Studii și cercetări, Biology 19, Bistrița, p. 75-84
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LYME DISEASE - A VERY ACTUAL MEDICAL FACT Liana M. DEAC
Abstract. Lyme disease is a zoonotic, vector-borne disease transmitted by the Ixodes tick (Centers for Disease Control and Prevention. 2004). The causative agent is named after the researcher Willy Burgdorfer, who first isolated the bacterium - Borrelia burgdorferi in 1982. Lyme disease is a bacterial infection which imitates a variety of illnesses and its severity can vary from person to person. It is then caused by the bacterium Borrelia burgdorferi and is transmitted to humans through the bite of infected blacklegged ticks. The signs and symptoms of Lyme disease vary and usually affect more than one system. The skin, joints and nervous system are affected most often. Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. Lyme disease is diagnosed based on the symptoma of the erythema migrans which appeared after the possibility of exposure to infected ticks. Laboratory testing is helpful if used correctly and performed with validated methods. Most cases of Lyme disease can be treated successfully with a few weeks of antibiotics. Steps to prevent Lyme disease include using insect repellent, removing ticks promptly, applying pesticides, and reducing tick habitat. The best currently available method for preventing infection with B. burgdorferi and other Ixodes species–transmitted pathogens is to avoid exposure to vector ticks. For prevention of Lyme disease after a recognized tick bite, routine use of antimicrobial prophylaxis or serologic testing is not recommended. Antibiotics can cure most cases of Lyme disease. The sooner treatment begins, the quicker and more complete the recovery. If left untreated, infection can spread to joints, the heart, and the nervous system. Key words: Lyme disease, signs, treatment, prevention. Introduction The disease is named after the towns of Lyme and Old Lyme, Connecticut, US, where a number of cases were identified in 1975. Although it was known that Lyme disease was a tick-borne disease as far back as 1978, the cause of the disease remained a mystery until 1981, when B. burgdorferi was identified by Willy Burgdorfer. Lyme disease is the most common tickborne infection in both North America and Europe. In the United States, Lyme disease is caused by Borrelia burgdorferi, which is transmitted by the bite of the tick species of Ixodes.
Regional Public Health Center Cluj-Napoca, Romania, str. Louis Pasteur nr. 6, 400046, Cluj-Napoca. Coresponding author:
[email protected]
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Clinical manifestations most often involve the skin, joints, nervous system, and heart. Early cutaneous infection with B. burgdorferi is called erythema migrans, which is the most common clinical manifestation of Lyme disease. Extra cutaneous manifestations are less commonly seen than in earlier years.The best currently available method for preventing infection with B. burgdorferi and other Ixodes-transmitted infections is to avoid tick-infested areas. Doxycycline (100 mg twice per day), amoxicillin (500 mg 3 times per day), or cefuroxime axetil (500 mg twice per day) for 14 days (range for doxycycline, 10–21 days; range for amoxicillin or cefuroxime axetil, 14–21 days, is recommended for treatment of adult patients with early localized or early disseminated Lyme disease associated with erythema migrans in the absence of specific neurologic manifestations and ten days of therapy is sufficient if doxycycline is used. For adult patients with early Lyme disease and the acute neurologic manifestations of meningitis or radiculopathy, the use of ceftriaxone (2 g once per day intravenously for 14 days is very good. General informations concerning Lyme disease Epidemiology. Lyme disease is endemic in Northern Hemisphere temperate regions (figure1). It is common in the northeastern, Midwest and western United States (Centers for Disease Control and Prevention - CDC, 2004).
Fig. 1. Countries with reported Lyme disease cases
In Europe, Lyme disease is caused by infection with one or more pathogenic European genospecies of the spirochaete B. burgdorferi sensu lato, mainly transmitted by the tick Ixodes ricinus. In USA the transmission is because of the tick, Ixodes scapularis and Ixodes pacificus, but in Asia mainly by Ixodes persculatus. Today, Lyme disease is the most prevalent tick-borne illness in the United States and its incidence is growing on each year there (figure 2). Borrelia burgdorferi is predominant in North America, but also exists in Europe.
