Title Lyme disease - a brief review and report of a case in Hong Kong

Author(s) Hodgkiss, IJ; Wong, YC; Chan, BSS

Citation Hong Kong Practitioner, 1995, v. 17 n. 8, p. 370-378

Issued Date 1995

URL http://hdl.handle.net/10722/44717

Rights This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

DISCUSSION PAPER

Lyme Disease - A Brief Review And Report Of A Case InHong Kong

I.J. Hodgkiss*, BSc, PhD, FLS, CBiol, FIBiol,FCIWEMReaderDepartment of Ecology & BiodiversityThe University of Hong Kong

Y.C. Wong, BLabTechScientific Officer/SupervisorDepartment of Clinical PathologyHong Kong Central Hospital

Ben S.S. Chan, BSc, PhDLecturerBiology DepartmentHong Kong Baptist University

Abstract

In a search for the spirochetes responsible forLyme disease in Hong Kong, a sixty year old female,with a clinical diagnosis of arthritis, was found tohave a rising antibody litre against Borreliaburgdorferi by indirect immunofluorescent assay(IFA).

This paper presents a brief review of Lymedisease, its epidemiology, clinical features, diagnosis,prevention and treatment, followed by a report ofthis first case of Lyme disease in Hong Kong.

Key words: Borrelia burgdorferi, indirectimmunofluorescent antibody (IFA),Lyme disease, rheumatoid factor,Treponema pallidum haemag-lutination assay (TPHA).

History

For Americans, a discussion of the history ofLyme borreliosis usually begins with the story oftwo persevering women, Polly Murray and JudithMensch of Old Lyme, Connecticut. In the early1970s, they were concerned about the occurrenceof arthritis in members of their families and infamilies of the neighbouring towns of Lyme andEast Haddam. Severe headaches, skin lesions,and subsequent recurring arthritic and neurologicsymptoms suggested to them that the physicians*diagnosis of "juvenile rheumatoid arthritis" waswrong. Their suspicion that something unusualwas happening was made known to theConnecticut State Health Department, whichsought help from Dr. Allen Steere of theRheumatology Department at Yale UniversityMedical School. In October 1975, he started aretrospective study that eventually led to thedescription of Lyme arthritis,1 which was laterchanged to Lyme disease,2 a new complexmultisystem disorder of unknown etiology.

Unknown to most Americans, however, is theearliest reference to manifestations of what todayis known as Lyme borreliosis. In as early as 1909,the Swedish physician, Dr. Arvid Afzelius,reported an elderly woman who had a ringlikeskin lesion where she had been bitten by thesheep tick, Ixodes ricinus? This characteristicexpanding skin lesion, erythema chronicummigrans (ECM), has long been associated withsheep tick bites,4-5 and with tick-bornemeningopolyneuritis in Europe.6'7 The association,between Lyme Disease and Ixodid ticks is nowwell recognized in Europe and the United States

"Address for correspondence:

370

Dr. I.J. Hodgkiss, Reader in Ecology & Biodiversity, The University of Hong Kong, Pokfulam Road, HongKong.

Hong Kong Practitioner 17 (8) August 1995

of America;8 it is noted as the most prevalent tick-borne illness in the coastal regions of NorthAmerica;9 and is of world-wide distribution,including China.10'11 These syndromes are nowoften subsumed under the name Lyme disease.

Although many theories have been proposedto explain its etiology,12"17 the causative agent ofLyme disease remained elusive until 1982, whenBurgdorferi and associates18 isolated thespirochete that bears his name Borrelia burgdorferifrom Ixodes dammini in New York, and linked itserologically to patients with Lyme disease. In thefollowing few years, numerous workers confirmedthe spirochete nature of the disease.19"23 Becauseit is infectious in origin but inflammatory or"rheumatic" in expression, Lyme disease, beyondits intrinsic interest as a new nosologic entity,presents a unique human model for an infectiousetiology of rheumatic disease.

