Reducing the risk of Plasmodium vivax after falciparum infections in co-endemic areas-a randomized controlled trial (PRIMA).

BACKGROUND: Plasmodium vivax forms dormant liver stages that can reactivate weeks or months following an acute infection. Recurrent infections are often associated with a febrile illness and can cause a cumulative risk of severe anaemia, direct and indirect mortality, and onward transmission of the parasite. There is an increased risk of P. vivax parasitaemia following falciparum malaria suggesting a rationale for universal use of radically curative treatment in patients with P. falciparum malaria even in the absence of detectable P. vivax parasitaemia in areas that are co-endemic for both species. METHODS: This is a multicentre, health care facility-based, randomized, controlled, open-label trial in Bangladesh, Indonesia and Ethiopia. Patients with uncomplicated falciparum malaria, G6PD activity of ≥70% of the adjusted male median (AMM) and haemoglobin levels ≥8g/dl are recruited into the study and randomized to either receive standard schizonticidal treatment plus 7-day high dose primaquine (total dose 7mg/kg) or standard care in a 1:1 ratio. Patients are followed up weekly until day 63. The primary endpoint is the incidence risk of any P. vivax parasitemia on day 63. Secondary endpoints include incidence risk on day 63 of symptomatic P. vivax malaria and the risk of any P. falciparum parasitaemia. Secondary safety outcomes include the proportion of adverse events and serious adverse events, the incidence risk of severe anaemia (Hb<5g/dl and <7g/dl) and/or the risk for blood transfusion, the incidence risk of ≥ 25% fall in haemoglobin with and without haemoglobinuria, and the incidence risk of ≥ 25% fall in haemoglobin to under 7g/dl with and without haemoglobinuria. DISCUSSION: This study evaluates the potential benefit of a universal radical cure for both P. vivax and P. falciparum in different endemic locations. If found safe and effective universal radical cure could represent a cost-effective approach to clear otherwise unrecognised P. vivax infections and hence accelerate P. vivax elimination. TRIAL REGISTRATION: NCT03916003 . Registered on 12 April 2019.

Venous malformations with severe localized intravascular coagulopathy treated with microwave ablation.

OBJECTIVES: To evaluate the safety and feasibility of microwave ablation for treating venous malformations (VMs) with severe localized intravascular coagulopathy (LIC). PATIENTS AND METHODS: Data for patients with the diagnosis of VMs coupled with severe LIC who underwent color Doppler-guided microwave dynamic ablation between January 2017 and June 2019 were retrospectively reviewed and analyzed. All patients had previously received sclerotherapy or other treatments with poor outcomes and gradual aggravation of coagulation abnormalities. Microwave treatment with "dynamic ablation" was performed with real-time color Doppler monitoring and was repeated if necessary after 3 months. Low-molecular-weight heparin (LMWH) was used to control consumptive coagulopathy. The therapeutic efficacy including coagulation function and lesion size was evaluated using the four-level scale developed by Achauer. RESULTS: Among 15 patients with extensive diffuse or multiple VMs, 10 patients presented with lesions in a single lower extremity, one in both lower extremities and the perineum, one in both upper extremities and the trunk, and three with multiple lesions. The patients underwent a total of 74 microwave ablation sessions, with an average of 4.9 sessions per person. Coagulation abnormalities were temporarily aggravated in 59 sessions within the first seven days post-ablation but improved to grade II (fair) a week later. From six months to three years after the ablation, the lesions improved to grade IV (excellent) in one patient, grade III (good) in six patients, and grade II (fair) in eight patients. Moreover, the coagulation function improved to grade IV in four patients, grade III in eight patients, and grade II in three patients, resulting in an efficiency rate of 80% (12/15). Post-ablation complications included fever, hemoglobinuria, and elevations in aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase. The patients with fever and hemoglobinuria recovered after specific therapeutic measures, but elevations in aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase recovered spontaneously without further interventions. CONCLUSIONS: Ablation coupled with anticoagulation can effectively treat VMs in patients with severe LIC and improve the long-term coagulation function.

[Hemoglobinuria in children hospitalized in Ouagadougou: short term inpatient care and prognosis]. / Hémoglobinurie chez l'enfant à Ouagadougou: prise en charge hospitalière et pronostic à court terme.

