Hello, everyone. I'm Dave Griffith. I'm Professor of Medicine at National Jewish Health in Denver, Colorado. I want to thank Christoph for the excellent talk and for his kind introduction. Uh this talk will focus on high risk patients and clinical findings, predictive of refractory mac pulmonary disease. These are my potential conflicts of interest. The talk will cover several topics including when is therapy appropriate and what are the clinical predictors of NTM disease progression and mortality? And lastly, I will discuss some newer objective measures for predicting disease progression and treatment response in the 2020 NTM guidelines. One of the first questions that was considered was should patients with anti and pulmonary disease be treated with antimicrobial therapy or followed for evidence of progression so called watchful waiting. And the recommendation in the guidelines was in patients who meet the diagnostic criteria for anti and pulmonary disease. We suggest initiation of treatment rather than watchful waiting, especially in the context of positive A FB sputum smears and cavitary lung disease. But elsewhere in the document, it is also stated importantly, just because a patient meets diagnostic criteria, grate and pulmonary disease, that does not necessarily mean antibiotic treatment is required. And of course, we all know that some patients with Mack lung disease in particular, have stable indolent or slowly progressive diseases. And in some of these patients watchful waiting may be the preferred course of action. It appears that these statements are contradictory. Uh but there is a rationale for both approaches. Patients with mac lung disease and bronchiectasis should all be started on air weight clearance, which can be transformative symptomatically. But more importantly and pertinent to this talk, patients who meet diagnostic criteria for mac lung disease and have bronchiectasis who start air weight clearance. As many as 10 to 15% of them can have sputum conversion without antibiotic therapy. In my opinion, airway clearance is necessary for any successful antibiotic treatment of mac lung disease and bronchiectasis. But if patients are continued on watchful waiting, they are at least engaged with a physician who's going to manage their brachia and evaluate the status of their mac lung disease periodically. Now, I'd like to look at some clinical predictors of NTM disease progression and mortality. Several studies have shown that over 50% of patients who meet diagnostic criteria for NTM lung disease are going to progress within 3 to 5 years. Some of the factors that predict that progression uh include male gender, older age comorbidities, low body mass index, elevated inflammatory indices such as sedimentation rate and crp radiographic factors, especially fibro cavitary disease and bacteriologic factors like bacterial load, which is reflected in a FB sputum smear results chai at all in an important study compared treatment outcomes between the fibro cavitary form of mac lung disease and the nodular brachia static form with cavities who were treated with guideline based therapy, composed of both oral therapy with or without injectable aminoglycoside. The culture conversion rate of patients with the nodular brachia static type with cavities was higher than that of the patients with fibro cavitary type. The conversion rates of those who received oral medications alone and those treated with oral medications and an injectable aminoglycoside were similar. Perhaps the most important finding is that patients with fibro cavitary type, mac lung disease with cavities could be treated with oral medications alone. I'd like to show a case that illustrates the importance of cavitation as a prognostic factor and some of the limitations of watchful waiting in this first ct cut. This is a woman in her mid sixties who had mild cough and sputum production and was evaluated with AC T scan and Sputum for a FP analysis that was culture positive format because she was mentally symptomatic. She and her doctors decided not to begin anim mycobacterial therapy. Approximately 18 months later, she had a chest radiograph which again shows a cavitary lesion in her right upper lobe, which although it is difficult to know, it certainly appears as though it may be slightly larger. She and her doctors again agreed not to begin an mycobacterial therapy but continued watchful waiting. Approximately two years later, uh again, with minimal symptoms, she had a chest CT scan showing enlargement of that right upper lobe cavity and perhaps the satellite cavity next to it. And again, uh she and her doctors decided not to begin treatment. But then uh approximately 18 to 24 months after that, it's clear that she has significant enlargement in the cavity. At this point, she did have ra radiographic and symptomatic progression and was started on ant mycobacterial therapy including intravenous AICA June, studied patients with newly diagnosed ant and pulmonary disease, looking for risk factors for mortality. He looked at patients with avium intracellular and abscessus disease. Overall, the 5, 10 and 15 year cumulative mortality rates were 12.4% 24% and 36%. Those factors significantly associated with with mortality included