Duke in DarwinEleni Boussios, MD, MSPHInfectious Diseases ConferenceApril 21, 2009

Duke

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”

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

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)

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

HistorySHX: Married From Granville county Retired Occasional ETOH No tobacco No illicit drugs Turkey hunter as hobbyFHX: No known illnesses

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!

Labs

15.16.1>---<96 47

128/87/14---------------<1363.9/28/1.5

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

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

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)

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

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

Rocky Mountains—a Misnomer

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

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

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

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

Disease Transmission

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

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

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

Case Fatality

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

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

Lab Findings

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

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

Positive IFA Reaction

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

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)

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

Australian SFG Diseases

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

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

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

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

References Chen L, Sexton D. What’s new in Rocky Mountain Spotted Fever. Infect Dis Clin

North Am. 2008 Sep;22(3): 415-432. Kirkland KB, Wlikinson WE, Sexton DJ. Therapeutic delay & mortality in cases of

Rocky Mountain Spotted Fever. Clin Infect Dis. 1995;20(5):1118-1121. Currie B, O’Connor L, Dwyer B. A new focus of scrub typhus in tropical Australia. Am

J Trop Med Hyg. 1993 Oct;49(4):425-429. 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.

http://www.cdc.gov