RHEUMATIC FEVER 462 Rheumatic fever De \201 nition Rheumatic fever is a delayed, multisystem disease that occurs following gro up A streptococcal infection of the pharynx. The pathogenesis and immune mechanisms are still not completely understood. The host \200 \231s humoral and cell-mediated immune response to the bacterium s antigens determine the s everity of the individual clinical response, although the virulence of the streptococcal sp ecies is also important. The strains of group A streptococcus associated with acute rheumat ic fever may express an M protein or antiphagocytic component in their cell wall. A decreas ing incidence of acute rheumatic fever in the United States over the past 50 years is corre lated with the falling incidence of streptococcal pharyngitis in chil- dren. This may be du e to changing strains of group A streptococcal infection. Spectrum of disease Rheumatic heart disease is a major cause of morbidity and mortality in low and middle income countries, and among underprivileged communities in high income coun- tries. Primary prevention of acute rheumatic fever is pos- sible with adequate antibiotic treatment of streptococcal throat infections. Diagnostic criteria \200 The modi \201 ed Jones criteria are commonly used to diag- nose the initial attack of acut e rheumatic fever. The probability of acute rheumatic fever is high when there is evidence of recent streptococcal infection (increase in the antistreptolysin O titre) with either tw o major, or one major and two minor manifestations. Permanent damage to heart valves may re sult from recurrent attacks of rheumatic fever. The other major manifestations are transien t and do not lead to permanent damage but are important in the diagnosis. Clinical presentation of acute rheumatic fever Key features in history and examination \200 There is normally a history of sore throat, which pre- cedes other symptoms by an average o f 3 weeks (range 1 \200\2235 weeks). The modi \201 ed Jones criteria for the diagnosis of acute rheumatic fever are necessary as the presentation is variable. A high index of clinic al suspicion is necessary. Arthritis \200 A migratory pattern of joint involvement is seen, with several joints being affected at any one time, with synovi- tis persisting for around a week before settling. However, despite the use of NSAIDs, the pain is often more severe than the clinical \201 ndings. Those joi nts involved normally include the large weight bearing joints, with a very small minority p resenting with only small joint involvement. Modi \201 ed Jones criteria for diagnosis of acute rheumatic fever, 1992 Major criteria \200 Carditis \200 Polyarthritis \200 Erythema marginatum \200 Subcutaneous nodules \200 Chorea Carditis \200 Cardiac symptoms are variable, and include non-speci \201 c chest discomfort or symptoms o f heart failure. New or changing murmurs may be found on examina- tion. The commonest is a mitral regurgitant murmur, although aortic regurgitation is also a feature. If extensive va lvular disease occurs, signs of congestive cardiac failure may be detected, needing urgent and aggressive therapy. Varying degrees of heart block are recognized. First degree heart b lock is asymptomatic and other sympto- matic forms may require pacing. Minor criteria \200 \200 \200 \200 Prolonged P \200\223R interval on electrocardiogram Arthralgia Fever Acute phase reactants Plus supporting evidence of a preceding streptococcal infection for both major and minor cr iteria Epidemiology \200 Chorea \200 Acute rheumatic fever is prevalent in developing coun- tries, where there is overcrowding a nd poor access to health care. The highest reported incidence of acute rheumatic fever is i n indigenous populations of Australia and New Zealand, although incidence is yet to be esta blished in many developing countries. The estimated annual number of cases in those popula- tions with a high incidence is 374 per 100 000 population in the 5 \200\22314 years age gr oup with 60% estimated to develop rheumatic heart disease. In the west, the incidence has d ropped to fewer than 1 per 100 000 population. An abrupt, non-rhythmic, involuntary movement disor- der is characteristic of Sydenham \200 \231s chorea or St Vitus \200\231 dance. Classically, these movements disappear during slee p but recur on waking and are present at rest. Facial muscles may also be involved and invo luntary grimacing and smiling may occur. Muscle weakness can be detected in the milking sig n when the patient is asked to squeeze the \201 ngers of the examiners hand. The patients grip contracts and releases continuously as if the patient were milking. Inappropriate beh avior is a manifestation of neurologi- cal involvement Skin involvement \200 Etiology and pathophysiology \200 Subcutaneous nodules lasting less than a month are painless and \201 rm. They vary in siz