Professor Andrzej Szczeklik (1938–2012): a European intellectual defining aspirin‑asthma and much more

Sven‑Erik Dahlén, Barbro Dahlén The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden

After a short period of cardiac illness, the heart moved back to Krakow to become the chairman of of Andrzej Szczeklik ceased to beat on the morn‑ the University’s Department of Allergy and Clin‑ ing of Friday, 3 February 2012. This ended the life ical Immunology, and in 1989, he became chair‑ on Earth of an extraordinary man, but his legacy man of the Department of Medicine at the Jag‑ will prevail. Driven by a relentless curiosity and iellonian University Medical College in Krakow. a compassion for science, his life achievements are Andrzej Szczeklik was always in the forefront of manifold and substantial in diverse areas. Among the inter­national scientific community, much due respiratory physicians and allergo­logists, he will to his prolific reading as well as regular exchange be remembered as the world‑leading authority on of ideas with colleagues all over the world. He aspirin‑asthma. At this juncture, it is particular‑ also trained abroad on many occasions, includ‑ ly ironic that Andrzej Szczeklik should be recog‑ ing monthly stints at the Karolinska Institutet in nized among cardio­logists due to his publication Stockholm and University of Uppsala, Sweden, as of a number of key basic and clinical findings re‑ well as at the University of North Carolina, Chapel lating to diagnosis and treatment of thrombosis Hill, United States. In the years 1985–1989, An‑ and cardiovascular disease. Current and future drew Szczeklik was a visiting professor at the Fac‑ generations of Polish medical students and spe‑ ulty of Medicine at the University of Sheffield, UK, cialists will remember him as Editor of the very King’s College School of Medicine, London, UK modern textbook of internal medicine, which is and Hochgebirgsklinik Davos­‑Wolfgang, Switzer‑ continuously updated with the most current sci‑ land. During 1990–1993, he was elected the Rector entific evidence. For some laymen, his name will (President) of the Copernicus Academy of Medi‑ be associated with the authorship of two fasci‑ cine in Krakow, and then Vice‑Rector of the Jagiel‑ nating books integrating profound knowledge on lonian University for Medical College (1993–1996). humanities, art and science into thoughtful per‑ Although he had formally been retired from his spectives on history, society, and above all, the life clinical duties for a few years, he continued to of human beings. We understand that for many be a very active and passionate leader of the re‑ people in Poland, Szczeklik will also be remem‑ search team in Krakow that arguably is the inter­ bered for his contributions to academic and so‑ nationally most recognized Polish centre within cietal freedom at times when many black shad‑ Respiratory Medicine and Allergology. From 2006 ows made life difficult. until present, he held the position of Vice‑Presi‑ Born in Krakow in 1938 as the son of the em‑ dent in the Polish Academy of Sciences and Arts. inent Polish Professor of Internal Medicine, Ed‑ During the time of Pope John Paul II, also from ward Szczeklik, it may be more than coinciden‑ Krakow, Szczeklik was a member of the scientif‑ tal that young Andrzej, mostly known as Andrew ic advisory committee of the Vatican. outside Poland, developed a deep commitment to The movement back to his hometown Krakow the improvement of the health of his fellow hu‑ initiated a scientifically very productive period Correspondence to: Prof. Sven-Erik Dahlen, MD, PhD, mans. He received his basic medical training in his in the early 1970s when, in particular, the sem‑ The Centre for Allergy Research, home town, Krakow, followed by a 1-year inter­ inal demonstration of the mechanism involved Karolinska Institutet, SE-171 77, nship at Monmouth Medical Center, New Jer‑ in aspirin­-intolerant asthma was made.1 This is Stockholm, Sweden, e-mail: [email protected] sey, in the United States in the early 1960s. Back Szczeklik’s most cited original paper. In this pa‑ Received: March 21, 2012. in Poland in 1963, he moved to the Academy of per, published in the British Journal of Medicine Accepted: March 21, 2012. Medicine in Wrocław where he obtained his PhD in 1975, eleven patients with previously report‑ Pol Arch Med Wewn. 2012; 122 in 1966 (“The activity of serum aminopeptidas‑ ed or documented intolerance to aspirin were (Special Issue): 20-22 Copyright by Medycyna Praktyczna, es in the diseases of liver and biliary tract”) and challenged orally at different occasions with Kraków 2012 continued to work as an inter­nist. In 1972, he rising doses of eight different analgesic drugs.

