First of all, I would like to say thank you to CHESS for allowing me to be here and giving me the honor to present the opening of this joint symposium between ELAD and CHESS about tuberculosis and COVID. My lecture is going to be titled The Global Impact of COVID and TB. I work in Monterrey in the University Hospital and the School of Medicine over there. I have no disclosures to mention. In the next few minutes, I'm going to try to describe the dual burden of two pandemics, COVID and tuberculosis, and how COVID impact in the control of the TB programs and try to see what is going on for the near future regarding TB. As a reminder, I would like to mention this, the NTB strategy that was launched for the World Health Organization in 2015. You can see here that this was the trend for tuberculosis at that time, and the WHO wanted to decrease the incidence and the deaths for tuberculosis on a level that they call elimination, not eradication, but elimination. Basically what I did, they promote the rapid diagnosis with molecular tests, the rapid treatment with new drugs, short therapies for patients with active influenza and tuberculosis. And we were doing like that. And when COVID was killing a lot of people at the end of 2020, we can see in the past year, sorry, tuberculosis was already there all over the world, mainly in Asia, Africa and Latin America, but we can say that we have the coexistence of two pandemics at that time. We can see the numbers before COVID. We have 10 million cases a year, globally a year, and with 1.4 millions of deaths from tuberculosis, and tuberculosis was considered the number one killer on that time for infectious diseases. On March 2020, most of the world was in the lockdown and that causes an explosion on tuberculosis. Let's see what happened with tuberculosis during the pandemic. Before we have to go ahead, I mean, before we have to go back and review a little bit about what was the spectrum of tuberculosis in the past year before the pandemic. The WHO published this global tuberculosis report this year. The 2019 report reflects the numbers from the past year. So we can see here 1.5 million deaths, number one killer for tuberculosis, and a crisis of drug-resistant tuberculosis, and very sad to see that just the minority of those patients were receiving inadequate treatment. Tuberculosis was considered in the list of the top 10 causes of death for any cause, and was killing more patients, more people than HIV on that year. And even we have a decrease in the number of cases, we have a decrease in the number of days in 2019, we were having an increasing rate of MDR tuberculosis that was affecting the children. Then the lockdown came, and we have a huge decrease in the TV notifications. That happened all over the world, not only in the poor countries with the highest incidence. And we can see that in spite that the cases were less cases, but the number of deaths were increasing in this year, in 2020, from 1.4 to 1.5 millions of deaths. And that was the first time that that happened in a decade. And the reason why the COVID was affecting all the branches of the health system, including the TV programs. And it's happened everywhere in the world, and our continent wasn't the exception. You can see here how the increase of deaths also happened here in America. With that data on hand, the WHO published this paper in the New England Journal. It's great that the WHO made a publication like this, but because of the importance of what was happening, they did it, and they state that the COVID pandemic has had the best effects on every aspect of global health, but tuberculosis services have been disproportionately affected. We can see some numbers. They published a sub-diagnostics of almost 4.2 million cases. They were, if they were not diagnosed, they were not treated. The deaths increased from 1.4 to 1.5, 15% reduction in the number of patients treated for MDR-TB, 25% decrease in cases treated for Latin tuberculosis, and the fundings for TB also were decreased because they were used for COVID. Another interesting publication found this, that 1 million of people did not receive any TB tests or treatment in 2020, and the consequences of that could be a development of more tuberculosis, more resistant tuberculosis, and also the spread of that. And according to what happened with tuberculosis, we know that when something wrong is made, the effects of that can last several years. So the trend was expected to be worse in the future years. Next year in 2020, we have a small recovery in the notification of cases, but we also have an increase in the number of deaths. We can see what happened in 2019 from 1.4. Then 1.5, and 21 was 1.6 million deaths. It was an increase in rates. And as I just said, the expectation is that that is going to be worse in the future years, beyond 2022. We still don't have the numbers for 2022, and we don't have the numbers for 2023, but as an official report, that is happening all over the world. Another very sad situation is what happened with children, 1.2 million of children affected for tuberculosis, a lot of deaths for