e, but may be as large as 2 cm, when they may mimic rheumatoid nodules. It is well established that group A beta haemolytic strep- tococcus causes acute rheumatic fever, but not by a direct toxic effect. CHAPTER 16 Musculoskeletal infection 463 Erythema marginatum is a pink or red rash generally found on the trunk and limbs, but with sparing of the face. The term marginatum describes the resolution of the rash from the cent er giving a ring like appearance. The lesions may come and go, and are normally associ- ate d with carditis. Intramuscular penicillin is preferred as it is more effec- tive than oral penicillin and en sures better compliance. Surgery Urgent valve replacement may be life saving in a patient with decompensating cardia c failure, and is a more com- mon cause of heart failure than myocardial disease in rheumat ic fever. If possible, repair of a damaged valve is preferred to prosthetic replacement. Minor manifestations \200 \200 Fever, up to 40 C, normally settles after 1 \200\2233 weeks. Abdominal pain is non-speci \201 c and usually begins at the start of the illness. Acute phase reactants are a non-spec i \201 c \201 nding. Physical therapies Current practice is that physical activity should be re- stricted until the acute episode has settled, and then should be built up slowly. There is no evidence-bas e for this advice. Investigations \200 Follow-up Regular follow-up is necessary and optimizes timing of val- vular heart disease s urgery. Throat cultures should be performed but are usually negative by the time rheumatic fever pr esents. Antistreptolysin O and anti-DNAse in paired sera at baseline and 2 weeks later may indicate recent strepto- coccal infection if there is an elevation in titres. ECG and echoc ardiography are useful to diagnose and monitor cardiac involvement, and will detect mild ca ses of carditis in patients who are asymtomatic. ECG is nec- essary to pick up elongated P \200\223R intervals. Typical valvu- lar lesions such as valve lea \202 et and chordal thic kening, lea \202 et shortening, mitral annular dilation, lea \202 et pro- lapse, and chor dal elongation are easily identi \201 ed. Synovial \202 uid is sterile. Joint involvemen t may be picked up on plain radiographs as non-speci \201 c soft tissue swelling. Patient advice \200 Good compliance with antibiotics is imperative to ensure lower risk of rheumatic heart dise ase. Patients should be encouraged to seek medical attention for future sore throats. Resources Guidelines WHO guidelines. Report of a WHO Expert Consultation. World Health Orga nization. ISBN-13 9789241209236 \200 Internet sites http://cks.library.nhs.uk/patient_information_ leaflet/Rheumatic_fever Natural history \200 \200 Mortality occurs in 5%. 60% develop rheumatic heart disease within 10 years of infection. http://www.patient.co.uk/showdoc/40000571/ www.who.int/cardiovascular_diseases/resources/ trs923/en/ Differential diagnosis The differential diagnosis of acute rheumatic fever includes septic arthritis, connective tissue diseases, Lyme disease, sickle cell anemia, infective endocard itis, leukemia, and lymphoma. http://www.worldheart.org/ http://kidshealth.org.nz/index.php/ps-page- name/centralpage/pi-id/58 ICD-10 codes Acute rheumatic fever (I00 \200\223I02) I00 Treatment Drug therapy \200 Rheumatic fever without mention of heart in- volvement (arthritis, rheumatic, acute or sub- acute) Rheumatic fever with heart involvement Excludes: chronic diseases of rheumatic orig in (I05 \200\223I09) un- less rheumatic fever is also present or there is evidence of recru descence or activity of the rheu- matic process Acute rheumatic pericarditis I01.0 Acute rh eumatic endocarditis I01.1 I01.2 Acute rheumatic myocarditis I01.8 Other acute rheumatic he art disease I01.9 I02 I02.0 I02.9 I05 \200\223I09 Chronic rheumatic heart diseases A Cochrane review identi \201 ed no cardiac bene \201 t in treat- ing rheumatic fever wit h gluocorticoids, aspirin, or intra- venous immunoglobulin. There is no evidence to support the use of glucocorti- coids in acute decompensating cardiac disease. Penicillin during th e acute attack has been inadequately studied. I01 Primary prevention \200 A recent systematic review concluded that giving antibi- otics to patients with sore throat s and symptoms sug- gestive of a streptococcal infection (pharyngeal exudates and enlarged tender cervical lymph nodes) reduced the risk of rheumatic fever by 70%. Eradicating povert y and overcrowding, and improving access to medical care in the developing world is also vi tal. Acute rheumatic heart disease, unspeci \201 ed Rheumatic chorea Rheumatic chorea with hear t involvement Rheumatic chorea without heart involvement References Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Secondary prevention \200 Cochrane Database Syst Rev 2004; 2: CD000023 Prevention of recurrent attacks of