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Fig. 2. Incidence of Lyme Disease in the United States, 1991-2006
Lyme disease is the most common tick-borne disease in North America and Europe, and one of the fastest-growing infectious diseases in the United States (MMWR, 2005). Of cases reported to the United States CDC, the ratio of Lyme disease infection is 7.9 cases for every 100,000 persons. The number of reported cases of the disease has been increasing, as are endemic regions in North America. Lyme disease prevalence is comparable among males and females. A wide range of age groups is affected, though the number of cases is highest among 10–19-year-olds. For unknown reasons, Lyme disease is seven times more common among Asians (Centers for Disease Control and Prevention. 2004). Lyme disease etiology and its transmission. The etiology of Lyme disease is caused by a bacteria named Borrelia burgdorferi (figure 3). Bacterium, Borrelia burgdorferi is a spirochete that causes Lyme Disease (Stanek et Strole, 2003). Borrelia, like most spirochetes, does have an outer membrane that contains an LPS-like substance, an inner membrane, and a periplasmic space which contains a layer of peptidoglycan. Therefore, it has a Gram-negative bacterial type cell wall, despite its staining characteristics.
Fig. 3. Borrelia burgdorferi - dark field illumination
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The Borreliae causing Lyme disease are divided into several "genospecies", three of which have been firmly established and are well accepted: Borrelia burgdorferi sensu stricto; Borrelia garinii; Borrelia afzelii. Borrelia burgdorferi invades the blood and tissues of various infected mammals and birds. The natural reservoir for Borrelia burgdorferi is thought to be the whitefooted mouse. Ticks transfer the spirochetes to the white-tailed deer, humans, and other warm-blooded animals after a blood meal on an infected animal. In humans, dogs, and many other animals, infection with Borrelia burgdorferi results in the pathology of Lyme disease. The Lyme disease bacterium, Borrelia burgdorferi, is spread through the bite of infected ticks. Ixodes ricinus is an indigenous hard tick species having a wide geographical distribution and can be infected with B. burgdorferi. Ixodes ricinus ticks cover a wide geographic region in the EU from Portugal to Russia and from North Africa to Scandinavia. This wide geographical distribution entails that this tick species can survive under various environmental conditions. Ixodes ricinus is a three-host tick: larvae, nymphs and adults (figure 4), feed on different hosts where larvae and nymphs prefers small to medium-sized animals and adults tend to feed on largesized animals. This tick species feeds on a broad range of mammals, birds and reptiles and frequently bites humans. Ticks can attach to any part of the human body but are often found in hard-to-see areas such as the groin, armpits, and scalp. In most cases, the tick must be attached for 36-48 hours or more before the Lyme disease bacterium can be transmitted. Most humans are infected through the bites of immature ticks called nymphs. Nymphs are tiny (less than 2 mm) and difficult to see; they feed during the spring and summer months. Adult ticks can also transmit Lyme disease bacteria, but they are much larger and may be more likely to be discovered and removed before they have had time to transmit the bacteria.
Fig. 4. Ixodes: larva, nymph, adult male, adult female, by CDC
There is no evidence that Lyme disease is transmitted from person-toperson. Lyme disease is caused by the bacterium Borrelia burgdorferi. Deer ticks, which feed on the blood of animals and humans (MMWR, 2005), can harbor the bacteria and spread it when feeding (figure 5).
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Fig. 5. Lyme disease cycle
Lyme disease acquired during pregnancy may lead to infection of the placenta and possible stillbirth; however, no negative effects on the fetus have been found when the mother receives appropriate antibiotic treatment. There are no reports of Lyme disease transmission from breast milk. Although no cases of Lyme disease have been linked to blood transfusion, scientists have found that the Lyme disease bacteria can live in blood that is stored for donation. There is no credible evidence that Lyme disease can be transmitted through air, food, water, or from the bites of mosquitoes, flies, fleas, or lice. Signs and Symptoms of Lyme Disease. Early localized stage (3-30 days post-tick bite) Red, expanding rash called erythema migrans –EM (figure 6) Fatigue, chills, fever, headache, muscle and joint aches, and swollen lymph nodes Some people may get these general symptoms in addition to an EM rash, but in others, these general symptoms may be the only evidence of infection (Centers for Disease Control and Prevention. 2004).