during biting, or by infective tick faecal matterthat is deposited on the skin and rubbed intothe bite. The spiral organisms of medicalsignificance include Leptospira, which causeshuman leptospirosis; Treponema, responsible forthe diseases known as treponematoses, such assyphilis;24 and Borrelia, which causes relapsingfever.25

Tick Vectors

Ticks are not insects, but related to spiders,scorpions and mites, and placed in the classArachnida.26 There are two families of ticks, theIxodidae (hard-bodied ticks) and the Argasidae(soft-bodied ticks), which differ morphologicallyand behaviourally. Ixodes is one of the thirteengenera of Ixodidae, and the principal vector of B.burgdorferi worldwide.27

Epidemiology

Lyme disease has now been recognized as aworldwide tickborne borreliosis of public healthimportance. It has become the leadingvectorborne infectious disease in the UnitedStates, with more than 40,000 cases reported tothe Centers for Disease Control in the 10-yearperiod 1982 to 1991.

The Hosts

The Ixodes vectors of B. burgdorferi that feedon humans as incidental hosts also parasitize alarge number of small, medium and large wild anddomestic animals, including hundreds of species ofmammals, reptiles and birds.28"30

Global Distribution

The Pathogen

Borrelia burgdorferi, the causative agent ofLyme disease,18 is a newly discoveredmicroaerophilic spirochete that is 2 to 20 \imlong but only 0.18 to 0.25 um wide, belonging tothe family Spirochaetaceae. B. burgdorferi occursmainly in wild white-footed mice, in deer, and inticks of the genus Ixodes. The ticks can transmitthe spirochete to humans by bites at any stageof the tick's life cycle (i.e. larval, nymph andadult). B. burgdorferi is injected into the skin ofan human victim either by infective tick saliva

Lyme disease is endemic in North America,across Europe to Asia, including the British Isles,western Europe and Russia (from the Baltic Statesto the Pacific Coast),31'33 China and Japan. 1W1'34'35

Although not yet confirmed by isolation, thedisease has also been reported from Africa, SouthAmerica, Australia and India.33'36"38

Clinical Features

Lyme disease is an illness having proteanmanifestations with symptoms that include:

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Lyme Disease

(1) an erythematous expanding red annular rashwith central clearing;

(2) fever, headache, stiff neck, nausea, andvomiting;

(3) neurologic complications such as facial nerve(Bell's) palsy and meningitis; and

(4) arthritis in about 50% of untreated patients.

These symptoms occur most frequentlyfrom May to November, when ticks are activeand numerous, and people are engaged in manyoutdoor activities. The most characteristicfeature of early Lyme disease is a skin rash,often referred to as erythema chronicummigrans (ECM), which appears shortly (3-32days) after a bite from an infected tick. Thelesion typically expands almost uniformly fromthe centre of the bite and is usually flat orslightly indurated with central clearing andreddening at the periphery. It is noteworthy,however, that many Lyme disease victims donot recall being bitten by a tick or do notdevelop classic ECM. Indeed one third of thepatients may not develop ECM. On the otherhand, at various intervals after the initial rash,some patients develop similar but smallermultiple secondary annular skin lesions that lastfor several weeks to months. In approximatelyhalf of the patients, the first sign to appear isa slowly expanding red rash at the site of thebite. Beginning as a small flat or raisedlesion, the rash increases in diameter in acircular pattern and over a period of weeks thediameter may reach 10-15 inches. It has anintense red border and a red centre resemblinga bull's eye. It can vary in shape and isusually hot to touch. The initial tick bite maybe distinguished from a mosquito bite becausethe latter itches, while a tick bite does not.39

Biopsy of these skin lesions reveals lymphocyticand plasmacytic infiltrates. Various flulikesymptoms such as malaise, fever, headache, stiffneck and arthralgias are often associated withECM. The spirochete eventually reaches thebrain, and within several weeks or months

about 15% of the patients develop meningitis,which may be accompanied by excruciatingheadaches and neck pain. There may beabnormalities of the nervous system that lastfor years, ranging from a mild tingling sensationin the limbs to encephalomyelitis, partialparalysis, or even mental deterioration. Withinseveral weeks after the onset of the disease,approximately 8% of patients show cardiacinvolvement indicated by heartbeat irregularity,dizziness or shortness of breath. Within 2weeks to 2 years after the beginning of thedisease, 80% of patients develop recurrentarthritis, and eventually the knees or otherlarge joints may become swollen and painful.