old age, male sex, low BM I chronic pulmonary aspergillosis, malignancy, chronic heart or liver disease and elevated sedimentation rate. This study also evaluated the impact of the infecting organism on mortality. Patients who had abscessus subspecies, abscessus and intracellular had higher mortality than those patients with mycobacterium, avium and mycobacterium abscessus mail disease. Radiographically, patients with fibro cavitary disease had significantly higher mortality than patients with nodular bronchia static disease. The nodular bronchia disease with cavitation patients also had significantly higher mortality than patients with just nodular bronch tadic disease. A more recent study with the so-called basis or B A CE S score was utilized for predicting mortality with anti in pulmonary disease period. It has also been utilized in patients with Bracho. The B A CE S stands for body mass index, age cavity erythrocyte sedimentation rate and sex. Each of these indices is assigned one point. The estimated five year risk of mortality was 1.2% with a score of zero and 83% with a score of five. They felt that the basis score would accurately predict mortality among patients with anti in pulmonary disease caused by these organisms. This is a graphic representation of the basis score and its association with mortality. You can see that once the basis score is three or above, mortality significantly increases the time to positive culture is determined by the number of days for a liquid medium culture to term positive. The longer the time for the culture to become positive in general, the better the prognosis time to positivity is a measure of the time that is required for a liquid medium culture to turn positive. In general, the longer the time to positivity, the better the prognosis. And conversely, the shorter the time to positivity, the worse the prognosis. In this study, the time of positivity and a FB smear grade were negatively correlated. Kind of positivity was associated with progressive NTM disease smear positivity and treatment initiation by three and six months. A threshold time of positivity of 10 days was also associated with mycobacterium Avium disease A FB smear positivity and treatment by three and six months. This graphic shows the distribution of time to positivity. Initially. Uh As you can see, most patients had a time to positivity greater than 10 days. Now, the association between time to positivity and markers of disease severity were multiple and included cavitation, bronchiectasis, multifocal, bronchos, smear positivity, progressive NTM disease and treatment initiation by three and six months. In a second study, Mingora. it all looked at time of positivity from 71 patients who were in the um Amic casein lapis inhalation suspension, so-called convert trial. Uh individuals with culture conversion by study treatment. Six were more likely to have a screening time of positivity more than five days compared with those who did not achieve culture conversion and had increasing time to positivity with time. The this uh uh these findings are shown graphically uh first with uh the initial time to positivity and its association with culture conversion, which is also demonstrated in the second slide which showed that with a time of positivity of five days or less, there was no sputum culture conversion uh in this study. And in a third study from the Netherlands Donno had all evaluated. 49 patients. Culture conversion occurred at six months and 34 non conversion in 15, a baseline time of positivity of more than seven days and a time of positivity of more than 15 days. After three months of treatment predicted that culture conversion would occur within the first six months of treatment. The last study I'd like to highlight is from him at all. Who evaluated the impact of time between diagnosis and treatment for anti inulin disease on culture conversion and all cause mortality. The study evaluated 712 patients who received at least six months of ant mycobacterial therapy. The median waiting period without antibiotics was about five months after treatment initiation, 67% of patients achieved culture conversion within six months, 19% of patients died. There was no association between the waiting period and six months. Culture conversion or death. The study also found that the six month culture conversion demonstrated a significant negative correlation with death and in a subgroup treated for more than 12 months. 12 month culture conversion was also associated with reduced death. The study suggests that for patients who are treatment refractory at six months, that an intervention resulting in sputum culture conversion could reduce NTM disease mortality. In summary predicting which patients will be treatment refractory is imprecise. The clinical factors that predict disease progression and mortality may predict poor response to therapy but that association has not been rigorously tested. However, the time to positive culture detecting is a promising objective measure which appears to be predictive for poor response to therapy and identifies patients who will be treatment refractory. What you do with that information is still unclear.
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