TB Technical Instructions for Panel Physicians: Implications for US PractitionersNovember 28, 2012

Eileen Napolitano: Good afternoon and welcome to the second medical update of this year. Today's Web based seminar is called TB Technical Instructions for Panel Physicians: Implications for U.S. Practitioners.

My name is Eileen Napolitano and I am the Deputy Director at the New Jersey Medical School Global Tuberculosis Institute, the sponsor of today's program. Each year approximately 400,000 immigrants and 50,000 refugees enter the United States.

The technical instructions, initiated in 1991, contain the requirements for overseas medical evaluation, including tuberculosis screening. The technical instructions were updated in 2007 and have important implications for U.S. practitioners. The objectives of this webinar are listed on this slide. In this seminar you will learn about the purpose of the TB Technical Instructions for panel physicians, and how and why they have changed.

Upon completion of this seminar, participants should be able to: describe the purpose and use of the TB technical instruction in the medical evaluation of persons emigrating to the United States, list the changes to the TB technical instructions to clarify their use in the examination of immigrants and refugees, explain how to implement the TB Technical Instructions to appropriately provide related medical consultation, and apply the TB Technical Instructions to the medical follow up of immigrants and refugees arriving in the U.S.

Our faculty today – excuse me, are Mr. Phil Lowenthal, Dr. Sundari Mase and Dr. Drew Posey. The seminar today will consist of several parts. After this introduction and some brief housekeeping details Dr. Mase will start this off with a background and overview of the TB technical instructions.

Then Dr. Posey will talk about the implementation of the technical instructions. We'll then hear again from Dr. Mase with several cases to illustrate some of the important points from the technical instructions. And finally, Mr. Lowenthal will join us for the discussion session in which you may share your thoughts and ask questions.

Our first speaker is Dr. Sundari Mase. Dr. Mase is the Team Lead for Medical Affairs in the Field Services and Evaluation Branch at the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention. She will be providing an overview and background of the TB Technical Instructions for panel physicians and will highlight the recent changes. Dr. Mase, I'll turn it over to you.

Sundari Mase: Great. OK. Well, over the course in the next 15 minutes, what I'd like to do is to briefly describe what the reasons were for changing from the 1991 TB Technical Instructions to the 2007 Culture and Directly Observed Therapy TB Technical Instructions and to note what those changes are.

So as Eileen mentioned that each year there's approximately 400,000 immigrants and 50,000 refugees that enter the United States. The Division of Global Migration and Quarantine has the regulatory authority to stipulate the requirements of the overseas medical examination via these technical instructions that apply not only to tuberculosis but to other diseases.

The Bureau of Population, Refugees and Migration (BPRM) is a state department bureau that's responsible for refugee resettlements and BPRM has contracted the International Organization for Migration to perform medical screenings for about 80 percent of the refugees and perhaps even a greater percentage now.

So the initial technical instructions for tuberculosis screening were issued in 1991. And really the rationale for overseas screening is specifically to screen TB suspects using these technical instructions to restrict the entry of infectious TB cases but to facilitate entry of the rest in a very seamless fashion with evaluation treatment per our guidelines, the ATS/CDC/IDSA standards and

then for the U.S. Health Department to follow up evaluation and treatment of non-infectious cases and that is cost effective on the stateside.

So what triggered the need for revisiting the TB technical instructions? Well on December 2003, the U.S. Department of State approved the resettlement of about 15,000 Laotian-Hmong refugees in the United States. Medical screening started in February 2004 and refugees began arriving in June 2004. Six months after refugees began arriving, CDC was notified of 31 active TB cases in this population in California out of approximately 6,000 refugees giving a case rate of 700 per 100,000 compared to the U.S. case rate of under 4 per 100,000.

Fifty percent of these cases were culture confirmed with multi-drug resistant TB, the resettlement was halted and there were investigations performed simultaneously by CDC in Thailand and in California. This is a picture of Wankat Kribat which is where many of these refugees were residing at that time.

So let's review the TB Technical Instructions from 1991. Prior to the 2007 instructions, there was no requirement for TB skin testing and chest x-rays were only performed in those greater than or equal to 15 years of age, smear microscopy was performed but no culture and there are limited requirements for TB treatment overseas, directly observed therapy was not specified.

In fact, once a patient became AFB smear negative on TB treatment overseas, they are allowed to travel the United States to complete their treatment.

So here is the 1991 Technical Instructions. So a chest radiograph was performed and based on the chest radiograph for those greater than or equal to 15 years of age; patients were either thought to have inactive TB, active TB or no TB. And as we all know, it's very hard to tell inactive from active TB just by a radiograph.

So at that time if the physician screening the patient thought that the chest x-ray was consistent with inactive TB, the patient was given a Class B2 status and this was valid for travel for six months and if they were felt to have active TB then of course they gave three sputum smears only. If the smears were

negative, they are considered to have non-infectious Class B1 status. If at least one of these smears is positive, they were thought to have infectious Class A status. And then of course based on the x-ray if it was completely normal they were thought to have no TB, given no classification and travel is valid for 12 months.

And again as I mentioned these Class A patients had limited treatment requirements overseas until considered non-infectious by negative smears and then were able to travel once considered non-infectious.

Clearly in this process there is the risk of missing active TB in several levels. First of all, if the chest x-ray was determined to be consistent with inactive TB, a patient could still have active TB, they simply wouldn't have had an evaluation. As I said, you can't really tell active from inactive TB based on the radiograph. And then of course the validity periods of six and 12 months give plenty of opportunity for a patient to potentially become infectious with active TB in those time periods and the lack of sputum culture requirement missed a lot of cases in this algorithm.

So the technical instruction revision really began in 2005, scientific literature was reviewed, there was input from a TB Technical Instruction working group consisting of TB experts from around the country and just as background as we know, one-third of the world is latently infected with the organism, there's approximately 8 to 9 million cases of active TB reported to WHO annually and somewhere around 1.8 million deaths reported to WHO annually.

This slide I put in just to show that TB case rates are very high in countries from where our immigrants and refugees are coming and that's one reason why we – to really focus on screening these folks overseas before arrival.

And again, data showing that the TB numbers of cases and proportion is increasing steadily over the years and that again has supported the need for enhanced screening in this population.

A study that was done in Vietnam looked at what the sensitivity of the 1991 TB TI were for picking up active TB by looking at approximately 1,180 patients that had abnormal chest radiographs obtaining both smears and

cultures on these patients. Based on smears alone, 82 patients were determined to have active tuberculosis, 7 percent.

But when cultures were added 183 additional patients were found to have active TB, doubling the number or actually tripling the number that would have been found with just smears alone. So the sensitivity of the 1991 technical instructions was found to be willfully low at 34 percent. Approximately two-thirds of TB cases were shown to be missed by not obtaining cultures.

And the reason that number is so high in this population is because it's active screening; most of these patients were not sick or symptomatic so they’re less likely to be smear positive and culture positive.

So here's who was involved in that revision, the collaborators for the revision of the TB Technical Instructions. And here are the basic changes that were made. It was determined that tuberculin skin test or an IGRA test should be performed in applicants two to 14 years of age in countries with WHO estimated TB incidence rates of greater than or equal to 20 per 100,000. And a chest x-ray would be required if the tuberculin skin test was greater than or equal to 10 millimeters or if the interferon gamma release assay was positive.

In addition, three sputum cultures were made a requirement in addition to smears for any applicant with an abnormal chest x-ray.

Drug susceptibility testing was a requirement – made a requirement on any positive cultures given that we – there are so much resistance found in certain populations that are screened overseas, depending on the country of origin.

