Do Babesia microti Hosts Share a Blood Group System Gene Ortholog, Which Could Generate an Erythrocyte Antigen That Is Essential for Parasite Invasion?

The United States of America (US) has the highest annual number of human babesiosis cases caused by Babesia microti (Bm). Babesia, like malaria-causing Plasmodium, are protozoan parasites that live within red blood cells (RBCs). Both infectious diseases can be associated with hemolysis and organ damage, which can be fatal. Since babesiosis was made a nationally notifiable condition by the Centers for Disease Control and Prevention (CDC) in January 2011, human cases have increased, and drug-resistant strains have been identified. Both the Bm ligand(s) and RBC receptor(s) needed for invasion are unknown, partly because of the difficulty of developing a continuous in vitro culture system. Invasion pathways are relevant for therapies (e.g., RBC exchange) and vaccines. We hypothesize that there is at least one RBC surface antigen that is essential for Bm invasion and that all Bm hosts express this. Because most RBC surface antigens that impact Plasmodium invasion are in human blood group (hBG) systems, which are generated by 51 genes, they were the focus of this study. More than 600 animals with at least one hBG system gene ortholog were identified using the National Center for Biotechnology Information (NCBI) command-line tools. Google Scholar searches were performed to determine which of these animals are susceptible to Bm infection. The literature review revealed 28 Bm non-human hosts (NHH). For 5/51 (9.8%) hBG system genes (e.g., RhD), no NHH had orthologs. This means that RhD is unlikely to be an essential receptor for invasion. For 24/51 (47.1%) hBG system genes, NHH had 4-27 orthologs. For the ABO gene, 15/28 NHH had an ortholog, meaning that this gene is also unlikely to generate an RBC antigen, which is essential for Bm invasion. Our prior research showed that persons with blood type A, B, AB, O, RhD+, and RhD- can all be infected with Bm, supporting our current study's predictions. For 22/51 (43.1%) hBG system genes, orthologs were found in all 28 NHH. Nineteen (37.3%) of these genes encode RBC surface proteins, meaning they are good candidates for generating a receptor needed for Bm invasion. In vitro cultures of Bm, experimental Bm infection of transgenic mice (e.g., a CD44 KO strain), and analyses of Bm patients can reveal further clues as to which RBC antigens may be essential for invasion.

Position paper on advancing sickle cell disease management in France by bridging the clinical practices and guidelines through expert insights.

In France, sickle cell disease (SCD) is the most common rare disease and represents the most prevalent genetic disorder, with 19,800 to 32,400 patients diagnosed in 2016 and 1:714 newborns affected in 2019. SCD is caused by a single mutation in the ß-globin gene, resulting in the production of abnormal hemoglobin (called HbS), chronic hemolytic anemia, and impaired red blood cell rheology. SCD patients face several severe acute and chronic complications, including stroke, acute chest syndrome (ACS), painful vaso-occlusive crisis (VOC), organ failure, and a high risk of infections. As patients' care pathway remains unclear in France, a roundtable advisory board meeting was organized in the country to provide insights into the management of SCD in alignment with clinical guidelines. The meeting brought together a panel of esteemed key opinion leaders (KOLs) in SCD management, encompassing both clinical practice and research. During the meeting, the KOLs discussed clinical practices and their alignment with French guidelines, identifying areas of concordance and discrepancy. They also addressed disparities in SCD clinical practices across regions and medical centers. The KOLs discussed the prophylactic and therapeutic options currently available for SCD patients in France, with a focus on transfusion therapies, especially automated red blood cell exchange (aRBCX). The results of this advisory board meeting provide a valuable platform for gathering expert perspectives on SCD management, clinical practices, guideline alignment, and the potential for contributions to guideline updates.

