Pulmonary/Critical Care

Spotlight: Pneumocystis Pneumonia in a Patient Without AIDS, A Clinical Vignette

September 20, 2017

Pneumocystis_carinii._Toluidine_blue_stain_PHIL_596_loresBy Martin Fried, MD

Peer reviewed

Learning Objectives

  • Why does impaired cellular immunity increase the risk for Pneumocystis jiroveci Pneumonia (PJP)?  How do acquired humoral immune deficiencies, such as the use of rituximab, increase the risk for PJP?
  • At what dose of chronic steroids use should patients be given prophylaxis for PJP?

Case Summary

The patient is a 35-year-old man with a history of psoriatic arthritis and complex regional pain syndrome on prednisone, methotrexate and abatacept who presented with two weeks of dyspnea on exertion and cough.  Three months prior to admission, the patient increased his dose of prednisone (from 10mg to 20mg daily) to better control his psoriatic arthritis.

Progressive dyspnea on exertion appeared two weeks prior to presentation and a nonproductive cough developed one week prior to presentation.  The patient also reported night sweats during this time but otherwise denied fevers, chills, chest pain or palpitations, leg swelling or wheezing.  He had no recent travel history, sick contacts or occupational exposures.

On arrival, the patient was afebrile with a heart rate of 114 beats per minute, a respiratory rate of 24 breaths per minute and an oxygen saturation of 92% on ambient air.  The physical exam was notable for fine crackles and bronchial breath sounds over the right mid-lower lung field.  Initial labs revealed white blood cell count of 21.9 K/uL with 80% neutrophils but was otherwise unremarkable. A rapid HIV test was negative.  Chest XR demonstrated right middle and lower lobe consolidations and left basilar hazy opacities consistent with multifocal pneumonia.  He was started on antibiotics for community acquired pneumonia and admitted to the hospital.

The patient’s dyspnea continued to worsen over the first two hospital days despite antibiotic therapy.  On hospital day 2 beta-d-glucan was noted to be positive (> 500 pg/mL).  Later that day his respiratory status decompensated necessitating ICU transfer and intubation.  Bronchial lavage identified Pneumocystis jiroveci on routine and PAS stain.  He was treated with IV TMP-SMX and prednisone. He recovered and was discharged to inpatient pulmonary rehabilitation.

Discussion

This case highlights a young, chronically ill, HIV-negative patient on chronic immunosuppressive medications who presented with worsening constitutional symptoms and dyspnea and was found to have PJP.   While this case raises many learning points, we narrowed our focus to two specific questions.  First we will review specific types of immunodeficiency, namely cellular versus humoral, and discuss implications on the risk for PCP.  The second question will address the evidence for giving antibiotics as prophylaxis for PCP pneumonia in patients who are on chronic steroids.

The pneumocystis pathogen-host interaction is well-described.[1] It used to be thought that colonization was ubiquitous and disease only occurred once immunodeficiency developed.  However, a number of laboratory, clinical and epidemiologic studies challenged this.  For example, pneumocystis strains vary within cities and infected patients’ strains tend to be more similar to their current location rather than their birth location.[2]

Mouse models to study pneumocystis infection often involve T-cell deficient animals which causes severe combined immunodeficiency (SCID).  In these mice, PCP infection develops quickly and spontaneously. These mice have intact neutrophils and macrophages, yet cannot clear the organism.  When CD4+ T cells are reconstituted the mice are able to clear the infection.[3]  CD4+ cells also generate interferon-g and lymphotactin, which function as potent chemokines.[4]   CD4+ activated alveolar macrophages produce large amounts of tumor necrosis factor (TNF), which further recruits inflammatory cells to participate in pathogen clearance.

An important feature of the case presented was the ongoing treatment with abatacept.  This biologic agent typically used for rheumatoid arthritis is a monoclonal antibody against CD80 and CD86 on T cells.  These cell-surface proteins provide the necessary co-signaling for T cell activation and proliferation.  The medication effectively induces a mild form of SCID.  In a similar case report of PCP in a patient being treated with abatacept, there was co-treatment with methotrexate.[5]  Although considered safe, there is an increased risk of the same invasive fungal infections with abatacept treatment as SCID patients often experience.[6]

Independent of the inflammatory response that it mediates, the pneumocystis infection is fairly benign.[7]  The pneumocystis-infected SCID mice described above had preserved oxygenation and lung function until later stages of the disease.  It wasn’t until splenic CD4+ T cells were reintroduced that these mice experienced impaired lung function and tissue oxygenation as a result of the dysregulated response.  An analogous phenomena occurs when HIV-positive patients initiate anti-retroviral therapy during PCP treatment causing the immune reconstitution inflammatory syndrome.[8]

This observation explains some of the clinical differences in pneumocystis infections in HIV-infected versus uninfected patients.  Those with HIV develop pneumonia that is characterized by indolent progression of the disease.  Bronchoalveolar lavage (BAL) in these patients demonstrates large numbers of organisms and few neutrophils (but abundant macrophages and CD8+ T cells).  In the HIV-uninfected population, PCP is fulminant with greater morbidity and mortality.[9]  BAL analyses in HIV-uninfected patients demonstrate few organisms that evoke a robust neutrophilic response with alveolar inflammation and oxidative damage.[10]

It also appears that the humoral immune response plays an important role in the pneumocystis infection response.  There have been reports of spontaneous outbreaks of PCP in B-cell deficient mice with fully intact cellular immune systems.[11]  Subsequent studies have noted that clearance of pneumocystis is dependent on B cells but not on pneumocystis-specific antibodies.[12]  This suggests that B cells play a role in T cell activation in the clearance of pneumocystis, and explains the risk imposed on patients getting rituximab therapy.  A Mayo Clinic review of PCP cases in patients exposed to rituximab demonstrated that while infection can occur during monotherapy it is much more common when used in combination with cytotoxic chemotherapy or high dose glucocorticoids.[13]

In the HIV-positive population the risk of PCP below a CD4+ T cell count of 200 makes the threshold at which to initiate primary prophylaxis straightforward.[14]  No such level exists for HIV-uninfected patients at risk for PCP, and as new immunosuppressive medications become more widely available this population will continue to grow.  One particularly challenging subset of at-risk HIV-uninfected patients are those on chronic glucocorticoids.  The 2011 American Thoracic Society guidelines recommend consideration of PCP prophylaxis in patients taking chronic steroids if the dose is greater than or equal to 20mg of prednisone daily for one month, especially if there are concomitant T cell deficits, cytotoxic or anti-TNF agents.[15]  This dose and duration first appeared in the literature in the late 1980s to mid-1990s with the publication of several case series of HIV-uninfected patients diagnosed with PCP.[16],[17],[18]   Prolonged corticosteroid use with concomitant immunosuppressive disease or medication was the common thread throughout the vast majority of these patients.  In these reports, one from Memorial Sloan Kettering Cancer Center (MSKCC) and two from the Mayo Clinic, the median daily dose was 20-80mg of prednisone daily for 9 weeks to 3 months.  The recommendation of 20mg daily prednisone for 4 weeks appears to be the MSKCC prophylactic policy that is then referenced-forward.[19] 

Summary:

Pneumocystis pneumonia is a life-threatening infection that was first recognized in the HIV-infected population.  In the early days of the AIDS epidemic the prevalence of PCP in patients with low CD4+ T cell counts helped us understand the importance of cellular immunity in controlling the infection.  The observed clinical differences between HIV-infected and HIV-uninfected patients with PCP clarified the role of a dysregulated immune response as the primary culprit in pulmonary damage due to pneumocystis.

Dr. Martin Fried is a chief resident, internal medicine, NYU Lutheran 

Peer reviewed by Dr. Howard Leaf, infectious diseases, NYU Langone Health

Image courtesy of Wikimedia Commons

References

[1] Thomas, Charles F., and Andrew H. Limper. “Current insights into the biology and pathogenesis of Pneumocystis pneumonia.” Nature Reviews Microbiology 5.4 (2007): 298-308. http://www.nature.com/nrmicro/journal/v5/n4/abs/nrmicro1621.html?foxtrotcallback=true

[2] Morris, Alison, C. Ben Beard, and Laurence Huang. “Update on the epidemiology and transmission of Pneumocystis carinii.” Microbes and infection 4.1 (2002): 95-103.

[3] Roths, J. B., Marshall, J. D., Allen, R. D., Carlson, G. A. & Sidman, C. L. Spontaneous Pneumocystis carinii pneumonia in immunodeficient mutant scid mice. Natural history and pathobiology. Am. J. Pathol. 136, 1173–1186 (1990).

[4] Wright, T. W., Johnston, C. J., Harmsen, A. G. & Finkelstein, J. N. Chemokine gene expression during Pneumocystis carinii-driven pulmonary inflammation. Infect. Immun. 67, 3452–3460 (1999).  https://www.ncbi.nlm.nih.gov/pubmed/10377126

[5] Ospina, Fabio E., et al. “Pneumocystis jirovecii pneumonia in a patient with rheumatoid arthritis treated with abatacept.” Case reports in rheumatology 2014 (2014).  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182847/

[6] Vallabhaneni, Snigdha, and Tom M. Chiller. “Fungal infections and new biologic therapies.” Current rheumatology reports 18.5 (2016): 1-10. https://www.ncbi.nlm.nih.gov/pubmed/27032792

[7] Ponce, Carolina A., et al. “Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population.” Clinical infectious diseases50.3 (2010): 347-353.

[8] Tasaka, Sadatomo, and Hitoshi Tokuda. “Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies.” Journal of Infection and Chemotherapy 18.6 (2012): 793-806. https://www.ncbi.nlm.nih.gov/pubmed/22864454

[9] Mansharamani NG, Garland R, Delaney D, Koziel H. Management and outcome patterns for adult Pneumocystis carinii pneumonia, 1985 to 1995: comparison of HIV-associated cases to other immunocompromised states. Chest 2000;118:704-11

[10] Limper, Andrew H., et al. “Pneumocystis carinii pneumonia: differences in lung parasite number and inflammation in patients with and without AIDS.”American review of respiratory disease 140.5 (1989): 1204-1209.  https://www.ncbi.nlm.nih.gov/pubmed/2817582

[11] Marcotte, Harold, et al. “Pneumocystis carinii infection in transgenic B cell-deficient mice.” Journal of Infectious Diseases 173.4 (1996): 1034-1037.

[12] Lund, Frances E., et al. “Clearance of Pneumocystis carinii in mice is dependent on B cells but not on P. carinii-specific antibody.” The Journal of Immunology 171.3 (2003): 1423-1430.

[13] Martin-Garrido, Isabel, et al. “Pneumocystis pneumonia in patients treated with rituximab.” CHEST Journal 144.1 (2013): 258-265.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694106/

[14] Stansell, John D., et al. “Predictors of Pneumocystis carinii pneumonia in HIV-infected persons. Pulmonary Complications of HIV Infection Study Group.” American journal of respiratory and critical care medicine 155.1 (1997): 60-66.

[15] Limper, Andrew H., et al. “An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients.”American journal of respiratory and critical care medicine 183.1 (2011): 96-128. http://www.atsjournals.org/doi/abs/10.1164/rccm.2008-740ST

[16] Arend, Sandra M., Frank P. Kroon, and Jan W. van’t Wout. “Pneumocystis carinii pneumonia in patients without AIDS, 1980 through 1993: an analysis of 78 cases.” Archives of internal medicine 155.22 (1995): 2436-2441.

[17] Sepkowitz, Kent A., et al. “Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital.” Jama 267.6 (1992): 832-837.

[18] Yale, Steven H., and Andrew H. Limper. “Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illnesses and prior corticosteroid therapy.” Mayo Clinic Proceedings. Vol. 71. No. 1. Elsevier, 1996.

[19] Sepkowitz, Kent A., Arthur E. Brown, and Donald Armstrong. “Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome: more patients, same risk.” Archives of internal medicine 155.11 (1995): 1125-1128. https://www.ncbi.nlm.nih.gov/pubmed/7763117

 

Oxygen-Induced Hypercapnia in COPD: What is the Mechanism?

