Transmissible diseases nwhich are passed through the bites of ticks: tick encephalitis, Lime disease. Leishmaniasis n(kala-azar).
http://intranet.tdmu.edu.ua/data/books/And-INF.pdf
VIRAL ENCEPHALITIS
Definition.
http://www.pdrhealth.com/diseases/viral–encephalitis
Viral encephalitis and nmyeloencephalitis is a group of an acute infectious diseases. These diseases nare accompanied by fever and lesion of the brain and (or) spinal cord. The ntitle “encephalomyelitis” descended from greek word n”encephalon” – brain, “myelon” – spinal cord. There are 2 ngroups of encephalites the primary encephalites and the secondary encephalites.
The primary encephalites are nindependent diseases, for example: Tick encephalitis and Japanese encephalitis.
The secondary encephalitis is nsyndrome of some other disease, for example: encephalitis due to measles, nsmallpox, herpetic infection.
Viral transmissive encephalites and nmyeloencephalites are diseases from group of arboviral infections. Arboviral ndiseases are characterized by endemic and seasonal spread, transmissive way of nthe transmission. All arboviral encephalites are zoonotic infections.
Arboviral encephalitis are naccompanied by general toxic syndrome, high temperature and mainly by damage of nthe central nervous system.
The agent of nthis group of the diseases are arboviruses, i.e. “arthropod-borne viruses”. The ngeneral characteristics of arboviruses is an ability to parasite in the norganism of animals and arthropods.
The history of nthe study of arboviral diseases is connected with yellow fever. Yellow fever nwas recognized as a disease in 1990 and virus was isolated in 1927.at the npresent time it is known about more than 450 types of arboviruses. There are 49 ngroups of arboviruses according to antigenic structure.
Arboviruses nare typical parasites of the birds, rodents, mammals, reptiles. Arboviruses nevoke latently persistent or subclinical infection in the organism of birds and nanimals. Human is included to ecological chain accidentally, and as rule he is nnot a source of the infection, except for some arboviral fevers, which having ndeclination to epidemic spread (Denge fever, yellow fever, flebothomic fever nand other). The group of arboviruses is detached on the basis of their general necology. The live cycle of viruses consists of viruses consists from the next nstages:
1. nReproductioin the organism of vertebral hosts.
2. nCrossing to attaching ninsects and reproduction in the organism of anthropoids.
3. nTransmissioby bite to new vertebrate hosts. The vertebrate hosts become the source of ninfection due to accumulation of virus in the blood.
The transfer nof arboviruses by anthropoids (gnats, ticks, mosquitoes) io mechanical nprocess. Virus, entering to the insect’s organism with blood is reproduced and naccumulated in the cells of the salivatory glands. It enters into the wound nwith saliva due to bite. The condition of the infection is concentration of nvirus in the saliva. The infection of anthropoids is also possible isufficiently high quantity of virus in the blood of vertebrate hosts. Arboviral ninfection doesn’t carry harm to anthropoids. Virus is preserved in the organism nof anthropoids during all life.
In infected nticks virus is transmitted transovarially. The forming posterity becomes ncarrier of virus, it may be able to transmit infection to the vertebrate hosts.
The tropical countries nare regarded as historical heartland of arboviruses. At the present time these ncountries are areas of the most spread of arboviral infections. The variety of nshapes of insects, the siderable density of the population of vertebrate hosts nand anthropoids and high temperature of air promote to spread of arboviral ninfections.
The important nfactor of the activity and epidemic manifestations of the focuses of arboviral ninfections is activity of human and violations of ecological balance. For nexample, Japanese encephalitis is registered in all regions of rise fields and nconditions of pigs. The irrigated rise fields are the places of fructify of nvectors of agents Culex mosquitoes and infected pigs are the reservoir of ninfection.
All arboviral infections are natural focal diseases. There are the next ngroups of arboviral diseases:
I. nArboviral nencephalites and encephalomyelites.
II. nArboviral nsystemic feverish diseases.
The next diseases are concerned to the first group:
1. nVenezuelaequine encephalitis is widespread in the northern, southern and central areas of America. The birds, rodents, monkey, mammals are the reservoir of virus. nAmount domestic animals-sheeps, goats and horses may be the source of ninfection. The mosquito is a factor of transmission. The lethal rate is 6 – 9% nin cases in adult and 35% in children.
2. nEasterequine encephalitis is widespread in the almost whole American continent. The nsources of infection are the horses and some kinds of the birds. The diseases nis transmitted by mosquitoes. The lethal rate is 70 – 75%.
3. nWesterequine encephalitis is widespread in the some regions of American continent. The nreservoir of infection is some kinds of the birds, snakes, frogs and horses. nThe disease is transmitted by mosquitoes. Lethal rate is 15%.
4. nSaint–Louis nencephalitis. It is widespread in the countries of American continent and on the nislands of Caribbean basin. The reservoirs of infection are pigeons, sparrows, nchickens and cattle. The factors of transmission are mosquitoes and ticks. The nlethal rate is 15 – 20%.
5. nIlheus nencephalitis is registered in some areas of the South and Central America. The nreservoir of infection has not been determined. The factor of transmission is nmosquitoes. There is no facts about lethal outcomes. Australian X – disease (
6. nScotland encephalitis (Scotland sheep’s nencephalitis). The disease is widespread mainly in Scotland, rarely in Northern England. The reservoir of infection iature is sheep. The factor of ntransmission is ticks. In human the course of the disease is light. There are nno lethal outcomes.
http://emedicine.medscape.com/article/1166498-overview#showall
Japanese nencephalitis and Tick encephalitis are widespread and more studied forms of narboviral infections.
JAPANESE nENCEPHALITIS.
http://emedicine.medscape.com/article/233802-overview
Synonyms: nMosquito, Autumn encephalitis.
Definition.
Japanese encephalitis is an acute nviral transmissive, seasonal zoonotic infection. The disease is characterized nby development of serious meningoencephalitis, expressive general toxic nsyndrome, high temperature. The disease is accompanied by high percent of ninvalidity and firm residual appearances.
The nclinical manifestations of Japanese encephalitis was described more than 100 nyears ago. However, this disease was considered as epidemic cerebrospinal nmeningitis. Japanese encephalitis was recognized as independent disease in 1924 nyear.
Etiology.
In 1933 Gayashi proved the viral netiology of the disease in Japan. In 1940 Shubladze and Smorodincev described nvirus in the Soviet Union. According to its characteristics virus is similar to nvirus of Sant-Louis encephalitis and West Nile-encephalitis. The agent of nJapanese encephalitis is virus from genus Flavivirus, family Togaviridae, necological group Arboviruses.
Flaviviridae nare small (40 nm diameter) enveloped viruses with single-stranded, npositive-sense RNA genomes. Virions form on the endoplasmic reticulum of ninfected cells are released by exocytosis or cell lysis. Flaviviruses are nreadily inactivated by heat (56°C, 10 minutes) detergents, ultraviolet irradiation, trypsidigestion, formaldehyde and chlorine and phenolic disinfectiants.
The viruses is replicated in a nvariety of vertabrate and arthropod cells in culture with or without producing ncytopathic effects extensive serolo relatedness, due to shared group-specific nantigens links members of the family; crossing is most extensive by nhemagglutination inhibition, intermediate by complement fixation and least by nneutralization tests.
Outbreaks of this disease has beeregistered in Japan, in Russia, China, Korea, Vietnam, Philippines, India, nIndonesia, Taiwan, Australia and on the coast of the Eastern Africa.
Epidemiology.
According nto its epidemic characteristics grassland, sea, coastal and forest forms of nnatural focuses are differentiated. The reservoir of infection is mammals and nbirds. During the epidemic outbreaks the patient may be he source of infectioand also the domestic animals (horses, cows, pigs). These sources lead to nformation of rural and urban focuses. The factor of transmission is mosquitoes nof family Culex. The disease is registered in August – October.
Pathogenesis.
After bite of mosquito arboviruses nenter into the blood stream. The agents enter with blood stream into the ncentral nervous system. The agents multiply and cause the edema of the soft ncerebral coverings and cerebral matter, edema and hyperemia of the cerebral nvessels. The small hemorrhages are observed in the covering and in the regioof the ophthalmic gyrus, striapallidaric system, where the formation of nmildnessial focuses is possible. After reproduction in considerable quantity ithe nervous system virus enters into the blood again and effects the vessels nand internal organs. There are venous overflow, hemorrhages, degenerative changes nin the vessels and parenchymal organs with serous – hemorrhagic edema of the nliver, kidneys, myocardium, and formed pneumonic focuses in the lungs.
Pathological anatomy.
The most severe of nmorphologic changes take place in the brain and spinal cord: differentiated nserous – hemorrhagic inflammation of the covering and of the matter of the ncranial and spinal cord. Perivascular infiltrations and granular infiltrations nare observed around vessels and nervous cells and zones of necrosis. The most nexpressive changes are in ophtalmic gyrus, substancia nigra, red matter, nolivia, cerebellum.
Clinical manifestation.
The nnext period of the disease are deferented: incubation period, initial, climax nperiod and reconvalescence. Incubation period is from 5 till 21 days, iaverade – 8-14 days.
Initial nperiod. The duration of ninitial period is 3-4 days. The onset of the disease is an acute with increase nof the temperature till 40-41°C. The ntemperature is accompanied by chill and severe headache, especially in the area nof forehead. At the same time the severe pains in the loin, stomach, nextremities, nausea, vomiting are observed. There are hyperemia of the face, nsclera, upper part of the chest, increased sweat. The npulse rate is accelerated till 120-140/min. The arterial pressure increases. nThe painful of muscles is frequently marked. Regidity of occipital muscles, nincrease of muscle’s tonus and increase of tendon reflexes are determined. Isevere course of the disease it may be death of the patient.
