Cutaneous Tuberculosis Disease: Challenges of Treatment

Cutaneous Tuberculosis Disease: Challenges of Treatment CHAPTER -1 CUTANEOUS TUBERCULOSIS INTRODUCTION: In this innovative world while progress in medicine has helped up to deal with many diseases Tuberculosis and Cutaneous Tuberculosis is still a challenge for doctors. A resurgence of Cutaneous Tuberculosis in areas of high HIV incidence, drug resistant present in patients with pulmonary tuberculosis and in immunosupressed patients are the main challenges for clinicians. (6) Cutaneous TB is caused by Mycobacterium tuberculosis, Mycobacterium bovis, Bacillus Calmette-Guerin (BCG) vaccinations and the Tuberculids whose pathogenesis is poorly understood. Cutaneous TB is very variable in its clinical presentation, significance prognosis. Factors which effect on variability are: The pathogenesity of the organism involved. The Previous treatment given. The Immune status of the patients which can be related to the presence of Acquired Immunodeficiency Syndrome (AIDS) or Immunosuppressive therapy. The Port of infection. Any Local factors like, the recent Trauma, the lymphatic drainage, the vascularity of area and the proximity to lymph nodes). PREVALANCE: Thirty years ago it was assumed world wide that tuberculosis would be eradicated in the developed countries, as its incidence increased only on by average 6 % in the United States and 10% in Europe between the years 1953 and 1985. However, in 1983 tuberculosis was declared a global emergency by the world Health Organization because of a sharp increase in incidence. (9) Among infectious diseases, Tuberculosis is an important cause of death. Tuberculosis was responsible for 6% of deaths worldwide. Global prevalence of TB currently is greater than 32%. More than 50% of new patient occurrences were in 5 Asian countries, i.e. India (largest worldwide patient load), China, Indonesia, Bangladesh, and Pakistan(ref ?) The current global burden of Tuberculosis is mind boggling. In 1997, the incidence of new Tuberculosis patients approached 8 million in addition to more than 16 million patients already diagnosed. Around 2 million people died of Tuberculosis in 1997 with a global fatality rate of 23%, fatality rates exceed 50% in some African countries in which there is a high HIV incidence. Approximately 8% of tuberculosis patients are HIV infected. (2) Prevalence of tuberculosis infection in 1985, 1995 and 2005 (10) Prevalence of tuberculosis has increased between 1985 and 2005.According to the World Health Organization case reports statistics, in 1985 there were around 3 million patients of tuberculosis of all types with the highest no of cases in Asia and Africa. In Asia the highest numbers of cases were in India, Pakistan, China, Philippines, Bangladesh, Afghanistan and Vietnam. In Africa the highest number of case were in Ethiopia, Nigeria, South Africa, Congo, Morocco and Tanzania. (10) During the last two decades the number of cases increased all over the world. In 1995 the total number of cases increased to 4.6 million and in 2005 to 7.5 million worldwide. In Asia in 2005 the highest numbers of cases were in India, China Pakistan. In Africa in 2005 the highest numbers of cases were in South Africa, Ethiopia Congo. (10) There is an increasing rate of tuberculosis in the developing countries is approximately 500/100,000/y. Great alarm has been the progressive increase in numbers of strains of tuberculosis that are resistant to antibiotics. Since 1984, that incidence of extra pulmonary tuberculosis has increased at even faster rate than that of pulmonary tuberculosis and is considered to be a diagnostic criterion in the case definition for AIDS. Because immunocompromised individual are at increased risk of extra pulmonary tuberculosis, so dermatologist are renewing their historic role in the diagnosis of cutaneous lesions of tuberculosis. (11) EPIDEMIOLOGY: Epidemiological analysis is used to detect the changing trends in the incidence and prevalence of mycobacterial disease in the community. The main objectives of these methods are to determine the natural behavior of disease and factors which affect his behavior and to calculate future trend if possible to help in the design of any control measures and to assess the usefulness of these measure.