September 28, 2016

2301_Major_Respiratory_OrgansBy Jonathan Glatt

Peer Reviewed 

It was my first week on the wards as a third-year medical student, and I found myself huddled with the team in a busy corner of the Bellevue ED, listening to a man cough and wheeze his way through an interview. He was an elderly patient with an extensive smoking history–a lifetime of a destructive habit that had dilated and distorted his lungs beyond repair. He told us, between bouts of breathlessness, of worsening dyspnea and copious sputum production over the past couple of days, riding into his diseased alveoli on the viral coattails of a recent upper respiratory infection. Armed with a presumptive diagnosis of acute chronic obstructive pulmonary disease (COPD) exacerbation, we proceeded to manage his symptoms in full force, dilating his bronchioles and suppressing his inflammation. However, when it came time to administer supplemental oxygen, to give this man some much-needed breaths of air…we held back. I can distinctly remember my resident saying: “Make sure to titrate his oxygen to a sat between 88 and 92 percent.” At that moment, my resident was of course concerned about hyperoxic hypercarbia, a phenomenon that all of us are taught about in medical school, in which increasing oxygen saturation in a chronic carbon dioxide retainer can inadvertently lead to respiratory acidosis and death.1

But where do these magic numbers 88 and 92 really come from? What is the evidence against high-flow oxygen therapy in these patients? In one randomized comparison trial based in Australia, over 400 patients with probable acute COPD exacerbation were treated by paramedics with either oxygen titrated to a saturation between 88-92% or high-flow oxygen therapy, all while en route to the hospital. The authors found that all-cause pre-hospital or hospital mortality was significantly less in those patients who had received oxygen by conservative titration, with a relative risk reduction of 58%; these patients were also less likely to develop subsequent respiratory acidosis.2 Based on this study, there appears to be strong prospective mortality evidence in favor of withholding high-flow oxygen from COPD patients.

Why does the phenomenon of hyperoxic hypercarbia occur in the first place? Is there any evidence to back up the traditional “hypoxic drive theory”–a theory that is still taught in some medical school classrooms (as well as certain shelf examination preparation materials that shan’t be named)? Or has this historical explanation been debunked in favor of some other underlying mechanism? The earliest studies that warned against uncontrolled oxygen therapy in COPD date back to the 1940s; one investigator at the time theorized that hypoxia provided a vital “stimulus” to breathe in these patients, at the level of the sinoaortic nerves.3 And so, the theory of hypoxic drive was born. It postulates that chronic retainers bear a blunted response to carbon dioxide levels (and to their proxy, low serum pH), and that these patients therefore rely to some degree on hypoxemia in order to breathe.

Over the following years, the hypoxic drive theory gained traction within the medical community. It was not until the early 1980s that it was seriously called into question, at least within the scientific literature. In one prospective study at the time, COPD patients with acute respiratory symptoms each received 100% oxygen supplementation, which was found to decrease their minute ventilation by an average of nearly 20% (via a decrease in both tidal volume and respiratory rate). Surprisingly, this initial decrease in minute ventilation almost entirely reversed on its own within the next several minutes, even as these patients remained on 100% oxygen. The authors noted that despite this near-complete restoration of minute ventilation, arterial carbon dioxide tensions still remained significantly elevated compared to control, an observation that could not be explained by decreased minute ventilation alone.4 They hypothesized that the primary explanation for hypercarbia in the setting of oxygen supplementation was not alteration in minute ventilation, as had previously been thought, but rather, ventilation-perfusion (V/Q) mismatch. They reasoned that these patients were experiencing a loss of hypoxic pulmonary vasoconstriction, the physiologic process that in healthy people accompanies alveolar hypoxia and serves to redirect blood flow away from under-ventilated lung in order to optimize the V/Q ratio.  This normal physiologic compensation, when overcome with excessive O2 administration, results in worsening V/Q ratios, that is to say, more areas in the lung where V/Q ratios are low and more areas of high V/Q.  The extreme high V/Q areas that have no flow (no Q) represent dead space. In a situation where total minute ventilation remains constant, an increase in dead space diminishes CO2 excretion and results in higher PaCO2 values.

Almost two decades later, another study was published in which pulmonary vasculature modeling software was used to reinforce that same conclusion, namely, that increased oxygen levels contribute to hypercarbia chiefly by inhibiting hypoxic vasoconstriction and increasing alveolar dead space, and only secondarily by diminishing minute ventilation.5

Another mechanism that likely contributes to oxygen-induced hypercapnia in COPD is the well-studied Haldane effect, which was first proposed in 1914.6 The Haldane effect revolves around the hemoglobin-carbon dioxide dissociation curve, which shifts to the right with increased levels of oxygen, thereby increasing arterial carbon dioxide tension in the blood. This increase in PaCO2 is due to the fact that oxygenated hemoglobin binds to carbon dioxide relatively poorly compared to deoxygenated hemoglobin, and thus deposits more carbon dioxide in the bloodstream. By virtue of their tachypnea, patients with acute COPD exacerbation are not able to compensate and excrete this excess carbon dioxide through their lungs as effectively as they otherwise would in the absence of respiratory distress. Indeed, in the aforementioned study by Aubier and colleagues, the authors estimated that fully one quarter of the effect of oxygen on hypercarbia could be attributed to the Haldane effect alone.4

Regardless of the underlying mechanism (or most likely, mechanisms)… primum non nocere! Oxygen should never be withheld from a patient in situations of doubt–that much is certain. However, it is also important to recognize the prospective evidence against high flow oxygen in acute COPD exacerbation. And so, as I look back on my first week on the wards, huddled in the Bellevue ED next to the man with the broken lungs, I can proudly say that my resident did good. By holding back, and not over-zealously treating, he proved that he was up to date on the latest evidence regarding oxygen supplementation in COPD, and he may very well have spared this man a complicated and extended hospital course. 

Jonathan Glatt is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Robert Smith, MD, Pulmonary, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

  1. Abdo WF, Heunks LM. Oxygen-induced hypercapnia in COPD: myths and facts. Crit Care. 2012;16(5):323-326. https://www.ncbi.nlm.nih.gov/pubmed/23106947
  2. Austin MA, Wills KE, Blizzard L, Walters EH, Wood-Baker R. Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ. 2010;341:c5462. https://www.ncbi.nlm.nih.gov/pubmed/20959284
  3. Donald K. Neurological effects of oxygen. Lancet. 1949;2:1056-1057.
  4. Aubier M, Murciano D, Milic-Emili J, et al. Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis. 1980;122(5):747-754. http://www.atsjournals.org/doi/10.1164/arrd.1980.122.5.747#.V-vuTU_ruDk
  5. Hanson CW 3rd, Marshall BE, Frasch HF, Marshall C. Causes of hypercarbia with oxygen therapy in patients with chronic obstructive pulmonary disease. Crit Care Med. 1996;24(1):23-28. https://www.ncbi.nlm.nih.gov/pubmed/8565533
  6. Christiansen J, Douglas CG, Haldane JS. The absorption and dissociation of carbon dioxide by human blood. J Physiol. 1914;48(4):244-271. http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.1914.sp001659/full#footer-citing

Diagnostic Challenges in Latent Tuberculosis Infection: A Brief Review of Available Tests and their Appropriate Use

July 15, 2015

Tuberculosis_symptomsBy: Miguel A. Saldivar, MD

Peer Reviewed 

“Indeterminate.” Many clinicians have expressed frustration when reading this word on a Quantiferon-TB Gold test result. The obligate follow-up question is: what is the next best step? Repeat the Quantiferon? Ignore it altogether and perform a Tuberculin Skin Test (TST) instead? Even worse, what happens when both tests are performed with discordant results? In order to answer some of these questions, this article begins with a very brief overview of Mycobacterium tuberculosis (TB) infection epidemiology. This is followed by a review of the tools currently available for the diagnosis of latent tuberculosis infection (LTBI). The last section explores some of the most important attributes of each test, which finally leads to a summary of a few of the current recommendations and the logic behind them.

A very brief overview of TB epidemiology and relevant definitions

Although it has been declared a global health emergency over 15 years ago by the World Health Organization (WHO), TB remains one of the leading infectious causes of morbidity in the world [5]. Every year, 8-10 million people globally develop active TB with an estimated 2 million annual deaths [2, 4, 5]. It is also estimated that one third of the world’s population (approximately 2 billion people) has LTBI [2, 6]. Definitions of LTBI vary slightly from organization to organization, but perhaps the most useful working definition is the one proposed by the World Health Organization (WHO): “a state of persistent immune response to prior-acquired Mycobacterium tuberculosis antigens without evidence of clinically manifested active TB” [18]. Persons with latent TB are classically considered to be not only asymptomatic but also noninfectious, and current evidence suggests that only 5-10% of people with LTBI develop active disease in their lifetime [1].

In the United States, the situation is slightly better than in other places in the world: the prevalence of active TB has declined from 6.2 cases per 100,000 people in 1998 to 4.2 cases per 100,000 in 2008. A TST survey in 2000 showed that approximately 11 million U.S. residents had LTBI, a 60% decline from 1972—although the decline was not uniform among all segments of the population and rates varied considerably [2, 7].

The currently available diagnostic tools

Despite the severity of this situation, the diagnostic tools for LTBI are not only few, but also have certain specific limitations. The most common tool in the arsenal of TB diagnosis is over 100 years old: the TST. It was not until 2001 that a new test became available, the QuantiFERON-TB test (QFT) (Cellestis Limited, Carnegie, Victoria, Australia). This was replaced in 2005 by its slightly more reliable descendant, the QuantiFERON-TB Gold test (QFT-G) (Cellestis Limited, Carnegie, Victoria, Australia), which in turn was replaced in 2007 by the most reliable version to date: the QuantiFERON-TB In-Tube test (QFT-IT) (Cellestis Limited, Carnegie, Victoria, Australia). Lastly, a separate tool that works on a similar mechanism as the Quantiferon tests became available in 2008: the T-SPOT.TB test (T-Spot) (Oxford Immunotec Limited, Abingdon, United Kingdom) [2].

In summary, three tools are currently in use for the diagnosis of LTBI, two of which fall under the same category:

  1. The time-honored Tuberculin Skin Test (TST)
  2. The Interferon-Gamma Release Assays (IGRAs), including:
    1. the QuantiFERON-TB In-Tube test (QFT-IT)
    2. the T-SPOT.TB test (T-Spot)

An Important Consideration

It is important to realize that both the TST and the IGRAs are useful for the diagnosis of latent TB, but have proven inadequate in the diagnosis of active TB. Three different systematic reviews/meta-analyses have consistently concluded that IGRAs can neither rule in nor rule out active TB (including extrapulmonary TB) [12, 13, 14]; the TST appears to have the same limitation.

The Tuberculin Skin Test 

The TST is the most commonly used tool worldwide for the diagnosis of LTBI. It consists of an intradermal injection of a poorly defined mixture of over 200 proteins derived from M. tuberculosis. A person with pre-existing cell-mediated immunity to these antigens will develop a delayed-type hypersensitivity reaction approximately 48-72 hours after the injection. This will cause swelling and induration at the site. A trained individual measures the lesion’s diameter, and the result is interpreted using pre-defined, risk-stratified cutoff points [1, 5, 6].

The Interferon-Gamma Release Assays

Just like the TST, the IGRAs (QFT-IT and T-Spot) measure a cell-mediated response. However, in the case of the IGRAs, a different aspect of the mechanism is analyzed. During infection, Th1 T-cells become sensitized to antigens naturally produced by M. tuberculosis and bind to them, releasing interferon-gamma (IFN-γ) in the process. The IGRAs work by using synthetic isolated antigens to induce a response in the existing T-cells of a patient’s whole blood sample. The T-cells bind to these antigens, their response is analyzed, and the results are interpreted by one of two protocols, depending on the specific IGRA:

QuantiFERON-TB In-Tube test

In the case of the QFT-IT, test antigens include early secretory antigenic target-6 (ESAT-6), culture filtrate protein 10 (CFP-10), and part of the peptide sequence for TB7.7. These antigens were specifically chosen because they are absent from BCG vaccine strains and most nontuberculous mycobacteria (with the exception of M. kansasii, M. szulgai, and M. marinum), thus increasing the QFT-IT’s specificity [2].

The test’s process is relatively simple: the antigens are incubated with the patient’s whole blood samples, and the amount of IFN-γ produced by T-cells is quantified via a single-step enzyme-linked immunosorbent assay (ELISA). The test relies on the basic principle that T-cells of an infected individual will release a significantly higher level of IFN-γ than those of a non-infected individual [3, 6].

In order to make the QFT-IT test more reliable, a total of three test tubes are provided for incubation (i.e. the test requires three blood samples): (1) the first one contains the test antigens, (2) the second one contains heparin alone (a negative control referred to as Nil), and (3) the third contains heparin, dextrose, and phytohemaglutinin (a positive control, referred to as the mitogen response). The results of the test are based on the amount of IFN-γ produced in each of the three test tubes, and the values of positive, negative, or indeterminate are defined based either on the manufacturer’s recommended criteria or on the criteria recommended by the specific country’s governing body (e.g. in the U.S., results are based on the criteria required by the FDA).

