The wildfire The wildfire fighter with fighter with arthritis and arthritis and

fatiguefatigue

ID Case ConferenceID Case Conference

Wednesday July 25Wednesday July 25thth, 2007, 2007

David P. Fitzgerald, MDDavid P. Fitzgerald, MD

HPIHPI► 38 yo WF with history of chronic low back pain 38 yo WF with history of chronic low back pain presenting in June 2007 with a 9 month history presenting in June 2007 with a 9 month history of a constellation of symptoms including of a constellation of symptoms including fatigue, arthralgia, headache and intermittent fatigue, arthralgia, headache and intermittent fever. fever.

► October 2006 - She reports an initial illness October 2006 - She reports an initial illness with fevers, headache and nausea/vomiting. with fevers, headache and nausea/vomiting. Was seen by her primary physician and noted to have a Was seen by her primary physician and noted to have a rash – which apparently began on her palms and soles rash – which apparently began on her palms and soles and spread over her trunk and face.and spread over her trunk and face.

She had serological testing for Rocky Mountain spotted She had serological testing for Rocky Mountain spotted fever and Ehrlichia and was treated empirically with fever and Ehrlichia and was treated empirically with doxycycline x10 days. Had resolution of hers sxs at doxycycline x10 days. Had resolution of hers sxs at that time.that time.

When she discontinued the doxycycline she developed When she discontinued the doxycycline she developed recurrence of low grade fevers, joint pain and fatigue recurrence of low grade fevers, joint pain and fatigue and was given another course of doxycycline. and was given another course of doxycycline.

HPIHPI

►December - Referred to UNC rheum for December - Referred to UNC rheum for continued arthralgias and fatiguecontinued arthralgias and fatigue Noted to not have any active arthritis Noted to not have any active arthritis or inflammation on physical examor inflammation on physical exam

RMSF serology (convalescent) done and RMSF serology (convalescent) done and consistent with recent infection. consistent with recent infection.

Rheum panel negative.Rheum panel negative.►Treated with another course of Treated with another course of doxycycline. doxycycline.

►Also treated with Mobic. Also treated with Mobic.

HPIHPI

► April - patient sought the opinion of a April - patient sought the opinion of a “tick borne illness” expert in Virginia – “tick borne illness” expert in Virginia – a member of the International Lyme and a member of the International Lyme and Associated Diseases Society (ILADS) Associated Diseases Society (ILADS)

Was diagnosed as having RMSF, ehrlichosis and Was diagnosed as having RMSF, ehrlichosis and babesiosis, despite negative RMSF, ehrlichia babesiosis, despite negative RMSF, ehrlichia and babesiosis serologies, negative babesiosis and babesiosis serologies, negative babesiosis DNA PCR and no history of travel to areas DNA PCR and no history of travel to areas endemic for this babesiosisendemic for this babesiosis

Prescribed a prolonged course of mepron, Prescribed a prolonged course of mepron, azithromycin and doxycycline but stopped after azithromycin and doxycycline but stopped after 3 weeks due to GI intolerance and a rash.3 weeks due to GI intolerance and a rash.

HPIHPI

► June - Referred to ID clinicJune - Referred to ID clinic► She had been off of antibiotics since She had been off of antibiotics since 5/30. 5/30.

► Reported feeling rather well. Reported feeling rather well. Her only complaints were intermittent low-Her only complaints were intermittent low-grade temps, up to low 99s. grade temps, up to low 99s.

moderate fatigue. moderate fatigue. mild aching back and neck. Does not notice mild aching back and neck. Does not notice any active inflammation in her joints.any active inflammation in her joints.

mild headache intermittently.mild headache intermittently. Denied night sweats, chills, weight loss.Denied night sweats, chills, weight loss. She says these symptoms are all progressing She says these symptoms are all progressing slightly over the last several days. slightly over the last several days.

HPIHPI

► Sick contactsSick contacts She does note sick contacts including her two She does note sick contacts including her two children who are age 4 and 6. children who are age 4 and 6.

She states that both of her children had “otitis She states that both of her children had “otitis media” and fever for which they were prescribed media” and fever for which they were prescribed amoxicillin in the fall. amoxicillin in the fall.