rheumatic fever is the most cost effective way of preven ting rheumatic heart disease. Penicillin remains the antibiotic of choice. Manyemba J, Mayosi MB. Penicillin for secondary prevention of rheumatic fever. Cochrane Dat abase Syst Rev 2002; 3: CD002227. World Health Organization. Rheumatic Fever and Rheumatic Heart Disease: Report of a WHO Expert Consultation. Geneva: WHO, 2001. BRUCELLOSIS 464 Brucellosis Brucellosis is a chronic granulomatous infection caused by intracellular bacteria, and is t he commonest zoonotic in- fection worldwide. Musculoskeletal manifestations Musculoskeletal involvement is the most common compli- catio n of brucellosis, affecting up to one-third of patients. \200 Three distinct forms exist \200\223 peripheral arthritis, sacroilii- tis, and spondylitis. Osteoarticular complicatio ns are sometimes linked to a genetic predisposition, with recent data suggesting an associa tion with HLA-B39. Sacroiliac involvement and spondylosis may occur espe- cially in adults, while children are more likely to develop a peripheral arthritis, osteomyelitis or soft ti ssue infec- tion, e.g. bursitis. Epidemiology Brucella infection is widespread in the developing world, but is also recogniz ed in the developed world. A high rate of infection has been reported in countries such as Turkey, Peru, Mexico, and Syria, although the reported cases are likely to be a signi \201 cant under-estimate of the true inci- dence. There is a relationship between the disease a nd socio- economic status, with lower social classes re \202 ecting the greater likelihood of ingestion of unpasteurized dairy products. Peripheral arthritis \200 Etiology \200 Peripheral arthritis is the most common musculo- skeletal manifestation and is non-erosive. Monoarthritis is the commonest presentation, although oligoarthritis is also relatively co mmon. A symmetrical small joint polyarthritis may re \202 ect a reac- tive mechanism, rath er than true polyarticular sepsis. Prosthetic joints can also be affected in peripheral art hritis. Children are particularly likely to present with peripheral arthritis. Although any joint may be affected, the large weight bearing joints are most commonly involved. Brucella belongs to the proteobacteria species, and there are six classic pathogens, of whi ch four are recognized human zoonoses. The four species are B. melitensis, B. abortus, B su is, and B canis. B. ovis is common is sheep, but has not been identi \201 ed in humans. B. maris affects mammalian sea life, but not land-based animals. Brucella are small, Gram neg ative bacteria, unusual as classic virulence factors, such as exotoxins or endotox- ins, ar e not produced, but infection occurs as a result of host invasion and persistence in that h ost through inhibi- tion of programmed cell death. The presence of rough or smooth lipopoly saccharide correlates with the virulence of the disease in humans. Brucella invades the muc osa, after which phagocytes ingest the organisms. The majority of brucellae are rapidly eli minated by phagolysosome fusion. 15 \200\22330% of bacteria survive in gradually evolving b rucel- lae-containing compartments that limit antibiotic action. Replication of the bacteri um takes place in the endoplas- mic reticulum without affecting host-cell integrity. After replication, brucellae are released with the help of haemolysins and induced cell necrosis. Sacroiliitis \200 Sacroiliitis in Brucella infection is almost always unilat- eral. Typically, a young male a dult presents with severe gluteal pain. There is an in \202 ammatory response on routine b lood testing but plain radiographs are unhelpful. MR demonstrates bone oedema and is the in vestigation of choice. Spondylitis \200 Spondylitis, is dif \201 cult to treat in this context and often results in residual damag e. It is commoner in older patients who have chronic disease. Patients complain of subacute /acute back pain. The lumbar spine is the usual site of involvement and the cervical spine the least frequently involved. Spondylitis is usually diagnosed with plain radiography, in which the characteristic Pons sign (a step-like erosion of the anterosuperior vertebral mar gin) can be identi \201 ed, or with scintigraphy and magnetic resonance imaging. MR also h as the bene \201 t of imaging nerve root involvement. Infection is aggressive causing exte nsive bone destruc- tion, often requiring a combination of antibiotic therapy and surgical debridement with stabilization. \200 \200 Risk factors for infection \200 Infection in humans occurs primarily through the con- sumption of infected, unpasteurized a nimal-milk prod- ucts, but can also occur through direct contact with infected animal parts (such as the placenta), and through the inhalation of infected aerosolized particles. Bruc ellosis is an occupational disease in shepherds, abat- toir workers, veterinarians, dairy-i