Directly observed therapy was made the standard of care for treatment of these patients once diagnosed with active tuberculosis overseas. And if drug-resistant, the Francis J. Curry international centers drug-resistant TB guidelines were to be used for the treatment of these cases. The validity period of the medical examination was also decreased, and I said, the likelihood of patients might progress from not – from being lately infected to having active disease or from being smear negative to smear positive could – is great within the six or 12-month period of time. So the validity period was

decreased to three months if the patient was felt to have Class B1 TB or was HIV co-infected and six months otherwise. So nobody could have a validity period of 12 months any longer.

Children 10 years of age or less were – would be allowed to travel while TB cultures were pending if they did not meet criteria for infectiousness and applicants who had TB treatment at a non-CDC approved site, in other words, a private hospital or another facility but not one of the panel sites needed to provide specific treatment documentation by Directly observed therapy and would have to wait one year post-treatment to undergo a repeat immigration medical examination.

So really a disincentive to not being treated by a CDC approved site. And basically no treatment equals no travel. So a patient has to be treated overseas to treatment completion if they want to come essentially to the country.

So let's take a look and it's kind of a bit of a summary of what I've already said but – so that it's very clear what we're talking about in WHO TB incidence countries greater than or equal 20 per 100,000, those patients two to 14 years of age would have now a skin test or interferon gamma release assay if less than 10 millimeters or if the IGRA was negative that patient would have no TB classification and could travel within six months.

If on other hand, the skin test was positive, greater than or equal to 10 millimeters or the interferon gamma release assay was positive, the patient would then get a chest x-ray which is a big difference from the previous 1991 Technical Instructions. If the chest x-ray is considered completely normal then the patient would get a classification of B2 status, meaning that they were felt to have latent TB infection and would be flagged for evaluation stateside once they arrived in the United States.

And again those who are HIV co-infected or HIV infected I should say would travel – needed to travel within three months, just given the increased potential for progression to active disease. If the patient have signs or symptoms or the chest x-ray was abnormal in any way or if they had HIV infection then they would need to give three sputum smears and cultures and

if they were all negative that would be – that would include the cultures, the patient would have a classification of Class B1 TB and would be followed up and could travel within only a three-month period.

If any of the smears were – smear or culture a positive, that is any of the specimens then the drug susceptibility testing will be performed on the positive culture and the patient would need to be treated to ATS/CDC/IDSA guidelines by directly observed therapy until therapy is complete and within – then could travel within the three-month period. So quite different from the 1991 TIs.

Now looking at the same algorithmic process for those greater than or equal to 15 years of age, there would be no treatment or testing for latent TB infection rather they get a chest x-ray and again the same algorithm if normal, travel within six months, signs or symptoms, abnormal chest x-ray or HIV infection, they would give three sputum smears and cultures, if all negative, Class B1 TB, if any smear was positive or culture positive, then again they'd be treated by our standards by DOT until therapy was complete and could then after therapy is complete could travel then within the three-month period.

And this just is for your own reference stating exactly what I've said showing the algorithm all together, again, in WHO TB incidence countries that had a rate of greater than or equal to 20 per 100,000, that's when the kids would get the TST or the interferon gamma release assay.

So then basically this then summarizes the travel validity periods and again summarizes that if the TB rate is greater than or equal to 20 per 100,000 the children between two and 14 would have TST or interferon gamma release assay; if it was positive then a chest x-ray.

If the patient was HIV infected or had TB signs or symptoms, again, they’d get a chest x-ray and if it's abnormal, they would have three sputum smears and cultures, if all negative Class B1, if one or more are positive, considered to be Class A and they’d have DOT, treatment under Directly Observed Therapy until cured. They could potentially qualify for a Class A waiver which when we listen to the cases I'll get into that.

So then in summary, comparing the two different TB Technical Instructions – I'm sorry, this is actually our classification slide just showing what the classes are now. So if the patient had a negative tuberculin skin test or a normal chest x-ray in those greater than or equal to 15, they'd have basically no classification.

If they are found to have TB disease, they're considered Class A. If they had an abnormal chest x-ray with sputum smears and cultures negative, they'd be considered Class B1 pulmonary; still need to be followed up on arrival. If they had extra pulmonary tuberculosis, then they're considered non-infectious and they'd be classified Class B1 extra pulmonary and actually could travel because they're non-infectious.

If the – and the children who had a tuberculin skin testing or interferon gamma release assays, if they were found to be positive on either of those test they'd have a Class B2 status and again be flagged for follow up once arrival in the United States. And then the last is Class B3 refers to those who are contacts to infectious TB cases, and these people, perhaps family members would then be flagged as Class B3 and would need to be followed up also upon arrival.

And another big part of the new 2007 TB Technical Instructions is the requirement for Directly Observed Therapy which did not exist in 1991 Technical Instructions and as we know DOT is an adherence-enhancing treatment strategy and is considered the standard of care for TB treatment here in the United States where a trained health care worker monitors a TB patient as the patient takes every dose of anti-TB medication; checking clearly for side-effects to medications prior to administration and checking to ensure that the patient actually ingests the medication without cheeking or spitting out or any other process.

So under the Culture and Directly Observed Therapy TB TIs, Directly Observed Therapy must be administered when TB disease that is Class A condition is present even if it's a clinical diagnosis, if the patients under treatment for active tuberculosis, they would require – they will be required to have Directly Observed Therapy.

So in summary comparing the 1991 TB Technical Instructions with the current Culture and DOT TB Technical Instructions; no skin testing was performed in 1991, there's no requirement and now we do have a requirement for those patients ages two through 14 if the country TB rate is greater than or equal to 20 per 100,000.

Chest x-ray was required for those greater than or equal to 15 years of age and the chest x-ray is required in that category as well as if a patient has a positive test for latent TB infection.

In the 1991 Technical Instructions, there's only requirement for smears, now culture and drug-susceptibility testing has been added for three specimens. There was no requirement for directly observed therapy in 1991 and now there is using new United States guidelines until treatment is completed. The validity period was six months if Class A or Class B back in 1991 and now is shorter.

And again, here the classes are similar, the Class A, you can't see the A but no classification if there's a normal evaluation. Class A if there's TB disease, Class B1 pulmonary, essentially the same except that now cultures have been added if cultures are negative.

Class B1 extra pulmonary remains the same, Class B2 now, used to refer to inactive tuberculosis and chest x-ray which of course we discussed is a bit of an anomaly since it’s difficult to call tuberculosis inactive based on the chest x-ray alone; now Class B2 refers to latent TB infection and the requirement for evaluation.

Class B3 used to refer to old or healed tuberculosis, again, a bit of an anomaly and now refers to a contact that needs to be evaluated.

So the key points to remember are that the Culture and Directly Observed Therapy TB Technical Instructions are really designed to improve overseas TB detection and decrease importation of TB into the United States. And implementation is occurring now and must be uniform and Drew Posey from

the Division of Global Migration and Quarantine is going to speak more about the implementation in just a minute.

So here's the link for the TB Technical Instructions and I will stop there, acknowledge these folks for my slides and turn this over to Drew.

Eileen Napolitano: This is Eileen, thank you Sundari for that excellent review of background information and for sharing the rationale behind the changes to these guidelines.

Next we will hear from Drew Posey – Dr. Drew Posey. Drew is the Team Lead for Medical Assessment and Policy in the Immigrant, Refugee and Migrant Health Branch at the Division of Global Migration and Quarantine in the Centers for Disease Control and Prevention.

He will be talking about how the Technical Instructions have been implemented thus far and the processes behind this role out both here and abroad. Drew, we will turn it over to you.