Fig. 6. Erythema migrans – EM
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Second stage of the disease. Untreated, the infection may spread from the site of the bite to other parts of the body, producing an array of specific symptoms that may come and go, including: additional EM lesions in other areas of the body, facial or Bell's palsy with loss of muscle tone on one or both sides of the face (figure 7), severe headaches and neck stiffness due to meningitis; pain and swelling in the large joints, such as knees, shooting pains that may interfere with sleep, heart palpitations and dizziness due to changes in heartbeat (Centers for Disease Control and Prevention. 2004). Neurological symptoms. Lyme disease can also affect the nervous system, causing symptoms such as stiff neck and severe headache -meningitis, temporary paralysis of facial muscles as in Bell's palsy numbness, pain or weakness in the limbs, or poor coordination. More subtle changes such as memory loss, difficulty with concentration, and a change in mood or sleeping habits have also been associated with Lyme disease. People with these latter symptoms alone usually don't have Lyme disease as their cause. Nervous system abnormalities usually develop several weeks, months, or even years following an untreated infection. These symptoms often last for weeks or months and may recur. These features of Lyme disease usually start to resolve even before antibiotics are started. Patients with neurologic disease usually have a total return to normal function.
Fig. 7. Loss of muscle tone in Bell's palsy
Late disseminated stage (months-to-years post-tick bite).Approximately 60% of patients with untreated infection may begin to have intermittent bouts of arthritis, with severe joint pain and swelling (Steere et al., 1987). Arthritis. Large joints are most often affected, particularly the knees (figure 8), caused by Lyme disease manifests differently than other causes of arthritis and must be distinguished from arthralgias (pain, but not swelling, in joints). Up to 5% of untreated patients may develop chronic neurological complaints months to years after infection. These include shooting pains, numbness or tingling in the hands or feet, and problems with short-term memory (Centers for Disease Control and Prevention. 2004).
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Fig . 8 Pain and swelling in the knees
Heart problems. Fewer than one out of 10 Lyme disease patients develops heart problems, such as an irregular, slow heartbeat, which can be signaled by dizziness or shortness of breath (Allen et al., 2004). These symptoms rarely last more than a few days or weeks. Such heart abnormalities generally appear several weeks after infection, and usually begin to resolve even before treatment. Other symptoms. Less commonly, Lyme disease can result in eye inflammation and severe fatigue, although none of these problems is likely to appear without other Lyme disease symptoms being present (Marques, 2008). Diagnosis and Laboratory testing. Lyme disease is diagnosed based on: signs and symptoms and a history of possible exposure to infected blacklegged ticks. Erythema migrans is the only manifestation of Lyme disease in the United States that is sufficiently distinctive to allow clinical diagnosis in the absence of laboratory confirmation (Centers for Disease Control and Prevention. 2004, Wright, 2012). Laboratory blood tests are helpful if are used correctly and performed with validated methods. Laboratory tests are not recommended for patients who do not have symptoms typical of Lyme disease (MMWR, 2005, Steere et al., 2008). Just as it is important to correctly diagnose Lyme disease when a patient has it, it is important to avoid misdiagnosis and treatment of Lyme disease when the true cause of the illness is something else. When serologic testing is indicated, CDC recommends testing first with an enzyme-linked immunosorbent assay – ELISA, or an indirect fluorescent antibody (IFA) test, followed by a more specific Western immunoblot -WB test to corroborate equivocal or positive results obtained with the first test (Hunfeld et al., 2002). None of these tests is useful in the diagnosis of early stages of Lyme disease since a primary serum immune response is just beginning. Furthermore, these tests are associated with a high degree of cross-reactivity, since sera from patients with Rocky Mountain spotted fever, relapsing fever, mononucleosis, syphilis, and rheumatoid arthritis often test positive for Lyme disease. Patients with early disseminated or late-stage disease usually have strong serological
