Identification of Patients Diagnosed with Rare and Emerging Diseases Utilizing the Trinetx Network: A Case Study of African and American Trypanosomiasis

Objectives: Due to large sample sizes, electronic medical records (EMR) databases have the potential to provide pivotal insights into patients diagnosed with rare, orphan, or emerging diseases. This study aimed to explore the patient profile of African and American trypanosomiasis, both vector-borne parasitic diseases, pre-and post the COVID-19 pandemic using the TriNetX Network. Method(s): From Jan 1, 2018 - Nov 30, 2019 (pre-COVID) and Jan 1, 2020 - Nov 30, 2021 (post-COVID) patients were queried from the TriNetX Global health research network, inclusive of 88 million patients from the United States (US), Europe, the Middle East, Africa, Latin America, and Asia Pacific. Eligible patients with an ICD-10 diagnosis code of African trypanosomiasis or American trypanosomiasis were identified (2280 patients on 22-Dec-2022) and analyzed separately, pre- and post-COVID. Result(s): We identified 340 patients pre- and 960 patients post-COVID with African trypanosomiasis and 960 patients pre- and 190 patients post-COVID with American trypanosomiasis. Most patients resided in the US. Pre-COVID African trypanosomiasis patients had a mean age of 38 and were 59% female while post-COVID patients had a mean age of 34 and were 57% female. Pre-COVID American trypanosomiasis patients had a mean age of 49 and were 57% female while post-COVID patients had a mean age of 49 and were 53% female. Top co-diagnoses included diseases of the respiratory (85%, 84%) and nervous systems (82%, 79%) for patients with African trypanosomiasis and diseases of the digestive (69%, 54%) and circulatory systems (68%, 61%) for patients with American trypanosomiasis in both the pre- and post-COVID cohorts, respectively. Conclusion(s): Using real-world EMR data we were able to obtain patient profiles for a rare disease (African trypanosomiasis) and a common, emerging disease (American trypanosomiasis). This informationsupportsutilizing EMR data for describing patient populations in rare, orphan, or emerging diseases, which may aid drug development for these indications.Copyright © 2023

Outlining the molecules tested in vivo for Chagas disease, Malaria, and Schistosomiasis over the last six years - a literature review focused on new synthetic drug identities and repurposing strategies.

BACKGROUND: COVID-19 disrupted NTD programs in 60% of countries, impairing public health goals. Thus, boosting NTD's research knowledge is pressing, and in vivo screening of candidates allows for the prospect of auspicious options based on their overall profile. OBJECTIVE: In this work, we highlighted the relevant research done between 2015-2021 in the fields of synthetic and repurposed drugs that were tested in vivo for Chagas disease, malaria, and schistosomiasis. METHODS: MEDLINE, PUBMED, CAPES PERIODIC, and ELSEVIER databases were used for a comprehensive literature review of the last 5 years of research on each area/disease. RESULTS: Overall, research focused on nitro heterocyclic, aromatic nitro, nucleoside, and metal-based scaffolds for analogue-based drug generation. Repurposing was widely assessed, mainly with heterocyclic drugs, their analogues, and in combinations with current treatments. Several drug targets were aimed for Chagas treatment, specific ones such as iron superoxide dismutase, and more general ones, such as mitochondrial dysfunction. For malaria, hemozoin is still popular, and for schistosomiasis, more general structural damage and/or reproduction impairment were aimed at in vitro analysis of the mechanism of action. CONCLUSION: Latest in vivo results outlined trends for each disease - for Chagas Disease, heterocyclics as thiazoles were successfully explored; for Malaria, quinoline derivatives are still relevant, and for schistosomiasis, repurposed drugs from different classes outstood in comparison to synthetic compounds. This study uprises the continuous development of Chagas disease, malaria, and schistosomiasis drugs, providing researchers with tools and information to address such unmet therapeutic needs.

Superoxide Dismutase Inhibitors against Malaria, Leishmaniasis, and Chagas Disease: Systematic Review.