Drew Posey: Well, thank you for the opportunity to discuss this and I think what Dr. Mase did was wonderful and it helped step this up and so I'm going to now focus on the implementation effort of these technical instructions that Dr. Mase just went through.

And I'll begin giving a little sense of the fact that this has been a phased implementation effort over the last several years once these new instructions were developed and first started to be implemented in 2007.

And as we’ve worked to phase it in we've based our plan around to prioritize based on factors such as the number of immigrants and refugees arriving in the United States, the source country's tuberculosis rate and source country’s contribution to the United States’ tuberculosis rate as alluded to, we think that this implementation effort can provide some benefits in the source countries to help develop the culture and directly observed therapy infrastructure as well as to help link panel physician programs with broader control efforts.

And we think that this has some benefits for the United States, particularly to help lower the tuberculosis rate and reduce transmission, particularly in the foreign born. To provide a sense of volumes and perspective, this is a graph showing the arrival flow of legal permanent residents to the United States over the last 112 years.

And as I think we're probably all familiar for our legal permanent resident arrivers each year, we're referring to status adjusters, persons who are already living in the United States and then trying to adjust their immigration status, those are persons who are examined within the United States by a civil surgeon and also referring to entrants which are your persons arriving on an immigrant visa or a refugee and those are the persons who are screened overseas by panel physicians and among those entrants, four percent arrived with a B classification in 2011.

And so roughly, out of the roughly 1 million each year, about half are persons examined overseas which has been the focus of this implementation effort and these panel physician Culture and DOT TB TIs.

So overseas there are 369 panel physician sites located in 151 jurisdictions or countries. The CDOT TB TIs or the TB TIs we're referring to have been implemented in 64 jurisdictions, there are 620 panel physicians worldwide and CDC has been able to visit approximately 20 countries per year during this implementation effort. And this – the map on the screen, the dots are for each panel physician site around the world.

So when we say that this has been implemented in 64 countries this translates to 77 percent of immigrant visa entrants arriving to the United States have been screened according to the Culture and DOT TB TIs but also means that about 77 percent of U.S. diagnosed foreign-born cases were born in countries where the TB TI have been implemented, and about 90 percent of the persons arriving in which there's a TB notification done – we'll talk more about in the notifications to receiving health departments later on but 90 percent of the persons arriving with a TB notification are from countries where the TB TIs have been implemented.

This map shows you where around the world the screening is currently being done according to these new technical instructions. The countries in red are where it has been occurring and I think we can see a lot of countries that we're very familiar with when we think about U.S foreign born TB control with many others and ultimately as we'll discuss, this does have to be put in place around the world such that the whole map except for the United States because that's where they're coming should be red.

So when we implement these technical instructions we have a certain overarching strategy that we try to follow and in particular when it comes to site visits. When we undertake a site visit to a country that is not yet screening according to the new TB TI, we want to evaluate and teach the panel physicians on the new instructions, inspect candidate laboratories as well as candidate DOT sites and meet with tuberculosis officials. It may be National Tuberculosis Program officials but within countries we try to identify who is active in tuberculosis and try to build relationships with them in order to accomplish implementation.

We work to educate the consular section staff members because they are the ones involved with the panel physicians and the applicants from the industries for their immigration work and then develop an implementation plan and perform focused follow-up as needed to carry that plan for ward to implementation.

Now let's look at the two big key areas as Sundari talked about, the laboratory and the treatment component. So for laboratories, this is actually picture on the left showing a technician in Vietnam, one of our largest source countries inspecting a sputum specimen that has been provided and also in the upper right, many of you may recognize that as a liquid culture machine known as the BACTEC MGIT 960 that's formed – it has been a real workforce and a back bone of many of the laboratories that have sprung up to help support this effort.

So we face some challenges around the world on the laboratory front. Around the world many national TB programs for their national guidelines and policies have a lack of a requirement for cultures as a standard of care.

So some of these bullets may seem a little redundant but they follow one another; with the lack of requirement for cultures, there's a subsequent lack of culture laboratories and from a lack of culture laboratories we find a lack of quality culture laboratories to be able to support this work and it also stands to reason then, we've also experienced a lack of second-line drug susceptibility testing related to a lack of capacity up front.

So to try address that in addition to partnering with different organizations and trying to build this relationship there have been new laboratories developed around the world, performing solid and liquid cultures and in some instances, second-line drug susceptibility testing in order for these panel physician sites to fulfill the requirements of these technical instructions.

So you see on the slide that new laboratories were developed in China, India, Kenya, Malaysia, Mexico, Nepal, Thailand and Vietnam, these have been some of our largest source countries through the years as well as some countries that have really had a very high burden of tuberculosis in their screening populations.

There are some other laboratories that while they may have been in existence they were really revamped and capacity greatly increased and as I mentioned a second ago, there's a few laboratories that are providing – performing second-line DST and this influx and infrastructure around the world and having laboratories move to second line DST is something we're really proud of and excited about and we think this really – is something like a great contribution for a screening programs but also can have other benefits that we'll allude to in a slide later on.

So let's talk about treatment for a second and this is – these pictures are from – showing some refugees receiving treatment for tuberculosis and I believe these are in Thailand and the Burmese refugee camp at a DOT site managed by the International Organization for Migration.

We found numerous challenges with the DOT such that in many countries but not all but in many, it has been easier to implement the laboratory component

than the treatment component. In many countries directly observed therapy just may not exist and that may not exist as a standard of care.

We find issues with first-line therapy. There still are national TB programs that use an eight-month regimen for a first-line treatment. What I'm specifically referring to there is the initiation phase may be similar to what we use in the United States but then they follow that with a six-month continuation phase of Isoniazid and Ethambutol , the WHO recommended this no longer be used. I think now a couple years ago and I was actually tempted to remove this from this slide but we had a site visit to a country a couple of months ago where they actually went to a proposed directly observed therapy site for the National TB Program and found boxes of Isoniazid and Ethambutol combination pills that are well within the expiration date and currently being used for treatment. So it is still being used.

For second-line drugs we have seen some big challenges. As many of you may know, there are limited manufacturers for second line drugs and limited supplies and I know that in the United States we've at times seen limitations in supplies of certain drugs. So that is definitely seen overseas.

As we all know some of these drugs are very, very expensive and interestingly some countries own National TB Programs or Ministries of Health may have import restrictions.

MDR-TB expertise can be lacking and there's been issues maneuvering with the Green Light Committee on this throughout the years. Through all of this we have forged – we worked hard to try to forge linkages between the screening programs in-country efforts. We have tried to be very aggressive about this because we believe that if we can improve screening for U.S. bound populations that can be great and wonderful as it pertains to identifying and treating TB in those folks.

But we're cognizant of an increase in TB infrastructure and expertise thorough this effort and we want this effort to be able to link with broader control efforts because we believe if this can make a contribution to in-country efforts then in some small way, we can begin to make a contribution more broadly

and in the long run if TB control is improved within source populations that helps TB control in the populations coming then to the United States.

There was an article a few years ago where – Kevin Schwartzman was the lead author that talked about that concept in investing in TB control and source countries in the long run could yield a greater return investment than merely fine tuning screening programs.

So we've tried to forge these linkages, I'm not going to go over all of them but we've seen some great things such as a novel public-private partnership in the Dominican Republic between the panel side and the National TB Program there. IOM has been a great help in some cities working with NTPs and actually helping import second-line drugs and we've even seen for our refugees coming to United States from Nepal a campwide tuberculosis program where not just the refugees coming through the screening programs are receiving these types of services but the entire camps have access to a culture-based DOT system for TB control.