Hemoglobin S target of <50% as compared to 30% in chronic red cell exchange for secondary stroke prevention in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) patients with a history of stroke are encouraged to receive chronic red blood cell exchange (RBCx) for stroke prevention. The American Society of Hematology guideline published in 2020 recommends an HbS target of <30%. However, this approach necessitates more frequent RBCx and more RBC units. UT Southwestern has devised a chronic exchange protocol that elevates the HbS target to <50% in patients with a low risk of stroke. STUDY DESIGN: This retrospective chart review study reviewed the medical records of patients receiving chronic RBCx with a target of HbS <50% over the past 10-year period to assess the safety of maintaining higher HbS targets in SCD patients with a low risk of cerebrovascular accidents (CVA). RESULTS: Among 49 SCD patients in the chronic RBCx program for secondary stroke prevention, 33 patients were maintained on an HbS target of <50% (average measured: 35.4%) for the duration of RBCx program enrollment (median 93.0 months, 95% CI, 83-99). Stroke or transient ischemic attack (TIA) clearly attributable to changing target HbS had not been identified among the 33 study subjects. Seven patients experienced conversion between the HbS targets of <50% and <30% HbS target. Significant reductions were observed in the frequency of RBCx and usage of blood volume in four of them. CONCLUSION: The findings suggest that liberalizing the HbS target could confer clinical flexibility without increasing the risk of CVA in a selective population. Further studies to fully evaluate the potential benefits of this approach are indicated.

Red blood cell exchange for SARS-CoV-2: A Gemini of therapeutic opportunities.

As of now, therapeutic strategies for the novel coronavirus (SARS-CoV-2) are limited and much focus has been placed on social distancing techniques to "flatten the curve". Initial treatment efforts including ventilation and hydroxychloroquine garnered significant controversy and today, SARS-CoV-2 outbreaks are still occurring throughout the world. Needless to say, new therapeutic strategies are needed to combat this unprecedented pandemic. Nature Reviews Immunology recently published an article hypothesizing the pathogenesis of TAM (Tyro3, Axl, and Mer) receptor signaling in COVID-19. In it they expressed that hypercoagulation and immune hyper-reaction could occur secondary to decreased Protein S (PROS1). And hypoxia has been recently discovered to significantly decrease expression of PROS1. Regarding the cause of hypoxia in COVID-19; NIH funded research utilizing state-of-the-art topologies has recently demonstrated significant metabolomic, proteomic, and lipidomic structural aberrations in hemoglobin (Hb) secondary to infection with SARS-CoV-2. In this setting, Hb may be incapacitated and unable to respond to environmental variations, compromising RBCs and oxygen delivery to tissues. The use of red blood cell exchange would target hypoxia at its source; representing a Gemini of therapeutic opportunities.

Automated RBC Exchange has a greater effect on whole blood viscosity than manual whole blood exchange in adult patients with sickle cell disease.

BACKGROUND: Blood transfusion is the cornerstone treatment to reduce the clinical severity of sickle cell disease (SCD), but we need to maintain the haematocrit (Hct) within an acceptable range to avoid a deleterious increase in blood viscosity. The aim of this study was to compare the effects of manual versus automated red blood cell (RBC) Exchange on haematological parameters and blood viscosity. STUDY DESIGN AND METHODS: This prospective, single-centre, open nonrandomized observational study included forty-three sickle cell patients: 12 had automated RBC Exchange and 31 manual RBC Exchange. Samples were collected in EDTA tubes just before and within one hour after the end of the RBC Exchange to measure the haematological parameters and blood viscosity. RESULTS: Both automated and manual RBC Exchange decreased haemoglobin S levels and leucocyte and platelet counts, but the decrease was greater for automated RBC Exchange. Manual RBC Exchange caused a significant rise in haematocrit and haemoglobin levels and did not change blood viscosity. In contrast, automated RBC Exchange decreased blood viscosity without any significant change in haematocrit and only a very slight increase in haemoglobin levels. The change in blood viscosity correlated with the modifications of haematocrit and haemoglobin levels, irrespective of the RBC Exchange procedure. When adjusted for the volume of RBC Exchange, the magnitude of change in each biological parameter was not different between the two procedures. CONCLUSION: Our study demonstrates that the automated RBC Exchange provided greater haematological and haemorheological benefits than manual RBC Exchange, mainly because of the higher volume exchanged, suggesting that automated RBC Exchange should be favoured over manual RBC Exchange when possible and indicated.

