On the Origin of Sensitivity and Specificity.

Although it is commonly said that the notions of sensitivity and specificity were first defined by Jacob Yerushalmy in 1947, the sensitivity and specificity of diagnostic tests have been assessed as far back as the early 1900s. These notions share a common origin with the development of serology. They were originally immunologic concepts, closely associated with the development of complement fixation reactions for syphilis. Here, the authors trace how immunologic sensitivity and specificity were transformed into diagnostic sensitivity and specificity. By relocating the origins of these concepts to the early 20th century, they highlight how these origins were bound to then-commonplace assumptions about specific infectious disease entities.

"In the Course of Routine Analysis": Re-Envisioning Research in State Departments of Health, 1920-1940.

During the interwar years, 1919-1939, State Department of Health (DOH) laboratories from around the United States provided scientific leadership and dedicated bench work to support the development of standardized laboratory technique. One important focus of the work was syphilis testing. In recent years, historians have explored the heated arguments and international debates surrounding the development of standardized methods. This article adds State Departments of Health to the venues in which scientists performed valuable research aimed at standardizing and improving analytic procedures. I argue that the research conducted in DOH laboratories to provide Progressive Era public health officials with accurate and efficient tools to control syphilis and other infectious diseases required significant innovation, international cooperation, and scientific creativity from scientists deeply engaged in multiple research projects. These endeavors offer an instructive venue for historians to begin to re-envision DOH laboratories as vibrant sites for scientific research, where work on standard methods was an enterprise of discovery and innovation.

The chequered history of the antiphospholipid syndrome.

Consideration of the chronology of advances in medical knowledge can provide useful insights into the pathogenesis, diagnosis and treatment of diseases. The antiphospholipid syndrome is an enigmatic disorder and this is reinforced by the misleading associated terminology, the adoption of which results directly from early discoveries relating to the condition. Thus the target antigen of the causative autoantibodies in antiphospholipid syndrome does not reside on phospholipid, and the frequently associated lupus anticoagulant is not restricted to subjects with systemic lupus erythematosus and, paradoxically, despite causing prolongation of clotting times in vitro it is associated with a pronounced tendency to thrombosis. Recognition of the antiphospholipid syndrome has its origins in the identification of subjects with so-called biological false-positive serological reactions for syphilis in the middle years of the last century. Since that time there have been considerable advances in our understanding of the pathogenesis of the disease and the clinical manifestations and associations, improved diagnostic accuracy and an evolving evidence base for optimal therapy. However many gaps in our knowledge remain.

[Since Wassermann to VDRL in the ancient Bacteriological Institute of Chile]. / Del Wassermann al VDRL en el antiguo Instituto Bacteriológico de Chile.

The author remembers, sometimes in a very personal and colloquial way, the successive adoption by the ancient Bacteriological Institute of Chile of different nontreponemal tests for the serological diagnosis of syphilis: Wassermann, Kahn and VDRL. The outstanding figures of some agents of those changes, like Rudolf Kraus, Eduardo Dussert and Reuben Kahn, are recreated in the words of first hand eyewitness.

[Seroimmunological studies by Dr Hideyo Noguchi - introduction and illustration of his seroimmunological research, with a connection to recent seroimmunology].

