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Systemic lupus erythematosus

Systemic lupus erythematous often abbreviated to SLE or lupus is a chronicsystemic autoimmune disease (or autoimmune connective tissue disease) thatcan affect any part of the body As occurs in other autoimmune diseases theimmune system attacks the bodyrsquos cells and tissue resulting in inflammation and tissue damage

SLE most often harms the heart joints skin lungs blood vessels liver kidneysand nervous system The course of the disease is unpredictable with periods of illness (called flares) alternating with remissions The disease occurs nine timesmore often in women than in men especially between the ages of 15 and 50

and is more common in those of non-European descent[3][4][5]

Signs and symptoms

Common symptoms of SLE

SLE is one of several diseases known as the great imitators because it oftenmimics or is mistaken for other illnesses SLE is a classical item in differentialdiagnosis because SLE symptoms vary widely and come and go unpredictablyDiagnosis can thus be elusive with some people suffering unexplainedsymptoms of untreated SLE for years

Common initial and chronic complaints include fever malaise joint painsmyalgias fatigue and temporary loss of cognitive abilities Because they are sooften seen with other diseases these signs and symptoms are not part of thediagnostic criteria for SLE When occurring in conjunction with other signs and

symptoms (see below) however they are considered suggestive

Dermatological manifestations

As many as 30 of sufferers have some dermatological symptoms (and 65suffer such symptoms at some point) with 30 to 50 suffering from the classicmalar rash (or butterfly rash) associated with the disease Some may exhibitthick red scaly patches on the skin (referred to as discoid lupus) Alopeciamouth nasal and vaginal ulcers and lesions on the skin are also possiblemanifestations



Musculoskeletal

The most commonly sought medical attention is for joint pain with the small joints of the hand and wrist usually affected although all joints are at risk TheLupus Foundation of America estimates that more than 90 percent of thoseaffected will experience joint andor muscle pain at some time during the courseof their illness

Unlike rheumatoid arthritis lupus arthritis is less disabling and usually does notcause severe destruction of the joints Fewer than ten percent of people withlupus arthritis will develop deformities of the hands and feet SLE patients are atparticular risk of developing osteoarticular tuberculosis

It is suggested that there might be an association between rheumatoid arthritis and SLE and that SLE is associated with an increased risk of bone fractures inrelatively young women

Hematological

Anaemia and other iron deficiencies may develop in up to 50 of cases Lowplatelet and white blood cell counts may be due to the disease or a side-effect of pharmacological treatment People with SLE may have an association withantiphospholipid antibody syndrome (a thrombotic disorder) whereinautoantibodies to phospholipids are present in their serum Abnormalitiesassociated with antiphospholipid antibody syndrome include a paradoxicalprolonged PTT Partial thromboplastin time (which usually occurs in hemorrhagicdisorders) and a positive test for antiphospholipid antibodies the combination of such findings have earned the term lupus anticoagulant -positive Anotherautoantibody finding in SLE is the anticardiolipin antibody which can cause afalse positive test for syphilis

Cardiac

A person with SLE may have inflammation of various parts of the heart such aspericarditis myocarditis and endocarditis The endocarditis of SLE ischaracteristically noninfective (Libman-Sacks endocarditis) and involves eitherthe mitral valve or the tricuspid valve Atherosclerosis also tends to occur moreoften and advances more rapidly than in the general population[14][15][16]

Pulmonary

Lung and pleura inflammation can cause pleuritis pleural effusion lupus

pneumonitis chronic diffuse interstitial lung disease pulmonary hypertensionpulmonary emboli pulmonary hemorrhage and shrinking lung syndrome

Renal

Painless hematuria or proteinuria may often be the only presenting renalsymptom Acute or chronic renal impairment may develop with lupus nephritisleading to acute or end-stage renal failure Because of early recognition andmanagement of SLE end-stage renal failure occurs in less than 5 of cases

A histological hallmark of SLE is membranous glomerulonephritis with wire loopabnormalities This finding is due to immune complex deposition along the

glomerular basement membrane leading to a typical granular appearance inimmunofluorescence testing

Neuropsychiatric

Neuropsychiatric syndromes can result when SLE affects the central orperipheral nervous system The American College of Rheumatology defines 19neuropsychiatric syndromes in systemic lupus erythematosus The diagnosis of



neuropsychiatric syndromes concurrent with SLE is one of the most difficultchallenges in medicine because it can involve so many different patterns of symptoms some of which may be mistaken for signs of infectious disease orstroke

The most common neuropsychiatric disorder people with SLE have is headachealthough the existence of a specific lupus headache and the optimal approach to

headache in SLE cases remains controversial Other common neuropsychiatricmanifestation of SLE include cognitive dysfunction mood disordercerebrovascular disease seizures polyneuropathy anxiety disorder andpsychosis It can rarely present with intracranial hypertension syndromecharacterized by an elevated intracranial pressure papilledema and headache with occasional abducens nerve paresis absence of a space-occupying lesion orventricular enlargement and normal cerebrospinal fluid chemical andhematological constituents

More rare manifestations are acute confusional state Guillain-Barreacute syndromeaseptic meningitis autonomic disorder demyelinating syndromemononeuropathy (which might manifest as mononeuritis multiplex) movement

disorder (more specifically chorea) myasthenia gravis myelopathy cranial neuropathy and plexopathy

Neurological

Neural symptoms contribute to a significant percentage of morbidity andmortality in patients with Lupus As a result the neural side of Lupus is beingstudied in hopes of reducing morbidity and mortality rate] The neuralmanifestation of lupus is known as Neuro Psychiatric Systematic LupusErythematosus (NPSLE) One aspect of this disease is severe damage to theepithelial cells of the blood-brain barrier

Lupus has a wide range of symptoms which span out throughout the body Theneurological symptoms include headaches[20] depression seizures cognitivedysfunction mood disorder cerebrovascular disease[20] polyneuropathy[20] anxiety disorder psychosis and in some extreme cases personality disorders[25]

Systemic

Fatigue in SLE is probably multifactorial and has been related to not only diseaseactivity or complications such as anemia or hypothyroidism but also paindepression poor sleep quality poor physical fitness and perceived lack of socialsupport[26][27]

Causes

There is no one specific cause of SLE There are however a number of environmental triggers and a number of genetic susceptibilities

1Genetics

The first mechanism may arise genetically Research indicates that SLE mayhave a genetic link SLE does run in families but no single causal gene has

been identified Instead multiple genes appear to influence a persons chance of developing lupus when triggered by environmental factors The most importantgenes are located in the HLA region on chromosome 6 where mutations mayoccur randomly (de novo) or may be inherited HLA class I class II and class IIIare associated with SLE but only class I and class II contribute independently toincreased risk of SLE

2 Environmental triggers

The second mechanism may be due to environmental factors These factors maynot only exacerbate existing SLE conditions but also trigger the initial onset



They include certain medications (such as some antidepressants andantibiotics) extreme stress exposure to sunlight hormones and infections UVradiation has been shown to trigger the photosensitive lupus rash and someevidence suggests that UV light might be capable of altering the structure of theDNA leading to the creation of autoantibodies Sex hormones such as estrogen play an important role in the occurrence of SLE and it is observed that duringreproductive years the frequency of SLE is 10 times greater in females than in

males

Researchers have sought to find a connection between certain infectious agents(viruses and bacteria) but no pathogen can be consistently linked to thedisease Some researchers have found that women with silicone gel-filled breastimplants have produced antibodies to their own collagen but it is not known howoften these antibodies occur in the general population and there is no data thatshow that these antibodies cause connective tissue diseases such as SLE Thereis also a small but growing body of evidence linking SLE to lipstick usage[34]

although lipstick manufacturers do not appear to be concerned about it

3Drug reactions

Drug-induced lupus erythematosus is a (generally) reversible condition thatusually occurs in people being treated for a long-term illness Drug-inducedlupus mimics SLE However symptoms of drug-induced lupus generallydisappear once the medication that triggered the episode is stopped There areabout 400 medications that can cause this condition the most common of whichare procainamide hydralazine quinidine and phenytoin[3]

Laboratory tests

1Antinuclear antibody (ANA) testing and anti-extractable nuclear antigen (anti-ENA) form the mainstay of serologic testing for SLE Several techniques are usedto detect ANAs Clinically the most widely used method is indirectimmunofluorescence The pattern of fluorescence suggests the type of antibodypresent in the patients serum

ANA screening yields positive results in many connective tissue disorders andother autoimmune diseases and may occur in normal individuals Subtypes of antinuclear antibodies include anti-Smith and anti-double stranded DNA (dsDNA)antibodies (which are linked to SLE) and anti-histone antibodies (which arelinked to drug-induced lupus) Anti-dsDNA antibodies are highly specific for SLE

they are present in 70 of cases whereas they appear in only 05 of peoplewithout SLE[3] The anti-dsDNA antibody titers also tend to reflect diseaseactivity although not in all cases[3] Other ANA that may occur in SLE sufferersare anti-U1 RNP (which also appears in systemic sclerosis) SS-A (or anti-Ro) andSS-B (or anti-La both of which are more common in Sjoumlgrens syndrome) SS-Aand SS-B confer a specific risk for heart conduction block in neonatal lupus[45]

Other tests routinely performed in suspected SLE are complement system levels(low levels suggest consumption by the immune system) electrolytes and renalfunction (disturbed if the kidney is involved) liver enzymes and complete bloodcount