We've talked about some of the challenges implementing I’ve highlighted – we see a lack of standard of care in many countries with things like cultures or directly observed therapy. So because of that lack of standard of care, we come across many folks who aren't familiar with more of this type of rigorous approach to tuberculosis and so whether to address that or just to educate people on the technical instructions themselves we worked hard during that time period to really establish and develop a comprehensive education program for panel physicians and it's involved many entities including in the first bullet to help address the basic tuberculosis education deficit we've seen in some countries.

The RTMCCs began allowing panel physicians to attend the clinical intensive courses and this has been really widely appreciated and we've always gotten great feedback on this, we think has been wonderful for panel physicians to come to the clinical intensive courses and be able to receive education first hand on the types of things that really underlie and helped to drive the development of these technical instructions.

We started holding training summits around the world where panel physicians could come in and receive training over a few day period; we've held nine of these beginning in 2008, the International Panel Physicians Association which is an association to represent panel physicians was formed over the last few years has become a partner in these and Cellestis has also been a co-sponsor.

We've had webinars including two most recently, we developed a LinkedIn site on our Web site, there's a panel physicians portal to try to crystallize and organize information in an easy way for panel physicians. We have an online training module and development and also we provide training directly for the consular officers given their unique and key role.

So the overseas training summit, I want to walk through the next several set of slides which is a time lapse showing the coverage we've been able to achieve in terms of countries that have had personnel come to a training; and again, this is something we're very excited about and proud of. So our first one was held in 2008 in Jordan, then in 2009 we held training summits in Nairobi – excuse me, Nairobi and Manila, in the Philippines. In 2010 we held training summits in New Delhi, Ghana and the Dominican Republic.

In 2011 we held summits in Thailand and Peru and earlier this year we've moved to a yearly model, we held one in Istanbul, Turkey to try to pull in more folks from Europe and the Middle East.

So you can see – and again, we're very excited about this that we've had over this implementation time period, panel physicians and counselor officers both from IOM and non-IOM on the panel physician side come to training – these training efforts from all the countries you've seen in red and we continue to work on how we can improve on this and get even greater attendance.

I mentioned earlier on the treatment issues a lack of MDR-TB expertise. Well, as we put this in place it was recognized early on that the physicians need to have a way, a lifeline if you will on difficult cases, whether they be drug-resistance or just complicated clinical scenarios and we've been able to work with DTBE and the RTMCCs on setting up a clinical consultation

system whereby the panel physicians can access the network through the RTMCCs that physicians in the United States access.

We think this has been a really outstanding and wonderful service that's been provided and a wonderful lifeline if you will for the panel physicians and you can see over a couple year period that this got going, a large number of consultations from a wide variety of countries and it's striking to me of the 53 during that time period almost half are for MDR-TB.

I think really underscoring the importance of this service and how valuable it is and why we get great feedback from panel physicians on it. So – but once this is implemented and things are in place, that doesn't mean our work is done, we do try to do different things to keep tabs on it and make sure there's good follow up and evaluation and monitoring activities and so we certainly conduct follow-up visits when needed.

But another thing I want to highlight is onsite really in-depth thorough TB evaluations that have been led by representatives of ACET and NTCA, these have been widely successful. We got – first one was in IOM in Thailand in 2007, we've now done five. The Santo Domingo, Dominican Republic one just concluded a month ago or earlier this month, actually.

We have found these to be invaluable from the DGMQ perspective to learn more and gain better insights into how – what we can do on these programs but especially for these programs themselves to have this caliber of experts to come in and work with them and evaluate them and teach them, and I think it really helps bridge the understanding between the panel physicians and what folks stateside maybe really interested in as well as for the folks stateside to have the access to these programs overseas and get a feel for what they're doing.

And so evaluation and monitoring activities are definitely something we work on and I'm hopeful as the years go by we can continue to do more of these types of evaluations.

So, how is this going and what does it mean so to speak? Well to give you a sense of how the data has shaped up, this is a slide from the Philippines, one of the largest panel sites on the world and the Philippines is one of the top source countries for immigrants as many of you know and this is a slide that compares the fiscal year before they implemented and the fiscal year after they implemented.

So they started screening according to the new instructions on October 1st, 2007, and so before then they were not doing cultures on persons who were smear negative. So we see – I want to draw your attention on the graph, you'll see these smear negative culture positive row where you see 306 in red, meaning the first year of screening they identified 306 people who are smear negative but culture positive and compare to the smear positive and culture positive row of 102.

And that dramatic increase, roughly a three-fold increase in yield consistent with the data that Dr. Mase showed from the study in Vietnam and is a pattern we see replicated in many, many countries. But this shows the tremendous increase in yield that can occur by moving to this culture-based system.

So, someone could ask, "Well, that sounds great." Does that have an effect state side? And Phil Lowenthal was the lead author of the study that came out a couple of years ago where in California, they looked at persons arriving to California from Mexico, the Philippines and Vietnam and they looked at those arriving with a B1 classification and their rate of tuberculosis before and after implementation. Meaning, when they had their follow-up exam, what percentage were diagnosed with tuberculosis?

And what this graph shows is that before the TBTIs were implemented, because this was implemented in October of '07 for Mexico and the Philippines in February of '08 for Vietnam, we see the rate of diagnosis post arrival around three and a half to five and a half percentage range. And then after it was implemented in these countries, we see it fall and now it's hovering in the .5 to 1.5 percent range, a decrease.

We're very excited about this. This is one of the things that for us is what it's really about, you know, being able to not just find these people, and diagnose them and treat them but see the gain in TB control stateside.

In Minnesota, they did an analysis that looked at how their foreign-born epidemiology has shifted and they find some decreasing rates of diagnosis in their population coming in among their immigrants and refugees. So we're very excited about that.

So aside from seeing some changes in the epidemiology and the case detection rates, we do think this can have an economic or is having an economic impact and is providing some cost segments to you as domestic programs.

When we look at our programs around the world and we have something called TB indicators where we require them to tell us the number of cases they're diagnosing, we know that they're diagnosing over a thousand persons worldwide of culture-positive tuberculosis amongst all these screening programs.

If 4 percent of those are MDR TB, that'd be about 40 MDR cases per year. So when we think about that and we look at costs of treatment in the United States and some of the published figures, we do believe this is a cost savings or perhaps cost aversion of upwards of 13 to maybe more than $30 million per year by this increasing detection and treatment overseas and freeing up those funds to be used elsewhere for other important activities at the receiving health departments. And I say that way because everyone is tight for funding right now.

But we do feel this is leading to some significant cost savings as we get these people diagnosed and treated overseas. So we're very excited about this program, but we do feel – we've come to a point where we need to – needed to figure out, and be working on wrap it up and close it out. And as we think about closing it out, we want one global standard for screening requirements for all the populations coming to the United States. We want to complete the gains in U.S. TB control among the foreign-born that can be achieved through

this program. We want to do this in a way that maintains CDC leadership in global TB control.

And so, we work on developing a closeout strategy where all panel physician programs would be screening according to these technical instructions by October 1st, 2013 or basically the first day of fiscal year 2014.

In working with the Department of State over the last several months, we're trying to develop a strategy. The Department of State issued a cable, which is their method of communicating with the embassies and consular sections around the world. And that cable is issued on August 30th of this year stated that all panel physicians worldwide should begin screening according to the culture and DOT TBTI as soon as able and no later than October 1st, 2013.

That date was selected because it would provide a concrete to the implementation plan. We believe this is achievable given the progress that has been made this far. It provides the implementing countries, at least 12 months of transition, at least 12 months at the time of this announcement in August. And it's beginning of new fiscal year for the U.S. government for many embassies, the start of a new fiscal year provides a good time for them to have new things begin.