Dr. Hideyo Noguchi (Noguchi) is the most well-known scientist in Japanese history because of his eventful life and research on syphilis and yellow fever; however, details of his scientific research, especially in the seroimmunological field, performed in the USA have not been recognized. More than 200 papers were published, mostly in English, and about half of them were published in J. Exp. Medicine. Arbitrary evaluation was performed of his research, recognizing the value of his seroimmunological studies. In this lecture, the background at that time and a small part of the contents of 10 papers on serology and biochemistry are introduced and explained, in connection with recent seroimmunology: (1) On snake venom: In the first experiment, under the guidance of Drs. Flexner and Mitchel, many new findings were obtained regarding bacteriolysis, hemolysis, leucolysis, and the toxicity of venoms in relation to antibody and complement. Especially, the bacteriolytic activity of serum induced by venom was disclosed later to be caused by the activation of alternative pathway of complement by a factor termed cobra venom factor. (2) Heat-stable anticomplementary factor: Preheating sera produced an anticomplementary factor, termed protectin. (3) The pleurality of cytolysins (natural antibody) in sera not only of mammals but also of a reptile and an amphibian was identified. (4) Toxin-antitoxin reaction: One of the fundamental analyses of the antigen-antibody reaction. (5) Gel diffusion of antigen and antibody. (6) Various factors affecting the Wassermann reaction, in which the butyric acid method to detect globulin was introduced. (7) A new and simple method for the serodiagnosis of syphilis. (8) A study of syphilis antigen, in which the antigenicity of acetone-soluble lipid was stressed. (9) Pure cultivation of Treponema pallidum. (10) Demonstration of T. pallidum in the brain. More than 40 papers on syphilis were published, for which he was nominated for the Nobel prize 3 times.

The 100th anniversary of Wassermann-Neisser-Bruck reaction.

August Paul von Wassermann (1866-1925), German bacteriologist, together with Albert Neisser (1855-1916), German dermatologist and venereologist, and Carl Bruck (1879-1944), German dermatologist and venereologist, developed the first serologic test for the diagnosis of syphilis. They published their first article about it on May 10, 1906 (Dtsch Med Wochenschr 1906;32:745). They made use of the idea of the complement fixation test of Jules Bordet (1870-1961) and Octave Gengou (1875-1957), so the Wassermann reaction is sometimes called Bordet-Wassermann reaction. The study was done at the Berlin Institute of Infectious Diseases (Berliner Institut für Infektionskrankheiten) and at the Breslau (Wroclaw) Department of Dermatology. The Wassermann reaction was used in the diagnosis of syphilis. The antigen used in it was prepared empirically. Originally, the so-called antigens were extracts of human or monkey tissue rich in Treponema pallidum. The most active one was a liver extract of a syphilitic fetus. Later on, the active substance, referred to as cardiolipin, was found in normal nonsyphilitic tissues, including the heart (usually bovine heart). Karl Landsteiner (1868-1943) identified the antigen involved in the Wassermann reaction as a lipoid substance, which finally was identified as diphosphatidylglycerol. Wassermann antibodies, produced in the course of syphilis infection, are reactive with cardiolipin in the presence of lecithin and cholesterol. The antigen-antibody reaction produces immune complexes, which results in complement fixation via the classic pathway; this may be used to determine the serum level of antibodies (if <1 microg/mL). In the final step, indicator cells (erythrocytes) together with a subagglutinating amount of antibodies (antierythrocyte antibodies) are added to the mixture. If there remains any complement left, these cells will be lysed; if it has been consumed by immune complexes, the amount of the remaining complement will be insufficient to produce the lysis of the red cells. In the first experiment of Wassermann et al, the reaction was positive exclusively with the sera of patients with syphilis, but it was soon discovered that some other diseases gave positive results in nonsyphilitic individuals. First such cases were reported in 1909. With the discovery of new and more specific tests for syphilis, the complement fixation tests of Wassermann type gradually went into oblivion. A new era in venereology was started with the discovery of T pallidum by Fritz Schaudinn (1871-1906) and Erich Hoffmann (1868-1954) in 1905, and the development of serology of syphilis by Wassermann, Neisser, and Bruck in 1906. Although the Wassermann reaction is no longer in use now, it should be emphasized that it was one of the very first serodiagnostic tests ever used in medical practice. Carl Bruck said in the 1920s: "This fortunate and unique mistake constituted the basis of a very important discovery, whose significance was both theoretical and practical."

[The centenary of Wassermann reaction--the future of serological diagnosis of syphilis, up-to-date studies]. / Stulecie odczynu Wassermanna--przyszlosc serologicznej diagnostyki kily w swietle najnowszych badan.

