Tuberculin

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Tuberculin
Mantoux tuberculin skin test.jpg
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Trade names Aplisol, Mantoux, PPD, others
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Tuberculin, also known as purified protein derivative, is a combination of proteins that are used in the diagnosis of tuberculosis. [1] This use is referred to as the tuberculin skin test and is recommended only for those at high risk. [2] Reliable administration of the skin test requires large amounts of training, supervision, and practice. Injection is done into the skin. [2] After 48 to 72 hours, if there is more than a five to ten millimeter area of swelling, the test is considered positive. [2]

Contents

Common side effects include redness, itchiness, and pain at the site of injection. [1] Allergic reactions may occasionally occur. [1] The test may be falsely positive in those who have been previously vaccinated with BCG or have been infected by other types of mycobacteria. [2] The test may be falsely negative within ten weeks of infection, in those less than six months old, and in those who have been infected for many years. [2] Use is safe in pregnancy. [2]

Tuberculin was discovered in 1890 by Robert Koch. [3] Koch, best known for his work on the etiology of tuberculosis (TB), laid down various rigorous guidelines that aided the establishment between a pathogen and the specific disease that followed that were later named Koch's postulates. [4] Although he initially believed it would cure tuberculosis, this was later disproved. [3] Tuberculin is made from an extract of Mycobacterium tuberculosis . [1]

It is on the World Health Organization's List of Essential Medicines. [5]

Medical uses

The test used in the United States at present is referred to as the Mantoux test. An alternative test called the Heaf test was used in the United Kingdom until 2005, although the UK now uses the Mantoux test in line with the rest of the world. Both of these tests use the tuberculin derivative PPD (purified protein derivative).[ citation needed ]

History

Hope for a cure

Tuberculin was invented by German scientist and physician Robert Koch in 1890. The original tuberculin was a glycerine extract of the tubercle bacilli and was developed as a remedy for tuberculosis. This was originally considered a cure for tuberculosis, given to patients in subcutaneous doses of a brownish, transparent liquid that was gathered through cultured filtrates. [6] However, the treatment did not result in the anticipated reduction of deaths.[ citation needed ]

When the tuberculin treatment was first given to patients in 1891, a febrile reaction that lasted between four and five hours was recorded in most patients. The symptoms of these reactions included a fever that was accompanied by vomiting, rigors, or other forms of constitutional symptoms. [6] After these symptoms became recurring in patients, Koch had noted how increasing dosages of the treatment over time resulted in quicker and more effective healing in the mild cases of tuberculosis, along with the more serious cases where progression was slower, yet still progressive. [6]

British efforts to set up "dispensaries" for the examination, diagnosis and treatment of poor citizens achieved better results, as the protocol of the Edinburgh System encompassed treatment of the homes and all contacts of the patients with TB. [7] As an example, Dr Hilda Clark's dispensary at Street, Somerset was especially noted for its efficacious treatment of the less severe cases. [7]

Clemens von Pirquet, an Austrian physician, discovered that patients who had previously received injections of horse serum or smallpox vaccine had quicker, more severe reactions to a second injection, and he coined the word allergy to describe this hypersensitivity reaction. Soon after, he discovered that the same type of reaction took place in those infected with tuberculosis. His observations led to the development of the tuberculin skin test. Individuals with active tuberculosis were usually tuberculin positive, but many of those with disseminated and rapidly progressive disease were negative. This led to the widespread but erroneous belief that tuberculin reactivity is an indicator of immunity to tuberculosis.[ citation needed ]

Effectiveness proclaimed

In Koch's time, close to one in seven Germans died of tuberculosis. For that reason, the public reacted euphorically to the discovery of the pathogen since it sparked hope for a cure. Until that time, the only effective remedy for an infectious disease was quinine, which was used to treat malaria.[ citation needed ]

At the Tenth International Medical Congress held in 1890 in Berlin, Koch unexpectedly introduced a cure for tuberculosis, which he called tuberculin. He did not reveal its composition, which was not unusual as it was not then customary to patent medicine, Phenazone being the only exception. The public trusted the famous physician and reacted enthusiastically. Koch was awarded the Grand Cross of the Order of the Red Eagle.[ citation needed ]