tuberculosis, 217,000 deaths, and 95% of these deaths, those children did not receive any treatment. Last year in October, the WHO confirmed that the incidence of new cases and the incidence of deaths was increased because of COVID. And this year in April, they also state that the crisis of MDR tuberculosis was ongoing all over the world. Let me tell you a little bit about what happened in Mexico, what was the impact of the lockdown. We have a decrease in case notification, a decrease in case treated. We stopped doing DOT and follow-up of the patient. As a consequence, there was an increase in treatment failures, community transmission, MDR TB cases, more extra-pulmonary cases, and more children with TB. And we are expecting for the future more cases and more deaths. I want to show you some data that we have from the last year, 2022. You can see here an increase of the incidence. We are beyond that what we have in 2019, an increase in the number of deaths here. We also have an increase in the number of children. We have an increase in the number of extra-pulmonary TB. 20% of our cases are extra-pulmonary and increasing the cases drug resistance. What happened here in the United States? The same. We have the effect of fall and rise in the incidence, a fall and rise in the MDR TB cases. Same with children. And maybe you as a developing country, a developed country may not be concerned about tuberculosis, but you have a population who has the greater risk to have active tuberculosis, a lot of migration, social determinants as homeless, alcohol, drug use, and other. And you have a lot of cases with diabetes. Diabetes is the main comorbidity here in the States. So you were having this before the pandemic. Now you are living like this, but you're having a reborn. Let's see what happened with the official numbers this year. So could COVID cause a global resurgence of tuberculosis? These are the expectations before COVID, 2 billion people. That means a quarter of the global population were having latent tuberculosis, and 10% of them will develop active TB, 200 millions of cases. But this is going to be worse because of COVID, and we are seeing that, more cases, more deaths. On the 90s, last century, we have the same situation with COVID, a resurgence of tuberculosis, that now the TB is affecting all the health programs in the world. We expect that the surge of TB will last more years, even COVID is not having that problem anymore. And since last year, some groups like TB Alliance are calling this the resurgence of tuberculosis. 40% of the TB cases on 2020 were not diagnosed or treated, so they are still over there. To control tuberculosis in the world, the United Nations recommended these 10 issues related mainly to the good treatment of TB, to improve the treatment of tuberculosis. Also the United Nations has the Sustainable Development Goals. Well, we go to 2019, no one of this has been reached before the pandemic, and now we can have crisis plus another crisis plus another crisis. So everything is there to have a resurgence of tuberculosis around the world. So I want to finish saying that TB diagnosis decreased during the lockdown, TB deaths increased in 2020, and we are facing an increase in the TB incidence all over the world. More MDR-TB cases, more TB in children, more extra-pulmonary TB, if we want to change that, we cannot expect different results if we keep doing things in the same way. Thank you for your attention. Thank you for the opportunity. I'm going to speak about the intersection of TB and diabetes, and unfortunately I think I don't have better news than Dr. Rendon just presented, but we'll try and be hopeful. So the intersection of TB and diabetes, these are my objectives, I have no disclosures. So just a word on global TB and diabetes in general. The map on the left is showing us the incidence of diabetes in 2021, and as we all know, diabetes affects pretty much every country and every region in the world. The darker the color, the higher the prevalence of diabetes. And then on the right, we have the estimated TB incidence across the world as well in 2021, and we see that there's a lot of overlapping areas between the two maps, and this is definitely of concern. Looking at estimates, diabetes on the left, again, type 2 diabetes is the line sloping drastically upwards, and we're expecting about a 60% increase from 2021 to 2050 in the rates of type 2 diabetes. The graph on the right you've seen already, and this is TB incidence, and again, you see that rise at the end there in 2021, with about a 4.5% increase in TB incidence in 2021. So what is the burden in 2019? We had 460 million diabetics globally. This is estimated to be about 700 million by 2045. In 2019, about 15% of all patients with TB had diabetes as controlled to the non-TB population, where it was about 9% of the population. This gives us about 1.5 million people with active TB and diabetes. In 2020, about 5% of people with TB in the U.S. had HIV, but 22% had diabetes. And this clearly varies among regions and groups, and even within countries themselves, you will see a lot of variation based