INTRODUCTION: Diseases caused by protozoa are one of the leading causes of death worldwide, especially in tropical regions such as Brazil. Chagas disease, leishmaniasis, and malaria are responsible for around 234 million cases and more than 400,000 deaths worldwide. Despite this scenario, drugs for these diseases have several limitations, which justifies the search for new treatments. Iron superoxide dismutase is a promising target for the drug design to treat patients with these diseases. It is a validated target and protects against oxidative stress. AIM: Thus, this systematic review aimed to synthesize evidence on the importance of superoxide dismutase in the drug design to treat patients with this protozoosis. METHODS: A search was performed for in vitro and in vivo studies, without publication and language restrictions, in MEDLINE (PubMed), LILACS (BVS), Science Direct, and EMBASE (Elsevier). Studies that pointed to the relationship between the reduction or increase in superoxide dismutase activity and the diseases were included. 23 studies were selected for the qualitative synthesis. RESULTS: The results showed that the inhibition or reduction of the enzyme activity decreases the degree of infection and reinfection and improves the results in treating these diseases. In contrast, the increase in activity caused a high degree of survival and resistance of the parasites. CONCLUSION: However, the overall quality of evidence is low and more studies with methodological rigor are provided.

Pfizer-BioNTech vaccine induces the production of cross-reactive antibodies against Trypanosoma cruzi proteins: A preliminary study.

OBJECTIVE: To evaluate the presence of cross-reactivity by anti-severe acute respiratory syndrome coronavirus 2 antibodies induced by the Pfizer-BioNTech vaccine against Trypanosoma cruzi proteins in a screening test. METHODS: Forty-three serum samples were obtained from personnel at the Hospital General Naval de Alta Especialidad in Mexico City who received one or two doses of the vaccine and were tested for T. cruzi infection using four tests: two 'in house' enzyme-linked immunosorbent assays (ELISAs), a commercial ELISA diagnostic kit and an immunoblot test. RESULTS: IgG antibodies against the T. cruzi proteins were present in the serum of unvaccinated subjects and subjects who had received one or two doses of the vaccine. The positivity of the samples against T. cruzi was ruled out by means of a Western Blot assay, where all samples were negative for T. cruzi. CONCLUSION: The data suggest that people convalescing from coronavirus disease 2019 and those who received the Pfizer-BioNTech vaccine exhibit cross-reactive antibodies against T. cruzi antigens in ELISA assays.

Re. Re.: "Immunothrombotic dysregulation in Chagas disease and COVID19: a comparative study of anticoagulation".

Re. Re.: "Immunothrombotic dysregulation in Chagas disease (CD) and COVID-19: a comparative study of anticoagulation": In the commentary on our paper, Hasslocher-Moreno made the point that indeterminate and digestive forms are not related to thromboembolic events, only thrombogenic alterations occur in CD with cardiopathy, however there is indirect evidence related to thombotic alterations, such as cerebral thrombosis. Our assertion is based on previous data discussed in this letter.

Preparing for Transplant - Screening and Prophylaxis of Donor and Recipients before Solid Organ Transplantation: Expert Group Opinion from South Asia

Infections are major cause of morbidity and mortality after transplantation. Although many infections are common worldwide, there are differences in various geographic locations. South Asia and India, in particular, has a very active transplant program for kidney and liver transplantation, however, there are no guidelines as how to screen and provide prophylaxis to solid organ transplant (SOT) recipients and donors for both specific infections prevalent in this region along with usual infections. Keeping this in mind, a working group was created comprising transplant physicians, surgeons, and infectious disease specialists from South Asia as well as experts from other countries. This working group developed guidelines based on published evidence, unpublished data from large centers in this region, along with expert opinion. This section of the guidelines deals with pretransplant screening of donors and recipients, which should be useful in dealing with transplants performed in this region for patients belonging to these countries, for those coming for transplantation from other countries, and for programs outside of South Asia who are screening donors and recipients from this region or who have spent significant time in this region. Copyright © 2022 Indian Journal of Transplantation Published by Wolters Kluwer - Medknow.

Small molecules containing chalcogen elements (S, Se, Te) as new warhead to fight neglected tropical diseases.

