Outpatient parenteral antimicrobial therapy for leishmaniasis: 13 years' experience at a large UK infectious diseases centre.

BACKGROUND: Leishmaniasis is a neglected tropical disease that is imported by travellers returning to the UK. Given the prolonged therapy required, outpatient treatment has been proven to be cost-effective and safe. METHODS: We describe cases of leishmaniasis treated through outpatient parenteral antimicrobial therapy (OPAT) over a 13-y period (March 2006-September 2018) at a large teaching hospital. RESULTS: A total of 26 episodes of leishmaniasis were treated successfully, with a mean saving of 14.2 bed-days/episode. Sodium stibogluconate was the most used antileishmanial (92%). CONCLUSIONS: Treatment of chronic infections via OPAT is now commonplace and this approach may be considered for other imported infectious diseases.

Overcoming roadblocks in the development of vaccines for leishmaniasis.

INTRODUCTION: The leishmaniases represent a group of parasitic diseases caused by infection with one of several species of Leishmania parasites. Disease presentation varies because of differences in parasite and host genetics and may be influenced by additional factors such as host nutritional status or co-infection. Studies in experimental models of Leishmania infection, vaccination of companion animals and human epidemiological data suggest that many forms of leishmaniasis could be prevented by vaccination, but no vaccines are currently available for human use. AREAS COVERED: We describe some of the existing roadblocks to the development and implementation of an effective leishmaniasis vaccine, based on a review of recent literature found on PubMed, BioRxiv and MedRxiv. In addition to discussing scientific unknowns that hinder vaccine candidate identification and selection, we explore gaps in knowledge regarding the commercial and public health value propositions underpinning vaccine development and provide a route map for future research and advocacy. EXPERT OPINION: Despite significant progress, leishmaniasis vaccine development remains hindered by significant gaps in understanding that span the vaccine development pipeline. Increased coordination and adoption of a more holistic view to vaccine development will be required to ensure more rapid progress in the years ahead.

A clinical study to optimise a sand fly biting protocol for use in a controlled human infection model of cutaneous leishmaniasis (the FLYBITE study).

Background: Leishmaniasis is a globally important yet neglected parasitic disease transmitted by phlebotomine sand flies. With new candidate vaccines in or near the clinic, a controlled human challenge model (CHIM) using natural sand fly challenge would provide a method for early evaluation of prophylactic efficacy. Methods : We evaluated the biting frequency and adverse effects resulting from exposure of human volunteers to bites of either Phlebotomus papatasi or P. duboscqi, two natural vectors of Leishmania major. 12 healthy participants were recruited (mean age 40.2 ± 11.8 years) with no history of significant travel to regions where L. major-transmitting sand flies are prevalent. Participants were assigned to either vector by 1:1 allocation and exposed to five female sand flies for 30 minutes in a custom biting chamber. Bite frequency was recorded to confirm a bloodmeal was taken. Participant responses and safety outcomes were monitored using a visual analogue scale (VAS), clinical examination, and blood biochemistry. Focus groups were subsequently conducted to explore participant acceptability. Results: All participants had at least one successful sand fly bite with none reporting any serious adverse events, with median VAS scores of 0-1/10 out to day 21 post-sand fly bite. Corresponding assessment of sand flies confirmed that for each participant at least 1/5 sand flies had successfully taken a bloodmeal (overall mean 3.67±1.03 bites per participant). There was no significant difference between P. papatasi and P. duboscqi in the number of bites resulting from 5 sand flies applied to human participants (3.3±0.81 vs 3.00±1.27 bites per participant; p=0.56) .  In the two focus groups (n=5 per group), themes relating to positive participant-reported experiences of being bitten and the overall study, were identified. Conclusions: These results validate a protocol for achieving successful sand fly bites in humans that is safe, well-tolerated and acceptable for participants. Clinicaltrials.gov registration: NCT03999970 (27/06/2019).

Vaccines against leishmaniasis: using controlled human infection models to accelerate development.