Previously the lupus erythematosus (LE) cell test was not commonly used fordiagnosis because those LE cells are only found in 50ndash75 of SLE cases and arealso found in some people with rheumatoid arthritis scleroderma and drugsensitivities Because of this the LE cell test is now performed only rarely and ismostly of historical significance[46]

Diagnostic criteria

Some physicians make a diagnosis on the basis of the American College of Rheumatology (ACR) classification criteria The criteria however wereestablished mainly for use in scientific research including use in randomized



controlled trials which require higher confidence levels so some people with SLEmay not pass the full criteria

Criteria

The American College of Rheumatology established eleven criteria in 1982which were revised in 1997 as a classificatory instrument to operationalise the

definition of SLE in clinical trials They were not intended to be used to diagnoseindividuals and do not do well in that capacity For the purpose of identifyingpatients for clinical studies a person has SLE if any 4 out of 11 symptoms arepresent simultaneously or serially on two separate occasions

Serositis Pleuritis (inflammation of the membrane around the lungs) orpericarditis (inflammation of the membrane around the heart) sensitivity =56 specificity = 86 (pleural is more sensitive cardiac is more specific)

Oral ulcers (includes oral or nasopharyngeal ulcers)

Arthritis nonerosive arthritis of two or more peripheral joints with tendernessswelling or effusion sensitivity = 86 specificity = 37

Photosensitivity (exposure to ultraviolet light causes rash or other symptoms of SLE flareups) sensitivity = 43 specificity = 96

Bloodmdashhematologic disordermdashhemolytic anemia (low red blood cell count) orleukopenia (white blood cell countlt4000microl) lymphopenia (lt1500microl) orthrombocytopenia (lt100000microl) in the absence of offending drug sensitivity =59 specificity = 89[49] Hypocomplementemia is also seen due to eitherconsumption of C3 and C4 by immune complex-induced inflammation or tocongenitally complement deficiency which may predispose to SLE

Renal disorder More than 05g per day protein in urine or cellular casts seen inurine under a microscope sensitivity = 51 specificity = 94

Antinuclear antibody test positive sensitivity = 99 specificity = 49

Immunologic disorder Positive anti-Smith anti-ds DNA antiphospholipidantibody andor false positive serological test for syphilis sensitivity = 85specificity = 93 Presence of anti-ss DNA in 70 of cases (though also positivewith rheumatic disease and healthy persons)

Neurologic disorder Seizures or psychosis sensitivity = 20 specificity = 98

Malar rash (rash on cheeks) sensitivity = 57 specificity = 96

Discoid rash (red scaly patches on skin that cause scarring) sensitivity = 18specificity = 99

The mnemonic to remember the 11 symptoms is SOAP BRAIN MD

Prevention

SLE is not understood well enough to be prevented but when the disease

develops quality of life can be improved through flare prevention The warningsigns of an impending flare include increased fatigue pain rash feverabdominal discomfort headache and dizziness Early recognition of warningsigns and good communication with a doctor can help individuals remain activeexperience less pain and reduce medical visits

As longevity of people with SLE increases the likelihood of complications alsoincreases in four areas cardiovascular disease infections osteoporosis andcancer Standard preventive measures screening for related diseases may benecessary to deal with the increased risks due to the side effects of medicationsExtra vigilance is considered warranted in particular for cancers affecting theimmune system



Pregnancy

While most infants born to mothers who have SLE are healthy pregnant motherswith SLE should remain under medical care until delivery Neonatal lupus is rarebut identification of mothers at highest risk for complications allows for prompttreatment before or after birth In addition SLE can flare up during pregnancyand proper treatment can maintain the health of the mother longer Women

pregnant and known to have the antibodies for anti-Ro (SSA) or anti-La (SSB)often have echocardiograms during the 16th and 30th weeks of pregnancy tomonitor the health of the heart and surrounding vasculature

Contraception and other reliable forms of pregnancy prevention is routinelyadvised for women with SLE since getting pregnant during active disease wasfound to be harmful Lupus nephritis was the most common manifestationOverall live-birth was 727 the most common causes of pregnancy loss werespontaneous abortion (miscarriage) and fetal death in utero Pregnancy outcomewas worse in SLE patients whose disease flared up during pregnancy

Treatment

The treatment of SLE involves preventing flares and reducing their severity andduration when they occur

Treatment can include corticosteroids and anti-malarial drugs Certain types of lupus nephritis such as diffuse proliferative glomerulonephritis require bouts of cytotoxic drugs These drugs include cyclophosphamide and mycophenolate

Hydroxychloroquine (HCQ) was the last medication approved by the FDA forlupus in 1955Some drugs approved for other diseases are used for SLE off-label

Medications

Due to the variety of symptoms and organ system involvement with SLE its

severity in an individual must be assessed in order to successfully treat SLE Mildor remittant disease can sometimes be safely left untreated If requirednonsteroidal anti-inflammatory drugs and antimalarials may be used A numberof potential treatments are in clinical trials

Disease-modifying antirheumatic drugs

Disease-modifying antirheumatic drugs (DMARDs) are used preventively toreduce the incidence of flares the process of the disease and lower the need forsteroid use when flares occur they are treated with corticosteroids DMARDscommonly in use are antimalarials such as plaquenil and immunosuppressants (eg methotrexate and azathioprine) Hydroxychloroquine is an FDA-approvedantimalarial used for constitutional cutaneous and articular manifestationsHydroxychloroquine has relatively few side effects and there is evidence that itimproves survival among people who have SLE[59] Cyclophosphamide is used forsevere glomerulonephritis or other organ-damaging complications Mycophenolicacid is also used for treatment of lupus nephritis but it is not FDA-approved forthis indication and FDA is investigating reports that it may be associated withbirth defects when used by pregnant women[61]

Immunosuppressive drugs



In more severe cases medications that modulate the immune system (primarilycorticosteroids and immunosuppressants) are used to control the disease andprevent recurrence of symptoms (known as flares) Depending on the dosagepeople who require steroids may develop Cushings syndrome side-effects of which may include obesity puffy round face diabetes mellitus large appetitedifficulty sleeping and osteoporosis Those side-effects can subside if and whenthe large initial dosage is reduced but long-term use of even low doses can

cause elevated blood pressure and cataracts

Numerous new immunosuppressive drugs are being actively tested for SLERather than suppressing the immune system nonspecifically as corticosteroidsdo they target the responses of individual [types of] immune cells Some of these drugs are already FDA-approved for treatment of rheumatoid arthritis[59]

See also Belimumab and Atacicept Lupuzor has given encouraging results in aphase IIb trial[62]

Analgesia

Since a large percentage of people with SLE suffer from varying amounts of

chronic pain stronger prescription analgesics (pain killers) may be used if over-the-counter drugs (mainly nonsteroidal anti-inflammatory drugs) do not provideeffective relief Potent NSAIDs such as indomethacin and diclofenac arerelatively contraindicated for patients with SLE because they increase the risk of kidney failure and heart failure

Moderate pain is typically treated with mild prescription opiates such asdextropropoxyphene and co-codamol Moderate to severe chronic pain is treatedwith stronger opioids such as hydrocodone or longer-acting continuous-releaseopioids such as oxycodone MS Contin or Methadone The Fentanyl duragesictransdermal patch is also a widely-used treatment option for the chronic paincaused by complications because of its long-acting timed release and ease of

use When opioids are used for prolonged periods drug tolerance chemicaldependency and addiction may occur Opiate addiction is not typically aconcern since the condition is not likely to ever completely disappear Thuslifelong treatment with opioids is fairly common for chronic pain symptomsaccompanied by periodic titration that is typical of any long-term opioid regimen

Lifestyle changes

Avoiding sunlight is the primary change to the lifestyle of SLE sufferers assunlight is known to exacerbate the disease Drugs unrelated to SLE should beprescribed only when known not to exacerbate the disease Occupational

exposure to silica pesticides and mercury can also make the disease worsen

Renal transplantation

Renal transplants are the treatment of choice for end-stage renal disease whichis one of the complications of lupus nephritis but the recurrence of the fulldisease is common in up to 30 of patients

Prognosis

SLE is considered incurable but highly treatable

In the 1950s most people diagnosed with SLE lived fewer than five yearsAdvances in diagnosis and treatment have improved survival to the point whereover 90 now survive for more than ten years and many can live relativelyasymptomatically Prognosis is normally worse for men and children than forwomen however if symptoms are present after age 60 the disease tends to runa more benign course Early mortality within 5 years is due to organ failure oroverwhelming infections both of which can be modified by early diagnosis andtreatment The mortality risk is fivefold when compared to the normal population



in the late stages which can be attributed to cardiovascular diseases acquiredfrom corticosteroid therapy the leading cause of death for people with SLE

To reduce potential for cardiovascular issues high blood pressure and highcholesterol should be prevented or treated aggressively Steroids should be usedat the lowest dose for the shortest possible period and other drugs that canreduce symptoms should be used whenever possible High serum creatinine

hypertension nephrotic syndrome anemia and hypoalbuminemia are poorprognostic factors

The ANA is the most sensitive screening test for evaluation whereas anti-Sm(anti-Smith) is the most specific The dsDNA (double-stranded DNA) antibody isalso fairly specific and often fluctuates with disease activity as such the dsDNAtiter is sometimes useful to monitor disease flares or response to treatment