ndustry professionals, and personnel in microbiological laboratories. One important epidemi ologic step in containing brucel- losis in the community is the screening of household memb ers of infected persons. Airborne transmission of brucellosis has created inter- est in Bru cella as a potential biological weapon. Multisystem disease \200 The reproductive system is the second most common site of focal brucellosis. Brucellosis ca n present as epididymoorchitis in men and can be dif \201 cult to diag- nose. Whether or n ot testicular infection results in sub- sequent infertility remains to be established. In w omen, brucellosis in pregnancy poses a risk of spontaneous abortion. Hepatitis is common, u sually presenting as a mild rise in transaminases. Liver abscess and jaundice are rare com- plications. Granulomas can be present in liver-biopsy specimens in cases of both B. melite nsis and B. abortus. Ascites is not uncommon. Clinical features \200 Fever is invariable, and can be spiking and accompanied by rigors if bacteraemia is present , but may be relapsing, mild, and protracted. Malodorous perspiration is almost pathognomon ic. Constitutional symptoms are generally present with non-speci \201 c malaise. Examinati on is often unremarkable, though lymphaden- opathy, hepatomegaly, or splenomegaly may be pr esent. \200 CHAPTER 16 Musculoskeletal infection 465 The central nervous system is involved in 5 to 7 percent of cases and may present with meni ngitis, encephalitis, meningoencephalitis, meningovascular disease, brain abscesses, or dem yelinating syndromes. The prognosis is often poor in these situations. Endocarditis remains the principal cause of mortality in infection due to brucellosis. It usually involves the aortic valve and urgent surgical valve replacement is often nec- essary. Early recognition, adequate antibiotic treatment, and the absence of signs of heart failure are all features which allow conservative management in the first instance although clinical deterioration i ndicates the need for surgical intervention. Respiratory complications of brucellosis are r are. Respiratory complications include lobar pneumonia and pleural effusions but are found in only around 16% of all cases of brucellosis. ELISA measures class M, G, and A immunoglobulins, which allows for a better interpretation of the clinical situation. A comparison with the serum agglutination test yields higher sen sitivity and speci \201 city. The development of a speci \201 c polymerase chain reac- ti on (PCR) is a recent advance. PCR is fast, can be per- formed on any body tissue, and can y ield positive results as soon as 10 days after infection. Treatment \200 Combination therapy is necessary as all monotherapies have an unacceptably high relapse rat e, The optimal treatment regime remains a matter of debate. In 1986, the World Health Organ ization issued guide- lines for the treatment of human brucellosis with both regimes includ ing doxycycline for a period of 6 weeks, in combination with either streptomycin for 2 \200 \2233 weeks or rifampin for 6 weeks. More recently, triple therapy with doxycycline, aminog lycoside, and rifampicin has been advocated. Most complications of brucellosis can be adequ ately treated with standard regimens. A prolonged triple regimen is used for neurobrucellos is. In spondylitis a duration of treatment of at least 3 months is standard. Rifampin is th e mainstay of treatment in cases of brucel- losis during pregnancy, in various combinations . Brucellosis in children is treated with combinations that are based on rifampin and trime thoprim \200\223sulfamethoxazole, and with aminoglycosides. Investigations \200 \200 Blood tests reveal a non-speci \201 c in \202 ammatory response. There may be a mild lymp hocytosis, but with an overall leuopaenia. Anemia may be present, but is mild. There may be a thrombocytopenia. Rarely, there may be a pancytopenia, thought to arise as a result of b one marrow involvement and hypersplenism. Cytopenias, either in combination or in isolation , may arise as a result of diffuse intravascular coagulation, hae- mophagocytosis, or immun ologically mediated cellular destruction. Synovial \202 uid microscopy and culture is neg ative. Synovial biopsies reveal non-speci \201 c histological changes. Aspirates from the olecranon or prepatellar bursae are negative for microscopy and culture. \200 \200 \200 \200 \200 Future developments A worldwide database is in development to record all cases of brucellos is and to facilitate large randomized controlled trial of therapy. Diagnosis The absolute diagnosis of brucellosis requires isolation of the bacterium from bl ood or tissue samples. The sensitivity of blood culture varies, from 15 to 70%. Bone marrow cultures are considered the gold standard for the diagnosis of brucellosis, since the rela tively high