T-SPOT.TB test

Unlike the QFT-IT, the T-Spot’s antigens include only ESAT-6 and CFP-10. The test relies on the same basic principle as the QFT-IT, but instead of using ELISA to measure the amount of IFN-γ produced, the T-Spot uses an enzyme-linked immunospot assay (ELISPOT) on separated and counted peripheral blood mononuclear cells (PBMCs) to quantify the number of cells producing IFN-γ. The secreting cells appear as “spots” in each test well. The T-Spot also includes three tubes (requiring three blood samples): the test antigens, a negative control (Nil), and a positive control (mitogen response) [1, 2].

The results are based on the quantified number of spots (i.e. a representation of IFN-γ-secreting PBMCs) and, just like the QFT-IT, the values of positive, negative, or indeterminate are defined either by using the manufacturer’s recommendations or the criteria required by the specific country’s governing body [2].

The pros and cons of each test

TST

Some of the advantages of the TST are readily apparent. First, it is inexpensive—costs will vary from region to region, but as an example, the Los Angeles County Department of Public Health in California lists a per patient cost of $12.95 for a TST, compared to $21.27 for an IGRA [17]. The TST is also widely available and does not require complicated or expensive laboratory equipment. Furthermore, staff can be easily trained to measure the diameter of the induration and, based on the established protocols, come up with an interpretation of the test result (i.e. positive or negative).

The drawbacks, unfortunately, are significant. The first challenges are logistic: the test requires that the patient return to the clinic 2-3 days after administration of the injection, and the results are based on observation by trained staff, which introduces an element of subjectivity and therefore becomes a source of potential variability in interpretation [1]. Additionally, there are multiple factors that can affect TST interpretation—some of which may not always be reported by the patient or known beforehand by the clinician. Examples of these are those listed by the American Thoracic Society in conjunction with the Centers for Disease Control and Prevention [16], and include a history of gastrectomy or jejunoileal bypass, immigration from a high-prevalence country within five years of testing, silicosis, diabetes, certain types of cancer, recent weight loss of >10% ideal body weight, and many more. A relatively simplified list of the interpretation criteria for the TST is listed by the CDC at the following hyperlink [20]: http://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm.

Furthermore, there are two known potential sources for false positives: nontuberculous mycobacterium (NTM) infection and prior BCG vaccination [1, 6]. A study published in 2006 looked specifically at these two potential confounders [8], and their conclusions were as follows:

  • If the BCG is received in infancy (i.e. within the first year of life), the effects on the TST are minimal—especially at greater than 10 years post-vaccination. Specifically, the study found that BCG vaccination in this group caused an overall rate of 8.5 false-positive TST reactions per 100 vaccines, with a rate of 2.6 false-positives per 100 vaccinations causing reactions of 15mm or more. When a TST was performed 10 years after vaccination, there was only one false positive per 100 vaccines.
  • By contrast, BCG received after infancy or given multiple times (delivery of booster doses is common practice in some countries) produces more frequent, persistent, and larger TST responses. In this case, an overall rate of 41.8 false-positive TSTs (10mm or more) per 100 vaccines was observed. Of these, approximately half of the reactions were measured at greater than 15mm. Furthermore, this effect persisted when re-tested 10+ years after vaccination, albeit with a reduced rate of 21.2 false positives per 100 vaccines.
  • NTM is not a clinically important cause of TST false positives, except in populations with a high prevalence of NTM sensitization and very low prevalence of TB infection, e.g., reasonably healthy adults in the Southern and Central U.S., certain parts of Sweden, and other industrialized countries.

Finally, false negatives may occur in particular patient subgroups, most importantly, the immunosuppressed—either due to medical conditions such as HIV infection, or iatrogenic immunosuppression, such as the immunosuppressive treatment of immune-mediated inflammatory diseases such as Crohn’s disease and rheumatoid arthritis [1, 5].

IGRAs (including QFT-IT and T-Spot)

The major advantage of IGRAs is their improved specificity in BCG-vaccinated patients, which is particularly important in countries where the BCG vaccine is administered after infancy or where booster shots are given [1, 6]. Logistically, the IGRAs only require one visit by the patient, result within 24 hours, and are free of the potential variability errors associated with TST placement and reading [2, 6].

A potential drawback of IGRAs is their significantly greater cost (including the need for specialized equipment) as compared to the TST; however, this cost may be offset by a decrease in false positives resulting in fewer resources spent evaluating and treating persons with positive test results [2, 5, 9]. Such a situation arises, for example, when testing BCG-vaccinated populations.

At least one study in the literature [6] argues that the main drawback of IGRAs is that their results “have not been validated prospectively, through follow-up of large cohorts, to determine the subsequent incidence of active TB.” This becomes particularly relevant in cases where an individual is IGRA-positive but TST-negative. This phenomenon remains unexplained, resulting in difficulties managing such patients.

When it comes to the immunosuppressed population, the available evidence suggests that IGRAs perform similarly to TST in detecting LTBI in HIV-infected individuals, and both TST and IGRAs have suboptimal sensitivity to detect active TB [1]. One could argue that the same limitations are likely to be present in the iatrogenically immunosuppressed population.

Finally, there is the question of whether a previous TST can affect IGRA results. The data are scarce at present, but a systematic review in 2009 concluded, “The TST appeared to affect IGRA responses only after 3 days and may apparently persist for several months” [10]. In other words, there is ongoing concern that a TST performed three or more days prior to an IGRA could lead to a false-positive IGRA.

Conclusions and pragmatic considerations when testing for LTBI

The information described above is but a glimpse into all of the current studies involving LTBI and its diagnostic challenges. In trying to summarize these into a pragmatic approach for the clinician, the following considerations seem reasonable:

Who to test

Both the TST and IGRAs may play a role in LTBI diagnosis. Use of these tests is appropriate among patients who are at risk for LTBI and would benefit from treatment (i.e. those at increased risk for developing active TB) [1, 2].

Who should NOT be tested

Generally, testing with TST and IGRAs should be avoided for persons at low risk for both latent infection and progression to active TB (unless they are likely to be at increased risk in the future) [2]. Additionally, as stated above, both tests have been shown to be inadequate for the diagnosis of active TB. If active TB is suspected, the clinician should proceed to acid-fast stain, culture, tissue pathology, imaging, bronchoscopy, etc. Consultation with an Infectious Diseases and/or Pulmonary specialist is warranted at this point.

Which test to use

Guidelines vary slightly from nation to nation—and within nations, from institution to institution. In general, the clinician should tailor the needs to the specific clinical scenario. That being said, given the overall characteristics of the available tests, some of the CDC’s 2010 recommendations state that “IGRA is preferred for testing persons from groups that historically have low rates of returning to have TSTs read” and “persons who have received BCG (as a vaccine or for cancer therapy).” On the other hand, “a TST is preferred for testing children aged <5 years” [2]. A full list of the CDC’s recommendations is beyond the scope of this article, but is available at the following website: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm.

If the choice of test hinges on BCG vaccination status and there is uncertainty regarding whether the patient has received the vaccine, the following BCG World Atlas [15] may prove useful to the clinician: http://www.bcgatlas.org/.

Should both tests be used sequentially? Simultaneously?

When a TST is read as borderline, the clinician may be tempted to draw an IGRA for confirmation. However, as mentioned above, there is ongoing concern about whether administration of a TST can produce a false-positive IGRA. The data are scarce at present and the question is still being studied, but in the interim, based on the findings of van Zyl-Smit et al’s systematic review [10], drawing an IGRA should be avoided if the patient has had a TST placed three or more days prior to the blood draw.

Regarding simultaneous use of both tests, a review of the literature revealed only one set of proposed guidelines for situations in which concurrent use of both tests is being considered: the Public Health Agency of Canada. Per its recommendation, if the clinician is to use both tests, in order to avoid problems with interpretation, blood samples for an IGRA should be drawn before or on the same day as placement of the TST [19].

Statistical validation of TST and IGRAs

The reader will have noticed that specific numbers for specificity, sensitivity, number needed to treat, and other statistical measures have not been listed. The reason for this is that assessments of such statistical measures (for both TST and IGRAs) vary widely depending on the source and, most importantly, are hampered by the basic fact that there is currently no gold standard to confirm a diagnosis of LTBI [2]. This is further complicated by the fact that test result interpretation criteria change from country to country, sometimes from organization to organization. Furthermore, determination of these values will change among different patient populations (e.g. infants, young children, HIV-positive patients, the immunocompromised, and so on). Sensitivity values for TST and IGRAs have been reported anywhere from ~60% to ~90% depending on the source, patient population, interpretation criteria, and so on.

That being said, in general, the IGRA’s sensitivity is estimated to be similar to that of the TST, but the specificity of IGRAs is generally considered to be higher—given that the antigens used in IGRAs are relatively specific to M. tuberculosis [2, 4]. There are discrepancies in the literature, but as an example, in persons unlikely to have M. tuberculosis infection, the CDC cites the QFT-IT’s specificity as 99%, compared to 85% for the TST [2]. Once again, these numbers will vary significantly based on the source, patient population, interpretation criteria, BCG status, and so on.

Thus, in summary, the choice of test should be based on the clinical scenario, institution-specific protocols, and expert recommendation (CDC, WHO, local Medical authorities).

A few additional considerations regarding result interpretation of both tests

Regarding the TST, when interpreting a positive value, it is important to consider more than just the size of the induration: the clinician should consider three different aspects: (1) the size of the induration, (2) the pretest probability of infection, and (3) the risk of disease if the person were truly infected [1].

Regarding IGRAs, “indeterminate” results are not uncommon with the QFT-IT—although this has improved when compared to its predecessors, the QFT and QFT-G. Indeterminate results are most often associated with age <5 years or >80 years, and with immunosuppression, e.g. from HIV infection or iatrogenic causes. In some instances, indeterminate results can be secondary to improper handling or insufficient samples (this is particularly true of the QFT and QFT-G, but also the QFT-IT). Per CDC recommendations, a repeat test can be useful when the initial IGRA was indeterminate and “a reason for testing persists,” or when assay measurements are unusual, e.g. when the mitogen response is lower than expected for the population being tested [2]. Otherwise, if available, a T-Spot may be more useful as it is associated with significantly fewer “indeterminate” results [2, 5]. If appropriate in such cases, a TST may also be considered. If doubt remains in spite of repeated, expanded testing, consultation with an Infectious Diseases specialist is warranted.

When to treat

A discussion regarding appropriate tests and treatment after the initial diagnosis of LTBI is beyond the scope of this article. However, a few items are worth mentioning: per the CDC’s recommendations, the diagnosis and treatment of M. tuberculosis infection should NOT be based on IGRA or TST results alone. Other considerations need to be included in the decision, such as epidemiologic and medical history, risk factors and overall clinical picture [2]. A useful tool for the clinician is the Online TST/IGRA Interpreter [11] at http://www.tstin3d.com/. This website helps the clinician estimate the risk of progression to active TB for an individual who has undergone TST or IGRA testing given the specific clinical picture, including items such as country of birth, age at immigration to a country with low TB incidence, existing comorbidities, and many more.

Mycobacterium tuberculosis infection is a complex, even elegant process with significant individual and public health implications. Clearly further research is needed in the field of diagnostics. In the meantime, it is the writer’s hope that this article sheds some light on the advantages and limitations of the currently available tests for latent disease, which will hopefully in turn assist the clinician in making a better-informed test choice.