SJOGRENrsquoS SYNDROME

Sjoumlgrens syndrome is an autoimmune disorder in which immune cells attack and

destroy the glands that produce tears and saliva Sjoumlgrens syndrome is also

associated with rheumatic disorders such as rheumatoid arthritis The hallmark

symptoms of the disorder are dry mouth and dry eyes In addition Sjogrens

syndrome may cause skin nose and vaginal dryness and may affect other

organs of the body including the kidneys blood vessels lungs liver pancreas

and brain

Sjoumlgrens syndrome affects 1-4 million people in the United States Most people

are more than 40 years old at the time of diagnosis Women are 9 times more

likely to have Sjoumlgrens syndrome than men

Signs and symptoms

The hallmark symptoms of the disorder are dry mouth and dry eyes (part of whatare known as sicca symptoms) In addition Sjoumlgrens syndrome may cause skinnose and vaginal dryness and may affect other organs of the body includingthe kidneys blood vessels lungs liver pancreas peripheral nervous system (distal axonal sensorimotor neuropathy) and brain

Sjoumlgrens syndrome is associated with increased levels of IL-1RA in CSF aninterleukin 1 antagonist suggesting the there was first increased activity in the



interleukin 1 system then an auto-regulatory up-regulation of IL-RA in attemptsto reduce the successful binding of Interleukin 1 to its receptors It is likely thatInterleukin 1 is the marker for fatigue however IL-1RA increases are observed inthe CSF and is associated with increased fatigue through cytokine inducedsickness behaviorPatients with secondary Sjoumlgrens syndrome also often exhibitsigns and symptoms of their primary rheumatic disorders such as Irritable Bowel Syndrome with symptoms associated with slow gastric transit

Diagnosis

Diagnosing Sjoumlgrens syndrome is complicated by the range of symptoms apatient may manifest and the similarity between symptoms from Sjoumlgrenssyndrome and those caused by other conditions Nevertheless the combinationof several tests can lead to a diagnosis of Sjoumlgrens syndrome

1Blood tests can be done to determine if a patient has high levels of antibodiesthat are indicative of the condition such as anti-nuclear antibody (ANA) andrheumatoid factor (because SS frequently occurs secondary to rheumatoidarthritis) which are associated with autoimmune diseases Typical Sjoumlgrens

syndrome ANA patterns are SSARo and SSBLa of which SSBLa is far morespecific SSARo is associated with numerous other autoimmune conditions butare often present in Sjoumlgrens

2The Schirmer test measures the production of tears a strip of filter paper isheld inside the lower eyelid for five minutes and its wetness is then measuredwith a ruler Producing less than five millimeters of liquid is usually indicative of Sjoumlgrens syndrome However lacrimal function declines with age or may beimpaired from other medical conditions A slit-lamp examination is done to lookfor dryness on the surface of the eye Salivary gland function can be tested bycollecting saliva and determining the amount produced in a five minute period Alip biopsy can reveal lymphocytes clustered around salivary glands and damage

to these glands due to inflammation

3Ultrasound examination of the salivary glands is the simplest confirmatory testand has the added advantage of being non-invasive with no complications Theparenchyma of the gland demonstrates multiple small-2-6 mm hypoechoiclesions which are representations of the lymphocytic infiltrates Often sialectasiswith calculi are demonstrated if the disease is advanced The sonographicfindings have excellent symptom corelation The other advantage of ultrasoundis that complications of the disease such as extra-nodal lymphomas can often bedetected as larger 1ndash4 cm hypoechoic intra-parenchymal masses

4A radiological procedure can also be used as a reliable and accurate way of diagnosing Sjoumlgrens syndrome A contrast agent is injected into the parotid duct (of Stensen) which is a duct opening from the cheek into the vestibule of themouth opposite the neck of the upper second molar tooth Widespread puddlingof the injected contrast scattered throughout the gland indicates Sjoumlgrenssyndrome

Treatment

There is neither a known cure for Sjoumlgrens syndrome nor a specific treatment to

permanently restore gland secretion Instead treatment is generallysymptomatic and supportive Moisture replacement therapies such as artificialtears may ease the symptoms of dry eyes (some patients with more severeproblems use goggles to increase local humidity or have punctal plugs insertedto help retain tears on the ocular surface for a longer time) Additionallycyclosporin (Restasis) is available by prescription to help treat chronic dry eye bysuppressing the inflammation that disrupts tear secretion Prescription drugs arealso available that help to stimulate salivary flow such as cevimeline (Evoxac)and pilocarpine Nonsteroidal anti-inflammatory drugs may be used to treatmusculoskeletal symptoms For individuals with severe complicationscorticosteroids or immunosuppressive drugs may be prescribed Also disease-



modifying antirheumatic drugs (DMARDs) such as methotrexate may be helpfulHydroxychloroquine (Plaquenil) is another option and is generally consideredsafer than methotrexate

Dry eyes

Punctal Plugs

In the advanced stage despite the use of tear replacement drops the eyesalways feel burning scratchy sore The sufferer is always aware of somediscomfort the eyes feel worse in the morning and late evening The use of tearreplacements drops has become tedious and ineffective At this point it may beappropriate to consider punctal plugs

Each eye has two sites at the inner corner of each eyelid where tears drain fromthe eye The upper eyelid puncta drains approximately 40 of your tears awayand the lower puncta drains away the remaining 60 of your tears If there is aproblem with the quantity of your tears as there is in Sjogrens diseaseplugging the lower puncta can result in the tears that you have remaining on the

eye longer

Punctal plugs can be inserted into the lower or upper tear drainage canals of theeyes The procedure takes only a few minutes and is painless It can be done inthe optometrist or ophthalmologists office Generally collagen plugs areinserted first These plugs will dissolve within a few days so it gives the patienta chance to see if there is any improvement in comfort Generally theimprovement is immediate If you wish to proceed with permanent plugs youmay although these too can be removed if necessary

Dental care

Preventive dental treatment is also necessary (and often overlooked by thepatient) as the lack of saliva associated with xerostomia (dry mouth) creates anideal environment for the proliferation of bacteria that cause dental caries (cavities) Treatments include at-home topical fluoride application to strengthentooth enamel and frequent teeth cleanings by a dental hygienist Existingcavities must also be treated as cavities that extend into the tooth can not beeffectively treated through teeth cleaning alone and are at a high risk of spreading into the pulp of the tooth leading to the loss of vitality and need forextraction or root canal therapy This treatment regimen is the same as thatused for all xerostomia patients such as those undergoing head and neckradiation therapy which often damages the salivary glands as they are more

susceptible to radiation than other body tissues

Unfortunately many patients not realizing the need for dental treatment do notsee a dentist until most of their teeth are beyond the point of restoration It isnot uncommon for a dentist to see a xerostomia patient with severe untreatablecaries in almost every tooth In such cases the only treatment is to extract all of the patients teeth and fit the patient for dentures

Prognosis

Sjoumlgrens can damage vital organs of the body with symptoms that may plateauor worsen but the disease does not go into remission as with other autoimmune

diseases Some people may experience only the mild symptoms of dry eyes andmouth while others have symptoms of severe disease Many patients are able totreat problems symptomatically Others are forced to cope with blurred visionconstant eye discomfort recurrent mouth infections swollen parotid glandshoarseness and difficulty in swallowing and eating Debilitating fatigue and jointpain can seriously impair quality of life Some patients can develop renalinvolvement (autoimmune tubulointerstitial nephritis) leading to proteinuriaurinary concentrating defect and distal renal tubular acidosis

Patients with Sjoumlgrens syndrome have a higher rate of non-Hodgkin lymphoma compared to both patients with other autoimmune diseases and healthy people



About 5 of patients with Sjoumlgrens syndrome will develop some form of lymphoid malignancy]Patients with severe cases are much more likely todevelop lymphomas than patients with mild or moderate cases[14] The mostcommon lymphomas are salivary extranodal marginal zone B cell lymphomas(MALT lymphomas in the salivary glands) and diffuse large B-cell lymphoma

Complications

Among the complications discussed above Sjoumlgrens syndrome in women whobecome pregnant has been linked to increased incidence of neonatal lupuserythematosus with congenital heart block requiring a pacemaker

KAWASAKI DISEASE

Kawasaki disease (KD) also known as Kawasaki syndrome lymph nodesyndrome and Mucocutaneous lymph node syndrome is an autoimmune disease that manifests as a systemic necrotizing medium-sized vessel vasculitisand is largely seen in children under 5 years of age

It affects many organ systems mainly those including the blood vessels skinmucous membranes and lymph nodes however its most serious effect is on theheart where it can cause severe coronary artery aneurysms in untreatedchildren Without treatment mortality may approach 1 usually within 6 weeksof onset With treatment the mortality rate is less than 001 in the US Thereis often a pre-existing viral infection that may play a role in its pathogenesis Theconjunctival and oral mucosa along with the epidermis (skin) becomeerythematous (red and inflamed)