So during this fiscal year, our division has a very aggressive travel schedule for the remaining countries, again, based on immigrant refugee volumes and TB burdens. And also, we can’t underscore the importance of our training activities as a way to help the remaining countries, whether that be through Webinars, which we've already done for panels and consular officers on this.

The panel physicians’ portal help disseminate information. And for the training summit, next year, we're going to have our 2013 summit here in Atlanta, Georgia, March 4th through 8th. And we're already seeing good turnout. As of today, we already have more than 50 panel physicians who’ve already registered to date, which we're really excited about and given we're still three months away from the summit.

So to change gears slightly, we've mentioned a few times the notifications to receiving health departments. And that is done through our electronic disease notification system. And so, EDN, as we call it, is great because DGMQ has a regulatory responsibility to provide information to receiving health department of arriving aliens with the notifiable condition. And so, EDN is the electronic system to fulfill this regulatory responsibility. For many of you who have been doing this work for a few years, you probably recognize that EDN replaces a previously used paper-based immigrant and migrant populations or IMP or IMP system.

But EDN has a couple of features that we really like. It provides you access to the recorded DS form information as well as off-stand overseas DS form. DS forms being the paperwork with the panel physicians complete on their examination.

And it also provides health departments with an electronic system to record and evaluate the outcome of the domestic follow-up evaluation. And that I think, particularly as we now start to think about the impact of these technical instructions that follow-up data in EDN just becomes more and more important as time goes by.

So this is a schematic to help show how the process works. So, overseas, panel physicians perform the screening of the applicants for immigration, the immigrants and refugees and they complete the DS forms, the overseas forms on the slide.

The immigrant or refugee arrives in the United States, that paperwork is routed to quarantine station officials who send it via FedEx each night to the EDN data entry center here in Atlanta. There is also, some of you may be aware, an interface with IOM so that we get some records electronically for those persons whom IOM examines overseas. That also makes its way through that interface for the data entry center and then the information is transmitted electronically through the receiving health department.

And then when the follow-up examinations occur, the information from those examinations is fed back into the EDN system. And finally, we've mentioned

that, you know, the bulk of this presentation from Dr. Mase's portion going through technical instructions and my portion talking about implementation is dealing with the overseas medical exam or the examination performed by panel physicians.

But we did want to mention there is the other path for immigration, the status adjuster path where those persons receive their examination in the United States by a civil surgeon, and they do have a set of technical instructions that they follow. There are some similarities. A few years ago, a new set of civil surgeon technical instruction went into effect, Dr. Mary Knott, the senior medical officer at DGMQ, led that effort and got input from DTBE and the TB community. And likewise, it helped transition to using modern standards of care; requirements for cultures, and also update guidance regarding LTBI infection. At that time, we worked on some issues with USCIS. But these have been in effect since 2008.

All right. And that is all the slides I have.

Eileen Napolitano: OK. Thank you, Drew, for your excellent presentation on the implementation and rollout of the technical instructions.

We will now turn back to Dr. Sundari Mase who will present some case examples for us. She will also ask a few questions which will require you to answer questions online. If you are listening in a group, you may want to designate one person to answer the questions for you.

Sudari, I will turn it over to you.

Sundari Mase: OK. So what I wanted to do was just to give a few examples of some cases that Drew mentioned that the Regional Training and Medical Consultation Centers, that are CDC funded are now providing consultation to panel physicians overseas for complicated, challenging or drug-resistant cases.

And I have two examples with such consultations that have happened in the last few years since we've implemented that program. The consultation service similar to the consultation provided for domestic TB cases, and any question can be asked, but we're finding that the questions that we're getting

from overseas panel sites are generally very complicated of MDR-XCR type cases, and I'll give an example of two of those.

And then I also want to give an example of a situation in which a class A waiver has been granted for a patient to come to United States despite being on TB, treatment for active TB disease and we at Division of TB Elimination work closely with the Division of Global Migration and Quarantine to hear these cases and try to help make a determination of whether the patient is infectious or not and whether they're extenuating circumstances that would compel the patient to arrive or come to this country before TB treatment is over.

And generally, it has to do with whether they would get better or – would get optimal care here with extra consultation for very challenging case. So, anyhow, let me go ahead with case number one, and there'll be a few questions, some of them are treatment related and please feel free to answer if you'd like.

So case number one, this is one of the consult case that came in to one of the regional training centers. So this is a 32-year-old Vietnamese female who – a visa applicant - with no prior history of TB that had no signs or symptoms of TB. Again, this is active screening, so often these people don't have signs or symptoms of TB. Sorry, I think – here we go.

Here's her chest x-ray. Now, as you can see, she has significant right upper lobe disease, possibly cavitary, infiltrates possibly right lower lobe that’s a trait as well. So, a chest x-ray that's pretty much consistent with TB.

She had three AFB smears and cultures that were positive on October 12th, 13th and 14th of 2011 and was referred to the panel site hospital for TB treatment by directly observed therapy. So she was an immigrant visa applicant and it was the panel site physician that consulted the regional training and medical consultation center.

She was started by the treating physician in Vietnam on a standard four-drug regimen per our standards. And shortly thereafter – sorry, it must have gone on here. Surely thereafter, DSTs for first-line drugs showed resistance to

isoniazid and streptomycin. But the isolate appeared to be susceptible with the rifampin, ethambutol, and PZA. The isoniazid was appropriately stopped in December 14th of 2011.

But she had persistent positive cultures for five months. So she did not culture convert on an appropriate regimen for INH-resistant disease. So, go ahead and feel free to ring in. What would be your next step? Would you repeat first-line drug susceptibility testing given that she’s still culture positive?

Repeat first line testing and perform second-line drug susceptibility testing, do both one and two and start an expanded MDR regimen or do one and two and perform some sort of a PCR-based test looking for mutations conferring resistance.

Certainly, when someone is still culture positive five months after being put on what we consider an appropriate treatment regimen, it's worrisome that something isn't right, that either there's further resistance that hasn't been detected or that patients maybe not absorbing meds, right, taking the meds appropriately, or something else is up.

So anyone of these answers would be appropriate I see that most people thought they would repeat first line DSTs, perform second line and start an expanded regimen. So let me go on and say – again, things aren't always done overseas the way that we would do here. So this facility, this panel site has the option to get a rapid test for drug resistance testing based on mutations, PCR-based assay. So this doctor sent the specimen for the Hain Genotype MTBDR plus assay and found that there were mutations associated with both isoniazid and rifampn resistance on January 31, 2012. And then he also repeated the first line drug susceptibility testing. But the phenotypic results showed just resistance to isoniazid and streptomycin and the isolate was still susceptible to rifampim, ethambutol, and PZA.

So basically a discordance between the genotypic and the phenotypic results, which is pretty complicated. So, the question that he asked through the consultation service was what should be done, in other words, what should be

the clinical approach given the discordant genotypic and phenotypic susceptibility results. In this patient who obviously or appears to have evidence of treatment failure since she have culture converted in five months. So what would people on the line – would you continue the current regimen based on the phenotypic result thinking that it's only INH resistant? Would you add moxifloxacin to the first-line regimen to boost the regimen or would you treat with an MDR TB regimen at this point given that you have mutations showing both isoniazid and rifampin resistance?

Well, I guess most of you could be consultants at one of our Regional Training and Medical Consultation Centers because that's exactly what the recommendation was.

So the consultant at the regional training and medical consultation center noted that even with the phenotypic evidence of rifampin susceptibility, there's genotypic evidence. In other words, mutation – a mutation was found showing resistance to rifampin. So, rifampin is likely compromised in this case.