INTRODUCTION: The purpose of this study was to analyze the epidemiological, diagnostic, therapeutic and evolutionary features of hemoglobinuria in children hospitalized in the Pediatric University Hospital Charles de Gaulle, Ouagadougou. METHODS: We conducted a cross-sectional descriptive study over the period 01st July-31st December 2014. All children aged 0-15 years hospitalized in the Department of Medical Pediatrics of the Pediatric University Hospital Charles de Gaulle and diagnosed with macroscopic hemoglobinuria during the study period were enrolled. RESULTS: Thirty-eight patients were included in the study. Hospitalization rate for hemoglobinuria was 1.9%. The average age of patients was 80.8 ± 44.1 months (ranging from 21 to 168). The study involved 23 boys (60.5%) and 15 girls (39.5%). The major clinical signs were: fever (86.8%), dark urines like « coca cola ¼ (86.8%), pallor (63.2%), hepatomegaly (50%). Glomerular filtration flow was less than 80 mL/min/1.73m2 in 23 patients (69.7%); 21 patients had Glucose-6-phosphate dehydrogenase (G6PD) deficiency. The main suspected causes of hemoglobinuria were: severe malaria, bacterial and viral infections, G6PD deficiency, biliary haemoglobinuric fever. Treatments included: artemisinin derivatives, antibiotics and antipyretics. One patient underwent dialysis. CONCLUSION: Hemoglobinuria is a symptom mainly causing diagnostic problems in our context. It is a severe disorder which can result in acute renal failure (ARF).

Recovery with a regular dose of antibiotics from bacillary hemoglobinuria in a Holstein cow.

One Holstein cow housed with 21 other cows exhibited clinical signs of pyrexia, anorexia and diarrhea along with severe hemoglobinuria. Hematological and biochemical analyses conducted before and after antibiotic therapy indicated severe hemolytic anemia and disruption of hepatic function. A general improvement in conditions was observed after an 11-day program of treatment comprising a regular dose of antibiotics and prescribed supportive therapies. A tentative diagnosis of bacillary hemoglobinuria was made based on the clinical and clinico-pathologic features on day 7. A molecular diagnosis was made by a PCR amplification of the flagellin gene of Clostridium haemolyticum using DNA extracted from the whole blood. The cow was diagnosed with the first recorded occurrence of bacillary hemoglobinuria of Holstein cattle in Japan.

Bacillary hemoglobinuria in Japanese black cattle in Hiroshima, Japan: a case study.

Three Japanese Black cows housed with 6 other cows exhibited main clinical symptoms of severe hemoglobinuria. Hematological analyses conducted after antibiotic therapy demonstrated severe anemia, and biochemical analyses indicated both severe hemolysis and disruption of hepatic function. One of the three cows died. Based on the above analyses and observation of typical clinical symptoms, a speculative diagnosis of bacillary hemoglobinuria was made, and immediate high-dose antibiotic treatment improved the general conditions of the surviving animals. Blood samples from the other 2 cows were collected sequentially after antibacterial therapy. Clostridium haemolyticum was detected by a nested polymerase chain reaction analysis of the blood samples. The cows were diagnosed with the second recorded occurrence of bacillary hemoglobinuria in Japan.

Successful treatment of bacillary hemoglobinuria in Japanese Black cows.

Four pasture-fed Japanese Black cows showed the main clinical symptoms of severe hemoglobinuria at different periods between 2003 and 2007. Hematological analyses at the first consultation revealed severe anemia, and biochemical analyses indicated both severe hemolysis and disruption of hepatic function. Although the first 2 patients died, the hemoglobinuria and general condition of the remaining 2 cows, who were immediately initiated on large doses of antibiotics, improved within 3 days. Clostridium haemolyticum was detected by polymerase chain reaction (PCR) analysis of the blood sample of 1 of the infected cows. Anti-fascioliasis medicine is administered, and since then, no case of hemoglobinuria has been observed. The cows were diagnosed with bacillary hemoglobinuria, and they represent the first few cases in Japan.

In vivo and in vitro studies of fetal hemoglobin induction by hydroxyurea in beta-thalassemia/hemoglobin E patients.

