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The case report by Blanco et al. in this issue of the journal [1] presents a young woman with PI*MZ alpha-1 antitrypsin deficiency and asthma who was treated with intravenous augmentation therapy with apparent stabilization of her asthma following this therapy. This case report, the first of its kind (to my knowledge) to examine the impact of augmentation therapy for asthma and the first to report using augmentation therapy for a PI*MZ individual, is both intriguing for the novelty of the observation and for its potential implications and, at the same time, challenging and troubling for the possibility that the uncritical reader could infer causality (i.e., that augmentation therapy somehow conferred the benefit) from the reported temporal correlation with improved asthma control in the single reported patient. Indeed, the pitfalls of making causal inferences from observational data, even if from large data sets, are well known and have been amply discussed [2-4]. Classic objects of misinterpretation include studies showing tight correlations between sunspot activity and business cycles [3] and intriguing (but clearly misleading) studies that show tighter correlation between stork sightings and birth rates in Germany [3, 4]. Surely, that business cycles respond to solar phenomena seems as implausible as that business cycles cause sunspots, though the unwary reader of these reports could easily infer either explanation (with equal shortsightedness). Are we prepared to suspend belief in reproductive biology based on the fact that stork sightings correlated with birth rates, even with those out-of-hospital [3, 4]? Surely, the hazards of inferring causation from correlation from large data sets, which are substantial as discussed here, are exaggerated when the correlation is with observations from a single individual, as is the case in the current case report [1]. Importantly, the authors who are distinguished scholars of alpha-1 antitrypsin deficiency, acknowledge the impossibility of inferring from this observation that augmentation caused the patient’s asthma to stabilize. Not stated explicitly in the paper but worthy of an important disclaimer in my view is that readers should not construe this observation as justifying use of augmentation therapy to treat asthma. Said more strongly, based on currently available information about the therapeutic effects of augmentation therapy, I believe that the critical reader will avoid any temptation based on “stork-birth rate reasoning” to prescribe augmentation therapy for asthma in PI*MZ (or any alpha-1 antitrypsin deficient) individuals. What then, does the current report offer? The report surely emphasizes the need for additional research regarding augmentation therapy and extends the range of issues for this research. Indeed, despite official recommendations [5], the weight of supportive observational data [5-7], and a concordant trend in the two available randomized placebo-controlled clinical trials [8, 9], the fundamental question of whether augmentation therapy slows the rate of emphysema progression in individuals with severe deficiency of AAT (i.e., PI*ZZ) remains the subject of debate among some. Whether augmentation therapy confers benefit for fibromyalgia in AAT deficient individuals (as has been suggested by one of the authors of the current report [10]) or for panniculitis [11, 12] as has been reported in a few individuals, remains equally unclear and in need of definitive study. This report adds an intriguing question to the list of questions warranting rigorous study regarding the effects of augmentation therapy, i.e., could augmentation therapy offer benefit for refractory asthma in individuals with severe or even mild AAT deficiency (i.e., PI*MZ individuals)? However lofty the articulation of these questions seems, formidable challenges to conducting rigorous studies to demonstrate causality in alpha1 antitrypsin deficiency persist. For example, though AAT deficiency is common, it is severely under-recognized [13-15] so that assembling subMonaldi Arch Chest Dis 2008; 69: 4, 155-156.

On the Evidence that Augmentation Therapy Helps Asthma: Are Storks Really Responsible for New Babies?