Emerging parasitic infections Northeast Branch, American Society of Microbiology 50th Annual Region I Meeting Randolph, Massachusetts October 21, 2015

CDC:DPDx

J. H. Maguire, M.D. Brigham and Women’s Hospital Boston, Massachusetts ,USA

Parasitic diseases: progress towards global eradication, elimination or intensified control • Guinea worm disease (dracunculiasis) • Malaria • Anthroponotic visceral leishmaniasis • Lymphatic filariasis • Onchoceciasis • African trypanosomiasis • Chagas disease

Threat of emerging parasites in the United States “Classical” tropical Endemic • Malaria • Free-living • Chagas disease amoebas • Leishmaniasis • Zoonotic helminths • Cysticercosis • Babesiosis • Strongyloidiasis • Toxoplasmosis • Cryptosporidiosis, cyclosporiasis

Reported cases of malaria: USA 2012

MMWR Morb Mortal Wkly Rep. 2014;63(12) 1687 reported cases of imported malaria in 2012

Visiting friends and relatives 66%

MMWR Morb Mortal Wkly Rep. 2014;63(12)

Malaria in the United States 1912

1882 CDC:

Currently • Not endemic • Most cases imported • Transfusion-associated • Congenital • Introduced Anopheles quadrimaculatus Malaria diagnosis • Thick and thin blood smears • Antigen capture assay (rapid tests) • PCR-based assays • Serology •CDC: molecular testing for genetic markers associated with resistance to antimalarial drugs

Chagas disease (American trypanosomiasis)

Trypanosoma cruzi Chagas disease: 1980s

• Infected: 16-18 million persons in 21 countries • 500,000 new cases/year • 50,000 deaths/year • Few countries with national control programs Chagas disease: controlI1991 •1991: Southern Cone initiative • Uruguay, Chile, Brazil: free of transmission by T. infestans 1997, 1998, 2006 • Argentina < 0.5% of children < 4 yrs infected Chagas disease, 201 5-6 million persons infected < 12,000 deaths/year How many persons with Chagas disease in the U.S.?

• CDC estimate (Bern 2009) • 300,000 persons infected • 30,000-45,000 cases of undiagnosed heart Number of infected disease persons in US > number • 63-315 cases of in 8 of the 21 “endemic” congenital Chagas countries disease/year (Maternal Child Health J. 2008;12:283-6) % positive Species (T. cruzi)

Triatomine bugs T. gerstaeckeri 43.8 T. neotomae 79.8 T. protracta 25.2 T. recurva 20.3 T. rubida 4.4 T. sanguisuga 1.3

11 potential vector species Mammals > 18 infected reservoir species Opossum 36

Racoon 67 Armadillo 29 Dogs 23 T. protracta

Trypanosoma cruzi Published autochthonous acute human cases Year State Patient 1955 Texas infant 1955 Texas infant 1982 California 56 year old woman 1983 Texas infant 1998 Tennessee infant 2006 Louisiana 74 year old woman 2006 Texas Infant Transfusion-associated transmission of Trypanosoma cruzi in the U.S. Country of Year Location donor 1987 California Mexico 1989 New York City Bolivia 1993 Houston unknown 1999 Miami Chile 2002 Rhode Island Bolivia

Screening of blood donors for T. cruzi infection in the US since January 2007

Some donors born in US - >85% donations screened - >2000 repeat ELISA/RIPA positive (10/2015) - ~1:25,000-30,000; highest rate in Florida (~1:3800)>California >Texas Donor-derived Chagas disease in the USA • 14 episodes of transplantation of organs from 14 donors seropositive for T. cruzi to 36 recipients (2001-2011); transmission occurred in 9 of 32 recipients Prevalence Prevalence

• Large numbers : chronic unrecognized infections • Small risk of vectorborne transmission • Non-vectorial transmission more important • Challenges • Prevention of transmission • Identification of infected persons • Treatment • Subclinically infected • Disease • Access to adequate medical care

Diagnosis of acute Chagas disease - Visualize parasites in blood (wet mount, blood smear, buffy coat) or tissue - Xenodiagnosis: high % of bugs positive - Culture (NNN, other media) - Available from CDC - High % of tubes positive - PCR (virtually always positive) - Serology (paired IgG sera)

