Common Helminthic Infections in the Middle East ESCMID Online Lecture Library © by Author

ESCMID PGTW PARASITIC INFECTIONS OF THE ARABIAN PENINSULA AL AIN, UAE 17-19 MARCH 2016 Common Helminthic Infections in the Middle East

Míriam J. Álvarez-Martínez M.D., Ph.D.

Microbiology Department Hospital Clinic, Barcelona (Spain) ISGlobal (Barcelona© by Institute author for Global Health) Faculty of Medicine-University of Barcelona [email protected] ESCMID Online Lecture Library LAS FALLAS- VALENCIA, SPAIN

OUTLINE

• Helminthic Infections – yesterday, today & always? Global Burden • Coinfections & Immunity • Strongyloides: Infection & Hyperinfection • Lymphatic Filariais© by author • Conclusions ESCMID Online Lecture Library

2008

Three generalESCMID migration routes ofOnline humans in prehistory Lecture hypothesized fromLibrary Asia to the Americas. (a) Represents the longest-standing hypothesis of a migration route through Beringia and into North America at the time of low sea level and glacial maximum (b) Parasite probe data are consistent with a Coastal migration or (c) Trans-Pacific migration © by author ESCMID Online Lecture Library

PHOTOGRAPH COURTESY DENNIS VAN GERVEN Metazoa

PlatyhelmintosPlatyhelminths NematohelmintosNematodes gusanosFlatworms planos gusanosRoundworms redondos

Soil CestodosCestodes TrematodosTrematodes Nematodos Filarial © by authorTransmitted Tapeworms Flukes worms tape worms flukes roundHelminths worms ESCMID Online Lecture Library GLOBAL BURDEN

• It is estimated that approximately one-third of the 3 billion people that live on less than 2 US dollars per day in developing regions of sub-Saharan Africa, Asia, and the Americas are infected with one or more helminths. • Human helminthic infections have both direct and indirect effects on malaria and HIV/AIDS in developing countries, where are frequenty© by author coendemic. • Coinfections have additive effects, such as severe anemia,synergisticESCMID Online effects, such Lecture as increased Library transmission of the malaria, HIV, and/or increased susceptibility to infection. Hotez et al. J Clin Invest. 2008 © by author ESCMID Online Lecture Library

Distribution of any STH infection in 2010. (A) The combined prevalence of any infection, based on geostatistical models for sub-Saharan Africa and available empirical information for all other regions. (B) The proportion of the global population infected (1.45 billion) by country. Pullan et al. Parasites & Vectors 2014 © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library

Hotez et al. J Clin Invest. 2008 © by author ESCMID Online Lecture Library © by author

ESCMID Online Lecture Pullan Libraryet al. Parasites & Vectors 2014 COINFECTIONS & IMMUNITY

Coinfection The simultaneous presence of 2 or more infections, which may ↑ disease severity and duration

Immune responses to Helminths Type 2 immunity involves the rapid activation of cells innate (eosinophils and basophils) and adaptive (CD4+ T cells that commit to the Th2 pathway) immune© by systems author Synthesize cytokine IL-4, which mediates the reactions that have been considered to be symptomatic of helminth infection IgEESCMID production, eosinophilia Online, and changes Lecture in the physiology Library of target organs (e.g., the intestine and lungs) associated with goblet cell hyperplasia and smooth muscle contraction. Hotez et al. J Clin Invest. 2008 Polarization of clonal expansion of CD4 +

Th1 Th2

Cellular immunity © by authorHumoral Immunity • IFN-γ • IL-4, IL-5, IL-10, IL-13, IgE • IL-2 • Antibodies response. ESCMID• TNF-β Online Lecture• Macrophages Library inhibition • Macrophages activation • Extracellular pathogens • Intracellular pathogens COINFECTIONS & IMMUNITY

What lies within? Helminth infection induces type 2 response & production of IL-4 that induces the AAmacs. A) Increased susceptibility to intestinal norovirus & respitarory influenza virus.

Damania et al. Cell Host & Microbe, 2014 S. stercoralis & HTLV-1

Montes M et al. PLoS Negl Trop Dis , 2009 S. stercoralis & HTLV-1

Figure 1. Patients with strongyloidiasis and HTLV-1 co-infection (n = 12) had more Strongyloides stercoralis larvae found in stool when compared to strongyloidiasis-only patients (n = 25).