The disorder was first described in 1967 by Dr Tomisaku Kawasaki in Japan

Signs and symptoms

High-grade fever (greater than 39 degC or 102 degF often as high as 40 degC or

104 degF) The duration of fever is on average one to two weeks in the

absence of treatment it may extend for three to four weeks However

when appropriate therapy is started the fever is gone after two days

Red eyes (conjunctivitis) bilateral without pus or drainage also known as

conjunctival injection

Anterior uveitis

Bright red chapped or cracked lips

Red mucous membranes in the mouth

Strawberry tongue white coating on the tongue or prominent red bumps

(papillae) on the back of the tongue

Red palms of the hands and the soles of the feet

Peeling (desquamation) palms and soles (later in the illness) peeling may

begin around the nails

Rash which may take many forms non-specific polymorphic non-itchy

but not vesicle-bullous lesions and appears on the trunk

Swollen lymph nodes (frequently only one lymph node is swollen and is

usually on onc side) particularly in the neck area[



Joint pain (arthralgia) and swelling frequently symmetrical Also arthritis

can occur

Irritability

Tachycardia (rapid heart beat)

Beaus lines (transverse grooves on nails

May find breathing difficult

Less common manifestations System Manifestations

GIT Diarrhea abdominal pain vomiting liver dysfunction pancreatitis Hydrops

gallbladder intussusception intestinal pseudo-obstruction ascites splenic

infarction

MSPolyarthritis and arthralgia

CVS Myocarditis pericarditis valvular heart disease

GUUrethritis prostatitis cystitis priapism Interstitial nephritis orchitis

nephrotic syndrome

CNS Aseptic meningitis and sensorineural deafness

RS Influenza-like illness plural effusion Atelectasis

Skin Erythema and induration at BCG vaccine site Beaus lines and finger

gangrene

Complications

The cardiac complications are the most important aspect of the diseaseKawasaki disease can cause vasculitic changes (inflammation of blood vessels)in the coronary arteries and subsequent coronary artery aneurysms Theseaneurysms can lead to myocardial infarction (heart attack) even in youngchildren Overall about 10ndash18 of children with Kawasaki disease developcoronary artery aneurysms with much higher prevalence among patients who

are not treated early in the course of illness Kawasaki disease and rheumaticfever are the most common causes of acquired heart disease among children inthe United States

DIAGNOSTICSphysical examination will demonstrate many of the features presented in thesigns amp symptoms

Blood tests

Complete blood count (CBC) may reveal normocytic anemia and

eventually thrombocytosis Erythrocyte sedimentation rate (ESR) will be elevated

C-reactive protein (CRP) will be elevated

Liver function tests may show evidence of hepatic inflammation and lowserum albumin

Other optional tests



Electrocardiogram may show evidence of ventricular dysfunction oroccasionally arrhythmia due to myocarditis

Echocardiogram may show subtle coronary artery changes or later trueaneurysms

Ultrasound or computerized tomography may show hydrops(enlargement) of the gallbladder

Urinalysis may show white blood cells and protein in the urine (pyuria and

proteinuria) without evidence of bacterial growth Lumbar puncture may show evidence of aseptic meningitis

Angiography was historically used to detect coronary artery aneurysmsand remains the gold standard for their detection but is rarely used todayunless coronary artery aneurysms have already been detected byechocardiography

Treatment

Children with Kawasaki disease should be hospitalized and cared for by aphysician who has experience with this disease When in an academic medical

center care is often shared between pediatric cardiology and pediatric infectious disease specialists (although no specific infectious agent has been identifiedyet)[ It is imperative that treatment be started as soon as the diagnosis is madeto prevent damage to the coronary arteries

Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasakidisease and is administered in high doses with marked improvementusually noted within 24 hours If the fever does not respond an additionaldose may have to be considered In rare cases a third dose may be givento the child IVIG by itself is most useful within the first seven days of onset of fever in terms of preventing coronary artery aneurysm

Salicylate therapy particularly aspirin remains an important part of the

treatment (though questioned by some) but salicylates alone are not aseffective as IVIG Aspirin therapy is started at high doses until the feversubsides and then is continued at a low dose when the patient returnshome usually for two months to prevent blood clots from forming Exceptfor Kawasaki disease and a few other indications aspirin is otherwisenormally not recommended for children due to its association with Reyessyndrome Because children with Kawasaki disease will be taking aspirinfor up to several months vaccination against varicella and influenza isrequired as these infections are most likely to cause Reyes syndrome

Corticosteroids have also been used especially when other treatments failor symptoms recur but in a randomized controlled trial the addition of corticosteroid to immune globulin and aspirin did not improve outcome In

cases of kawasaki disease refractory to IVIG cyclophosphamide andplasma exchange have been investigated as possible treatments withvariable outcomes

There are also treatments for iritis and other eye symptoms Anothertreatment may include the use of Infliximab (Remicade) Infliximab worksby binding tumour necrosis factor alpha

Prognosis

With early treatment rapid recovery from the acute symptoms can be expectedand the risk of coronary artery aneurysms greatly reduced Untreated the acute

symptoms of Kawasaki disease are self-limited (ie the patient will recovereventually) but the risk of coronary artery involvement is much greater Overallabout 2 of patients die from complications of coronary vasculitis Patients whohave had Kawasaki disease should have an echocardiogram initially every fewweeks and then every one or two years to screen for progression of cardiacinvolvement

It is also not uncommon that a relapse of symptoms may occur soon after initialtreatment with IVIG This usually requires re-hospitalization and re-treatment

Treatment with IVIG can cause allergic and non-allergic acute reactions asepticmeningitis fluid overload and rarely other serious reactions Overall life-



threatening complications resulting from therapy for Kawasaki disease areexceedingly rare especially compared with the risk of non-treatment

Epidemiology

By far the highest incidence of Kawasaki disease occurs in Japan (175 per100000) though its incidence in the United States is increasing Kawasakidisease is predominantly a disease of young children with 80 of patientsyounger than five years of age The disease affects boys more than girlsKawasaki was extremely uncommon in Caucasians until the last few decadesApproximately 2000-4000 cases are identified in the United States each year

StevensndashJohnson syndrome

StevensndashJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) aretwo forms of a life-threatening condition affecting the skin in which cell death causes the epidermis to separate from the dermis The syndrome is thought tobe a hypersensitivity complex affecting the skin and the mucous membranesAlthough the majority of cases are idiopathic the main class of known causes ismedications followed by infections and (rarely) cancers

History

Stevens-Johnson Syndrome is named for Albert Mason Stevens and FrankChambliss Johnson American pediatricians who in 1922 jointly published adescription of the disorder in the American Journal of Diseases of Children

Signs and symptoms

SJS usually begins with fever sore throat and fatigue which is misdiagnosedand usually treated with antibiotics Ulcers and other lesions begin to appear inthe mucous membranes almost always in the mouth and lips but also in thegenital and anal regions Those in the mouth are usually extremely painful andreduce the patients ability to eat or drink Conjunctivitis of the eyes occurs inabout 30 of children who develop SJS A rash of round lesions about an inchacross arises on the face trunk arms and legs and soles of the feet but usuallynot the scalp

Causes

SJS is thought to arise from a disorder of the immune system

1Infections

It can be caused by infections (usually following infections such as herpessimplex virus influenza mumps cat-scratch fever histoplasmosis Epstein-Barrvirus mycoplasma pneumoniae or similar)

2Medicationdrugs



It can be caused by adverse effects of drugs (allopurinol diclofenac etravirineIsotretinoin aka Accutane fluconazole] valdecoxib sitagliptin oseltamivirpenicillins barbiturates sulfonamides phenytoin azithromycin oxcarbazepinezonisamide modafinil[5] lamotrigine nevirapine pyrimethamine ibuprofenethosuximide carbamazepine nystatin and gout medications)

Although StevensndashJohnson Syndrome can be caused by viral infections

malignancies or severe allergic reactions to medication the leading causeappears to be the use of antibiotics and sulfa drugs

Medications that have traditionally been known to lead to SJS erythemamultiforme and toxic epidermal necrolysis include sulfonamides (antibiotics)penicillins (antibiotics) barbiturates (sedatives) lamotrigine and phenytoin (egDilantin) (anticonvulsants) Combining lamotrigine with sodium valproate increases the risk of SJS

Non-steroidal anti-inflammatory drugs are a rare cause of SJS in adults the riskis higher for older patients women and those initiating treatment Typically thesymptoms of drug-induced SJS arise within a week of starting the medication

People with systemic lupus erythematosus or HIV infections are more susceptibleto drug-induced SJS

SJS has also been consistently reported as an uncommon side effect of herbalsupplements containing ginseng SJS may also be caused by cocaine usage

3Genetics

In some East Asian populations studied (Han Chinese and Thai) carbamazepine-

and phenytoin-induced SJS is strongly associated with HLA-B1502 (HLA-B75) anHLA-B serotype of the broader serotype HLA-B15 A study in Europe suggestedthat the gene marker is only relevant for East Asians Based on the Asianfindings similar studies were performed in Europe which showed 61 of allopurinol-induced SJSTEN patients carried the HLA-B58 (B5801 allele -phenotype frequency in Europeans is typically 3) One study concluded evenwhen HLA-B alleles behave as strong risk factors as for allopurinol they areneither sufficient nor necessary to explain the disease

Treatment

SJS constitutes a dermatological emergency All medications should bediscontinued particularly those known to cause SJS reactions Patients withdocumented mycoplasma infections can be treated with oral macrolide or oraldoxycycline

Initially treatment is similar to that for patients with thermal burns andcontinued care can only be supportive (eg intravenous fluids and nasogastric orparenteral feeding) and symptomatic (eg analgesic mouth rinse for mouthulcer) Dermatologists and surgeons tend to disagree about whether the skinshould be debrided[3]



Beyond this kind of supportive care there is no accepted treatment for SJS Treatment with corticosteroids is controversial Early retrospective studiessuggested that corticosteroids increased hospital stays and complication rates

