Vector-borne Infections Allison Liddell, M.D. Infectious Diseases September 22nd, 2003

Clinical Vignette 28yo FBI agent on temporary assignment in the Nantahala forest in Western North Carolina presents with acute onset fever, chills, headache 3 days after Memorial Day. Exam: confused, ill appearing, a few petechiae present on wrists and ankles Labs: platelets=75K, mild leukocytosis, mildly elevated transaminase LP with 75 WBC, mostly lymphocyes with protein=154

Tick-Borne Infections in the U.S. Lyme disease Rocky Mountain spotted fever Ehrlichiosis Tularemia Babesiosis Colorado tick fever Tick-borne relapsing fever Tick-borne encephalitis Tick paralysis Q Fever

Tick Classification

Questing tick

Rocky Mountain Spotted Fever Described in late 1900’s in Bitter Root Valley Caused by infection with Rickettsia rickettsii Obligate intracellular, requires cell culture to cultivate

RMSF transmission Maintained transovarially in ticks Tick vectors are hard ticks: Dermacentor variabilis (eastern US) D. andersoni (western US) A. americanum (south-southwestern US)

Parola, Clin Infect Dis 2001 Mar 15;32(6):897-928

RMSF epidemiology Most cases occur May – September Highest rate in children 5 - 9 years Exposure to dogs, grassy areas risk factor 8.5% mortality (Billings et al)

TDH Website

TDH Website

RMSF Clinical Manifestations Incubation period 2 - 14 days Onset with fever, myalgias, headache GI findings may mimic an acute abdomen Rash appears 3 - 5 days after onset of fever Meningismus and CSF pleocytosis may occur WBC usually normal, platelets may be decreased Hyponatremia occurs in 50%

RMSF Diagnosis Serology IF staining of tissue specimen PCR under development

RMSF Outcome N=6388 over 1981-1998 Annual case-fatality rate 3.3% Risk factors for mortality: Old age Chloramphenicol only Tetracycline not primary therapy Treatment delayed > 5 days Holman et al JID 2001

Clinical Vignette 54 yo WM farmer in Missouri presents with 3 day h/o high fevers, chills, headache and marked malaise in June Exam notes a confused, ill-appearing man but is otherwise unremarkable Labs note transaminases 3 x normal, platelets 115K, WBC 2.1, CSF 32WBC, protein 127

History of Ehrlichiosis 1935 - E. canis-hemorrhagic illness in Algerian dogs 1950s – E. sennetsu-mononucleosis-like illness in Japan 1986 – Ehrlichiosis-patient in Detroit after tick bites in Arkansas 1991 - E. chaffeensis cultured from patient at Fort Chaffee in Arkansas

Genus Ehrlichia Small gram-negative bacteria closely related to Rickettsiae Obligate intracellular parasites Infect circulating blood elements Reside and replicate within membrane-bound cytoplasmic vacuoles Vertebrate reservoirs and arthropod vectors

Ehrlichia ewingii First discovered in dogs with granulocytic ehrlichiosis, 1992 Disease is milder than E. canis infection Manifestations include fever, lethargy and polyarthritis Found to date in dogs in Missouri, Arkansas, Oklahoma and N. Carolina Member of E. canis genogroup (cross-reactivity) Experimental transmission by A. americanum

Ehrlichiae Causing Human & Veterinary Disease

Human Ehrlichiosis Symptoms HME HGE Fever 97 94-100 Headache 81 61-85 Myalgia 68 78-98 Malaise 84 98 Rash 36 2-11 Confusion 20 17 Dumler et al, Annu. Rev. Med. 1998. 49:201-213

Human Ehrlichiosis Clinical Spectrum DIC Pancytopenia Encephalitis/Meningitis Pulmonary infiltrates/Respiratory failure Gastrointestinal bleeding Renal Failure

Human Ehrlichiosis Laboratory Findings Leukopenia Thrombocytopenia Elevated transaminases Hyponatremia >4-fold elevation in IFA PCR

RMSF/Ehrlichiosis Treatment Adults: Doxycycline 100 mg bid Children: Doxycycline 3 mg/kg/day in 2 divided doses Duration: 3 days after defervescence, minimum 5-7 days

Clinical Vignette 34 yo WF owner of a campground presents with a nonhealing lesion on the right index finger for 2 weeks, adjacent to the nail bed. Failed Augmentin and acyclovir by PCP for “infected paronychia” Exam notes an ulcerated lesion and regional adenopathy