"Dual-gene" malaria-resistance: Therapeutically-rational exchange (T-REX) of group-O sickle trait and group-O C-traittrait red blood cells can be evaluated in Benin and Nigeria.

BACKGROUND: Using indicators of disease severity, clinicians can predict which Plasmodium falciparum (Pf) malaria patients being treated with artesunate or quinine are likely to die despite these drugs. Effective "rescue adjuncts" are needed when drugs alone are inadequate. "Therapeutically-rational exchange" (T-REX) of special malaria-resistant red blood cells (RBCs) has been proposed to optimize adjunctive exchange transfusion. METHODS: Studies were reviewed that (1) quantified how group-O status and "sickle-trait" (HbAS) and "C-trait" (HbAC) hemoglobins affect Pf mortality, risk of thrombosis, or birth outcomes for women with pregnancy associated malaria (PAM), (2) reported prevalences of "dual-gene" malaria-resistant RBCs, or (3) reflected the level of exchange-transfusion and malaria-related expertise in Benin and Nigeria. RESULTS: Data show that the malaria- and thrombosis-resistance of RBCs depend on specific genes and the patient's clinical status and medical history. In malaria-endemic Benin and Nigeria, prevalences of "dual-gene" malaria-resistant group-O HbAS and group-O HbAC RBCs are substantial, and both malaria- and exchange-related expertise are outstanding. CONCLUSIONS: T-REX of "dual-gene" malaria-resistant RBCs is feasible in Benin and Nigeria and warrants evaluation as a rescue adjunct for 3 subsets of Pf-malaria patients. For therapeutic use, group-O HbAS RBCs are likely to be more effective than non-O HbAS RBCs for Pf-infected patients who (1) have a history of thrombosis or (2) are taking birth-control hormones while group-O HbAC RBCs may substantially improve birth outcomes for women with PAM. Studies suggest it is prudent to assume - until proven otherwise - that T-REX of "dual-gene" malaria-resistant RBCs can improve ("personalize") rescue of these patient subsets.

Pathology's historic 2019 incoming residents: Why "the internationalization of pathology" may markedly advance transfusion medicine and cellular therapeutics.

OBJECTIVES: This study had two objectives: (1) to determine if, in the United States of America (US), the proportion of non-US citizen international medical graduates (non-US IMGs) entering pathology residencies had increased (again) in 2019 and (2) to assess how this multi-year trend might impact transfusion medicine in the US. METHODS: The most recent (2019) "National Resident Matching Program" (NRMP) data were analyzed. To assess potential future impact, using controversies related to Plasmodium falciparum (Pf) malaria, conflicting US and non-US perspectives were reviewed. Differences between published US and non-US views were identified regarding, for example, the value of Pf-resistant ("variant") red blood cells (RBCs) and exchange transfusions. RESULTS: Year 2019 is the first year non-US IMGs were the largest group to fill residency-training positions for a major US specialty via the "Main Residency Match." Also notable, US and non-US views were found to differ markedly regarding (1) the value and safety of Pf-resistant RBC variants and exchange transfusions, and (2) the threat of drug-resistant Pf-malaria parasites. Non-US clinicians and researchers seem more concerned about Pf-malaria, and their interest in cellular therapies seems greater and more optimistic. CONCLUSIONS: In 2019, the historically high proportion of non-US IMGs among incoming pathology residents dramatically highlights the steady demographic shift that began years ago: "the internationalization of pathology" in the US. Fortunately, a review of publications related to exchange transfusion, Pf-malaria, and variant RBCs suggests non-US IMGs may markedly promote and advance cell therapies such as therapeutically-rational exchange (T-REX) of disease-resistant RBCs.