Neglected tropical diseases (NTDs) encompass a group of infectious diseases with a protozoan etiology, high incidence, and prevalence in developing countries. As a result, economic factors constitute one of the main obstacles to their management. Endemic countries have high levels of poverty, deprivation and marginalization which affect patients and limit their access to proper medical care. As a matter of fact, statistics remain uncollected in some affected areas due to non-reporting cases. World Health Organization and other organizations proposed a plan for the eradication and control of the vector, although many of these plans were halted by the COVID-19 pandemic. Despite of the available drugs to treat these pathologies, it exists a lack of effectiveness against several parasite strains. Treatment protocols for diseases such as American trypanosomiasis (Chagas disease), leishmaniasis, and human African trypanosomiasis (HAT) have not achieved the desired results. Unfortunately, these drugs present limitations such as side effects, toxicity, teratogenicity, renal, and hepatic impairment, as well as high costs that have hindered the control and eradication of these diseases. This review focuses on the analysis of a collection of scientific shreds of evidence with the aim of identifying novel chalcogen-derived molecules with biological activity against Chagas disease, leishmaniasis and HAT. Compounds illustrated in each figure share the distinction of containing at least one chalcogen element. Sulfur (S), selenium (Se), and tellurium (Te) have been grouped and analyzed in accordance with their design strategy, chemical synthesis process and biological activity. After an exhaustive revision of the related literature on S, Se, and Te compounds, 183 compounds presenting excellent biological performance were gathered against the different causative agents of CD, leishmaniasis and HAT.

Deaths Related to Chagas Disease and COVID-19 Co-Infection, Brazil, March-December 2020.

We analyzed epidemiologic characteristics and distribution of 492 deaths related to Chagas disease and coronavirus disease (COVID-19) co-infection in Brazil during March‒December 2020. Cumulative co-infected death rates were highest among advanced age groups, persons of Afro-Brazilian ethnicity and with low education levels, and geographically distributed mainly in major Chagas disease‒endemic areas.

False positive serology of prepandemic chagasic samples with SARS-CoV-2 antigen.

OBJECTIVE: To determine whether prepandemic sera from patients with Chagas disease recognise SARS-CoV-2 antigens. MATERIALS AND METHODS: Forty sera from patients with Chagas disease were tested for the presence of IgG cross-reactivity against the nucleocapsid protein (NP) and spike (S) SARS-CoV-2 proteins by ELISA. Positive samples were tested again using a different ELISA and CLIA, both against NP. RESULTS: None of the sera from patients with Chagas disease, previously confirmed as positive for the presence of anti-Trypanosoma cruzi antibodies reacted against the SARS-CoV-2 S protein, and six samples tested positive for the NP antigen (15%). The six positive samples were re-tested, five remained positive by ELISA and all were negative by CLIA. CONCLUSION: According to our data, false-positive results might be a concern in the detection of SARS-CoV-2 antibodies in patients with Chagas disease.

Building the social innovation for health ecosystem in Latin America: Experiences and learning from SIHI-LAC

Social innovation for health has grown in relevance and momentum across Latin America.1-5 Yet, the potential of social innovation for health appears mostly untapped, with one reason for this being the limited investment to build strong ecosystems that can support social innovation initiatives.6-8