Dr. Miguel A. Saldivar, MD is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Howard Leaf, MD, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons 

References

 

  1. Pai M, Denkinger CM, Kik SV, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev. 2014 Jan;27(1):3-20. doi: 10.1128/CMR.00034-13. PMID 24396134. http://cmr.asm.org/content/27/1/3.long

 

  1. Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection – United States, 2010. MMWR Recomm Rep. 2010 Jun 25;59(RR-5):1-25. PMID 20577159. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm

 

  1. Smith DS. Interferon Gamma Release Assays. Stanford University. http://web.stanford.edu/group/parasites/ParaSites2006/TB_Diagnosis/Interferon%20Gamma%20Release%20Assays.html

 

  1. Lalvani A. Diagnosing tuberculosis infection in the 21st century: new tools to tackle an old enemy. Chest. 2007 Jun;131(6):1898-906. PMID 17565023. http://journal.publications.chestnet.org/article.aspx?articleid=1085168

 

  1. Lalvani A, Pareek M. Interferon gamma release assays: principles and practice. Enferm Infecc Microbiol Clin. 2010 Apr;28(4):245-52. doi: 10.1016/j.eimc.2009.05.012. Epub 2009 Sep 24. PMID 19783328. http://www.elsevier.es/en-revista-enfermedades-infecciosas-microbiologia-clinica-28-articulo-interferon-gamma-release-assays-principles-13149868

 

  1. Landry J, Menzies D. Preventive chemotherapy. Where has it got us? Where to go next? Int J Tuberc Lung Dis. 2008 Dec;12(12):1352-64. PMID 19017442. http://www.ingentaconnect.com/content/iuatld/ijtld/2008/00000012/00000012/art00005?token=0051132cf33437a63736a6f3547414c7d703444532e5b6f644a467b4d616d3f4e4b3485763504194f

 

  1. Bennett DE, Courval JM, Onorato I, et al. Prevalence of tuberculosis infection in the United States population: the national health and nutrition examination survey, 1999–2000. Am J Respir Crit Care Med. 2008 Feb 1;177(3):348-55. Epub 2007 Nov 7. PMID 17989346. http://www.atsjournals.org/doi/abs/10.1164/rccm.200701-057OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed#.VOpDnnaR_RI

 

  1. Farhat M, Greenaway C, Pai M, Menzies D. 2006. False-positive tuberculin skin tests: what is the absolute effect of BCG and nontuberculous mycobacteria? Int. J. Tuberc. Lung Dis. 10:1192–1204. PMID 17131776. http://www.ingentaconnect.com/content/iuatld/ijtld/2006/00000010/00000011/art00003?token=00561c5878e77900a6855c5f3b3b47465248703b444549794624734f582a2f4876753375686f49530b0a5c

 

  1. Marra F, Marra CA, Sadatsafavi M, et al. Cost-effectiveness of a new interferon-based blood assay, QuantiFERON-TB Gold, in screening tuberculosis contacts. Int J Tuberc Lung Dis. 2008 Dec;12(12):1414-24. PMID 19017451. http://www.ingentaconnect.com/content/iuatld/ijtld/2008/00000012/00000012/art00014?token=00501d71712f1753f11c939412f415d766b2544453a4a6c7b73516f253048296a7c2849266d656cc

 

  1. van Zyl-Smit RN, Zwerling A, Dheda K, Pai M. Within-subject variability of interferon-g assay results for tuberculosis and boosting effect of tuberculin skin testing: a systematic review. PLoS One. 2009 Dec 30;4(12):e8517. doi: 10.1371/journal.pone.0008517. PMID 20041113. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008517

 

  1. Law S, Menzies D, Pai M, et al. The Online TST/IGRA Interpreter. McGill University & McGill University Health Center, Montreal Quebec. Canada. http://www.tstin3d.com/

 

  1. Metcalfe JZ, Everett CK, Steingart KR, et al. Interferon-γ release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis. J Infect Dis. 2011 Nov 15;204 Suppl 4:S1120-9. doi: 10.1093/infdis/jir410. 21996694. http://jid.oxfordjournals.org/content/204/suppl_4/S1120.full?sid=1dad36e7-34b2-4950-a694-108659642e9b

 

  1. Sester M, Sotgiu G, Lange C, et al. Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2011 Jan;37(1):100-11. doi: 10.1183/09031936.00114810. Epub 2010 Sep 16. PMID 20847080. http://erj.ersjournals.com/content/37/1/100.long

 

  1. Fan L, Chen Z, Hao XH, et al. Interferon-gamma release assays for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. FEMS Immunol Med Microbiol. 2012 Aug;65(3):456-66. doi: 10.1111/j.1574-695X.2012.00972.x. Epub 2012 Jun 18. PMID 22487051. http://femsim.oxfordjournals.org/content/65/3/456

 

  1. Zwerling A, Behr M, Verma A, et al. The BCG World Atlas. A Database of Global BCG Vaccination Policies and Practices. McGill University & McGill University Health Center, Montreal Quebec. Canada. PLoS Med. 8:e1001012. http://dx.doi.org/10.1371/journal.pmed.1001012. http://www.bcgatlas.org.

 

  1. Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection. American Journal of Respiratory and Critical Care Medicine, Vol. 161 (2000). Supplement: American Thoracic Society/Centers for Disease Control and Prevention-Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection (2000), pp. S221-S247. doi: 10.1164/ajrccm.161.supplement_3.ats600. http://www.atsjournals.org/doi/full/10.1164/ajrccm.161.supplement_3.ats600#.VOoQsnaR_RI

 

  1. Direct Costs of TST/IGRA Cost Effectiveness. Los Angeles Department of Public Health, Division of HIV and STD Programs. State of California. http://publichealth.lacounty.gov/dhsp/MAC/IGRAcosteffectiveness.pdf

 

  1. World Health Organization (WHO). Guidelines on the Management of Latent Tuberculosis Infection. ISBN: 978 92 4 154890 8. WHO reference number: WHO/HTM/TB/2015.01. http://www.who.int/tb/publications/ltbi_document_page/en/

 

  1. Updated Recommendations on Interferon Gamma Release Assays for Latent Tuberculosis Infection. An Advisory Committee Statement of the Canadian Tuberculosis Committee. Volume 34, ACS-6, October 2008. http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/08vol34/acs-6/index-eng.php.

 

20. Fact Sheets: Tuberculin Skin Testing. Cetners for Disease Control and Prevention. http://www.cdc.gov/tb/publications/factsh

Lung Cancer Screening with Low-Dose CT Scans

May 9, 2014

By Susanna Jeurling

Peer Reviewed

The U.S. Preventive Services Task Force (USPSTF) recently finalized its position regarding annual low-dose computed tomography (LDCT) scanning for early detection of lung cancer. The grade B recommendation states that individuals between the ages of 55 and 80 with a 30 pack-year history or more of smoking who are current smokers or who have quit within the last 15 years should undergo annual LDCT screening, based on the results of the National Lung Screening Trial [1]. Lung cancer is the leading cause of cancer deaths in the United States and accounts for as many cancer deaths as breast, prostate, colon, and pancreatic cancer combined. Every year, 160,000 patients will die from lung cancer [2]. Nearly 60% of patients will have metastatic disease at the time of diagnosis and the combined 5-year survival rate for all types of lung cancer is only 17% [3]. An effective screening test for lung cancer could significantly improve survival rates. Randomized controlled studies of screening patients at high risk of lung cancer based on age and smoking history with chest X-rays and sputum samples did result in earlier detection of more lung cancers but unfortunately failed to demonstrate improvement in mortality rates [4]. The advent of dose-modulated CT scanning has allowed for a more sensitive and specific method of examining the lung parenchyma and opened up the possibility of truly effective lung cancer screening. In 2012, the National Lung Screening Trial (NLST), the largest and most expensive randomized controlled trial of a screening test ever undertaken, was completed. The trial enrolled over 50,000 current and former smokers aged 55 to 74 with a 30 pack-year or greater history at 33 centers nationwide and is the basis for the recent USPSTF recommendation [5]. The subjects were randomly assigned to either low dose LDCT or chest X-ray for 3 consecutive years. Positive screening results were then followed up with diagnostic procedures. Overall, the study found a 20% reduction in lung cancer mortality in the LDCT group, with 247 deaths from lung cancer per 100,000 person-years in the LDCT group vs 309 deaths per 100,000 person-years in the X-ray group. Estimates done by Ma and colleagues at the American Cancer Society predict that 5.2 million men and 3.4 million women in the United States would meet criteria for screening defined by the National Lung Screening Trial based on data from the 2010 National Health Interview Survey. Given the rate of lung cancer mortality within this population, derived from the National Health and Nutrition Examination Survey (NHANES-III), the authors estimate 12,000 deaths from lung cancer would be prevented annually if wide-scale LDCT screening were implemented across the United States [6]. Using modeling studies based on data from the NLST trial, the USPSTF concluded that screening up to age 80 could extend survival in the absence of serious medical co-morbidities and that only an estimated 10-12% of screen-detected cancers were “overdiagnosed,” meaning they would not have been detected in the patient’s lifetime without screening.

While a 20% reduction in mortality and the potential to avert 12,000 deaths from lung cancer annually are impressive results, screening and subsequent diagnostic and therapeutic interventions are not risk-free. The main drawbacks of screening to the individual patient are radiation exposure, poor specificity (73.4% in NLST), and potential complications of follow-up diagnostic procedures. Overall, the NLST found that LDCT scanning has a positive predictive value of 3.8%, meaning that over 96% of people with a positive scan who potentially undergo further diagnostic workup with additional imaging or biopsy will not have lung cancer. (The USPSTF model estimates a positive predictive value of 5%.) Ultimately, 7% of subjects in the NLST group with a positive scan underwent a biopsy procedure, of whom only 53% had confirmed disease. Given that the average case of lung cancer is diagnosed at age 70, are we willing to subject asymptomatic 55 year olds to additional radiation and potential biopsies as part of the diagnostic workup of a positive scan that is misleadingly worrisome in over 96% of people?

For a certain subset of patients, that risk may be worth it. Kovalchik and colleagues at the National Cancer Institute re-examined the data from the NLST and stratified the subjects in both arms into quintiles based on 5-year risk of death from lung cancer. Stratification was based on a risk-prediction model that weighed mortality from lung cancer vs death from other causes and incorporated validated risk factors for the development of lung cancer including age, body-mass index, family history of lung cancer, pack-years of smoking, years since smoking cessation, and pre-existing pulmonary conditions. Overall, 60% of patients with the highest risk of death accounted for over 88% of preventable lung cancer deaths from screening. They calculated the number needed to screen to prevent one lung cancer death to be 5276 in the lowest quintile vs 161 in the highest quintile [7]. A clinically useful risk stratification tool that further refined selection criteria among heavy smokers aged 55 to 74 to target those at greatest risk would maximize the benefits of LDCT scanning by boosting pretest probability and positive predictive value.

Although formal analysis of the cost effectiveness of widespread screening and subsequent treatment using final data from the NLST has not yet been generated, researchers at Harvard Medical School used preliminary data from the trial released in 2010 to generate estimates of the cost-effectiveness of screening. They found that annual screening of current and former smokers aged 50–74 would cost between $126,000– $169,000 per quality adjusted life year (QALY). By comparison, the authors estimate that smoking cessation therapy costs approximately $17,000 per QALY, given the current quit rates [8]. Additionally, the authors of the NLST point out that screening and subsequent diagnostic workup, including additional radiographic imaging, were done at advanced tertiary care facilities with dedicated chest radiologists and thoracic surgeons, and these necessary conditions may not generalize across the country. The cost and accessibility considerations may be especially relevant, given that the rate of smoking is over 60% higher among individuals below the poverty line (29%) than those above (17.9%) [9]. In an increasingly cost-conscious age of medicine, these estimates make it difficult to imagine that large-scale screening efforts would be economically feasible.

The National Lung Screening Trial clearly demonstrates that annual low dose CT screening of high-risk individuals results in earlier detection and reduced mortality from lung cancer. Yet the high false-positive rate coupled with the additional radiation exposure and the potentially risky follow-up procedures resulting from a positive scan complicate the decision for patients and their doctors on whether to screen. From a societal perspective, it is unlikely that widespread screening of at-risk individuals is cost-effective or even feasible. The National Lung Screening Trial represents real progress in developing an effective screening test for lung cancer, but without further refinement in the selection criteria and development of cheaper, less invasive diagnostic follow-up, widespread LDCT scanning does not yet constitute a viable screening test for lung cancer.