concentration of Brucella in the reticuloendothelial system makes it easier to detect the organism. Bacterial elimination from the bone marrow equates to a full and adequ ate response to antibiotic therapy, although repeated bone marrow exami- nation is both inv asive and uncomfortable, and therefore not routinely repeated. Cure is based on clinical gr ounds, and by the absence of symptoms. A residual bacterial load is found in a signi \201 cant number of patients who are clini- cally well, even 3 years after \200\230successful \200\231 treatment. Patient advice Advice includes avoiding ingestion of unpasteurized dairy products, and care ful hygiene in those who work closely with animals. Good compliance with antibiotic regimes must be stressed, as rates of relapse are higher in those with poor compliance. Resources ICD-10 codes A23 Brucellosis References Al Dahouk S, Tomaso H, Nockler K, Neubauer H, Frangoulidis D. Laboratory-based d iagnosis of brucellosis \200\223 a review of the literature. Part I: techniques for direct detection and identi \201 ca- tion of Brucella spp. Clin Lab 2003; 49: 487 \200\223505. Serology \200 The serum agglutination test remains the most popular diagnostic tool for brucellosis. Titr es above 1:160 are con- sidered diagnostic with a relevant clinical presentation. Seroconve rsion can also be used in diagnosis. Drawbacks of this include the inability to diagnose B. canis infections; cross-reactions with a number of other organ- isms including E. coli, Sa lmonella urbana, Yersinia enteroco- litica, and Vibrio cholerae, and the percentage of case s in which seroconversion does not occur. Serum agglutination tests have a major drawback i n that they are not suitable for patient follow-up, since titres can remain high for a prol onged period. Indirect enzyme-linked immunosorbent assays (ELISAs) typically use cytoplasmi c proteins as antigens. Ariza J, Bosilkovski M, Cascio A, et al. Perspectives for the treatment of brucellosis in t he 21st century: the Ioannina recommendations. PloS Med 2007; 4: e317. \200 Ariza J, Pujol M, Valverde J, et al. Brucellar sacroiliitis: \201 ndings in 63 episodes a nd current relevance. Clin Infect Dis 1993; 16: 761 \200\2235. Pappas G, Akritidis N, Bosil kovski M, Tsianos E. Brucellosis. N Engl J Med 2005; 352: 2325 \200\22336. Reguera JM, Alarcon A, Miralles F, Pachon J, Juarez C, Colmenero JD. Brucella endocarditis: clinical, diagnostic, and therapeutic approach. Eur J Clin Microbiol Infect Dis 2003; 22: 647 \200\22350. Shaalan MA, Memish ZA, Mahmoud SA, et al. Brucellosis in children: clinical observations in 115 cases. Int J Infect Dis 2002; 6: 182 \200\2236. Young EJ. Serologic diagnosis of human brucellosis: analysis of 214 cases by agglutination tests and review of the literature. Re v Infect Dis 1991; 13: 359 \200\22372. LYME DISEASE 466 Lyme disease Lyme disease, named after Old Lyme, Connecticut, where it was \201 rst described, is the most common tick borne in- fection. The clinical features were originally described in 1977 and Borrelia burgdoferi was isolated in 1982. days, and the macule expands to a red-purple well demarcated rash, near or around the site of the tick bite. This may remain uniform or become ring like. The area of erythema varies from 2 to 60 cm in diameter. The area of erthythema grows by 1cm per day, and usually last between 3 \200\2234 weeks before settling spontaneously. Other symptoms include fever, mala ise, headache, arthralgia/myalgia, and lymphadenopathy. Lymphadenosis cutis benigna is a ra re manifestation, which is a purple nodule that forms on the skin of the face or on the nip ple. Acute neuroborreliosis develops in around 15% of patients within months of infection. Symptoms of neu- roborreliosis include meningitis, cranial neuropathies (particularly of th e facial nerve), and radiculopathy. The radiculopathy usually combines motor and sensory co m- ponents and is associated with severe pain. Carditis occurs in less 5% of patients, and presents as atrioventricular heart block, or left or right bundle branch block. Eye involve ment presents as conjunctivitis or uveitis. Joint pain is often migratory although synoviti s is rare. Epidemiology In the UK, the incidence is estimated at 0.3/100 000, and is up to 155/100 000 in Slovakia, where the highest incidence is reported. Incidence is also high in Austria, G ermany, and Sweden. In the USA, incidence is estimated at 8.2/100 000. In the UK, more than half the cases are acquired in south west England, with the majority of cases reported in the summer months. Lyme disease is not a noti \201 able disease. Global warming is expecte d to increase the incidence of vector-borne diseases as milder weather increases tick activ ity for a longer proportion of the year. An increase in tick numbers of 10-fold is believed to have occurred since 1986. Etiology Borrelia burgdorferi