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Eleni Boussios, MD, MSPH Infectious Diseases Conference April 21, 2009

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1 Eleni Boussios, MD, MSPH Infectious Diseases Conference April 21, 2009
Duke in Darwin Eleni Boussios, MD, MSPH Infectious Diseases Conference April 21, 2009

2 Duke This case took place a few years ago when I was working at the VAMC, which is across the street from Duke. For those of you who don’t know, here’s the US & Duke is located in NC; this is a picture of Duke’s main campus featuring Duke Chapel & this is a picture of the VAMC

3 History CC: 59-year-old, African-American man with fevers
Symptoms x 7days Generalized malaise Subjective fevers Nasal congestion with yellow discharge Cough productive of white sputum Decreased oral intake with nausea Vomited (non-bloody, non-bilious) day prior to admission “Dehydrated and weak” Complained of moderate frontal headache Seen by doctor 2 days after symptom onset & started on amoxicillin for “sinusitis”

4 Review of Symptoms No vision changes, neck pain, neck stiffness, sore throat, ear pain, oral lesions, chest pain, shortness of breath, abdominal pain, diarrhea, dysuria, urethral discharge, rash, or joint complaints No recent change in medications aside from amoxicillin No recent travel No sick contacts

5 Past History Coronary artery disease with past MI Hyperlipidemia
Cerebrovascular disease with past stroke DVT LLE on warfarin anticoagulation Cardiac arrhythmia on procainamide (has failed other treatments)

6 Medications HCTZ 25mg PO daily Lisinopril 5mg PO daily
Metoprolol 25mg PO twice daily Niacin 500mg PO TID Nitroglycerin 0.4mg SL PRN Procainamide 1500mg PO Q12H Warfarin 9mg PO QHS

7 History SHX: Married From Granville county Retired Occasional ETOH
No tobacco No illicit drugs Turkey hunter as hobby FHX: No known illnesses

8 Exam T: 39.9 initial SBP of 80  after 3L of NS 111/67
GEN: well-appearing male, alert, oriented, NAD HEENT: dry mm, no JVD, no LAD, no oral lesions, no nuchal rigidity, posterior OP clear, boggy nasal mucosa with mucous stranding PULM: CTA bilaterally, no rhonchi, crackles, rales, or wheezes CV: RRR without murmur ABD: soft, + BS, NT/ND, no rebound or guarding, no organomegaly EXT: no edema, no joint swelling NEURO: CN 2-12 intact, good historian, no focal deficits GU: negative for occult blood SKIN: no rash!

9 Labs 15.1 6.1>---<96 47 128/87/14 ---------------<136
3.9/28/1.5 1.2/212 249/184 Amylase 60 D-dimer: 0.62 Fibrinogen: 460 CK: 493 INR: 3.03 PTT: 66 Ca: 8.8 Mg: 1.9 PO4: 2.4 UA: 13 RBC Blood and urine cultures: NGTD HIV: negative Hepatitis A, B, C: negative CXR: no infiltrate

10 Turkey Hunting Presentation was in late March (spring in NC)
Found several ticks on his body after turkey hunting in the previous weeks He was admitted to hospital to the ICU Commenced doxycycline 100mg twice daily empirically He responded well to treatment & was transferred to the general medicine floor couple days later & discharged home shortly thereafter

11 Diagnosis RMSF The presumptive diagnosis was Rocky Mountain Spotted Fever Rapidly responded to treatment Diagnosis subsequently confirmed by convalescent antibody titers or IFA (indirect fluorescent antibody test) The final diagnosis was RMSF which was confirmed subsequently by convalescent antibody titers & was demonstrated by his rapid response to treatment

12 Rocky Mountain Spotted Fever (RMSF)
Caused by Rickettsia rickettsii, a gram-negative, obligate intracellular bacterium Genus Rickettsia Family Rickettsiaceae Orientia is other genus in family Most common rickettsial infection in the US Presentation ranges from mild to fulminant

13 History Originally recognized in 1896 in the Snake River Valley of Idaho Called “black Measles” By 1900s the recognized geographic distribution grew to broadly encompass the US Dr. Howard T. Ricketts identified the organism & epidemiology of the disease in 1908 Research done at the Rocky Mountain Laboratory Dr. Ricketts ironically died of typhus in 1910 Apparently he would often inject himself with a pathogen

14 Rocky Mountains—a Misnomer
A bit of a misnomer as there are actually very few cases in the Rocky Mountains & should more aptly be called NC Spotted Fever

15 Epidemiology Occurs throughout the US, Canada, Mexico, Central America, & parts of South America Most prevalent in SE & south central US NC accounts for >41% of the cases in 2005 Most occur in the spring & early summer Average annual incidence is 2.2 cases per million persons in the US each year But can occur at any time of the year, especially in NC