Susanna Jeurling is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Michael Tanner, MD, Executive Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1. Moyer VA on behalf of U.S. Preventive Task Force. Screening for lung cancer: USPTF recommendation statement.” Ann Intern Med. 2013 Dec 31. doi:10.7326/M13-2771. Link to USPSTF home page: http://www.uspreventiveservicestaskforce.org/uspstf13/lungcan/lungcanfinalrs.htm

2. American Cancer Society. Cancer Facts and Figures 2012. Atlanta, GA: American Cancer Society; 2012.

3. Howlader N, Noone AM, Krapcho M, (eds) et al. SEER cancer statistics review, 1975-2010. National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2010

4. Henschke CI, Shaham D, Yankelevitz DF, Altorki NK. CT screening for lung cancer: past and ongoing studies. Semin Thorac Cardiovasc Surg. 2005; 17(2):99-106. http://www.ncbi.nlm.nih.gov/pubmed/16087075

5. National Lung Screening Trial Research Team, Church TR, Black WC, Aberle DR, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013;368(21):1980-1991. http://www.ncbi.nlm.nih.gov/pubmed/23697514

6. Ma J, Ward EM, Smith R, Jemal A. Annual number of lung cancer deaths potentially avertable by screening in the United States. Cancer. 2013 Apr 1;119(7):1381-1385. http://www.ncbi.nlm.nih.gov/pubmed/23440730

7. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med. 2013;369(3):245-254. http://www.ncbi.nlm.nih.gov/pubmed/23863051

8. McMahon PM, Kong CY, Bouzan C, et al. Cost-effectiveness of computed tomography screening for lung cancer in the United States. J Thorac Oncol. 2011(11):1841-1848. http://www.ncbi.nlm.nih.gov/pubmed/21892105

9. Centers for Disease Control and Prevention. Current cigarette smoking among adults—United States, 2011.” Morbidity and Mortality Weekly Report. 2012;61(44):889–894. http://www.cdc.gov/vitalsigns/AdultSmoking/

Mystery Quiz-The Answer

January 10, 2013

Elizabeth Mulaikal MD, Vivian Hayashi MD, Robert Smith MD

The answer to the mystery quiz is pulmonary Mycobacterium kansasii infection. The patient’s clinical presentation of fevers and night sweats suggested an infectious process or B symptoms due to lymphoma. The initial chest radiograph (image 1) demonstrated a left hilar mass which was noted to be larger on a subsequent chest radiograph (images 2 and 4)) 1 month later. This increase in size over a short duration again suggested an infectious etiology. Importantly and a key to the case, the CT images demonstrated unilateral hilar lymphadenopathy with regions of central low attenuation and evidence of enhancingrims following intravenous contrast administration (image 5). The low density areas may represent caseous or possibly liquefication necrosis. Additionally, there is a mixed reticulo-nodular and airspace infiltrate lateral to the enlarged left hilum (image 6). These radiographic findings are strongly suggestive of  mycobacterial disease associated with HIV infection, especially in patients with severely reduced CD4 cell counts. In New York City, M. tuberculosis would be most likely, followed by M kansasii which may be indistinguishable from M tuberculosis on imaging. M avium complex is less likely to cause an inflammatory reaction of this degree in patients with AIDS; pneumonitis and lymphadenopathy are relatively uncommon in this setting. The presence of M avium complex is more often a marker of severe immunocompromise in HIV patients. Culture is required for definitive diagnosis, but nucleic acid testing can suggest the diagnosis before culture results are available. Other differential diagnostic considerations include pulmonary Kaposi’s sarcoma with intrathoracic lymphadenopathy, but unlikely without cutaneous disease, and lymphoma, which typically lacks the low-density attenuation seen here.Without a history of residence in an endemic area, Histoplasmosis is also unlikely.

M kansasii is a common cause of non-tuberculous mycobacterial lung disease in HIV positive patients.Tap water is thought to be the most likely environmental source of exposure, and person-to-person transmission does not occur. Affected individuals are typically severely immunosuppressed with CD4 counts less than 50/cmm. The clinical and radiographic features closely resemble that of M.tuberculosis. Classically, patients present with fevers, night sweats, weight loss, productive cough,and dyspnea. Treatment generally includes isoniazid, rifampin, and ethambutol, but trimethoprim-sulfamethoxazole, macrolides, and floroquinolones have also proven to be efficacious.

Our patient was initially placed in respiratory isolation for possible M tuberculosis infection. Sputum samples showed AFB on smear, but PCR testing for M tuberculosis and M avium complex was negative. Sputum culture ultimately grew M kansasii. The patient was placed on isoniazid, rifabutin, ethambutol,and moxifloxacin for an intended duration of 18 months.

Mystery Quiz

December 21, 2012

Elizabeth Mulaikal MD, Vivian Hayashi MD, Robert Smith MD

The patient is a 55 year old African American male with a 60 pack year history of tobacco use and AIDS,who presented with 1 month of intermittent fevers and weight loss. His most recent CD4 count and viral load were 2/cmm and 50,623 copies/mL, respectively. Prior opportunistic infections included pneumocystis pneumonia and thrush. He was previously homeless, but currently resides in a Single Room Occupancy Housing. Upon presentation he complained of occasional night sweats, but no shortness of breath, cough, sputum production, or hemoptysis. Vital signs were notable for a fever of101.5F, but the patient was otherwise normotensive with a room air saturation of 98%. On physical examination he appeared cachectic and the lung fields were clear. Labs showed a WBC count of 3.6k/cmm with 47% neutrophils and 13% bands, and an LDH of 364 U/L.


What is the most likely diagnosis?

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Xopenex: Is it worth the money?

August 16, 2012

By Han Na Kim

Faculty Peer Reviewed

Case:

The patient is a 50-year-old woman with history of steroid-dependent, severe, persistent asthma since childhood and coronary artery disease who presented with dyspnea and URI symptoms admitted for management of asthma exacerbation. Patient received nebulized albuterol treatment every two to four hours, and on hospital day two, patient developed persistent sinus tachycardia to heart rate of 120s believed to be secondary to albuterol therapy. Given her tachycardia, would it be safer to prescribe levalbuterol rather than albuterol?

Inhaled short acting β2 -adrenergic receptor agonists are the mainstay of asthma treatment and the most effective drugs for inducing airway smooth muscle relaxation and reversing bronchoconstriction. Albuterol, the most commonly used β2 -agonist in the treatment of asthma, is a 50:50 racemic mixture of R-albuterol and S-albuterol. The two isomers have different activities and pharmocologic properties due to biologic stereoselectivity. The R-albuterol has a 100-fold greater binding affinity for the β2-receptor than S-albuterol and mediates the bronchodilatory effect of the drug [1]. The clinical significance of S-albuterol remains controversial but S-albuterol has increased bioavailability and is metabolized 10-fold more slowly than levalbuterol resulting in greater serum concentration and longer circulation time after administration of racemic albuterol than R-albuterol [2]. The S-albuterol isomer was initially thought to be inert but some animal studies found it to augment inflammatory stimuli and cause smooth muscle contraction [3]. Clinical studies demonstrated that S-albuterol has no bronchodilatory activity but is preferentially retained in the lungs because of longer half-life than that of R-albuterol [4,5,6] and some suggest that it may be responsible for parodoxical bronchospasm in asthmatics with regular albuterol use [7]. Such negative implications of S-albuterol have led to the development and use of pure R-albuterol form known as levalbuterol, which is also marketed under the brand name Xopenex.

The notion of a therapeutic advantage of levalbuterol over albuterol has been the subject of much controversy. Some studies suggest that when equivalent mass of R-albuterol administered as levalbuterol vs racemic albuterol form is compared, greater bronchodilation and less dose-related β-adrenergic mediated adverse effects such as tachycardia are seen with levalbuterol. It should be noted that the mechanism of tachycardia from the use of β2 -adrenergic receptor agonists is not only mediated by reflex tachycardia in response to vasodilation from stimulation of receptors on peripheral vasculature, but also from the direct stimulation of β2-adrenergic receptors located in both the left ventricle and the right atrium, leading to increased heart rate [8].

Nelson et al reported that in chronic stable asthmatics, levalbuterol provides a better therapeutic index than a standard dose of racemic albuterol [9]. In a double-blind, parallel-group trial funded by Seprocor, the maker of Xopenex, 362 patients with chronic stable asthma were randomized to one of the following treatment groups: levalbuterol 0.63 mg, levalbuterol 1.25mg, racemic albuterol 1.25 mg, 2.5 mg racemic albuterol, or placebo via nebulizer three times daily for 28 days. The primary endpoint was peak change in FEV1 after 4 weeks. Peak change in FEV1 after first dose was higher in combined levalbuterol group compared to combined racemic albuterol group (0.92 and 0.82 L, respectively; P = 0.03). At 4 weeks, peak change in FEV1 was higher in combined levalbuterol group but the difference was not statistically significant (0.84 and 0.74 L, respectively). When different doses are compared, levalbuterol 1.25 mg showed the greatest peak improvement (mean FEV1 change of 43% and 37% after first dose and 4 weeks respectively) while and levalbuterol 0.63 mg and racemic albuterol 2.5 mg had similar peak improvements (mean FEV1 change of 38% vs 36% after first dose respectively and 35% vs 35% after 4 weeks respectively). It is unclear whether the higher mean FEV1 change seen with levalbuterol 1.25 mg compared with other doses is statistically significant as no P value was reported.

There were also dose-related β-adrenergic mediated increases in mean ventricular heart rate relative to predose values. Levalbuterol 1.25 mg and racemic albuterol 2.5 mg treatment groups demonstrated a similar increase in heart rate ranging from 3.6 to 4.9 beats per minute respectively. Levalbuterol 0.63mg treatment arm had significantly lower change in heart rate compared to racemic albuterol 2.5 mg treatment group. Overall, treatment with levalbuterol 0.63 mg resulted in improvement in lung function that was similar to 2.5 mg racemic albuterol and was associated with smaller change in heart rate. The study suggested that the greater improvement in pulmonary function seen with levalbuterol alone compared to equal dose of levalbuterol given as part of racemicalbuterol was likely due to negative effects of S-albuterol.

Similar results were also found in pediatric population. In a randomized, double-blind, placebo-controlled, cross over study by Gawchik et al, 33 patients (age range 3-11) with chronic stable asthma were treated with levalbuterol, racemic albuterol or placebo in single dose during 4 treatment visits [10]. Levalbuterol 1.25 mg had the greatest improvement in pulmonary function measured in change in FEV1 (0.51L, 36.8%) and levalbuterol 0.63 mg (0.41L, 31.1%) and racemic albuterol 2.5 mg (0.40L, 27.9%) had comparable effects. Notably, this study was also supported by Sepracor.

In contrast, a study by Lötvall et al demonstrated a comparable therapeutic ratio for levalbuterol and racemic albuterol [11]. In this double-blind, cross over study, 20 asthmatic patients (age range 24-70; mean age 50 yrs) were randomized to receive R-albuterol (dose range 6.25-1600 ug), S-albuterol (6.25-1600 ug), RS-albuterol/racemic albuterol (12.5-3200 ug), or placebo once a day on 4 study days, each separated by a minimum of 3-day washout period. The FEV1 was measured 20 minutes after dosing. Both R- and RS-albuterol produced dose-dependent increases in FEV1 and at the highest doses of R- and RS-albuterol, FEV1 change from baseline were comparable giving potency ratio of 2:1. S-albuterol was found to have no effect on FEV1 compared with placebo and thus concluded to be clinically inactive. In terms of β-adrenergic effects, R- and RS-albuterol had dose-dependent increases in heart rate with similar increases at the highest dose (levalbuterol: 12.4 +/-3.0 beats/min; albuterol: 14.0 +/- 2.9 beats/min).

Furthermore, in a retrospective chart review of patients aged 18 or older presenting to ED with acute airflow obstruction no difference in changes in heart rate was observed when equivalent doses of R-albuterol were administered [12]. Patients treated with scheduled levalbuterol or albuterol doses within 24 hours of admission were included and 35 cases in each treatment group were analyzed. Primary analysis was performed on day 1 and 3 and found statistically significant difference in changes in heart rate between the two groups. However the difference between the two groups was 2.7 beats per minute, not a clinically significant one. Secondary subgroup analysis was performed on patients with tachycardia at baseline (n= 23 in albuterol group, n=18 in levalbuterol group) and the two treatment groups had no significant difference in changes in heart rate following treatment on either day 1 or 3. Surprisingly in tachycardic patients, levalbuterol provided no benefit in heart rate compared to albuterol with higher quantity of R-albuterol.

Similar findings were reported in a prospective, randomized, crossover study by Lam and Chen, where 20 ICU patients with and without tachycardia admitted to MICU and SICU requiring β2-agonist therapy every 4 hours to maximize respiratory function were randomized to levalbuterol 1.25 mg or albuterol 2.5 mg treatment [13]. No significant difference in changes in heart rate was found between the two groups although the study did not perform power analysis and thus patient sample may have been too small to detect it.

Thus, a review of literature suggests that there is currently no compelling reason to use levalbuterol over albuterol especially given the cost. Levalbuterol costs 5 to 25 times more than albuterol. Many studies reporting greater efficacy or therapeutic index with levalbuterol treatment over albuterol are of questionable quality funded by the pharmaceutical company. The claim that levalbuterol has a relatively lower cardioaccelerating effect compared to albuterol does not appear to be clinically supported in studies of the general population or in patients with baseline tachycardia. Furthermore, despite preclinical studies suggesting a theoretical clinical benefit, any therapeutic advantage of levalbuterol over albuterol on pulmonary function is still debated and requires further research. So before you write that nonformulary Xopenex order for your tachycardic asthma patient, think again.

Dr. Han Na Kim is a recently graduated internal medicine resident of NYU Langone Medical Center.