Climax nperiod is characterized by progressive symptoms of nthe local damage of the brain. Meningeal syndrome increases. The depression of nconsciousness till coma is marked. Psychial disorders appear frequently: ndelirium, hallucinations.
Muscular ntonus of pyramidal and extrapyramidal character increases. Muscular nhypertension spread on masticatory and occipital muscles. In deep damage of npyramidal system spastic hemipareses, monopareses and paralyses may arise.
Isevere course of the disease clonic and tonic cramps develop. In some patients nstereotynia is marked frequent repetition identical motions.
During examination of the blood nneuthrophilic leukocytosis with shift of the formula to the left is observed, nESR increases. During cerebrospinal puncture, liquor is transparent. The light nlymphocytic pleucytosis is observed. The pressure of cerebrospinal liquor nincreases.
The nduration of the period of reconvalescence is 4-7 weeks. nThe temperature is usually normal or subfebrile. Some signs of the organic ndamage of the brain are preserved (hemiparesis, disorder of the co-ordinatioof the motions, muscular, weakness, psychical violations). The late ncomplications occur (pneumonia, pyelonephritis, bedsores).
Complications nand outcomes.
The nmost common complication is syndrome of edema of the brain. It may be also npneumonia. In the case of the recovery the residual manifestations such as firm nparalyses of the limbs are observed. Sometimes psychical changes occur with nconsiderable decrease of intellect till to ideotia.
Prognosis. Japanese encephalitis is severe disease with lethal rate from 25% ntill 80%. Death becomes more frequently during the first 7 days in state of ncoma, bulbaric appearances and cramps.
Diagnostics.
The ndiagnosis in based on the epidemiological data, season, typical clinical sighs. nDiagnosis is confirmed by isolation of virus from the blood and cerebrospinal nfluid at the first days of the disease. The serological methods of diagnostics nmay be used from the second week of the disease (complement fixation, indirect nhemagglutination, reaction of neutralization of virus).
The differential diagnosis is nperformed with tick encephalitis, serous meningitis and encephalites of the nother etiology.
Treatment.
Specific ntreatment is performed with use of hyperimmune horse’s serum and ngammaglobulins. Pathogenetic therapy includes desintoxicative therapy, ndiuretics, hyperbaric oxygenation. During of the period of the recovery the nmassage, physiotherapy is conducted. Dibasol, prozerin, galantamin are also nprescribed.
Prophylaxis.
Specific prophylaxis in the nendemic regions is performed with help of killed vaccine. It is necessary to nvaccinate as people as domestic agricultural animals in focuses of infection. nDuring epidemic outbreaks passive immunization of the people is performed by nspecific gammaglobulin. The methods of prophylaxis are use of repellents and nthe defense from the mosquitoes.
TICK ENCEPHALITIS.
Synonyms: spring-summer, distant-eastern tick encephalomyelitis.
As a new nozologic one the tick nencephalitis was discovered in 1937 on the Distant East by Chumakov, Chubladze nand other in the special expedition. The lider of this expedition was a famous nscientist L. A. Zilber. During a short period it was established the agent and nthe factor of transmission of the disease. The epidemiological features of tick nencephalitis, clinical manifestations, pathomorphology was studied, also it was nexploited the methods of specific prophylaxis and treatment. The original course nof the disease as two-wave- like type (milk fever) was described by Smorodincev nand Chumakov in 1951-1954. In this case the agent of the disease was isolated nfrom goat and cow milk.
Etiology.
The nagent of tick encephalitis is treated to Species Flavivirus in ecological group nArboviruses. This is RNA-virus, covered by a protein membrane. In connectiowith the peculiarities in antigenic structures viruses are divided on west and neast types, causing various nozogeographical forms of tick encephalitis.
Virus is very well cultivated at nthe hen’s embryos and also on the different cell’s cultures. The white mousses, nmonkeys, goat, sheep and horses may be used as laboratory model for study of ninfection. Virus is unfirm to high temperature and different physical and nchemical agents.
Epidemiology.
Tick encephalitis is typical nseasonal natural – focal transmissive infection. The basic reservoir and ncarrier of Arbovirus is ixodes ticks of varies types. The tick becomes infected nthrough 6 – 7 days after sucking of blood from infected organism (different ntypes of mammals, squirrels, moles, porcupines, rats, field mousses and also a nman). The viruses are in the lymphatic system of the tick. Then they spread and nconcentrate in the sexual organs and salivary glands. Viruses are preserved nduring all life of the tick (till 4 years). The tick transfers viruses ntransovarially to the next generations of the ticks.
The infection of the ticks is nsupported with help of many forest’s mammals. There is an alimentary way of the ntransmission of infection in tick encephalitis due to use unboiled goat or cow nmilk.
There are 3 types of focuses of nthe disease: natural focuses; transitional with changes of biocenosis in a ngiven territory; antropurgic. Tick encephalitis is registered in antropurgic nfocuses in 70% of all cases. The morbidity has seasonal character (May – June). nThe focuses of tick encephalitis are known in Central Europe,
http://emedicine.medscape.com/article/1166498-overview#a0104
Pathogenesis.
The entrance gates are mainly the nskin, but the intestinal mucous membrane may be also a place of the entrance. nVirus enters into the lymphatic nodes, internal organs and central nervous nsystem. Viruses multiply in the cells of the central nervous system. The virus ncauses the degeneration of the cells, multiplies in the mesenchymal cells and nsupported the inflammation. The inflammatory process is concentrated mainly ithe gray matter of the brain and spinal cord, especially the motile neurones of nthe brain and cervical part of the spinal cord. The middle brain, thalamus nhypothalamus and cerebellum is also involved into the process.
Pathological anatomy.
Edema of the cerebral membranes nand the brains matter are marked and also the dilatation and hyperemia of the nvessels of the various calibres, hemorrhages. The extensive proliferation of nthe glial cells, necrobiosis of the frontal borns of the cervical part of the nspinal cord, reticular formation and nucleus of cranial nerves are also nobserved. Hemorrhages are observed in mucous membranes of the stomach, nintestine, extensive hyperemia of the internal organs.
Clinical nmanifestations.
Incubatioperiod is 10 – 14 days, but it may be from 3 till 60 days. The onset of the ndisease is an acute, with high temperature till 40,0 – 41,00C. The ndisease is accompanied by chill, severe headache, pains in the loin, regiopains in the eye’s balls. In some cases short prodromal period occurs: nweakness, fatigue, headache, sleeplessness, sometimes psychic violations. The nnext phases are differented in the course of the disease: initial phase with npredominance of general toxic syndrome; the phase of neurological disorders nwith different variants of the lesion of the central nervous system; the phase nof outcomes (recovery or residual manifestations – pareses, paralyses).
There nare 5 principal forms of the disease:
1. Feverish form
2. Meningeal form
3. Meningoencephalitic form
4. Meningoencephalomyelytic form
5. Polyradiculoneuritic form
http://emedicine.medscape.com/article/1166498-clinical#showall
It’s worth to underline that the nsevere paralytic forms of tick encephalitis is occur more frequently due to neastern variant of the course (Distant East, Siberia). In accordance with ngravity of the course of the disease the next types of Tick encephalitis are ndifferented:
1. nLight form with fever during 3-5 days, signs of the nserious meningitis and recovery during 3-5 weeks.
2. nMiddle serious form with meningeal symptoms and nrecovery during 1.5-2 month.
3. nSerious forms with high lethal rate, lingering ncourse, uncomplete recovery with pareses and paralyses.
The nfulminate forms are known too. The fulminate forms may finished by death of the npatient during the first day of the disease.
Iusual course of tick encephalitis the signs of the damage of the central nnervous system are noted from the first days or sometimes from the first hours n(pareses, paralyses of the limbs, cramps, disorders of the cerebral nerves.
The nviolation of the consciousness is observed. It is possible delirium, soporotic nstate, coma. There is hyperemia of the face, neck and chest, conjunctivitis. nThe decreased arterial pressure, bradycardia, muffed heart tones are marked. Iserious course of the disease myocardiodystrophy develops. It may be ndevelopment of acute heart failure. Frequently, the disorders of the nrespiratory center are revealed. It may lead to respiratory failure. It is npossible the development of edema of lungs on the background of disorder of nmyocardium.
Ialimentary infection the disorders of intestine is noted. It is accompanied by nmeteorism, constipations, hepatolienalic syndrome. In the peripheral blood nexpressive neurotrophilic leukocytosis with the shift of the formula to the nleft, increased ESR are observed.
Feverish nform of tick encephalitis is characterized by the ncourse quality with development of general toxic syndrome.
Meningeal nform is characterized by ndevelopment by general toxic syndrome and signs of serous meningitis. The nsevere headache, fever, vomiting are noted. The meningeal signs are revealed: nrigidity of occipital muscles, Brudsyndky’s symptoms, Kernig’s symptom. In some cases the cramps and loss of conciousness may observed. Icerebrospinal puncture the increased pressure of liquor is noted. During ntesting cerebrospinal liquor the lymphocytic pleocytosis, increased of ncontainment of protein, sugar and chlorides are determined.
Meningoencephalitic nform is accompanied by ndiffusive or local disorder of the brain. In diffusive disorder the nmanifestations of brain’s coma come out on the first plan. The gravity of the nstate increases due to progressiving of edema of brain: from light soporosic nstate till deep coma. In state near coma the hallucinations may be observed and nalso delirium, psychomotoric excitement. Cramps of skeletal muscles are marked. During local damage of the nervous system the neurological symptoms nare determined in zone of the damage of the substance of central nervous nsystem. Thus in damage of the while substance of the cerebral brain spastic nparalysis and pareses of the extremities may arise on depending localization of nthe pathological process and damages of the cranial nerves and also disorder of nthe speech. Frequently, hyperkinesises and attacks of the cramps are observed.
