Most individuals with drug-resistant TB caught it from someone else, study suggests

By Dr Deepu

study published online in the New England Journal of Medicine suggests most individuals who have drug-resistant tuberculosis caught it from someone else. In the past, some experts and physicians believed that drug resistance resulted from ineffective treatment with tuberculosis medications. The study was conducted in KwaZulu-Natal, South Africa.
       Tracked TB that is resistant to at least four key drugs and found that 69% of the victims had never received treatment, which suggests “that they had acquired it from others with extensively drug-resistant TB.”
       This study might be a eye opener for the prevention of transmission of disease to the health care workers by the drug resistant TB patients and also the family members of the patients who are at a highest risk.

  Recently in our practice we encountered a young nursing student in her teens, who contracted MDR tuberculosis and had to be put on standard TB regimen for MDR.

Chest challenge of the week

By Dr Deepu
Chest challenge #1

Find the answer here

8th edition New TNM staging of lung cancer- Changes from 7th edition

In preparation for the 8th edition of the TNM classification for lung cancer the IASLC and their statistical partners at Cancer Research And Biostatistics (CRAB) established a new data base (5). This collected data on another 94,708 cases of lung cancer diagnosed between 1999 and 2010, treated by all modalities of care, donated by 35 institutions in 16 countries around the globe. After exclusions 77,156 remained for analysis, 70,967 cases of non-small cell lung cancer (NSCLC) and 6,189 cases of small-cell lung cancer (SCLC). 
      Analysis of the cases of NSCLC has allowed proposals to be formulated for revisions to the T, N and M descriptors and categories, and the resultant TNM Stage groupings. 
         The proposals the T descriptors have been published . Size continues to be an important determinant and will become a descriptor for all of the T categories from T1 to T4 inclusive. The T size cut points of the 7th edition will be retained, vis 2, 3, 5 and 7 cms, and new cut points at 1 and 4 cms have been proposed. As a result new T categories have been created and others have been reassigned. In addition tumours invading the diaphragm have been reclassified as T4 and tumours extending within 2 cms of the carina, but without invasion of the carina itself, or those tumours associated with collapse or consolidation of the whole lung have been down-staged to T2. The resultant T categories are shown in Table along with the proposals for N and M categories.
         It is recommended that the N categories of the 7th edition be retained. Exploratory analysis of surgically resected, pathologically classified cases has suggested that the prognostic significance of the anatomic location of involved nodes can be augmented if combined with the number of involved nodes in N1 and N2 locations and the use of this sub-classification has been proposed for testing in the 8th edition .
     The proposals for the M classification retain the existing category of M1a . The category of M1b has been re-assigned to describe a form of extremely limited "oligometastatic" cases in which there is a single metastatic deposit in one distant organ. A new category of M1c has therefore emerged to describe the commoner situation in which there are multiple metastases in one or more distant sites. 
       The resultant T N M Stage groupings, derived from recursive partitioning and amalgamation analyses were refined by the committee by study of their statistical features and clinical relevance and are shown in Table. As in the 7th edition the IASLC Staging and Prognostic Factors Committee have attempted to resolve some issues in which data is limited by review of the literature and by consensus. These include how one should assess tumour size in the small tumours of mixed density increasing common when evaluation CT screen detected cancers. The committee's recommendation is that it should be the solid element on imaging, or the invasive component on pathological examination which should be measured to determine T size . In a series of articles the committee has given advice as to how one should classify the various scenarios in which multiple tumours are discovered in the lung(s) .
     The IASLC has submitted all of these proposals to the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC), the 2 bodies that regulate the TNM classification for all tumour sites globally. The 8th edition is due to be published this Autumn. The IASLC will have extensive educational products available to attendees at the 17th World Conference on Lung Cancer, to be held in Vienna from the 4th to the 7th of December 2016.

Proposed T, N and M descriptors for the 8th edition of TNM for Lung Cancer (changes to the 7th edition are highlighted in BOLD and RED

