LEPROSY & LYME DISEASE Discovered in 1873 by Dr G Armauer Hansen. Leprosy is also called Hansen's disease. leprosy which affects the nervous system, the skin, the eyes and the upper respiratory tract of a human. Leprosy has been recognized since biblical times. Leprosy affects 12-15 million people worldwide. In thirteenth century there were about 200 leper hospitals By fifteenth century it was no longer endemic in England. Now leprosy is rare in the UK and USA. Mainly people who have a weakened immune system get infected. It can be passed on by coughing, sneezing or by through open skin to skin contact. It usually infects children aged 10-14 and adults aged 35-44. Causative agent: Mycobacterium leprae There is no animal reservoir Mode of transmission: it is directly related to overcrowding and poor hygiene. Infection is acquired by prolonged contact with patients with lepromatous leprosy. The organism is discharged in large numbers in nasal secretions and from skin lesions. In United States, leprosy occurs primarily in Texas, Louisiana, California & Hawaii. They are Gram positive bacilli. It can be stained by Ziehl-Neelsen staining, the acid fast bacilli are arranged singly, in parallel bundles (like rolls of cigarettes). Cultivation: M. leprae cannot be grown in artificial culture media. Animal models have been used for experimental infection with M. leprae –foot pad of mouse, Nine – banded armadillos. The generation time is found to be 12 -13 days. The bacillus Mycobacterium leprae, is a slow growing organism with a preference for cooler temperatures. Therefore, the skin, the nose, the ear lobes, certain peripheral nerves and the slightly cooler anterior part of the eye are, in particular, affected by leprosy. Incubation time is about 5 years, but may be longer. The photograph on the right shows nasal discharge containing many red-stained bacilli. Multibacillary leprosy patients develop ulcers in the nasal septum, with heavy loads of M. leprae. A septum perforation finally causes the collapse of the nose in such patients. Virulence properties: Cell wall of the bacilli is made up of – four layers The outer most layer is composed of mycosides- a major component is the phenolic glycolipid – 1 (PGL-1). This protects the bacilli from host cell enzyme and suppresses cell mediated immunity. Pathogenesis: The organism replicates intracellularly, typically within skin histocytes, endothelial cells and the Schwann cells of nerves. There are two distinct forms of leprosy- 1. Tuberculoid leprosy 2. Lepromatous leprosy There are several intermediate forms between the two extremes How do we diagnose it? How the pain is caused- When a person with leprosy So he keeps walking until the blister gets a blister, it does not hurt. bursts and becomes infected. Still without pain, the infection At this time the bone is destroyed gets deeper and attacks the and the foot becomes more and bone. more deformed. Clinical disease classification Based on number of lesions & bacilli in lesions: Paucibacillary leprosy- no bacilli in lesion (TT,BT) Multibacillary leprosy – bacilli present in lesions (LL, BL) Ridley Jopling‘s classification based on immune status (Lepromine test) & histopathology Indeterminate, Tuberculoid, BT, BL, Lepromatous Ridley- Jopling Classification 18 19 Clinical presentation: Indeterminant type: early unstable tissue reaction with mild transient tissue lesion. Often resembling maculo-anaesthetic patches. Lesions heal spontaneously or may progress to TT or LL type. In tuberculoid leprosy- Disease occurs when the cell mediated immune response is partially effective Lesions are characterized by blotchy red lesions with anesthetic areas on face, trunk and extremities. Lesions are solitary or few in number. Lesions have a raised, erythematous margin and a flat center. Nerve damage due to the cell mediated immune response causes a loss of sensation to touch, temperature, and pain within the lesion Granulomas containing giant cells are formed. A skin biopsy reveals many lymphocytic and epithelial cells, but no AFB. The lepromin test is +ve In tuberculoid leprosy the organisms are much more sparse but characteristic granuloma form in the dermis. Hypopigmented Macule Lesions on the face in Tuberculoid Leprosy Tuberculoid Lesion 2. Lepromatous leprosy: The disease occurs when there is defective cell mediated immunity against the organism May involve all areas of the skin and lesions have a waxy, nodular appearance. There is destruction of cutaneous nerves. The skin may thicken and fold. Foamy histiocytes are seen. There is a loss of eyebrows and eyelashes There may be destruction of the nasal septum and the nasal mucosa is loaded with organisms. The skin and mucous membrane lesions contain large number of organism. The lepromin test is -ve Lepromatous leprosy: Loss of Eyebrows/Eyelashes Arm Nodules in Lepromatous