20 POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2012; 122 (Special Issue) Figure 19 Professor Szczeklik in his office, 2nd Department of Internal Medicine, Jagiellonian University Medical College, Krakow, 1995

Indomethacin, mefenamic acid, flufenamic acid, translational medicine before the term was coined. and phenylbutazone triggered bronchoconstric‑ That seminal study, as often is the case, occurred tion in therapeutic or lower doses, whereas even in a very creative environment. And so, the group high doses of salicylamide, para­cetamol, benzy‑ included a pharmaco­logist, Ryszard Grygewski, damine, and chloroquine were tolerated. The pro‑ also from Krakow. Gryglewski had trained with pensity of the drugs to elicit adverse reactions cor‑ Sir John Vane in London and had been a member related directly with their ability to inhibit pros‑ of the team which in the beginning of the 1970s taglandin bio­synthesis in vitro. These results un‑ discovered that the common mode of action of equivocally demonstrated that the intolerance anti‑inflammatory NSAIDs was to inhibit pros‑ reaction was related to inhibition of prostaglan‑ taglandin formation. This was one of the reasons din bio­synthesis. Sadly enough, even today there why Sir John was awarded the Nobel Prize in are occasional deaths due to failure among health Physiology or Medicine in 1982 for the discov‑ professionals to recognise that the intolerance is eries on prostaglandins and other compounds, a class effect of all nonsteroidal anti‑inflammato‑ together with Sune Bergström and Bengt Sam‑ ry drugs (NSAIDs) that inhibit the cyclo‑oxyge‑ uelsson from the Karolinska Institutet. Szczek‑ nase (COX) reaction. Such unfortunate subjects lik had long been intrigued by the clinical fea‑ may have been given ibuprofen as an alternative tures of aspirin intolerance, which were inciden‑ when they have reported intolerance to aspirin. tally first described in the Polish city of Poznan Furthermore, this original study also showed that a few years after aspirin had been introduced as patients with NSAID intolerance generally toler‑ an analgesic.4 Together with Gryglewski, it was ate salicylates and para­cetamol (acetaminophen). now possible to design the pivotal study to test This has much later been explained by the discov‑ the hypothesis that the clinical reactions were ery that these two NSAIDs are only weak inhib‑ related to the anti‑inflammatory properties of itors of the COX‑1 isoenzyme, which is now rec‑ the drugs. The pharmaco­logic effects of the drugs ognised as the target of drugs that elicit the in‑ on prostaglandin bio­synthesis in vitro were as‑ tolerance reaction. Accordingly, Szczeklik and his sessed by bio­assay on the rat stomach strip. This team have alone2 or in collaboration with others3 was at that time the state-of-the-art method for shown that aspirin/NSAID‑intolerant asthmat‑ measurement of prostaglandins. The prostaglan‑ ics tolerate selective COX‑2 inhibitors. dins were generated by incubating bovine sem‑ It should be appreciated that this first dem‑ inal vesicle microsomes with arachidonic acid, onstration of the relation between prostaglan‑ also the best available method. The clinical re‑ din bio­synthesis and clinical reaction truly was sponse was evaluated in challenge protocols which

Professor Andrzej Szczeklik (1938–2012): a European intellectual defining aspirin‑asthma and much more 21 Szczeklik developed. Moreover, it should be rec‑ one recurrent impression acknowledged by most ognised that this was a demanding provocation that have worked with aspirin‑intolerant asthma study where eleven subjects were challenged each was in fact verified in the study. Thus, surpris‑ with different NSAIDs on up to eight occasions. ingly, 15% of the patients in the study were un‑ Szczeklik has also contributed to studies asso‑ aware of intolerance to aspirin and learnt about ciated with the other main reason for Sir John it only after having provocation tests performed. being awarded a Nobel Prize, namely the discov‑ In fact, this happened also when Szczeklik visited ery of prostacyclin as an antiplatelet vasodilator. Japan. On his first visit, his hosts said that they Thus, together with Gryglewski he performed rarely saw these patients, but when they started the first intravenous injections of prostacyclin to do provocations after his visit, the prevalence 5 (PGI2) in humans and reported in The Lancet and of aspirin‑intolerant asthma turned out to be as