Peer reviewed by John Papadopoulos, MD, Clinical Assistant Professor, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[1] Penn RB, Frielle T, McCullough JR, Aberg G, Benovic J. Comparison of R-,S-, and RS-albuterol interaction with human β1 -and β2 -adrenergic receptors. Clin Rev Allergy Immunol. 1996;14:37-45. (http://www.springerlink.com/content/j0807676m6um0178/)

[2] Ameredes BT, Calhoun WJ. Levalbuterol Versus Albuterol. Current Allergy and Asthma Reports 2009;9:401-409. (http://www.springerlink.com/content/g268k805jt6443r4/)

[3] Handley DA. Single-isomer beta-agonist. Pharmacotherapy 2001;21(3 pt. 2):21S-27S. (http://www.ncbi.nlm.nih.gov/pubmed/11253864)

[4] Lipworth BJ, Clark DJ, Koch P et al. Pharmacokinetics and extrapulmonary β2adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers. Thorax. 1997; 52:849-52. (http://www.ncbi.nlm.nih.gov/pubmed/9404370)

[5] Dhand R, Goode M, Reid R et al. Preferential pulmonary retention of (S)-albuterol after inhalation of racemic albuterol. Am J respir Crit Care Med. 1999; 160:1136-1141. (http://ajrccm.atsjournals.org/cgi/content/full/160/4/1136)

[6] Gumbhir-Sha K, Kellerman DJ, De-Graw S et al. Pharmacokinetic and pharmacodynamic characteristics and safety of inhaled albuterol enantiomers in healthy volunteers. J Clin Pharmacol. 1998; 38: 1096-106. (http://jcp.sagepub.com/content/38/12/1096.abstract)

[7] Handley DA. The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists. J Allergy Clin Immunol. 1999; 104(2, pt. 2):S69-76. (http://www.ncbi.nlm.nih.gov/pubmed/10452791)

[8] Sears MR. Adverse effects of beta-agonists. J Allergy Clin Immunol. 2002; 110 (6 Suppl):S322-8. (http://www.ncbi.nlm.nih.gov/pubmed/12464943)

[9] Nelson HS, Bensch G, Pleskow W et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 1998; 102: 943-52. (http://www.ncbi.nlm.nih.gov/pubmed/9847435)

[10] Gawchik SM, Saccar CL, Noonan M, Reasner D, DeGraw S. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999; 103:615-621. (http://www.ncbi.nlm.nih.gov/pubmed/10200010)

[11] Lötvall J, Palmqvist M, Arvidsson P et al. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol 2001;108:726-31. (http://www.ncbi.nlm.nih.gov/pubmed/11692096)

[12] Scott VL. Frazee LA. Retrospective Comparison of Nebulized Levalbuterol and Albuterol for Adverse Events in Patients With Acute Airflow Obstruction. Am J Ther 2003;10:341-347. (http://www.ncbi.nlm.nih.gov/pubmed/12975718)

[13] Lam S, Chen J. Changes in heart rate associated with nebulized racemic albuterol and levalbuterol in intensive care patients. Am J health-Syst Pharm. 2003;60: 1971-1975 (http://www.ncbi.nlm.nih.gov/pubmed/14531242)

Bystander CPR: How Much Does It Help?

July 18, 2012

By Andrew L. Weinstein

Faculty Peer Reviewed

You have just completed a certification course in basic life support and are competent at performing cardiopulmonary resuscitation (CPR) using chest compressions, a CPR mask, a bag-valve mask with impedance threshold device, and an automated external defibrillator (AED), all interventions recommended by the American Heart Association (AHA) to improve circulation following a sudden cardiac arrest.[1] On your way home from the training center you see a man collapse and rush over to find him unresponsive, not breathing, and pulseless. You immediately initiate the “chain of survival” by ordering someone nearby to call 911 and someone else to search for an AED. You begin chest compressions, but fearing this man may have communicable diseases and a CPR mask or bag-valve mask is not available, you refrain from performing mouth-to-mouth ventilation. The emergency medical service (EMS) personnel arrive 5 minutes later and take over the resuscitation effort. The scene clears and you wonder: how much did my actions help this man’s chances of survival? Did failure to deliver rescue breaths hurt these chances?

Each year over 300,000 Americans suffer an out-of-hospital cardiac arrest (OHCA), defined as a cessation of cardiac mechanical activity that occurs outside of the hospital and is confirmed by the absence of circulation signs.[2,3] Though an OHCA can occur from noncardiac causes such as trauma or drowning, the majority of such events have a primary cardiac cause and a poor 6.5% overall survival rate to hospital discharge.[2] For most of these victims the scenario described above is the best they can realistically hope for, as only 8.6% of OHCAs are witnessed by EMS.[4] In the remaining cases, initiation of the chain of survival depends on family members or strangers while the victim’s chances of survival falls 7-10% every minute without bystander CPR until defibrillation.[2] Considering that the median time delay between calling 911 and EMS arrival is 5.3 minutes,[4,5] it is vital that bystanders perform CPR as soon as possible.

Even when bystanders witness an OHCA, studies show that they perform CPR in the minority of cases. According to the Center for Disease Control and Prevention (CDC) surveillance data on victims of OHCA of presumed cardiac cause who received CPR in the prehospital setting between 2005 and 2010,[6] the overall survival rate to hospital discharge was 9.6%. Although 37.6% of OHCA events were witnessed by bystanders, only 43.8% of them performed CPR and increased survival rate to 11.2% compared with 7.0% in victims who did not receive CPR prior to EMS arrival (p<0.001). In other words, the CDC’s analysis showed bystander CPR to have a 37.5% relative risk reduction and a number needed to treat of 24. To put this effect into perspective, aspirin given to prevent major cardiovascular events has a number needed to treat of 253 in patients without clinical evidence of cardiovascular disease.[7]

Research indicates that the infrequent performance of bystander CPR is due, in large part, to a reluctance to perform mouth-to-mouth ventilation. In a 1995 survey, only 15% of 975 respondents reported a willingness to perform chest compressions with mouth-to-mouth ventilation on a stranger, whereas 68% responded that they would “definitely” perform chest compressions alone if it were offered as an effective alternate CPR technique.[8] Since then, many studies have examined survival rates between conventional CPR, which includes rescue breathing, and compression-only CPR, and concluded that omitting ventilations from the bystander sequence confers no negative impact.[1, 9-11] As a result, the AHA Guidelines now recommend that “laypersons should be encouraged to do compression-only CPR if they are unable or unwilling to provide rescue breaths” on the basis that provision of compression-only CPR is superior to no CPR.[7,9]

Lastly, it should be noted that in addition to bystander CPR, several other parameters have been identified as significant predictors of OHCA survival. They include the location of the cardiac arrest, the presenting arrest rhythm, who first applied the AED, and whether there was a return of spontaneous circulation (ROSC) in the field.[4-6,12] The CDC reported that 84.1% of OHCAs occurred in the home and had a survival rate of 7.0%, whereas OHCAs that occurred in public had a survival rate of 20.2%. Of the bystander-witnessed OHCAs, an AED was applied prior to EMS arrival in 3.7% of cases, wherein survival rate was 23.5%. If the victim was found in a shockable arrest rhythm, survival rate was 27.1%, and if ROSC on the field was achieved, survival rate was 26.3%. Although understanding the reasons for these varying OHCA survival rates is important, and is explored extensively in the literature,[6,12] it is beyond the scope of this discussion.

From a young age we hear the mantra, “CPR saves lives.” We see CPR instructional posters on the walls of eating establishments and resuscitation efforts in action movies and TV shows. Although the prognosis of OHCAs remains poor, bystander CPR has been found to contribute a 4.2% overall increase in survival to hospital discharge compared with calling 911 alone. However, studies show that only a minority of bystanders perform CPR, discouraged by the thought of performing mouth-to-mouth ventilations on a stranger. Perhaps if these onlookers had known that compression-only CPR may be as effective as conventional CPR, many lives could have been saved. Now that compression-only CPR is recommended by the AHA guidelines, hopefully more bystanders will embrace the opportunity to help an OHCA victim’s chances of survival.

Andrew L. Weinstein is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Dr. Kevin Felner, MD, Pulmonary, Critical Care, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Field JM, Hazinski MF, Sayre MR, et al. Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S640-656. http://circ.ahajournals.org/content/122/18_suppl_3/S640.long

2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18–e209. http://circ.ahajournals.org/content/123/4/e18.long

3. Jacobs I, Nadkarni V, Bahr J, et al. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa). Circulation. 2004;110(21):3385–3397. http://circ.ahajournals.org/content/110/21/3385.long

4. Weisfeldt ML, Everson-Steward S, Sitlani C, et al. Ventricular tachyarrhythmias after cardiac arrest in public versus at home. N Engl J Med. 2011;364:313-21. http://www.nejm.org/doi/full/10.1056/NEJMoa1010663

5. Weisfeldt ML, Sitlani CM, Ornato JP, et al. Survival after application of automatic external defibrillators before arrival of the emergency medical system: evaluation in the resuscitation outcomes consortium population of 21 million. J Am Coll Cardiol. 2010;55:1713-1720. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008654/?tool=pubmed

6. McNally B, Robb R, Mehta M, et al. Out-of-hospital cardiac arrest surveillance – cardiac arrest registry to enhance survival, United States, October 1, 2005 – December 31, 2005. MMWR. 2011;60(SS08);1-19. http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6008a1.htm

7. Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: A meta-analysis of randomized trials. Am Heart J. 2011;162(1):115-124.e2. http://www.ahjonline.com/article/S0002-8703(11)00272-9/fulltext

8. Locke CJ, Berg RA, Sanders AB, et al. Bystander cardiopulmonary resuscitation: concerns about mouth-to-mouth contact. Arch Intern Med. 1995;155:938–43.

9. Sayre MR, Berg RA, Cave DM, Page RL, Potts J, White RD; American Heart Association Emergency Cardiovascular Care Committee. Hands-only (compression-only) cardiopulmonary resuscitation: a call to action for bystander response to adults who experience out-of-hospital sudden cardiac arrest: a science advisory for the public from the American Heart Association Emergency Cardiovascular Care Committee. Circulation. 2008;117(16):2162-7. http://circ.ahajournals.org/content/117/16/2162.long

10. Hallstrom A, Cobb L, Johnson E, Copass M. Cardiopulmonary resuscitation by chest compression alone or with mouth-to-mouth ventilation. N Engl J Med. 2000;342:1546-1553. http://www.nejm.org/doi/full/10.1056/NEJM200005253422101

11. Rea TD, Fahrenbruch C, Culley L, et al. CPR with chest compressions alone or with rescue breathing. N Engl J Med. 2010;363:423-33. http://www.nejm.org/doi/full/10.1056/NEJMoa0908993

12. Sasson C, Rogers MAM, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2010;3:63-81. http://circoutcomes.ahajournals.org/content/3/1/63.long

What are the Barriers to Using Low Dose CT to Screen for Lung Cancer?

February 23, 2012

By Benjamin Lok

Faculty Peer Reviewed

Lung cancer is the most common cause of cancer deaths globally [1] and responsible for an estimated 221,120 new cases and 156,940 deaths in 2011 in the United States.[2] Presently, the United States Preventive Services Task Force, the National Cancer Institute (NCI), the American College of Chest Physicians, and most other evidence-based organizations do not recommend screening for lung cancer with chest x-ray or low-dose helical computed tomography (CT) due to inadequate evidence to support mortality reduction.[3] This recommendation, however, may soon change.

LOW-DOSE CT SCREENING REDUCES MORTALITY

In October 2010, the NCI announced that the National Lung Screening Trial (NLST) was concluded early because the study showed that low-dose CT screening, when compared with screening by chest radiography, resulted in a 20.0% relative reduction in lung cancer-related mortality and an all-cause mortality reduction of 6.7%. The number needed to screen with low-dose CT to prevent one lung cancer death was 320.[4] This report, published in the August 4th, 2011 issue of the New England Journal of Medicine, is the first randomized controlled trial of lung cancer screening to show a significant mortality benefit.

The trial enrolled 53,454 high-risk current and former smokers aged 55 to 74 years who had a history of at least 30 pack-years. Former smokers (52% of the total) had to have quit only recently–within the last 15 years. They underwent three annual screenings with CT or chest X-ray and then were followed for an additional 3.5 years. Suspicious screening results were three-fold higher in the low-dose CT group compared to radiography across all three screening rounds (24.2% vs 6.9%). More than 90% of the positive screening tests in the first round of screening led to follow-up, mainly consisting of further imaging, with invasive procedures rarely performed. More cancers were diagnosed after the screening period in the chest radiography group compared to those screened by low-dose CT, suggesting that radiography missed more cancers during the screening period. Furthermore, cancers detected in the low-dose CT arm were more likely to be early-stage compared to those discovered after chest radiography.