Leprosy symmetrical enlargement of the peripheral nerves. Active, Neglected Nodulous Lepromatous Leprosy Lesions on Face Leprosy-Classic Facial Appearance: Patient with chronic M Leprae infection that has led to collapse of nasal septum and subsequent development of classic "Leonine Facies." Patient has lost digits of hand secondary to leprosy as well. Damage Due to Secondary Infection: Deformed Foot and Leg Intermediate forms: There is a hypopigmented macule There may or may not be sensory loss within the macule The macule may completely resolve Differences between LL &TL Feature LL TL Bacilli in lesion numerous Scanty / absent CMI deficient Adequate Lepromin test negative Positive Infectivity Highly infectious Non infectious Mycobacterial ab detected Not detected Prognosis poor good Histopathology Tuberculoid - epithelioid granulomas with scarce or no bacilli. Lepromatous hemisphere, granulomas containing modified macrophages called lepra cells, with numerous bacilli seen. In borderline leprosy, both types of granulomas may coexist (epithelioid or lepra cells). LEPROMIN TEST Intradermal delayed type Hypersensitivity test to study the CMI in leprosy (Mitsuda in 1919) Antigens for the test Bacillary lepromin – purified bacterial components from foot pad of mice or armedillos Uses It is not a diagnostic test Disease classification Prognosis assessment Assessment of immune status of individual. Lepromin positive indicates resistance to infection. After the onset of therapy, patients with lepromatous leprosy often develop a Reactionary state - Erythema nodosum leprosum (ENL) This is an antibody mediated reaction in which immune complexes are formed It is characterized by painful, erythematous nodules. It is seen mainly along the extensor surfaces of the tibia and ulna; neuritis; and uveitis. Erythema nodosum leprosum Laboratory diagnosis: Specimen collected: skin biopsy or nasal scrapings Acid fast stain- is done to demonstrate the bacilli. Lipid laden macrophages called ―foam cells‖ containing acid fast bacilli are seen. In tuberculoid form the appearance of typical granuloma is sufficient for diagnosis. Skin smears 39 Cigar bundle appearance 40 Animal inoculation 9 banded Armadillo Foot pad of mice Treatment: Dapsone (diamino diphenyl sulfone) is given. Now combination therapy is recommended. e.g. Dapsone, rifampin and clofazimine for lepromatous leprosy Dapsone and rifampin for tuberculoid form. Treatment is given for at least 2 years. Thalidomide is the treatment of choice for ENL reactions. Other Mycobacterial skin infections: Mycobacterium marinum these prefer cooler tempt. Mycobacterium ulcerans & cause skin infections M. marinum is associated with water and marine organisms. Human infections follow trauma, often minor such as a graze acquired while climbing out of swimming pool or while cleaning acquarium. Incubation period is 2-8 wks. Initial lesion appears as small papules, which may enlarge and ulcerate. The lesions are granulomas hence the name ‗swimming pool granuloma‘ or ‗fish-tank granuloma‘. M. ulcerans cause chronic painless cutaneous ulcers known as ‗Buruli ulcers‘. Fish tank granuloma - Borrelia species are loosely coiled, motile spirochetes that stain readily with Giemsa and Sliver stain. Observed by darkfield microscopy. They can be cultured in bacteriologic media containing serum or tissue extracts. They are transmitted by arhtropods They cause two major diseases- Lyme disease Relapsing fever General Considerations The syndrome of relapsing fever consists of two clinical entities: Epidemic relapsing fever caused by Borrelia recurrentis (LBRF) and transmitted by the human body louse and Endemic relapsing fever caused by Borrelia hermsii and other spp. (TBRF) and transmitted by soft ticks (Ornithodorous). Essentials of Diagnosis of relapsing fever: The most common presentation is fever with rash, headache, shaking chills, myalgias, arthralgias, and during the acute phase hepatosplenomegaly. Louse-borne relapsing fever (LBRF) is epidemic, caused by B. recurrentis, and characterized by one or two relapses. Tick-borne relapsing fever (TBRF) is endemic, caused by Borrelia hermsii & several Borrelia species, and characterized by multiple clinical relapses. Organisms can be visualized in blood smears of febrile patients, unlike other spirochetal pathogens, using dark-field microscopy or Giemsa or Wright stains. Helical (3-10 spirals) spirochetes, motile (flagella). Weil-Felix reaction: Proteus OX-K agglutinin titers are elevated (this is more common in LBRF). LYME DISEASE Essentials of Diagnosis of lyme disease Most common in the northeastern, upper midwestern, and western parts of the United States. Borrelia burgdorferi is the longest (20-30 µm) and narrowest (0.2-0.3 µm) spirochete member of the Borrelia genus and has the fewest flagella (7-11). Erythema migrans (EM) is a red expanding