(8) Even though 1 of 3 individuals on this planet is infected with tubercle bacillus, the incidence of Cutaneous TB appears low. In areas such as India or China where TB prevalence is high, cutaneous manifestations of TB (overt infection or Tuberculids) are found in less than 0.1% of persons seen in dermatology clinics. The frequency of patients with Cutaneous Tuberculosis seen between 1980 and 1993 in a hospital dermatology clinic in Madrid was 16 per 10,304 which was 0.14%. In a ten year retrospective survey of patients seen in governmental dermatology clinics in Hong Kong between 1983 and 1992, the detected incidence of Cutaneous Tuberculosis among patients was 179 per 267,089 which was 0.07%. Among patients with Cutaneous Tuberculosis only15% had classic Cutaneous Tuberculosis and 85% had tuberculids. In that classical cutaneous tuberculosis approximately 5% had lupus vulgaris, 5% had Tuberculosis Verrucosa cutis and 5% had scrofuloderma. (2) In a tertiary-care hospital in northern India, 0.1% of dermatology patients seen between 1975 and 1995 had Cutaneous Tuberculosis. Lupus vulgaris was the most common manifestation around 55%, followed by scrofuloderma 27%, TB Verrucosa cutis 6%, tuberculous gumma 5%, and tuberculids occurred in 7%. (2) FREQUENCY: USA: In the United States, tuberculosis cases decreased from 84,304 cases in 1953, when national reporting was first began, to 22,201 in 1985.   This represented fairly steady decline of about 5.8% per year. However, the turn down in tuberculosis cases stopped in between 1985 and 1992. In 1992 the annual number of cases increased by 20% to 26,673 cases. (12) The increases were concentrated geographically in several states, with over 90% of the 14,871 cases in California, Florida, New Jersey, New York, and Texas and demographically tuberculosis occurred in racial and ethnic minorities, in people aged 25 to 44, males and in those born abroad. Especially troubling, and indicative of increasing transmission of new infections, was a 36% increase in tuberculosis among children 4 years old or younger. Tuberculosis appears to be on the decline again in the United States as numbers with only 14,871 cases in 2003. (12) Reported tuberculosis cases in United States, 1982-2002 (12) The percentage of Tuberculosis patients who were born abroad individuals was 42%. People born in Mexico, the Philippines, and Vietnam account for one half of born abroad Tuberculosis patients in the United States. The Tuberculosis rate among born abroad people was 4 to 6 times higher than for US-born peoples. Minimum estimates of the proportion of TB patients with coincident HIV infection were approximately 10-15%. Among people aged 25-44 years, this proportion increased to 20-30%. (12) The fundamental origin of this new Tuberculosis epidemic in troubled states reflects a minimum of four major factors including (1) the involvement of Tuberculosis with the HIV epidemic, (2) the increased migration from countries where Tuberculosis is common, (3) the spread of Tuberculosis in congested settings (health-care facilities, prisons, homeless shelters), and (4) the worsening of the basic health-care infrastructure. (2) Molecular typing of Mycobacterium tuberculosis isolates in the United States in a restriction fragment-length polymorphism study suggests more than one third of new patient incidence results from people-to-people transmission, and the remainder result from reactivation of latent infection. Approximately 1 of 13 Mycobacterium tuberculosis isolates currently shows a form of drug resistance. (2) The modern introduction of biological agents that block tumor necrosis factor-alpha in the treatment of rheumatoid arthritis, psoriasis, and several other autoimmune disorders has additional raised about the necessity of the identification of patients with latent Tuberculosis. At present, several hundred cases of Tuberculosis have been reported in patients who receive these tumor necrosis factor-alpha antagonists. (2) HISTORY: Tuberculosis has an ancestry which can be traced to the earliest history of mankind. It was recognized as a contagious disease by the time of Hippocrates and Aristotle in 350 BC. Signs of skeletal Tuberculosis were identified in Europe since Neolithic times and in ancient Egypt around 3700 BC in mummified bodies. Evidence of TB appears in Biblical scripture, in Chinese literature dating back to around 4000 BC, and in religious books in India around 2000 BC. (5) During1600s and 1800s tuberculosis was known ass the Great White Plague in Europe.   Other names for Tuberculosis were Phthisis which was from Greek term phthinein, meaning to waste away, scrofula which were used for swellings of the lymph nodes of the neck and consumption which were used as progressive wasting away of the body.(2) In 1826 Laennec first reported cutaneous tuberculosis which he called PROSECTOR WART. Following Laennec, Rokitansky and Virchow described the histological features in detail comparing them to those of visceral tuberculosis. (6) The Incidence of TB increased with population density and urban development so that by the Industrial Revolution in Europe in 1750, it was responsible for more than 25% of adult deaths. Indeed, in the early 20th century, TB was the leading cause of death in the United States. In 1882, a German biologist ROBERT KOCH presented his discovery of the organism that caused TB. NEIL FINSEN won the Nobel Prize in Medicine in 1903 for introducing UV light into the treatment of skin TB. (2) With the help of better living conditions and the introduction of the antibiotic streptomycin on 20th November 1944, the number of reported TB patients in the United States steadily declined around 126,000 TB patients in 1944, 84,000 in 1953, 22,000 in 1984, and 14,000 in 2004.