CHAGAS SCREENING PROGRAM IN A PUBLIC SAFETY NET HOSPITAL IN QUEENS: CHALLENGES AND SUCCESSES

STATEMENT OF PROBLEM/QUESTION: Chagas disease (CD) is a lifelong protozoan parasitic infection that if left untreated can result in cardiomyopathy in a third of cases;a screening program can identify individuals with chronic asymptomatic disease. DESCRIPTION OF PROGRAM/INTERVENTION: Elmhurst Hospital is a public safety net hospital in Queens serving a diverse community with many immigrants from Mexico, Central and South America. An estimated 8 million people in Latin America and 300,000 in the US are living with CD. We implemented a Chagas screening program in the Elmhurst adult primary care clinic. Our electronic health record (EHR), Epic, captures patient diversity by including 200 ethnic background options;we used this field to identify at-risk patients. Patients waiting for their appointment were brought into a private area and educated about CD by a Spanish-speaking volunteer. They were asked their country of origin, their ability to recognize the Reduviid bug, and the type of house they grew up in. Written educational materials about CD in Spanish provided by CDC website were given to patients. Once a patient accepted screening the provider received a secure chat in the EHR instructing them to order the Chagas serology. All patients have been kept on a secure list, and all are called for follow-up regardless of their results. Patients who test positive receive a follow-up plan that includes cardiac testing and referral to the Infectious Diseases (ID) clinic. Education about immigrant health and CD was provided to faculty, nurses and residents by ID specialists. MEASURES OF SUCCESS: The number of patients accepted and screened for CD. FINDINGS TO DATE: From June to November 2021, 340 patients in the Elmhurst medicine clinic were approached about their risk for CD. Of these migrants 36% were from Mexico, 51% were from S. America and 13% were from Central America. 23% of these patients grew up in an adobe house and 26% recognized the reduviid bug from a picture. Of 324 at-risk individuals asked about previous Chagas knowledge, only 7% were familiar with CD. 203 patients were tested with final results, 18 refused testing, 37 tests are pending for the next visit, and 82 were not ordered. 2 were positive on the screening ELISA with confirmation pending;CDC has suspended testing during the COVID-19 pandemic. Family members will be screened if confirmatory testing is positive. KEY LESSONS FOR DISSEMINATION: For practices serving large atrisk populations, a Chagas screening program can help to address a healthcare disparity. Partnership with ID specialists is essential for this process to succeed. Having an EHR that captures diverse demographic information identifies atrisk patients and is critical to the success of such a program. Challenges include having to obtain confirmatory testing at CDC which involves a patient returning for a follow-up visit and another blood draw. PCP champions can be a useful resource to sustain CD screening in the future. Low awareness of CD in our patient population suggests that community outreach to at-risk individuals is needed to increase awareness.

A 51-YEAR-OLD MAN WITH WEIGHT LOSS AND CARDIOGENIC SHOCK

CASE: A 51-year-old man without significant past medical history presented to our hospital with dyspnea on exertion. SARS-CoV-2 was detected on routine occupational screening 2 months prior to admission. He subsequently reported a 100lb weight loss, during which time he experienced dysgeusia and ate primarily cereal, sandwiches, and potatoes and consumed nearly no fruits or vegetables. Three weeks prior to admission he developed postprandial nausea and vomiting and anorexia. A week later he developed progressive epigastric pain, lower extremity edema, and dyspnea while walking around the college campus where he worked as a security guard, and sought medical attention. He did not have fever, chills, night sweats, cough, orthopnea, paroxysmal nocturnal dyspnea, rash, or diarrhea. He had not seen a doctor in 20 years and took no medications. He did not drink alcohol, smoke cigarettes, or use illicit substances. Vital signs were T 36.6°F HR 104 BP 149/111 RR 20 and SpO2 97%. Physical examination revealed a cachectic man with bitemporal wasting, sunken orbits, poor dentition, and severe periodontal disease. JVP was 14cm of H2O at 45°. An S3 was present. The abdomen was tender to palpation in the mid epigastrium. The extremities were cool with 3+ pitting edema. Pancreatitis was diagnosed after discovery of markedly elevated lipase levels and peripancreatic fat stranding on abdominal CT. TTE showed biventricular systolic dysfunction with LVEF 15%. He developed cardiogenic shock complicated by oliguric renal failure, congestive hepatopathy and obtundation, requiring ICU transfer for diuresis and inotropic support. Further workup revealed deficiencies of thiamine, zinc, and vitamins A, C, and D. A regadenoson myocardial perfusion PET/CT showed no flow-limiting coronary artery disease, and workup for inflammatory, infectious, and toxic-metabolic causes of heart failure was unrevealing. While COVID myocarditis and multisystem inflammatory syndrome in adults (MIS-A) were considered, ultimately, a diagnosis of wet beriberi was made. After 5 months of aggressive nutritional supplementation via percutaneous gastrostomy tube and initiation of guideline-directed medical therapy, LVEF improved to 53% and weight increased by 35lbs. IMPACT/DISCUSSION: Wet beriberi is a potentially underrecognized cause of dilated cardiomyopathy in resource-rich areas. Within 3 months, thiamine deficiency can cause high-output heart failure due to impaired myocardial energy metabolism and dysautonomia. Risk factors include alcohol use disorder, prolonged vomiting, and history of bariatric surgery. CONCLUSION: The laboratory evaluation of non-ischemic dilated cardiomyopathy should include measurement of serum thiamine, carnitine, and selenium levels in select patients, alongside iron studies, ANA, screening for HIV, Chagas disease, and viral myocarditis, and genetic testing in patients with a suggestive family history. Empiric thiamine repletion should be considered in all critically ill patients with evidence of malnutrition.