Optimizing exchange transfusion for patients with severe Babesia divergens babesiosis: Therapeutically-Rational Exchange (T-REX) of M antigen-negative and/or S antigen-negative red blood cells should be evaluated now.

Babesia divergens is an intraerythrocytic parasite, which is the major cause of babesiosis in Europe. For years, clinicians have been publishing stunning case reports that describe how some - but not all - conventional red blood cell (RBC) exchange transfusions have saved the lives of severely ill babesiosis patients. Due to markedly different patient outcomes, clinicians agree that new treatments and additional studies are needed. Here we argue that we should evaluate "therapeutically-rational exchange" (T-REX) in which the RBCs used to replace Babesia-parasitized RBCs are special disease-resistant RBC genetic variants (instead of the nondescript, "standard issue" RBCs used in conventional exchanges). T-REX seems prudent because with conventional exchange only some units of "standard issue" RBCs may be disease-resistant, while other units may not protect or may even promote disease. The random selection of RBCs for conventional RBC exchange may explain why clinical outcomes can vary dramatically. Fortunately, researchers have found that M antigen-negative (M-) and S antigen-negative (S-) RBCs resist invasion by B. divergens. Thus, we recommend evaluating T-REX of RBC variants that are B. divergens invasion-resistant: RBCs that are (1) M-, (2) S-, or (3) both M- and S-. By using only Babesia-resistant RBCs, T-REX eliminates the risk of unintentionally infusing Babesia-susceptible RBCs that might increase the severity of babesiosis. Because the T-REX variation of the conventional RBC exchange procedure is feasible, safe, and biologically plausible, we feel T-REX of Babesia-resistant RBCs should now be evaluated.

Babesia parasitemia rebound after red blood cell exchange.

Babesiosis is an increasingly recognized disease which may benefit from therapeutic apheresis (Category II/Grade 2C). Vulnerable populations include the splenectomized, those aged >50, those with malignancies, and the immunocompromised. In the setting of parasite levels > 10%, significant anemia, renal impairment, pulmonary compromise, or hepatic dysfunction, RBC exchange can rapidly reduce parasite burdens and decrease the bioavailability of proinflammatory cytokines. No previous report has shown such a rapid rebound in parasitemia despite adequate organism removal. Herein, we report a case of severe babesiosis in a splenectomized 56 year old male with a past medical history significant for benign multiple sclerosis. Following a week of flu-like symptoms, the patient presented to an outside hospital with anemia, elevated bilirubin, thrombocytopenia, and 15% of his RBCs containing Babesia forms on a peripheral smear. Despite initiation of appropriate antimicrobials, subsequent transfer to our facility revealed worsening parasitemia (25%), tachypnea, and hypoxia. An emergent two volume RBC exchange was performed, resulting in 15% post-exchange parasitemia. Twelve hours later, the parasitic burden had climbed to 30%. A second RBC exchange reduced the parasite burden to 1.5%. His post-procedural course was significant for diminishing periodic increases in parasitemia despite continued antimicrobial therapy. Rapid increases in parasitic burden following RBC exchanges can occur and post-procedural surveillance of parasitemia should be closely monitored to expedite additional exchanges.

Establishing an institutional therapeutic apheresis registry.

