERS-CoV (Appendix B). These are included in the data collection form in Appendix B under the section for “exposures” and include specific aspects of timing, frequency and duration of exposure(s). The questionnaire should be administered each time sera are collected. The study questionnaire for the use of all cases and contacts can be found in Appendix B.

  
2.4.4  PREVENTION OF MERS-COV  TRANSMI SSION IN FRONT-LINE STAFF

Before study implementation, front-line staff, including all study personnel, will be trained in infection control procedures (standard, contact, droplet or airborne precautions), including proper hand hygiene and the correct use of surgical or respiratory face masks, if necessary, not only to minimize their own risk of infection when in close contact with patients during home visits and elsewhere, but also to minimize the risk of staff becoming a vector of MERS-CoV transmission between subjects or households.

<SNIP>

2.5.2.1  VIROLOGIC TESTING

MERS-CoV case definitions are described above and can be found at:
http://www.who.int/csr/disease/coronavirus_infections/case_definition/en/index.html

As of 6 June, to consider a case as laboratory-confirmed, one of the following conditions must be met:

• positive RT-PCR or other validated molecular assays for at least two different specific targets
  on the MERS-CoV genome
  OR
• one positive RT-PCR assay for a specific target on the MERS-CoV genome and an additional
  different PCR product sequenced, confirming identity to known sequences of the new virus.
  

A positive PCR assay for a single specific target without further testing is considered presumptive evidence of MERS-CoV infection. Final classification of cases will depend on clinical and epidemiological information, combined with laboratory data. Member States are requested to immediately notify WHO of any confirmed or probable case. 

Full details for virologic laboratory testing of MERS-CoV can be found here:

http://www.who.int/csr/disease/coronavirus_infections/LaboratoryTestingNovelCoronavirus_21Dec12.pdf.

<SNIP>

3.0  STUDY  ENDPOINTS AND STATISTICAL ANALYSES

The following section discusses the endpoints – that is, what will be measured and calculated using the data that are collected in this study – for the primary objectives, including statistical advice.

 
3.1  STUDY OUTCOME MEASURES
3.1.1  PRIMARY OUTCOMES

  
The following will be assessed as study endpoints corresponding to the study’s primary objectives: 

1. Evaluate source(s), risk exposures, and (modifiable) risk factors for human infection with MERS-CoV
2. Estimate the age-specific frequency of MERS-CoV infection (as measured by virologic and serologic tests) in relation to human and other exposures
3. Describe the full spectrum of clinical disease associated with MERS-CoV infection
4. Quantify proportion of asymptomatic/sub-clinical; mild illness; and severe illness(hospitalization/ICU/death) with MERS-CoV infection.

(Continue . . . . )

 

 

There is much more in this document, including a contract tracking line list and a multi-page questionnaire for contacts of MERS cases that asks about everything from living arrangements to previous medical history and habits (smoking & alcohol consumption), to recent travel history, to contact with animals in an attempt to gather the clearest possible picture of the risk factors involved in contracting this virus.

With cases and contacts being tested across multiple countries or regions it becomes increasingly important to standardize the methods by which they are investigated. As you might expect, standardized protocols make the comparison and collation of data  far easier.  

 

While it doesn’t always get as much attention as the high-tech work being done with molecular virology, it is often good old fashioned shoe-leather epidemiology – the tracking down of contacts, the gathering of extensive histories, and the laborious compiling and analysis of epidemiological line lists – that ends up telling  us the most about how an outbreak is spreading.

Italy: Unconfirmed Media Reports On MERS Contact Testing

 

 

 

# 7358

 

A story has been kicking around the Italian media since last evening regarding contacts of the traveler recently returned from Jordan hospitalized with the MERS coronavirus. The reports state that `10 to 12’ contacts have tested positive for the MERS-CoV, but all remain asymptomatic and are not hospitalized.

 

Crof wrote about it here,this FluTrackers thread has multiple media reports, and ProMed Mail put out an RFI in the middle of the night.

 

All of the media stories seem to stem from remarks offered by Professor Alessandro Bartoloni, head of infectious diseases at AOU Careggi. Importantly, most of the stories indicate that samples have been forwarded to a national lab for confirmation.

 

So far, I’ve been unable to get any corroboration from the World Health Organization or via the Italian Ministry of Health site, and the story doesn’t appear to have been picked up by Reuters or AP.

 

As you might imagine – if true – this story could represent a major change in how this virus (at least in this Italian cluster) is behaving.  

 

But before we go down that rabbit hole, we really need official corroboration, confirmatory re-testing (to rule out PCR contamination and/or false positives), and then we need to give these patients a few days to see if they all remain `mild’ or asymptomatic.

If there is anything to this story, we ought to hear more about it later today.