lesion with central clearing that is commonly seen during the early stage of Lyme disease. The most common systems affected are the skin (EM), the joints (arthritis), the CNS (facial palsy), and the heart (conduction defects). Serology is not standardized; it is insensitive in early infection and does not distinguish active from inactive infection. Grows in Barbour-Stoenner-Kelly medium from skin biopsy and other specimens. Polymerase chain reaction (PCR) can be useful in synovial-fluid analysis. It has limited value with blood, CSF, and urine. What is Lyme disease? Most common tick/insect-borne disease in the U.S. A disease that can cause skin, joint, heart and nervous system problems. Lyme disease can affect people of all ages. Named after the town of Lyme, Connecticut where it was first described in 1976. In US the regions primarily affected are- states along the North Atlantic seaboard; the northern Midwestern states, and the West coast- California. 80% cases occurred in 4 states have been from- New York, Connecticut, Pennsylvania, & New Jersey. General Considerations Lyme disease is a tick-borne illness caused by the spirochete B. burgdorferi. Lyme disease can be divided into Stage 1: Early disease (EM) Stage 2: Disseminated infection Stage 3: Late disease (persistent infection). The first stage involves the skin, followed by stages 2 and 3, which often affect the skin, joints, CNS, and heart. Epidemiology. Lyme disease is the most common vector-borne infection in the United States. It is transmitted by ticks from the genus Ixodes. The Ixodes tick goes through a 2-year life cycle that is composed of three stages: larva, nymph, and adult. Tick larvae acquire the spirochete via a blood meal from an infected host. Both the nymph and female adult infect humans. A tick must be attached for at least 24 h to transmit the spirochete. Ixodes ticks in the northeastern and midwestern United States belong to the Ixodes dammini (scapularis) species In the western United States to Ixodes pacificus In Europe to Ixodes ricinus In Asia to Ixodes persulcatus. The main reservoir of the organism consists of small mammals, especially the white – footed mouse, upon which the nymph feeds. Deer, horses, dogs, and other larger mammals are an obligatory host in the tick‘s lifecycle but are not an important reservoir of the organism. Most cases have their onset during summer and occur in association with hiking, camping, and residence in wooded, rural, or coastal areas. Ticks that cause Lyme disease Black-legged (or deer) tick: Transmits Lyme disease to humans. Found in north-central and northeastern U.S. Lone star tick: Found in Texas and has been known to transmit Lyme disease. Rocky Mountain tick: Can transmit Lyme disease as well as Rocky Mountain spotted fever. Ticks that cause Lyme disease Lone Star Tick (Amblyomma americanum) Black-legged Tick (Ixodes scapularis) Rocky Mountain Tick (Dermacentor andersoni ) Microbiology.: B. burgdorferi is the longest (20-30 µm) and narrowest (0.2- 0.3 µm), and has the fewest flagella (7-11). This organism can be grown from skin biopsy and other specimens on an artificial medium called Barbour- Stoenner-Kelly at 33°C. The B. burgdorferi surface membrane is studded with lipoproteins called outer-surface proteins (OSPs) A, B, C, D, E, and F. Other prominent antigens include flagellar protein heat shock protein protoplasmic cylinder antigen B. burgdorferi is capable of altering its surface lipoproteins by recombining gene cassettes in a manner that resembles the mechanism of antigenic variation among the relapsing fever borreliae. The antigenic variability seen among different isolates has important implications for serologic tests and vaccine development. In the United States, most strains belong to the genomic group B. burgdorferi sensu stricto In Europe most strains belong to the groups known as B. garinii and B. afzelii. Pathogenesis: After inoculation in the skin, B. burgdorferi replicates within the dermis producing EM and spreads hematogenously to other organs. The organism has tropism for the skin, joints, heart and CNS. A rise in immunoglobulin M (IgM) is detected within 2-3 weeks after the onset of infection. An increase in IgG and IgA is established after 2-3 months of infection. Host genetic factors may determine the likelihood of tissue damage; for example, patients with human leukocyte antigens DR4 and DR2 may be more susceptible to chronic arthritis. Lyme Disease: Signs and Symptoms Stages of Lyme disease: Stage 1 (Early stage) – 3 to 30 days after bite. Flu-like symptoms develop within 7 – 14 days. Symptoms include fatigue, headache, fever and chills, muscle and joint pain, nausea, vomiting, dizziness and, a non-productive cough. Skin lesion(s) may appear as a small red circular rash around the bite and expand. Secondary skin rashes appear in nearly 80% of