Much of the damage to the body causedby B. burgdorferi has been attributed to theendotoxin in the outer membrane of thespirochete. The endotoxin is believed tostimulate macrophages to produce interleukin-1,a regulator of the body's immune response.Over-production of this regulator accounts forthe fever, skin rash and recurrent arthritis thatare characteristics of Lyme disease/0 The latemanifestations of Lyme disease may includemigratory and polyarticular arthritis, neurologicand cardiac involvement with cranial nervepalsies and radiculopathy, myocarditis andarrhythmias. Lyme arthritis typically involves aknee or other large joint. It may enter achronic phase, leading to destruction of boneand joints if left untreated. Interestingly, Lymearthritis is less common in Europe than in theUSA, but neurologic complications are moreprevalent in Europe. Unique strain variationsexpressing antigenic subtypes between Europeanand North American isolates of B. burgdorferiprobably explain these dissimilarities.

Diagnosis

Like syphilis, Lyme disease produces adiverse number of clinical symptoms that canbe confused with many other disease entities.

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Hong Kong Practitioner 17 (8) August 1995

In many cases the clinical differential is oftencomplex resulting in heavy reliance on thelaboratory to provide diagnostic evidence.1'2-41-42

However, successful isolation and culture of B.burgdorferi from skin lesions, blood and jointand cerebrospinal fluid in suspected cases ofLyme disease is rare,19'42 and most commonnonspecific laboratory tests are not helpful inthe differential diagnosis. Thus, serologic testsprovide the most important confirmatoryevidence of all stages of Lyme disease and maybe the only way of diagnosing atypical cases.The most commonly used serologic tests are theenzyme-linked immunosorbent assay (ELISA)and indirect fluorescent-antibody assay (IFA)which detect the specific antibody against B.burgdorferi. Since antibodies to otherspirochetes, including Treponema pallidum, cancross-react, differential diagnosis must beundertaken using tests such as VDRL, TPHAor RPR for all specimens showing a positivereaction towards 8. burgdorferi.

In serum, specific IgM antibody titresagainst B. burgdorferi usually reach a peakbetween the third and sixth week after theonset of disease; specific IgG antibody titresrise more slowly and are generally highestmonths later when arthritis is present.

On 19 October 1990, the CDC definedcase criteria for reportable disease.43 Lymedisease is one of the diseases for which theCDC established diagnostic clinical and

'laboratory criteria, as follows:

Clinical case definition - Erythema migrans,or at least one late manifestation.

Laboratory criteria for diagnosis - isolationof B. burgdorferi from clinical specimen, ordemonstration of diagnostic levels of IgM andIgG antibodies to the spirochete in serum ofCSF, or significant change in IgM or IgGantibody response to B. burgdorferi in pairedacute and convalescent-phase serum samples.

Treatment and Prevention

For early stage treatment, in order ofpreference, oral tetracycline 250mg four timesa day, phenoxy-methyl penicillin 5OOmg fourtimes a day, or erythromycin 250mg four timesa day each for 10 to 20 days depending on theresponse, is suggested.44

For meningitis and cranial or peripheralneuropathies, intravenous penicillin G 20 millionU a day in six divided doses for 10 days iseffective therapy.43

For established Lyme arthritis, treatmentwith intra-muscular benzathine penicillin 2.5million U weekly for 3 weeks has been provento be successful.46 The affected joint should beat rest, and accumulated fluid should beremoved by needle aspirations.

In vitro and in vivo susceptibility tests havesuggested that cefuroxime may be an effectivealternative therapy for Lyme disease.47

A few simple precautions will help reducepossible exposure to Borrelia-infected ticks andincrease protection against Lyme disease.These include wearing clothing that fullyprotects the body and using repellents thatcontain DEET (diethyltoluamide).48 Peopleshould be made aware of the typical earlysymptoms of infection, such as the characteristicskin rash. The potential for human contactwith Ixodes ticks as a cause of occasional casesof locally acquired spotted fever must not beoverlooked.