The consultant also said that he would obtain second-line drug susceptibility testing right away and treat it with an empiric MDR TB regimen based on these results. And we see this discordance even here at CDC lab and other labs in our country where there is an evidence of genotypic resistance, but not phenotypic – and in this case, I think the really key point is the patient is not doing well. She is bacteriologically still positive, culture positive. And although we don't have – we weren't given data as to whether she – her chest x-ray was worse or better or whether she was clinically worse or better, we know that she's bacteriologically failing.

The other recommendations by our consultant were to get molecular testing, if at all possible, for fluoroquinolones and aminoglycosides as our CDC lab now does through their molecular detection and drug resistance service. And also stated that they may consider using rifampin but not count it as part of the regimen given that the likelihood that it's effective is low since the patient was still culture positive.

Monitor monthly, screen for adverse reaction with second line agents and call back as needed. And one thing to note here is that the panel site can call back for ongoing consultation to – and if the patient – if a physician, whoever it is, has called once already, they'll be rerouted to the same consultant. But there's continuity of care. So, in this case, I think the panel physician was able to go ahead and treat the patient as if MDR-based on the consultation.

So let me go on to case number two and three in the interest of time and we'll take questions at the end. So this is another consultation that came in to one of our Regional Training and Medical Consultation Centers, a 31-year-old female U.S. immigrant visa applicant who's diagnosed with smear negative culture positive, INH resistant pulmonary tuberculosis.

And here's her x-ray, clearly again, abnormal showing right lower lobe effusion, pleural effusion, likely with sort of – I can get that little pointer here with some tracking – if you were to get a lateral decubitus to probably layer out. And likely a right lower lobe infiltrate as well that might be hidden behind the effusion.

So this patient was started on rifampin, pyrazinamide, and ethanbutol. She weighed 35 kg so that rifampin dosage appeared to be correct for her weight. And she was started by direct observed therapy on November 2nd, 2011. Apparently had some nausea after two weeks, but didn't report her symptoms until she's had a month of doses and when she had her liver function test done, this is actually what was in the consult note that her SGPT was 35 times the upper normal limit, which I find hard to believe that's what the physician reported.

So what would be your next step? And again, you know, there's really no correct answer but just to get us to think about it would you stop medications or continue medications and follow clinically or would you consult an expert? And of course, these aren't mutually exclusive, one and three could be done as well. But what would be the first thing you would do?

So I think most people would stop medications given that we have such high elevations and liver function tests. This is the kind of situation in which potentially you get in to real trouble with hepatotoxicity and liver failure.

So – and of course, consulting an expert would be also a good idea and could have put fourth option of doing both of those things. So the medications were stopped. Once the liver function tests were normalized again, this physician in the panel site restarted medications at a lower dose.

I could have put in a polling question here, but just in the interest of time, let me say that to give lower doses of the same medications is generally not what we would do in the phase of hepatotoxicity from medications. We would probably more likely stop on medications and restart them sequentially to figure out which medication is causing this because the likelihood that this patient will again have toxicity is high if the same medications are given.

But that's what this patient – panel physician did prior to consulting our training centers. Then again, of course, as we would expect, the liver function tests once again were elevated at four and a half times of upper normal limit. And I guess at this point, the regimen to be used – and I haven't put in a polling question, but clearly at this point, what the panel physician wanted to know when consulting our team to see is what would be the next approach and what regimen would be appropriate.

So our consultant appropriately stated that they are concerned about the low dose of rifampin, 300 milligrams per day and stated that with INH resistant disease, we don't want to under-dose the rifampin and risk the development of further resistance.

So rather than just answer the question, generally, our consultants through the RTMCCs try to address the whole picture for the patient, and that's why this consultant weighed in on the doses. And also stated that in all likelihood, PZA could be the most likely offender. And as we would do per our guidelines, restart rifampin and the ethambutol together given that ethambutol is not hepatotoxic and check liver function test. And if the liver function tests remain normal, do not start PZA again, add a fluoroquinolone to boost the

regimen and repeat the drug susceptibility testing to ensure no further acquired resistance. And this patient did well. That liver function abnormality appeared to be due to PZA. There was actually quite a bit of back and forth between the consultant and panel physician and the patient completed treatment and did well.

So there were two examples of the kinds of consultations that our Regional Training and Medical Consultation Centers are getting from some overseas sites. So let me move on to case number three, which is our adoptee case. We have a lot of requests in adoptees overseas from different countries, whether it'd be China or Ethiopia. These are the common places where we get these requests from.

For waivers for these kids because kids are considered generally to be non- infectious with paucibacillary disease. They don't – they’re not often smear positive with cavitary upper lobe disease as adults are. They often have primary TB. And generally speaking because they're so much less likely to be infectious, the thought is that U.S. adoptee – that is the parents that are adopting the child would rather see the child treated here in the United States than treated oversees with treatment completion. So we get a lot of this requests and with DGMQ, we listen to each one of these cases or review each one of these cases individually looking at the circumstances, the x-rays, the amount of treatment given and make a determination as to whether from the TB standpoint, we make a determination of whether the child could be infectious and then DGMQ makes a decision on whether the patient should get a waiver to come to the country early before treatment is completed or not.

So here's an example of a case like this, two-year-old Chinese adoptee, diagnosed with scrofula or TB lymphadenitis. In a certain province in China in mid-December 2009, the patient was hospitalized for TB treatment but not at the panel site facility, had no evaluation for pulmonary TB in the hospital where she was admitted. And the U.S. adoptive parents then arranged for panel site evaluation.

January of 2010, the patient was evaluated at the panel site, had a skin test. It was 16 millimeters and had a biopsy showing changes consistent with TB

from the biopsy. The chest x-ray was performed, which I'll show in a minute, and gastric aspirates collected – were collected at the panel site. Again, these evaluations are generally done per U.S. standards at panel site. So gastric aspirates are sent, and the child was returned to her province to continue treatment while waiting for results.

So here's the child's x-ray. Again, it's a little bit – a little difficult perhaps to interpret. But there appears to be some abnormality in the left side, left upper lobe, possibly, you know, left – some increased markings and possibly some left lower lobe disease as well, and possibly some calcified mediastinal nodes

That was definitely an abnormal x-ray and the lateral here doesn't really add that much but shows similar findings. So interestingly enough, all three of the gastric aspirates are smear negative but ended up being culture positive. And the drug susceptibility test results showed resistance to all first line drugs and streptomycin and were performed twice to verify that there was any kind of an error.

So it was pretty clear that the child had MDRTB. So what might be your next steps here? Stop the first line drugs, obtain second line drug susceptibility tests, start an expand MDRTB regimen, refer back to the panel site for treatment and, of course, all of the above is one of the choices or no vote.

OK. Let's go ahead and close the poll. I want to leave about 10 minutes for questions. So, all of you could be the RTMCC consultant I supposed because I agree with all of the above. So in this case, the patient actually completed the initiation phase of TB treatment at her hospital in her province, the province because the results weren't available yet that patient had extensive resistance, but was reevaluated at the panel site on February 25th, 2010. At that time it was about 10 kg. Was found to have two red, swollen supraclavicular lymph nodes that were three by nine. I think – I'm not sure that's centimeters. I think it was transcribed incorrectly, probably not that big. But that's what it was said in the panel physician's note.

Asymptomatic per adopter family and another chest x-ray is obtained, was felt by the panel physician to be largely unchanged. This could just be in – as a

result of technique. But it really does appear that there is an abnormality in this area still. And the patient had not been on an MDR regimen yet, so it could even be a little bit worse. So, the panel physician thought it was about the same. Here’s a lateral that doesn't add much.