INTRODUCTION: Leishmaniasis is a neglected tropical disease that is defined by the World Health Organization as vaccine preventable. Although several new candidate vaccines are in development, no vaccine has successfully reached the market for human use. Several species of Leishmania cause human disease and have co-evolved with their respective sand fly vectors. These unique relationships have implications for initiation of infection and vaccine development. An approach to vaccine development for many infectious diseases is the use of controlled human infection models (CHIMs). AREAS COVERED: We describe the history and recent development of experimental and deliberate infection using Leishmania in humans and the rationale for developing a new sand fly-initiated CHIM to progress leishmaniasis vaccine development. Examples from other infectious diseases are discussed in the context of the development of a new leishmaniasis CHIM. We also reflect upon the manufacture of the challenge agent, practical considerations, safety, ethics, and regulatory issues. EXPERT OPINION: A new cutaneous Leishmania CHIM is being developed to enable testing of vaccines in the development pipeline. Questions remain about the use of such CHIMs to determine effectiveness of vaccines against visceral leishmaniasis. However, such a CHIM will be invaluable in expediting time to market for vaccines.

Assessing public perception of a sand fly biting study on the pathway to a controlled human infection model for cutaneous leishmaniasis.

BACKGROUND: A controlled human infection model (CHIM) involves deliberate exposure of volunteers to pathogens to assess their response to new therapies at an early stage of development. We show here how we used public involvement to help shape the design of a CHIM to support future testing of candidate vaccines for the neglected tropical disease cutaneous leishmaniasis, a disease transmitted by the bite of infected sand flies in tropical regions. METHODS: We undertook a public involvement (PI) consultation exercise to inform development of a study to test the safety and effectiveness of a sand fly biting protocol using uninfected sand flies (FLYBITE: ClinicalTrials.gov ID NCT03999970 ) and a CHIM using Leishmania major-infected sand flies (LEISH_Challenge: ClinicalTrials.gov ID NCT04512742 ), both taking place in York, UK. We involved 10 members of the public including a patient research ambassador and a previous CHIM volunteer. The session took place at The University of York, UK and examined draft study volunteer-facing material and included the CHIM study design, potential adverse events and therapeutic interventions at study endpoints. A discussion of the scientific, ethical, humanitarian and economic basis for the project was presented to the participants to provoke discourse. An inductive, thematic analysis was used to identify the participants' key concerns. RESULTS: Themes were identified relating to i) quality of volunteer-facing written information, ii) improving study design, and iii) factors to motivate involvement in the research. Group participants responded positively to the overall study aims. Initial concerns were expressed about potential risks of study involvement, but further explanation of the science and mitigations of risk secured participant support. Participants provided advice and identified improved terminology to inform the volunteer-facing material. Lastly, treatment options were discussed, and excision of any cutaneous lesion was favoured over alternatives as a treatment. CONCLUSION: The consultation exercise provided invaluable information which led to improved study design and enhanced clarity in the volunteer-facing material. The session also reinforced the need to maintain public trust in scientific rigour prior to initiation of any study. The investigators hope that this description strengthens understanding of PI in clinical research, and encourages its use within other studies.

Our research team is designing a type of research study known as a controlled human infection model (CHIM). In CHIM studies, volunteers are exposed to infections on purpose and then studied to help understand diseases. Similar experiments, where humans are infected deliberately, have been used for hundreds of years to help test treatments. CHIM studies have already been used more recently to help test vaccines for diseases such as malaria.The disease leishmaniasis, a disease affecting millions each year, is spread by the bite of an infected sand fly in tropical countries. There are currently no vaccines for leishmaniasis that are available for use in humans. It is thought that by using CHIM studies, new vaccines might be tested and then approved more quickly. Scientific researchers have had many discussions about how useful CHIM studies are, especially in terms of the science behind them, the safety of volunteers and the ethics of these studies. Researchers also understand how important it is to involve the public in designing and carrying out research, especially studies involving humans, to get an independent point-of-view. We have therefore involved the public, in some parts of designing this research, in a group discussion. We also included a person who has already taken part in a different CHIM study. These discussions have had an important effect and have changed how we plan to carry out our future research studies. We also hope that this description will encourage other researchers to include the public when planning future research.