Montes M et al. PLoS Negl Trop Dis , 2009 S. stercoralis & HTLV-1

Montes M et al. PLoS Negl Trop Dis , 2009 © by author ESCMID Online Lecture Library STRONGILOIDIASIS

Vadlamudi et al. Clin Mol Allerg 2006 • Acute Strongyloidiasis – It occurs during the penetration of the filariform larvae in the host Local skin reaction • Chronic Strongyloidiasis – Clinical syndrome characterized by the establishment of the parasites in the host Intestine, respiratory, skin • Hyperinfection – High acceleration of autoinfection within the life cycle. © by author – The larvae are confined to own locations cycle: intestines, lungs and skin. ESCMID Online Lecture Library – Motivated by alteration of the immune status of the host.

Igual Adell et al.. EIMC, 2007 © by author ESCMID Online Lecture Library

Three scenarios for different rates at which rhabditiform larvae become filariform in the intestinal lumen and complete an internal parasitic cycle Genta et al. Clin Microb Rev, 1982. • Disseminated Strongyloidiasis – Massive dissemination of filariform larvae to the lungs, liver, heart, central nervous system, and endocrine glands • Severe Disseminated Strongyloidiasis – Complicated bacterial infection from intestinal flora. – High mortality – Frequency 1.5 -2.5% – Result of the disruption of the integrity of the intestinal wall by© theby high author penetration filariform from the intestinal lumen. ESCMID– Recurrent Onlinemeningitis byLecture E.coli Library

Igual Adell et al.. EIMC, 2007 HYPERINFECTION & CORTICOSTEROIDS

• Corticosteroids are main factor in triggering hyperinfection. • <10 days of corticosteroids cause hyperinfection. • Subconjunctival / parenteral corticosteroids.

• No cases of hyperinfection after immunosuppression with nonsteroidal agents. © by author • Hyperinfection not associated with the degree of immunosuppression,ESCMID Online but the AGENTLecture used toLibrary suppress immunity. 2 © by author 1 ESCMID Online Lecture Library

Vadlamudi et al. Clin Mol Allerg 2006 WHO TO TEST

• Patients with clinical manifestations and epidemiologic exposure (including unexplained eosinophilia, urticarial or serpiginous skin lesions, or pulmonary or gastrointestinal symptoms) • Immunosuppressed patients (steroid and other immunosuppressive treatments, HTLV-1 infection, hematologic malignancy, malnutrition, AIDS) with unexplained eosinophilia, history of characteristic skin lesions, or epidemiologic exposure. Transplant candidates should also be tested prior to immunosuppression if they have a potential exposure history . • Asymptomatic individuals such as immigrants, refugees, long-term travelers, or military personnel who have© been by in areas author known to be endemic for strongyloidiasis, even if their last exposure was decades prior . • In endemic regions, patients with invasive infections caused by enteric organismESCMIDs (especially systemicOnline gram-negative Lecture bacterial infections)Library without an obvious cause.

Novel approaches to the diagnosis of Strongyloides stercoralis infection

Buonfrate et al, CMI, 2015

© by author A Baermann apparatus as used to isolate Strongyloides stercoralis stages from coprocultures. F, 150mm glass or plastic funnel; W, tap water at ESCMID43°C; FL (dashed line) fluid Onlinelevel in funnel; SB, SampleLecture basket Library shown to right in exploded view (FCC, fecal charcoal culture contents; KW, two layers of Kimwipes or other laboratory tissue; LRM Lucite ring with nylon mesh affixed with cement; T, rubber or plastic tubing; PC, pinch clamp; CV, catch vessels, conical centrifuge tube, or beaker.

Barda et al., 2013 1. IFAT- in house method, (Ag S. stercoralis ) >S 2. NIE-ELISA ,(31 kDa recombinant Ag) 3. NIE-LIPS (Luciferase Immnunoprecipitation System) >E 4. Bordier ELISA , (Ag de larvas de S. ratti) 5. IVD ELISA (Ag de larvas de S. stercoralis) © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library LYMPHATIC FILARIASIS

• Lymphatic filariasis is one of the oldest and most debilitating neglected tropical diseases. LF is caused by parasitic worms of nematodes family of Filariodidae that are transmitted to humans by mosquitoes of the genus Culex, Anopheles and Aedes

• 120 million people from 81 countries are infected with LF. • 1.43 billion live in areas where filariasis is endemic and are at risk of infection. Approximately 65% of those at risk reside in WHO’s South-East Asia Region, 30% in the African Region and the remainder in other parts of the tropical world.

• Eastern Mediterranean region has© anby estimated author at-risk population of 12.6 million people, accounting for approximately 1% of the global disease burden.

• LymphaticESCMID filariasis is endemic Online in Egypt, LectureSudan, South Sudan Library and Yemen. In Sudan, South Sudan and Yemen, lymphatic filariasis is co-endemic with onchocerciasis. The situation in four other countries remains uncertain and needs epidemiological investigation: Djibouti, Islamic Republic of Iran, Saudi Arabia and Somalia.