OBJECTIVE: Some, but not all, beta-thalassemia/hemoglobin E (beta-thal/HbE) patients respond to hydroxyurea treatment. It would be helpful if patient responses to hydroxyurea could be screened in vitro to identify responders and nonresponders before beginning in vivo treatment. MATERIALS AND METHODS: Thirteen beta-Thal/HbE patients were treated with hydroxyurea orally for 2 years at a starting dose of 5 mg/kg/day for 5 days/week with escalation to a maximum of 10 mg/kg/day. For comparison, erythroid cells obtained from peripheral blood of the same patients 1 year after they had stopped hydroxyurea treatment were treated with hydroxyurea in vitro. The gamma-globin mRNA was measured by real-time reverse-transcription polymerase chain reaction, fetal hemoglobin (HbF) by high-performance liquid chromatography, (G)gamma- and (A)gamma-globin chains by Triton X-100 acid urea polyacrylamide gel electrophoresis. RESULTS: Treatment of cells in primary culture with 30 microM hydroxyurea for 96 hours significantly increased the fractional HbF content in beta-Thal/HbE patients. The (G)gamma:(A)gamma-globin mRNA was induced 0.30- to 8-fold in vitro and 0.30- to 6-fold in vivo (r(2) = 0.51, p = 0.16 by paired t-test); the fractional HbF content was induced 0.50- to 19-fold in vitro and 0.30- to 12-fold in vivo (r(2) = 0.61, p = 0.20) and the (G)gamma:(A)gamma-globin chain ratio was increased 0.80- to 1.40-fold in vitro and 1- to 1.20-fold in vivo (r(2) = 0.62, p = 0.13). CONCLUSION: The correlation of in vivo and in vitro results of HbF synthesis and globin mRNA suggest that in vitro testing may predict the in vivo response.

[Pulmonary emboli in sclerotherapy for peripheral vascular malformations under general anesthesia; a report of two cases].

Sclerotherapy with absolute ethanol and/or polidocanol is a well-established therapeutic modality for the treatment of peripheral vascular malformations, although systemic complications such as hemoglobinuria and pulmonary embolism could occur. We report two cases of pulmonary embolism associated with sclerotherapy for peripheral vascular malformations. Two patients, a 17-year-old man and a 17-year-old woman, undergoing absolute ethanol sclerotherapy for vascular malformations of the leg developed pulmonary embolism after injection of ethanol. Pulmonary embolism, suspected by the clinical symptoms such as hypoxia and hypocapnia, was confirmed by the pulmonary scintigraphy showing minimal pulmonary defects. Hemoglobinuria was also observed with injection of ethanol. Patients recovered rapidly with heparin and urokinase therapy. The review of perioperative complications with sclerotherapy for peripheral vascular malformations in our institution for past four years revealed that complications were observed in 18 out of 88 patients (20.5%), and in 32 out of 183 cases (17.5%). Major complications were hemoglobinuria, pulmonary embolism, shivering and delayed emergence from general anesthesia. We conclude that sclerotherapy for vascular malformations under general anesthesia is a risky procedure and this must be carefully managed with keen monitoring of Spo2 and Etco2.

Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) arises from a somatic mutation of the PIG-A gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system. We tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components, in patients with PNH. METHODS: Eleven transfusion-dependent patients with PNH received infusions of eculizumab (600 mg) every week for four weeks, followed one week later by a 900-mg dose and then by 900 mg every other week through week 12. Clinical and biochemical indicators of hemolysis were measured throughout the trial. RESULTS: Mean lactate dehydrogenase levels decreased from 3111 IU per liter before treatment to 594 IU per liter during treatment (P=0.002). The mean percentage of PNH type III erythrocytes increased from 36.7 percent of the total erythrocyte population to 59.2 percent (P=0.005). The mean and median transfusion rates decreased from 2.1 and 1.8 units per patient per month to 0.6 and 0.0 units per patient per month, respectively (P=0.003 for the comparison of the median rates). Episodes of hemoglobinuria were reduced by 96 percent (P<0.001), and measurements of the quality of life improved significantly. CONCLUSIONS: Eculizumab is safe and well tolerated in patients with PNH. This antibody against terminal complement protein C5 reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH.