Tularemia History McCoy & Chapin 1910 “plague-like disease” of rodents in Tulare Co. CA Bacterium Tularense Edwards Francis 1928 - 800 cases isolated organism proved vector named the disease developed culture and serology methods noted risk to workers

Parola, Clin Infect Dis 2001 Mar 15;32(6):897-928

Tularemia Epidemiology 1368 cases 1990-2000 All states except Hawaii, but predominately MO, AK, OK & SD Reinstated on nationally notifiable list 2000 (n=142) Type A (biogroup tularensis) Multiple vectors (tick, deerfly) >250 animal species rabbits hares muskrats Other transmission carnivores direct contact inhalation/ingestion Peak incidence 1939

Outbreak 2001 Pneumonic Tularemia 15 patients in Martha’s Vineyard 11 primary pulmonary 1 death Feldman et al, N Engl J Med 2001 Nov 29;345(22):1601-6

Tularemia Clinical Manifestations Ulceroglandular black based ulcer tender regional lymphadenopathy  bubo Typhoidal Oculoglandular Primary pulmonary

Tularemia Diagnosis Titers 4-fold increase single > 1:160 Skin test Culture – notify laboratory

Tularemia Treatment Streptomycin 1 gm iv q12h for 10 days Gentamicin 5 mg/kg/d for 10 days Tetracycline/chloramphenicol associated with 15-20% relapse Quinolones Excellent in vitro activity Limited data, anecdotal experience suggests efficacy Live attenuated vaccine for high risk groups

Tularemia Complications Pneumonia  abscess, effusion Rhabdomyolysis Acute renal failure Meningitis Pericarditis

Lyme Most commonly reported tick-borne infection in U.S. 1993-1997, mean 12,451 annual cases (CDC)

Lyme History Cluster of cases near Lyme, CT 1975 Johnson RC, Schmid GP, Hyde FW, Steigerwalt AG, Brenner DJ. Borrelia burgdorferi sp. nov.: etiological agent of Lyme disease. Int J Syst Bacteriol 1984; 34:496 7.

Lyme epidemiology B. burgdorferi sensu lato Tick vector Black-footed mouse reservoir White-tailed deer host Birds and mammals implicated in Europe

Lyme Disease Early Manifestations Erythema migrans (90%) Occurs 8-14 days after bite Single lesion, average size 15cm Systemic symptoms may be present Secondary lesions may occur Carditis Aseptic meningitis Bell’s palsy

Lyme Disease Late Manifestations Arthritis Knees involved in 90% Usually resolves, 1-2 weeks May recur CNS disease (rare in children)

Lyme Disease Diagnosis Serology ELISA Western blot Culture on BSK-II media 57-85% sensitive skin Blood, CSF, synovial fluid Warthin-Starry stain PCR

Lyme Disease Treatment of Early Disease Doxycycline (  8 years of age) Ampicillin Penicillin allergic: cefuroxime axetil or erythromycin Duration 14 - 21 days

Lyme Disease Treatment-Disseminated & Late Disease Multiple skin lesions Oral, 21 days Isolated facial palsy Oral, 21 -28 days Arthritis Oral, 28 days Persistent arthritis Parenteral, 14 - 21 days Carditis Parenteral, 14 - 21 days CNS Parenteral, 14 - 21 days

Lyme Disease Vaccine recombinant B. burgdorferi lipidated outer-surface protein A (rOspA) Antigen not expressed in host Antibody is taken up into tick and bacteria destroyed in vector 0, 1 and 12 months As of February 25, 2002 LYMErix™ off the market

Southern Tick-Associated Rash Illness (STARI) Similar EM rash Long-term and serious complications not reported Responds to doxycycline Organism by PCR B. lonestari No culture 639 cases in Texas 1986-1996

Clinical Vignette 25yo male camper in Montana presents with a 2 week history of intermittent fevers. Initially he had a high fever with headache, red eyes, jaundice, severe body aches, and after about 3 days a diffuse red rash on his trunk. The fever resolved, then about a week later recurred without the other symptoms.