Besides that the signs of the nviolations by innervation of the eyes (diplopia, ptosis, squint) and damages of nthe nucleuses of the cranial nerves may observed depending on localization of nviral damages of the brain.
Bulbaric symptoms (dysphonia, ndysarthria, dysphagia) arise due to damage of the basis of the brain. Iincrease of bulbaric appearances the lethal outcomes may be due to disorder of nthe breath and asphyxia.
Meningoencephalopolyomyelitic nform of the disease is ncharacterized by general toxic, meningeal syndromes and sings of diffusive nencephalitis, local encephalitis and damage of grey matter of spinal cord. Due nto this flabby pareses develop from 3 – 4 days of the disease, especially of nthe muscles of the neck, upper extremities and shoulder belt. Rarely the interribal muscles and diaphragm are damaged. nSubsequently the atrophy of the muscles of the neck, shoulder belt and hands ndevelop. The head turns down towards the chest. The volume of the movements of nthe upper extremities is limited harshly, till full loss of the functions. Irare cases, the damages of the lower extremities may be too, with violation of nthe function of the pelvic reservoirs.
Polyradicyloneurotic nform of tick encephalitis is manifested by general ntoxic, meningeal symptoms and signs of the damage of the radices and peripheral nnerves.
Two-wave nmeningoencephalitis (two-wave milk fever) is nregistered in European focuses of tick encephalitis. This form is characterized nby development of two phases of the temperature reaction. The duration of every nwave is 2-15 days with interval 1-2 weeks. The first wave of the temperature is naccompanied by predominance of general toxic syndrome. The second wave is ncharacterized by development of meningeal signs with frequent positive dynamics nand complete recovery without residual appearances.
http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/viral_encephalitis?open
Diagnostics.
The diagnosis of tick encephalitis nis based on the epidemiological and laboratory data.
The nspecific diagnostics is concluded in detachment of the virus from the blood and ncerebrospinal liquor in the early periods of the disease (4 – 7 day). The ndifferent cultures are used for this purpose – chicken’s embryo, kidney’s nepithelium and other. Besides that, the biological method of the of infectioby material from the sick infant white mouses is used. The identification of nthe viruses may be performed also with help of the method of the fluorescence nantibodies. The diagnosis may be confirmed nserologically by method of pair serums with help of the reaction complement nfixation, indirect hemagglutination and neutralization.
The differential diagnosis of tick nencephalitis is performed with meningites and encephalites of other etiology n(meningococcal infection, tuberculosis, viral diseases), with polyomyelitis, nvascular damages of the brain, with coma of different genesis (uremic coma, ndiabetic coma), tumors of the central nervous system, abscess of the brain. nIt’s worth to underline the leading role of the epidemiological anamnesis.
http://emedicine.medscape.com/article/1166498-workup#showall
Treatment.
The nspecific treatment of tick encephalitis is performed with help antiencephalitic ndonor’s gammaglobulin, which is injected in a dose of 5 – 10 ml intramuscularly nduring 3 days. The course of the treatment is necessary to repeat in to severe nform of encephalitis.
The npathogenetic therapy plays the great role. The remedies for desintoxication, ndehydration, sedative remedies are used and hyperbarric oxygenation. In severe ncases the artifical ventilation of the lungs is necessary.
Prophylaxis.
The prophylaxis of tick nencephalitis is performed in the area of the disease. The active specific prophylaxis is performed by epidemic evidences nover 1 month till appearance and activity of the ticks. The living or nkilled attanuative vaccines are used. The vaccine is injected subcutaneosly ia dose of 1,0 ml three times with interval 3 – 4 months. The revaccination is nperformed one time every year (1,0 ml of vaccine, subcutaneously).Besides that nthe measures of the individual prevention are used special clothes, repellents. n
Encephalitis is an acute inflammation nof the brain.
Encephalitis with meningitis is known as meningoencephalitis.
|
Contents |
Main article: Viral encephalitis
Viral encephalitis can be due neither to the direct effects of an acute infection, or as one of the sequelae nof a latent infection.
It can be caused by a bacterial ninfection such as bacterial meningitis spreading directly to the brain (primary nencephalitis), or may be a complication of a current infectious disease syphilis n(secondary encephalitis). Certain parasitic or protozoal ninfestations, such as toxoplasmosis, malaria, or primary amoebic meningoencephalitis, ncan also cause encephalitis in people with compromised nimmune nsystems. Lyme disease and/or Bartonella henselae may also cause nencephalitis.
Another cause is granulomatous amoebic encephalitis
Patients with encephalitis nsuffer from fever, nheadache and nphotophobia nwith weakness and seizures also common. Less commonly, stiffness of the neck ncan occur with rare cases of patients also suffering from stiffness of the nlimbs, slowness in movement and clumsiness depending on which specific part of nthe brain is involved. The symptoms of encephalitis are caused by the brain’s ndefense mechanisms activating to get rid of the infection. Other symptoms cainclude drowsiness nand coughing.
Adult patients with nencephalitis present with acute onset of fever, headache, confusion, and nsometimes seizures. Younger children or infants may present irritability, nanorexia and fever.
Neurological examinations nusually reveal a drowsy or confused patient. Stiff neck, due to the irritatioof the meninges covering the brain, indicates that the patient has either nmeningitis or meningeoncephalitis. Examination of the cerebrospinal fluid obtained by a lumbar npuncture procedure usually reveals increased amounts of protein and white nblood cells with normal glucose, though in a significant percentage of npatients, the cerebrospinal fluid may be normal. CT scan often is not helpful, as cerebral nabscess is uncommon. Cerebral abscess is more common in patients with nmeningitis than encephalitis. Bleeding is also uncommon except in patients with nherpes nsimplex type 1 encephalitis. Magnetic resonance imaging offers better nresolution. In patients with herpes simplex encephalitis, electroencephalograph nmay show sharp waves in one or both of the temporal lobes. Lumbar puncture nprocedure is performed only after the possibility of prominent brain swelling nis excluded by a CT scan examination. Diagnosis is often made with detection of nantibodies in the cerebrospinal fluid against a specific viral agent (such as nherpes simplex virus) or by polymerase chain reaction that amplifies nthe RNA or DNA of the virus nresponsible (such as varicella zoster virus).
Treatment is usually symptomatic. nReliably tested specific antiviral agents are available only for a few viral nagents (e.g. acyclovir nfor herpes simplex virus) and are used with nlimited success for most infection except herpes simplex encephalitis. In patients nwho are very sick, supportive treatment, such as mechanical ventilation, is nequally important.
Main article: Encephalitis lethargica
Encephalitis lethargica is an atypical form nof encephalitis which caused an epidemic from 1917 to 1928, resulting in millions of deaths nworldwide. Those who survived sank into a semi-conscious state that lasted for ndecades until the Parkinsons drug L-DOPA was used to revive those still alive in the late 1960s nby Oliver nSacks.
There have been only a small nnumber of isolated cases in the years since, though in recent years a few npatients have shown very similar symptoms. The cause is now thought to be neither a bacterial agent or an autoimmune response following infection.
In a large number of cases, ncalled limbic encephalitis, the pathogens responsible nfor encephalitis attack primarily the limbic nsystem (a collection of structures at the base of the brain responsible for nemotions and many other basic functions).
Lyme disease
(Redirected from Lyme borreliosis)
Jump to: navigation, nsearch
|
Lyme Disease |
|
Classificatio and external resources |
|
|
|
Fig. 1. Nymphal and adult deer ticks can be carriers of Lyme disease. Nymphs are about the size of a poppy seed. |
Lyme disease, or borreliosis, nis an emerging infectious disease caused by nat least three species nof bacteria nbelonging to the genus nBorrelia.[1] nBorrelia burgdorferi sensu nstricto is the main cause of Lyme disease in the United nStates, whereas Borrelia afzelii and Borrelia garinii cause nmost European ncases. The ndisease is named for the
Lyme disease is the most common tick-borne disease ithe Northern Hemisphere. Borrelia is ntransmitted to humans by the bite of infected ticks belonging to a few species nof the genus Ixodes n(the so-called “hard ticks”). Early symptoms may include fever, headache, nfatigue, depression, and a characteristic circular skin rash called erythema migrans. Left untreated, later nsymptoms may involve the joints, heart, and central nervous system. In most cases, the ninfection and its symptoms are eliminated by antibiotics, nespecially if the illness is treated early. Late, delayed, or inadequate ntreatment can lead to the more serious symptoms, which can be disabling and ndifficult to treat. Occasionally, symptoms such as arthritis npersist after the infection has been eliminated by antibiotics, prompting nsuggestions that Borrelia causes autoimmunity.
Some groups have argued that “chronic” Lyme ndisease is responsible for a range of medically unexplained symptoms nbeyond the recognized symptoms of late Lyme disease, and that additional, nlong-term antibiotic treatments are needed. Of four randomized controlled trials of nlong-term ceftriaxone nand doxycycline ntreatment in patients with ongoing symptoms, two found no benefit, and two nfound inconsistent benefits with significant side effects and risks from the nantibiotic treatment. Most expert groups, including the Infectious Diseases Society of nAmerica and the American Academy of Neurology, have nfound that existing scientific evidence does not support a role for nBorrelia nor ongoing antibiotic treatment in such cases. However, the narea is controversial, with a few doctors, patient advocacy groups and npoliticians continuing to argue that long-term treatment is beneficial, this ndispute has led to legal action over treatment guidelines.
Symptoms
Lyme disease can affect nmultiple body systems and produce a range of symptoms. Not all patients with nLyme disease will have all symptoms, and many of the symptoms are not specific nto Lyme disease but can occur with other diseases as well. The incubatioperiod from infection to the onset of symptoms is usually one to two weeks, nbut can be much shorter (days), or much longer (months to years). Symptoms most noften occur from May through September, because the nymphal stage of the tick nis responsible for most cases. Asymptomatic ninfection exists, but occurs in less than 7% of infected individuals in the nUnited States. Asymptomatic infection may be much more common among those ninfected in Europe.