The social hygienist Alfred Grotjahn described the arrival of tuberculin in Greifswald: "Finally the great day also arrived for Greifswald on which the Clinic for Internal Medicine was to carry out the first inoculations with tuberculin. It was celebrated like the laying of a foundation stone or the unveiling of a monument. Doctors, nurses and patients dressed in snowy white and the director, garbed in a black frock coat, stood out against a background of laurel trees: ceremonial address by the internist, execution of the vaccination on selected patients, a thunderous cheer for Robert Koch!" [8]

Koch attempted to profit from his discovery, which was held against him since he had conducted his research at a public institution using public money. He demanded that the Ministry of Culture finance an institute to be used exclusively for tuberculin production, and estimated the annual profit at 4.5 million marks. Koch also hinted that he had received offers from the US. [9] At the time, regulations for testing medicines did not yet exist. According to Koch, he had tested tuberculin on animals, but he was unable to produce the guinea pigs which had allegedly been cured. [10] : 106  He seemed unconcerned by the evidence that humans had a more dramatic reaction to tuberculin versus his laboratory animals, exhibiting fever, pains in their joints, and nausea. [10] : 101  In addition to other test subjects, he tested tuberculin on Hedwig Freiberg (his mistress and later wife), who was 16 years old at the time. She relates in her memoirs that Koch had told her that she could "possibly get quite sick" but that she was "not likely to die". [9]

Ineffectiveness as a cure

In February 1891, a medical trial was performed on 1769 patients to whom tuberculin was administered, and the results made clear that it was not a true cure. Tuberculin failed to provide any form of protective action as only 1% of people in the trial were cured, 34% of people showed only a slight amount of improvement, 55% of the patients showed little to no change in their health, and 4% died due to the treatment having no effect. [6]

After tuberculin was on the market, articles reporting successful treatments appeared in professional publications and the public media, only to be followed by the first reports of deaths. At first, the negative reports were not viewed with alarm, as the doctors were, after all, experimenting on seriously ill patients. [10] : 133f 

After performing autopsies on the corpses, Rudolf Virchow proved that not only did tuberculin not kill the bacteria, it even activated latent bacteria. [10] : 136  When Robert Koch was forced to reveal the composition of his "secret cure", it was discovered that he himself did not precisely know what it contained. Before tuberculin was released to the public, Koch had initially tested the treatment on himself to determine its toxicity to the human body, which is no longer considered a reliable or acceptable method for establishing drug safety. [6] It was an extract of tuberculosis pathogens in glycerine, and the presence of the dead pathogens themselves could also be confirmed.[ clarification needed ]

Koch asked the Prussian Minister of Culture for time off and went to Egypt, which was interpreted as an attempt to escape from the German public. A heated debate took place in the Prussian parliament in May 1891. Koch remained convinced of the value of his cure. In 1897, he presented a modified form of tuberculin, which was also ineffective as a therapeutic agent. This presentation, and numerous other indications, suggest that he did not intend to commit a "tuberculin scam" (a common accusation), but that he had deluded himself.[ citation needed ]

Historical perspective and legacy

The medical historian Christoph Gradmann has reconstructed Koch's beliefs regarding the function of tuberculin: the medicine did not kill the bacteria but rather initiated a necrosis of the tubercular tissue, thus "starving" the tuberculosis pathogen. [10] : 100f  This idea was then outside customary medical theories, as it remains today.[ citation needed ]

The tuberculin scandal was understood as a cautionary tale in regards to testing medicine. Emil von Behring's introduction of his diphtheria antitoxin in 1893 had been preceded by lengthy clinical testing, and the serum was only slowly introduced into practical use, accompanied by a critical discussion among qualified experts. [11] Paul Ehrlich also proceeded with conspicuous caution in 1909 when introducing the first synthetically produced chemotherapeutic agent, Salvarsan, as a cure for an infectious disease, syphilis.[ citation needed ]