There are no randomized trials of corticosteroids for SJS and it can be managedsuccessfully without them

Other agents have been used including cyclophosphamide and cyclosporine but

none have exhibited much therapeutic success

Intravenous immunoglobulin (IVIG) treatment has shown some promise inreducing the length of the reaction and improving symptoms

Other common supportive measures include the use of topical pain anesthetics and antiseptics maintaining a warm environment and intravenous analgesics

An ophthalmologist should be consulted immediately as SJS frequently causesthe formation of scar tissue inside the eyelids leading to corneal vascularizationimpaired vision and a host of other ocular problems

Also an extensive physical therapy program ensues after the patient isdischarged from the hospital

Prognosis

SJS proper (with less than 10 of body surface area involved) has a mortalityrate of around 5 The risk for death can be estimated using the SCORTENscale which takes a number of prognostic indicators into account Otheroutcomes include organ damagefailure cornea scratching and blindness

Epidemiology

Stevens-Johnson syndrome is a rare condition with a reported incidence of around 26 to 61cases per million people per year In the United States thereare about 300 new diagnoses per year The condition is more common in adultsthan in children Women are affected more often than men with cases occurringat a three to six ratio

GUILLAIN-BARRE SYNDROME

Also known as Infectious polyneuritis Acute inflammatory demyelinatingpolyneuropathy Landrys ascending paralysis

It is sometimes called Landrys paralysis after the French physician who firstdescribed a variant of it in 1859

The syndrome was named after the French physicians Guillain Barreacute and Strohlwho were the first to describe it in 1916

Guillain-barreacute syndrome is a disorder in which the bodys immune system

attacks part of the peripheral nervous system

Guillain-Barre Syndrome (GBS) is an acute condition that involves progressivemuscle weakness or paralysis It is an autoimmune disorder in which the bodyrsquosimmune system attacks its own nervous system causing inflammation thatdamages the cover (myelin sheath) of the nerve This damage (calleddemyelinazation) slows or stops the conduction of impulses through the nerve

The impairment of nerve impulses to the muscles leads to symptoms that may



include muscle weakness paralysis spasms numbness tingling or pins-and-needle sensations andor tenderness Affected patients may become so weakthat they have trouble breathing and their heart rate becomes abnormal

In Guillain-Barre syndrome your immune system mdash which usually only attacksforeign material and invading organisms mdash begins attacking the nerves thatcarry signals between your body and your brain Specifically the nerves

protective covering (myelin sheath) is damaged and this interferes with thesignaling process causing weakness numbness or paralysis

Classification

Six different subtypes of GuillainndashBarreacute syndrome (GBS) exist

Acute inflammatory demyelinating polyneuropathy (AIDP) is the mostcommon form of GBS and the term is often used synonymously with GBS It iscaused by an auto-immune response directed against Schwann cell membranes

Miller Fisher syndrome (MFS) is a rare variant of GBS and manifests as adescending paralysis proceeding in the reverse order of the more common formof GBS It usually affects the eye muscles first and presents with the triad of ophthalmoplegia ataxia and areflexia Anti-GQ1b antibodies are present in 90of cases

Acute motor axonal neuropathy (AMAN)[8] aka Chinese ParalyticSyndrome attacks motor nodes of Ranvier and is prevalent in China andMexico It is probably due to an auto-immune response directed against theaxoplasm of peripheral nerves The disease may be seasonal and recovery canbe rapid Anti-GD1a antibodies[9] are present Anti-GD3 antibodies are found

more frequently in AMAN

Acute motor sensory axonal neuropathy (AMSAN) is similar to AMAN butalso affects sensory nerves with severe axonal damage Like AMAN it isprobably due to an auto-immune response directed against the axoplasm of peripheral nerves Recovery is slow and often incomplete[10]

Acute panautonomic neuropathy is the most rare variant of GBS sometimesaccompanied by encephalopathy It is associated with a high mortality rateowing to cardiovascular involvement and associated dysrhythmias Impairedsweating lack of tear formation photophobia dryness of nasal and oral mucosaitching and peeling of skin nausea dysphagia constipation unrelieved bylaxatives or alternating with diarrhea occur frequently in this patient groupInitial nonspecific symptoms of lethargy fatigue headache and decreasedinitiative are followed by autonomic symptoms including orthostaticlightheadedness blurring of vision abdominal pain diarrhea dryness of eyesand disturbed micturition The most common symptoms at onset are related toorthostatic intolerance as well as gastrointestinal and sudomotor dysfunction(Suarez et al 1994) Parasympathetic impairment (abdominal pain vomitingobstipation ileus urinary retention dilated unreactive pupils loss of accommodation) may also be observed

Bickerstaffrsquos brainstem encephalitis (BBE) is a further variant of GuillainndashBarreacute syndrome It is characterized by acute onset of ophthalmoplegia ataxiadisturbance of consciousness hyperreflexia or Babinskirsquos sign (Bickerstaff 1957Al-Din et al1982) The course of the disease can be monophasic or remitting-relapsing Large irregular hyperintense lesions located mainly in the brainstemespecially in the pons midbrain and medulla are described in the literature BBEdespite severe initial presentation usually has a good prognosis Magneticresonance imaging (MRI) plays a critical role in the diagnosis of BBE

A considerable number of BBE patients have associated axonal GuillainndashBarreacutesyndrome indicative that the two disorders are closely related and form acontinuous spectrum



CLINICAL MANIFESTAIONS

Typical symptoms include

Loss of reflexes in the arms and legs

Low blood pressure or poor blood pressure control

Muscle weakness or loss of muscle function (paralysis)

In mild cases there may be weakness instead of paralysis

May begin in the arms and legs at the same time

May get worse over 24 to 72 hours

May occur in the nerves of the head only

May start in the arms and move downward

May start in the feet and legs and move up to the arms and head

Numbness

Sensation changes

Tenderness or muscle pain (may be a cramp-like pain)

Uncoordinated movement

Other symptoms may include

Blurred vision

Clumsiness and falling

Difficulty moving face muscles

Muscle contractions

Palpitations (sensation of feeling the heart beat) ndash AUTONOMIC FUNCTION

RISK FACTORS

The exact causes of Guillain-Barre Syndrome (GBS) are not known It is neither

contagious nor hereditary A viral or bacterial infection causes allergic reaction

which damages the protective sheath around the peripheral nerves

(demyelination) leading to cessation of signal passage to muscles which causes

tingling weakness and eventual short-term paralysis

Generally a viral or bacterial infection precedes the onset of GBS The infections

are as follows

Flu and Common cold

Gastrointestinal viral infection

Infectious mononucleosis

Viral hepatitis



Campylobacteriosis (usually from eating undercooked poultry)

Porphyria (rare disease of red blood cells)

Bacterial infections (such as salmonella poisoning)

Hodgkins disease (tumor of the lymph glands - the small bean-sized organs

that carry white blood cells)

Immunization (such as the influenza vaccine) in very rare cases

Diagnostic TestsPatient history is important in diagnosis The progression of ascending paralysisndash starting with feet or hands and advancing upward - is a typical presentationAbout 50 of cases also include a history of a recent mild infection or illness likea sore throat a cold the flu or diarrhea Several tests are commonly used todiagnose or confirm the disease and sometimes to monitor recovery

Nerve conduction velocity ndash tests the speed at which impulses travel through anerve The nerve conduction velocity test uses electrodes placed on the skinover peripheral nerves and measures the amount of time it takes for an impulseto travel between electrodes

Electromyography (EMG) - measures the electrical activity of muscles fibers TheEMG test measures the electrical activity within muscle fibers by placing aneedle electrode through the skin directly into the muscle and measuring theelectrical activity of that muscle It is usually done in conjunction with a nerveconduction velocity test

Cerebrospinal fluid (CSF) evaluation ndash to identify the presence of increasedprotein For this test a needle is inserted into the spine between vertebrae and asmall amount of fluid is withdrawn While some protein is normally present anincreased amount without an increase in the white blood cells in the CSF may beindicative of GBS

TREATMENT

There is no known cure for Guillain-Barre syndrome The goal of treatment is tolessen the severity of the illness and accelerate the recovery There are also anumber of ways to treat the complications of the disease

Plasmapheresis

Plasmapheresis or plasma exchange seems to reduce the severity and durationof a Guillain-Barreacute episode Plasmapheresis is a process of mechanicallyremoving autoantibodies from the blood The blood is passed through a cellseparator which either spins the blood at high speed or filters the bloodthrough a membrane The cells are returned to the body while the plasma (fluid)which contains the offending antibodies is discarded The plasma is replacedwith other fluids

High-dose immunoglobulin therapy

In high-dose immunoglobulin therapy doctors give intravenous injections of theproteins that in small quantities the immune system uses naturally to attackinvading organisms Investigators have found that giving high doses of theseimmunoglobulins derived from a pool of thousands of normal donors to Guillain-Barreacute patients can lessen the immune attack on the nervous system

Respiratory Support



The most critical part of the treatment for this syndrome consists of keeping thepatients body functioning during recovery of the nervous system This cansometimes require placing the patient on a respirator a heart monitor or othermachines that assist body function