Stage 1: Early localized infection
Fig. 2. Commobullseye rash pattern associated with Lyme disease
Fig. 3. Characteristic n”bulls-eye” rash caused by Lyme disease
The classic sign of early nlocal infection with Lyme disease is a circular, outwardly expanding rash ncalled erythema chronicum migrans (also nerythema migrans or EM), which occurs at the site of the tick bite 3 to 32 days nafter being bitten. The rash is red, and may be warm, but is generally npainless. Classically, the innermost portion remains dark red and becomes indurated; nthe outer edge remains red; and the portion in between clears, giving the nappearance of a bullseye. nHowever, partial clearing is uncommon, and the bullseye pattern more ofteinvolves central redness.
Erythema migrans is thought to occur in about 80% of ninfected patients. Patients can also experience flu-like nsymptoms such as headache, muscle nsoreness, fever, nand malaise. nLyme disease can progress to later stages even in patients who do not develop a nrash.
Stage 2: Early ndisseminated infection
Within days to weeks after nthe onset of local infection, the borrelia nbacteria may begin to spread through the bloodstream. Erythema chronicum migrans may develop nat sites across the body that bear no relation to the original tick bite. Another nskin condition, which is apparently absent in North American patients but noccurs in Europe, is borrelial lymphocytoma, na purplish lump that develops on the ear lobe, nipple, or scrotum. Other ndiscrete symptoms include migrating pain in muscles, joint, and tendons, and nheart palpitations and dizziness caused by changes in heartbeat.
Acute neurological nproblems, which appear in 15% of untreated patients, encompass a spectrum of ndisorders. These include facial or Bell’s npalsy, which is the loss of muscle tone on one or both sides of the face, nas well as meningitis, nwhich involves severe headaches, neck stiffness, and sensitivity to light. Radiculoneuritis ncauses shooting pains that may interfere with sleep as well as abnormal skisensations. Mild encephalitis may lead to memory loss, nsleep disturbances, or mood changes. Iaddition, some case reports have described altered mental status as nthe only symptom seen in a few cases of early
Stage 3: Late persistent infection
Fig. 4. Deer ntick life cycle
After several months, nuntreated or inadequately treated patients may go on to develop severe and nchronic symptoms that affect many parts of the body, including the brain, nnerves, eyes, joints and heart. Myriad ndisabling symptoms can occur, including permanent paraplegia nin the most extreme cases.
Chronic nneurologic symptoms occur in up to 5% of untreated patients. A polyneuropathy nthat involves shooting pains, numbness, and tingling in the hands or feet may ndevelop. A neurologic syndrome called Lyme encephalopathy is associated with nsubtle cognitive problems, such as difficulties with concentration and nshort-term memory. These patients may also experience profound fatigue. nHowever, other problems such as depression and fibromyalgia nare no more common in people who have been infected with Lyme than in the ngeneral population. Chronic encephalomyelitis, nwhich may be progressive, can involve cognitive impairment, weakness in the nlegs, awkward gait, facial palsy, bladder problems, vertigo, and back pain. In rare cases untreated nLyme disease may cause frank psychosis, which has been mis-diagnosed as schizophrenia nor bipolar disorder. Panic attack and anxiety caoccur, also delusional behavior, including somatoform ndelusions, sometimes accompanied by a depersonalization nor derealization syndrome, where the person begins to feel detached from themselves nor from reality.
Lyme arthritis usually naffects the knees. In a minority of patients arthritis can occur in other njoints, including the ankles, elbows, wrist, hips, and shoulders. Pain is oftemild or moderate, usually with swelling at the involved joint. Baker’s ncysts may form and rupture. In some cases joint erosion occurs.
Acrodermatitis chronica atrophicans n(ACA) is a chronic skin disorder observed primarily in Europe among the nelderly. ACA begins as a reddish-blue patch of discolored skin, often on the nbacks of the hands or feet. The lesion slowly atrophies over several weeks or nmonths, with the skin becoming first thin and wrinkled and then, if untreated, ncompletely dry and hairless.
Cause
Main article: Lyme disease microbiology
Fig. 5 Borrelia bacteria, the causative agent of Lyme ndisease. Magnified 400 times.
Fig. 6. Ixodes nscapularis, the primary nvector of Lyme disease in eastern North America.
Lyme disease is caused by Gram-negative nspirochetal nbacteria nfrom the genus Borrelia. nAt least 11 Borrelia species have been discovered, 3 of which are knowto be Lyme-related. The Borrelia species that ncause Lyme disease are collectively known as Borrelia burgdorferi sensu lato, nand show a great deal of genetic ndiversity.
The group Borrelia burgdorferi sensu lato nis made up of three closely-related species that are probably responsible for nthe large majority of cases: B. burgdorferi sensu nstricto (predominant in North nAmerica, but also present in Europe), B. afzelii, and B. garinii (both npredominant in Eurasia). nSome studies have also proposed that B. bissettii and B. valaisiana nmay sometimes infect humans, but
Transmission
Lyme disease is classified as a zoonosis, as it nis transmitted to humans from a natural nreservoir among rodents by ticks that feed on both sets of hosts. nHard-bodied ticks of the genus Ixodes are the main vectors of Lyme disease. Most infections are ncaused by ticks in the nymphal nstage, as they are very small and may feed for long periods of time nundetected. nLarval ticks are very rarely infected. Tick nbites often go unnoticed because of the small size of the tick in its nymphal nstage, as well as tick secretions that prevent the host from feeling any nitch or pain from the bite. However, transmission is quite rare, with only nabout 1% of recognized tick bites resulting in Lyme disease; this may be due to nthe fact that an infected tick must be attached for at least a day for ntransmission to occur.
In Europe the vector is Ixodes nricinus, which is also called the sheep tick or castor bean tick. IChina Ixodes persulcatus n(the taiga tick) is probably the most important vector. In North America, the nblack-legged tick or deer tick (Ixodes nscapularis) is the main vector on the east coast. The lone star tick (Amblyomma americanum), which is found nthroughout the Southeastern United States as far west nas Texas, is nunlikely to transmit the Lyme disease spirochete Borrelia burgdorferi, nthough it may be implicated in a related syndrome called southern tick-associated rash nillness, which resembles a mild form of Lyme disease. On the West Coast of the United States, nthe main vector is the western black-legged tick (Ixodes npacificus). The tendency of this tick species to feed predominantly ohost species such as lizards that are resistant to Borrelia infectioappears to diminish transmission of Lyme disease in the West.
While Lyme spirochetes have been found in insects iaddition to ticks, reports of actual infectious transmission appear to be rare. nLyme spirochetes have been found in semen and breast milk, however transmissioof the spirochete by these routes is not known to occur. Congenital ntransmission of Lyme disease can occur from an infected mother to fetus through the placenta during npregnancy. nThe risk for fetal harm is much higher in the first three months of pregnancy nthan later. Prompt antibiotic treatment almost always prevents fetal harm. nPregnant Lyme-disease patients cannot be treated with the first-choice nantibiotic, doxycycline (see below), as it is potentially harmful for the nfetus. Instead, erythromycin is usually given; it is less effective against the ndisease but harmless for the fetus.
Tick borne nco-infections
Ticks that transmit B. nburgorferi to humans can also carry and transmit several other parasites nsuch as Theileria microti and Anaplasma phagocytophilum, which ncause the diseases babesiosis and human granulocytic anaplasmosis n(HGA), respectively. Among early Lyme disease patients, depending on their nlocation, 2-12% will also have HGA and 2-40% will have babesiosis.
Co-infections complicate Lyme symptoms, especially ndiagnosis and treatment. It is possible for a tick to carry and transmit one of nthe co-infections and not Borrelia, making diagnosis difficult and ofteelusive. The Centers for Disease Control (CDC)’s nemerging infections diseases department did a study in rural New Jersey nof 100 ticks and found that 55% of the ticks were infected with at least one of nthe pathogens.
Diagnosis
Lyme disease is diagnosed nclinically based on symptoms, objective physical findings (such as erythema migrans, facial npalsy, or arthritis), na history of possible exposure to infected ticks, as well as serological blood ntests. When making a diagnosis of Lyme disease, health care providers nshould consider other diseases that may cause similar illness. Most but not all npatients with Lyme disease will develop the characteristic bulls-eye rash, but many may not recall na tick bite. Laboratory testing is not recommended for persons who do not have nsymptoms of Lyme disease.
Because of the difficulty in culturing Borrelia bacteria in the nlaboratory, diagnosis of Lyme disease is typically based on the clinical exam nfindings and a history of exposure to endemic Lyme areas. The EM rash, which does nnot occur in all cases, is considered sufficient to establish a diagnosis of nLyme disease even when serologic blood tests are negative. Serological testing ncan be used to support a clinically suspected case but is not diagnostic by nitself.
Diagnosis of late-stage Lyme ndisease is often difficult because of the multi-faceted appearance which camimic symptoms of many other diseases. For this reason, a reviewer called Lyme nthe new “great imitator.” Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid arthritis, fibromyalgia, nchronic fatigue syndrome (CFS), lupus, or other autoimmune nand neurodegenerative diseases.
Laboratory testing
Several forms of laboratory testing for Lyme disease nare available, some of which have not been adequately validated. The most nwidely used tests are serologies, which measure levels of specific antibodies in a npatient’s blood. These tests may be negative in early infection, before the nbody has produced significant quantites of antibody, but they are considered a nreliable aid in the diagnosis of later stages of Lyme disease.