other journals on the beneficial effect of PGI2 on frequent in Japan as around other centres with the peripheral circulation in arteriosclerosis. Al‑ the experience of the syndrome. After that many together, many out of some 650 publications important contributions to our knowledge about that Szczeklik authored concerned effects of ei‑ the syndrome have been made by colleagues in cosanoids and other messenger molecules such Japan, as well as in other Asian countries. as nitric oxide on haemostasis and cardiovascular Following the AIANE experience, Szczeklik responses, aiming to gain a better understanding has almost every year during the past decade ar‑ of cardiac and vascular diseases. ranged a very friendly gathering in Krakow of clin‑ Szczeklik and his team have over the past 35 ical and basic scientists with an inter­est in aspi‑ years performed a step‑wise dissection of the key rin‑intolerant asthma. This HANNA (European mechanisms in aspirin/NSAID‑intolerant asthma Network on Hypersensitivities to aspirin and oth‑ that have taught us most of what we know about er NSAIDs) meeting was initially partly funded this enigmatic syndrome. So far, the best expla‑ by the European Union supported GA2LEN net‑ nation of the pathophysiology in aspirin‑intoler‑ work of excellence for asthma and allergy, but ant asthma, namely that the patients for some with time Szczeklik covered most of the costs reason are particularly dependent upon the abil‑ himself. The meetings were very inter­active and

ity of PGE2 to stabilise mast cells, rests consider‑ always managed to bring in participants that had

ably on the observation that inhalation of PGE2 new findings and ideas to share. We will now cer‑ blocks the aspirin‑induced bronchoconstriction tainly miss Andrew much at future meetings, but in aspirin‑intolerant asthma.6 Although we still we are convinced that they will continue in his

do not understand why this “PGE2‑dependence” spirit, and piece by piece the mysteries of aspirin‑ develops in this particular group of patients, it -intolerant asthma will be unraveled.

is clear that inhibition of PGE2 formation with NSAIDs has detrimental effects and is associat‑ References 7 ed with mast cell activation. 1 Szczeklik A, Gryglewski RJ, Czerniawska‑Mysik G. Relation­ship of Aspirin‑intolerant asthma is arguably the most inhibition of prostaglandin bio­synthesis by analgesics to asthma attacks in well-defined phenotype of asthma. With an adult aspirin‑sensitive patients. Br Med J. 1975; 1: 67-69. 2 Szczeklik A, Nizankowska E, Bochenek G, et. al. Safety of a spe‑ onset and a preponderance among women, sub‑ cific COX‑2 inhibitor in aspirin‑induced asthma. Clin Exp Allergy. jects characteristically suffer from chronic rhino‑ 2001; 31: 219-225. -sinusitis and nonallergic asthma where ingestion 3 Dahlén B, Szczeklik A, Murray JJ; Celecoxib in asthma study group. Celecoxib in patients with asthma and aspirin intolerance. N Engl J Med. of aspirin and other NSAIDs will induce broncho- 2001; 344: 142. constriction. The natural history and much of 4 Hirschberg VGS. [Report of one case of adverse reaction to aspirin]. the clinical features of aspirin‑intolerant asthma Dtsch Med Wochenschr. 1902; 28: 416. German. have been established by a pan‑European proj‑ 5 Szczeklik A, Nizankowski R, Skawinski S, et al. Successful ther‑ apy of advanced arteriosclerosis obliterans with prostacyclin. Lancet. ect that Szczeklik initiated in the 1990s. Togeth‑ 1979; 1: 1111-1114. er with, in particular, his long‑time close collab‑ 6 Szczeklik A, Mastalerz L, Nizankowska E, Cmiel A. Protective and bron‑ orator, Professor Ewa Niżankowska-Mogilnicka, chodilator effects of prostaglandin E and salbutamol in aspirin‑induced asth‑ ma. Am J Respir Crit Care Med. 1996; 153: 567-571. Szczeklik had the vision to create a database of 7 Sladek K, Szczeklik A. Cysteinyl leukotrienes overproduction and mast aspirin-intolerant asthmatics from all over Eu‑ cell activation in aspirin‑provoked bronchospasm in asthma. Eur Respir rope and take advantage of the emerging com‑ J. 1993; 6: 391-399. puter technology. There were, however, many 8 Szczeklik A, Nizankowska E, Duplaga M and the AIANE (The Europe‑ an Network on Aspirin‑Induced Asthma) Investigators. Natural history of steps between the vision and the completion of aspirin­‑induced asthma. Eur Respir J. 2000;16: 432-436. the project. For example, the personal computers were at that time still at a very primitive stage and there were many hurdles on the road to comple‑ tion. The team struggled on and in the end data from 500 patients were collected. This is the larg‑ est collection of subjects with aspirin‑intolerant asthma ever systematically characterised. Despite origins from 16 centres in ten European countries, the clinical picture of aspirin‑intolerant asthma was remarkably homo­genous.8 As inclusion in the study required provocation verified diagnosis,

22 POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2012; 122 (Special Issue)