PrimeCuts: This Week in the Journals

June 8, 2009

picture-287Kathir Palanisamy MD

Faculty Peer Reviewed

Let’s start the week with an update about the swine flu before turning our attention to tuberculosis. The New York Times reported on 6/5/09 that there have been 623 confirmed cases, 375 hospitalizations, and eight confirmed deaths linked to the swine flu in the U.S. To put that into perspective, the seasonal flu claims 1000 lives, on average. NYC health officials continue to urge those citizens with complicating medical factors as well as those with severe symptoms to seek medical attention. (1)

For a more national perspective, the CDC in their continuously updated section dedicated to the swine flu reported that as of 6/3/09 all fifty states had reported cases of swine flu though the overall activity appeared to be decreasing. The US government has also initiated the process of manufacturing a H1N1 vaccine, which can take several months to complete. More immediately it has distributed 25% of the strategic national stockpile, which includes Tamiflu and protective gear to states. (2)

The New York Times reported further on the CDC efforts in another article. This article hypothesized that the avian flu scare may have actually prepared us well for this year’s swine flu outbreak. Due to past experience with avian flu, the federal government had 50 million doses of Tamiflu, new vaccine factories, and emergency plans already in place. However, the article also highlighted shortcomings which include the fact that Americans often go to work when ill because 48% of them have no paid sick leave, and that emergency rooms have become overwhelmed by worried patients with no health insurance. (3)

Shifting to the medical literature, we find many articles focused on TB. TB continues to be the second leading cause of infectious disease death after HIV in the world. The New England Journal of Medicine featured several articles about Tuberculosis, the first of which, “The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis” presents the results from the first stage of a two-stage, phase two trial of a mycobacterial ATPase synthase inhibitor, diarylquinoline for use in patients with multi-drug resistance TB. The investigators randomly assigned 47 patients to two groups, one of which received diarylquinoline TMC207 in addition to a five drug regimen consisting of kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizidone and the other who received placebo plus the same five-drug regimen. The primary endpoint was conversion of sputum cultures. The study found that the addition of diarylquinoline to the five drug regimen decreased the time to conversion and increased the percentage of patients who had sputum conversion. Importantly, the medication was generally well tolerated with most symptoms being mild to moderate and only nausea being adverse event reported to be significantly increased. Based on these results, the authors conclude that is a promising drug that appears to be ready for wider testing and would be a welcome addition to our treatment of multidrug resistant TB. (4)

The next article in the New England Journal titled “Overseas screening for Tuberculosis in US-bound Immigrants and Refugees” validates the current US screening policies for TB. This study differs from its predecessors by examining follow-up at a national level from the CDC notification system, rather than from the state and local levels which is what was previously done. The screening process has two parts, an overseas component with follow up in the US. The first part consists of a medical exam conducted by a licensed local physician which includes laboratory tests as well as a posterior/anterior chest x-ray. If the patient has any symptoms or chest x-ray findings suggestive of TB, three sputums are collected on consecutive days. Patients are considered to have smear-positive TB if they have a chest x-ray that is consistent with active TB and sputum or sputa that stained positive for acid-fast bacilli. They are considered to have smear-negative TB if their chest x-ray was consistent with active TB but the sputa were negative. They were considered to have inactive TB if the chest x-ray was suggestive of prior TB that was currently inactive, and no TB if the chest x-ray is normal. Those classified with smear-positive TB are given two options. The first option is to undergo treatment until they are smear-negative for a specified amount of time, at which time they are reclassification as having inactive TB. The second option is to undergo treatment until they are smear-negative and then apply for a medical waiver. These people are then instructed to come to a US public health agency to seek further treatment. Upon arrival in the US, their medical examination forms are collected and sent to the CDC quarantine station. The CDC then notifies health departments of immigrants carrying overseas diagnosis of TB, and health department physicians are asked to follow up and assign a post-arrival diagnosis.

The investigators looked at demographic data from 2,714,223 immigrants and 378,506 refugees between 1999 and 2005. There were 26,075 smear-negative cases of TB and 22,716 inactive TB cases classified overseas. After follow-up post-arrival, active TB was diagnosed in 7% of persons with smear-negative TB and 1.6% in persons with inactive tuberculosis. The authors conclude that that the current approach to TB surveillance is a necessary and valuable use of healthcare dollars. (5)

Another article from the New England Journal that we will discuss is a piece reexamining the role of granulomas in TB, entitled “The Granuloma in Tuberculosis – Friend or Foe?” The current dogma about granulomas in TB is that they are necessary for the containment of TB. Indeed in patients with intact immune systems granulomas are present while they are absent in those with compromised immune systems. Past observations of the role of granulomas in TB containment are limited by use of models involving sacrificed animals. This forces investigators to draw conclusions about a dynamic process from static observations. A better examination of the dynamic process was provided in a recent study by Davis and Ramakrishman, utilizing the zebrafish embryo. They observed that uptake of Mycobacterium marinum by zebrafish macrophages leads to cell death. These infected cells attract uninfected macrophages, which subsequently become infected. Knockout of the bacterial virulence region, ESX1, resulted in less recruitment of uninfected cells and less granuloma formation. While there are important differences between zebrafish and humans, these results suggest that interruption of the cycle of mycobacterial infection could lead to development of novel TB medications. (6)

Our last stop on this tour of this week’s literature with a focus on TB is a study published in the Annals of Internal Medicine entitled “Predictors of Extensively Drug-Resistant Pulmonary Tuberculosis”. The incidence of extensively drug-resistant, EDR TB is 40,000 cases annually, however little is known about predictors of EDR TB. This study from Estonia attempts to identify risk factors resulting in EDR/MDR. The world health organization defines MDR as TB with resistance to rifampicin & isoniazid and EDR as MDR with additional resistance to any quinolone and at least one second line injectable drug, such as kanamycin, capreomycin or amikacin. (7) This cross-sectional, country wide study reviewed all patients with culture confirmed TB from January 2003 to December 2005 looking specifically at demographic characteristics, socioeconomic status, TB related data and HIV status. They identified 1163 patients with TB, of whom 5.2% had EDR and 16.9% had MDR. Factors that increased risk of developing MDR/EDR were previous TB treatment (OR= 10.5), co-infection with HIV (OR= 3.1), homelessness (OR= 2.7), and ethanol abuse (OR= 2.0). This study confirms many assumptions about the origins of multi-drug resistant TB. (8)

Dr. Palanisamy is a second year internal medicine resident at NYU Medical Center.

Reviewed by Michael Poles MD, Associate Editor, Clinical Correlations

1. “City Reports Eighth Death Connected With Swine Flu” New York Times 6/5/2009

2. H1NI Flu (Swine Flu)

3. “Avian Flu Fears Said to Help U.S. Prepare for Swine Flu” New York Times 6/4/2009

4. Diacon A, Pym A,Grobusch M. The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis. NEJM. 2009 June 4; 360(23);2397-2405.

5. Liu Y, Weinberg M, Ortega L. Overseas Screening for Tuberculosis in U.S.-Bound Immigrants and Refugees. NEJM. 2009 June 4; 360(23);2406-2415

6. Rubin E. The Granuloma in Tuberculosis – Friend or Foe? NEJM. 2009 June 4; 360(23);2471-2473


8. Killman K, Altraja A. Predictors of Extensively Drug-Resistant Pulmonary Tuberculosis. Annals of Internal Medicine. 2009 June 2; 150(11);766-775