American Thoracic Society Annual Meeting: San Diego, CA, May 15-20, 2009

The American Thoracic Society’s (ATS) Annual International Conference featured a special update session on the Influenza A (H1N1) pandemic. Ironically, several thousand of the anticipated 15,000-16,000 attendees cancelled travel plans to attend the conference because of their governments’ recommendations against travel to the United States. The conference is one of the largest gatherings of researchers, clinicians, and healthcare workers in the field of respiratory medicine and has been a preferred venue for the presentation of breakthrough scientific developments in that area. The entire program listings and abstracts are available on the ATS journal website.

“A Silver Bullet”

One of the most exciting developments in the management of bacterial respiratory infections is the new class of antimicrobials called silver carbene complexes (SCCs). SCCs have already been shown to be effective in the treatment of resistant strains of bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and Klebsiella pneumonia, which are common in institutionalized patients. The SCCs are encapsulated into L-tyrosine polyphosphate nanoparticles to achieve a timed-release effect. Thus, dosing of the SCCs is only once per day, and the nanoparticles retain antimicrobial activity over 3 days. The particles are less than a micron in size and can be delivered easily to the alveoli using small-droplet nebulization. To date, the SCCs have shown antimicrobial effectiveness against all bacteria that have been tested, including MRSA, Klebsiella, Pseudomonas, Bacillus anthracis (anthrax), and Yersinia pestis (plague), and they are currently being tested against extremely drug-resistant mycobacterium tuberculosis. The SCCs’ mechanism of action is inference with a bacteria’s copper-dependent enzyme systems (intracellular energy production) and DNA replication. The design of the delivery molecule is intended to make it compatible with water solutions so it can be given by nebulization for lung infections, but is also compatible with intravenous administration. In vivo animal testing and limited human clinical trials have found no adverse effects. The patent owner of SCCs states that it can easily be produced commercially in large quantities, and that the production process is not expensive, so ultimate retail cost should not be high. The obvious additional use of SCCs beyond healthcare applications is for defense against and treatment of bacterial agents used as biological or terrorist weapons. Its demonstrated safety and broad applications should help hasten support for completion of necessary clinical trials and approval by the Food and Drug Administration.

“Search and Destroy”

Researchers from the University College London reported preliminary success with a novel cancer chemotherapy employing adult mesenchymal stem cells (MSCs). These MSCs are autologous adult stem cells that can be readily harvested from a patient’s bone marrow. The MSCs are then engineered to carry a protein (tumor necrosis factor-alpha [TNF-alpha]) that will induce an apoptotic cascade in a target cell when activated. The MSC is also armed with a tetracycline promoter trigger, so it will only activate apoptosis in the presence of the promoter. Researchers have found that MSCs are naturally attracted to or can “home in on” cancer cells because of the chemokines that are produced by most cancer cells. The observation of this unique attraction led to the inspiration that they could use this homing trait of MSCs to selectively deliver tumoricidal agents to cancer cells. TNF is an ideal agent because it induces cell death in the target cell with no collateral damage to adjacent healthy tissues. Arming the MSC with a promoter trigger is even a more elegant intervention, in that it allows the chemotherapists to turn the MSC on or off with the tetracycline promoter. Successful in vitro experiments led to in vivo trials in a mouse model. Metastatic breast cancer was induced in a susceptible mouse strain, and then the mice were treated with MSC. The results were a dramatic shrinkage of the metastatic lesions in all mice and a cure or elimination of all metastatic lesions in 40% of the mice. In neither the in vitro nor the mouse experiment was there any evidence of damage to healthy cells or tissues. In vitro tests have shown effectiveness of MSC against a wide variety of cancer types. It was an additional boon that the treatment employs the noncontroversial adult stem cells that can be sourced from the patient. It is definitely a stay-tuned research area, as they have now begun human clinical trials.

Influenza A (H1N1)

The ATS conference featured a special session on the H1N1 pandemic with presentations by the director of the Pulmonary Intensive Care Unit in Mexico City, a viral geneticist, state and federal public health officials, and a director from the Centers for Disease Control and Prevention (CDC) Emergency Operations Center. A live webcast of this session can be viewed free of charge at the ATS website (www.thoracic.org). The influenza geneticists point out that it is not appropriate to label this influenza pandemic “swine flu.” The genetics of the new H1N1 virus show that it has mutated from human, avian, and swine precursors. There is also some concern that there may be more than one mutation active in this pandemic. The reports from the Mexican experience have indicated mostly mild disease with predominantly children and younger to middle-aged adults infected. The relative sparing of older adults may indicate some residual immunity from an older strain of flu virus. Persons hospitalized and deaths in Mexico have been primarily in the young and middle-aged adult groups. This atypical epidemiology of severe cases has led some to speculate on the “cytokine storm” theory in healthy hosts. A cytokine storm is thought to be an immune system over-response to a new virus. The over-production of inflammatory cytokines can cause respiratory failure from massive pulmonary edema. The CDC has been issuing weekly reports on continuing developments in the pandemic (www.cdc.gov/h1n1flu). They point out that it is fortunate for the Northern hemisphere that the pandemic has started at the end of our traditional flu season, since the flu virus typically has lower infectivity in the summer months. The CDC will be watching the pandemic closely in the Southern hemisphere, as that area is entering its flu season. Observations from their experience can be valuable in forecasting important characteristics of this virus and aid in planning for our flu season this coming fall and winter (severity, infectivity, viral types, vaccine response, antiviral therapies/resistance, hospitalization, and mortality patterns). There is grave concern about the upcoming flu season and what preparations may be necessary. All aspects of the health system may be strained, especially public health and primary care resources and availability of antiviral vaccines and therapies. If the virus proves to be particularly virulent, there could also be a shortage of critical care services and equipment such as ventilators. The ATS and CDC websites (see above) have excellent clinical reviews of current treatment recommendations, and these will be updated as more is learned about the H1N1 virus’s behavior.

COPD: “A Systemic Disease”

There was an entire symposium at the ATS conference re-characterizing chronic obstructive pulmonary disease (COPD) as a systemic rather than only a pulmonary disease. Virtually all patients with moderate or more severe COPD suffer from multiple comorbidities. More than 70% of deaths in persons with COPD are from comorbid conditions rather than from their pulmonary disease. Those with COPD have a higher likelihood of having one or more of the following list of conditions than their age-matched controls: cardiovascular disease, anemia, depression, anxiety, hypertension, diabetes, osteoporosis, cachexia, cancer, hypogonadism, myopathy, and renal failure. Recent research has shown that the pulmonary pathology in COPD is an abnormal and very destructive inflammation in the lungs of genetically susceptible individuals who have exposure to noxious fumes or gases. This abnormal inflammation produces destructive cytokines and proteases that are not only responsible for damage to lung parenchyma, but also appear to be directly linked to the development of other diseases such as osteoporosis, myopathy, cachexia, hypogonadism, cardiovascular disease, and cancer. It is less clear whether other commonly associated comorbidities such as hypertension, diabetes, depression, anemia, and renal failure are directly related to pulmonary pathology or indirectly linked to the physical, nutritional, and social deficits in lifestyle that accompany COPD. COPD is known to be underdiagnosed: 50% of the 24 million persons with COPD are not diagnosed, and many of those who are diagnosed are undertreated. It was the conclusion of the symposium presenters that clinicians should be more alert to and active in diagnosing persons with COPD. They also urged that when clinicians make the diagnosis of COPD, they actively look for the common comorbidities associated with that disease. It is evident that treating COPD can improve management of some comorbidities, and, vice-versa, managing comorbidities reduces death and disability in persons with COPD.

Severe Acute Respiratory Syndrome

In 2002, the severe acute respiratory syndrome (SARS) outbreak in East Asia had the world bracing for a pandemic. The corona virus agent proved to be very virulent with a 10% mortality rate, but not as infective as the influenza virus, with only 8000 cases worldwide. Fortunately this has given researchers some time to work on antiviral therapies for SARS. Little progress had been made in finding an antimicrobial that was effective against SARS until this year. Researchers from the University of Iowa have discovered a lectin protein isolated from algae that holds great promise for therapy against SARS and other corona viruses. The protein is called Griffithsin (GRFT), and its mechanism of action appears to be an alteration of the virus’s sugar molecules that line the viral envelope, which are necessary for the virus to attach to and invade human cells. If the virus can’t enter the human cell, it is unable to replicate itself. A mouse experiment using mice that were exposed to the SARS virus and then treated at 2, 4, and 10 days after infection with either GRFT or placebo demonstrated a dramatic protective effect in the GRFT-treated animals. Only 30% of the untreated mice survived, whereas 100% of the GRFT-treated mice survived. The untreated mice showed 20 times more plaque-forming viral units, 35% greater weight loss, and extensive necrotizing bronchitis and pulmonary edema as compared to the GRFT-treated mice. There are no human studies at present to evaluate GRFT treatment other than the naturally occurring disease, but researchers are continuing to study GRFT in animal models and are evaluating a prophylaxis model, as well as post-infection treatment.

Obstructive Sleep Apnea

Clinicians should add obstructive sleep apnea (OSA) to the list of diseases that warrant cautionary advice to patients regarding driving a car. It has been shown that poorly controlled OSA can result in drowsiness and decreased daytime alertness, but now, new research from Oxford Centre for Respiratory Medicine in the United Kingdom demonstrated that this is especially a concern for driving safety. They developed a 90-minute simulated driving experience that they administered to OSA subjects (N = 38) and healthy age- and sex-matched controls (N = 20). The test was conducted in the afternoon and measured steering ability, crashes, and brake reaction time using electroencephalogram (EEG), extra-ocular eye movement, and video monitoring. The tests were conducted under three sets of conditions: after a normal night’s sleep (8 hr); after a restricted night’s sleep (4 hr); and after consuming a moderate amount of alcohol (3 drinks for men, 2 drinks for women). The OSA group under the conditions of restricted sleep had significantly more crashes, problems with steering, and slower brake reaction time than controls, and they also had more crashes with alcohol exposure. In the OSA group, micro-sleeps (brief episodes of sleep by EEG) and prolonged eye closures (greater than 2 sec) were the strongest predictors of crash incidents (odds ratio, 19.2 and 7.2, respectively). The researchers concluded that persons with OSA should avoid driving if they have not had a full night’s sleep, and they should avoid even moderate alcohol consumption before prolonged (90 min) driving. The Oxford Centre for Respiratory Medicine presented another study suggesting a link between OSA and diabetic retinopathy (DR). In a previous report, the Centre found that OSA has an increased prevalence in adult-onset diabetes, a rate of 23% in their sample. The individuals with diabetes in their registry have had annual eye screening with retinal photo images. They found that persons with diabetes with concurrent OSA had a 54% prevalence of DR as compared to 31% in those with diabetes without OSA. Presence of OSA was the strongest independent predictor of DR, more so than length of time of diabetes, diabetic glucose control, or hypertension. The researchers concluded that more study is needed to understand this association and to determine whether OSA treatment may have an impact on the development of DR. However, they felt that their findings did warrant a recommendation to clinicians to look for OSA in their patients with adult-onset diabetes and if OSA is present, to monitor diligently for the development of DR.

COPD: Pharmaceutical Costs vs Cost of Care

COPD is an expensive disease with total costs estimated to have been over $42 billion in the United States in 2007 and direct costs over $26 billion. At least 50-75% of direct costs are due to emergency department, hospital, and unscheduled office visit care. Using data sets of commercially insured Medicare beneficiaries, a group of researchers examined the risks and costs of this urgent/emergent care in elderly persons with COPD that largely reflects disease exacerbations or loss of control. The retrospective study group was a cohort of persons over age 65 years with the diagnosis of COPD, but without the concurrent diagnosis of asthma, who had available pharmaceutical and treatment cost data for the years 2003-2005. Patients who had been treated with a fluticasone proprionate/salmeterol combination 250/50 mcg (FSC) were compared to those who had been treated with anticholinergics (ATC; ipratropium alone or in combination with albuterol, or tiotropium). Compared to the ATC-treated patients (N = 9354), patients treated with FSC (N = 3336) had an 18% lower risk of a having a COPD-related hospital or emergency event (HR = 0.82 [95% CI, 0.75-0.89]). In cost analysis, adjusted cost differences for COPD-related total, inpatient, emergency department, and outpatient costs were significantly lower for the FSC group as compared to the ATC group (-$1127, -$860, -$24, -$281, respectively; all P < 0.05), although pharmacy costs were higher in the FSC group (+$267). Researchers concluded that FSC is associated with a significantly lower risk of having a COPD-related hospital or emergency event and lower medical and total costs as compared to ATC in older, commercially insured Medicare beneficiaries.

Dr. Keenan is a retired professor from the Department of Family medicine, University of Minnesota, Minneapolis.