Diagnosis of chronic T. cruzi infection

Serology (specific IgG antibodies) - No assay with 100% specificity, sensitivity - Use 2 different assays (antigens, techniques) - Confirmation for discordant results (RIPA, Western blot) -- but no gold standard Parasitological tests less sensitive than serology - Blood smears always negative - Blood culture, xenodiagnosis - PCR-based assay (CDC, others)

Leishmaniasis • Transmission:phlebotomine sandflies • >20 species infect humans, all but 2 zoonotic • Three major clinical presentations; HIV coinfection

Visceral

Cutaneous Mucosal Visceral leishmaniasis • 62 (?79) countries; 200,000-400,000 new cases/year • 90% cases in India, Bangladesh, Nepal, Sudan, South Sudan, Ethiopia, Brazil • Zoonotic (Leishmania infantum= L. chagasi) • Anthroponotic (L. donovani) PLoS One. 2012; 7(5): e35671, WHO, worldmapper.org

Visceral leishmaniasis in the USA • Before 1999: sporadic cases – imported dogs – dogs that never traveled • 1999: 41% of foxhounds in kennel NY state infected with L. infantum • 2000-2003: 18 states, Canada • >1000 dogs infected (~12,000 tested) • Lu. shannoni: competent vector • No human cases • Transmission: – vectorborne not demonstrated – dog-to-dog – transfusion Schantz P, Duprey Z. 2006

Visceral Leishmaniasis: Diagnosis

• Bone marrow/ splenic aspirate for smears, cultures (NNN, other media), PCR • Serological tests (DAT, ELISA,k39) positive

• Serology now primary test for confirming suspected kala-azar in many endemic settings

90% of cases: Afghanistan,Pakistan, Syria, Saudi Arabia, Algeria, Iran, Brazil, Peru Cutaneous leishmaniasis in the US • 39 cases of Leishmania mexicana reported in Texas, 2 cases in Oklahoma (Am J Trop Med Hyg 2013,88:157). • Reservoir: woodrats (Neotoma) • Vector: Lutzomyia anthopora • Expansion to north and east • Cutaneous leishmaniasis in travelers • CDC: 82% New World (especially Costa Rica, Peru); 18% Old World

U.S. Military: Middle East • Operation Desert Storm: viscerotropic leishmaniasis – 500,000 soldiers, 9 cases – 4/9 afebrile; 3/9 no organomegaly; 1 subclinical; 1 after 2 years – Leishmania tropica: new syndrome – concern for transfusion-induced transmission • Afghanistan (2001-2006): L. tropica, major (>30,000 cases, mostly civilian, in 2011) • Iraq (2003-2006) – Almost 2000 cases (L.major) – 5 visceral cases – Treatment issues Magill NEJM 1993,328:1383; Aronson MSMR 2007,14:2.

• Afghanistan-L. tropics epidemic 2002 (100,000 cases in Kabul • L. major in Syria Cutaneous leishmaniasis: diagnosis • Serology (usually negative) • Specimens for parasitology: – Biopsy (2-3 mm punch) – Aspirate of lesion or lymph node – Scraping• of lesion (#10 blade) – Ideally >1 method, multiple specimens • Parasitological diagnosis: – Giemsa-stained smear – Tissue section for histology – Culture (NNN, Schneider’s, others) – PCR-based assay Taenia solium Cysticercosis T. saginata and T. solium taeniasis • Diagnosis: examination of stool for eggs; examination of passed segments • ELISA for coproantigen, DNA probes (stool), serum immunoblot (T. solium only): more sensitive, not widely available • Treatment: niclosamide, praziquantel

Taenia solium Taenia saginata Cysticercosis • Neurocysticercosis • Parenchymal • Ventricular, subarchnoid, spinal, ocular • Extraneural

Neurocysticercosis Clinical picture depends on location, number, size and stage of cysticerci, intensity of host response

Garcia HH: Lancet Neurology Cysticercosis: 50 million persons infected •Leading cause of preventable late-onset epilepsy •In endemic areas accounts for ~30% of cases of seizures Los Angeles County, California: Annual Incidence of Diagnosed Neurocysticercosis