In 1907, Clemens von Pirquet further developed tuberculin as a testing agent for diagnosing tuberculosis, but this was his own achievement, independent of any of Robert Koch's ideas. The company Meister Lucius & Brüning AG (later Hoechst AG) in Frankfurt/Höchst purchased the large leftover stocks of tuberculin and the company later began production under the leadership of Koch's student Arnold Libbertz. [12]

When Koch first discovered and released the testing process for tuberculosis, there was no realization of how widely this type of diagnostic test would be used. With the various clinical trials and observations made through the differing responses to tuberculin in patients with and without tuberculosis, new methods that corresponded to the backbone of this treatment began to arise. The continued use of new methods that further eliminated systemic symptoms that were caused by a local reaction at the injection site allowed for other medical advances. These included the Pirquet cutaneous test, the Moro percutaneous path test, the Mantoux intracutaneous test, and the Calmette conjunctival test. [6]

With experience gained from the tuberculin skin test during the greater part of the last century, the current body of medical knowledge and advances were made possible by Robert Koch. Through the failures and successes of tuberculin, more than ever before is known about the causes and symptoms of tuberculosis and the measures to prevent it. In addition, the discovery of the tuberculin skin test paved the way to the world's understanding of many other mycobacterial infections as well as certain fungal infections. [13] Coupled with that, there has been more profound research and discoveries on the immune systems of humans and animals as the idea of skin testing broadened. The in-depth understanding of diagnostic tests was not present until the tuberculin skin test was discovered. [13]

Related Research Articles

<span class="mw-page-title-main">Robert Koch</span> German physician and bacteriologist (1843–1910)

Heinrich Hermann Robert Koch was a German physician and microbiologist. As the discoverer of the specific causative agents of deadly infectious diseases including tuberculosis, cholera and anthrax, he is regarded as one of the main founders of modern bacteriology. As such he is popularly nicknamed the father of microbiology, and as the father of medical bacteriology. His discovery of the anthrax bacterium in 1876 is considered as the birth of modern bacteriology. Koch used his discoveries to establish that germs "could cause a specific disease" and directly provided proofs for that germ theory of diseases, therefore creating the scientific basis of public health, saving millions of lives. For his life's work Koch is seen as one of the founders of modern medicine.

<span class="mw-page-title-main">Paul Ehrlich</span> German physician and scientist (1854–1915)

Paul Ehrlich was a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy. Among his foremost achievements were finding a cure for syphilis in 1909 and inventing the precursor technique to Gram staining bacteria. The methods he developed for staining tissue made it possible to distinguish between different types of blood cells, which led to the ability to diagnose numerous blood diseases.

<span class="mw-page-title-main">Tuberculosis</span> Infectious disease

Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in which case it is known as latent tuberculosis. Around 10% of latent infections progress to active disease which, if left untreated, kill about half of those affected. Typical symptoms of active TB are chronic cough with blood-containing mucus, fever, night sweats, and weight loss. Infection of other organs can cause a wide range of symptoms.

<span class="mw-page-title-main">Mantoux test</span> Immunological method to test for tuberculosis

The Mantoux test or Mendel–Mantoux test is a tool for screening for tuberculosis (TB) and for tuberculosis diagnosis. It is one of the major tuberculin skin tests used around the world, largely replacing multiple-puncture tests such as the tine test. The Heaf test, a form of tine test, was used until 2005 in the UK, when it was replaced by the Mantoux test. The Mantoux test is endorsed by the American Thoracic Society and Centers for Disease Control and Prevention. It was also used in the USSR and is now prevalent in most of the post-Soviet states, although Soviet mantoux produced many false positives due to children's allergic reaction.