T	Primary Tumour
Tx	Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0	No evidence of primary tumour
Tis	Carcinoma in situ
T1	Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)
T1(mi)	Minimally invasive adenocarcinoma
T1a	Tumour 1 cm or less in greatest dimension
T1b	Tumour more than 1 cm but not more than 2 cm in greatest dimension
T1c	Tumour more than 2 cm but not more than 3 cm in greatest dimension
T2	Tumour more than 3cm but not more than 5 cm; or tumour with any of the following features  : - Involves main bronchus regardless of distance from the carina, but without involvement of the carina. Invades visceral pleura. Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung
T2a	Tumour more than 3 cm but not more than 4 cm in greatest dimension.
T2b	Tumour more than 4 cm but not more than 5 cm in greatest dimension.
T3	Tumour more than 5 cm but not more than 7 cm in greatest dimension, or  directly invades any of the following structures: chest wall (including parietal pleura and superior sulcus tumours), phrenic nerve, parietal pericardium; or associated with separate tumour nodule(s) in the same lobe as the primary.
T4	Tumour more than 7 cm in greatest dimension, or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; or associated with separate tumour nodule(s) in a different ipsilateral lobe to that of the primary.
N	Regional Lymph Node Involvement
Nx	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis.
N1	Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2	Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3	Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
M	Distant Metastasis
M0	No distant metastasis
M1	Distant metastasis present
M1a	Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or pericardial nodule(s) or malignant pleural or pericardial effusion
M1b	Single extrathoracic metastasis
M1c	Multiple extrathoracic metastases in one or several organs.

 Proposed Stage Groupings for 8th edition of TNM for Lung Cancer (changes to the 7th edition are highlighted in yellow, bold and underlined).

New Guidelines Published for Discontinuing Mechanical Ventilation in ICU

By Dr Deepu

The American College of Chest Physicians (CHEST) and the American Thoracic Society (ATS) have published new guidelines for discontinuing mechanical ventilation in critically ill adults. The goal of the guidelines is to help physicians and other health care professionals determine when patients with acute respiratory failure can breathe on their own and to provide clinical advice that may increase the chances for successful extubation.

Mechanical ventilation is a life saver, and studies have shown that at any particular moment about 40 percent of all patients in the intensive care unit are breathing with the help of a mechanical ventilator. However, mechanical ventilation can lead to complications, including infections and injury to the lungs and other organs.

Reducing the length of time patients are on mechanical ventilation decreases the risk of these complications, but premature removal from mechanical ventilation can produce other complications and increase mortality.
Based on a systematic review of medical studies, the committee’s recommendations for acutely hospitalized adults on mechanical ventilation for more than 24 hours are:

For patients at high risk for extubation failure who have passed a spontaneous breathing trial (SBT), we recommend extubation to preventative non-invasive ventilation (NIV). The committee found evidence that transitioning to non-invasive ventilation reduced ICU length of stay and short- and long-term mortality. The authors emphasized that in these patients NIV should begin immediately after extubation “to realize the outcome benefits.”
We suggest that the initial SBT be conducted with inspiratory pressure augmentation rather than T-piece or CPAP. The committee wrote that conducting the initial SBT with pressure augmentation was more likely to be successful, produced a higher rate of extubation success and was associated with a trend towards lower ICU mortality.
We suggest protocols attempting to minimize sedation. The committee found that sedation protocols reduced ICU length of stay. However, the protocols did not appear to decrease time on the ventilator or reduce short-term mortality. The authors could not recommend one protocol over another but said the burden of providing sedation by any of the protocols was “very low.”
We suggest protocolized rehabilitation directed toward early mobilization. The committee wrote that patients receiving the intervention spent less time on the ventilator and were more likely to be able to walk when they left the hospital. However, their mortality rate appeared unchanged. The authors noted the exercises created additional work for ICU staff that might have come at the expense of other care priorities.
We suggest managing patients with a ventilator liberation protocol. The committee said that patients managed by protocol spent on average 25 fewer hours on mechanical ventilation and were discharged from the ICU a day early.  However, their mortality rate appeared unchanged.
We suggest performing a cuff leak test in patients who meet extubation criteria and are deemed at high risk for post-extubation stridor. The committee suggested that the test should be used only in patients with a high risk of stridor (abnormal breathing caused by blockage of windpipe) after extubation. Although patients passing the test had lower stridor and reintubation rates, the authors wrote that a high percentage of patients who failed the test could be successfully extubated.
For patients who failed the cuff leak test but are otherwise ready for extubation, we suggest administering systemic steroids at least 4 hours before extubation. The committee said that clinical judgment should take priority over test results, and systemic steroids should be administered to these patients at least 4 hours before extubation. The authors added that the short duration of the steroid therapy was likely to improve success rates without resulting in adverse events.
Download the complete guidelines from here

ICS/LABA exacerbation benefit outweighs pneumonia

By Dr Deepu

The benefit of a fixed-dose inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) combination in reducing exacerbations of chronic obstructive pulmonary disease (COPD) far outweighed any risk for pneumonia in a post hoc analysis of the 48-week FORWARD study.