90 80 70 60 50 40 30 20 10 0 1973 1975 1977 1979 1981 1983 Richards et al., 1985

Cysticercosis: United States

 1320-5050 new cases yearly

 Cause of 8-10% of cases of epilepsy in several emergency rooms in Los Angeles and Houston

 Most in immigrants from Latin America

 7-10% acquired locally (household clusters)

Hospitalizations for cysticercosis in USA • Nationwide Inpatient sample (8 million hospitalizations/yr) • 2003-2012: 23,266 hospitalizations for cysticercosis • $1.1 billion hospital charges • > than that of all other NTDs combined

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 6, June 2015 Serodiagnosis • ELISA • Western blot (immunoblot) • Sensitivity: serum > CSF • 100% specific • Detects extraneural and neural infection • May be (+) in inactive infection • Highly sensitive (97%) unless single lesion present (<70%) • Serum antigen (capture EIA)-less sensitive than immunoblot; ?useful for monitoring Rx, including subarachnoid; detects viable cysts not seen on CT

Strongyloidiasis: Case history • 73 old man with idiopathic primary fibrosis • Underwent single right lung transplant • Admitted 7 weeks later with shortness of breath, abdominal, diarrhea, petechial rash • Lifelong resident of New England • Donor: homeless, country of origin unknown Sputum and stool

Strongyloides stercoralis: rhabditiform and filariform larvae • Despite ivermectin and albendazole: progressive respiratory insufficiency, renal insufficiency • Death on the 23rd hospital day • Further investigation of the donor indicated that he had been born in Central America. – Serological testing showed antibodies to Strongyloides stercoralis – Of the 5 recipients of organ from the donor, 4 developed disseminated strongyloidiasis and 3 died

Strongyloidiasis in transplant recipients • Hyperinfection syndrome (prior infection) – Fatality rate >50% in immunocompromised – All potential recipients screened at BWH • Donor-derived Strongyloidiasis – Over one dozen cases reported in literature – Mortality approaches 50% – Survivors typically maintained on intermittent ivermectin therapy (eg, 2 doses every 2 weeks for 2 months)

• Filariform larvae circulate in bloodstream as part of normal life cycle (autoinfection) • Increased replication and dissemination may result from conditioning of donor with steroids or stress pre-mortem

DPDX Strongyloidiasis and organ transplantation in the United States • Organ Procurement and Transplantation Network (mandate) and American Society of Transplantation (guidance) • Screen screening living kidney donors for strongyloidiasis if from an endemic area with IgG antibody test +/- stool exam: – Persons who lived in tropics/subtropics – Persons with eosinophilia and travel history – Persons with exposure to soil in SE USA or Appalachia

Strongyloidiasis in the United States • Endemic in rural Appalachia and SE USA, – Prevalence in children in 1980s ~3% – 2013 survey in rural Kentucky: prevalence 1.9% (7 of 378 persons; 2 < 35 yrs old) • Transmission in mental health and long- term health facilities • Prevalent among immigrants and refugees (Brazilians living in Boston area 5.8%, foreign-born HIV patients in Atlanta 26%, regugees from Sudan 46%)

Uncomplicated strongyloidiasis

• > 50% asymptomatic Diagnosis • Eosinophilia in ~50% • Stool examination • Epigastric pain, nausea, Duodenal diarrhea • aspirates • Larva currens, urticaria, • Serolgical other rash testing • Treat confirmed or highly suspect cases with ivermectin • 83% with eosinophilia – Following treatment: 45% (3 months), 29% (6 months), 50% 9-18 months) • Serology: • Those with persistent eosinophilia or Ab ratio >0.6 retreated with sucess Fatal meningitis in two five-year boys with no common exposures, Maricopa County, Arizona,

Headache Neck stiffness Death 03:00 Admission Hospital A Child #1

Headache Neck stiffness Death 23:43 Admission Hospital B Child #2

10/06 10/07 10/08 10/09 10/10 10/11 10/12 10/13 Lumbar puncture (one child): increased pressure, 5000 PMNs, 3500 RBCs, protein 360, glucose 10; ?parasites seen at post-mortem Naegerial Amebas (Naegleria fowleri) seen post- mortem in the cerebrospinal fluid and in sections of brain from both boys Amebas (Naegleria fowleri) seen by immunoflourescence in sections of brain from both boys