16 Cases Per Year Reportable disease since 1920s
Incidence varies greatly from year to year Incidence anywhere from 250 to 1200 cases a year E.g. only 395 cases reported in 1997 yet 1843 reported in 2005 Etiology of variations unclear Reportable disease in the US since the 1920s. Over the last 50-years about 250 to 1200 cases a year though many cases probably go unreported Incidence varies substantially from year to year Actual incidence likely much higher than what is reported

17 Disease Transmission The main vector the American dog tick (Dermacentor variabilis) Dermacentor andersoni (the Rocky Mountain wood tick) primary vector west of the Mississippi River Transmitted via a tick bite Adult feeds for about 2 weeks R rickettsii is in the salivary glands & is reactivated & transmitted during blood meal 1/3 of patients do not recall tick bite or tick contact Pictured the American Dog Tick Transmission can also occur via hemolymph through a crushed tick & lab acquired RMSF infection has occurred Bio-safety level 3

18 American Dog Tick Life Cycle
R rickettsii maintain in the wild by a lifecycle of transmission between ticks & small mammals that are not adversely affected by the disease Ticks both vectors & natural hosts/reservoirs Maintained throughout all 4 lifecycles Humans accidental “dead-end” hosts Dogs also play role in transmission Once a tick is infected with one rickettsia it cannot be infected with another It does not harm the tick

19 Disease Transmission In order from left to right: Rocky Mountain Wood Tick, the Common Brown Tick, & the Cayenne Tick. The first, is the main vector for RMSF west of the Mississippi River. The Common Brown Tick was implicated in outbreaks of RMSF in Arizona. The Cayenne Tick as well as the Yellow Dog Tick are the main vectors of transmission in Central & South America

20 Clinical Manifestations
Symptoms 2 to 14 days after being bitten by an infected tick (incubation period from 2-14 days) Most between 5 & 7 days after exposure Onset often sudden Early symptoms: fever, headache, malaise, myalgias, arthralgias, & nausea, +/- vomiting Abdominal pain that can be severe Other symptoms: cough, bleeding, edema, confusion, focal neurologic deficits, & seizures

21 Rash Most develop rash within 3-5 days of symptoms
Only 14% have rash on the 1st day < 50% develop rash in 1st 72 hours Rash never occurs in up to 10% of patients ("spotless" RMSF) Typical rash begins on the ankles and wrists & spreads both centrally & to the palms and soles Begins as a macular or maculopapular & becomes petechial Urticaria & pruritus are not present Rash is often absent when the patient first contacts a physician Rash can be overlooked in dark skinned people Lack of rash can confound diagnosis & can result in increased mortality

22 Decision to Treat & Deadly Outcomes
Must not delay treatment! Decision to treat Is based on the occurrence of typical symptoms in patients from endemic areas Duke retrospective study of 94 patients with RMSF, those treated within 5 days of symptom onset were much less likely to die vs. those treated after 5 days (6.5% vs. 22.9%) Over 90% of patients saw a Dr. within the 1st 5 days of illness but less than ½ received anti-rickettsial treatment 3 independent predictors of failure to treat: 1) no rash 2) presentation within the 1st 3 days of illness & 3) presentation between Aug 1st & April 30th

23 Case Fatality 612 deaths from RMSF between 1983 & 1998 in the US
Age specific incidence of RMSF in the US between & case fatality ratio by group Fatality rations are highest in the very young & elderly

24 Treatment Doxycycline 200mg/day in 2 divided doses for adults & children >45kg 2.2mg/kg/dose Q12H for children <45kg Some places (Duke) give a single loading dose of 200mg to critically ill patients Pregnant women should be treated with chloramphenicol 50/mg/kg/day in 4 divided doses Treat at least 3 days after the patient becomes afebrile Most patients are cured within 5-7 days of treatment Risk of giving tetracycline to a child considered less than risk of treating with chloramphenicol Typical treatments recs for at least 3-7 days or until afebrile for 2-3 days

25 Diagnosis NO completely reliable diagnostic test in the early phases of illness when therapy should be commenced Therefore, if RMSF is suspected given the clinical presentation, one should treat! The diagnosis can be later confirmed by skin biopsy or serological testing For example, If you are in an endemic area in the early spring & summer, you treat if you suspect RMSF Sometimes hard to distinguish from early meningitis therefore if you clinically suspect that, then you should perform an LP & treat with ceftriaxone until diagnosis confirmed

26 Lab Findings Normal white count Thrombocytopenia
Reduced fibrinogen concentration Elevated fibrin split products Hyponatremia Elevated aminotransferases & bilirubin Azotemia Prolonged PTT & INR Renal failure & elevated creatinine CSF: WBC <100 PM or lymphocytic predominance Moderately elevated protein normal glucose