Tick-borne Relapsing Fever Dutton JE, Todd JL. The nature of tick fever in the eastern part of the Congo Free State, with notes on the distribution and bionomics of the tick. Br Med J 1905; 2:1259 60. Described tick relapsing fever Borrelia duttonii transmitted by Ornithodoros moubata in W. Africa 13 species of Borrelia genus Ornithodoros Noctural feeder Short attachment worldwide

Parola, Clin Infect Dis 2001 Mar 15;32(6):897-928

Tick-borne Relapsing Fever acute onset of high fever with chills, headache, myalgia, arthralgia, and coughing Hemorrhage, iritis or iridocyclitis, hepatomegaly, or splenomegaly rash at the end of the first febrile episode Primary episode 3 days neurological findings B. turicatae (U.S.) B. duttonii (Africa) Jaundice ( 7%) case-fatality rate 2%-5% intensity of episodes decreases with time Mean period between episodes 8 days

Tick-borne Relapsing Fever Borreliae in peripheral blood of febrile patients. Sensitivity 70% (darkfield microscopy or Giemsa or Wright's stain). Quantitative buffy coat Serology not useful PCR Jarisch-Herxheimer reaction doxycycline (Penicillin, erythromycin, or ceftriaxone)

Tick-Transmitted Diseases Prevention Avoid tick-infested areas Wear protective clothing that covers exposed areas Use DEET - containing insect repellants Spray permethrin on clothes Remove attached ticks promptly Do not squeeze

Clinical Vignette 45yo BM with h/o Hodgkin’s in remission 5 years after chemo/XRT for Stage 4 disease, presents with acute fever, fatigue, abdominal pain, SOB/DOE, in June in New Jersey. Exam: hepatosplenomegaly, hyperdynamic precordium, pale.

Babesiosis Hemoprotozoan Babesia microti and Babesia divergens similar vector, animal reservoir and geographic distribution as Lyme Multiplication of the blood stage parasites is responsible for the clinical manifestations of the disease

Babesiosis more severe in patients who are immunosuppressed, splenectomized, and/or elderly diagnosis by thick and thin smear Treatment with clindamycin + quinine or atovaquone + azithromycin exchange transfusion has been used in severely ill patients with high parasitemias

Babesiosis

Clinical Vignette 48 yo male presents with acute onset episodic fever abdominal pain, headache, myalgias and nausea/vomiting, then profuse sweats. Recent trip to Thailand looking for exotic bird species. Exam notes tender right and left upper quadrant and splenomegaly Labs note pancytopenia

Malaria 300–500 million infections worldwide and approximately 1 million deaths annually (CDC) Plasmodium falciparum, P. vivax, P. ovale, or P. malariae infected female Anopheles mosquito blood transfusion or congenital Fatal cases are due to falciparum (“knobs”) P. vivax and P. ovale parasites can persist in the liver (natural infection only) P. malariae acute illness rare in normal hosts, causes chronic infection (GN)

Malaria Chloroquine-susc mefloquine resistance Dominican Republic, Haiti Central America west of the former Panama Canal Zone Egypt some countries in the Middle East mefloquine resistance borders of Thailand with Burma (Myanmar) and Cambodia western provinces of Cambodia eastern states of Burma (Myanmar) Fansidar resistance Amazon River Basin area of South America, Southeast Asia other parts of Asia large parts of Africa

Malaria fever and influenzalike symptoms chills, headache, myalgias, and malaise Classic paroxysm Chill Spike Sweat can occur at intervals Falciparum less exact Vivax/ovale tertian Malariae quartian anemia and jaundice, seizures, mental confusion kidney failure, coma, and death 6 days after initial exposure to several months after chemoprophylaxis

Malaria Diagnosis Peripheral smear Hypoglycemia Lactic acidosis Vivax/ovale Falciparum No mature forms High parasitemia (directly related to mortality in nonimmune) Multiple ring forms/cell Infects all ages Hypoglycemia Lactic acidosis Hemolysis Acute renal failure Pancytopenia

Malaria Treatment Hospitalize if nonimmune and suspect falciparum Different drug than prophylaxis Halofantine cross resistant w/mefloquine Start 2nd drug later If vivax/ovale need Primaquine Artemisin if mefloquin/cholorquine resistance Exchange transfusion if parasitemia >15% in nonimmune

Malaria Prevention transmission occurs primarily between dusk and dawn well-screened areas, mosquito nets, clothes that cover DEET (N,N-diethylmetatoluamide) pyrethroid-containing flying-insect spray in living and sleeping areas