individuals with Lyme disease. Lyme Disease – Skin Rash Multiple Erythema Migrans (Skin rash) Lyme Disease – Skin Rash Multiple Erythema Migrans (Skin rash) Stage II– May occur weeks or months after the onset of Lyme disease. Cardiac and neurologic involvement predominates. Myocarditis with various forms of heart block occurs. Acute (aspetic) meningitis and cranial neurophathies also occur – like seventh palsy (Bell‘s palsy) are prominent during this stage. In Stage 3: Arthritis usually of large joints e.g. Knees, is characteristic findings. Chronic progressive central nervous system disease also occurs. What are the signs of Lyme disease? Rash May look like a ―bull‘s eye‖ or a ―target‖ Sore muscles Very tired Swollen joints Sometimes it can be very bad 68 Diagnosing Lyme Disease Notify a doctor if you become ill after being bitten by a tick. A diagnosis will be made based on clinical signs and symptoms and the results of a blood test. Diagnosis is done by serological tests by ELIZA: detecting IgM or rising titer of IgG antibody Indirect Immunofluorescence test. IgM is detectable 2 weeks after infection and peaks 3-6 weeks. A positive test result should be confirmed by Western Blot analysis. Detection of spirochetal DNA by PCR is useful in synovial fluid (75-85% of sensitivity). However, the sensitivity of PCR in CSF, blood, or urine samples has not been well established. Prevent Lyme Disease Check for ticks daily Avoid tick areas Cover up with light colored clothing + tuck pants in socks! Make your yard safer—create a dry path between woods Before and your yard. Use bug spray After 71 Pets can get Lyme Disease, too. Check your pet for ticks after it has been outside. There are collars, sprays, powders, and other treatments to stop ticks from biting your pet. Ask your veterinarian for advice on protecting your pet from tick bites. 73 Other facts Lyme disease cannot be transmitted person-to-person. People being treated with antibiotics for Lyme disease should not donate blood. Scientists have found that the Lyme disease bacteria can live in blood stored for donation. You cannot get Lyme disease from eating venison or squirrel meat. Differential Diagnosis Lyme disease mimics many different diseases. The EM lesion may be confused with streptococcal cellulitis, erythema multiforme (the latter lesions tend to be smaller, urticarial, or vesicular and may occur on mucosal surfaces), and erythema marginatum (these lesions are smaller and migrate rapidly in minutes to hours). Lyme arthritis can be distinguished from other rheumatoid diseases, such as acute rheumatic fever, based on the EM lesion and the brief episode of synovitis. The chronic form of Lyme arthritis may resemble pauciarticular juvenile rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome, and reactive arthritis caused by members of the Salmonella, Shigella, Campylobacter, and Yersinia genera. This form of arthritis may also be associated with rubella, hepatitis B, or echoviruses. The aseptic meningitis in Lyme disease may resemble enteroviral, leptospiral, or early tuberculous meningitis. Treatment: Antibiotic therapy Doxycycline and amoxicillin are used for two to four weeks in early cases. For more severe forms or late-stage disease, treatment with intravenous ceftriaxone or penicillin is more effective. A recombinant vaccine containing outer surface protein (OspA) of the organism is available. It is recommended for people living in endemic area. Remember, 77 You can prevent Lyme Disease by Keeping Ticks off your Body! 2. Each of the following statements concerning Mycobacterium leprae is correct EXCEPT: A) In lepromatous leprosy, large numbers of organisms are usually seen in acid fast stained smears. B) The organism will grow on bacteriologic media in 3-6 weeks. C) Prolonged therapy (9 months or longer) is required to prevent recurrence. D) Skin tests for delayed hypersensitivity are useful diagnostically. 4.Which one of the following statement is TRUE about lepromatous leprosy A. neuropathy occurs before skin lesions B. skin lesions are typically anaesthetic C. skin lesions are typically symmetrical D. the lepromin test is positive 5. You observe a 40-year-old man begging on a street in a town in India. He has clawing of the fourth and fifth digits with loss of distal parts of the digits of both hands, strongly suggesting leprosy. The causative agent of this disease A) is susceptible to isoniazid and rifampin B) grows in parts of the body that are cooler than 37°C C) can be cultured in the laboratory using Middlebrook 7H11 medium D) is seen in high numbers in biopsies of tuberculoid leprosy lesions E) commonly infects people in Texas, because armadillos are hosts of Mycobacterium leprae. Mims: 2nd edition- chapter 23 Levinson : 7th edition-chapter 48 Jawetz: 23rd edition-chapter 45.
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