on the group that you are looking at. The fact is that diabetes is rising much faster in places where TB is already at a medium to high incidence. And if we look at this, and I know you can't see all of the countries here, but this is the Americas region of WHO, or what PAHO covers, the incidence of comorbid diabetes amongst people with TB disease is about 10%, and the top three countries there are Mexico, Guatemala, and the U.S. So there's the potential for an enormous increase in the burden of active TB that's attributed to diabetes. I think these graphs you just saw, so I will skip them, only to say that in the Americas, both TB and deaths from TB are increasing. This map is showing us something a little bit different. So here we're looking at how much TB is attributable to diabetes in a population. So if the individual did not have diabetes, they would likely not have active TB. And the darker the color, again, the higher the incidence, the higher the attributable risk to diabetes. And you can see many of the same regions of the world that we have been talking about. If we look particularly in the Americas, you can see that diabetes accounts for just under 20,000 cases of tuberculosis, with the other risk factors right now having a higher attributable risk, but obviously the fuel is certainly there for the TB diabetes sort of co-epidemic to worsen. And then this is interesting. So when we talk about diabetes, there are really many different phenotypes within that population. And this study was done at the U.S.-Mexico border, and they had a cohort of patients with active TB, about 25% of whom had diabetes, so very high. And the strongest association between TB and diabetes was amongst the youngest diabetics. These are type 2 diabetics, so they are adults, but amongst the youngest group. And you can see that here, that the rate of active TB was much higher the younger the age. And so this may be a particular phenotype or a particular group of diabetics that we really need to look at more closely. So let's talk a little bit about the actual impact and outcomes of diabetes on tuberculosis. So we all know the pathophysiology. We start out inhaling the tuberculosis bacteria, we become infected, and then a small percentage of us will go on to develop active TB. And then even a smaller proportion of us may end up having a TB relapse or dying from our tuberculosis. So what does diabetes do to this natural history or this progression? And you can see that the darker and the thicker the arrow, the more evidence we have that diabetes really worsens the outcome in that area. So if you start with just latent TB infection, are diabetics at higher risk of latent tuberculosis infection? There's not a lot of data on this. There's perhaps, though, a modest effect of about 1 to 2 to 1.6 times the risk among diabetics. And there does seem to be a dose response, so even patients who are pre-diabetic seem to have a slightly higher risk of latent TB infection. But there are a lot of study limitations here. What about going on to develop active TB once you are latently infected? And this is where we know that diabetics have about three times the risk of developing active TB as non-diabetics. And in the U.S., at least, Hispanic Americans are about 2 to 3 times the risk of other diabetics. What about once you develop active TB? What happens then amongst diabetics? It seems that diabetes increases the severity, worsens the chest radiography, so there is more cavitation, there is more extensive disease, and diabetics tend to have more smear and culture positivity. They also seem to have slower culture conversion, even if they are on the correct medications. There is some evidence that maybe if we tighten the glycemic control and treat diabetes at the same time, that our outcomes may improve. In terms of relapse, diabetics, at least in some small studies, have four times the risk of relapse. They interestingly have an increased risk of drug-resistant TB as well. And as I said, their disease extent seems to be much more extensive than non-diabetics, and perhaps this is why their mortality is also double a non-diabetic. So without going into too much of these details of really how does diabetes have such profound effects on active TB, some of the hypotheses are that diabetes is a pro-inflammatory state and causes altered macrophage function against tuberculosis, which are very important in defense against TB. There may be reduced antibacterial activity from neutrophils, especially in uncontrolled diabetes, glycated proteins can accumulate, and these may impair some of the immune response that we expect to see amongst patients who are infected with TB. Interestingly, there have been some studies looking at metformin as an adjunct to people with tuberculosis, mostly who have diabetes, but also a few studies that have looked at non-diabetics and really utilizing metformin as an anti-inflammatory sort of host-directed defense. So this is one study that was done in Taiwan, and the red line are patients who are on metformin, the blue line are patients not on metformin, these are diabetics. And