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

<span class="mw-page-title-main">Addison's disease</span> Endocrine disorder

Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adrenal glands, causing adrenal insufficiency. Symptoms generally come on slowly and insidiously and may include abdominal pain and gastrointestinal abnormalities, weakness, and weight loss. Darkening of the skin in certain areas may also occur. Under certain circumstances, an adrenal crisis may occur with low blood pressure, vomiting, lower back pain, and loss of consciousness. Mood changes may also occur. Rapid onset of symptoms indicates acute adrenal failure, which is a clinical emergency. An adrenal crisis can be triggered by stress, such as from an injury, surgery, or infection.

<span class="mw-page-title-main">Mycobacterial cervical lymphadenitis</span> Human medical condition

The disease mycobacterial cervical lymphadenitis, also known as scrofula and historically as king's evil, involves a lymphadenitis of the cervical lymph nodes associated with tuberculosis as well as nontuberculous (atypical) mycobacteria.

The Heaf test, a diagnostic skin test, was long performed to determine whether or not children had been exposed to tuberculosis infection. The test was named after F. R. G. Heaf. Also known as the Sterneedle test, it was administered by a Heaf gun, a spring-loaded instrument with six needles arranged in a circular formation which was inserted in the wrist or shoulder.

<span class="mw-page-title-main">Tine test</span> Medical test for tuberculosis

The tine test is a multiple-puncture tuberculin skin test used to aid in the medical diagnosis of tuberculosis (TB). The tine test is similar to the Heaf test, although the Mantoux test is usually used instead. There are multiple forms of the tine tests which usually fall into two categories: the old tine test (OT) and the purified protein derivative (PPD) tine test. Common brand names of the test include Aplisol, Aplitest, Tuberculin PPD TINE TEST, and Tubersol.

<span class="mw-page-title-main">Tuberculosis diagnosis</span>

Tuberculosis is diagnosed by finding Mycobacterium tuberculosis bacteria in a clinical specimen taken from the patient. While other investigations may strongly suggest tuberculosis as the diagnosis, they cannot confirm it.

The lepromin skin test is used to determine what type of leprosy a person is infected with. It involves the injection of a standardized extract of the inactivated "leprosy bacillus" under the skin. It is not recommended as a primary mode of diagnosis.

<span class="mw-page-title-main">Clemens von Pirquet</span>

Clemens Peter Freiherr von Pirquet was an Austrian scientist and pediatrician best known for his contributions to the fields of bacteriology and immunology.

Charles Mantoux was a French physician and the developer of the eponymous serological test for tuberculosis.

<span class="mw-page-title-main">Miliary tuberculosis</span> Medical condition

Miliary tuberculosis is a form of tuberculosis that is characterized by a wide dissemination into the human body and by the tiny size of the lesions (1–5 mm). Its name comes from a distinctive pattern seen on a chest radiograph of many tiny spots distributed throughout the lung fields with the appearance similar to millet seeds—thus the term "miliary" tuberculosis. Miliary TB may infect any number of organs, including the lungs, liver, and spleen. Miliary tuberculosis is present in about 2% of all reported cases of tuberculosis and accounts for up to 20% of all extra-pulmonary tuberculosis cases.

Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI) is when a person is infected with Mycobacterium tuberculosis, but does not have active tuberculosis (TB). Active tuberculosis can be contagious while latent tuberculosis is not, and it is therefore not possible to get TB from someone with latent tuberculosis. The main risk is that approximately 10% of these people will go on to develop active tuberculosis. This is particularly true, and there is added risk, in particular situations such as medication that suppresses the immune system or advancing age.

Interferon-gamma release assays (IGRAs) are diagnostic tools for latent tuberculosis infection (LTBI). They are surrogate markers of Mycobacterium tuberculosis infection and indicate a cellular immune response to M. tuberculosis if the latter is present.

<span class="mw-page-title-main">History of tuberculosis</span> Aspect of history

The history of tuberculosis encompasses the origins of the disease, tuberculosis (TB) through to the vaccines and treatments methods developed to contain and mitigate its impact.