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reactivity. Antibodies may persist for months or years following successfully treated or untreated infection. Thus, seroreactivity alone cannot be used as a marker of active disease. Neither a positive serologic activity nor a history of previous Lyme disease assures that an individual has protective immunity (Auwaerter et al., 2004). Repeated infection with B. burgdorferi has been documented. New tests may be developed as alternatives to one or both steps of the two-step process. Before CDC will recommend new tests, their performance must be demonstrated to be equal to or better than the results of the existing procedure, and they must be FDA approved. Other Types of Laboratory Testing as some laboratories offer Lyme disease testing using assays whose accuracy and clinical usefulness have not been adequately established. Treatment. Antibiotic treatment is the central pillar in the management of Lyme disease. In vitro studies have shown that B. burgdorferi is highly susceptible to several antimicrobial drug classes, including tetracyclines, most penicillins, and many second- and third-generation cephalosporins (Hunfeld et al., 2002). The macrolides that have been systematically studied are less effective than the other antibiotic therapies. Patients treated with appropriate antibiotics in the early stages of Lyme disease usually recover rapidly and completely. Antibiotics commonly used for oral treatment include doxycycline, amoxicillin, or cefuroxime axetil. Patients with certain neurological or cardiac forms of illness may require intravenous treatment with drugs such as ceftriaxone or penicillin. For detailed recommendations on treatment, consult the 2006 Guidelines for treatment developed by the Infectious Diseases Society of America. The National Institutes of Health (NIH) has funded several studies on the treatment of Lyme disease which show that most patients recover when treated with a few weeks of antibiotics taken by mouth. Lingering symptoms after treatment (post-treatment Lyme disease syndrome) are still possible (PTLDS). Approximately 10-20% of patients with Lyme disease have symptoms that last months to years after treatment with antibiotics5. These symptoms can include muscle and joint pains, cognitive defects, sleep disturbance, or fatigue. The cause of these symptoms is not known, but there is no evidence that these symptoms are due to ongoing infection with B. burgdorferi. There is some evidence that PTLDS is caused by an autoimmune response, in which a person's immune system continues to respond, doing damage to the body’s tissues, even after the infection has been cleared. Studies have shown that continuing antibiotic therapy is not helpful and can be harmful for persons with PTLDS. The National Institutes of Health –NIH, has funded several studies on the treatment of Lyme disease which show that most patients recover when treated with a few weeks of antibiotics taken by mouth (Wormser et al., 2003).
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Prevention of Tick Bites. The best method for preventing infection with B. burgdorferi and other Ixodes-transmitted infections is to avoid tick-infested (MMWR, 2005). Frequent visual inspection of skin and clothes may help to identify ticks prior to attachment, thus allowing removal before infection can be transmitted. Attached ticks should be removed promptly, preferably with the aid of fine-tip forceps If a portion of the mouth parts of the tick remains embedded in the skin, only topical disinfection of the site is suggested, because attempts to remove this material can cause tissue damage and are unnecessary as the risk of Lyme disease is unaffected. Use of protective clothing (long-sleeved shirt tucked into pants and long pants tucked into socks) may interfere with tick attachment by increasing the time required for ticks to find exposed skin, thus facilitating their recognition and removal. Wearing light-colored clothing to provide a background that contrasts with the tick is often recommended as a common sense precaution to enhance the ability to see and