NLST STUDY LIMITATIONS

Lung cancer-specific deaths were 247 and 309 per 100,000 person-years in the low-dose CT and chest radiography groups, respectively, and this was statistically significant (P=0.004).[4] The internal validity of the study is firm, based on similar baseline characteristics and rates of follow-up between the two study groups.[4-6] Whether these results can be applied to the general population, however, is uncertain. Trial participants were, on average, younger urban dwellers with a higher level of education than a random sample of smokers 55 to 74 years old [4-5], which might have increased adherence in the study. Furthermore, radiologists interpreting the screening images had additional training in reading low-dose CT scans and presumably greater experience due to high workload.

COST EFFECTIVENESS

One major barrier to implementation of any screening program is its cost. Eventual analysis of the results from the NLST will definitively answer this question; however, a recent Australian study can provide us some with some provisional guidance.[7] Manser and colleagues examined the cost effectiveness of CT screening in a baseline cohort of high-risk male current smokers aged 60 and 64 with an assumed annual incidence of lung cancer of 552 per 100,000 and determined that the incremental cost-effectiveness ratio was $105,090 per quality-adjusted life year (QALY) saved.[7] This is less than the generally accepted upper limit of $113,000 per QALY in the United States, but far above the $50,000 per QALY threshold that many authors of cost-effectiveness are advocating.[8] The NLST study population had an approximate annual incidence of lung cancer of 608.5 per 100,000[4], which is similar to the incidence rate in the Australian analysis. Though this extrapolation is purely speculative, it suggests that if the upper limit of $113,000 per QALY were the cut-off, low-dose CT screening in the United States may be cost-effective.

IMPORTANCE OF IDENTIFYING HIGH-RISK PATIENTS

A second important issue to address is the identification of patients most likely to benefit from CT screening. In the Australian study, for the patient risk group with an annual incidence of lung cancer of 283 per 100,000 it costs $278,219 per QALY saved.[7]. The national incidence in the US in 2006 was 63.1 per 100,000 person-years.[9] To screen the average person in the US general population would be an astronomical expenditure of resources (greater than $1 million per QALY saved), dramatically increase the false-positive rates from screening, and promote unnecessary exposure to carcinogenic radiation. Accordingly, only high-risk patients (eg, advanced age, positive family history, and heavy smoking history) should be considered for this screening modality.

ADDITIONAL BARRIERS AND ISSUES

The United Kingdom Lung Screening Trial investigators listed other issues that will need to be addressed prior to implementation of a screening program:[10]

1. Synchronization of CT technique and scan interpretations

2. Value of the diagnostic work-up techniques for positive screening findings and establishing standards for follow-up

3. Optimal surgical management of detected nodules in patients

4. Optimal screening interval for both screen-negative and screen-positive patients

5. Continued study and collaboration by academic organizations, federal institutions and policymakers.

CONCLUSIONS ON HOW TO COUNSEL PATIENTS

With all this in mind, how are we to counsel patients interested in lung cancer screening? First, only high-risk patients for lung cancer should be considered for low-dose CT screening. Even in the high-risk NLST cohort, positive images were false roughly 95% of the time in both study arms.[4] In patients at lower risk, these false-positive rates will undoubtedly be much higher. Second, patients should be informed about the potential harms from detection of benign abnormalities requiring follow-up and potential invasive interrogation, which can result in adverse outcomes. Finally, even with the exciting revelation of mortality reduction by a lung cancer screening modality, smoking cessation will remain one of the most important interventions in reducing mortality from lung cancer.

Benjamin Lok is a 4th year medical student at NYU School of Medicine

Peer reviewed by Craig Tenner, MD, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74-108.

2. American Cancer Society. Cancer facts and figures 2011. http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2011.  Accessed July 7, 2011.

3. National Cancer Institute: PDQ® Lung Cancer Screening. 2011; http://cancer.gov/cancertopics/pdq/screening/lung/HealthProfessional. Accessed July 21, 2011.

4. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.

5. National Lung Screening Trial Research Team. Baseline characteristics of participants in the randomized national lung screening trial. J Natl Cancer Inst. 2010;102(23):1771-1779.

6. Sox HC. Better evidence about screening for lung cancer. N Engl J Med. 2011;365(5):455-457.

7. Manser R, Dalton A, Carter R, Byrnes G, Elwood M, Campbell DA. Cost-effectiveness analysis of screening for lung cancer with low dose spiral CT (computed tomography) in the Australian setting. Lung Cancer. May 2005;48(2):171-185.

8. Weinstein MC. How much are Americans willing to pay for a quality-adjusted life year? Med Care. 2008;46(4):343-345.

9. American Lung Association. State of lung disease in diverse communities, 2010. http://www.lungusa.org/assets/documents/publications/lung-disease-data/solddc_2010.pdf. Accessed July 28, 2011.

10. Field JK, Baldwin D, Brain K, et al. CT screening for lung cancer in the UK: position statement by UKLS investigators following the NLST report. Thorax. 2011;66(8):736-737.

Why Are Asthma Patients Noncompliant With Their Inhalers?

January 11, 2012

By Kristen Mattei

Faculty Peer Reviewed

I distinctly remember being 9 years old, sitting in my doctor’s office after a cold left me struggling for breath, doubled over and wheezing, when he told me that I had asthma. At first I didn’t believe the diagnosis, despite the fact that the albuterol inhaler he had given me was like a breath of life after running suicides on the soccer field. I wasn’t sick or weak! My father insisted I needed to “build my breath up,” and I believed, as he did, that enough running would cure me of all my ills. I remember, more distinctly still, looking disdainfully at the steroid inhaler the doctor had given me, with its clunky plastic “spacer,” a device designed for babies who couldn’t take the medication properly. I took the inhaled corticosteroid (ICS) only sporadically until giving up on it completely. While I had conceded that the albuterol helped, the concept that I needed to take a medication daily was too much to bear, and although the results of taking albuterol were apparent, this other inhaler provided no relief of symptoms, and after a week of solid use, my attacks still came. What good was the thing?

Regular use of inhaled anti-inflammatory agents plus bronchodilators is the mainstay of asthma treatment and can provide excellent control of symptoms with few side effects. Unfortunately, most asthmatic patients fail to take their medications as prescribed, with compliance rates as low as 30%. The reasons for such high non-compliance rates are complex and varied. Buston and Wood found, in a 2000 study that asked adolescents to describe their reasons for non-compliance, that 50% of those questioned attributed their non-compliance to forgetfulness. They reported that changes in daily routines, such as vacations, holidays, and weekends made them less likely to remember to take their daily medication. The perceived ineffectiveness of the medication also caused adolescents to miss doses, as they felt fine. Denial, difficulty using the inhaler, inconvenience, embarrassment, and fear of side effects were all noted to contribute to poor compliance among adolescents.[1] Children who suffered the negative consequences of poor compliance, such as hospitalization, and those whose parents were most persistent in reminding their children to take their medication, were more likely to comply with their medication regimens.[2]

Children may be guilty of invincibility and forgetfulness, but adults are no more compliant than their younger counterparts when it comes to medication compliance, and for many similar reasons. Adults are just as likely as children to misunderstand or forget their disease management, they hold similar fears of medication side effects and dependence, and they are often unable to properly take their medications. Even those with severe illness misuse their medications. Only 50% of patients on nebulizer or oxygen therapy properly follow their treatment plans.[3]

The proper management of chronic diseases requires an honest partnership between the doctor and patient, but patients are reluctant to disclose their non-compliant behaviors and doctors have a difficult time exposing improper medication use. A good doctor-patient relationship begins with rapport building. Nonverbal behaviors, such as leaning forward to reduce social distance and active listening to indicate attention, coupled with praise of compliance and encouragement, can send a powerful message to newly diagnosed patients that their doctor is a partner in treatment and not an adversary.[3] The 11-item asthma-specific version of the Beliefs About Medicine Questionnaire can identify patient doubts and concerns about medications so that physicians can identify poor adherence and their patients’ personal barriers to treatment and can then properly tailor treatments that will lead to better compliance.[4]

Fifty percent of adults and children fail to use metered-dose and dry-powder inhalers properly. Many have trouble timing inhalation with medication release, and spacers are bulky and inconvenient.[5] Patients should be asked to demonstrate inhaler use at each visit and instructed on proper technique. Devices that check inhalation rates can assist patients at home.[4] However, after instruction, 50% of adults continue to use inhalers improperly. In such cases oral agents should be strongly considered.[5] Tailoring therapies to the individual patient is a must. The use of combined inhalers or oral medications, repeated attempts at training, easy-to-use inhalers, and dry powder inhalers for children and the elderly can improve compliance substantially.[3]

I’m not exactly sure what factors led to my noncompliance as a young patient. I experienced embarrassment at the diagnosis, I felt distant from my white-haired PCP, and I failed to understand the concept of chronic disease treatment and the use of my long-acting corticosteroid inhaler. My father certainly nagged me about using the thing enough, but it never sank in until I ended up hospitalized at 16, frightened that something as insignificant as asthma could have such a serious consequence. A 1994 study conducted by Yeung and colleagues demonstrated the observer effect beautifully. The simple act of knowing they were being monitored led patients to be more compliant with their asthma medications [6]. Perhaps it is that simple. Once you have explained the diagnosis; once you have gone over the medications, their uses, benefits, and side effects; once you have seen the technique and adjusted the dosing; let your patients know that you are tracking their progress. Perhaps if my doctor had asked, I would have express my doubts about the need for an ICS and I could have avoided years of dangerous poor disease control.

Kristen Mattei is a 4th year medical student at NYU School of Medicine

Peer reviewed by Linda Rogers, MD, Pulmonary Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Buston KM, Wood SF. Non-compliance amongst adolescents with asthma: listening to what they tell us about self-management. Fam Pract. 2000;17(2):134-138.  http://fampra.oxfordjournals.org/content/17/2/134.long

2. van Dellen QM, Stronks K, Bindels PJ, Ory FG, van Aalderen WM, the PEACE Study Group. Adherence to inhaled corticosteroids in children with asthma and their parents. Respir Med. 2008;102(5):755-763.  http://www.sciencedirect.com/science/article/pii/S0954611107005057

3. Chapman KR, Walker L, Cluley S, Fabbri L. Improving patient compliance with asthma therapy. Respir Med. 2000;94(1):2-9.  http://www.ncbi.nlm.nih.gov/pubmed/10714473

4. Haughney J, Price D, Kaplan A, et al. Achieving asthma control in practice: understanding the reasons for poor control. Respir Med. 2008;102(12):1681-1693.  http://www.mendeley.com/research/achieving-asthma-control-in-practice-understanding-the-reasons-for-poor-control/

5. Crompton GK. How to achieve good compliance with inhaled asthma therapy. Respir Med. 2004;98 Suppl B:S35-S40.  http://www.ncbi.nlm.nih.gov/pubmed/15481287

6. Yeung M, O’Connor SA, Parry DT, Cochrane GM. Compliance with prescribed drug therapy in asthma. Respir Med. 1994;88(1):31-35.

Does Perioperative Smoking Cessation Improve outcomes?

January 6, 2012

By Benjamin Wu, MD

Faculty Peer Reviewed

Mr. T is a 53-year-old man, with history significant for cholelithiasis. He decides to have an elective cholecystectomy after years of biliary colic. Mr. T is an active smoker and wanted to know if he should stop smoking prior to surgery?

Smoking is associated with adverse outcomes in surgery, however debate continues regarding the safety of perioperative smoking cessation. The current understanding of perioperative smoking cessation follows that smokers who stop smoking close to surgery have a higher risk of pulmonary and overall perioperative surgical complications. Warner et al first described the phenomenon in 1989 when he demonstrated that patients who stopped smoking less than two months prior to surgery had four times as many pulmonary complications compared to patients who stopped smoking for greater than two months. They surmised that the increased complication rate was likely from decreased cough and increased sputum production. [1,3] This prevailing wisdom continued with Smetana who suggested in 1999, ten years later, that smoking cessation must be initiated and continued eight weeks prior to surgery to prevent increased pulmonary complications. [2] If patients have an increased risk of adverse outcomes as described by Warner et al, would it be prudent to continue smoking if surgery is less than 4 to 8 weeks away? Most physicians would say absolutely not. There is a growing body of literature that is beginning to show that 4 to 8 weeks of smoking abstinence does not increase pulmonary or overall perioperative complication rates in surgical patients. [5,6]

Moller chipped away at the status quo in 2002 and analyzed data from 120 patients who were assigned to a smoking intervention program 6 to 8 weeks prior to surgery or to standard care. The study addressed the question of an ideal time to stop smoking: would 6 weeks be sufficient to show decreased complications? Moller found that smoking cessation 6 to 8 weeks before surgery actually reduced the overall complication rate (52% vs. 18% control). The study also found that pulmonary complications occurred at the same rate for the intervention group compared to the control group (2% vs. 2% control). [6] Moller also showed a decreased relative risk for any complication (RR 0.34; 95%, CI 0.17-0.58). [6]Subsequently, Sorensen and Jorgensen examined 60 patients who were randomly assigned to either abstinence or continued smoking 2 to 3 weeks prior to surgery. They also found that with even a few weeks of smoking cessation there was no difference between those who stopped smoking and those who continued smoking in pulmonary or overall complication rate. Interestingly, their study group demonstrated 11% pulmonary complications in the intervention group and 16% in the control group. [7] When the researchers compared both groups for overall surgical complications the intervention group had no significant improvement when compared to the control group (intervention 41% vs. control 43%). [7] Both of these articles showed that varying lengths of smoking cessation had no difference in pulmonary complications and decreased a risk for overall complications.