you can see that this is, we're looking at survival. Survival was actually much improved in people on metformin, and so much so that in the second graph, those are now non-diabetics being compared to diabetics on metformin, where their survival was very similar. Another group looked at radiographic findings and found that diabetics on metformin had a lower incidence of cavitary disease. So metformin may have a role to play in this TB diabetes epidemic. How else can diabetes impact tuberculosis? Well, we know that there are a lot of drug interactions, particularly when we use rifampin or rifamicins. Certainly rifampin will metabolize our oral hypoglycemics, such as the sulfonylureas, and this may lead to worsened diabetic control. There are many overlapping toxicities as well, so diabetics have peripheral neuropathy, and then we put them on isoniazid, which may worsen their peripheral neuropathy and may make it difficult for them to continue treatment. And I think this is the most interesting, and perhaps a place where we can intervene, is the bioavailability of TB drugs in diabetics. The study, the graphs I'm showing you on the right are from a small study looking at rifampin drug levels in the continuation phase, so in the latter part of TB treatment. And this is looking just at rifampin levels, and you can see that diabetics had a much lower rifampin drug level, given the same doses, about six times lower than patients without diabetes. Now when this study was repeated in the intensive phase, so in that first two months of TB treatment, and when they matched diabetics based on weight to non-diabetics, so patients who had TB and diabetes, and they were the same weight as patients with only TB, they found that the rifampin levels were not different. So it's a little unclear. Is it that diabetics, as they gain weight during treatment for TB, are now at risk for having lower levels of rifampin? Or is there something more to this story? We also know from other studies that higher levels of isoniazid and rifampin are associated with a faster time to culture conversion. And these are some of the possibilities as to why this happens. Are there issues with drug absorption in diabetics? Is there decreased protein and drug binding? And one of the challenges, we could just say, okay, increase the doses of rifampin. We know rifampin is safe. And then measure the drug levels. Well, in many parts of the world, we have fixed drug combinations of our TB medications, and it may be challenging to do that. This is a study looking at therapeutic drug monitoring in the state of Virginia, where they have been doing therapeutic drug monitoring for many years. They found that about 17% of their TB cases had diabetes. And they looked at patients who were sort of slow responders to their TB treatment. And many of these patients had diabetes as well. And again, they found that the drug levels were quite low. And so they started doing therapeutic drug monitoring and would adjust the levels of the tuberculosis medications. And they found that the time to culture conversion was shorter. So from 62 days down to 42 days. And the two-month culture conversion increased from about 50% to 80%. Now, TDM is not easy. You really need specialized labs and a lot of coordination with the TB clinic. And so this may be a challenge in a lot of places. What about the impact of TB on diabetes? Well, it turns out that TB also is associated with temporary hyperglycemia. This may improve during treatment. As you see here, these are patients who had high A1Cs when they started antitubercular treatment. And it improved, especially in the new diabetics, as treatment continued. And this was without specific diabetes medications. So probably, especially in new diabetics, we should be monitoring their A1Cs and their glucoses during treatment to see if they revert to non-diabetic. So what about the feasibility of integrating TB and diabetes care together? Would that improve outcomes? And this is something that the WHO has been talking about for some time. They published this about 10 years ago as a framework, not necessarily recommendations or guidelines, but as a framework that we should be thinking about how to integrate TB and diabetes care together. In America's region, some of these efforts have been made, and a number of guidelines have been established, and many countries are now reporting on a couple of these parameters. So one is the number of TB patients tested for diabetes, and then the proportion of those tested who actually have diabetes. So in 2020, which is not a nice year to look at in general, but in 2020, 22 countries tested about 47,000 people who had TB for diabetes. So this was about half the population, and they found a 13% prevalence. And so clearly, the overall uptake of this framework is really variable. So what should we be doing? What about screening people with active TB for diabetes? Well, some of the challenges may be the availability of screening tests in TB clinics. What do we do with all the diabetics that we find? Is there someone somewhere for them to go and for their diabetes to