remove ticks before attachment. A recent study, however, suggested that an Ixodes tick species present in Europe (Ixodes ricinus) may be more attracted to light-colored than darker-colored clothing (Hayes et al., 2003). These findings require confirmation before any change in recommended practice should be considered. Insect repellents that contain N, N-diethyl-3-methylbenzamide (DEET) applied to the skin or clothing provide additional protection but may require reapplication for maximum effectiveness. After returning indoors, skin that was treated with DEET should be washed with soap and water. Permethrin (a synthetic pyrethrin) is available in a spray solely for application to clothing (it is inactivated by skin lipids and is particularly effective because it kills ticks on contact. Rezumat. Boala Lyme este o zoonoză transmisă de muşcătura de căpuşe din genul Ixodes (Centers for Disease Control and Prevention. 2004). Agentul cauzator al maladiei este numit după numele cercetătorului Willy Burgdorfer, care izolează pentru prima oară bacteria - Borrelia burgdorferi în 1982. Boala Lyme este o infecţie bacteriană, care poate mima un număr mare de alte îmbolnăviri, fiind numită de aceea şi boala cu 1000 de feţe. Borrelia burgdorferi este agentul etiologic al bolii, dar transmiterea ei se face prin muşcătura de căpuşă. Semnele şi simptomele îmbolnăvirii sunt variabile. Pielea, dar şi sistemul nervos sunt cel mai des afectate. La nivelul pielii apare un rash tipic, numit eritem migrator, care este patognomonic pentru boală. Pot apărea şi alte simptome asociate, ca: febră, cefalee, astenie. Diagnosticul B. Lyme se pune pe baza prezenţei eritemului migrator, apărut după muşcătura de căpuşă infectată. Testele de laborator, prin varietatea lor, ajută şi ele diagnosticul de îmbolnăvire. Majoritatea cazurilor de boală pot fi tratate cu succes, vreme de câteva săptămâni, cu antibiotice. Repelantele joacă un bun rol în prevenirea apariţiei bolii, dar cea mai bună masură este evitarea expunerii la muşcătura căpuşelor din genul Ixodes, infectate cu Borrelia burgdorferi. Nu se foloseşte pentru profilaxie tratamentul de rutină cu antibiotice, cum nici testele serologice nu sunt recomandate în acest scop. Antibioticele în mai multe cure aplicate pot vindeca B. Lyme. Cu cât tratamentul este început mai
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repede, cu atât este asigurată şi vindecarea bolii, iar infecţia nu poate difuza spre inimă sau sistemul nervos.
REFERENCES: STEERE, A.C., COBURN, J., GLICKSTEIN, L., 2004, The emergence of Lyme disease. J. Clin. Invest.; 113(8):1093. AUWAERTER, P.G., AUCOTT, J, DUMLER, J.S., 2004, Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment. Expert Rev Mol Med.; 6 (2):1-22. CENTERS FOR DISEASE CONTROL AND PREVENTION. 2004, Lyme diseaseUnited States: 2001– 2002; 53:365-9. HAYES, E.B., PIESMAN, J., 2003. How can we prevent Lyme disease? N. Engl. J. Med.; 348:2424-30. HUNFELD, K.P., Kraiczy, P., Kekoukh, E., Schafer, V., Brade, V., 2002, Standardized in vitro susceptibility testing of Borrelia burgdorferi against wellknown and newly developed antimicrobial agents possible implications for new therapeutic approaches to Lyme disease. Int J Med Microbiol; 291 (Suppl 33):12537. HUNFELD, K.P., RUZIC-SABLJIC, E., NORRIS, D.E., KRAICZY, P., STROLE, F., 2005, In vitro susceptibility testing of Borrelia burgdorferi sensu lato isolates cultured from patients with erythema migrans before and after antimicrobial chemotherapy. Antimicrob Agents Chemother.; 49:1294-301 MARQUES, A., 2008, Chronic Lyme disease: a review. Infect Dis Clin North Am; 22:341-60. MMWR, 2005, CDC Surveillance Summary, 54:125. STANEK, G., STRLE, F., 2003, Lyme borreliosis, Lancet; 362:1639-47. STEERE, A.C., SCHOEN, R.T., TAYLOR, E., 1987, The clinical evolution of Lyme arthritis. Ann. Intern. Med. 107:725-731. STEERE, A.C., 2003, Duration of antibiotic therapy for Lyme disease. Ann. Intern. Med. 138:761-2. STEERE, A.C., Mchugh, G., DAMLE, N., SIKAND, V.K., 2008, Prospective study of serologic tests for lyme disease. Clin. Infect. Dis. 47 (2): 188–95. WORMSER, G.P., FISH, D., 2003, Lyme disease. In: Baddour L, Gorbach SL, editors. Therapy of infectious diseases. Philadelphia: Saunders; p. 697-719. WRIGHT, W.F., RIEDEL, D.J., TALWANI, R., GILLIAM, B.L., 2012, Diagnosis and management of Lyme disease, Am. Fam. Physician 85 (11): 1086-93.