(2) MODE OF TRANSMISSION: Tuberculosis is an airborne contagious disease that occurs after inhalation of infectious droplets expelled from patients with laryngeal or pulmonary Tuberculosis during coughing, sneezing, or speaking. Each cough can generate more than 3000 infectious droplets. Droplets are so small around 1 to 5 micro meter, that they remain airborne for hours. (2) The likelihood that disease transmission will occur depends upon the infectiousness of the tuberculous patient, the environment in which exposure takes place, and the duration of exposure. Roughly 20% of people in the infected household contact develop infection. Micro epidemics have occurred in closed environments such as transcontinental flights and submarines. Tuberculin sensitivity develops 2 to 10 weeks after infection and usually is lifetime. (2) Because Tuberculosis induces a powerful immune response, individuals with positive tuberculin reactions are at a considerably lower risk of acquiring new tuberculous infection. In HIV-infected individuals, active Tuberculosis is more likely to occur from reactivation of existing disease than from superinfection with a new mycobacterial strain. (2) Without treatment, an estimated 10% lifetimes possibility exists of developing active disease after tuberculous infection, 5% occurs within the first 2 years and 5% thereafter. An Increased risk of acquiring active disease occurs during HIV infection, Intravenous drug abuse, diabetes mellitus, silicosis, immunosuppressive therapy, cancer of the head and neck, hematological malignancies, end-stage renal disease, intestinal bypass surgery or gastrectomy, chronic malabsorption syndromes and low body weight. Infants younger than two years are associated with increased risk. (2) 1) DIRECT INHALATION: The most common mode of entry via portal in to the lungs usually resulting from the Inhalation of airborne droplets containing a few bacilli, expectorated by individuals with â€Å"open† pulmonary disease.(8) 2) INDIRECT INHALATION: A) Ingestion: Less often bacilli may be swallowed and lodge in to the tonsil or in the wall of the intestine. These infections are chiefly related to the consumption of contaminated milk products. (8) 3) INOCULATION: Cutaneous tuberculosis manifestations depend upon the method of cutaneous inoculations, which may be exogenous that is from an out side source, may occur by autoinoculation, or may be by endogenous .Direct exogenous inoculation in an individual not previously infected with tuberculosis causes primary tuberculosis infection, will led to the tuberculous ‘chancre or to tuberculosis Verrucosa cutis depending upon the immune status of the patient. Another example of exogenous transmission is lupus vulgaris at the site of BCG vaccination. (9) Endogenous transmission can occur by continuous extension of tuberculous process underlying the skin as in scrofuloderma, by the way of lymphatic as in lupus vulgaris and by hematogenous spread as in acute miliary tuberculosis or lupus vulgaris. (9) Infrequent mode of transmission is direct implantation in to the skin through cuts and abrasions. These troubles usually in persons, working with infected material or cultures of tubercle bacilli. These skin lesions were called as â€Å"Prosector warts† (8) CLASSIFFICATION OF CUTANEOUS TUBERCUCLOSIS: Cutaneous tuberculosis clinical manifestations comprise a considerable number of skin changes, usually sub classified in to more or less distinct disease forms. Classification depends on morphology more recently mode of transmission or the immunological state of host, but none of them satisfies completely. 1)INOCCULATION TUBERCUCLOSIS (Exogenous Source) Tuberculosis chancre Warty tuberculosis(Verruca cutis) Lupus vulgaris(some) 2) SECONDARY TUBERCULOSIS (Endogenous source) A) Contiguous spread Scrofuloderma B) Auto-inoculation Orifical tuberculosis 3)HAEMATOGENOUS TUBERCULOSIS Acute miliary tuberculosis Lupus vulgaris(some) Tuberculous gumma 4)ERUPTIVE TUBERCUCLOSIS (Tuberculids) A) Micropapular Lichen scrofulosorum B) Papular Papular/Papulonecrrotic TB C) Nodular Erythema induratum(Bazin) Nodular Tuberculids (CLASSIFICATION OF TUBERCULOSIS, MODIFIED FROM beyt et al) (4) CHAPTER-2 CLASSIFICATION OF MYCOBACTERIA: Tuberculosis is an infectious disease which is caused by the Mycobacterium species. Mycobacteria are acid fast, non-sporulating, non-motile weakly gram positive organisms. TEM micrograph of Mycobacterium tuberculosis Table 3: Kingdom Bacteria Phylum Actinobacteria Order Actinomycetales Suborder Corynebacterineae Family Mycobacteriaceae Genus Mycobacterium Scientific classification by Lehmann Neumann. (3) In 1950s