The antibodies from lymphocyte secretions (ALS) assay is an immunological assay to detect active diseases like tuberculosis, cholera, typhoid etc. Recently, ALS assay nods the scientific community as it is rapidly used for diagnosis of Tuberculosis. The principle is based on the secretion of antibody from in vivo activated plasma B cells found in blood circulation for a short period of time in response to TB-antigens during active TB infection rather than latent TB infection.

<span class="mw-page-title-main">Infectious diseases (medical specialty)</span> Medical specialty dealing with the diagnosis, control and treatment of infections

Infectious diseases or ID, also known as infectiology, is a medical specialty dealing with the diagnosis and treatment of infections. An infectious diseases specialist's practice consists of managing nosocomial (healthcare-acquired) infections or community-acquired infections. An ID specialist investigates and determines the cause of a disease. Once the cause is known, an ID specialist can then run various tests to determine the best drug to treat the disease. While infectious diseases have always been around, the infectious disease specialty did not exist until the late 1900s after scientists and physicians in the 19th century paved the way with research on the sources of infectious disease and the development of vaccines.

<span class="mw-page-title-main">National Tuberculosis Institute</span> Indian Government institute

The National Tuberculosis Institute (NTIB) is a Government of India institute, under the Directorate General of Health Services, Ministry of Health and Family Welfare, dedicated to advanced research on Tuberculosis. The Institute is located along Bellary Road, in Bengaluru, Karnataka state, India.

References

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  2. 1 2 3 4 5 6 "Tuberculin Skin Testing". www.cdc.gov. Archived from the original on 9 January 2017. Retrieved 8 January 2017.
  3. 1 2 Comstock GW (2013). "Tuberculosis". In Evans AS (ed.). Bacterial Infections of Humans: Epidemiology and Control. Springer. p. 605. ISBN   9781475711400. Archived from the original on 2017-01-09.
  4. ↑ Tyagi JS (2006-09-01). "The timeless legacy of Robert Koch". Resonance. 11 (9): 20–28. doi:10.1007/BF02834330. ISSN   0973-712X. S2CID   82004821.
  5. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. 1 2 3 4 5 6 Huebner RE, Schein MF, Bass JB (December 1993). "The tuberculin skin test". Clinical Infectious Diseases. 17 (6): 968–975. doi:10.1093/clinids/17.6.968. JSTOR   4457498. PMID   8110954.
  7. 1 2 National Conference on the Prevention of Destitution (1911: London); London School of Hygiene and Tropical Medicine (1911). Report of the proceedings of the public health section [of the National Conference...], held at the Caxton Hall, Westminster, on May 30th and 31st, and June 1st and 2nd, 1911 [electronic resource]. London School of Hygiene & Tropical Medicine Library & Archives Service. London : P.S. King & Son.{{cite book}}: CS1 maint: numeric names: authors list (link)
  8. ↑ Grotjahn A (1932). Erlebtes und Erstrebtes: Erinnerungen eines sozialistischen Arztes. Berlin: Herbig. p. 51.
  9. 1 2 Vasold M, Koch R (2002). Robert Koch: der Entdecker von Krankheitserregern ; [eine Biographie]. Heidelberg: Spektrum der Wissenschaft Verlagsges. pp. 80–81. ISBN   978-3-936278-21-7.
  10. 1 2 3 4 5 Gradmann C (2009). Laboratory Disease: Robert Koch's Medical Bacteriology. Baltimore: Johns Hopkins University Press. ISBN   978-0-8018-9313-1.
  11. ↑ Gradmann C (June 2008). "Locating therapeutic vaccines in nineteenth-century history". Science in Context. 21 (2): 145–160. doi:10.1017/S026988970800166X. PMID   18831134. S2CID   7523937.
  12. ↑ Bäumler E (1989). Farben, Formeln, Forscher. Hoechst und die Geschichte der industriellen Chemie in Deutschland. München and Zürich: Piper. p. 67.
  13. 1 2 Snider DE (March 1982). "The tuberculin skin test". The American Review of Respiratory Disease. 125 (3 Pt 2): 108–118. doi:10.1164/arrd.1982.125.3P2.108 (inactive 31 January 2024). PMID   7041719.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
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