Second line drug susceptibility testing was ordered and the patient was placed on a pretty reasonable MDR TB regimen including an injectable fluroquinolone and three other drugs that the isolate was likely to be susceptible to, including linezolid, which is a pretty – a fairly expensive and effective drug that we use here in the United States. So it was a good regimen.

The patient also being two-year-old had a head CT and a lumbar puncture, both considered to be normal in this particular laboratory four white blood cells was considered normal. And the head CT was normal.

But the gastric aspirates smear taken in March 9, 2010 was still positive. And the patient continued to be asymptomatic and was actually accepted by the receiving county of origin in United States where the parents, the adopting parents lived. So that was – that's one requirement that they need to be accepted by the receiving jurisdiction.

So in this case, the patient has not been on appropriate treatment for the two months that she's been on treatment. She still has a positive gastric aspirate smear, but is asymptomatic. So I guess that, you know, you probably don't have the data to make the decision, but would you think a waiver for immigration right away should be granted for this child? In other words, what's the likelihood if the child is infectious and what's the likelihood if the child would have optimal care in the receiving jurisdiction rather than in the panel site? I mean, I supposed the way to look at it is what would be best for the child is the way to look at this, I suppose.

So I'll give you a few seconds to weigh in. OK. Let's go ahead and close the poll. So you made a decision that jointly, you know, we at the Division of TB Elimination felt that the child was very unlikely to be infectious given that she was asymptomatic, there were no sputum specimens to guide the decision.

But the likelihood is very, very low that this child would be infectious and the Division for Global Migration and Quarantine then made the decision to grant this child a waiver and immigration in the United States is expedited. And again, the reason was to ensure within the care of the adopting parents for the patient.

So I'll stop there and see if there's any questions. Those are the case presentations.

Eileen Napolitano:Thank you, Sundari, for these great examples, of the kinds of cases presenting at the panel sites. I did also want to introduce Mr. Phil Lowenthal who will be joining the discussion period. Phil is an epidemiologist with the Surveillance and Epidemiology Section in the Tuberculosis Control Branch at the California Department of Public Health.

He was involved in the piloting of these new TB Technical Instructions in California, and is here and available to provide his insights on the field experience with these instructions.

So let me post the first question– one of the first questions that we received. And, Sundari, I think this can go to you. Are there any plans to use Gene Xpert to screen all culture positive applicants?

Sundari Mase: Yes, that's actually a great question. And since this is an implementation question, I'm going to send that to Drew because, Drew, you would know.

Drew Posey: Yes, I can answer that. And I agree, it's a great question, and something that gets – we get asked about a lot and gets discussed. So, right now, the panel physicians – at one part of your question, they are able to use molecular tests, such as Gene Epert or the Hain line probe assay. And some panel sites do, as it pertains to running those tests to try to get an earlier indication of someone may have multidrug resistance tuberculosis and by having an earlier diagnosis get either the full second line DST and focus on treatment sooner.

But at this point, we don't allow those tests to be used in lieu of cultures for the purpose of screening or clearing someone in order to obtain a visa. And the reason is because of the fact that there is a drop-off and sensitivity

between liquid cultures and the Gene Xpert test. So for now we still require the cultures for clearance purposes to get the visa.

Eileen Napolitano: Thank you very much. Another question that came in via the internet or – perhaps it's more of a comment. And that is that many immigrants say their chest x-rays were taken by immigration officials upon arrival. And additionally, there is – they don't usually come with their drug susceptibly tests. Can you comment on that?

Drew Posey: This is Drew. I can comment on that. That is good to know that occasionally we do hear about persons saying their chest x-rays are taken by the folks at the port of entry specifically the customs and border patrol officers when they immigrate and so we can follow-up and try to get that reminder out to those officers again that they should not be taking those films.

And just so folks know, persons may arrive with either their plain chest x-ray film or if it's a location using digital x-rays, they may have a CD with them. And in terms of not having drug susceptibly testing results, that's something if we know of specific instances, that's a little better to target because the panel physicians are supposed to include that with their medical information. And so if anyone does see a trend unique to one country or a few countries that can always let us know when we can follow up directly with those programs overseas to make sure that is included.

Eileen Napolitano: Excellent. Thank you very much.

Dr. Clark: Hi. This is Dr. Clark. You mentioned to what you said about patients coming, I haven't had a – many patients that are active. But a lot of them have had their physical and everything done and their chest x-ray automatically done at – before leaving the country to come in to United States. But they don't come with any paperwork, so then we have to do it again when we find out that they're QuantiFERON is positive or their PPD is positive.

And that surprises me because they're actually positive. If they're positive here, they'll only be here a couple of months, and they were positive when they left their country if they had been tested instead of just having a chest x-ray done. And they state that they only had a chest x-ray done, they're not

aware that they had a blood test or a PPD test. So I'm not sure if they're screening them that way and just saying, "OK, well, your chest x-ray is fine. When you come here" – and they're very resistant to want to go on latent TB medication because no one explained it to them.

Drew Posey: This is Drew. I think that's a great point. And a couple of things come to mind. As soon as we went through, from what you said a few things could be playing out – just try to go through them in no particular order. But from what Dr. Mase described, the skin testing and IGRA overseas is only done for the applicants 2 to 14 years of age where the TB rate in the country is placed 20 per 100,000 or greater.

So persons 15 and up would only get an x-ray and – you're absolutely right, they would not get a skin test or an IGRA test done. The other thing that comes to mind from what you're describing is in the notification system for EDN, that whole apparatus, EDN does notifications for all arriving refugees regardless of their examination findings, all 50,000 or more refugees who arrive each year. There's notification EDN.

However, for the immigrants, notifications are only done if there was a TB classification on the overseas exam. And so, I mentioned that because you mentioned folks coming in and not having paperwork on them. If by a chance you're seeing someone who had a – who did not have a TB classification overseas, meaning someone who had a normal exam basically.

There would not be a notification on them if they were an immigrant. I don't know if that information is helpful.

Dr. Clark: No, it's helpful. I have two other one quickly. I know that people have questions. One is a question for Dr. Mase about the genotype, phenotype with the case that you presented. If the genotype was resistant, then unless you have funding or something, why would someone, let's say, do the phenotype, especially if you know that you're most likely going to not treat them with the two resistant medications.

And then my second comment before you answer that is that I actually am concerned sometimes with my patients who are American patients and some

immigrants who have been in the United States for a long time because – and treated because what I'm finding is that they are at risk for TB. But when people are looking at that, they are asking them questions for college and for school. And if they answer no to it, it’s at the bottom of the line of the college form or the school form, it comes out that all the questions were answered no. They don't need a TB test.

Yet, when they come to me to now fill out their green card, I'm telling them they need one. And actually, when I look into their risk factors, they should have had one. I'm not sure who's making up these forms for college and school here.

Sundari Mase: Right. Great questions. First of all, there are instances where you can have genotypic resistance, but it's a silent mutation and it doesn't confer phenotypic resistance. And we have those cases. They're rare. But I think really having both tests, is appropriate to kind of dictate how to proceed. And then looking at the patient to see how they're doing. In this case, you know the key thing was the patient was doing well. So you wanted – you would want to go with the test during resistance simply because she was acting as if she was resistant. So using both tests is appropriate. In this case, it was great the panel site could actually have access to the molecular testing method.

Now, the second question, in college – colleges and school, generally, we do try to prioritize patients based on the initial questions if we're testing them because it's a way of performing targeted testing. And yes, you're going to miss certain numbers of people by doing it that way. But, you know, the data suggest they just screening everybody who enters college or who is in certain grade in school isn't really cost effective and doesn’t lead to great detection of real LTBI or for case finding.

So that's my reason why that exists. But, of course, when you see them for a green card, and obviously other risk factors, it's appropriate then to test them and proceed as you would otherwise.