Both children broke out into a diffuse rash one to Both children broke out into a diffuse rash one to two days after starting the antibiotic. This was two days after starting the antibiotic. This was called a drug reaction and the antibiotics were called a drug reaction and the antibiotics were discontinued. They were switched to new discontinued. They were switched to new antibiotics. antibiotics.

She states that her children did not experience She states that her children did not experience sore throat or lymphadenopathy. sore throat or lymphadenopathy.

Daughter continued for prolonged period with some Daughter continued for prolonged period with some arthralgias and back pain and has had an MRI as arthralgias and back pain and has had an MRI as work upwork up

PMHPMH

►1. Chronic low back pain. 1. Chronic low back pain. ►2. Hypercholesterolemia. 2. Hypercholesterolemia. ►3. Status post tonsillectomy and 3. Status post tonsillectomy and adenoidectomy in 1975. adenoidectomy in 1975.

►4. Fracture of left foot in 1993. 4. Fracture of left foot in 1993. ►5. Kidney stone in 2001. 5. Kidney stone in 2001. ►6. C-section for 2 of her 6. C-section for 2 of her children in 2000 and 2002. children in 2000 and 2002.

Social HistorySocial History

► Lives with her husband and two children. Lives with her husband and two children. ► They have several outdoor pets including They have several outdoor pets including dogs, cats, horses, and mules. dogs, cats, horses, and mules.

► She works for the US Fish and Wildlife She works for the US Fish and Wildlife Service. Service. She spends most of her days out doors in the She spends most of her days out doors in the forest. forest.

Frequent tick bites and other insect bitesFrequent tick bites and other insect bites

► In her spare time, she rides horses avidly. In her spare time, she rides horses avidly. ► She denies any tobacco or illicit drugs. She denies any tobacco or illicit drugs. She very rarely drinks beer or wine. She very rarely drinks beer or wine.

FHFH

►Her father had CABGHer father had CABG►Her mother is a breast cancer Her mother is a breast cancer survivor and also has essential survivor and also has essential thrombocytosis and Sjogren's thrombocytosis and Sjogren's syndrome. syndrome.

►She has a sister with melanoma. She has a sister with melanoma. ►Her maternal grandmother has Her maternal grandmother has rheumatoid arthritis rheumatoid arthritis

Allergies/MedicationsAllergies/Medications

► AllergiesAllergies Pencillin – rash Pencillin – rash and hivesand hives

Sulfa – rash and Sulfa – rash and hiveshives

► MedicationsMedications Mobic prnMobic prn

Physical examPhysical exam► T 36.3, pulse of 68, and T 36.3, pulse of 68, and

blood pressure of 106/66 RR blood pressure of 106/66 RR 16 Sat 98%16 Sat 98%

► HEENT: Pupils are equal, HEENT: Pupils are equal, round, reactive to light and round, reactive to light and accommodation. Extraocular accommodation. Extraocular movements are intact. Sclerae movements are intact. Sclerae are anicteric. Oropharynx is are anicteric. Oropharynx is clear without any lesions or clear without any lesions or thrush. thrush.

► NECK: Supple. There is no NECK: Supple. There is no anterior cervical, posterior anterior cervical, posterior cervical or supraclavicular cervical or supraclavicular lymphadenopathy. There is no lymphadenopathy. There is no axillary or inguinal axillary or inguinal lymphadenopathy noted. lymphadenopathy noted.

► HEART: Regular rate and HEART: Regular rate and rhythm. No murmurs, rubs, or rhythm. No murmurs, rubs, or gallops. gallops.

► LUNGS: Clear to auscultation LUNGS: Clear to auscultation bilaterally. bilaterally.

► ABDOMEN: Soft, nontender, ABDOMEN: Soft, nontender, nondistended, no nondistended, no hepatosplenomegaly. hepatosplenomegaly.

► EXTREMITIES: No clubbing, EXTREMITIES: No clubbing, cyanosis or edema. cyanosis or edema.

► SKIN: Nails, the patient SKIN: Nails, the patient has on her left thumb area has on her left thumb area at the distal portion of at the distal portion of her thumbnail, which her thumbnail, which appears to be lifted off appears to be lifted off of the base and has some of the base and has some brown discoloration. brown discoloration.

