Beyond the Blue:
What Fellows Are Reading in Other Journals
Venous Thromboembolism Prophylaxis, Shorter Courses
of Isoniazid for Tuberculosis, and the Microbiome
in Asthma
Timothy M. Fernandes1, Carmen Taype-Roberts1, and Jinghong Li1
1
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California, San Diego, San Diego, California
Recommended Reading from the University of California, San Diego Pulmonary and Critical Care Medicine Training
Program; Nick H. Kim, M.D., Program Director
Lederle FA, et al. Venous Thromboembolism Prophylaxis
in Hospitalized Medical Patients and Those with Stroke:
A Background Review for an American College of
Physicians Clinical Practice Guideline. Ann Intern Med (1)
Reviewed by Timothy M. Fernandes, M.D.
Venous thromboembolism (VTE) in acutely ill, hospitalized
medical patients remains a common and potentially preventable
condition associated with significant morbidity and mortality. Al-
though thromboprophylaxis may prevent VTE events, the risks
of bleeding may increase. In this meta-analysis conducted as
a background review for the American College of Physicians
(ACP) Clinical Practice Guideline, the authors searched the
Cochrane Library and MEDLINE for randomized, controlled
trials of pharmacological and mechanical forms of prophylaxis.
Forty trials met inclusion criteria. The use of heparin decreased
the incidence of pulmonary embolism (odds ratio [OR], 0.70;
95% confidence interval [CI], 0.56 to 0.87) in medical and stroke
patients and had a nonsignificant effect on mortality with a trend
toward benefit (relative risk [RR], 0.93; 95% CI, 0.86 to 1.00; P ¼
0.056). Importantly, reduction in thrombosis risk came at the
expense of an increase in the risk of major bleeding (an out-
come that varied in its definition in the individual trials from
a bleed that required transfusion to fatal hemorrhage) (OR,
1.61; 95% CI, 1.23 to 2.10). For every 1,000 patients treated, 3
pulmonary emboli were prevented but 4 patients had major
bleeding. There was no evidence that mechanical prophylaxis
was beneficial and compression stockings increased the risk of
skin damage in stroke patients (RR, 4.02; 95% CI, 2.34 to 6.91).
The authors completed an exhaustive review of literature that
included only well-designed, randomized trials of hospitalized,
medical patients for analysis. Their work had excellent external
validity and allowed the ACP to recommend use of thrombopro-
phylaxis only in “higher risk” hospitalized medical patients, and
not in “lower risk” patients. These recommendations are similar
to the American College of Chest Physicians’ clinical practice
guidelines for VTE prevention (2). Clearly, there are substantial
(Received in original form April 4, 2012; accepted in final form May 30, 2012)
Correspondence and requests for reprints should be addressed to Nick Kim, M.D.,
Division of Pulmonary and Critical Care Medicine, Department of Internal Med-
icine, 9330 Campus Point Drive, MC 7381, La Jolla, CA 92037-7381. E-mail:
h33kim@ucsd.edu
Am J Respir Crit Care Med Vol 186, Iss. 3, pp 286–287, Aug 1, 2012
Copyright ª 2012 by the American Thoracic Society
DOI: 10.1164/rccm.201204-0618RR
Internet address: www.atsjournals.org
risks and benefits to providing prophylaxis to hospitalized medical
patients because many are at higher risk for both thrombosis and
major bleeding. Unfortunately, there is no widely accepted and
validated risk-tool that discriminates thrombosis risk and bleed-
ing risk. More work is needed to determine which patients at
high risk for thrombosis have a net clinical benefit when given
thromboprophylaxis. As prevention of hospital-associated VTE
becomes a quality measure, we must remember that the deci-
sion to provide thromboprophylaxis must be made on a patient-
to-patient basis rather than adopting reflexive strategies to provide
prophylaxis to everyone without assessing risk.
References
1. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism
prophylaxis in hospitalized medical patients and those with stroke:
a background review for an American College of Physicians Clinical
Practice Guideline. Ann Intern Med 2011;155:602–615.
2. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ,
Balekian AA, Klein RC, Le H, et al. Prevention of VTE in nonsurgical
patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed. American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest 2012;141:e195S–e226S.
Samandari T, et al. 6-Month versus 36-Month Isoniazid
Preventive Treatment for Tuberculosis in Adults with HIV
Infection in Botswana: A Randomized, Double-Blind,
Placebo-Controlled Trial. Lancet (3)
Reviewed by Carmen Taype-Roberts, M.D., Ph.D.
Current World Health Organization (WHO) guidelines for HIV-
infected people living in tuberculosis (TB)-endemic countries rec-
ommend isoniazid preventive therapy (IPT) for 6 months (4). This
is a double-blind, randomized, placebo-controlled trial of 6-month
versus 36-month IPT of TB in HIV-infected adults in Botswana.
Eight hundred and twenty-one completed 6 months of open-label
isoniazid and started placebo (control group), and 834 completed
6 months of open-label isoniazid and started 30 months of isoni-
azid. The TB incidence was 1.26% per year in the control subjects
compared with the prolonged IPT subjects (0.72%; P ¼ 0.047). In
the control group, 13 of 216 (6%) with a positive tuberculin skin
test (TST) developed TB in comparison with 4 of 252 (1.6%)
receiving prolonged IPT (P ¼ 0.02). Prolonged IPT in people
with a positive TST was associated with greater efficacy and less
mortality (P ¼ 0.03).