The serological laboratory ntests most widely available and employed are the Westerblot and ELISA. nA two-tiered protocol is recommended by the CDC: the sensitive ELISA test is performed nfirst, and if it is positive or equivocal then the more specific Western blot is run. The nreliability of testing in diagnosis remains controversial, however studies show nthe Western blot IgM nhas a specificity of 94–96% for patients with clinical symptoms of early Lyme ndisease.
Erroneous test results have been widely reported iboth early and late stages of the disease. These errors can be caused by nseveral factors, including antibody cross-reactions from other infections nincluding Epstein-Barr virus and cytomegalovirus, nas well as herpes simplex virus.
Polymerase chain reaction (PCR) tests for nLyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease nspirochete. PCR tests are susceptible to false-positive results from poor nlaboratory technique. Even when properly performed, PCR often shows false-negative results with blood and CSF nspecimens. Hence PCR is not widely performed for diagnosis of Lyme disease. nHowever PCR may have a role in diagnosis of Lyme arthritis because it is highly nsensitive in detecting ospA DNA in synovial fluid. With the exception of nPCR, there is no currently practical means for detection of the presence of the norganism, as serologic studies only test for antibodies nof Borrelia. High titers of either immunoglobulin G (IgG) or nimmunoglobulin M (IgM) antibodies to Borrelia antigens indicate disease, nbut lower titers can be misleading. The IgM antibodies may remain after the ninitial infection, and IgG antibodies may remain for years.
Western blot, ELISA and PCR ncan be performed by either blood test via venipuncture nor cerebrospinal fluid (CSF) via lumbar npuncture. Though lumbar puncture is more definitive of diagnosis, antigecapture in the CSF is much more elusive; reportedly CSF yields positive results nin only 10–30% of patients cultured. The diagnosis of neurologic infection by Borrelia nshould not be excluded solely on the basis of normal routine CSF or negative nCSF antibody analyses.
New techniques for clinical ntesting of Borrelia infection have been developed, such as LTT-MELISA
, which is capable of nidentifying the active form of Borrelia infection (Lyme disease). nOthers, such as focus floating microscopy, are under investigation. New nresearch indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis.
Some nlaboratories offer Lyme disease testing using assays whose accuracy and nclinical usefulness have not been adequately established. These tests include nurine antigen tests, PCR tests on urine, immunofluorescent staining for cell nwall-deficient forms of Borrelia burgdorferi, and lymphocyte transformation tests. nThe CDC does not recommend these tests and a 2005 review by Aguero-Rosenfeld et. nal. in Clinical Microbiology Reviews stated that their use is n”of great concern and is strongly discouraged“.
Imaging
Single photon emissiocomputed tomography (SPECT) imaging has been used to look for cerebral hypoperfusion nindicative of Lyme encephalitis in the patient. Although SPECT is not a ndiagnostic tool itself, it may be a useful method of determining braifunction.
In Lyme disease patients, cerebral hypoperfusion of nfrontal subcortical and cortical nstructures has been reported. In about 70% of chronic Lyme disease patients nwith cognitive symptoms, brain SPECT scans typically reveal a pattern of global nhypoperfusion in a heterogeneous distribution through the white nmatter. This pattern is not specific for Lyme disease, since it can also be nseen in other central nervous system (CNS) syndromes such as HIV encephalopathy, viral nencephalopathy, chronic cocaine use, and vasculitides. nHowever, most of these syndromes can be ruled out easily through standard nserologic testing and careful patient history taking.
The presence of global cerebral hypoperfusion deficits non SPECT in the presence of characteristic neuropsychiatric features should ndramatically raise suspicion for Lyme encephalopathy among patients who inhabit nor have traveled to endemic areas, regardless of patient recall of tick bites. nLate disease can occur many years after initial infection. The average time nfrom symptom onset to diagnosis in these patients is about 4 years. Because nseronegative disease can occur, and because CSF testing is ofteormal, Lyme nencephalopathy often becomes a diagnosis of exclusion: once all other npossibilities are ruled out, Lyme encephalopathy becomes ruled in. Although the naberrant SPECT patterns are caused by cerebral vasculitis, a vasculitide, braibiopsy is not commonly performed for these cases as opposed to other types of ncerebral vasculitis.
Abnormal magnetic resonance imaging (MRI) nfindings are often seen in both early and late Lyme disease. MRI scans of npatients with neurologic Lyme disease may demonstrate punctuated white nmatter lesions non T2-weighted images, similar to those seen in demyelinating nor inflammatory disorders such as multiple sclerosis, systemic lupus erythematosus (SLE), or ncerebrovascular disease. Cerebral atrophy and brainstem neoplasm has nbeen indicated with Lyme infection as well.
Diffuse white matter pathology can disrupt these nubiquitous gray matter connections and could account for deficits nin attention, memory, visuospatial ability, complex cognition, and emotional nstatus. White matter disease may have a greater potential for recovery thagray matter disease, perhaps because neuronal loss is less common. Spontaneous remission can occur in multiple sclerosis, and nresolution of MRI white matter hyper-intensities, after antibiotic treatment, nhas been observed in Lyme disease.
Prevention
Attached ticks should be nremoved promptly. Protective clothing includes a hat and long-sleeved shirts nand long pants that are tucked into socks or boots. Light-colored clothing nmakes the tick more easily visible before it attaches itself. People should use nspecial care in handling and allowing outdoor pets inside homes because they cabring ticks into the house.
A more effective, community nwide method of preventing Lyme disease is to reduce the numbers of primary nhosts on which the deer tick depends such as rodents, other small mammals, and ndeer. Reduction of the deer population may over time help break the nreproductive cycle of the deer ticks and their ability to flourish in suburbaand rural areas.
An unusual, organic approach to control of ticks and nprevention of Lyme disease involves the use of domesticated guineafowl. Guineafowl are nvoracious consumers of insects and have a particular fondness for ticks. nLocalized use of domesticated guineafowl may reduce dependence on chemical pest-control nmethods.
Management of host animals
Lyme and all other deer-tick-borne diseases can be nprevented on a regional level by reducing the deer population that the ticks ndepend on for reproductive success. This has been demonstrated in the ncommunities of Monhegan, Maine and in Mumford Cove,
For example, in the US, it is suggested that by nreducing the deer population to levels of 8 to 10 per square mile (from the ncurrent levels of 60 or more deer per square mile in the areas of the country nwith the highest Lyme disease rates), the tick numbers can be brought down to nlevels too low to spread Lyme and other tick-borne diseases. However, such a ndrastic reduction may be impractical in many areas.
Vaccination
A recombinant vaccine nagainst Lyme disease, based on the outer surface protein A (OspA) of B. nburgdorferi, was developed by GlaxoSmithKline. nIn clinical ntrials involving more than 10,000 people, the vaccine, called LYMErix, was nfound to confer protective immunity to Borrelia in 76% of adults and n100% of children with only mild or moderate and transient adverse neffects. LYMErix was approved on the basis of these trials by the U.S. Food and Drug Administration n(FDA) on December 21, 1998.
Following approval of the nvaccine, its entry in clinical practice was slow for a variety of reasons nincluding its cost, which was ofteot reimbursed by insurance companies. nSubsequently, hundreds of vaccine recipients reported that they had developed autoimmune nside effects. Supported by some patient advocacy groups, a number of class-action lawsuits were filed against nGlaxoSmithKline alleging that the vaccine had caused these health problems. nThese claims were investigated by the FDA and the U.S. Centers for Disease Control n(CDC), who found no connection between the vaccine and the autoimmune ncomplaints.
Despite the lack of evidence that the complaints were ncaused by the vaccine, sales plummeted and LYMErix was withdrawn from the U.S. nmarket by GlaxoSmithKline in February 2002, in the setting of negative media coverage and fears of vaccine side effects. The fate of LYMErix was described ithe medical literature as a “cautionary tale” an editorial in Nature cited the withdrawal of LYMErix as ainstance in which “unfounded public fears place pressures on vaccine ndevelopers that go beyond reasonable safety considerations.” The original ndeveloper of the OspA vaccine at the Max Planck Institute told Nature: n”This just shows how irrational the world can be… There was no nscientific justification for the first OspA vaccine [LYMErix] being npulled.”
New vaccines are being researched using outer surface nprotein C (OspC) and glycolipoprotein as methods of immunization.
Tick nremoval
Folk remedies for tick removal tend to be ineffective, nand offer no advantages in preventing the transfer of disease. Generally, the nrecommended method to is to simply pull the tick straight out with a tweezers. nData suggests that the prompt removal of an infected tick, within approximately n36 hours, reduces the risk of transmission to nearly zero; however the small nsize of the tick, especially in the nymph stage, may make detection difficult.
Treatment
Antibiotics nare the primary treatment for Lyme disease; the most appropriate antibiotic ntreatment depends upon the patient and the stage of the disease. The nantibiotics of choice are doxycycline (in adults), amoxicillin n(in children), erythromycin (for pregnant women) and ceftriaxone, nwith treatment lasting 14 to 21 days. Alternative choices are cefuroxime nand cefotaxime. nTreatment of pregnant women is similar, but tetracycline should not be used.
A double blind, randomized, placebo-controlled nmulticenter clinical study indicated that 3 weeks of treatment with intravenous nceftriaxone, followed by 100 days of treatment with oral amoxicillin did not nimprove symptoms any more than just 3 weeks of treatment with ceftriaxone. The nresearchers noted that the outcome should not be evaluated after the initial nantibiotic treatment but rather 6–12 months afterwards. In patients with nchronic post-treatment symptoms, persistent positive levels of antibodies did nnot seem to provide any useful information for further care of the patient.
In later stages, the bacteria disseminate throughout nthe body and may cross the blood-brain barrier, making the infection more ndifficult to treat. Late diagnosed Lyme is treated with oral or IV antibiotics, nfrequently ceftriaxone for a minimum of four weeks. Minocycline nis also indicated for neuroborreliosis for its ability to cross the blood-braibarrier.