Apheresis was first performed as a therapeutic procedure in the 1950s. The first national therapeutic apheresis (TA) registry was established in Canada in 1981 and other national registries followed, including two attempts at establishing an international TA registry. There is no national registry in the United States. Our large, academic, tertiary hospital has a very active TA service. We created a TA database to track all procedures performed by the apheresis service by transferring data from paper appointment logs and the electronic medical records into a Microsoft Access database. Retrospective data from each TA procedure performed at UAB from January 1, 2003 through December 31, 2012 were entered, including the type of procedure, indication, date, and patient demographics. Microsoft Excel was used for data analysis. During the 10-year period, our TA service treated 1,060 patients and performed 11,718 procedures. Of these patients, 70% received therapeutic plasma exchange (TPE), 21% received extracorporeal photopheresis (ECP), 4.5% received red cell exchange (RCE), 4.2% received leukocytapheresis, and 0.6% underwent platelet depletion. Among the procedures, 54% were TPEs, 44% were ECPs, 1.3% were RCEs, 0.5% were leukocytaphereses, and 0.1% were platelet depletions. According to the current literature, national and international TA use is underreported. We believe that the UAB TA registry provides useful information about TA practices in our region and can serve as a model for other institutions. Furthermore, data from multiple institutional registries can be used for clinical research to increase the available evidence for the role of TA in various conditions. J. Clin. Apheresis 31:516-522, 2016. © 2015 Wiley Periodicals, Inc.

Apheresis for babesiosis: Therapeutic parasite reduction or removal of harmful toxins or both?

Babesiosis is a potentially life-threatening illness caused by intraerythrocytic protozoan parasites of the genus Babesia that are transmitted most commonly by Ixodes ticks, and rarely from blood transfusion or congenitally. Clinical presentations of babesiosis include asymptomatic infection, mild to moderate disease, or severe disease. Antibiotics such as atovaquone plus azithromycin or clindamycin and quinine can be used effectively to treat this disease in most cases, however in high risk populations, the mortality rate can be as high as 20% despite therapy. Therapeutic exchange transfusion has been used in severe babesiosis and is of apparent therapeutic benefit. It is not entirely clear through what mechanism therapeutic exchange transfusion may help patients. Data suggests that in addition to parasite load reduction, it is possible that therapeutic exchange transfusion removes toxins generated by babesia infection. There are many remaining questions that need to be addressed regarding exchange transfusion for babesiosis. J. Clin. Apheresis 31:454-458, 2016. © 2015 Wiley Periodicals, Inc.

Two Cases of Cerebral Malaria Treated with Therapeutic Erythrocytapheresie / 대한수혈학회지

Cerebral malalria is a life-threatening complication of Plasmodium falciparum infection. RBC exchange transfusion (RCE) can reduce the burden of parasitemia in this situation. We have experienced two cases of cerebral malaria treated with automated RBC exchange as an adjunct to standard chemotherapy. Case 1: A 42-year-old male was referred to the emergency room with a history of 3 days of fever after having returned from Congo. Peripheral blood smear showed the P. falciparum parasitemia of 70-80%. Quinidine and doxycycline were administered but, mental state started to deteriorate. He underwent RCE on hospital day 2 to reduce the parasitemia to 10% after 8 hours. No parasite could be found on day 3 after the RCE. Case 2: A 62-year-old male was referred to the emergency room with a history of 3 days of fever after having returned from Cameroon. P. falciparum parasitemia was 10% on peripheral blood smear. Quinidine and doxycycline were immediately started but headache developed abruptly and he underwent RCE on hospital day 3. After 8 hours following the completion of RCE, parasitemia decreased to less than 1%. Automated RBC exchange transfusion can rapidly reduce the burden of parasitemia and achieve improvement of neurologic symptom and sign in patients with cerebral malaria.

Therapeutic RBC Exchange in a Patient with Severe Plasmodium Falciparum Infection / 대한수혈학회지

With increasing travel to tropical area, the number of patients with imported malaria in this country is increasing. RBC exchange transfusion has proposed as a adjunct therapy for very severe falciparum malaria to reduce the parasite load rapidly. We report a patient with severe Plasmodium falciparum infection with 26% of erythrocyte parasitized, treated with RBC exchange transfusion in addition to conventional chemotherapy. The exchange of 1200 mL of red blood cells was carried out with 7 packed red cells using automatic cell separator. This patients recovered from his disease despite respiratory distress syndrome and acute renal failure. We conclude that RBC exchange is a useful adjunct to conventional chemotherapy and should be considered in patients with severe and complicated falciparum malaria.