is a Gram negative, highly motile, corkscrew-shaped bacterium . There are 3 species, B. burg- doferi sensu strictu, B. garinii, and B. afzelli. The \201 rst is the only species found in USA, whereas all 3 are found in Eu- rope. All 3 speci es cause arthritis, but B. garinii may cause neuroborreliosis and B. afzellii is the specie s most likely to cause chronic skin involvement. \200 Late Lyme disease \200 \200 Borrellia infection may persist for years. Acrodermatitis chronica atrophicans is a chronic skin condition that is oedematous and violacious in color. It is not normally seen until 1 2 months after infection. It may progress over years to a paper like skin atrophy. Rare com plications include squamous cell carcinoma and B cell lymphoma. Chronic neuroborelliosis is rare, but may present with chronic encephalitis, encephalomyelitis, peripheral neu- ropath y, and cerebral vasculitits. Pathogenesis Around 80 ticks are implicated in the transmission of infec- tion to humans. I xodes ricinus is the hard tick which carries B. burgdorferi. It is has a lifecycle of 3 yea rs, and feeds on hosts such as deer, which may be infected with B. burgdor- feri. Once infe cted, the adult tick then feeds on other unin- fected mammals such as deer, small rodents a nd humans, and therefore transmits infection. It is estimated 25% of ticks are infected wit h B. burgdorferi. Ticks are almost invis- ible on human skin. However, they grow up to 10 m m and are visible as black specks having ingested the blood of the host. They feed primaril y in the spring and summer and feeding can take up to 6 days to complete. Ticks are able to move about on the host and therefore can be found on unexposed skin. \200 Lyme arthritis In the USA, 60% of patients with untreated borelliosis de- velop joint manif estations, although this is less common in Europe re \202 ecting the spectrum of clinical features caused by the different Borellia species. Joint disease typically oc- curs in late disease and is usually intermittent with acute \202 ares followed by ever-shortening rem issions. The distri- bution is usually mono- or oligoarticular, involving knees, elbows, an d ankles, although other joints may be affected. Large joint effusions are common. Tenosyno vitis and bursi- tis are rare. Infection of the host occurs via the tick bite. The reac- tion site contains lymphocytes, m acrophages, and plasma cells, which release pro-in \202 ammatory cytokines. The spirochaet e then disseminates widely over the next weeks to blood, heart, brain, muscle, bone, spleen , liver, brain, and eye, although some hosts are asymptomatic. Most patients recover with t reatment, although 10% of patients develop a chronic arthritis. Whether this is due to resi stant infection or an autoimmune-medicated in \202 ammatory response remains unclear. Investigations A low grade in \202 ammatory response may be seen, although bloods may also be normal. RF and ANA are usually nor- mal, although chronic infection may result in a low grade seropositivity. Synovial aspirates reveal leucocytosis, but cultures are negative. Clinical features Erythema migrans, lymphadenosis cutis benigna, menin- gopolyneuritis (Ban nwarth syndrome) and acrodermatitis chronica atrophicans are pathognomonic features of Lyme disease. These are discussed below. Prognosis Erosions are rare even in chronic arthritis. 90% of patients are asymptomatic fol lowing treatment. Oral antibiotics are useful even in chronic disease. A minority of patien ts do not respond to antibiotics, suggesting an autoimmune response from the host against i nfection. Long-term antibiotic therapy to eradicate chronic disease remains controversial. Natural history Early Lyme disease \200 Erythema migrans is the most common clinical manifes- tation (75%). The incubation period v aries from 3 to 32 CHAPTER 16 Musculoskeletal infection 467 Post-Lyme syndrome A small number of patients who are treated for Lyme dis- ease continue t o complain of fatigue, myalgias, and memory disturbance, which are usually mild. or culture. Eradication is usually undertaken using paren- teral antibiotic therapy. Post-Lyme syndromes This does not appear to be improved by antibiotic therapy. Diagnosis IgM and IgG antibodies speci \201 c for Borrelia burgdoferi should be performed, with a rise in IgM detectable from 2 to 4 weeks following infection and the peak in IgM at 6 \200\2238 weeks. After that a rise in IgG antibodies is detected. For screening, a sensi tive ELISA is appropriate, followed by an immunoblot, with a higher sensitivity for con \201 rmation. Culture of erythema migrans biopsies has a yield of 50%, similar to that of p lasma during the early stages of infec- tion. CSF culture has a yield of 10% in neuroborell iosis. Other treatment options NSAIDs, simple analgesia, and physiotherapy have impor- tant roles. DMARDs have a role in