Therapeutic efficacy of atovaquone against the bovine intraerythrocytic parasite, Babesia divergens.

This study demonstrates the activity of the hydroxynaphthoquinone (HNQ), atovaquone, against Babesia divergens, the cause of a rare but lethal form of human babesiosis. In vitro studies showed that unlike other anti-malarial drugs, the HNQs studied have a high level of anti-babesial activity and atovaquone was more active than imidocarb, the most effective compound used so far for human B. divergens babesiosis and also used routinely for the treatment of bovine babesiosis. Atovaquone also proved to be extremely active against B. divergens in gerbils (Meriones unguiculatus). Acute fulminating infections were effectively treated with as little as 1.0 mg/kg with increasing effectiveness up to 10 mg/kg, which compares well with the activity of imidocarb. Although immunosuppression with dexamethasone slowed the decline of parasitemias after treatment with atovaquone, gerbil survival was unaffected. Pretreatment of gerbils with 4 daily low doses of atovaquone did not have any effect on the development of subsequent infections. However, if treatment was continued after infection, daily doses as low as 0.5 mg/kg effectively suppressed the parasites.

Minocycline-induced hemolytic anemia.

A case of drug-induced immune hemolytic anemia is described. A 2 year old boy exhibited sudden anemia and hemoglobinuria after administration of minocycline (MINO). The specific immunoglobulin G antibody against MINO was demonstrated in the patient's serum by western blotting. This is a rare example where anti-minocycline immune complex-mediated hemolysis was responsible for an intravascular hemolytic process.

Studies on human erythrocyte glutathione-S-transferase from HbAA, HbAS and HbSS subjects.

The activities of human erythrocyte glutathione-S-transferase (EC 2.5.1.18) obtained from 53 subjects of both sexes aged between 5 and 25 years of HbAA (20), HbAS (13) and HbSS (20) were determined. The results, expressed in IU/g Hb, obtained for the various genotypes were: HbSS = 14.6 +/- 3.4; HbAS = 4.7 +/- 1.1; HbAA = 2.7 +/- 0.8. The observed differences were found to be statistically significant (p less than 0.001). Kinetic analysis showed similar Michaelis constants (Km) of the enzyme irrespective of the genotype, indicating structural and functional similarities of the enzyme from the various genotypes. A mean (+/- SD) percentage increase of 63.8 +/- 4.9 was obtained for the red cell glutathione-S-transferase activity in the presence of dithionite, while a mean (+/- SD) decrease of 38.8 +/- 1.9% was obtained in the presence of 0.3 mM haemin. These findings suggest an increased activation of the enzyme in HbSS and HbAS subjects (as compared with HbAA subjects) possibly by an increased generation of electrophilic substrates in the red cell of these subjects.

Danazol treatment for paroxysmal nocturnal hemoglobinuria.

Danazol was administered to two patients with paroxysmal nocturnal hemoglobinuria (PNH) with a dramatic effect on the hematological findings. The patients, 31- and 41-year-old females, were initially diagnosed as having aplastic anemia, and were initially treated with anabolic steroid and immunosuppressive therapy, respectively. Sugar water and Ham tests turned positive at the start of danazol therapy in the former patient and after two months in the latter patient. This drug produced a dramatic improvement in the hemoglobin level and the platelet count and showed few side effects in the patients. A possible mechanism of action of danazol for PNH is briefly discussed.

Haptoglobin therapy for possible prevention of renal failure following thermal injury: a clinical study.

Hemolysis does not necessarily result in acute renal failure in severely burned patients, but free serum hemoglobin may play some important role in the development of renal damage. This controlled study of the effects of haptoglobin administration in severely burned patients presenting with hemoglobinuria produced the following results: As long as free hemoglobin was present in the plasma, free serum haptoglobin remained undetectable. Free serum hemoglobin dropped rapidly after haptoglobin treatment, whereas the free serum hemoglobin levels in control patients remained unchanged for at least 12 hours. The time required for macroscopic hemoglobinuria to clear showed a statistically significant difference between the haptoglobin-treated patients and the control patients. Some patients among the haptoglobin-treated group had prolonged hemolysis and hemoglobinuria which might have cleared with additional doses of haptoglobin.