Challenges of addressing neglected tropical diseases amidst the COVID-19 pandemic in Africa: A case of Chagas Disease.

Chagas Disease (CD) is an infectious, neglected tropical disease (NTD) that has affected over 1.7 billion people worldwide. Unfortunately, most countries usually put little effort into mitigating the spread of NTDs, having weak public health approaches, diagnostic delays, and ineffective clinical management guidelines and resources. However, the ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the coronavirus SARS-CoV-2, exacerbates the impact of NTDs. In this review, we examine the subsequent changes that have been imposed on CD prevention and treatment. Articles from Google Scholar and PubMed were extracted which satisfied our inclusion criteria. From our data, we gather that COVID-19 has - from preventive measures to treating patients - greatly affected every stage in the fight against CD. For instance, co-infection of CD and COVID-19 puts patients at higher risk for cardiomyopathy (i.e., atrial fibrillation, chronic heart failure), yet no clinical guidelines were established for co-infected patients. To mitigate the spread of CD during the COVID-19 pandemic, further investigations on the impacts of co-infections and vaccines that can be developed to treat such conditions are warranted.

The COVID-19 Pandemic: An Opportunity to Assess the Global Health Status

According to WHO: "As long as one child is infected all countries are at risk to get 200,000 new cases per year" [6, 7]. * TB claims 1.5 million lives each year. Three million cases were missed by the detection systems and the funding to combat the disease was back to the 2016 level that year [8-10]. * The number of cholera cases remains high and many are not reported. [...]it can be re-introduced into many countries like it was in Haiti in the 2010 [11-13]. * Due to the sylvatic cycle in Africa yellow fever cannot be realistically eradicated [14-17]. * Because of the cattle and wild animal reservoirs of Trypanosoma rhodesiense in East Africa, sleeping sickness cannot be practically eradicated. * In 2007, WHO announced a renewed strategy to eliminate Chagas' disease by 2010. The main problems linked to the elimination of malaria have not been tackled like: deforestation, agricultural expansion, infrastructure development, the biological differences in Anopheles species adapted to different landscapes, human and mosquito migrations, travelers, climate change [24-26]. * The discovery of a dog-fish cycle in Chad renders a lasting elimination of dracunculiasis improbable [27-28]. Most worrisome are the trends for the diseases mentioned above and there is no sign of imminent or short term eradication. [...]lack of capacity is the main obstacle to adequate healthcare in developing countries [30]. * Quantitatively, data are dismal [31]. * Quality wise, the gap is huge and increasing [32]. * Unfortunately, the evolution in various places is not toward improvement particularly in Sub-Saharan Africa. * Questions have not been raised on the unreliable origin and misutilization of resources.

What about infection in travellers, migrants and refugees

Several factors have been linked to emerging infectious diseases including new agents (coronaviruses, zika virus), extension of geographical areas (schistosomiasis, dengue, West Nile, zika virus), increase in incidence (HIV, tuberculosis) and travel/migration (Chagas disease, cysticercosis). According to the World Migration Report 2020, the number of international migrants reached 272 million globally in 2019, and nearly two-thirds were labour migrants. Epidemiological evidence about infectious diseases and neuroinfection among travellers, migrants and refugees will be reviewed. Traveller's diarrhoea, dengue fever and other tropical diseases are reported in travellers. Re-emergence of infections in Europe includes chikungunya, dengue and malaria. Migration of asymptomatic people spread American trypanosomiasis in non-endemic areas and cases have been reported in Europe, Japan, and North-America. Neurocysticercosis is a common cause of seizures among South American migrants in USA. Migrants may be asymptomatic carriers (Chagas, HTLV-1). The involvement of CNS may occur in viral infections (HIV, HTLV-1, dengue, zika), malaria, schistosomiasis (myeloradiculopathy), Chagas disease (encephalitis, stroke), etc. Refugees may be at slightly higher risk of infectious diseases including tuberculosis, HIV, hepatitis and schistosomiasis. Systematic reviews have found that tuberculosis and hepatitis B and C prevalence is higher among migrants arriving in Europe, and the prevalence of antimicrobial resistance and infections was higher in refugees and asylum seekers than in other migrant groups. Infectious diseases in migrants may be explained by a higher prevalence in migrants' countries of origin, barriers to health care in host/transit countries, and poor living conditions. These factors are especially relevant in vulnerable populations (refugees, documented migrants).