Chemoprophylaxis mefloquine or chloroquine 1–2 weeks before doxycycline and atovaquone/proguanil 1–2 days before continuously while in malaria-endemic areas 4 weeks (chloroquine, doxycycline, or mefloquine) after 7 days (atovaquone/proguanil) after Terminal prophylaxis with Primaquine final 14 days fatal hemolysis in those who are G6PD deficient

Chemoprophylaxis pregnancy Long history of chloroquine and quinine use Data supports safety of mefloquine in 2nd an 3rd trimester Data in first trimester sketchy, patient must weigh risks No Doxycycline or Primaquine No data for Malarone

Malaria Information http://www.cdc.gov/travel Voice information service 1-877-FYI-TRIP CDC Malaria Hotline (770-488-7788) from 8:00 a.m. to 4:30 p.m. Eastern time CDC Emergency Operation Center at 770-488-7100 page person on call for the Malaria Epidemiology Branch.

Clinical Vignette 72 yo WM alcoholic with CAD presents with 3 day h/o fever, myalgias, headache followed by acute onset confusion and tremulousness Works as a nursery sales rep and travels frequently to East Texas No improvement on levaquin EKG afib CSF notes elevated protein and lymphocytic pleiocytosis

Viral Encephalitis arthropod-borne Alphaviridae Eastern Equine Western Equine Bunyaviridae LaCrosse Flaviviridae St. Louis Powassan (ticks) Japanese Tick-borne (ticks) West Nile Culex

Arboviral Activity Louisiana 2001 SLE Human Cases EEE Equine Cases EEE Human Cases SLE Avian Cases EEE Mosquito Pools WNV Equine Cases WNV Human Cases WNV Avian Cases SLE 5 Human Cases Outbreak or Cluster with Human Case(s)

Eastern Equine Eastern US Ave. 4 cases/year Togaviridae, genus Alphavirus 35% mortality 35% permanent neuro defect

St. Louis Encephalitis Aseptic meningitis or encephalitis Majority subclinical or mild illness Intermittent epidemic transmission - up to 3,000 cases per year (1975) Culex mosquitoes Elderly - biological risk factor Low SES areas - environmental risk factor Outdoor occupation - exposure risk factor

St. Louis Encephalitis Largest outbreaks in 15 years occurred in 1990 Urban transmission in west first recognized in 1987 Deterioration of inner cities, global warming may increase vector abundance and transmission Unpredictable and intermittent occurrences of outbreaks Multiple environmental, biological and social factors contributing to disease occurrence Virus maintenance and overwintering cycle

La Crosse Encephalitis Frank encephalitis progressing to seizures, coma majority of infections subclinical or mild 70 cases/year Case-fatality ratio <1% Social costs from adverse effects on IQ and school performance woodland habitats in treehole mosquito (Aedes triseriatus) and vertebrate hosts (chipmunks, squirrels); survives winter in mosquito Vector uses artificial containers (tires, buckets, etc.) in addition to treeholes

La Crosse Encephalitis Children <16 years old: biological risk factor Residence in woodland habitats environmental risk factor Containers at residence environmental risk factor Outdoor activities: behavioral risk factor Traditional endemic foci in the great-Lakes states Increased case incidence in mid-Atlantic states Rural poor most affected Disease is considerably under-reported

West Nile Virus First isolated from a febrile adult woman in the West Nile District of Uganda in 1937 Ecology was characterized in Egypt in the 1950s. Cause of severe human meningoencephalitis in elderly patients during an outbreak in Israel in 1957 Equine disease first noted in Egypt and France in early 1960s. Outbreak of West Nile-Like Viral Encephalitis -- New York, 1999. MMWR, 1999:48(38);845-9 Update: West Nile-Like Viral Encephalitis -- New York, 1999. MMWR, 1999:48(39);890-2

West Nile Virus in the U. S. September 19, 2003

Clinical Epidemiology Incubation period 3 - 14 days 20% develop “West Nile fever” 1 in 150 develop meningoencephalitis Advanced age primary risk factor for severe neurological disease and death

West Nile Fever: Classic Clinical Description Mild dengue-like illness of sudden onset Duration 3 - 6 days Fever, lymphadenopathy, headache, abdominal pain, vomiting, rash, conjunctivitis, eye pain, anorexia Symptoms of West Nile fever in contemporary outbreaks not fully studied

Symptoms of Hospitalized Patients with West Nile Virus, New York City, 1999 Fever 90% Weakness 56% Nausea 53% Vomiting 51% Headache 47% Change in mental status 46% Diarrhea 27% Rash 19% Lymphadenopathy 2%