► NEUROLOGIC: The patient is NEUROLOGIC: The patient is alert and oriented x3 with alert and oriented x3 with nonfocal neuro exam. nonfocal neuro exam. Cranial nerves II through Cranial nerves II through XII are grossly intact. XII are grossly intact.

Data Data

► November 2006November 2006 WBC 4.0WBC 4.0

► Nml diffNml diff Hgb 12.7Hgb 12.7 Plts 218Plts 218 Basic panel and LFTs wnlBasic panel and LFTs wnl ANA negativeANA negative RMSF serologies RMSF serologies “negative”“negative”

Lyme IgM and IGG Lyme IgM and IGG negativenegative

RMSF serology ”negative”RMSF serology ”negative” Basic panel and LFTS WNLBasic panel and LFTS WNL

► December 06December 06 WBC 5.2 HGB 13.6 Plt WBC 5.2 HGB 13.6 Plt 196196

EBV serologies c/w EBV serologies c/w prior infxnprior infxn

CMV IGG and IGM – negCMV IGG and IGM – neg RMSF IFA RMSF IFA 1:1601:160 (nml<1:20)(nml<1:20)

RMSF LA <1:16 (nml RMSF LA <1:16 (nml <1:16)<1:16)

EHRLICHIA IGG EHRLICHIA IGG 1:641:64 (nml<1:64) (nml<1:64)

Ehrlichia IGM<1:20 Ehrlichia IGM<1:20 (nml<1:20) (nml<1:20)

LabsLabs

► April 2006April 2006► Ehrlichiosis HGE IgG < 1:64. Ehrlichiosis HGE IgG < 1:64. ► HGE IgM < 1-20. HGE IgM < 1-20. ► RMSF IgG and IgM listed as negative. RMSF IgG and IgM listed as negative. ► Lyme Western blot IgG negative except for Lyme Western blot IgG negative except for 1 reactive band at the 41 KD. 1 reactive band at the 41 KD.

► Lyme Western Blot IgM all bands negative. Lyme Western Blot IgM all bands negative. ► Babesiosis antibody IgG negative at < Babesiosis antibody IgG negative at < 1:16 1:16 IgM negative at <1: 20. IgM negative at <1: 20. Babesiosis DNA which was not detected. Babesiosis DNA which was not detected.

SummarySummary

►38 yo WF wildfire fighter with 38 yo WF wildfire fighter with frequent insect exposure with 8-9 frequent insect exposure with 8-9 months of relapsing fevers, months of relapsing fevers, arthralgias, fatigue following an arthralgias, fatigue following an initial illness with fever, HA, initial illness with fever, HA, N/V and rash.N/V and rash.

►Serological evidence of old RMSF Serological evidence of old RMSF and ehrlichia infectionand ehrlichia infection

►Sxs resolve somewhat with Sxs resolve somewhat with doxycycline but then recurdoxycycline but then recur

Diagnostic testingDiagnostic testing

►HIV seronegative and pooled HIV seronegative and pooled negativenegative

►Hep A, B and C negativeHep A, B and C negative►Parvovirus B 19 PCR positive on Parvovirus B 19 PCR positive on 33.5 (out of 45) cycles 33.5 (out of 45) cycles

►Parvovirus IgM positive 4.55 (nml Parvovirus IgM positive 4.55 (nml < 1.25)< 1.25)

►Parvovirus IgG positive 5.05 Parvovirus IgG positive 5.05 (nml<0.9)(nml<0.9)

Parvovirus B 19Parvovirus B 19

► Erythrovirus genus within the family Erythrovirus genus within the family ParvoviridaeParvoviridae Small non-enveloped SS DNA virusSmall non-enveloped SS DNA virus Humans are only known hostHumans are only known host Replicates in erythroid progenitor cells of Replicates in erythroid progenitor cells of bone marrow and inhibit erythropoesisbone marrow and inhibit erythropoesis

► Discovered in 1975 while screening units Discovered in 1975 while screening units of blood for Hep B (sample 19 in panel B of blood for Hep B (sample 19 in panel B was a false positive)was a false positive)

► First associated with clinical disease First associated with clinical disease in 1981in 1981

Parvovirus B 19Parvovirus B 19

Respiratory transmission, vertical Respiratory transmission, vertical transmission or blood transfusionstransmission or blood transfusions

