Initiation of Therapy for Active TB

We have discussed the initiation of TB therapy on a few occasions already this year, including a case where a patient developed toxicity to the medications.  Downtown Toronto we are very fortunate to have fast access to input from our infectious disease colleagues as well as specialized TB clinics, but in other locations starting a patient on TB therapy may fall into the scope of practice of a general internist.  This week's blog post will outline a basic approach to treating a patient for TB based on the Canadian guidelines.   

What do I need to do before starting therapy?

·         Counseling:

o   Importance of adherence to therapy

§  Many patients participate in Directly Observed Therapy (DOT) through the Department of Public Health.

o   Avoidance of alcohol and hepatotoxic medications (ie. acetaminophen, herbal remedies)

o   Need to seek immediate medical attention if the following develop:

§  Symptoms of acute hepatitis such as nausea, vomiting, right upper quadrant pain, jaundice

§  Changes in vision

§  Rash

·         Baseline Testing

o   CBC, lytes, creatinine

o   Liver panel

o   Hepatitis A/B/C and HIV

o   Uric acid

o   Visual acuity, red-green color discrimination

What regimen should I start empirically in most patients?

Drug	Daily Dose	Side Effects	Duration
Rifampin (RMP)	10mg/kg Max 600mg	Drug interactions, hepatitis, rash, cytopenias	6 months
Isoniazid (INH)	5mg/kg Max 300mg	Hepatitis, rash, neuropathy, CNS toxicity, anemia	6 months
Pyrazinamide (PZA)	20-25mg/kg Max 2000mg	Hepatitis, arthralgias, rash, gout	2 months
Ethambutol (EMB)	15-20mg/kg 1600mg	Ocular toxicity, rash	2 months*
Pyridoxine	25mg	Prevention of peripheral neuropathy from INH	While on INH

* Can be stopped as soon as sensitivities back if pan-sensitive

How do I monitor patients once they have been started on therapy?

·         Monitoring Disease Activity:

o   Patients who are AFB smear positive require weekly smears until negative

o   Once smears are negative, cultures should be done at 2 months, and 6 months prior to completion of therapy

·         Monitoring for Complications:

o   Patients on active therapy should be seen at least monthly and should be assessed at each visit for adverse reactions

o   There are no clear guidelines regarding how frequently to repeat liver enzymes

§  This is currently based on clinical judgment and baseline risk for toxicity

What happens if my patient develops drug-induced hepatitis?

·         Risk of hepatitis:

o   Pyrazinamide > Isoniazid > Rifampin

·         Immediate action is required if the transaminases are > 5x ULN or the patient becomes jaundiced

o   Stop all three of the above drugs

o   Start alternative regimen with a fluoroquinolone + one other agent

·         Once transaminases normalize, reintroduce rifampin, followed by isoniazid, followed by pyrazinamide

Special Circumstances:

·         Treatment considerations are different in the following scenarios, and expert consultation should be sought:

o   HIV-associated TB

o   Extrapulmonary TB

o   Multi-drug resistant TB

The information in this blog post was adapted from the Canadian Tuberculosis Standards, 7^th Edition, Chapter 5: Treatment of Tuberculosis Disease.  It can be accessed at www.respiratoryguidelines.ca/sites/all/files/CTB_Standards_EN_Chapter%205.pdf. 

For additional reading check out:

Horsburgh CR, Barry CE, Lange C. Treatment of tuberculosis. NEJM. 2015; 373:2149-2160.

Approach to Dyspnea in a Patient with an Underlying Malignancy

--> In morning report this week, we discussed the case of a woman with a known history of breast cancer presenting with shortness of breath.  This case highlighted that although the most common etiologies for dyspnea seen on GIM are still very much applicable in this setting, we have to broaden our differential to consider additional causes, some of which are life threatening.   Dr. Abdullah provided a very helpful framework for approaching the differential diagnosis as outlined below:

 A few additional points to consider when working through this differential based on our discussion in Morning Report:

1.    A thorough treatment history is very helpful!      

·      What chemotherapy did they receive and when?

·      When was their last dose of radiation?

·      Was their left ventricular ejection fraction measured before and after treatment (typically with a MUGA)?

·      When was their last staging/surveillance imaging?  What did it show?

2.    VTE is not only more common in patients with cancer, it is also associated with poor prognosis^1.  Unless there is a clear alternate cause, many of these patients will need a CT PA.

·      This will also provide a lot of additional useful information, such as evidence of infection or pericardial effusion, which may not be evident on CXR.

3.    If a pericardial effusion causing tamponade crosses your mind, you need to rule it out.

·      In addition to dyspnea, most patients with tamponade will also have tachycardia, elevated JVP, enlargement of the cardiac silhouette on chest x-ray and pulsus paradoxus.  On the contrary, less than half of patients will exhibit hypotension, muffled heart sounds or characteristic ECG changes.² 

·      It can be a challenging diagnosis to make based on physical exam alone so  have a low threshold to order a TTE.  If the patient had a CT chest, it is also helpful to check the report for presence of a pericardial effusion with the caveat that the size tends to be overestimated on CT.

4.    Radiation pneumonitis typically occurs four to twelve weeks post-radiation whereas fibrotic disease takes six months to 2 years to manifest.

·      Certain types of chemotherapy can increase the risk of radiation-induced lung injury.  These agents include bleomycin, doxorubicin and cyclophosphamide, among others.³ 

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5.    For respiratory infections in this patient population, consider your choice of antibiotic therapy carefully.

·      Many of these patients will have had extensive health care exposures, previous infections and will be immunosuppressed. 

·      Check previous cultures, if available.  However, broader initial therapy and more extensive investigations including CT chest +/- bronchoscopy may be required depending on the degree of immunosuppression.

1.         Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. Sep 5 2013;122(10):1712-1723.

2.         Roy CL, Minor MA, Brookhart MA, Choudhry NK. Does this patient with a pericardial effusion have cardiac tamponade? Jama. Apr 25 2007;297(16):1810-1818.

3.         Graves PR, Siddiqui F, Anscher MS, Movsas B. Radiation pulmonary toxicity: from mechanisms to management. Semin Radiat Oncol. Jul 2010;20(3):201-207.

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The Canadian Cancer Society has helpful information about chemotherapy and its side effects (including organ-specific side effects) for both patients and healthcare providers on their website at http://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/chemotherapy-and-other-drug-therapies/chemotherapy/side-effects-of-chemotherapy/?region=on.