The Current Investigation

The incidence of Lyme disease has beenincreasing considerably world-wide since 1975, butit has never been documented in Hong Kong; andthe local situation regarding the disease isunknown. In an attempt to investigate its

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occurrence in Hong Kong, since August 1992, asurvey of seroprevalence has been conducted inpatients with a clinical diagnosis of arthritis.

Blood samples of patients with a clinicaldiagnosis of arthritis were collected from tendifferent clinical laboratories in Hong Kong.Whole blood specimens were centrifuged to obtainsera for assay by indirect immunofluorescentantibody (IFA) titre to Borrelia burgdorferi (Lyme-spot IF, Ref. 75941 Bio Merieux, France); torheumatoid factor by agglutination of IgG coatedlatex particles (RA80, Eiken Chemical, Japan);and for antibodies against Treponema pallidum byhaemaglutination assay (TPHA, Fujirebio Inc.,Japan) and the rapid plasma reagin card test(RPR reditest, Biokit, Spain) following themanufacturers' instructions. Other clinical andlaboratory data relating to the patients were alsocollected and recorded as additional information.

For a potential patient to be defined aspositive for antibody to Borrelia burgdorferi, thepatient had to have a clinical diagnosis of arthritis,

a titre of 1:160 or greater for antibody to Borreliaburgdorferi by indirect immunofluorescent antibody(IFA), together with non-reactive results in theremaining three assays, namely: (a) rheumatoidfactor (RA), (b) Treponema pallidumhaemaglutination assay (TPHA) as well as (c)rapid plasma reagin (RPR).49

Case Report

In September 1992, a sixty year old femalepatient recruited into the scheme mentionedabove with joint pains but no other symptoms ofarthritis was found to provide the results shown inTable 1. The patient, who had travelled to the USand Australia prior to seeking medical assistance,had no previous history of skin lesions, etc. Shewas later treated only with a two weeks course oftetracycline 250mg q.i.d. and has since recoveredfrom her arthritis. The Borrelia burgdorferiantibody titre (IFA) in her blood sample hasfallen from 1:320 to less than 1:160 nine monthsafter the treatment.

Table 1: Laboratory results of the first reported Lyme disease patient in Hong Kong

Test

Haemoglobin

Haematocrit

Red cell count

White cell count

ESRHepatitis B surface antigen

Uric Acid

Rheumatoid factor (RA)

TPHA

RPRANABorrelia burgdorferi

antibody titre (IFA)

First sample

Second sample (4 weeks apart)

Nine months after treatment

Result (unit)

13.8 (g/dL)

41(%)

4.4 (x 1012/L)

7.4 (x lO'/L)

35 (mm/hr)

Negative

45 (mg/L)

Negative

Negative

Non-reactive

Negative

Positive 1:160

Positive 1:320

Negative < 1:160

Reference range

12.0 - 16.0

36-48

4.0 - 5.0

5.0 - 10.0

0-20Negative25-75NegativeNegativeNon-reactiveNegative

< 1:160

374

Discussion

The situation regarding Lyme disease in HongKong is unclear. Although little is known aboutthe prevalence of the Ixodes ticks in this area,there are several possible routes for Lyme diseaseto gain entrance into Hong Kong.

1. Domestic animals, such as dogs and cats, arefound to be commonly infested by B.burgdorferi carrying Ixodes ticks in endemicareas.50"52 But pets imported into Hong Kongare not known to have been de-ticked beforeentrance. Ixodes ticks have been noted inpets visiting local veterinarians.53

2. 49 species of birds have been found to beinfested by Ixodes ticks,29 and migrating birdshave already been suspected to be a route oftransmitting Lyme disease.54

3. Other than Ixodes ticks, possible transmissionof B. burgdorferi to humans by blood-suckinginsects such as fleas, mosquitoes and horseflies has been reported.55136

4. The tremendously high volume of visitors, re-immigrants, and travellers to and fromendemic areas each year has increased largelythe possibility of Lyme disease infection.