Although there were 13 extra pneumonia events when a fixed-dose combination of beclometasone diproprionate and formoterol fumarate (Foster, Chiesi Farmaceutici SpA) was used as compared to formoterol fumarate alone, there were 123 fewer moderate to severe COPD exacerbations over a 342-day analysis period.
The FORWARD study was a two-arm trial designed to compare the efficacy and safety of fixed-dose treatment with beclometasone diproprionate and formoterol fumarate versus formoterol fumarate alone in 1,199 patients with severe COPD.

For inclusion in the study, patients had to have a post-bronchodilator forced expiratory volume in 1 second below 50% of predicted and a forced vital capacity ratio of less than 0.7. They also had to have a smoking history of 10 pack-years or more, and a history of at least one COPD exacerbation in the previous 12 months that had required treatment or hospitalization (Eur RespirJ. 2013;41[1]:12-7).

After a 2-week run-in period, where all patients received a 24-mcg dose of formoterol fumarate, patients were randomized to continue treatment with formoterol fumarate or to receive the fixed-dose combination of beclometasone diproprionate 400 mcg and beclometasone diproprionate 24 mcg for 48 weeks.

A total of 1,186 patients, most of whom were male (69%) with a mean age of 64 years, formed the intention-to-treat population.

Published results (Respir Med. 2014;108[8]:1153-62) showed that the combination of the ICS beclometasone diproprionate and the LABA formoterol fumarate (Chiesi Farmaceutici SpA) was associated with a 28% reduction in the annual rate of moderate to severe exacerbations versus the LABA alone.

The adjusted rate of exacerbations per patient per year was 0.80 in patients treated with the ICS/LABA combination versus 1.12 for those treated with just the LABA, with an adjusted rate ratio of 0.72 (P less than .001).

The published data also showed that pneumonia was reported by 23 patients (3.8%) treated with the ICS/LABA and by 11 (1.8%) treated with the LABA only.

For the new analysis,  pneumonia and COPD exacerbations were looked in more detail, plotting out the cumulative number of events over time and also characterizing the types of pneumonia in more detail.

All patients had a chest x-ray to confirm the presence of pneumonia, he said, there were 35 cases of pneumonia, 24 occurring in patients treated with the fixed-dose beclometasone diproprionate and formoterol fumarate combination and 11 in patients treated only with formoterol fumarate.

Of these cases, 25 required in-hospital treatment – 16 patients in the ICS/LABA arm and 9 in the LABA-only arm. There were three instances of patients acquiring pneumonia in hospital – two in the ICS/LABA and one in the LABA-only arm.

There were also two fatal cases of pneumonia – one in each treatment group. Neither were thought to be related to either of the treatments.

These findings are in line with a recent review of the use of ICS for COPD by the European Medicines Agency (EMA/488280/2016), which noted that “overall the benefits of inhaled corticosteroid medicines in treating COPD continue to outweigh their risks and there should be no change to the way in which these medicines are used.”

The European Medicines Agency advised that patients and clinicians need to “be alert for signs and symptoms of pneumonia, bearing in mind that the clinical features of pneumonia overlap with those of a worsening (exacerbation) of the underlying disease.”

Results of IMPULSIS on extension trial released.

By Dr Deepu

The interim findings from the INPULSIS-ON extension trial were presented at the European Respiratory Society (ERS) International Congress 2016 in London.

The findings were consistent with those previously reported from the INPULSIS Phase 3 trials (INPULSIS-1 and -2). The interim analysis from the extension trial demonstrated that nintedanib slows disease progression in IPF patients. In addition, long-term treatment with nintedanib  (up to 51 months) was associated with manageable side effects in most patients, with diarrhea being the most frequently reported side effect.

Results from the interim analysis of INPULSIS-ON demonstrated that in terms of forced vital capacity (FVC, a measure of lung function) in IPF patients who continued nintedanib treatment in the extension trial, the change between baseline and week 48 and between weeks 48 and 96 was similar to what was seen in IPF patients who were on active treatment with Ofev in the 52-week INPULSIS clinical trials.

Findings from the trials on the effect of nintedanib on FVC demonstrated that:

In INPULSIS, the mean FVC change from baseline to week 52 was −89mL compared to –203mL for placebo-treated patients;

In INPULSIS-ON, the mean FVC change for patients who continued treatment was −96 mL from baseline to week 48;

In INPULSIS-ON, the mean FVC change for patients who continued treatment was −124mL from week 48 to week 96;

In INPULSIS and INPULSIS-ON, the average exposure to Ofev was around three years (35.7 months).

Two additional sub-group analyses from the trials revealed that treatment with Ofev has a beneficial effect on the annual rate of FVC decline regardless of the patients’ baseline lung impairment, providing additional evidence of the benefits of the drug in slowing disease progression in a range of IPF patients.

nintedanib is a small molecule tyrosine kinase inhibitor, which has been approved and marketed globally for treating IPF in adults. nintedanib blocks multiple signaling pathways that may be involved in the scarring of lung tissue and fibrotic processes, reducing disease progression in IPF and slowing lung function decline.