This is a well-designed randomized, double blind, placebo-
controlled study performed in Botswana. TB incidence in Bot-
swana (including HIV coinfection) was reported as 503 per
Beyond the Blue: What Fellows Are Reading in Other Journals
100,000 inhabitants in 2010. The findings of the present study
should be applied in the context of TB-endemic countries. It
is highly recommended to view the supplemental material as
it limits the generalizability and provides data of cumulative
death incidence, antiretroviral therapy (ART), and isoniazid-
resistant strains. The study demonstrates that 36 months of
IPT decreases the incidence and mortality of TB if patients
are TST positive. The benefit is lost if this regimen is given to
TST-negative patients. The beneficial effect of isoniazid could
be potentiated by the initiation of ART, type of ART, and
the lack of randomization in the initiation of ART. On the basis
of these results, it would be counterproductive to treat TST-
negative, HIV-infected patients and put them at unnecessary risk
of toxicity and drug resistance. However, it would be reasonable to
give this regimen to TST-negative individuals whose CD41 cell
count is less than 200 cells/mm3. Although the WHO recommends
36 months of IPT in HIV-infected patients living in TB-endemic
countries, irrespective of TST, TST should be done if possible. In
addition, a follow-up study of these patients will give us further
information to assess whether TB protection still persists.
References
3. Samandari T, Agizew TB, Nyirenda S, Tedla Z, Sibanda T, Shang N,
Mosimaneotsile B, Motsamai OI, Bozeman L, Davis MK, et al. 6-month
versus 36-month isoniazid preventive treatment for tuberculosis in adults
with HIV infection in Botswana: a randomised, double-blind, placebo-
controlled trial. Lancet 2011;377:1588–1598.
4. World Health Organization; Stop TB Department and Department of
HIV/AIDS. Guidelines for intensified tuberculosis case finding and
isoniazid preventive therapy for people living with HIV in resource
constrained settings. 2011. Available from http://www.who.int/hiv/pub/
tb/9789241500708/en/index.html
Huang YJ, et al. Airway Microbiota and Bronchial
Hyperresponsiveness in Patients with Suboptimally
Controlled Asthma. J Allergy Clin Immunol (5)
Reviewed by Jinghong Li, M.D., Ph.D.
Acute respiratory infections are well-known triggers of asthma
exacerbations. Studies in patients with asthma (6) and patients
with chronic obstructive pulmonary disease (7) suggest that the
airway microbiota might be an important contributor to the
heterogeneity of the diseases. The relationship between airway
microbiota and the clinical features of asthma remains unclear.
As part of the NHLBI Asthma Clinical Research Network
(ACRN) Macrolides in Asthma (MIA) clinical trial, the authors
reported the association between the composition of airway
microbiota and clinical features of asthma.
This is a multicenter pilot study of 65 subjects with asthma re-
ceiving standard inhaled corticosteroid (ICS) treatment compared
287
with 10 healthy subjects. Culture-independent methods, high-
density phylogenetic microarray analysis, and clone library se-
quencing analysis were used to profile the microbiota data from
bronchial brushings. The relationship between airway microbiota
and bronchial hyperresponsiveness was examined. The patients
were subsequently randomized to clarithromycin or placebo ther-
apy. Bronchial hyperresponsiveness was reassessed after clarithro-
mycin therapy. The authors found that subjects with asthma had
significantly higher bacterial burden (P ¼ 0.008) and diversity in
their airways than did healthy subjects. The types and relative
abundance of bacteria were significantly correlated with the de-
gree of airway hyperresponsiveness (P , 0.003). Subjects with
asthma with higher bacterial diversity before clarithromycin treat-
ment had greater reduction in bronchial hyperresponsiveness af-
ter treatment (P ¼ 0.03).
This study offered detailed evaluation of the airway micro-
biota and the clinical features of asthma. The findings suggest
that bacterial abundance and diversity are associated with the
degree of bronchial hyperresponsiveness in subjects with
asthma. However, in this study, post–clarithromycin treat-
ment changes in airway microbiota were not studied. Therefore,
the correlation between the airway microbiota and the clinical
response to clarithromycin remains unclear. Relatively few
healthy subjects were studied, and patients with asthma without
ICS were not included.
To date, we rely on culture-based methods to identify bacte-
rial infection and to determine the appropriate treatment. How-
ever, the conventional culture techniques afford low sensitivity.
Novel culture-independent molecular approaches offer more de-
tailed evaluation of the airway microbiota that may better inform
the composition and role of bacteria in asthma. These findings
could improve our understanding of suboptimally controlled
asthma, and potentially lead to new and much-needed therapies
for these patients.
Author disclosures are available with the text of this article at www.atsjournals.org.
References
5. Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J,
Woyke T, Allgaier M, Bristow J, Wiener-Kronish JP, et al. Airway
microbiota and bronchial hyperresponsiveness in patients with sub-
optimally controlled asthma. J Allergy Clin Immunol 2011;127:372–381.
e1–3.
6. Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, Davies J,
Ervine A, Poulter L, Pachter L, et al. Disordered microbial com-
munities in asthmatic airways. PLoS One 2010;5:e8578.
7. Erb-Downward JR, Thompson DL, Han MK, Freeman CM, McCloskey
L, Schmidt LA, Young VB, Toews GB, Curtis JL, Sundaram B, et al.
Analysis of the lung microbiome in the “healthy” smoker and in
COPD. PLoS One 2011;6:e16384.