REBISTART: Adherence of Patients with Multiple Sclerosis to Treatment with Subcutaneous Interferon Beta in the Context of a Patient Support Program.

INTRODUCTION: Treatment adherence is a critical success factor in the disease-modifying therapy (DMT) of multiple sclerosis (MS). The REBISTART study prospectively evaluated adherence in patients using components of a patient support program (PSP). METHODS: The 12-month non-interventional multicenter study examined the real-world adherence to subcutaneously (sc) injected interferon beta-1a (Rebif®). Patient-assessed adherence was measured by a visual analog scale (VAS) and the Morisky Medication Adherence Scale (MMAS). Objective adherence data were obtained by readouts from the RebiSmart® injection device. RESULTS: Of 333 patients, 70.9% used the nursing service as the core component of the PSP. Self-assessed VAS-based adherence was stable over time at 94.0-96.3%. Similarly, MMAS score (maximum 4) was 3.8-3.9 at all visits, also reflecting high self-assessed adherence. In 269 patients using the RebiSmart® injection device, mean readout-based objective adherence was similarly high (93.0-98.4% throughout visits). At last available visit, VAS-based adherence was independent of participation in the PSP nursing service (93.1% with participation versus 91.7% without it). Adherence was also independent of injection method or disease-related measures, including fatigue, depression, cognition, and quality of life. The most frequent reason for the premature discontinuations (38.7% of patients) was "change of treatment" (10.0%). DISCUSSION: We suggest that subgroups that may specifically benefit from PSP include patients who live alone, use multiple comedications, and are affected by cognitive impairment, depression, and/or fatigue. Further studies should investigate the potential usefulness of PSPs in these populations. CONCLUSIONS: Very high adherence rates independent of the PSP nursing service over 1 year of treatment indicate that IFN beta-1a sc is an easy-to-use and well-tolerated disease-modifying drug. TRIAL REGISTRATION NUMBER: Vfa.de: No. 892. https://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_892 .

Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.

Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate-mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6-14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg-1 single dose; n = 364) or to artesunate-mefloquine (antimalarial dosage: artesunate 4 mg kg-1 and mefloquine 8 mg kg-1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate-mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate-mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of -2.5% (95% confidence interval (CI) -9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate-mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate-mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .

Baseline Liver Ultrasound Findings in Preschool Children From the Praziquantel in Preschoolers Trial in Lake Albert, Uganda.

BACKGROUND: Periportal fibrosis is a late-stage manifestation of chronic infection with Schistosoma mansoni . