The articles focus on a variety markers (from cardiovascular to metabolic) and includes a handful of thorough reviews of the integration of these measures in panel studies in general. One article, by Edith Chen and Wei-Jun Jean Yeung, summarizes the measurement of respiratory health in longitudinal social science surveys.

It’s a detailed and useful review of pulmonary function measurements and a helpful synthesis of the important perspective – and research synergies – that such measurements add to social science surveys. The authors also summarize some of the measurement issues and the limitations that equipment cost and training pose to the widespread adoption of spirometry.

This group of articles got me thinking about the lack of longitudinal health social science surveys in global health – particularly ones conceived and fielded by local investigators and institutions. I’m sure there must be some and I’d love to learn about them if they exist. It seems to me that affordable spirometry equipment with in-built technology to assure high quality measurements is really a priority if we’re to see valuable panel data collected from low and middle-income settings anytime soon.

This week the American Academy of Allergy, Asthma and Immunology has published a report on air filters and air cleaners that should help answer that question. The entire report is available free via PubMed.

Actually it goes well beyond that, with a thorough review of air filtration, the characteristics of airborne particulates – including allergens and particulate matter – and the range of available filter/cleaning strategies and technologies, from portable room air cleaners, to HVAC and powered electric filters.

One of the more interesting conclusions of the report is that air cleaning and filtration be viewed as a strategy for minimizing disease progression rather than as a treatment. As the report puts it, “It is not logical to expect that the observed disease state symptoms, often the result of previous prolonged exposures either in the home, other environments, or both, will abate within a few weeks or even months after the placement of an air-cleaning device or filter in the home environment. Other factors, especially source control and ventilation, might play a more important role than attempts to clean the air after the fact by means of filtration.”

They recommend that more rigorous and lengthy trials are needed before definitive recommendations on the efficacy of air filtration in improving disease can be made. Obviously there is a big role in these studies for more robust baseline and prospective data on symptoms and symptom severity, medication use and various objective markers (lung function). But I really like their idea of blinding and placebo-controlling the studies.

The group concludes that, given the current evidence, use of effective air filtration does reduce indoor levels of ambient particulates, that “that might trigger disease processes themselves.”

What to use? “Portable room air cleaners with HEPA filters, especially those that filter the breathing zone during sleep, appear to be beneficial. For the millions of households with forced air HVAC systems, regular maintenance schedules and the use of high-efficiency disposable filters appear to be the best choices.”

Novel technology automatically tracks where and when attacks occur

Beginning next week, Madison-based Reciprocal Sciences, with funding from the US Centers for Disease Control and Prevention, will launch a new study to learn more about the problem of rural asthma in the Midwest. The study follows a recent report by the CDC that rates of asthma in rural areas have been underestimated.

“Our analyses of national survey data suggest that asthma is as prevalent in rural areas as in urban areas,” says Teresa Morrison, medical epidemiologist in the Air Pollution and Respiratory Health Branch at CDC. “Our goal is to document patterns of asthma symptoms among rural residents in Midwestern states, and learn more about possible environmental exposures that potentially lead to asthma attacks.”

In the past, studies have relied on interviews and questionnaires to collect data on asthma. But now, volunteers who live in rural areas in the Midwest will be able to record their symptoms when and where they happen, using an innovative tool that Reciprocal Sciences unveiled last year. The device, called the Spiroscout, is a GPS-enabled inhaler that pinpoints the exact geographic location and time when the inhaler is used.

“For the first time, scientists will have definitive information about exactly where and when rural residents have symptoms,” says study director David Van Sickle, PhD, “and we can use that to identify important patterns in the disease.”

Participants in the six-month study will also be testing additional asthma management tools developed by Reciprocal Sciences, including a text messaging system designed to help people with asthma remember to take their daily medication.

Participation in the study is limited to 150 participants. Interested individuals can call (608) 554-0750, email info@reciprocalsciences.com or visit the project website for more information.

Overall asthma control: The relationship between current control and future risk (E. Bateman et al. – JACI)

Very interesting retrospective analysis of five studies which examines the relationship between asthma control (assessed by questionnaire and guideline criteria) and the risk of future instability and exacerbations in asthma. Bateman and colleagues report that the percentage of patients achieving asthma control increased with time, irrespective of treatment, and not suprisingly, that asthma control score at baseline associated with exacerbation rates. In addition, the authors used Markov analysis to examine the transitional probability of change in control status throughout the studies. The finding: “A Controlled or Partly Controlled week predicted at least Partly Controlled asthma the following week (≥80% probability). The better the control, the lower the risk of an Uncontrolled week. The probability of an exacerbation was related to current state.”

Socioeconomic risk factors for lung function decline (Johannessen et al. – ERJ)

Interesting new report from a cohort study of more than 1,600 adults who performed spirometry in 1996-97 and again in 2003-6 that found gender-specific associations between different aspects of SES (socioeconomic status) and lung function decline. “Lower education and low occupational status were associated with larger male lung function decline…SES did not affect female lung function decline. However, marital status was a significant predictor; unmarried females had less decline than both married and widowed females” in both FEV1 and FVC.

Lessons learned from variation in response to therapy in clinical trials (Szefler and Martin – JACI )

“In the past, we viewed lack of response to asthma medications as a rare event. Based on recent studies, we now expect significant variation in treatment response for all asthma medications.” Szefler and Martin discuss how findings from multi-center asthma research networks (ACRN and CARE) are providing valuable new information about interindividual variability in response to a number of important controller medications. Using patient “characteristics, such as age and allergic status, and biomarkers, such as bronchodilator response, exhaled nitric oxide, and urinary leukotrienes,” can help physicians predict response and “personalize asthma treatment at the time of initiating long-term control therapy.”

Measuring asthma control: a comparison of three classification systems (O’Byrne et al. – ERJ)

In this paper, O’Byrne and colleagues compared three popular methods of assessing asthma control: The Asthma Control Questionnaire (ACQ-5) and two criteria based measures from the Global Initiative for Asthma (GINA) and Gaining Optimal Asthma ControL (GOAL) study. The review analyzed data from more than 8,000 subjects in three trials of the same asthma treatments. GINA and GOAL criteria provided similar assessments of asthma control, however, the ACQ-5 “detected clinically important improvements” in a large number of patients that according to other criteria remained uncontrolled. “ACQ-5 is more responsive to change in a clinical trial setting than a categorical scale.”

Social determinants of asthma [Cruz et al. - ERJ]
Editorial accompanying a report in ERJ by Sembajwe et al. on the relationship between gross national income, the prevalence of symptoms and doctor diagnosis of asthma. Cruz et al. review the interesting bimodal association between socioeconomic status and asthma and offer some thoughts on the puzzle, and the important distinction between risk of asthma ever and current symptoms: “Gross national product per capita is generally associated with both an increasing prevalence of wheezing ever and wheezing in the last 12 months. However, the prevalence of current symptoms is modifiable by current exposures (to allergens and environmental pollution,as well as other factors) and by effective treatment. Thus,even where prevalence is low, the burden of disease may be high, and poverty emerges as an important risk factor for current symptoms of asthma.”

What Genes Tell us about the Pathogenesis of Asthma and COPD [Weiss - AJRCCM]
“Recently a series of Genome Wide Association Study manuscripts (GWAS) in asthma and COPD have been published. These papers suggest that, in part, asthma and COPD have a common genetic origin, and that this common origin, is due to polymorphisms in genes that are involved with the development of the lung.”

Hygiene Hypothesis wanted: Dead or Alive [Linneberg letter and Douwes and Pearce reply - IJE]
This month IJE has published an interesting exchange between Allan Linneberg (http://bit.ly/9hunjr) and Douwes and Pearce (http://bit.ly/bd0Lz0), who suggest that “detailed exposure assessment strategies for both allergens and other potentially protective co-exposures are likely to shed new light on the roles of these exposures in the development of asthma and the validity of the hygiene and allergen tolerance hypotheses more generally.”

Follow up discussion to an editorial (PDF) published in 2008 by Jeroen Douwes and Neal Pearce, called, “The end of the hygiene hypothesis?” which concluded that “New aetiological theories of global asthma prevalence are, therefore, required that are more consistent with the epidemiological evidence and which take into account factors affecting the time trends for both allergic and non-allergic asthma.”

Rapid reduction in hospitalizations after an intervention to manage severe asthma (ERJ – Souza-Machado et al.) – Evaluation of the Programme for Control of Asthma in Bahia (ProAR) which focused on providing free management of severe asthma. Achieved an 82% decline in asthma hospital admissions between 1998-2006, and report an “inverse correlation between provision of medication for asthma and hospitalization.”

Different definitions in childhood asthma: how dependable is the dependent variable? (ERJ – van Wonderen et al.) – Amazing review of 122 papers yielded 60 different definitions of asthma. “Prevalence estimates varied between 15.1% and 51.1% depending on the asthma definition used. The percentage of children whose posterior asthma probability was in the area of clinical indecision varied from 14.9% to 65.3%.” Conclusion – “Variation in definitions and its effect on the performance of prediction models may be another source of otherwise inexplicable variation in daily clinical decision making.”

Confirmation of Asthma in an Era of Overdiagnosis (ERJ – Luks et al.) – Following up on their recent report that 30% of adults with a physician diagnosis of asthma did not have asthma when objectively assessed, this article demonstrates that, “For the majority with a previous physician diagnosis of asthma only pre- and post- bronchodilator spirometry and a single methacholine challenge test are required to confirm asthma.”

Changes in the Prevalence of Asthma in Adults since 1966: The Busselton Health Study (ERJ – James et al.) – Cross-sectional respiratory health surveys of Busselton adults conducted in 1966, 1969, 1972, 1975, 1981, 1990 and in 2005-07 indicate that increased rates of doctor-diagnosed asthma are “partly explained by increased symptoms and atopy”; however, “factors such as diagnostic transfer and increased awareness of asthma have also contributed to the rise in prevalence.”

As a result, I’ve been thinking about the scope of attention in global health, and about populations and settings that are, for some reason, out of focus right now; one group in particular came to mind.

Between sessions I wrote a short piece on the topic – It’s up now over at Pulse + Signal.

One of my favorites was a talk by Peter Wittner, of consulting group Interpharm, who gave a very interesting talk on the evolution of the respiratory (inhaled) generic market and the dissolving boundary between the traditional innovators and the generic manufacturers.

A recent article in the Economist – “Generically Challenged,” from the World in 2010 issue – lays out the growing interest of the major innovators in the generics drug companies, prompted in part by the “looming patent cliff.” According to EvaluatePharma, the total sales of prescription drugs at risk from patent expiry is set to more than double from 2010 to 2011. Vijay Vaitheeswaran argues that government attempts to control prices are propelling generics in high income countries, while in low income countries it is the growing middle classes. In fact, emerging economies already make up more than half of total global pharmaceutical sales.

Back in London, Wittner drew attention to the appeal of the branded generics approach. These are products made of off-patent formulations but sold for premium price. By his account, one company (Norton) was able to recognize that a lengthy generic name (sodium cromoglycate, rather than Intal) was hindering physicians from writing a prescription. In response, they adopted a branded generic approach, raised the price of their product, and labeled it Cromolyn. The Economist predicts that the major drugs firms are set to aggressively enter the branded generics market next year. It highlights a number of recent acquisitions and alliances between the big drugs firms and Asian generics firms like Ranbaxy.

Wittner also outlined the barriers facing the generics companies (such as proving bioequivalence) and some of the complicated struggles around patents in the respiratory drug market. There are several examples that illustrate how skilled generics companies have become at attacking weak patents; he discussed the recent European challenges to the Seretide and Symbicort patents in particular.

Finally, Wittner offered great bit on the lateral thinking and agility of generics companies, who are developing and protecting innovative new respiratory delivery devices and active pharmaceutical ingredients (API). He closed with some observations on the uncertainty around the potential competitors set to emerge from the Asian market and outlined some of the competitive advantages that Asian companies have, including a favorable regulatory environment.

The article notes how major India health companies, like Ranbaxy and Apollo – long focused on the upper classes – are now racing down the pyramid and helping stir up a powerful mix of cheap, innovative and radical solutions that will leapfrog the rich world. Not surprisingly, consulting firm Technopak Healthcare estimates that spending on health care in India is expected to rise from $40 billion last year to $323 billion in 2023.

Successful firms are rejecting technology whose costs don’t justify the benefits, and focusing on tools and techniques that spare resources and improve outcomes. The head of Fortis, a Delhi-based hospital chain, told the magazine, “We got out of this arms race a few years ago.”

In fact, several examples illustrate how new outfits are providing basic approaches, embracing economies of scale, and enthusiastically adopting health information technology and reshaping their services around it, increasing efficiency and cutting errors and costs at the same time. (LifeSpring Hospitals – an increasingly well known and funded chain of maternal and child health hospitals is given as an example). The article also describes the tendency for innovative new firms to leverage the sliding scale – subsidizing care for the poor by charging affluent customers more.

I witnessed this type of pricing a number of years ago among Indian pharmaceutical companies. At the time, most offered lines of asthma medications targeting different socioeconomic segments of the population. It is a business model that brings to mind durable goods, but was (and remains) largely unfamiliar to people in high income countries. In India, old oral medications, such as theophylline, are still widely used by practitioners who prescribe them specifically to patients at the lower end of the market; expensive newer drugs never reach the public hospitals or the bulk of the population. Cipla, for example, manufactures an inhaled combination of beclomethasone and salbutamol. Neither of these are the most efficacious medications currently available in their classes but they are both generic, low-cost compounds. Cipla representatives call the combination – sold under the trade name Aerocort – “the poor man’s Seroflo,” in reference to the company’s top of the line fluticasone and salmeterol combination product. As one executive told me: “Aerocort is much cheaper and it’s the same type of combination. So, a lot of people use that.”

Paul Yock, head of the bio-design laboratory of Stanford University, is quoted in the Economist piece as saying that the international med-tech giants have so far “looked at need, but been blind to cost,” and argues that the industry will find inspiration in India.

Perhaps GE already has. The company recently launched their Healthymagination campaign, a US$6 billion effort to re-strategize how the organization develops medical technology in order to emphasize the delivery of affordable equipment. A full post on that to come.

On the airplane yesterday I read a great article from the Lancet – Medicine prices, availability, and affordability in 36 developing and middle-income countries – that I’d been carrying around for a while but never gotten to. It describes the development of a standardized method by WHO and Health Action International to routinely measure medicine prices, availability and affordability and make international comparisons. The full-text of the article and an accompanying editorial are available online for free. 

The paper presents the results of 45 surveys done in 36 countries, and notes that more than 50 surveys have now been done – with results available here. 

The article has a handful of striking statistics. For example, they report that medicines account for 20-60 percent of health spending in developing and transitional countries, compared with 18 percent in OECD countries. In addition, up to 90 percent of the populations in developing countries pay for medicines out of pocket, making, them “the largest family expenditure after food.”

In a nutshell, the project involved a multistage clustered sample of health care facilities in urban centers and outlying areas. Surveys examined a standard list of 30 core medicines that indicate a range of treatments for common acute and chronic conditions. The core medicines are “recommended, usually as first-line courses of treatment, in global, regional, and national treatment guidelines…Most are on the WHO Model List of Essential Medicines.” Up to 20 supplemental locally-relevant medicines were also included. A complete manual (and much more) is available online.  

While there are interesting findings regarding antibiotics used for respiratory infections, I’m going to limit my notes and comments to antiasthma medications.

Two drugs for asthma were included in the basket of 15 medicines that were represented in at least 80 percent of the surveys:

• Beclomethasone (0.05mg/dose) inhaler
• Salbutamol (0.1mg/dose) inhaler

However, specific data for beclomethasone was not included in the report, so I’m focusing on the results for salbutamol.

Availability – Low public and private sector availability

Overall, public sector availability of surveyed generics ranged from 29 to 54 percent across WHO regions.

Public section availability of salbutamol was very poor – only 29 percent (the lowest) overall. It ranged from 5 percent in Southeast Asia, 14 percent in Africa, 35 percent in Eastern Mediterranean, 42 percent in Europe, 48 percent in Western Pacific, to 88 percent in the Americas.

Private sector availability was a bit better overall (61 percent) – still the lowest of the target medications – with availability ranging from a low of 47 percent in Africa to a high of 79 in southeast Asia.

Price – Below the international reference price across most regions

Overall, private sector patients paid 9-25 times international reference prices for generic products and over 20 times international reference prices for originator products across WHO regions.

Surprisingly, however, the median price ratio for salbutamol inhalers was below the international reference price in all WHO regions except for the Americas; in a couple of regions (Africa, Southeast Asia) it was substantially lower.

Affordability – Not enough info to judge affordability of real-world asthma treatment

The report estimates affordability using the salary of the lowest-paid unskilled government worker to establish the number of day’s wages needed to purchase a course of treatment (30 day supply) for a variety of acute and chronic conditions (respiratory infection, diabetes, asthma and ulcer).

Unfortunately, the course of treatment for asthma only refers to a salbutamol inhaler; even though data on beclomethasone were collected, they are not included or reported (nor is any other anti-inflammatory).

Nevertheless, the authors report affordability for a month of inhaled salbutamol of 1.2-4.4 days in the private sector (originator brands) across regions, 0.6-5 days for private sector lowest priced generics; and 0.6-15 days for public sector lowest priced generics.

They note another shortcoming in the evaluation of affordability: That a substantial portion of the populations in many of these regions may earn less than the daily wage of the lowest-paid government worker. And they suggest that “further work is underway to identify alternative measures of affordability that could be included in the WHO/HAI methodology.”

The Indian setting

One other thing about the report that I found interesting. India – with its pricing regulations and vigorous domestic pharmaceutical industry (large number of generic manufacturers)  – appears to be have several lessons for efforts to improve the availability and affordability of medicines. In fact, the situation there is so unique that the manuscript reports the results from India separately.

For example, the availability of private sector generics was higher in India than in upper middle-income countries, while the median price ratios were much lower in India compared to other low income, lower-middle income and upper-middle income countries.

Moreover, median price differences between originator brands and lowest-priced generics in the private sector were also much lower in India (6% compared to over 300% in other low and lower-middle income countries).

Summary

With increasing demand for treatment of chronic respiratory disease in many low and lower-middle income countries, the value and timeliness of this report and methodology can’t be overstated. A more detailed analysis of typical asthma regimens – and some possible low-cost alternatives – should be at the center of global respiratory health efforts; improved public sector support for chronic respiratory disease medications is needed too.

As the authors write, “Increased emphasis should be placed on reducing the cost of these medicines in light of the high burden of non-communicable diseases. The affordability of chronic disease treatment is further constrained by the frequent need for more costly combination therapies and by the ongoing nature of treatment.”

News that El Salvador has recently become the first country to order from the Global Asthma Drug Facility hopefully indicates some progress, at last, “to increase availability, lower prices, and improve affordability of [asthma] medicine in all regions and at all levels of country development.”