Physical Therapy

There is a great possibility that physical therapy will be started soon after thepatient becomes medically stable This treatment can range from having thephysical therapist perform stretching for the patient while they are unable tomove to starting to get the patient out of bed and walking again It is importantto maintain joint range of motion in the early stages to maintain flexibility andprevent bed sores Aquatic therapy will often be started early on in recovery aswell to help intiate movement Currently it is thought that too much exercisewhile still in the recovery phase can be damaging to the patient The physicaltherapist will be sure to monitor the intensity and keep it to a tolerable level Asable therapy will then be transfered to the land working on walking functionaltasks balance and much more

Possible Complications

Breathing difficulty (respiratory failure)

ContracturesContractures of joints or other deformity

Deep vein thrombosisDeep vein thrombosis (blood clots that form whensomeone is inactive or confined to bed)

Increased risk of infections

Low or unstable blood pressure

Paralysis that is permanent

Pneumonia

Skin damage (ulcersulcers)

Sucking food or fluids into the lungs (aspirationaspiration)

MALARIA

Malaria is a mosquito-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium It is widespread in tropical and subtropical regions including parts of the

Americas (22 countries) Asia and Africa Each year there are more than 250 million cases

of malaria killing between one and three million people the majority of whom are young

children Malaria is commonly associated with poverty and can indeed be a cause of povertyand a major hindrance to economic development

Five species of the plasmodium parasite can infect humans the most serious forms of the

disease are caused by Plasmodium falciparum Malaria caused by Plasmodium vivax Plasmodium ovale and Plasmodium malariae causes milder disease in humans that is notgenerally fatal A fifth species Plasmodium knowlesi is a zoonosis that causes malaria in

macaques but can also infect humans

Malaria is naturally transmitted by the bite of a female Anopheles mosquito When amosquito bites an infected person a small amount of blood is taken which contains malaria

parasites These develop within the mosquito and about one week later when the mosquito

takes its next blood meal the parasites are injected with the mosquitos saliva into the person

being bitten



Signs and symptom

Symptoms of malaria include fever shivering arthralgia (joint pain) vomiting anemia

(caused by hemolysis

) hemoglobinuria retinal damage and convulsions

The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor

and then fever and sweating lasting four to six hours occurring every two days in P vivaxand P ovale infections while every three days for P malariae P falciparum can have

recurrent fever every 36ndash48 hours or a less pronounced and almost continuous fever For

reasons that are poorly understood but that may be related to high intracranial pressurechildren with malaria frequently exhibit abnormal posturing a sign indicating severe brain

damage Malaria has been found to cause cognitive impairments especially in children It

causes widespread anemia during a period of rapid brain development and also direct braindamage This neurologic damage results from cerebral malaria to which children are more

vulnerable Cerebral malaria is associated with retinal whitening which may be a useful

clinical sign in distinguishing malaria from other causes of fever

Causes

1Malaria parasites

Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa

) In humans

malaria is caused by P falciparum P malariae P ovale P vivax and P knowlesi[22][23]

P falciparum is the most common cause of infection and is responsible for about 80 of all

malaria cases and is also responsible for about 90 of the deaths from malaria Parasitic Plasmodium species also infect birds reptiles monkeys chimpanzees and rodents There

have been documented human infections with several simian species of malaria namely Pknowlesi P inui P cynomolgi P simiovale P brazilianum P schwetzi and P simiumhowever with the exception of P knowlesi these are mostly of limited public health

importance

Malaria parasites contain apicoplasts an organelle usually found in plants complete with

their own functioning genomes These apicoplast are thought to have originated through the

endosymbiosis of algae and play a crucial role in various aspects of parasite metabolism egfatty acid bio-synthesis To date 466 proteins have been found to be produced by apicoplasts

and these are now being looked at as possible targets for novel anti-malarial drugs

2 Mosquito vectors and the Plasmodium life cycle

The parasites primary (definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus while humans and other vertebrates are secondary hosts Young

mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the

infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands A

mosquito becomes infected when it takes a blood meal from an infected human Once

ingested the parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the mosquito gut This produces an ookinete that penetrates

the gut lining and produces an oocyst in the gut wall When the oocyst ruptures it releasessporozoites that migrate through the mosquitos body to the salivary glands where they are

then ready to infect a new human host This type of transmission is occasionally referred to

as anterior station transfer The sporozoites are injected into the skin alongside saliva whenthe mosquito takes a subsequent blood meal

Only female mosquitoes feed on blood thus males do not transmit the disease The females

of the Anopheles genus of mosquito prefer to feed at night They usually start searching for a



meal at dusk and will continue throughout the night until taking a meal Malaria parasitescan also be transmitted by blood transfusions although this is rare

Pathogenesis

The life cycle of malaria parasites in the human body A mosquito infects a person by taking

a blood meal First sporozoites enter the bloodstream and migrate to the liver They infectliver cells (hepatocytes) where they multiply into merozoites rupture the liver cells and

escape back into the bloodstream Then the merozoites infect red blood cells where they

develop into ring forms trophozoites and schizonts which in turn produce further merozoitesSexual forms (gametocytes) are also produced which if taken up by a mosquito will infect

the insect and continue the life cycle

Malaria in humans develops via two phases an exoerythrocytic and an erythrocytic phase

The exoerythrocytic phase involves infection of the hepatic system or liver whereas theerythrocytic phase involves infection of the erythrocytes or red blood cells When an

infected mosquito pierces a persons skin to take a blood meal sporozoites in the mosquitos

saliva enter the bloodstream and migrate to the liver Within 30 minutes of being introducedinto the human host the sporozoites infect hepatocytes multiplying asexually and

asymptomatically for a period of 6ndash15 days Once in the liver these organisms differentiate

to yield thousands of merozoites which following rupture of their host cells escape into the blood and infect red blood cells thus beginning the erythrocytic stage of the life cycle The

parasite escapes from the liver undetected by wrapping itself in the cell membrane of the

infected host liver cell

Within the red blood cells the parasites multiply further again asexually periodically breaking out of their hosts to invade fresh red blood cells Several such amplification cycles

occur Thus classical descriptions of waves of fever arise from simultaneous waves of

merozoites escaping and infecting red blood cells

Some P vivax and P ovale sporozoites do not immediately develop into exoerythrocytic- phase merozoites but instead produce hypnozoites that remain dormant for periods ranging

from several months (6ndash12 months is typical) to as long as three years After a period of

dormancy they reactivate and produce merozoites Hypnozoites are responsible for longincubation and late relapses in these two species of malaria

The parasite is relatively protected from attack by the bodys immune system because for

most of its human life cycle it resides within the liver and blood cells and is relatively

invisible to immune surveillance However circulating infected blood cells are destroyed inthe spleen To avoid this fate the P falciparum parasite displays adhesive proteins on the

surface of the infected blood cells causing the blood cells to stick to the walls of small blood

vessels thereby sequestering the parasite from passage through the general circulation andthe spleen This stickiness is the main factor giving rise to hemorrhagic complications of

malaria High endothelial venules (the smallest branches of the circulatory system) can be

blocked by the attachment of masses of these infected red blood cells The blockage of these

vessels causes symptoms such as in placental and cerebral malaria In cerebral malaria thesequestrated red blood cells can breach the blood brain barrier possibly leading to coma

Although the red blood cell surface adhesive proteins (called PfEMP1 for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system they do not

serve as good immune targets because of their extreme diversity there are at least 60variations of the protein within a single parasite and effectively limitless versions within

parasite populations The parasite switches between a broad repertoire of PfEMP1 surface

proteins thus staying one step ahead of the pursuing immune system

Some merozoites turn into male and female gametocytes If a mosquito pierces the skin of an

infected person it potentially picks up gametocytes within the blood Fertilization and sexual

recombination of the parasite occurs in the mosquitos gut thereby defining the mosquito as



the definitive host of the disease New sporozoites develop and travel to the mosquitossalivary gland completing the cycle Pregnant women are especially attractive to the

mosquitoes and malaria in pregnant women is an important cause of stillbirths infant

mortality and low birth weight particularly in P falciparum infection but also in other species infection such as P vivax

Diagnosis

Blood smear from a P falciparum culture (K1 strain) Several red blood cells have ring

stages inside them Close to the center there is a schizont and on the left a trophozoite

Since Charles Laveran first visualised the malaria parasite in blood in 1880 [41] the mainstay

of malaria diagnosis has been the microscopic examination of blood

Fever and septic shock are commonly misdiagnosed as severe malaria in Africa leading to a

failure to treat other life-threatening illnesses In malaria-endemic areas parasitemia does notensure a diagnosis of severe malaria because parasitemia can be incidental to other

concurrent disease Recent investigations suggest that malarial retinopathy is better

(collective sensitivity of 95 and specificity of 90) than any other clinical or laboratoryfeature in distinguishing malarial from non-malarial coma[42]

Although blood is the sample most frequently used to make a diagnosis both saliva and urine

have been investigated as alternative less invasive specimens

Symptomatic diagnosis

1Microscopic examination of blood films

The most economic preferred and reliable diagnosis of malaria is microscopic examination

of blood films because each of the four major parasite species has distinguishing

characteristics Two sorts of blood film are traditionally used Thin films are similar to usual blood films and allow species identification because the parasites appearance is best

preserved in this preparation Thick films allow the microscopist to screen a larger volume of

blood and are about eleven times more sensitive than the thin film so picking up low levels

of infection is easier on the thick film but the appearance of the parasite is much moredistorted and therefore distinguishing between the different species can be much more

difficult With the pros and cons of both thick and thin smears taken into consideration it is

imperative to utilize both smears while attempting to make a definitive diagnosis