27 Diagnosis—Skin Biopsy & Serology
Skin biopsy: using direct immunofluorescence is 70% sensitive & 100% specific Indirect fluorescent antibody (IFA) test: Antibodies appear 7-10 days after illness onset (95% sensitive) Convalescent antibody titer 14 to 21 days after the onset of symptoms (min 1:64) False-negatives likely in the first 5 days of symptoms because antibodies not yet detectable False negative in patients treated within 48 hrs because they do not develop detectable convalescent antibody titers Skin biopsy can quickly establish the diagnosis using a punch biopsy with direct immunofluorescence staining which will reveal the organism & can provide a diagnosis within hours if the test is available locally—if there’s a rash present! Sensitivity rapidly declines after therapy has begun with a tetracycline (within 48 hrs) IFA testing is available at all state health departments in the US& through several large reference labs (detect IgM or IgG antibodies) Generally want to get paired specimens of antibody titers in the early & convalescent phases to compare the two

28 Positive IFA Reaction Shown here is a positive IFA reaction to RMSF in human serum

29 Other Diagnostic Tests
Blood cultures* Enzyme immunoassay Complement fixation Latex agglutination Indirect hemagglutination Microagglutination Whole blood PCR not useful but some labs can perform PCR on skin biopsies Blood cultures are highly sensitive & specific but only available in specific research labs

30 Other US Tick-Borne Infections
Ehrlichiosis (Ehrlichia chaffeensis) Human granulocytic anaplasmosis (Anaplasma phagocytophilum) Lyme disease (Borrelia burgdoferi) STARI/southern tick-associated rash illness (Borrelia lonestari) Babesiosis (Babesia microti) On top is the lone star tick which is the vector for STARI Beneath is the Ixodes scapularis tick which is the vector for ehrlichiosis, Lyme, & Babesiosis

31 Other Rickettsial SFG Diseases
Rickettsia of the spotted fever group (SFG) cause human illness throughout the world Many have been newly identified in recent years 20 species currently known Their clinical & epidemiological characteristics vary but they all share 3 common features: All cause fever, headache, & abdominal pain All are arthropod borne Rash &/or eschar occur in most Australia: Queensland tick typhus, Flinders Island spotted fever, Australian spotted fever, Murine typhus, & Scrub typhus

32 Australian SFG Diseases
Blue: Scrub typhus Red: Murine typhus Yellow: Queensland Tick Typhus Green: Flinders Island Spotted Fever Light Blue/Aqua: Australian Spotted Fever

33 Queensland Tick Typhus
Caused by R. australis Occurs along the entire east coast of Australia Transmitted by the scrub tick (Ixodes holocyclus) Circulates between ticks, rodents, & small marsupials & incidental human infection Eschar at the site of the tick bite occurs in ½ to a third Regional LAD Maculopapular, petechial, or vesicular rash

34 Flinders Island & Australian Spotted Fever
Recognized by an Australian GP in the 1980s in patients living in the Bass Straits between Tasmania & the mainland R. honei Mild disease A fourth develop a necrotic inoculation lesion at the site of bite ½ localized LAD Almost all with fever, headache, & myalgias Skin rash maculopapular but rarely petechial Australian Spotted Fever is caused by a subspecies of R. honei

35 Scrub Typhus Orientia tsutsugamushi (previously R. tsutsugamushi)
Gram negative coccobacillus Mite-borne (chiggers) Endemic to Queensland Has been found in the NT Symptoms: headache, high fever, & myalgias ½ with non-pruritic macular or maculopapular rash that begins in the abdomen & spreads to the extremities Petechiae rare Some develop eschar at site of tick bite

36 Scrub Typhus Other symptoms: LAD, nausea, vomiting, diarrhea, cough, meningitis, encephalitis, pericardial effusion Bloods: thrombocytopenia, elevated LFTs, elevated creatinine, & leukopenia Diagnosis: serology/IFA, skin biopsy, culture*, blood PCR* Confirmed cases of scrub typhus acquired in Litchfield Park since 1990 Lymphohistiocytic vasculiti is path hallmark sign on biopsy

37 References Chen L, Sexton D. What’s new in Rocky Mountain Spotted Fever. Infect Dis Clin North Am Sep;22(3): Kirkland KB, Wlikinson WE, Sexton DJ. Therapeutic delay & mortality in cases of Rocky Mountain Spotted Fever. Clin Infect Dis. 1995;20(5): Currie B, O’Connor L, Dwyer B. A new focus of scrub typhus in tropical Australia. Am J Trop Med Hyg Oct;49(4): Sexton DJ. Treatment of Rocky Mountain spotted fever. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2008. Sexton DJ. Clinical Manifestations & Diagnosis of Rocky Mountain spotted fever. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2008. Sexton DJ. Other spooted fever group rickettsial infections. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2008.


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