Worldwide distributionWorldwide distribution Late winter and early summerLate winter and early summer During outbreaks in schools 25-50% During outbreaks in schools 25-50% of children and 20% of susceptible of children and 20% of susceptible staff infectedstaff infected

>70% of adults have IgG levels +>70% of adults have IgG levels +

ClinicalClinical

Causes a spectrum of clinical manifestationsCauses a spectrum of clinical manifestations 25% completely asymptomatic25% completely asymptomatic 50% with non specific flu-like illness50% with non specific flu-like illness 25% with classic EI or arthralgia25% with classic EI or arthralgia Biphasic patternBiphasic pattern

►Incubation period 4-14 daysIncubation period 4-14 days►First week after infection have intense viremia First week after infection have intense viremia with non specific flu like illness with fever, with non specific flu like illness with fever, malaise, myalgia, HA and pruritismalaise, myalgia, HA and pruritis

Hematological abnormalities with reticulocytopenia, Hematological abnormalities with reticulocytopenia, decreased hemoglobin, leukopenia and TCPdecreased hemoglobin, leukopenia and TCP

►In the following week develop rash or arthralgiaIn the following week develop rash or arthralgia

Course of diseaseCourse of disease

Virologic, immunologic & clinical Virologic, immunologic & clinical course following B19 infection. course following B19 infection.

►See Figure 143-3 in:See Figure 143-3 in:

Mandell, Bennett, & Dolin: Mandell, Bennett, & Dolin: Principles and Practice of Principles and Practice of Infectious Diseases, 6th ed. Infectious Diseases, 6th ed.

Full text available via the UNC-CH Full text available via the UNC-CH LibrariesLibraries

Fever/rash of childhoodFever/rash of childhood

►First Disease – MeaslesFirst Disease – Measles►Second disease – Scarlet feverSecond disease – Scarlet fever►Third disease – RubellaThird disease – Rubella►Fourth disease – enterovirus Fourth disease – enterovirus (coxsackie and echo)(coxsackie and echo)

►Fifth disease – Erythema Fifth disease – Erythema InfectiosumInfectiosum

►Sixth disease – HHV6/7 – infantim Sixth disease – HHV6/7 – infantim subitum or Roseala infantumsubitum or Roseala infantum

Erythema infectiosumErythema infectiosum

► Slapped cheek following non specific Slapped cheek following non specific viral illnessviral illness

► Constitional sxs coincide with viremiaConstitional sxs coincide with viremia► 2-5 days later rash develops2-5 days later rash develops

Slapped cheek with erythematous malar Slapped cheek with erythematous malar eruption eruption

followed by a reticulated or lacy rash on followed by a reticulated or lacy rash on trunk or extremitiestrunk or extremities

► By the time the rash develops the child By the time the rash develops the child feels well and is no longer contagious feels well and is no longer contagious (detectable IgM – clears viremia)(detectable IgM – clears viremia)

ArthritisArthritis

► One of the viral causes of arthritisOne of the viral causes of arthritis► Can present with acute arthritis or be Can present with acute arthritis or be mistaken for rheumatoid arthritis if no mistaken for rheumatoid arthritis if no rash presentrash present

► More common in adults and especially womenMore common in adults and especially women► Usually symmetricUsually symmetric► Frequently involve small joints of hands, Frequently involve small joints of hands, wrists, knees and feetwrists, knees and feet

► 75% develop rash (but <20% with malar rash)75% develop rash (but <20% with malar rash)► Usually resolve in 3 weeksUsually resolve in 3 weeks

ArthritisArthritis

► May be persistent or recurringMay be persistent or recurring► May be misdiagnosed as RAMay be misdiagnosed as RA► However does However does notnot cause joint destruction cause joint destruction► B19 DNA has been found in joint fluid, but B19 DNA has been found in joint fluid, but unclear if it infects synovial cellsunclear if it infects synovial cells

► Often will have associated malaise, fever, Often will have associated malaise, fever, fatigue, GI sxsfatigue, GI sxs

► Can have asymptomatic periods between Can have asymptomatic periods between flaresflares

► One half of patients with chronic course One half of patients with chronic course meet the ARA criteria for RAmeet the ARA criteria for RA

► Absence of nodules or erosions helps Absence of nodules or erosions helps differentiate differentiate