patients with treatment resistant disease who have not settled with eradication therapy. Controversies The role of long-term antibiotics in patients with chronic symptoms remains a n area of great debate, especially in the USA. Current medical opinion does not support the use of long-term antibiotic therapy, despite a vocal patient body. There are calls for Lym e disease to become a noti \201 - able disease, especially since the incidence of infectio n is increasing. PCR PCR is not routinely available, although DNA can be iso- lated in a number of different tissues, e.g. skin, CSF, synovial \202 uid, blood, and urine. A negative PCR does not ex clude Lyme disease. Patient advice Education should cover those who enjoy woodland or for- est walks or cycling , with awareness of where ticks are found, the time of year when ticks are more common, the ir appearance on the skin, and the importance of seeking medical advice if a skin rash shou ld develop. Clothing should cover arms and legs. Removal of ticks from the skin should be e ncouraged using tweezers, but care should be taken to remove all the tick \200\231s body. Treatment Antibiotics should be prescribed on the basis of clinical symptoms. Asymptomatic patients with positive serology should not be treated on the basis of serology alone. Oral therapy is usually with doxycycline, with amoxicillin reserved for children or in pregnancy . Intravenous therapy is usually with ceftriaxone or cefotaxime. Jarisch \200\223Herxhei- m er reaction is reported in the \201 rst few days of therapy and glucocorticoid cover is n ecessary in symptomatic patients. NSAIDs and simple analgesia have a role. The risks of ora l, parenteral, and intra-articular glucocorticoid therapy remain controversial because of t he potential risk of reactivation of infection. Resources Support groups www.lymediseaseaction.org.uk Internet support Health protection agency center for infection control. Holborn,London. Ava ilable at: Erythema migrans Antibiotics should be initiated as soon as erythema migrans is diagnosed. The antibiotic of choice is doxycy- cline 200 mg daily for 14 \200\22321 days. http://www.hpa.org.uk/infections/about/ surveillance/surveillance_menu.htm. and www.cdc.gov/mmwR/review/mmwrhtml/mm5317a4.htm Arthritis and acrodermatitis Most patients will respond to oral antibiotics, although some will require antibiotics intravenously for up to 3 months to abolish joint symptoms. The be ne \201 t of doxycycline is that it also has a mild anti-in \202 ammatory effect, althoug h this should be borne in mind when planning antibiotic duration as it may mask ongoing joi nt symptoms. Acrodermatitis re- sponds well to oral antibiotics. Neurological involvement r equires intravenous antibiotic therapy. ICD-10 codes M01.2 Arthritis in Lyme disease References Blackwood T. The ubiquitous tick. Br Trav Health Ass J 2007; 10: 34. Luger SW, P aparone P, Wormser GP, et al. Comparison of cefurox- ime axetil and doxycycline in treatmen t of patients with early Lyme disease associated with erythema migrans. Antimicrob Agents C hemother 1995; 39: 661 \200\2237. Neuroborelliosis 3 weeks of therapy is probably suf \201 cient in patients with neurologic al involvement. Oral therapy is adequate in facial palsy alone, although parenteral therapy is more appropri- ate in a patient with extensive disease. Mullegger RR. Dermatological manifestations of manifestations of Lyme borreliosis. Eur J Dermatol 2004; 14: 296 \200\223309. Schnarr S, Franz J, Krause A, Zeidler H. Lyme borreliosis. Best Pract Res Clin Rheumatol 2006; 20: 1099 \200\223118. Tonks, A. Lyme Wars. Br Med J 2007; 335: 910 \200\22312. Treatment resistant disease This needs to be distinguished from post-Lyme syndrome and cont inuing infection should be established by PCR VIRAL ARTHRITIS 468 Viral arthritis Arthralgia associated with viral infection is common and usually self-limiting over a perio d of weeks, although oc- casionally follows a more chronic course. Viral arthropathy is als o reported following vaccination. The pattern of joint involvement is usually a symmetrical polyarthropathy, with women more commonly affected than men or children. Permanent joint d amage is rare. Some viral infections are commonly associated with arthralgia, such as mumps or rubella, although it is less common in others, such as varicella or adenovirus. Virus i s seldom isolated from synovial \202 uid. IgG antibodies against B19 are within the range expected for age, and B19 DNA has been foun d within the tissues of patients with normal joints. Patients with acute parvovirus B19 inf ection can meet the criteria for rheumatoid arthritis, and may transiently become seroposit ive. B19 DNA has been isolated from synovial \202 uid and tissue from patients with rheum atoid arthritis, and those patients who express HLA-DR4 are more likely to develop chronic arthritis