One hundred years after the discovery of the infectious agent of syphilis and implementation of the first serological test for the diagnosis of syphilis, important progress in the evaluation of host immune response against Treponema (T.) pallidum infection has been made. The paper focuses on the new modifications of non-treponemal tests (the use of synthetic cardiolipin and lecithin in Venereal Disease Research Laboratory--VDRL test and the application of the VDRL antigen to immunoenzymatic assays) as well as of treponemal tests. Original treponemal antigens are replaced by recombinant and synthetic antigens (TpN44,5- TmpA, TpN15, TpN17 and TpN47) and by antigens obtained after sequencing of the complete T. pallidum genome (Tp0453, Tp0257 and Tp92) in modifications of immunoenzymatic assays. The new diagnostic strategy, namely the examination of the number of cells producing T. pallidum specific antibodies is also presented. Despite the progress achieved in studies on humoral response in syphilis during last years, the practical application of new tests in diagnosis of the infection requires further studies.

Breve histórico da sífilis e evolução do diagnóstico laboratorial no período de 2005 a 2016 / Brief history of syphilis and evolutive diagnosis laboratory in the period 2005-2016

Essa revisão explorou dois aspectos: a evolução do diagnóstico laboratorial, quantitativamente, com análise de 12.328 dados da produção laboratorial (de 2005 a 2016) e o histórico epidemiológico, com abordagem qualitativa (descritiva). Com o objetivo de traçar um panorama e apresentar as ações laboratoriais, avaliou-se o impacto no diagnóstico com a implantação do teste treponêmico TPHA (2007) e atendimento aos fluxogramas I-A (2011) e I-B (2014), da Portaria nº 3.242/GM/MS/2011(revogada em 2016). Para traçar a trajetória epidêmica do sífilismo no contexto social, do Brasil colonial à atualidade, buscou-se a literatura científica nas bases de dados PubMed, Scielo, Lilacs, PAHO, BVS, Google Acadêmico, elegendo os descritores isolados/agrupados: sífilis/congênita, sorodiagnóstico da sífilis, saúde pública. Das 200 publicações avaliadas por leitura exploratória, seletiva, analítica e interpretativa, 63 foram selecionadas para descrever a sífilis nos aspectos já mencionados. A ausência de dados laboratoriais e epidemiológicos dificulta o conhecimento das transformações do processo de manifestação da sífilis e adoção de medidas corretivas/preventivas para seu combate. Esse estudo detectou, com originalidade, pontos vulneráveis na execução do ensaio; necessidade de estratégias para melhoria da qualidade do diagnóstico laboratorial e, do ponto de vista epidemiológico, a inserção de políticas públicas específicas para atenção ao grupo de pessoas em idade fértil.

This review explored two aspects: quantitative evolution of the laboratory diagnosis with analysis of 12,328 laboratory data (2005/2016) and, epidemiological history with a qualitative (descriptive) approach. With aim of to draw a panorama and to present the laboratory actions was evaluated the impact from treponemic test (TPHA, 2007) in the diagnosis and attendance to flowcharts IA (2011)/IB (2014), of Ordinance Nº 3,242 /GM/MS/ 2011 (repealed in 2016). For drawing the syphilis epidemic trajectory in the social context, since Brazil colony to the currently scientific literature was searched in the databases PubMed, Scielo, Lilacs, PAHO, BVS, Google Scholar, choosing the isolated / grouped descriptors: syphilis / congenital, serodiagnosis, public health. From 200 publications selected 63 evaluated by exploratory, selective, analytical, interpretive reading, to describe syphilis in all aspects mentioned above. The lack of epidemiological and laboratorial data makes it difficult to know the changes in the syphilis manifestation process, and to adopt corrective/preventive measures to combat it. This original study detected vulnerability in the assay execution, need for strategies formulation to improve the laboratory diagnosis quality and, from an epidemiological point of view insertion of specific public policies for attention to childbearing age people group.

The Tuskegee Syphilis Experiment: biotechnology and the administrative state.

