INT J TUBERC LUNG DIS 7(12):1115–1116 FOUNDERS OF OUR KNOWLEDGE © 2003 IUATLD Clemens Freiherr von Pirquet and the tuberculin test IN FEBRUARY 1909, Clemens von Pirquet pub- lished a seminal article in the Journal of the American Medical Association in which he described an intra- dermal tuberculin skin test.1 In this paper, von Pirquet not only described his pioneering first use of intrader- mal tuberculin testing, but he also reported the re- markable insights into the pathogenesis of tubercu- losis that he gained from his observations of tuberculin reactions in children. By any measure, Clemens Freiherr von Pirquet was a remarkable individual.2,3 The youngest son of a bar- onet (hence the title Freiherr), he was born on 12 May 1874 on the estate of his family at Hirschstetten near Vienna, Austria. As he had no hope of inheriting fam- ily land, he began to study for the priesthood. During a pilgrimage to Lourdes in 1894 he apparently had an Figure Clemens Freiherr von Pirquet. Pencil drawing by Theresa epiphany and decided to abandon religion and study S K Chung. Reproduced with permission from Daniel, T M (ref- erence 3). medicine, a profession his disapproving family deemed unworthy for a man of his social status. He received his medical degree from the University of Graz in The tuberculin test paper published in JAMA in 1900. After 6 months of further study in Berlin, he 1909 is a true landmark. Preceded several months undertook further training with Theodur Escherich at earlier by presentations at medical meetings and brief the Universitäts Kinderklinik of the St Anna Chil- journal reports, this elegant exposition begins by not- dren’s Hospital in Vienna. He became Escherich’s ing that previously immunized individuals given small- principal assistant and was joined by the somewhat pox vaccine develop a cutaneous reaction at the site of younger Béla Schick. inoculation after 24 hours. Knowing that Koch’s tuber- The next decade was one of extraordinary accom- culin produced reactions in tuberculous persons when plishment. He studied the emerging field of immunol- given subcutaneously, von Pirquet correctly reasoned ogy with Rudolf Kraus, the first person to demon- that it would evoke a cutaneous reaction when given strate precipitation of antibody and antigen, but von intradermally. He used a smallpox vaccination lancet Pirquet did not enjoy the laboratory environment and to give the tuberculin, and set 5 mm as the cut-point returned to the clinical arena after only 6 months. for a positive response. Only the later introduction of There he used his uncanny skills of clinical observa- the intradermal syringe technique by Charles Man- tion to make a number of remarkable observations. toux and the preparation of PPD by Florence Seibert re- Life-saving horse antiserum to diphtheria toxin had mained to establish modern tuberculin testing methods. been introduced by Emil von Behring; Paul Moser Von Pirquet did not stop with the simple observa- had developed an equine antiserum to streptococci, tion that tuberculous children reacted to tuberculin. and it was being used at the Kinderklinik to treat scar- He reported that it took ‘some weeks’ after infection let fever. Von Pirquet noted that the serum made chil- for tuberculin reactivity to develop. He noted that dren sick, and in April 1903 he communicated the first some apparently healthy children also reacted, and he description of serum sickness in a letter to the Acad- considered them to have latent tuberculosis, a term emy of Sciences in Vienna. In this letter he noted that a only recently resurrected. He further noted that young second exposure to serum resulted in a much acceler- children under two years of age generally had mani- ated reaction. In 1906 he introduced the terms allergy fest disease when infected, whereas older children and allergen in a paper in which he extended his obser- commonly did not. He also reported that some chil- vations to other infectious diseases, to reactions to dren were anergic, including those with measles and foods such as strawberries and shell fish, and to hay miliary tuberculosis. Finally, once again ahead of his 4 fever. In this paper he more clearly described the anam- time, he proposed two-step testing, with repeat test- nestic response, which he had originally described in his ing after one week of those who did not react to the letter to the Vienna Academy of Sciences. first tuberculin test. What was lacking from von Pirquet’s elegant exposition? He erred in attributing KEY WORDS: von Pirquet; tuberculosis; tuberculin test; history tuberculin reactivity to antibodies. Concepts of cellu- of medicine lar immunity would have to wait until 1941, when 1116 The International Journal of Tuberculosis and Lung Disease Merrill Chase transferred delayed hypersensitivity his chronically depressed wife, Maria, took potas- in guinea pigs using cellular exudates containing sium cyanide in a double suicide. lymphocytes. Thomas M. Daniel, MD Von Pirquet’s work was recognized, and he was Professor Emeritus of Medicine and soon courted both by the Pasteur Institute in Paris in International Health Paris and by Johns Hopkins University in Baltimore. Center for International Health He turned down the former to become the first pro- Case Western Reserve University School of Medicine fessor of pediatrics at Johns Hopkins in 1909. He was Cleveland, OH 44106-4978, USA 34 years old. He stayed at Hopkins for only a year, e-mail: [email protected] leaving because his income from his pediatric practice in Baltimore was insufficient. He was offered a full- References time salary of $7500, but he felt that that sum was 1 Von Pirquet C. Frequency of tuberculosis in childhood. JAMA inadequate. He returned to Vienna and assumed the 1909; 52: 675–678. post vacated by the death of his mentor, Theodur 2 Wagner R. Clemens von Pirquet. His life and work. Baltimore, Escherich. During the remaining decade of his life, he MD: Johns Hopkins Press, 1968. focused his attention on nutrition. He made no fur- 3 Daniel T M. Pioneers of medicine and their impact on tuberculo- sis. Rochester, NY: University of Rochester Press, 2000: 132– ther enduring medical contributions. 155. Von Pirquet’s candle burned brightly but briefly. It 4 Von Pirquet C. Allergie. Muenchener Med Wochenschrift 1906; was extinguished on 28 February 1929, when he and 53: 1457–1458..