be managed? Overall, though, the answer for screening patients with active TB for diabetes is yes. That probably has the most evidence behind it. What about screening for TB disease among people who have diabetes, so the opposite? This seems to be relatively low yield. Diabetic clinics are certainly not set up to be testing sputum, but perhaps we can focus on some of the highest risk individuals in some of the highest risk regions. Should we screen people who have, should we screen diabetics for latent TB infection? There's really no direct evidence, and the scale up here would be immensely challenging, but these are some of the things that I think we are looking forward to. I think just for sake of time, I'm going to go through this first example, and we'll look at the second example. So this was a pilot project in Mexico looking at about 15 primary care sites where they integrated both TB and diabetes management together. About 10% of diabetics were screened for TB in this population. 40% of the TB patients were screened for diabetes. It turns out that the patients who were managed in this joint pilot program had greater TB treatment success, and their A1Cs, shown here, declined during their TB treatment. It took testing about 71 diabetics to find one case of active TB in this group. The healthcare workers said it was really hard to do this. We were really limited by time, and we didn't have all the supplies available that we needed. So the data is there. It does seem to improve outcomes, increase detection, and better outcomes, but the data is pretty limited. And of course, the cost effectiveness will really vary based on the incidents and what is available. So just in my last kind of minute or two here, is there any specific guidance or recommendation for how we should treat somebody with active TB and diabetes when they have both those conditions together? Well, really there's no specific guidance. Maybe there will be in the next set of guidelines, but there are some suggestions and some things that make sense. So one is about duration of TB treatment, which currently for drug-susceptible TB is six months. We know that there's a higher rate of relapse in people who have cavities and who have a positive two-month culture. And we also know that many of those patients are diabetics. So certainly if they fall into that category, you would extend their treatment out to nine months. But perhaps if they only have one of those things, they have cavities, but they're diabetic, you may also consider extending their treatment duration, because their likelihood of relapse is likely higher. There are some countries and some TB programs that now treat all diabetics who have active TB for nine months. And I think there is a new short-course four-month regimen for drug-susceptible TB. We do not really yet know what the makeup of that population was. I think it would be interesting to see how the diabetics in that group fared and whether four months with that newer regimen is adequate. TB medications, so we can look at weight. And if we can adjust the dose, we should probably be adjusting the doses of their TB medicines as they gain weight. We can more frequently monitor for adverse effects and counsel those patients. And if you have the availability and the resources, you can consider therapeutic drug monitoring. In terms of management of diabetes itself, certainly the first line would be metformin. And perhaps there's some evidence that it has more than just impact on diabetes management. Sulfonylureas, which we certainly don't use a whole lot of anymore, will have lower efficacy when you use rifampin at the same time. If you have a patient with active TB who you've screened for diabetes, as the guidelines tell you you should, and you find them to be a newly diagnosed diabetic, if their A1C is under 8, it's recommended that you repeat their A1C during their treatment for TB. Because they may improve on their own just with TB treatment, certainly if it's higher than they need co-management for their diabetes. And then the newer diabetic drugs, we're really not sure what the drug interactions are yet with rifampin. For the most part, they seem to be unaffected. And then, of course, counseling patients on their other risk factors, tobacco use, alcohol use, cardiovascular risks. Many TB deaths are actually cardiovascular deaths, as with diabetes. So my summary, diabetes is fueling TB in many regions globally. People with TB disease should be screened for diabetes. Advanced disease and TB diabetics may warrant longer therapy, out to nine months. And we should try as best we can to manage the whole patient. And this is a quote from the Bali Declaration in 2015, which was a collaboration between the World Diabetes Federation and the union. That TB and diabetes represent two of the greatest global health challenges of our time, and their convergence represents a looming co-epidemic. That this co-epidemic threatens progress against TB. We could add COVID in here as well, make it a triple epidemic. And that based on what we have learned from past co-epidemics, particularly TB and