Post-Lyme disease symptoms nand “chronic” Lyme disease
Confusingly, the term n”chronic Lyme disease” is often applied to several different sets of npatients. One usage refers to people with the symptoms of untreated and ndesseminated late-stage Lyme disease who are suffering from the symptoms of nthis stage of the disease: these are arthritis, peripheral neuropathy and/or nencephalomyelitis. The term is also applied to people who have had the disease nin the past and some symptoms remain after antibiotic treatment, this is also ncalled post-Lyme disease syndrome. A third and controversial use of the term napplies to patients with non-specific symptoms such as fatigue who show no nobjective evidence that they have been infected with Lyme disease in the past, nsince the standard diagnostic tests for infection are negative.
Up to one third of Lyme disease patients who have ncompleted a course of antibiotic treatment continue to have symptoms such as nsevere fatigue, sleep disturbance, and cognitive difficulties, with these nsymptoms being severe in about 2% of cases. While it is undisputed that these npatients can have severe symptoms, the cause of these symptoms and appropriate ntreatment is controversial. The symptoms may represent “for all intents nand purposes” fibromyalgia/chronic fatigue syndrome. A few doctors nattribute these symptoms to persistent infection with Borrelia, or ncoinfections with other tick-borne infections such as Ehrlichia nand Babesia. nOther doctors believe that the initial infection may cause an autoimmune nreaction that continues to cause serious symptoms even after the bacteria nhave been eliminated by antibiotics.
Four randomized controlled trials have beeperformed in patients who have persisting complaints and a history of Borrelia ninfection. Some of these patients had evidence of an ongoing Borrelia ninfection and almost all of them were previously treated with antibiotics. The nauthors of all four trials concluded that their results did not support nlong-term antibiotic therapy. Of these four studies,
- two studies showed no benefit from 30 days of IV ceftriaxone and 60 days of oral doxycycline, concluding that “treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo”.
- one study showed an improvement only in fatigue after 28 days of IV antibiotics, an effect that was significant only in a group of patients that never had antibiotics previously. The results may have been compromised by unblinding, and detected a large placebo effect. This trials also saw several cases of life-threatening side effects, concluding that “repeated courses of antibiotic treatment are not indicated for persistent symptoms following Lyme disease including those related to fatigue and cognitive dysfunction, particularly in light of the frequency of serious adverse events.”
- one study reported a improvement in fatigue in a subset of patients and a transient improvement in cognition after 10 weeks of IV antibiotics, but concluded that the treatment was “not an effective strategy for sustained cognitive improvement.” These patients had also been ill for many years and had taken many antibiotic courses. Also, this study performed ad hoc statistical analysis and its results were questionably significant.
n
Additionally, an advocacy organization called the International Lyme nAnd Associated Diseases Society (ILADS) argues that “chronic” nLyme disease is responsible for a range of medically unexplained symptoms nbeyond the known manifestations of late Lyme disease, with or without any nevidence of past or present infection. It has questioned the generalizability nand reliability of some of the above trials and the reliability of the current ndiagnostic tests. Most medical authorities, including the Infectious Diseases Society of nAmerica, the American Academy of Neurology, and nthe National Institutes of Health, have nconcluded that there is no convincing evidence that Borrelia is involved nin the various syndromes of “chronic Lyme disease”, and recommend nagainst long-term antibiotic treatment as ineffective and possibly harmful. nThere are significant side effects and risks of prolonged antibiotic therapy, nand at least one death has been reported from complications of a 27-month ncourse of intravenous antibiotics for an unsubstantiated diagnosis of n”chronic Lyme disease”.
Treatment of post-Lyme ndisease symptoms
Antibiotic treatment is the ncentral pillar in the management of Lyme disease. However, in the late stages nof borreliosis, symptoms may persist despite extensive and repeated antibiotic ntreatment. Although it is possible that these chronic symptoms are due to neither autoimmunity nor residual bacteria (see immunological studies below), no Borrelia DNA ncan usually be detected in the joints after antibiotic treatment, which nsuggests that the arthritis may continue even after the bacteria have beekilled. Lyme arthritis that persists after antibiotic treatment may be treated nwith hydroxychloroquine or methotrexate. nCorticosteroid ninjections into the affected joint are not recommended for any stage of Lyme arthritis. n
Patients with chronic neuropathic npain responded well to gabapentin monotherapy with residual pain after nintravenous ceftriaxone treatment in a pilot study. Some antibiotics nmay have a dual effect on Lyme disease, since minocycline nand doxycycline nhave anti-inflammatory effects in addition to their antibiotic actions. Indeed, nminocycline is used in other neurodegenerative nand inflammatory ndisorders such as multiple sclerosis, Parkinson’s disease, Huntington’s disease, rheumatoid arthritis (RA) and ALS.
Alternative ntherapies
Fig. 7. Portable Mild Hyperbaric nChamber 40″ diameter
A number of other alternative ntherapies have been suggested, though clinical trials have not been conducted. For nexample, the use of hyperbaric oxygen therapy, as an adjunct nto antibiotics for Lyme has been discussed. Though there are no published data nfrom clinical trials to support its use, preliminary results using a mouse model suggest nits effectiveness against B. burgdorferi both in vitro nand in vivo. nAnecdotal clinical research has suggested that antifungal azole medications nsuch as diflucan ncould be used in the treatment of Lyme, but the use of these drugs has yet to nbe tested in a controlled study.
Alternative medicine approaches include bee venom nbecause it contains the peptide melittin, which has been shown to exert inhibitory effects non Lyme bacteria in vitro; no clinical trials of this treatment have beecarried out, however.
Prognosis
For early cases, prompt treatment nis usually curative. However, the severity and treatment of Lyme disease may be ncomplicated due to late diagnosis, failure of antibiotic treatment, and nsimultaneous infection with other tick-borne diseases (co-infections) including nehrlichiosis, nbabesiosis, nand bartonella, nand immune suppression in the patient.
A meta-analysis npublished in 2005 found that some patients with Lyme disease have fatigue, njoint or muscle pain, and neurocognitive symptoms persisting for years despite nantibiotic treatment. Patients with late stage Lyme disease have been shown to nexperience a level of physical disability equivalent to that seen in congestive heart failure. In rare cases, nLyme disease can be fatal.
Pathophysiology
Borrelia burgdorferi can spread throughout the nbody during the course of the disease and has been found in the skin, heart, njoint, peripheral nervous system, and central nervous system. Many of the signs nand symptoms of Lyme disease are a consequence of the immune response to the nspirochete in those tissues.
B. burgdorferi is injected into the skin by nthe bite of an infected Ixodes tick. Tick saliva, which accompanies the nspirochete into the skin during the feeding process, contains substances that ndisrupt the immune response at the site of the bite. This provides a protective nenvironment where the spirochete can establish infection. The spirochetes nmultiply and migrate outward within the dermis. The host ninflammatory response to the bacteria in the skin causes the characteristic ncircular
Days to weeks following the tick bite, the spirochetes nspread via the bloodstream to joints, heart, nervous system, and distant skisites, where their presence gives rise to the variety of symptoms of ndisseminated disease. The spread of B. burgdorferi is aided by the nattachment of the host protease plasmin to the surface of the spirochete. If untreated, the nbacteria may persist in the body for months or even years, despite the nproduction of anti-B. burgdorferi antibodies by the immune system. The nspirochetes may avoid the immune response by decreasing expression of surface nproteins that are targeted by antibodies, antigenic variation of the VlsE surface nprotein, inactivating key immune components such as complement, nand hiding in the extracellular matrix, which may interfere with nthe function of immune factors.
In the brain B. burgdorferi may induce astrocytes nto undergo astrogliosis (proliferation followed by apoptosis), nwhich may contribute to neurodysfunction. The spirochetes may also induce host ncells to secrete products toxic to nerve cells, including quinolinic nacid and the cytokines IL-6 and TNF-alpha, which can produce fatigue and nmalaise. Both microglia nand astrocytes secrete IL-6 and TNF-alpha in the presence of the spirochete. nThis cytokine response may contribute to cognitive impairment.
A developing hypothesis is that the chronic secretioof stress hormones as a nresult of Borrelia infection may reduce the effect of neurotransmitters, nor other receptors in the brain by cell-mediated npro-inflammatory pathways, thereby leading to the dysregulation of nneurohormones, specifically glucocorticoids nand catecholamines, nthe major stress hormones. This process is mediated via the hypothalamic-pituitary-adrenal axis. nAdditionally tryptophan, a precursor to serotonin nappears to be reduced within the central nervous system (CNS) in a number of ninfectious diseases that affect the brain, including Lyme. Researchers are ninvestigating if this neurohormone secretion is the cause of neuropsychiatric ndisorders developing in some patients with borreliosis.
Immunological nstudies
It is possible that exposure nto the Borrelia bacterium during Lyme disease causes a long-lived and ndamaging inflammatory response. This would be a form nof pathogen-induced autoimmune disease. The production of this reaction might nbe due to a form of molecular mimicry, where Borrelia avoid nbeing killed by the immune system by resembling normal parts of the body’s ntissues. It is therefore possible that if some chronic symptoms come from aautoimmune reaction, this could explain why some symptoms persist even after nthe spirochetes have been eliminated from the body. This hypothesis may explaichronic arthritis that persists after antibiotic therapy, similar to rheumatic nfever, but its wider application is controversial.