Management of Cardiovascular Disease in Patients With COVID-19 and Chronic Chagas Disease: Implications to Prevent a Scourge Still Larger.

Cardiovascular diseases (CVD) are the most important cause of morbidity and mortality in the general population. Because the high prevalence of COVID-19 and chronic Chagas disease (CCD) where the latter is endemic, all such diseases will likely be observed in the same patient. While COVID-19 can provoke generalized endotheliitis, which can lead to a cytokine storm and a hyper-coagulable state culminating into in-site and at a distance thrombosis. Therefore, small-vessel coronary artery disease (CAD), cerebrovascular disease, thromboembolism, and arrhythmias are prominent findings in COVID-19. In CCD, small-vessel CAD, cardioembolic stroke, pulmonary embolism, heart failure and arrhythmias are frequently observed as a result of a similar but less intense mechanism. Consequently, the association of CCD and COVID-19 will likely increase the incidence of CVD. Thus, doctors on the frontline should be on the alert for this diagnostic possibility so that the proper treatment can be given without any delay.

Challenges and Promises for Obtaining New Antiprotozoal Drugs: What’s Going Wrong?

Infections by protozoa can cause some of the most serious human diseases, particularly in tropical regions. However, the number of available drugs used to treat such diseases tends to be limited with relatively high toxicity, and the vast majority of such drugs were developed in the 1920s to 1970s. The development of antiprotozoal drugs has been hindered owing in part to: (1) the highly complicated life cycles of such organisms and their ability to avoid innate immune defences;(2) challenges associated with culturing such organisms particularly in different phases of their growth and amplification;and (3) a lack of investment in biomedical research aimed at developing treatments for tropical diseases that do not tend to affect more affluent countries. Indeed, only three new drugs have entered into clinical trials in recent times, highlighting the tremendous gap in knowledge that should be bridged to more effectively treat protozoal infections.

Impact of COVID-19 In-hospital Mortality in Chagas Disease Patients.

The COVID-19 virus infection caused by the new SARS-CoV-2 was first identified in Rio de Janeiro (RJ), Brazil, in March 2020. Until the end of 2021, 504,399 COVID-19 cases were confirmed in RJ, and the total death toll reached 68,347. The Evandro Chagas National Institute of Infectious Diseases from Oswaldo Cruz Foundation (INI-Fiocruz) is a referral center for treatment and research of several infectious diseases, including COVID-19 and Chagas disease (CD). The present study aimed to evaluate the impact of COVID-19 on in-hospital mortality of patients with CD during the COVID-19 pandemic period. This observational, retrospective, longitudinal study evaluated all patients with CD hospitalized at INI-Fiocruz from May 1, 2020, to November 30, 2021. One hundred ten hospitalizations from 81 patients with CD (58% women; 68 ± 11 years) were evaluated. Death was the study's main outcome, which occurred in 20 cases. The mixed-effects logistic regression was performed with the following variables to test whether patients admitted to the hospital with a COVID-19 diagnosis would be more likely to die than those admitted with other diagnoses: admission diagnosis, sex, age, COVID-19 vaccination status, CD clinical classification, and the number of comorbidities. Results from multiple logistic regression analysis showed a higher risk of in-hospital mortality in patients diagnosed with COVID-19 (OR 6.37; 95% CI 1.78-22.86) compared to other causes of admissions. In conclusion, COVID-19 infection had a significant impact on the mortality risk of INI-Fiocruz CD patients, accounting for one-third of deaths overall. COVID-19 presented the highest percentage of death significantly higher than those admitted due to other causes during the COVID-19 pandemic.