HIV, we must act early and decisively to avoid a large number of avoidable deaths. And I guess I'll try and leave on a positive note, to some degree. The thing I've seen the most in the last few years that is improving is advocacy. Advocacy from the communities most affected. And I think, you know, we have a role to play there as well, to support them and to make sure that they have resources to really, you know, stand up and say, don't make any decisions without us. Because with us, you're much stronger. So thank you. Thank you, Dr. Dunkers, Dr. Ranzibia, Dr. Rendon, Dr. Patawala, for the invitation. It's a pleasure to be here. Well, the next topic is talking about DNA phytoinhibitors and management of TB. And I prepared a case, a real case, to start this presentation. So there you go. At first, I don't have any financial disclosure, except that I had some patented technology for latent TB infection, immuno-diagnostics, which I'm not going to be talking about that today. Otherwise, not really on financial relationships. So I think Dr. Rendon did a wonderful job on going over the current state of the global TB epidemics. I will go quickly on that and focus on the TB diagnosis and management in patients who are receiving DNA phytoinhibitors, but also other immunodepressive medications that now are coming up into our armamentarium. So first, this only case is a young woman we saw several years ago, 18 years old, from Iowa. Non-smoker, had recurring pneumonia, for which she was referred to us. She had prior two months to that, had sore throat, dry cough, intermittent fevers, treated locally with courses of azithromycin and amoxicillin, clobonate, and without improvement. She developed worsening symptoms and night sweats, anorexia, weight loss, and developed GI symptoms, including constipation, diarrhea, abdominal and generalized achiness. Her primary care history was significant for ulcerative colitis, five years prior to that, treated with 5-mercaptopurine three years prior to this, and then started on infliximab to control her disease two years prior to this presentation. This is her GI follow-through variant testing, which was unrevealing at the beginning of her assessment. And back then, when she was started on infliximab, she had a negative tubercle skin test. So there's a history. She was born and raised in Iowa, a low TB incidence area, a little cousin. She's a college student and works in a local pizzeria. And no TB contact that she knows, no environmental trouble exposure, so nothing to suspect TB. No recurrent drug use or alcohol intake. She was not diabetic. But she had, because of GI symptoms, some local CT abdomen and pelvis testing, which shows some faint pulmonary infiltrates and a moderate amount of intraperitoneal fluid in the deep pelvis. That was diagnosed with an ulcer, a radiologist. And they once treated as a bowel exacerbation with 20-day course of ciprofloxacin and prednisone for suspected pneumonia and possible flare-up. So this is the lung views of the abdominal CT. I encourage you to do that. I think it's always very informative. You can sneak into those views. And certainly she had already some nodularity, peripherally, that were non-normal. And in lower cuts, you also could see those. Sometimes those are not specific. But in this context, I think it was relevant, especially with recurrent pneumonias. And this is the CT cuts at the pelvic level, which show the fluid level. So for the review of this CT scan, she also a little bit of plenomegaly with some hypolucency areas as well as some caking or thickening of the momentum and some nodules inside the peritoneal space beside the peritoneal fusion. So significant findings there in some of those immunosuppressed and concerning for potential disseminating infection. So a few days later, she was not doing better. She had this CT showing already more miliary type of pattern. But not only that, also consolidation features in the left lung and very concerning for disseminating infection. So she was admitted. She had mild fever, wasn't hypoxemic, had some ronchi or was unrevealing physical extermination. So for mild tenderness, mild splenomegaly. And the results labs were normal. She was HIV-negative. Fungal testing was all negative. She had a quantiferon for worse water death setting positive, which is in this case actually important because it raised the concern that she was exposed to TB. She had a bronch. And bronch was actually HIV-positive and BAL with immunocompromised host protocol, we call it. So with white cast for fungal viral infection was also weak positive for AFB. The local pulmonologist did a transcutaneous transbronchial biopsy and showed necrotizing melanomas. Staining was negative for fungi and AFB. But this outside pulmonologist sent this specimen for GeneXpert, which is not a normal indication in the U.S., which was actually very, very good because both the BAL and bronchial washing were positive. And she was diagnosed quickly. And at the time she was already in our hospital. We retrieved that information. We promptly start her treatment. So this, she was pan-sensitive and