Ecology
Urbanization and other anthropogenic nfactors can be implicated in the spread of Lyme disease to humans. In many nareas, expansion of suburbaeighborhoods has led to the gradual deforestatioof surrounding wooded areas and increasing border contact between humans and ntick-dense areas. Human expansion has also resulted in a gradual reduction of nthe predators that normally hunt deer as well as mice, chipmunks and other nsmall rodents – the primary reservoirs for Lyme disease. As a consequence nof increased human contact with host and vector, the likelihood of transmission to nLyme residents has greatly increased. Researchers are also investigating npossible links between global warming and the spread of vector-borne ndiseases including Lyme disease.
The deer tick (Ixodes scapularis, the primary nvector in the northeastern U.S.) has a two-year life cycle, first progressing nfrom larva to nymph, and then from nymph to adult. The tick feeds only once at neach stage. In the fall, large acorn forests attract deer as well as mice, nchipmunks and other small rodents infected with B. burgdorferi. During nthe following spring, the ticks lay their eggs. The rodent population the”booms”. Tick eggs hatch into larvae, which feed on the rodents; thus nthe larvae acquire infection from the rodents. At this stage, tick infestatiomay be controlled using acaricides (miticides).
Adult ticks may also transmit disease to humans. After nfeeding, female adult ticks lay their eggs on the ground, and the cycle is ncomplete. On the West Coast of the United States, nLyme disease is spread by the western black-legged tick (Ixodes pacificus), nwhich has a different life cycle.
The risk of acquiring Lyme disease does not depend othe existence of a local deer population, as is commonly assumed. New research nsuggests that eliminating deer from smaller areas (less than 2.5 ha or 6 acres) may in fact lead nto an increase in tick density and the rise of “tick-borne disease nhotspots”.
Epidemiology
Northern hemisphere temperate regions are most nendemic for Lyme disease.
Africa
In Northern Africa B. burgdorferi sensu lato nhas been identified in Morocco, Algeria, Egypt and Tunisia.
Lyme disease in sub-Saharan is presently unknown, but nevidence indicates that Lyme disease may occur in humans in this region. The nabundance of hosts and tick vectors would favor the establishment of Lyme infectioin Africa. In East Africa, two cases of Lyme disease have been reported in Kenya.
Asia
B. burgdorferi sensu lato infested ticks are being nfound more frequently in Japan, as well as in Northwest China and far easterRussia. Borrelia nhas been isolated in Mongolia as well.
Australia
In Australia there is no definitive evidence for the existence nof B. burgdorferi or for any other tick-borne spirochete that may be nresponsible for a local syndrome being reported as Lyme disease. Cases of nneuroborreliosis have been documented in Australia but are often ascribed to ntravel to other continents. The existence of Lyme disease in Australia is ncontroversial.
Canada
Due to changing climate the rank of ticks able to ncarry Lyme disease has expanded from a limited area of Ontario to include areas nof southern Quebec, Manitoba, northern Ontario, the Maritimes and parts of the nPrairies provinces.
Europe
In Europe, cases of B. burgdorferi sensu lato ninfected ticks are found predominantly in central Europe, particularly in Slovenia and Austria, but have nbeen isolated in almost every country on the continent. Incidence in SoutherEurope, such as Italy and Portugal, is much lower.
South nAmerica
In South America tick-borne disease recognition and noccurrence is rising. Ticks carrying B. burgdorferi sensu lato, as well nas canine and human tick-borne disease, have been reported widely in Brazil, but the nsubspecies of Borrelia has not yet been defined. The first reported case nof Lyme disease in Brazil was made in 1993 in Sao Paulo. B. burgdorferi sensu stricto nantigens in patients have been identified in Colombia and Bolivia.
CDC map showing the nprevalence of Lyme disease in the United States, particularly its concentratioin the Boston-WashingtoD.C. Northeast Corridor, and Western Wisconsin.
Lyme disease is the most common tick-borne disease iNorth America and Europe and one of the fastest-growing infectious diseases ithe United States. Of cases reported to the United States CDC, the ratio of nLyme disease infection is 7.9 cases for every 100,000 persons. In the testates where Lyme disease is most common, the average was 31.6 cases for every n100,000 persons for the year 2005.
Although Lyme disease has been reported in 49 of 50 nstates in the U.S, about 99% of all reported cases are confined to just five ngeographic areas (New England, Mid-Atlantic, East-North Central, South nAtlantic, and West North-Central). New 2008 CDC Lyme case definition guidelines nare used to determine confirmed CDC surveillance cases. Effective January 2008, nthe CDC gives equal weight to laboratory evidence from 1) a positive culture nfor B. burgdorferi; 2) two-tier testing (ELISA screening and WesterBlot confirming); or 3) single-tier IgG (old infection) Western Blot. nPreviously, the CDC only included laboratory evidence based on (1) and (2) itheir surveillance case definition. The case definitioow includes the use of nWestern Blot without prior ELISA screen.
The number of reported cases of the disease have beeincreasing, as are endemic regions in North America. For example, it had npreviously been thought that B. burgdorferi sensu lato was hindered iits ability to be maintained in an enzootic cycle in California nbecause it was assumed the large lizard population would dilute the prevalence nof B. burgdorferi in local tick populations, but this has since beebrought into question as some evidence has suggested that lizards can become ninfected. Except for one study in Europe, much of the data implicating lizards nis based on DNA detection of the spirochete and has not demonstrated that nlizards are able to infect ticks feeding upon them. As some experiments suggest nlizards are refractory to infection with Borrelia, it appears likely their ninvolvement in the enzootic cycle is more complex and species-specific.
While B. burgdorferi is most associated with nticks hosted by white-tailed deer and white-footed mice, Borrelia afzelii is most nfrequently detected in rodent-feeding vector ticks, Borrelia garinii and nBorrelia valaisiana appear to be associated with birds. Both rodents and nbirds are competent reservoir hosts for B. burgdorferi sensu stricto. nThe resistance of a genospecies of Lyme disease spirochetes to the nbacteriolytic activities of the alternative complement pathway of various host nspecies may determine its reservoir host association.
Leishmaniasis
Fig. 8. Leishmaniasis
Leishmaniasis is a disease caused by nprotozoan parasites that nbelong to the genus Leishmania and is transmitted by the bite of certaispecies of sand nfly (subfamily Phlebotominae). Two genera transmit Leishmania nto humans: Lutzomyia nin the New World and Phlebotomus in the Old World.
Most forms of the disease are ntransmissible only from animals (zoonosis), but some can be spread between humans. Humainfection is caused by about 21 of 30 species that infect mammals. These include nthe L. donovani complex with three species (L. donovani, L. infantum, nand L. chagasi); the L. mexicana complex with 3 main species (L. nmexicana, L. amazonensis, and L. venezuelensis); L. tropica; L. nmajor; L. aethiopica; and the subgenus Viannia with four maispecies (L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, nand L. (V.) peruviana). The different species are morphologically nindistinguishable, but they can be differentiated by isoenzyme nanalysis, DNA sequence analysis, or monoclonal antibodies.
Cutaneous leishmaniasis is the most commoform of leishmaniasis. Visceral leishmaniasis is a severe form iwhich the parasites have migrated to the vital organs.
Classification
Leishmaniasis may be divided into the following types:
· Post-kala-azar dermal leishmaniasis n
Geography and epidemiology
Fig. 9. A 1917 case of Cutaneous Leishmaniasis in the Middle East, known then locally as “Jericho nButtons” for the frequency of cases near the ancient city of Jericho
Leishmaniasis can be ntransmitted in many tropical and sub-tropical countries, and is found in parts of nabout 88 countries. Approximately 350 million people live in these areas. The nsettings in which leishmaniasis is found range from rainforests in Central and nSouth America to deserts in West Asia and the Middle East. It affects as many nas 12 million people worldwide, with 1.5–2 millioew cases each year. The nvisceral form of leishmaniasis has an estimated incidence of 500,000 new cases nand 60,000 deaths each year. More than 90 percent of the world’s cases of visceral leishmaniasis are in India, nBangladesh, Nepal, Sudan, and Brazil.
Leishmaniasis is found nthrough much of the Americas from northern Argentina to nsouthern Texas, nthough not in Uruguay nor Chile, and has nrecently been shown to be spreading to North Texas. nDuring 2004, it is calculated that some 3,400 troops from the Colombian army, noperating in the jungles near the south of the country (in particular around nthe Meta and Guaviare departments), were infected with Leishmaniasis. nApparently, a contributing factor was that many of the affected soldiers did nnot use the officially provided insect nrepellent, because of its allegedly disturbing odor. It is estimated that nnearly 13,000 cases of the disease were recorded in all of Colombia throughout n2004, and about 360 new instances of the disease among soldiers had beereported in February 2005.
The disease is found across nmuch of Asia, though nnot Southeast nAsia, and in the Middle East. Within Afghanistan, nleishmaniasis occurs commonly in Kabul– partly due to bad sanitation and waste left uncollected nin streets, allowing parasite-spreading sand flies nan environment they find favorable. In
Africa, in particular the East nand North, nis home to cases of Leishamaniasis. The disease is spreading to SoutherEurope but is not found in Australia or Oceania.
Leishmaniasis is mostly a disease of the Developing nWorld, and is rarely known in the developed nworld outside a small number of cases, mostly in instances where troops are nstationed away from their home countries. Leishmaniasis has been reported by U.S. troops stationed in Saudi nArabia and Iraq nsince the Gulf nWar of 1990, including visceral leishmaniasis.[12][13][14] nIn September 2005 the disease was contracted by at least four Dutch nmarines who were stationed in Mazari nSharif, Afghanistan, and subsequently repatriated for treatment.