following parvo- virus infection. Investigations \200 Pathogenesis The pro-in \202 ammatory consequences of viral infection are complex and invo lve a number of different pathways. Different viruses modify or in \202 uence particular c ellular responses. The main effects of viral infection include: \200 Acute parvovirus B19 causes the presence of IgM anti- bodies and, later, IgG antibodies are detectable. PCR is useful in patients who are immunocompromised and unable to mount an ant iviral antibody response, but may be positive for over 12 months following infection making interpretation dif \201 cult. Target the cells of innate immunity, by infecting mono- cytes promoting pro-in \202 ammato ry cytokine secretion. Impairment of antigen presenting cell function, e.g. HIV, CMV, and E BV infection result in impaired B cell function. Induction of autoantibody production, e.g. EBV induced IgG production with cross-reactivity against lupus associ- ated autoantigens, and parvovirus B19 may induce anti- bodies against other cellular antigens. Induction of T cell immunity by depletion of thymic T cells, or modi \201 cation of autoreactive T cell f unction, a mechanism also implicated in the pathogenesis of autoimmune diseases such as rhe umatoid arthritis. Directly damage synovial cells, e.g. EBV, HTLV-1, rubella, and Ross Rive r virus may directly infect synovial cells, and with an increased expression of double stra nded RNA which is arthritogenic. Parvovirus B19, an extracel- lular virus, results in immun e complex formation and deposition within the joint resulting in an in \202 ammatory respo nse and antibody formation. Treatment Symptom relief is the mainstay of therapy, with either simple analgesics or non-s teroidal anti-in \202 ammatory drugs. There is no vaccine currently available. Alphaviral infections There are 26 viruses in the genus Alphavirus. These are spherical vir uses that contain an RNA-containing nuceleo- capsid surrounded by a lipid layer. Transmissi on is cyclical and occurs between arthropods (normally mosquitos) and mammalian hosts, such as humans. Infection rates rise when mosquitos are prevalent, usually in the monsoon sea- son. Recognizing a history of travel in patients with alpha- virus infection is paramount t o making the diagnosis. Ross River virus causes more than 8000 cases per annum in Australia and the West Paci \201 c. Barmah Forest virus is less prevalent in Australia and causes m yalgias, and occasionally arthritis. Ockelbo and Pogosta are prevalent in Scandana- via. Ch ikungunya is found mostly in Africa and Asia. Human parvovirus B19 Human parvovirus B19 is one of the Erythrovirus genus and is a small D NA virus. Transmission is usually via inhala- tion, but can occur via blood products or ver tically from mother to fetus. Infection is often seen in early spring. Clinical features \200 The most common symptoms include rash, fever, arthral- gia and systemic upset after an incu bation period of up to 10 days. Subclinical infections are thought to be common and childre n are often spared joint involvement. The joint involvement ranges from a mild migratory po l- yarthralgia to a systemic synovitis involving the small joints primarily. Myalgia may be prominent. Clinical features \200 \200 The majority of infections are subclinical. Most present 2 weeks after infection with fever and ery- thema infectiosum or a slapped cheek appearance. 50% of adults and 10% of child ren are reported to have a symmetrical small joint and knee arthralgia. Joint symptoms are commoner in women than men. Resolution of arthralgia within 3 weeks is usual, although 1 in 5 women have more prolonged symptoms. An erosive arthropathy is reported, but is rare. New presentations and \202 ares of lupus have been linked with infection due to parvovirus B 19. Non-rheumatological manifestations include hydrops foetalis and fetal death. Hematologi cal, neurological, and cardiac sequelae of infection have been reported. Diagnosis \200 \200 The history of travel is particularly important in patients with rash, fever, and arthralgi a/myalgia who have trav- elled to endemic areas. Paired sera are needed, as IgM speci \201 c for alphavirus may persist for years, and should be collected around 10 days apart. A 4- fold increase in the titre is usually characteristic. \200 Treatment of alphavirus Treatment is mainly supportive and consists of simple anal- gesia, non-steroidal anti-in \202 ammatory drugs, and mobiliza- tion as joint symptoms settle. The association of human parvovirus B19 and rheumatoid arthritis \200 Although an association between parvovirus B19 and rheumatoid arthritis has been postulated , the link remains tenuous. CHAPTER 16 Musculoskeletal infection 469 Mumps Mumps is more likely to affect men, with an incidence of 0.44%. paired sera collected 2 weeks apart is also indicative of recent infection.