What is lymphatic filariasis (LF)?

 Caused by three species of parasitic worm: Wuchereria bancrofti, Brugia malayi and B. timori  Transmitted to humans by mosquitoes

Source: www.dpd.cdc.gov/dpdx Slide Module 1 Background 38 What is lymphatic filariasis (LF)?

 The commonest clinical manifestations are lymphoedema, which affects 15 million people, and scrotal hydrocoele, which affects 25 million men

Slide Module 1 Background 39 What is lymphatic filariasis (LF)? Endemic in 73 countries; 1.39 billion people at risk of infection (2011)

Slide Module 1 Background 40 Global Programme to Eliminate Lymphatic Filariasis (GPELF)

 In 1997, the World Health Assembly resolved to eliminate lymphatic filariasis as a public health problem (WHA resolution 50.29).  In 2000, the GPELF was launched by WHO

Goal: Global elimination by 2020 Aim 1. Stop the spread of infection: interrupt transmission by MDA © by author

Aim 2. Reduce the suffering caused by the disease: morbidityESCMID management Online and disabilityLecture prevention Library

Slide Module 1 Background 41 Monitoring and evaluation during MDA

Mapping MDA Fail Surveillance

Yes Pass Mf or Ag≥1% TAS

Baseline Mid-term Follow-up (optional) [Eligibility] M&E

 Prevalence of Mf or Ag can be used in mapping.  Coverage is monitored at each MDA round to determine whether the goal of at least 65% coverage of the total population© was bymet. author  After at least five rounds of effective MDA, the impact is evaluated at sentinel and spot- check sites.  If ESCMIDall the eligibility criteria Onlineare met, a transmission Lecture assessment Library survey (TAS) is conducted before deciding to stop MDA.  TAS is repeated twice during post-MDA surveillance phase.

Module 1 Background Diagnostic tests for TAS

Mapping MDA Surveillance

Fail

Yes Pass Mf or Ag≥1% TAS

Baseline Mid-term Follow-up (optional) [Eligibility]

M&E

Mapping MDA TAS Surveillance Blood film or ICT or ICT or Brugia RapidTM test ESCMIDICT OnlineBlood film or ICT LectureBrugia Library RapidTM Potential for future use: test Antibody, xenomonitoring

Module 1 Background MDA

GPELF recommends mass administration:  of a combination of medicines: . diethylcarbamazine (DEC) + albendazole (in countries not co-endemic for onchocerciasis) . ivermectin + albendazole (in countries co-endemic for onchocerciasis)  of single-dose treatment for at least 5 years  to all eligible individuals in the entire endemic area

The objective is to achieve: • a reduction in the density© ofby microfilariae author circulating in the blood of infected individuals and • a reduction in the prevalence of infection in the entire community to levelsESCMID at which it is Onlineassumed that Lecturemicrofilariae can Library no longer be transmitted by mosquito vectors to new human hosts.

Module 1 Background Diagnostic tests for TAS

 Areas endemic for W. bancrofti: ICT

 Areas endemic for Brugia spp.: Brugia RapidTM test

 Areas endemic for both W. bancrofti and Brugia spp.: both diagnostic tests, with testing evaluated separately against© critical by authorcut-offs ESCMID Online Lecture Library

Slide 45 Module 1 Background Diagnostic tests for TAS

Field assay Detection target

Blood film Microfilariae

ICT Filarial antigen

Slide 46 Module 1 Background Programmatic steps for interrupting transmission

Post-MDA Mapping MDA surveillance Verification

1. Mapping the geographical distribution of the disease. 2. MDA for 5 years or more to reduce the number of parasites in blood to levels that will prevent© mosquitoby author vectors from transmitting infection. 3.ESCMIDPost-MDA surveillance Online after MDALecture is discontinued. Library 4. Verification of elimination of transmission.

Slide 47 Module 1 Background © by authorWHO recommends an integrated approach to the control of neglected tropical diseases ESCMID Online Lecture Library SUMMARY

• Helminths are interacting with humans since ancient times. • Helminths are the most common infectious agents of humans in developing countries and produce a high global burden of disease. • WHO recommends an integrated approach to the control of neglected tropical diseases. • Immunology response to helminthic infections is type 2. • Helminth co-infections are favored by immunological dysregulation. • Hyperinfection is not associated© by with author the degree of immunosuppression, but the agent (Strongyloides & corticosteroids) • StrongyloidesESCMID screening Online before immunosuppresion. Lecture Library • LF & MDA

ACKNOWLEDGEMENTS