Runyon classified the atypical mycobacteria according to their ability to form pigment, their rate of growth colony characteristics. This classification also includes obligate human pathogens and facultative human pathogens. (1) Today more then 60 species of mycobacteria are identified. Around 41 of these were included in the approved lists of bacterial names in 1980. (9) 30 species of mycobacterium are known that can cause disease in humans. The most common causative organism includes: Mycobacterium tuberculosis Mycobacterium Leprae. Atypical mycobacteria. The species which produce disease in tuberculosis primary complex include: Mycobacterium tuberculosis. Mycobacterium Bovis. Mycobacterium Africanum. Sometimes Bacillus Calmette Guerin (BCG) may also cause disease. (1) MEDICAL CLASSIFICATION: For the purpose of diagnosis treatment mycobacteria can be classified in several major groups. Mycobacterium tuberculosis complex, which can cause tuberculosis by the pathogens Mycobacterium tuberculosis, M Bovis, M Africanum M microti. Mycobacterium Leprae, which causes Hansens disease. Nontuberculous mycobacteria are the mycobacteria which can cause pulmonary disease, lymphadenitis, and skin disease disseminated disease. SLOW GROWING MYCOBACTERIA RUNYON GROUP 1)Obligate human pathogens M. tuberculosis-bovis group including bacillus Calmette-Guerin(BCG) M Africanum (not included in runyon classification 2)Facultative Human pathogens M. kansasii I M. marinum I M. simiae I M. scrofulaceum II M. szulgai II M. gordanae II M. avium-intracellualr complex III M. haemophilum III M. Ulcerans III M. xenopi III 3) Nonpathogens M. flavescen II M. terrae complex III M. trivale III M. gastri III RAPIDLY GROWING MYCOBACTERIA 1))Facultative Human pathogens M. fortuitum I V M. chelonae I V M. abscessus I V 2) Nonpathogens M. smegmatis I V M. phlei I V M. vaccae I V others STAINING CHARACTERISTICS OF MYCOBACTERIA: Mycobacteria are aerobic, facultative, intracellular non-spore forming and non-motile curved rods measuring 0.2- 0.5 by 2-4 um. Mycolic acid rich long chain glycol lipids and phospholipoglycans, a mycocides present in the cell wall of mycobacteria protect them. (2) Mycobacteria do not gram stain readily but their most valuable staining characteristic is Acid Fastness. This ability retains carbol fuchin dye after washing with acid or alcohol occurs because of the high content of cell wall mycolic acids, fatty acids other lipids. Other staining methods used include Dietrele, auramine-Rhodamine and phenolic acridine orange stains. Nocardia rhodococcus, legionella dadei, isospora cryptosporidium also share acid fastness. (1) The Ziehl-Neelson acid-fast stain, while highly specific for mycobacteria, is relatively insensitive, and recognition requires at least 10,000 bacilli per mL; most clinical laboratories currently use a more sensitive auramine-rhodamine fluorescent stain (auramine O). Routine culture uses a nonselective egg medium called Lowenstein-Jensen or Middlebrook 7H10 and often requires more than 3-4 weeks to grow because of the 22-hour doubling time of mycobacterium tuberculosis. Radiometric broth culture, BACTEC radiometric system of clinical specimens significantly reduces time 10 to 14 d for mycobacterial recovery. DNA probes specific for mycobacterial ribosomal RNA categorize species of clinically significant isolates after recovery. In tissue, polymerase chain reaction (PCR) amplification techniques can be used to detect Mycobactereria tuberculosis-specific DNA sequences and thus, small numbers of mycobacteria in clinical specimens. (2) The cell wall of mycobacteria consist of: (3) Outer lipids Mycolic acid Polysaccharides(arabinoglactan) Peptideglycan Plasma membrane. Lipoarrabinomannan(LAM) Phosphatidylinositol mannoside. Cell wall skeleton. PATHOGENESIS: The most common site for Tuberculosis disease is lungs and 85% of TB patients present with pulmonary symptoms. The most common sites of extrapulmonary disease are mediastinal, retroperitoneal, and cervical lymph nodes, vertebral bodes, adrenals, meninges, and the GI tract. Pathology of these lesions is similar to those in the lung. Extrapulmonary TB can occur as part of a primary or late generalized infection or as a reactivation site that may, coexist with pulmonary reactivation. (2) Mycobacterium tuberculosis is an obligate pathogen. It is a slender aerobic rod, characterized by high lipid content. This lipid is responsible for resistance to phagocytosis. Identification of organism is easy in tuberculous chancre, scrofuloderma, orificial lesions and the miliary variant. This may be difficult to find or absent in lupus vulgaris, gummata and warty tuberculosis. The organism is highly resistant to drying to drying and therefore can retain infectivity by inoculation or contamination of minor wounds. (19) The reaction of the bacterium depends on: the size of inoculum. the virulence of organism. <