Like syphilis, Lyme disease has been called a"great imitator" and is often difficult to diagnoseclinically. Less than one third of patientspresenting with ECM recall having been bitten byticks.57-58 Up to 50% of patients presenting withLyme arthritis may not recall the pathognomonicECM rash, flulike illness, or tick bite.59 The ECMrash may be unrecognized or mistaken for anotherannular dermatosis. Even in endemic areas of theUnited States, such as eastern New York and

Hong Kong Practitioner 17 (8) August 1995

Connecticut, ECM went unrecognized by mostphysicians until the early 1980s. In children, therash can be totally missed, when occurring in thescalp area or other unobserved locations.2-60

In almost all clinical bacteriologicalinvestigations, laboratory culture of causativemicroorganisms is the prime tool for diagnosis;however, for the screening of Lyme disease,laboratory culture is not a practical option.Isolation of Borrelia burgdorferi from blood serum,joint fluid, cerebrospinal fluid, or tissue hasproven to be very difficult, if not impossible.Successful positive cultures have been reported inless than 5% of patients with otherwise provenLyme disease.22

Nearly all patients with Lyme arthritis haveantibodies to Borrelia burgdorferi detectable intheir sera. Antibody screening, therefore, remainsthe most practical method for the detection of thedisease, pending the discovery of a better, morereliable, faster methodology. False-positiveresults, attributable to antibodies cross-reactive toBorrelia burgdorferi, can also be seen, however, inthe serum of patients with other spirochetalinfections.57 Thus, confirmation of the diagnosisof Lyme disease is only possible if results obtainedfrom the TPHA and RPR test are negative.

Routine laboratory testing is often not helpfulin the differential diagnosis of Lyme disease, sincesome patients with Lyme disease may not havelaboratory abnormalities. Table 2 summarizeslaboratory findings during early Lyme disease,where rheumatoid factor (RF) and ANA aretypically absent from the sera of Lyme diseasepatients1 and, as can be seen from the results, lessthan 60% showed any abnormality.

Table 2: Laboratory Findings in Early Lyme disease.23

Test Number of patients (%) with abnormal values* Median (range) of abnormal values

HaematocritLeukocytes >10 cells x lO'/mm3

ESR >20 mm/hrIgM >250 mg/dL

37 (12)24 (8)

166 (53)104 (33)

35 (31 - 36)12 (11 - 18)35 (21 - 68)

310 (252 - 930)

'Total number of patients = 314

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Lyme Disease

The availability of laboratory tests and theawareness of clinicians for ordering the testtherefore play the most important roles indiagnosing the disease. However, most clinicallaboratories in Hong Kong do not carry out thetest for Lyme disease and it is not included in"arthritis profile test". A recent survey of eightlocal laboratories revealed that clinicians orderedthe test for Lyme disease less than once per yearper laboratory. It is not surprising that, althoughLyme disease is such a worldwide illness,previously there has not been one single caseofficially reported in Hong Kong.

It has been reported that Lyme disease isendemic in China in the forested northeasternregions, particularly in Hailongjiang and JilinProvinces;10 yet little is known about Ixodid ticksin Hong Kong. It is not known whether this firstreported case of Lyme disease is due to a localinfection or not. However, the clinicalmanifestations together with a seropositive risingtitre of antibody to Borrelia burgdorferi by IFA hasalready met the criteria for national reporting ofLyme disease in the United States.43 TheDepartment of Health of the Hong KongGovernment has confirmed with the authors thatno cases of Lyme disease have been reported inHong Kong61 and, therefore, we consider thepresent investigation to be the first. The possiblereservoirs of the vectors for the spirochete -Borrelia burgdorferi - are now being studied.

Acknowledgements

The University of Hong Kong for financialand supervisory support; Dr. Chi Wing Chan,Consultant Pathologist at the Hong Kong CentralHospital for reviewing the manuscript; all thosewho gave of their time during the survey; and thepatients involved for their cooperation. •

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