Barrera et al in 2005 prospectively studied pulmonary complications in lung cancer patients who underwent thoracotomies. They examined 300 lung cancer patients who were non-smokers, past quitters (>2months prior to surgery), recent quitters (< 2 months prior to surgery), and continuous smokers. The researchers found that the pulmonary complication rate was 19% between recent quitters and 23% in on-going smokers. [8] When comparing those who stopped smoking 8 weeks before surgery and those who continued to smoke until time of surgery no paradoxical increase in pulmonary complications was found in this study. [8] Furthermore, they found that independent risk factors for developing pulmonary complications were patients who had lower predicted DLCO (OR 1.42; 95% CI 1.17-1.70), smoking more than 60 pack years (OR 2.54; 95% CI 1.28-5.04), and primary lung cancer (OR 3.94; 95% CI 1.34-11.59). [8] Barrera provided further evidence that smoking cessation demonstrated no increased risk when comparing patients who continued to smoke and those who stopped smoking less than 8 weeks prior to surgery. Unfortunately, the patients who were recent smokers had high variation in the length of smoking cessation in the study.

More recently, Lindstrom et al published a small, multi-center, randomized control trial showing that smoking cessation prior to surgery reduces any postoperative complications. The researchers examined outcomes of 117 general and orthopedic surgical patients in a 4 week pre-operative period. The intervention group received intensive smoking cessation with the goal of abstinence, while the control group received the standard of care including neutral and general information about the harms of smoking. The researchers’ main outcome was any postoperative complication within 30 days. They demonstrated a relative risk reduction of 0.51 (95%, CI 0.27-0.97) of any postoperative complication with only 4 weeks of smoking cessation. They recorded no pulmonary complications in the intervention group and only one pulmonary complication in the control group. Furthermore, they established a number needed to treat (NNT) of 5 (95%; CI 3-40). [9] In 2010, Moller studied breast cancer patients who required surgery in less than 4 weeks. Researchers examined 130 patients were assigned to either brief intervention or standard care. Patients in the brief intervention arm had 2 days preoperative to 10 days postoperative of smoking abstinence. The researchers showed that postoperative complications between those patients who stopped smoking and those patients who continued were similar with a relative risk of 1.00 (95%; CI 0.75-1.33). They concluded that brief cessations are not of clinical relevance. [10] Again, conclusions were based upon a short follow up period and different types of surgery.

The Cochrane Review subsequently examined a series of eight clinical trials for the effect of smoking cessation programs upon pulmonary and overall complications. [11] They found that several studies showed no difference or even possibly reduced rates of pulmonary complications. [6,7,9,11] The authors of the review concluded that perioperative intervention 4 to 8 weeks prior to surgery with nicotine replacement therapy (NRT) is supported by evidence and likely to reduce any complication (RR 0.70; 95% CI 0.56-0.88). [11]

Another recent systematic review and meta-analysis in the Archives of Internal Medicine examined nine studies that compared surgical patients who recently quit smoking and those who continued smoking. The meta-analysis showed no difference between quitting within 8 weeks before surgery compared to continued smoking for any perioperative complication (RR 0.78; 95% CI 0.57-1.07). [3] The researchers did further analysis with studies that validated self-abstinence from smoking and showed that the trend favored recent quitters, however, no significant difference was seen between those patients who continued to smoke and recent quitters (RR 0.57; 95% CI, 0.16-2.01). [3] Interestingly, when researchers looked at four studies that examined pulmonary complications they saw a trend that favored higher risk in recent quitters, but the relative risk crossed 1 (1.18; 95% CI 0.95-1.46). [3] This trend can be explained by the increased weight placed on Warner’s research (80.76%) compared to other studies that showed no difference between quitters and smokers. [2] The authors also suggest that certain surgeries or patient populations could be at higher risk for pulmonary complications. However, in aggregate, the evidence shows no difference between those who stopped smoking compared to those who continued to smoke. A limitation noted by the authors was that the category of recent quitters consisted of significant heterogeneity, in that the category included patients who stopped smoking anywhere from 2 days to 8 weeks prior to surgery. They also noted that only three studies validated abstinence with urinary cotinine testing or exhaled carbon monoxide reading, lending higher quality to these studies. [3] And the meta-analysis found that two studies showed increased cough reflex in those who stopped smoking and two studies showed decreased cough reflex in those who stopped smoking. In other words, there is no satisfactory conclusion for the assumption that decreased cough reflex causes pulmonary complications. [3]

Conclusions reached by both observational studies, randomized control trials, and meta-analyses suggest that smoking cessation does not increase pulmonary or perioperative complications, and it may reduce complications four weeks prior to surgery. [6]Moreover, a short period of cessation prior to surgery showed no significant changes in clinical outcomes. [10] Ideally, patients should stop smoking 8 weeks prior to surgery, but if not possible, cessation of smoking 4-8 weeks prior to surgery will not adversely affect pulmonary and perioperative complications contrary to conclusions established by Warner. [2,10]Certain prospective and randomized controlled trials suggest that even 4 weeks of smoking cessation may decrease pulmonary and any perioperative complications. [7,9,11] The limitations of many of these studies include small sample sizes, limitation to single centers or if multi-centered regionally isolated to Europe, limited follow-up, as well as the significant heterogeneity in amount of smoking, time to surgery, and type of surgery across studies. Broader studies will need to be performed to examine the ideal time to stop smoking, with standardized complications and types of surgeries. Multi-center and multi-national studies must be performed to increase the generalizability of conclusions.

Mr. T stops smoking 4 weeks prior to surgery and aside from issues with post-surgical pain control does very well. The patient decides to continue with his smoking abstinence and is smoke-free to this day.

Conclusions

1. Smoking cessation 4 to 8 weeks prior to surgery carries no significant difference compared to the continuation of smoking until surgery, with respect to pulmonary or any post-operative complications. Emerging evidence suggests that smoking cessation may actually reduce postoperative complications. [7,8]

2. Pulmonary Function Tests and amount of smoking may better predict pulmonary complications in smokers. [8]

3. Further research should be completed to determine the ideal time to stop smoking prior to surgery, but even brief episodes of smoking cessation may be beneficial for the patient. [10,11]

Dr. Benjamin Wu is a 2nd year resident at NYU Langone Medical Center

Peer Reviewed by Nishay Chitkara, MD, Medicine (Pulmonary) at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Warner MA, Offord KP, Warner ME, Lennon RL, Conover MA, Jansson-Schumacher U. “Role of preoperative cessation of smoking and other factors in postoperative pulmonary complications: a blinded prospective study of coronary artery bypass patients.” Mayo Clin Proc. 1989 Jun;64(6):609-16. http://www.ncbi.nlm.nih.gov/pubmed/2787456

2. Smetana GW. “Preoperative pulmonary evaluation.” N Engl J Med. 1999 Mar 25;340(12):937-44.  http://www.ncbi.nlm.nih.gov/pubmed/10089188

3. Myers K, Hajek P, Hinds C, McRobbie H. Stopping Smoking Shortly Before Surgery and Postoperative Complications: A Systematic Review and Meta-analysis. Arch Intern Med. 2011 Mar 14. [Epub ahead of print, cited 2011, March 22]

4. Warner DO.Perioperative abstinence from cigarettes: physiologic and clinical consequences. Anesthesiology. 2006 Feb;104(2):356-67.  http://www.ncbi.nlm.nih.gov/pubmed/16436857

5. Johnson RG, Arozullah AM, Neumayer L, Henderson WG, Hosokawa P, Khuri SF. “Multivariable predictors of postoperative respiratory failure after general and vascular surgery: results from the patient safety in surgery study.” J Am Coll Surg. 2007 Jun;204(6):1188-98.  http://www.ncbi.nlm.nih.gov/pubmed/17544077

6. Møller AM, Villebro N, Pedersen T, Tønnesen H. “Effect of preoperative smoking intervention on postoperative complications: a randomised clinical trial.” Lancet. 2002 Jan 12;359(9301):114-7.  http://www.ncbi.nlm.nih.gov/pubmed/11809253

7. Sørensen LT, Jørgensen T. “Short-term pre-operative smoking cessation intervention does not affect postoperative complications in colorectal surgery: a randomized clinical trial.” Colorectal Dis. 2003 Jul;5(4):347-52.  http://www.ncbi.nlm.nih.gov/pubmed/12814414

8. Barrera R, Shi W, Amar D, Thaler HT, Gabovich N, Bains MS, White DA. Smoking and timing of cessation: impact on pulmonary complications after thoracotomy. Chest. 2005 Jun;127(6):1977-83.  http://www.ncbi.nlm.nih.gov/pubmed/15947310

9. Lindström D et al. “Effects of a perioperative smoking cessation intervention on postoperative complications: a randomized trial.” Ann Surg. 2008 Nov;248(5):739-45.  http://www.ncbi.nlm.nih.gov/pubmed/18948800

10. Thomsen T, Tønnesen H, Okholm M, Kroman N, Maibom A, Sauerberg ML, Møller AM. “Brief smoking cessation intervention in relation to breast cancer surgery: a randomized controlled trial.” Nicotine Tob Res. 2010 Nov;12(11):1118-24.  http://www.ncbi.nlm.nih.gov/pubmed/20855414

11. Thomsen T, Villebro N, Møller AM.Interventions for preoperative smoking cessation.Cochrane Database Syst Rev. 2010 Jul 7;(7):CD002294.  http://www.ncbi.nlm.nih.gov/pubmed/20614429

Mystery Quiz- The Answer

December 14, 2011
Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is Kaposi’s sarcoma. The CXR shows bilateral confluent airspaceopacities which have a wide differential diagnosis in this case. The CT narrows the differential.  Specifically, the opacities appear to emanate from the central hilar areas, cuff the airways, and fan out into the more distal airspaces (Images 3 and 4).  This appearance is very suggestive of Kaposi’s sarcoma. CT scans may also reveal mediastinal lymphadenopathy and large pleural effusions which are not present in our case.  The absence of fever and chronicity of one month argue against bacterial pathogens such as pneumococcus and legionella.  Of note, there is an absence of cavitation as seen in necrotizing infections, scant ground glass opacity as found in pneumocystis pneumonia, and an absence of predominant nodularity as might be seen in pulmonary lymphoma.  Kaposi’s sarcoma was the most common neoplastic disease of patients with HIV infection and low CD4 counts early in the AIDS epidemic. It results from an additional infection with HHV-8. Inflammatory pathways involve vascular tissue; pathology typically shows spindle cells sometimes accompanied by blood in the vascular spaces.  Also, the lesions are commonly seen in the large airways as red-to-purple plaques, sometimes spreading throughout all the visualized airways.  There is still debate about whether Kaposi’s sarcoma is truly a neoplasm given the cellular multiclonality that is often reported.  Cutaneous Kaposi’s is by far the most common presentation, and pulmonary involvement is seen in about 30% of cases.  The GI tract is also commonly involved in as many as 40% of cases.  Kaposi’s was seen much more frequently in the 1980s but inexplicably declined in incidence even before the HAART era which further hastened the decline.

Our patient underwent bronchoscopy which revealed red plaques throughout most of the airways .  The transbronchial biopsy showed spindle cells that stained positive for CD 34, a marker of early hematopoietic and vascular-associated tissue.  No pathogens were found on BAL or biopsy. These findings confirmed the diagnosis of Kaposi’s sarcoma.  The patient was treated with ten cycles of liposomal doxorubicin along with HAART.  His recovery was quite dramatic, as can be seen on a CT scan six years after his presentation (Image 5).  The patient also gained weight and increased his CD4 count to nearly 300 cells/cmm.