that was, she did well with therapy. So I think Dr. Rendon already highlight this, just to go quickly, TB still is huge, not outside the U.S., but still present in the U.S. It's still increasing in incidence and mortality. We have more and more early forms of TB being diagnosed, especially asymptomatic TB. Especially in these patients, it can be tricky to diagnose. And a lot of these patients don't have enough cough to produce sputum. So we have to be promptly taking different strategies to diagnose these patients. And TB can be transmitted not only by cough, but also by tidal breathing. Recent research has demonstrated that. And as I said, if you intervene quickly, there's been studies and modeling showing that early diagnosis can prevent TB disease progression and transmission by 50%. And there's a lot of MDR-TB in many areas in the world and has been increasing. And that's also increasing. So without further ado, we have some questions. I don't think we had the chance to edit this on the audio response format. But the question was, okay, what is the relative risk of TB in patients with TNF-alpha lockers or inhibitors? And the question is more than 60%, and sometimes even 250%, depending on the type of immunosuppressive for TNF-alpha inhibitors utilized. And these are the initial ones being approved, at least in the U.S. And Tarnasep is a resolvable mediator. The other ones are directly attached to the TNF-alpha receptors. And they have different type of risk for TB. Infliximab is a stronger immunosuppressant. You tend to have more TB earlier compared to Tarnasep. And this is a FDA monitor trial. In the U.K., similar findings. We had more than the solvable form of TNF-alpha inhibitors. And interestingly, the Adalewin map has a higher increase rate afterwards. And notice that these incidents start to pick up not only after a few months, but really after a year. So these patients are being treated with TNF-alpha inhibitors for a long time and then develop this, like a case of this young woman, about two years afterwards. So something to keep in mind. They can have negative screen testing. And in Spain, for instance, they do periodic testing in patients with potential exposure. So every year they do the screen testing. So they're not only TNF-alpha blockers, the only ones we need to be concerned, which are in the higher risk category for routine screening, but also the JAK inhibitors are also in that category. And we have utilized some of these in COVID-19 and then turned out to be not that effective. And then the other one is anti-CD52 that I'd like to zoom up. And this is based on a review from the European Society of Clinical Microbiology that has called a group of experts to review all the data. And this is data also from the U.K. Now there's a number of other agents that have theoretical uncertain risk that face HIV or TB screening. It's either in the package label or it's being recommended. So among those is anti-IL-6, tocilizumab is one of them, IL-12 and 23, the P40 subunit, the Lustekinumab, as well as IL-17. Many of these agents are used in rheumatology as well as in dermatology. And anti-IL-1, as well as anti-CD28. And there's one of the integrins which is used also in inflammatory bowel disease, vedolizumab, which is listed in the package label to be screened. So not that many cases being reported on these, but these are the ones in theory that can decrease the immune system, interfere in the immune system and prone to have increased TB risk incidents. There's also some others, immunomodulins that are not biologicals, like liflutamide and teriflutamide, as well as some others. And many others are coming up and we have to keep tune. I think the guidelines are not catching up with this. That's why I had to pull up all these reference. There are many others that are being low risk and not routine screening unless there are other risk factors. And we're not counting here for patients who are being on therapy for prevention or rejection for transplant. But for instance, the drugs that we commonly use for asthma, they're considered low risk, as well as the anti-CD20. Obviously some of these patients could be receiving all immunosuppressant and can add on to the immune risk, a complaint factor for CD5, as well as this type of integrin that seems to be less risky than the vedolizumab. So the other question I brought, if I may, is about the testing, how you do the testing. And the question was, which one do you use, TST or Agra or both? And the Agra, they are actually low sensitive for this type of patient with immunosuppressed. And the Agra testing seems to be more indeterminate as much as the patient became more immunosuppressed. And that has been shown in the area I will show. But the Agra tests are no more sensitive to a TST. And the TST are less specific to Agra tests, but they still have value in some patients, especially the ones who had a potential risk to be infected. And the negative testing on both tests do not allow the infection on this woman had it initially. So there's some data that comes from their systematic review for screening in LTBI and this