The central issue of the Tuskegee Syphilis Experiment was property: property in the body and intellectual property. Once removed from the body, tissue and body fluids were not legally the property of the Tuskegee subjects. Consequently, there was not a direct relationship between a patient and research that used his sera. The Public Health Service (PHS) was free to exercise its property right in Tuskegee sera to develop serologic tests for syphilis with commercial potential. To camouflage the true meaning, the PHS made a distinction between direct clinical studies and indirect studies of tissue and body fluids. This deception caused all reviews to date to limit their examination to documents labeled by the PHS as directly related to the Tuskegee Syphilis Experiment. This excluded other information in the public domain. Despite the absence of a clinical protocol, this subterfuge led each to falsely conclude that the Tuskagee Syphilis Experiment was a clinical study. Based on publications of indirect research using sera and cerebrospinal fluid, this article conceives a very history of the Tuskagee Syphilis Experiment. Syphilis could only cultivate in living beings. As in slavery, the generative ability of the body made the Tuskegee subjects real property and gave untreated syphilis and the sera of the Tuskegee subjects immense commercial value. Published protocols exploited the Tuskegee Syphilis Experiment to invent and commercialize biotechnology for the applied science of syphilis serology.

The Julius Rosenwald Fund syphilis seroprevalence studies.

In 1929 the Julius Rosenwald Fund, in conjunction with the Public Health Service (PHS), sponsored a syphilis seroprevalence study in the South characterized as a humanitarian effort to benefit the health of rural African Americans. The study reported extraordinarily high rates of positive Wassermann tests, even among children. Despite the unreliability and nonspecificity of this test, modern authors continue to indict these subjects as syphilitic. However, there was no consistent relationship between syphilis and a positive Wassermann test. Additional treponemal pathogens that potentially caused false-positive tests could explain the results. After public outcry to the Tuskegee Syphilis Experiment, the Rosenwald study acquired new significance. It was used as evidence to bolster the argument that Tuskegee was a consequence of humanitarian motives that became captive to misguided methods of researchers at the Venereal Disease Division of the PHS. Humanitarianism implies the acknowledgement of a right invested in the recipient; health is an end in itself. However, African Americans were necessary as a source of cheap labor for competition in the world cotton markets and as a restraint on the market value of white labor in manufacturing. The administrative structure of the PHS, not zealous individuals, adopted utilitarianism as its paradigm for human research. Syphilis seroprevalence was a calculated use of public health as a means to economic development.

[The significance of Karl Landsteiner's works for syphilis research]. / Die Bedeutung der Arbeiten Karl Landsteiners für die Syphilisforschung.

On January 7th 1905, more than five months before the detection of T. pallidum, Karl Landsteiner began his work on syphilis research together with notable members of the Viennese School of Medicine, namely Ernest Finger, Rudolf Müller, Viktor Mucha, Otto Pötzl and others. Extensive animal experiments led to the formulation of the Finger-Landsteiner Law and provided the basic facts for the Jadasson-Lewandowsky Law. Attempts of active or passive immunization were unsuccessful and, indeed, were still a failure in 1990 after implementation of the latest tools of modern research, including gene technology. Dark-field microscopy was introduced for the detection of T. pallidum by Landsteiner and Mucha. These authors noted that serum of syphilitic patients inhibited the movements of T. pallidum and, thus, observed the basic principle underlying the T. pallidum immobilization test (= TPI = Nelson-Mayer test). Finally, Landsteiner, Müller and Pötzl discovered that it was not an antibody specific to T. pallidum that reacted in the Wassermann reaction, but "autotoxic" substances, which they called reagines. During the 1970's and 1980's it was discovered that these reagines are autoantibodies directed against parts of the inner envelope of the mitochondria.

The introduction of diagnostic and treatment innovations for syphilis in post-war VD policy: "L'expérience belge".

In this article, the introduction of the Wassermann Test and arsenic-based drugs in Belgian post-war venereal disease (VD) policy is discussed (for the period of 1900-1930). Pre-war advances in clinical medicine, the development of the Wassermann Test and arsenical drugs, as well as war conditions, were important in putting syphilis on the public agenda in Belgium. However, the way in which new diagnostic and therapeutic techniques and devices were incorporated within post-war VD policy depended on the reconciliation of a range of political, professional and moral agendas of interested health-political parties. Finally, a successful post-war VD policy depicted in terms of <> is discussed.