Life ncycle
Fig. 10. Life cycle of Leishmania
Leishmaniasis is transmitted nby the bite of female phlebotomine sandflies. The sandflies inject the ninfective stage, metacyclic promastigotes, during blood meals (1). nMetacyclic promastigotes that reach the npuncture wound are phagocytized by macrophages (2) and transform into amastigotes n(3). Amastigotes multiply in infected cells and affect different ntissues, depending in part on which Leishmania species is involved (4). nThese differing tissue specificities cause the differing clinical nmanifestations of the various forms of leishmaniasis. Sandflies become infected nduring blood meals on an infected host when they ingest macrophages infected nwith amastigotes (5,6). In the sandfly’s midgut, the parasites ndifferentiate into promastigotes (7), which multiply, differentiate into nmetacyclic promastigotes and migrate to the proboscis (8)
Signs nand symptoms
The symptoms of leishmaniasis nare skisores which erupt weeks to months after the person affected is bitten by nsand flies. Other consequences, which can become manifest anywhere from a few nmonths to years after infection, include fever, damage to the spleen and liver, and anaemia.
In the medical field, nleishmaniasis is one of the famous causes of a markedly enlarged spleen, which nmay become larger even than the liver. There are four main forms of nleishmaniasis:
- Visceral leishmaniasis – the most serious form and potentially fatal if untreated.
- Cutaneous leishmaniasis – the most common form which causes a sore at the bite site, which heal in a few months to a year, leaving an unpleasant looking scar. This form ca progress to any of the other three forms.
- Diffuse cutaneous leishmaniasis – this form produces widespread skin lesions which resemble leprosy and is particularly difficult to treat.
- Mucocutaneous leishmaniasis – commences with skin ulcers which spread causing tissue damage to (particularly) nose and mouth
n
Fig. 10. Cutaneous nleishmaniasis ulcer on left forearm
Diagnosis
Leishmaniasis is diagnosed ithe haematology laboratory by direct visualization of the amastigotes n(Leishman-Donovan bodies). Buffy-coat preparations of peripheral blood or naspirates from marrow, spleen, lymph nodes or skin lesions should be spread oa slide to make a thin smear, and stained with Leishman’s or Giemsa’s stain (pH 7.2) for 20 minutes. nAmastigotes are seen with monocytes or, less commonly ieutrophil iperipheral blood and in macrophages in aspirates. They are small, round bodies n2-4μm in diameter with indistinct cytoplasm, a nucleus and a small nrod-shaped kinetoplast. Occasionally amastigotes may be seen lying nfree between cells.
Treatment
There are two common therapies containing antimony (knowas pentavalent antimonials), meglumine antimoniate (Glucantime) and nsodium stibogluconate (Pentostam). It nis not completely understood how these drugs act against the parasite; they may ndisrupt its energy production or trypanothione nmetabolism. Unfortunately, in many parts of the world, the parasite has become nresistant to antimony and for visceral or mucocutaneous leishmaniasis, but the nlevel of resistance varies according to species. Amphotericin n(AmBisome) is now the treatment of choice; its failure in some cases to treat nvisceral leishmaniasis (Leishmania donovani) has been reported in Sudan, nbut this may be related to host factors such as co-infection with HIV or tuberculosis nrather than parasite resistance.
Miltefosine n(Impavido), is a new drug for visceral and cutaneous leishmaniasis. The cure rate of miltefosine iphase III clinical trials is 95%; Studies in Ethiopia show nthat it is also effective in Africa. In HIV immunosuppressed people who are ncoinfected with leishmaniasis it has shown that even in resistant cases 2/3 of nthe people responded to this new treatment. Clinical trials in Colombia showed na high efficacy for cutaneous leishmaniasis. In mucocutaneous cases caused by nL.brasiliensis it has shown to be more effective than other drugs. Miltefosine nreceived approval by the Indian regulatory authorities in 2002 and in Germany nin 2004. In 2005 it received the first approval for cutaneous leishmaniasis iColombia. Miltefosine is also currently being investigated as treatment for nmucocutaneous leishmaniasis caused by Leishmania braziliensis in Colombia, nand preliminary results are very promising. It is now registered in many ncountries and is the first orally administered breakthrough therapy for nvisceral and cutaneous leishmaniasis. (More, et al., 2003). In October n2006 it received orphan drug status from the US Food and Drug nadministration. The drug is generally better tolerated than other drugs. Maiside effects are gastrointestinal disturbance in the 1–2 days of treatment nwhich does not affect the efficacy. Because it is available as an oral nformulation, the expense and inconvenience of hospitalisation is avoided, which nmakes it an attractive alternative.
Fig. 11. Paromomycin nis said to be an inexpensive (US$10) and effective treatment for leishmaniasis.
The Institute for OneWorld Health nhas reintroduced the drug paromomycin for treatment of leishmaniasis, results with nwhich led to its approval as an orphan drug. nThe Drugs for Neglected Diseases nInitiative is also actively facilitating the search for novel therapeutics. nA treatment with paromomycin will cost about $10. The drug had originally beeidentified in 1960s, but had been abandoned because it would not be profitable, nas the disease mostly affects poor people. The Indian government approved nparomomycin for sale in August 2006.
Drug-resistant leishmaniasis nmay respond to immunotherapy (inoculation with parasite antigens plus nan adjuvant) nwhich aims to stimulate the body’s own immune system to kill the parasite.
Several potential vaccines nare being developed, under pressure from the World Health Organization, but as of 2006 nnone is available. The team at the Laboratory for Organic Chemistry at the nSwiss Federal Institute of Technology (ETH) in Zürich are trying to desiga carbohydrate-based vaccine. The genome of the parasite Leishmania major nhas been sequenced, possibly allowing for identification of proteins that are nused by the pathogen but not by humans; these proteins are potential targets nfor drug treatments.
Fig. 12. Peganum nharmala
The compound vasicine (peganine), found in the nplant Peganum harmala, has been tested in vitro nagainst the promastigote stage of Leishmania donovani, the causative agent of nvisceral leishmaniasis. It was shown that this compound induces apoptosis in Leishmania npromastigotes. “Peganine hydrochloride dihydrate, besides being safe, was nfound to induce apoptosis in both the stages of L. donovani via loss of mitochondrial ntransmembrane potential.”
Another alkaloid harmine found in Peganum nharmala, because of its appreciable efficacy in destroying intracellular nparasites as well as non-hepatotoxic and non-nephrotoxic nature, harmine, ithe vesicular forms, may be considered for clinical application ihumans.”
HIV Protease inhibitors have been found to be nactive against Leishmania species in two in vitro studies in Canada and India. nThe study reported that the intracellular growth of Leishmania parasites
Biology
Fig. 13. A microbiologist nworking on L. major in a biocontainment nhood
Leishmaniasis is caused by infection with the pathogen Leishmania. nThe genomes of nthree Leishmania species (L. major, L. infantum and L. nbraziliensis) have been sequenced and this has provided much informatioabout the biology of the parasite. For example it is now understood that in Leishmania nprotein-coding genes are organized as large polycistronic units in a nhead-to-head or tail-to-tail manner; RNA polymerase II transcribes long npolycistronic messages in the absence of defined RNA pol II promoters; and Leishmania nhas unique features with respect to the regulation of gene expression iresponse to changes in the environment. The new knowledge from these studies nmay help identify new targets for urgently needed drugs, and aid the ndevelopment of vaccines.
Vaccines
Currently there are no vaccines iroutine use. However, the genomic sequence of Leishmania has provided a rich nsource of vaccine candidates. Genome-based approaches have been used to screen for novel nvaccine candidates. One study screened 100 randomly selected genes as DNA vaccines nagainst L. major infection in mice. Fourteen reproducibly protective nnovel vaccine candidates were identified. A separate study used a two-step nprocedure to identify T cell antigens. Six unique clones were identified: nglutamine synthetase, a transitional endoplasmic reticulum ATPase, elongatiofactor 1gamma, kinesin K-39, repetitive protein A2, and a hypothetical nconserved protein. The 20 antigens identified in these two studies are being nfurther evaluated for vaccine development.
History
Descriptions of conspicuous lesions similar to ncutaneous leishmaniasis (CL) has been discovered on tablets nfrom King Ashurbanipal from the 7th century BC, some of which may nhave been derived from even earlier texts from 1500 to 2500 BC. Muslim physicians nincluding Avicenna nin the 10th century AD gave detailed descriptions of what was called Balkh sore. In 1756, nAlexander Russell, after examining a Turkish npatient, gave one of the most detailed clinical descriptions of the disease. nPhysicians in the Indian subcontinent would describe it as nKala-azar (pronounced kālā āzār, the Urdu, Hindi and Hindustani phrase for black fever, kālā nmeaning black and āzār meaning fever or disease). As for the new world, evidence nof the cutaneous form of the disease was found in Ecuador and Peru in pre-Inca npotteries depicting skin lesions and deformed faces dating back to the first ncentury AD. 15th and 16th century texts from the Inca period and from Spanish colonials mention “valley nsickness”, “Andean sickness” or “white nleprosy” which are likely to be CL.
Who first discovered the organism is somewhat ndisputed. It is possible that Surgeon major Cunningham of the British nIndian army saw it first in 1885 without being able to relate it to the ndisease. Peter Borovsky, a Russiamilitary surgeon working in Tashkent, conducted research into the etiology of oriental nsore, locally known as Sart sore, and in 1898 published the first naccurate description of the causative agent, correctly described the parasite’s nrelation to host tissues and correctly referred it to Protozoa. However, because nhis results were published in Russian in a journal with low circulation, his npriority was not internationally acknowledged during his lifetime. In 1901, Leishman identified certain organisms ismears taken from the spleen of a patient who had died from “dum-dum nfever” (Dum_Dum nis an area close to Calcutta) and in 1903 Captain Charles nDonovan (1863–1951) described them as being new organisms. Eventually Ronald Ross nestablished the link with the disease and named the organism Leishmania ndonovani. The disease was a major problem for Allied troops fighting in Sicily during nthe Second World War, and it was then that research by Leonard nGoodwin showed that Pentostam was an effective treatment.