From the thick film an experienced microscopist can detect parasite levels (or parasitemia)

down to as low as 00000001 of red blood cells Diagnosis of species can be difficult

because the early trophozoites (ring form) of all four species look identical and it is never

possible to diagnose species on the basis of a single ring form species identification isalways based on several trophozoites

2Antigen tests

Malaria antigen detection tests are a group of commercially available tests that allow the rapid

diagnosis of malaria

For areas where microscopy is not available or where laboratory staff are not experienced at

malaria diagnosis there are commercial antigen detection tests that require only a drop of blood Immunochromatographic tests (also called Malaria Rapid Diagnostic Tests Antigen-

Capture Assay or Dipsticks) been developed distributed and fieldtested These tests use

finger-stick or venous blood the completed test takes a total of 15ndash20 minutes and theresults are read visually as the presence or absence of colored stripes on the dipstick so they

are suitable for use in the field The threshold of detection by these rapid diagnostic tests is in

the range of 100 parasitesmicrol of blood (commercial kits can range from about 0002 to 01 parasitemia) compared to 5 by thick film microscopy One disadvantage is that dipstick tests



are qualitative but not quantitative - they can determine if parasites are present in the blood but not how many

3Molecular methods

Molecular methods are available in some clinical laboratories and rapid real-time assays (for example QT-NASBA based on the polymerase chain reaction

) are being developed with the

hope of being able to deploy them in endemic areas

PCR (and other molecular methods) is more accurate than microscopy However it is

expensive and requires a specialized laboratory Moreover levels of parasitemia are notnecessarily correlative with the progression of disease particularly when the parasite is able

to adhere to blood vessel walls Therefore more sensitive low-tech diagnosis tools need to be

developed in order to detect low levels of parasitemia in the field[49]

Prevention

Methods used in order to prevent the spread of disease or to protect individuals in areas

where malaria is endemic include prophylactic drugs mosquito eradication and the

prevention of mosquito bites The continued existence of malaria in an area requires acombination of high human population density high mosquito population density and high

rates of transmission from humans to mosquitoes and from mosquitoes to humans If any of

these is lowered sufficiently the parasite will sooner or later disappear from that area ashappened in North America Europe and much of Middle East However unless the parasite

is eliminated from the whole world it could become re-established if conditions revert to a

combination that favors the parasites reproduction Many countries are seeing an increasingnumber of imported malaria cases due to extensive travel and migration

Prophylactic drugs

Several drugs most of which are also used for treatment of malaria can be taken

preventively Modern drugs used include mefloquine ( Lariam) doxycycline (available

generically) and the combination of atovaquone and proguanil hydrochloride ( Malarone)Doxycycline and the atovaquone and proguanil combination are the best tolerated with

mefloquine associated with higher rates of neurological and psychiatric symptoms The

choice of which drug to use depends on which drugs the parasites in the area are resistant to

as well as side-effects and other considerations The prophylactic effect does not beginimmediately upon starting taking the drugs so people temporarily visiting malaria-endemic

areas usually begin taking the drugs one to two weeks before arriving and must continuetaking them for 4 weeks after leaving (with the exception of atovaquone proguanil that onlyneeds be started 2 days prior and continued for 7 days afterwards) Generally these drugs are

taken daily or weekly at a lower dose than would be used for treatment of a person who had

actually contracted the disease Use of prophylactic drugs is seldom practical for full-timeresidents of malaria-endemic areas and their use is usually restricted to short-term visitors

and travelers to malarial regions This is due to the cost of purchasing the drugs negative

side effects from long-term use and because some effective anti-malarial drugs are difficult

to obtain outside of wealthy nations



Quinine was used historically however the development of more effective alternatives suchas quinacrine chloroquine and primaquine in the 20th century reduced its use Today

quinine is not generally used for prophylaxis The use of prophylactic drugs where malaria-

bearing mosquitoes are present may encourage the development of partial immunity

Vector control

Efforts to eradicate malaria by eliminating mosquitoes have been successful in someareasbut vector control programs in conjunction with the monitoring and treatment of

infected humans eliminated it from those regions In some areas the draining of wetland

breeding grounds and better sanitation were adequate

Malaria was successfully eradicated or controlled also in several tropical areas by removingor poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva

stages for example by filling or applying oil to places with standing water

Indoor residual spraying

Indoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of homes in malaria affected areas After feeding many mosquito species rest on a nearby

surface while digesting the bloodmeal so if the walls of dwellings have been coated with

insecticides the resting mosquitos will be killed before they can bite another victim

transferring the malaria parasite

The first pesticide used for IRS was DDT DDT (from its trivial name

dichlorodiphenyltrichloroethane) is one of the most well-known synthetic pesticides

Although it was initially used exclusively to combat malaria its use quickly spread to

agriculture In time pest-control rather than disease-control came to dominate DDT use

and this large-scale agricultural use led to the evolution of resistant mosquitoes in manyregions

DDT may now be more effective as a method of disease-control

Mosquito nets and bedclothes

Mosquito nets help keep mosquitoes away from people and greatly reduce the infection andtransmission of malaria The nets are not a perfect barrier and they are often treated with an

insecticide designed to kill the mosquito before it has time to search for a way past the net

Insecticide-treated nets (ITNs) are estimated to be twice as effective as untreated nets and

offer greater than 70 protection compared with no net

The distribution of mosquito nets impregnated with insecticides such as permethrin or

deltamethrin has been shown to be an extremely effective method of malaria prevention and

it is also one of the most cost-effective methods of prevention ITNs have been shown to be

the most cost-effective prevention method against malaria and are part of WHOrsquosMillennium Development Goals (MDGs)

While distributing mosquito nets is a major component of malaria prevention community

education and awareness on the dangers of malaria are associated with distributioncampaigns to make sure people who receive a net know how to use it

Vaccination

Immunity (or more accurately tolerance) does occur naturally but only in response to

repeated infection with multiple strains of malaria

Vaccines for malaria are under development with no completely effective vaccine yet

available The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live radiation-attenuated sporozoites providing

protection to about 60 of the mice upon subsequent injection with normal viable



sporozoites Since the 1970s there has been a considerable effort to develop similar vaccination strategies within humans It was determined that an individual can be protected

from a P falciparum infection if they receive over 1000 bites from infected irradiated

mosquitoes

Other methods

Education in recognizing the symptoms of malaria has reduced the number of cases in someareas of the developing world by as much as 20 Recognizing the disease in the early stages

can also stop the disease from becoming a killer

Education can also inform people to cover over areas of stagnant still water eg Water Tanks

which are ideal breeding grounds for the parasite and mosquito thus cutting down the risk of the transmission between people This is most put in practice in urban areas where there are

large centers of population in a confined space and transmission would be most likely in

these areas

The Malaria Control Project is currently using downtime computing power donated byindividual volunteers around the world (see Volunteer computing and BOINC) to simulate

models of the health effects and transmission dynamics in order to find the best method or

combination of methods for malaria control This modeling is extremely computer intensivedue to the simulations of large human populations with a vast range of parameters related to

biological and social factors that influence the spread of the disease It is expected to take a

few months using volunteered computing power compared to the 40 years it would havetaken with the current resources available to the scientists who developed the program

TreatmentThe treatment of malaria depends on the severity of the disease Uncomplicated malaria is

treated with oral drugs Whether patients who can take oral drugs have to be admitteddepends on the assessment and the experience of the clinician Severe malaria requires the

parenteral administration of antimalarial drugs The traditional treatment for severe malaria

has been quinine but there is evidence that the artemisinins are also superior for the treatmentof severe malaria Active malaria infection with P falciparum is a medical emergency

requiring hospitalization Infection with P vivax P ovale or P malariae can often be treated

on an outpatient basis Treatment of malaria involves supportive measures as well as specificantimalarial drugs Most antimalarial drugs are produced industrially and are sold at

pharmacies

DENGUE FEVER

Dengue fever are acute febrile diseases transmitted by mosquitoes which occur in thetropics can be life-threatening and are caused by four closely related virus serotypes of the

genus Flavivirus

It is also known as breakbone fever since it can be extremely painful It occurs widely in

the tropics Unlike malaria dengue is just as prevalent in the urban districts of its range as inrural areasDengue is transmitted to humans by the Aedes (Stegomyia) aegypti or more rarely

the Aedes albopictus mosquito The mosquitoes that spread dengue usually bite at dusk and

dawn but may bite at any time during the day especially indoors in shady areas or when theweather is cloudy

The WHO says some 25 billion people two fifths of the worlds population are now at risk

from dengue and estimates that there may be 50 million cases of dengue infection worldwide

every year The disease is now endemic in more than 100 countries



Signs and symptoms

The disease manifests as fever of sudden onset associated with headache muscle and joint

pains (myalgias and arthralgias mdashsevere pain that gives it the nickname break-bone fever or

bonecrusher disease) distinctive retro-orbital pain and rash

The classic dengue rash is a generalised maculopapular rash with islands of sparing Ahemorrhagic rash of characteristically bright red pinpoint spots known as petechiae can

occur later during the illness and is associated with thrombocytopenia It usually appears first

on the lower limbs and the chest in some patients it spreads to cover most of the body