Neurological Presentations of West Nile Virus Infection New York City 1999 Encephalitis/meningoencephalitis 62% Meningitis 32% Complete flaccid paralysis 10% Confused with Guillain-Barre syndrome EMG and nerve conduction velocity-both axonal and demyelinating lesions, with axonal lesions most prominent Preliminary data 2002 Complaints of weakness out of proportion to exam Myoclonus nearly a universal finding Some patients have Parkinsonian Previous series Ataxia, extrapyramidal signs, cranial nerve abnormalities, myelitis, optic neuritis, seizures

West Nile Virus 489 WNV-viremic donors as of 9/16/03 two cases of blood transfusion-associated WNV in 2003, (TX and Nebraska). Both encephalitis and are recovering. In 2003, all blood banks screening for West Nile virus and will not take donations from people w/fever and headache in the week prior

Serological Analysis of A WN Case Days IgM IgG Patient WN SLE DEN2 JE P.I. (WN) (SLE) CSF 8 26.91 1.78 nd nd nd nd S1 9 9.1 4.16 160 20 <10 10 S2 34 6.7 4.62 1280 20 <10 20 Positive n.a. 9 6.5 >5120 2560 2560 320 Control

1999 and 2000 Serosurvey Results Location Participants Positives Seroprevalence (%) NYC 1999 Queens 677 19 2.6 NYC 2000 Staten Is. 871 4 0.46 NYS 2000 Suffolk Co. 834 1 0.12 CT 2000 Fairfield Co. 731 0.0

Clinical Vignette 59 yo Mexican immigrant admit with 3 month history of progressive shortness of breath, PND, orthopnea, LE edema.

Chagas’ Disease American trypanosomiasis (Trypanosoma cruzi) 16-18 million people are infected 50,000 will die each year. poorly constructed houses found in the rural areas of the above-mentioned countries are at elevated risk of infection. Houses constructed from mud, adobe, or thatch present the greatest risk.

Chagas’ Disease Reduviid bugs, or "kissing bugs" in South and Central America deposits feces on a person's skin at night rubs the feces into the bite wound, an open cut, the eyes, or mouth. Transplacental, congenital or breastfeeding. By blood transfusion Uncooked food contaminated with infective feces of "kissing bugs." one-third chronic symptoms develop after 10-20 years. average life expectancy decreases by an average of 9 years.

Chagas’ Disease Acute: Indeterminate (asymptomatic): Chronic: 1% of cases. Romaña's sign fatigue, fever, enlarged liver or spleen, and swollen lymph glands. rash, loss of appetite, diarrhea, and vomiting occur. infants and in very young children cerebral edema symptoms last for 4-8 weeks. Indeterminate (asymptomatic): Chronic: CHF megaesophagus, megacolon in immune compromised, including persons with HIV/AIDS, Chagas disease can be severe.

Chagas’ Disease Diagnosis smear serology

Clinical Vignette September 9, 1981, a 72-year-old male from Edinburg, Texas, developed fever and weakness 16 days after being bitten by tsetse flies during a hunting trip in northwest Tanzania. Several days after onset of fever, he noticed a raised, tender, erythematous nodule (6-8 cm in diameter) on the posterior aspect of his right arm.

East African Trypanosomiasis six patients have shared several characteristics: exposure to infected tsetse flies while visiting game parks in eastern or southern Africa, development of acute, febrile illness consistent with Trypanosoma brucei rhodesiense infection 1-21 days after visiting detectable typanosomes on peripheral blood smears, and recovery after appropriate therapy. Only 2/5 showed clear evidence of central nervous system (CNS) involvement; both patients had elevated CSF protein, increased CSF cell count, and trypanosomes in the CSF.

East African Trypanosomiasis Suramin is recommended for hemolymphatic stage does not cross the blood-brain barrier, Melarsoprol, (relatively toxic) +/- suramin when infection involves the CNS trypanosomes are observed in the CSF morula cells of Mott or an elevated CSF IgM is strongly suggest CNS involvement elevated CSF cell count usually should be monitored for CNS involvement during treatment and at regular intervals for 1-2 years thereafter

Don’t forget Dengue Plague Yellow fever Onchocerciasis Loaiasis West African Trypanosomiasis Typhus Q fever Louse-borne relapsing fever Leischmaniasis