patient with TNF alpha and other immunosuppressive biologicals. There's high variability. Data is not of great quality. Neither Agra was consistent, more sensitive to a TST. And the risk factor for TB are predicted for positivity. So they do tend to be predictive for infection. And the immunosuppressed therapies significantly reduce the quantifer and TST positivity. This is as much as 60%, 70% for quantifer, especially the prior version, TST about 70%. So, and they also tend to have a lot of indeterminate results. And so there's limited prospective data about how predictive they are. But in general, the most recent guidelines from Dr. Robinson and the ATS group and endorsed by IDSA and ERS calls for potential use in both in patients who have potential risk. Just to get a sense of our immunosuppression, because in HIV, we have a way to measure that. And when we study patients with active TB and do quantifer, only 61% are positive. TSP about 72%. So neither Agra tests are consistent, more sensitive to TST. So we don't use that to diagnose these patients nor to rule that out. There's a lot of indeterminate results. And the lower the CD4 count is, the higher the indeterminate results are. So both tests perform similarly, and therefore, similar recommendation. You can use both in patients who are severely immunosuppressed. So lastly, about the diagnosis for someone suspected to have active TB, like this woman. So in patients suspected of TB, unable to produce sputum, which are the following is the most rapid and accurate diagnostic test for TB. We know that Agra is not. I mean, it can help you to increase or decrease your pre-test probability, but it's not absolute. The AFB smear and bronchial washing VAL can be attempted. But more so, you do have also PCR, real-time PCR, like an expert. It's, as I said, not a label in the U.S. There are many studies showing that it has a strong diagnostic accuracy when you add it to the VAL or bronchial washing. Certainly, you need to have this, especially in several cultures, to get drug-susceptible testing besides the rifampin resistant that you get from the gene expert. And transplant care, obviously, can be attempted. If you're thinking about some other conditions, DNA alfalfa blockers can also give granulomatous disease without infection. So it's important to keep that in mind. So the answer on this one is expert on the bronchial washing of VAL. So, yes, I have a couple minutes just to reiterate. I discussed this earlier in my other talk, but basically a gene expert is an excellent tool to diagnose for AFB positive and AFB negative with great sensitivity and specificity. Decreased on AFB negative cases, but increased detection rate by at least 25% in many places in the world, expert has replaced AFB staining. And interest drug-resistant testing for rifampin as a marker of MDR-TB is excellent performance for this platform. And in terms of other utilization of this type of diagnostic platform, if we utilize pleural fluid, it's less sensitive. You know, it's a postulatory condition, but has excellent specificity for CNS infection and meningitis, has a very robust diagnostic performance for a fine needle of TB lymphoiditis, also excellent performance. Gastroaspirate, moderate performance, but very important in kids where this is commonly used. Urine testing has a strong, robust performance, as well as bronchoscopy. These are the two initial large series, but many others came up afterwards. And for rifampin-resistant in these non-pulmonary specimens, still have a strong accuracy. So, in general, the ultra in settings where you have those, has higher sensitivity expense of specificity, and very helpful in smear-negative cases, HIV-positive cases, and rifampin-resistant detection is the same. Things to keep in mind, when TB occurs in patients with TNFFA blockers, especially on these antireceptor agents, you can have disseminated disease, extra-pulmonary disease, increased rapid progressive disease. You can have also bacterial pneumonia, NTM. A number of fungal infections have been reported with these drugs, as well as viral infections, reactivation, latent viral infections, and non-infectious pulmonary, amyostrinal, granulomatous diseases, which are usually non-necrotizing, important to keep in mind when you diagnose these patients. So, take-home points, TNFFA inhibitors, and other biologicals, including the risk of TB. A screening for LTBI is recommended in many of those patients. Keep it on your guidelines. Disseminated amyloid forms can occur in these patients, can be difficult to diagnose. And the TNFFA inhibitors and biologicals increase the risk in the different ways. And some of them, dilobimab, infliximab, more than eternacept, and they're very well risked in other biologicals. And the gene expert and other rapid diagnostic testing should be considered to be added to maximize your sensitivity and quick diagnosis. And always keep in mind, there's regional experts that can help you out for diagnostic and treatment management in these difficult cases. That's it. Thank you.

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