Patterns of thromboembolic pulmonary vascular disease in COVID-19.

SARS-CoV-2 (COVID-19) is associated with increased thrombosis. Here, we demonstrate patterns of pulmonary vascular disease in COVID-19 including classical acute pulmonary embolism and subsegmental perfusion defects in the absence of acute pulmonary embolism suggestive of microvascular thrombosis.

Characterization of a new Leishmania major strain for use in a controlled human infection model.

Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIMs) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical strain of Leishmania major. Two fresh strains of L. major from Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.

Anakinra in the treatment of protracted paradoxical inflammatory reactions in HIV-associated tuberculosis in the United Kingdom: a report of two cases.

Paradoxical reactions, including immune reconstitution inflammatory syndrome (IRIS), are common in patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB). Paradoxical reactions may confer substantial morbidity and mortality, especially in cases of central nervous system (CNS) TB, or through protracted usage of corticosteroids. No high-quality evidence is available to guide management in this scenario. Interleukin-1-mediated inflammation has been implicated in the pathophysiology of TB-IRIS. We describe two cases where anakinra (human recombinant interleukin-1 receptor antagonist) was used as steroid-sparing therapy for life-threatening protracted paradoxical inflammation in HIV-associated TB. In the first case of disseminated TB with lymphadenitis, protracted TB-IRIS led to amyloid A amyloidosis and nephrotic syndrome. In the second case of disseminated TB with cerebral tuberculomata, paradoxical inflammation caused unstable tuberculomata leading to profound neuro-disability. In both cases, paradoxical inflammation persisted for over a year. Protracted high-dose corticosteroid use led to adverse events yet failed to control inflammatory pathology. In both patients, anakinra successfully controlled paradoxical inflammation and facilitated withdrawal of corticosteroid therapy. Following anakinra therapy, nephrotic syndrome and neuro-disability resolved, respectively. Anakinra therapy for protracted paradoxical inflammation in HIV-associated TB may be a viable therapeutic option and warrants further research.

West Nile Virus Infection in Travelers Returning to United Kingdom from South Africa.

West Nile virus (WNV) is an arthropod-transmitted flavivirus that causes West Nile fever and may infrequently cause neuroinvasive disease in humans. We present 2 cases of confirmed WNV infection, 1 of severe encephalitis and 1 of mild febrile illness, in a couple returning to the United Kingdom from South Africa.

Bilateral Ocular Myositis Associated with Whipple's Disease.

PURPOSE: To describe the clinical features of a Caucasian female patient with a history of treated gastrointestinal Whipple's disease (WD) who developed new-onset diplopia, with a description of the histopathological features of the extraocular muscle biopsies. METHODS: A previously fit 38-year-old Caucasian female presented with acute-onset diplopia after being on a sustained medication regime for biopsy-proven gastrointestinal WD. A magnetic resonance imaging scan of her orbits with gadolinium revealed diffuse enhancement of the bellies of the extraocular muscles bilaterally, particularly the medial rectus, superior rectus, and superior oblique muscles, consistent with an infiltrative myositis. She underwent unilateral extraocular muscle biopsies. RESULTS: The extraocular muscle biopsies contained macrophages between the muscle fibres. These contained periodic acid-Schiff-positive cytoplasmic granules. Immunohistochemistry with an antibody raised to Tropheryma whipplei showed positive staining of the same macrophages. Transmission electron microscopy confirmed the presence of effete T. whipplei cell membranes in lysosomes. CONCLUSION: This case describes bilateral WD-associated extraocular muscle myositis. The exact mechanism for this unusual presentation is unclear, but both a WD-associated immune reconstitution inflammatory syndrome and treatment failure are possibilities, with a good response observed to antibiotic therapy and adjunctive corticosteroids.