Primary Amebic Meningoencephalitis Naegleria fowleri • Thermophilic, free-living, chlorine sensitive ameba • Ubiquitous in warm fresh water (40-45°C; 104-113°F) • 133 cases 1962-2014, 3 survivors • Cases associated with freshwater lakes, rivers, and hot springs, sinus irrigation • Mostly southern USA , but in warm years, as far north as Minnesota • Typically children (median 11 yrs) with recreational water contact • Associated with nasal irrigation http://www.cdc.gov/parasites/naegleria/infection-sources.htm

Investigation (Maricopa County and Arizona State Health Department, CDC): • First US occurrence of simultaneous cases • Children had no contact with each other • Only exposure to recreational water: • Child A: grandfathers’ bath tub with water jets Child B: new unchlorinated home pool • •

Common exposure: municipal water system

N

0.5 miles

#1

• Supplies 2300 households #2 • untreated (unfiltered and unchlorinated) water

• treatment not required for groundwater systems that meet EPA bacterial and turbidity standards

• well water temperature ~ 87°F Balamuthia mandrillaris • Free-living ameba • Natural habitat: ?soil • Infection via nasal passages/skin • In human beings, causes skin lesions and single or highly lethal single or multiple space-occupying lesions of the brain (granulomatous amebic encephalitis) • Clinical infection reported in immunosupressed persons, alcoholics, debilitated persons, and occasionally healthy persons (children, elderly) Balamuthia mandrillaris • Identification: histopathology, tissue culture, direct immunofluorescence, immunohistochemistry, PCR, serology • Prevalence in US unknown: 3.6% landscapers and 2.5% blood donors in Arizona seropositive • Three organ donors donated organs to 13 recipients: 4 (untreated) died, 9 treated (miltefosine or pentamidine, azithromycin, albendazole, sulfadiazine, fluconazole )

survived Emerg Infect Dis 2014,20:1443, Radiology Case 2013,7:9;Am J Transplant 2014; 14:1417 Zoonotic helminth infections

Cutaneous larva migrans (creeping eruption) Cutaneous larva migrans (creeping eruption) • Infection with dog or cat hookworms (Ancylostoma braziliensis, others) • Contact of bare skin with contaminated, usually sandy, soil • Diagnosis: clinical • Treatment • ivermectin 200 mcg/kg PO QD x1-2 days • albendazole 400 mg PO QD x3 days

Nematode larva found in brain biopsy of 9-year- old boy from Monterey County, California, who developed headaches, fatigue, and loss of coordination Diagnosis: Baylisascaris procyonis MRI Brain Scans of Patients with Baylisascaris Neural Larva Migrans From Gavin et al., 2002

Case 1 demonstrating Case 2 demonstrating bilateral hyperintense signal abnormal hyperintense of periventricular white signal of cerebellar matter (arrows) hemispheric white matter (arrow)

Visceral larva migrans (Toxocara canis, T. catis, Baylisascaris procyonis) Toxocara canis, catis • Usually young children; pica • Asymptomatic eosinophilia (covert toxocariasis) • Fever, hepatomegaly, respiratory and neurological symptoms, rash (visceral larva migrans) • Ocular larva migrans • Diagnosis: serology (EIA-using excretory- secretory antigen toi detect IgG) • 30% dogs < 6 mos; 14% of US population infected Dirofilaria immitis Dirofilaria immitis

Heartworm society

Dirofilaria immitis Heartworm society Prevalence of D. immitis antigens in dogs

D. Bowman et al. / Veterinary Parasitology 160 (2009) 138–148 Threat of emerging parasites in the United States “Classical” tropical Endemic • Malaria • Free-living • Chagas disease amoebas • Leishmaniasis • Zoonotic helminths • Cysticercosis • Babesiosis • Strongyloidiasis • Toxoplasmosis • Cryptosporidiosis, cyclosporiasis