Dr. Clark: And I'm also a primary care, so it's hard when you see a patient with treated fracture, in California move to Connecticut and you find out, "Wait a second,

what do you mean your wife was never tested?" You know, he was getting the treatment quarantined at home.

So, yes, when I tested her now, she's positive, of course, she's probably positive five years ago when he was being treated. So people are getting missed in the – in regularly everyday life system that should be tested. Thank you then.

Eileen Napolitano: Thank you. We have a question about children, and that question is – and perhaps, Phil, you could share your California experience about this. In the case of a child, is this child that you are notified about with LTBI, are they showing up at local health departments or do you find that they're going to primary care physicians?

Phil Lowenthal: Hi. Yes. So we found with the two to 14-year-old children who arrive with a B2 LTBI classifications that they're primarily showing up at the local health department. And the health departments are actively going and, you know, contacting arrivers who have a B classification. They're, you know, of course, prioritizing persons who are TB suspects who had an abnormal chest x-ray on their overseas screening. But some health departments depending funds and resources are also contacting and scheduling follow-up evaluations with the B2 latent TB infection arrivers. So, yes...

Eileen Napolitano: And there's a follow up to that question, which is – so in the – as you are following up on this children, if they were under the care of private provider, would you – have you found that to be acceptable if you receive the information?

Phil Lowenthal: That's – yes, that's been the main challenge, is getting the information and transmitted from private provider to the health department. But, yes, that's acceptable from the state health department perspective.

Eileen Napolitano: Excellent. Thank you. Another question that has come in online relate to the HIV status. The questioner understood that HIV screening was no longer conducted for immigration purposes. And if that's the case, how is the co-infection status determined?

Drew Posey: This is Drew. I can take that. So, it's a great question. And the person who asked the question is absolutely right, that HIV testing is no longer a required component medical examination. What we have told panel physicians who are, by in large, well aware that it's an important risk factor for TB and important to know about someone's HIV status, is that when they diagnose someone with tuberculosis disease, that as you counsel that person about the importance of HIV testing and offer that testing. But it is up to the applicant as to whether they get that testing done and then where they have that testing. But there is counseling regarding HIV status for all TB cases.

Eileen Napolitano: Excellent. Thank you. Yes, go ahead, Mark.

Mark Labato: Yes, hi. Drew, this question is for you, we had this year an11-year-old adoptee from China who had pulmonary tuberculosis that was evaluated by the panel physician to put on four drugs. And for whatever reason, because she was living in an orphanage, the local doctor continued treatment.

And so, when we had worked with DGMQ, agreed that she was not infectious. But in review of her treatment records, there was some interruptions, there was a period of time where she was only on INH and rifampin during the induction phase. And so – and we're able to get the record from the treating physician, but not totally figure out the reasoning for this treatment.

And so, I guess my question is, is there a requirement that the person's treatment be under the – either direct management or at least consultation by the panel physicians, because, you know, we had difficulty in putting together a regimen once she got here. And I'm not sure, you know why her treatment was handed back to the local physician by the panel physician.

Drew Posey: This is Drew. So, it's a great question. And so, the DOT requirement in the technical instructions is that someone receive treatment according to a rigorous DOT standard. It can be done more than one way. There are programs such as the Philippines, which got discussed, where they have a DOT program in house.

It can be done as what was mentioned with the Dominican Republic where I reference their public private partnership where it is actually the national TB

program that is providing the directly observed therapy, or other, you know – there's a range in terms of other clinics that are able to do this – that the panel physicians work with. The key being the rigorous requirement. So, I hope that is helpful. On your specific case, unfortunately, I can't recall the specifics of that, but from what you're describing, maybe I'll find I'd be interested knowing more about that scenario so that we can provide any follow up in China that might be appropriate.

Mark Lobato: Yes, I don't think the question was the DOT since she was an orphanage so much as the drugs that were being used for the treatment. But, yes, we – I got the records through your division so I can send them to you.

Drew Posey: Yes. And the other point, I apologize that I missed that specific aspect of your question. Programs are supposed to be use regimens that follow the CDC/ IDSA/ATS guidelines, so. And that's a firm requirement of the program.

Mark Lobato: OK. Thank you.

Eileen Napolitano: Go ahead, Peter.

Peter Davidson: Hi. The first question is I'm curious why were the 1991 technical instructions so lax to begin with? I think Dr. Mase did a really good job in summarizing and really highlighting some considerable weaknesses. But I'm just curious why – I've always been curious why these guidelines were, you know, kind of very broad to begin with.

And then also, the second was more detailed with case presentation number one. Do you know what the concentration of rifampin would have been in the overseas drugs susceptibility testing? Because I know when we've been presented with discordant phenotypic versus genotypic results, that's kind of a question that comes up depending on which laboratory you're looking at. You could well be testing at a..you know, a lower concentration of rifampin where genetically you observe, you know, a change in the DNA sequence. But if you're not really challenging the organism typically it appears to be, I guess...

Sundari Mase: Yes, it could appear to be susceptible. Right. Let me take the second question and Drew can take the first. But just – I'm not sure exactly what concentration is tested at. But I know that...

Peter Davidson: Also, just – do you know that they're using same standards that we would here?

Sundari Mase: Right. You know, Drew maybe better to speak to that as well because these labs that are being – have quality control overseas and they are supposed to be using the kind of standards that out labs do. So Drew, maybe you can weigh in.

Drew Posey: You're exactly right. We're striving for very rigorous labs overseas.

Sundari Mase: And the testing is very similar – you know, even here in our country, different labs test drugs with different methods and different concentrations, and that's why we have discordance often. So your point is well taken, but I think there's some fairly standard concentrations that rifampin is tested at, like, any drug. So probably at – I don't know, I want to say maybe one and – I'm not sure. I have to go back and look. But we do have instances though that we have this discordance that we see, even here at CDC lab that's real, and then you really have to look at the individual patient to try to make a decision on how to treat them.

And, Drew, the first question, did you want to answer that?

Drew Posey: Absolutely. It's a great question. And if I'm paraphrasing correctly, it's the 1991 TB Technical Instructions why were they select in broad. My understanding is in 1991 when those came out, you know, maybe that those are pretty good. But over the years, we did let them get lax and didn't keep up with the modern standards of care, particularly on the culture front.

And even though we're talking about, you know, this time period of sort of 2005-7 in terms of developing this technical instructions and starting to implement them, there was a recognition before then that a smear-only system was probably inadequate and insensitive. And that helped form some of the

impetus of the Vietnam study that Sundari mentioned done by DGMQ and DTBE that had a publication date of 2006.

But as we know that, you know, the work then would have transpired well before that. And that was the case with that study. So there was – I can't speak to, you know, what exactly the tenure was in '91. But as the years went on, there was a definite recognition that they were likely inadequate which led to a study and work being done and the weight of evidence just became clear we needed to try to make that change and then try to implement it.

Sundari Mase: Yes. And if I can just add that the amount of resources that DGMQ has put in to establishing the ability to do cultures like this overseas is incredible, and being able to have quality control for the cultures and drug susceptibility testing.

It's been a monumental task. And I think back in 1991, the thought was, "Well, let's just find the most infectious patients and make sure that they're treated." And now, of course, the objective is to find all infectious patients and ensure treatment – ensure that there's no – that as few as possible that are going to fall to the cracks. So it's a different standard that we have now too I think.

Eileen Napolitano: OK. Thank you very much. I would like to think our great faculty for this webinar. Thanks to Dr. Sundari Mase. Thank you to Drew Posey and thanks for Phil Lowenthal for sharing his California experience.

Thanks for joining us today and have a good afternoon.