There may also be severe retro-orbital pain (a pain from behind the eyes that is distinctive toDengue infections) and gastritis with some combination of associated abdominal pain

nausea vomiting coffee-grounds-like congealed blood or diarrhea Some cases develop

much milder symptoms which can be misdiagnosed as influenza or other viral infection whenno rash or retro-orbital pain is present Febrile travelers from tropical areas may transmit

dengue inadvertently to previously Dengue free populations of Aedes (Stegomyia) aegypti

mosquitoes having not been properly diagnosed for Dengue Patients only transmit Denguewhen they are febrile and bitten by Aedes (Stegomyia) aegypti mosquitoes or (much more

unusually) via blood products The classic dengue fever lasts about two to seven days with a

smaller peak of fever at the trailing end of the disease (the so-called biphasic pattern)recovery may be associated with prolonged fatigue and depression Clinically the platelet

count will drop until after the patients temperature is normal Cases of DHF also show

higher fever variable hemorrhagic phenomena including bleeding from the eyesnosemouth

and ear into the gut and oozing blood from skin pores thrombocytopenia andhemoconcentration When Dengue infections proceed to DHF symptoms DHF causes

vascular leak syndrome which includes fluid in the blood vessels leaking through the skin

and into spaces around the lungs and belly This fluid loss and severe bleeding can cause

blood pressure to fall then Dengue Shock Syndrome (DSS) sets in which has a highmortality rate Neurological manifestations such as encephalitis may also occur

Diagnosis

The diagnosis of dengue is usually made clinically The classic picture is high fever with nolocalising source of infection a rash with thrombocytopenia and relative leukopenia - low

platelet and white blood cell count Dengue infection can affect many organs and thus may

present unusually as liver dysfunction renal impairment meningo-encephalitis or gastroenteritis

Fever headaches eye pain severe dizziness and loss of appetite

Hemorrhagic tendency (positive tourniquet test spontaneous bruising bleeding frommucosa gingiva injection sites etc vomiting blood or bloody diarrhea)

Thrombocytopenia (lt100000 platelets per mmsup3 or estimated as less than 3 platelets

per high power field)

Evidence of plasma leakage (hematocrit more than 20 higher than expected or dropin hematocrit of 20 or more from baseline following IV fluid pleural effusion

ascites hypoproteinemia)

Encephalitic occurrences

Dengue shock syndrome is defined as dengue hemorrhagic fever plus

Weak rapid pulse

Narrow pulse pressure (less than 20 mm Hg)

Cold clammy skin and restlessness

Dependable immediate diagnosis of dengue can be performed in rural areas by the use of Rapid Diagnostic Test kits which also differentiate between primary and secondary dengue

infections



Serology and polymerase chain reaction (PCR) studies are available to confirm the

diagnosis of dengue if clinically indicated Dengue can be a life threatening fever

One test is called Platelia Dengue NS1 Ag assay or NS1 antigen test for short made

by Bio-Rad Laboratories and Pasteur Institute introduced in 2006 allows rapid

detection before antibodies appear the first day of fever

PreventionThere is no tested and approved vaccine for the dengue flavivirus There are many ongoing

vaccine development programs Among them is the Pediatric Dengue Vaccine Initiative set

up in 2003 with the aim of accelerating the development and introduction of denguevaccine(s) that are affordable and accessible to poor children in endemic countries

TREATMENT

The mainstay of treatment is timely supportive therapy to tackle circulatory shock due tohemoconcentration and bleeding

Close monitoring of vital signs in the critical period (up to 2 days after defervescence- the departure or subsiding of a fever) is critical

Oral rehydration therapy is recommended to prevent dehydration in moderate to

severe cases Supplementation with intravenous fluids may be necessary to preventdehydration and significant concentration of the blood if the patient is unable to

maintain oral intake

A platelet transfusion may be indicated if the platelet level drops significantly (below

20000) or if there is significant bleeding The presence of melena may indicate

internal gastrointestinal bleeding requiring platelet andor red blood cell transfusion

Aspirin and non-steroidal anti-inflammatory drugs should be avoided as these drugs

may worsen the bleeding tendency associated with some of these infections Patientsmay receive paracetamol acetaminophen preparations to deal with these symptoms if

dengue is suspected



Musculoskeletal

The most commonly sought medical attention is for joint pain with the small joints of the hand and wrist usually affected although all joints are at risk TheLupus Foundation of America estimates that more than 90 percent of thoseaffected will experience joint andor muscle pain at some time during the courseof their illness

Unlike rheumatoid arthritis lupus arthritis is less disabling and usually does notcause severe destruction of the joints Fewer than ten percent of people withlupus arthritis will develop deformities of the hands and feet SLE patients are atparticular risk of developing osteoarticular tuberculosis

It is suggested that there might be an association between rheumatoid arthritis and SLE and that SLE is associated with an increased risk of bone fractures inrelatively young women

Hematological

Anaemia and other iron deficiencies may develop in up to 50 of cases Lowplatelet and white blood cell counts may be due to the disease or a side-effect of pharmacological treatment People with SLE may have an association withantiphospholipid antibody syndrome (a thrombotic disorder) whereinautoantibodies to phospholipids are present in their serum Abnormalitiesassociated with antiphospholipid antibody syndrome include a paradoxicalprolonged PTT Partial thromboplastin time (which usually occurs in hemorrhagicdisorders) and a positive test for antiphospholipid antibodies the combination of such findings have earned the term lupus anticoagulant -positive Anotherautoantibody finding in SLE is the anticardiolipin antibody which can cause afalse positive test for syphilis

Cardiac

A person with SLE may have inflammation of various parts of the heart such aspericarditis myocarditis and endocarditis The endocarditis of SLE ischaracteristically noninfective (Libman-Sacks endocarditis) and involves eitherthe mitral valve or the tricuspid valve Atherosclerosis also tends to occur moreoften and advances more rapidly than in the general population[14][15][16]

Pulmonary

Lung and pleura inflammation can cause pleuritis pleural effusion lupus

pneumonitis chronic diffuse interstitial lung disease pulmonary hypertensionpulmonary emboli pulmonary hemorrhage and shrinking lung syndrome

Renal

Painless hematuria or proteinuria may often be the only presenting renalsymptom Acute or chronic renal impairment may develop with lupus nephritisleading to acute or end-stage renal failure Because of early recognition andmanagement of SLE end-stage renal failure occurs in less than 5 of cases

A histological hallmark of SLE is membranous glomerulonephritis with wire loopabnormalities This finding is due to immune complex deposition along the

glomerular basement membrane leading to a typical granular appearance inimmunofluorescence testing

Neuropsychiatric

Neuropsychiatric syndromes can result when SLE affects the central orperipheral nervous system The American College of Rheumatology defines 19neuropsychiatric syndromes in systemic lupus erythematosus The diagnosis of








Neurological



Systemic


Causes


1Genetics








males



3Drug reactions


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Diagnostic criteria





Criteria















Prevention






Pregnancy




Treatment




Medications












Analgesia





Lifestyle changes





Prognosis
















and brain




Signs and symptoms






Diagnosis








Treatment






Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected








Neurological



Systemic


Causes


1Genetics








males



3Drug reactions


Laboratory tests






Diagnostic criteria





Criteria















Prevention






Pregnancy




Treatment




Medications












Analgesia





Lifestyle changes





Prognosis
















and brain




Signs and symptoms






Diagnosis








Treatment






Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




males



3Drug reactions


Laboratory tests






Diagnostic criteria





Criteria















Prevention






Pregnancy




Treatment




Medications












Analgesia





Lifestyle changes





Prognosis
















and brain




Signs and symptoms






Diagnosis








Treatment






Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




Criteria















Prevention






Pregnancy




Treatment




Medications












Analgesia





Lifestyle changes





Prognosis
















and brain




Signs and symptoms






Diagnosis








Treatment






Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected



Pregnancy




Treatment




Medications












Analgesia





Lifestyle changes





Prognosis
















and brain




Signs and symptoms






Diagnosis








Treatment






Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected







Analgesia





Lifestyle changes





Prognosis
















and brain




Signs and symptoms






Diagnosis








Treatment






Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected














and brain




Signs and symptoms






Diagnosis








Treatment






Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




Diagnosis








Treatment






Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




Dry eyes

Punctal Plugs



eye longer


Dental care




Prognosis







Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




Complications


KAWASAKI DISEASE




Signs and symptoms







Anterior uveitis















can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




can occur

Irritability







infarction




nephrotic syndrome




gangrene

Complications




Blood tests














Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected









Treatment









Prognosis








Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




Epidemiology




History


Signs and symptoms


Causes


1Infections


2Medicationdrugs










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected










3Genetics



Treatment













Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected











Prognosis


Epidemiology















Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected






Classification























Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected














Numbness

Sensation changes




Blurred vision



Muscle contractions


RISK FACTORS







are as follows

Flu and Common cold



Viral hepatitis













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected













TREATMENT


Plasmapheresis




Respiratory Support




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




Physical Therapy









Pneumonia



MALARIA











being bitten



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected



Signs and symptom












Causes

1Malaria parasites


) In humans





importance



















Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




Pathogenesis








































Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected






Diagnosis

























2Antigen tests












3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected




3Molecular methods








Prevention








Prophylactic drugs


















Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected






Vector control




























Vaccination










mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected





mosquitoes

Other methods






these areas












pharmacies

DENGUE FEVER


genus Flavivirus










Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected



Signs and symptoms




















Diagnosis












Weak rapid pulse




infections











TREATMENT











dengue is suspected











TREATMENT











dengue is suspected

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