Trial indicates Ofev slows progression in IPF patients

By Dr Deepu

The interim findings from the INPULSIS-ON extension trial were presented at the European Respiratory Society (ERS) International Congress 2016 in London.

The findings were consistent with those previously reported from the INPULSIS Phase 3 trials (INPULSIS-1 and -2). The interim analysis from the extension trial demonstrated that nintedanib slows disease progression in IPF patients. In addition, long-term treatment with nintedanib  (up to 51 months) was associated with manageable side effects in most patients, with diarrhea being the most frequently reported side effect.

Results from the interim analysis of INPULSIS-ON demonstrated that in terms of forced vital capacity (FVC, a measure of lung function) in IPF patients who continued nintedanib treatment in the extension trial, the change between baseline and week 48 and between weeks 48 and 96 was similar to what was seen in IPF patients who were on active treatment with Ofev in the 52-week INPULSIS clinical trials.

Findings from the trials on the effect of nintedanib on FVC demonstrated that:

In INPULSIS, the mean FVC change from baseline to week 52 was −89mL compared to –203mL for placebo-treated patients;

In INPULSIS-ON, the mean FVC change for patients who continued treatment was −96 mL from baseline to week 48;

In INPULSIS-ON, the mean FVC change for patients who continued treatment was −124mL from week 48 to week 96;

In INPULSIS and INPULSIS-ON, the average exposure to Ofev was around three years (35.7 months).

Two additional sub-group analyses from the trials revealed that treatment with Ofev has a beneficial effect on the annual rate of FVC decline regardless of the patients’ baseline lung impairment, providing additional evidence of the benefits of the drug in slowing disease progression in a range of IPF patients.

nintedanib is a small molecule tyrosine kinase inhibitor, which has been approved and marketed globally for treating IPF in adults. nintedanib blocks multiple signaling pathways that may be involved in the scarring of lung tissue and fibrotic processes, reducing disease progression in IPF and slowing lung function decline.

Add-on Tiotropium Therapy Improves Asthma

By Dr Deepu

At least 40% of asthma patients remain symptomatic despite treatment with inhaled corticosteroids with or without long-acting β2-agonists. The long-acting anticholinergic bronchodilator tiotropium (Spiriva Respimat/Boehringer Ingelheim) has been incorporated into the Global Initiative for Asthma 2015 treatment strategy as an add-on therapy option for patients with a history of asthma exacerbations, and the clinical efficacy and safety of add-on tiotropium therapy have been established in adults across differing asthma severity levels.

Now, two randomized, double-blind, parallel-group twin trials reported in Respiratory Medicine have shown that add-on tiotropium therapy helps to control asthma in symptomatic patients regardless of many patient characteristics. These findings indicate that add-on tiotropium therapy could be useful for a wide range of asthma patients who still have asthma symptoms despite treatment with other agents.

In these two international, multicenter trials, add-on therapy with tiotropium improved lung function and asthma symptom control and reduced the risk of asthma exacerbation episodes and worsening of asthma in symptomatic asthma patients taking an inhaled corticosteroid with a long-acting β2-agonist, regardless of patient age, allergic status, and degree of airway obstruction at baseline.

The trials enrolled 912 patients with severe, symptomatic asthma who had been taking at least 800 μg of budesonide or the equivalent as well as a long-acting β2-agonist for at least 4 weeks. Currently symptomatic patients between the ages of 18 and 75 years with a history of asthma of at least 5 years and an initial diagnosis before age 40 years were eligible to participate in the study. Moderate or persistent airflow limitation at the initial screening visit and at least one exacerbation in the last year requiring systemic glucocorticoid therapy were also requirements for study participation.

Patients were randomly assigned in a 1:1 ratio to receive either tiotropium, 5 μg once daily via the Respimat Soft Mist inhaler (Boehringer Ingelheim), or placebo for 48 weeks.

The study investigators measured the following asthma parameters:
Peak force expiratory volume in 1 second (FEV1)
Trough FEV1
Time to first severe exacerbation
Time to first episode of worsening asthma
Results from the seven-question Asthma Control Questionnaire
Subgroup analysis of the relation between these parameters and patients’ baseline characteristics indicated that, compared with placebo, once-daily  tiotropium improved lung function and control of asthma in these patients independently of a broad range of characteristics including gender, body mass index, disease duration, age at asthma onset, FEV1 percentage predicted at screening, and FEV1 reversibility.