DiagnosisDiagnosis

► Acute infectionAcute infection Serology – IgM – measurable 7-10 days after Serology – IgM – measurable 7-10 days after exposure and for several months after exposure and for several months after ► IgG – fourfold increase in IgG is also diagnosticIgG – fourfold increase in IgG is also diagnostic

PCR – can be detected for months following PCR – can be detected for months following infection (especially in bone marrow and synovial infection (especially in bone marrow and synovial fluid)fluid)

► Previous infectionPrevious infection Document for pregnancy with positive IgGDocument for pregnancy with positive IgG

► Reactivation or chronic infectionReactivation or chronic infection Confirmed by demonstrating the presence of virus Confirmed by demonstrating the presence of virus over a prolonged periodover a prolonged period

IgM may also be measurable over long periods if pt IgM may also be measurable over long periods if pt is immunocompetentis immunocompetent

Failure to dx in pts with persistent arthritis is Failure to dx in pts with persistent arthritis is common as IgM may be negativecommon as IgM may be negative

TreatmentTreatment

►For arthritis main treatment is For arthritis main treatment is NSAIDSNSAIDS Usually resolvesUsually resolves

►For persistent viremia with For persistent viremia with clinical disease in clinical disease in immunocompromised patients IVIG immunocompromised patients IVIG is usedis used

Manifestations of B19 Manifestations of B19 InfectionInfectionCommonCommon

Asymptomatic infectionAsymptomatic infection Transient aplastic crisisTransient aplastic crisis Erythema infectiosumErythema infectiosum Hydrops fetalisHydrops fetalis Acute and chronic arthropathyAcute and chronic arthropathy Chronic or recurrent bone marrow Chronic or recurrent bone marrow suppression in immunocompromised suppression in immunocompromised hostshosts

Manifestations of B19 Manifestations of B19 InfectionInfectionLess CommonLess Common

► SkinSkin Vesiculopustular eruptionVesiculopustular eruption Henoch-Schonlein purpuraHenoch-Schonlein purpura Thrombotic thrombocytopenic purpuraThrombotic thrombocytopenic purpura ““Gloves and socks” syndromeGloves and socks” syndrome

► HematologicalHematological AnemiaAnemia ThrombocytopeniaThrombocytopenia LeukopeniaLeukopenia Benign acute lymphadenopathyBenign acute lymphadenopathy Hemophagocytic syndromeHemophagocytic syndrome

Manifestations of B19 Manifestations of B19 InfectionInfectionLess CommonLess Common

► VasculitisVasculitis Polyarteritis nodosaPolyarteritis nodosa Wegener’s granulomatosisWegener’s granulomatosis

► LiverLiver Hepatocellular enzyme elevationsHepatocellular enzyme elevations Non-A, non-B, non-C fulminant liver Non-A, non-B, non-C fulminant liver failurefailure

► Nervous systemNervous system ParesthesiasParesthesias MeningitisMeningitis Sensorineural hearing lossSensorineural hearing loss

Viral causes of Viral causes of arthritisarthritis

► ParvovirusParvovirus► Hepatitis A, B and CHepatitis A, B and C► Rubella and rubella vaccineRubella and rubella vaccine► Alpha virusesAlpha viruses

Chikungunya, Ross river, Barmah forest, O’nyong-Chikungunya, Ross river, Barmah forest, O’nyong-nyong, Karelian fever, Ockelbo, Pogostanyong, Karelian fever, Ockelbo, Pogosta

► MumpsMumps► EnterovirusesEnteroviruses► AdenovirusAdenovirus► Herpes viruses –VZV, EBV, HSV, CMVHerpes viruses –VZV, EBV, HSV, CMV► HIVHIV

ParvovirusParvovirus

►Discovered in 1974Discovered in 1974►Only member of family Only member of family Parvoviridae known to be Parvoviridae known to be pathogenic in humanspathogenic in humans

►CausesCauses►Erythema infectiosum – fifth Erythema infectiosum – fifth diseasesdiseases

Search PubMedSearch PubMed

►Human Parvovirus B19Human Parvovirus B19 Case ReportsCase Reports ReviewsReviews Differential DiagnosisDifferential Diagnosis Drug TherapyDrug Therapy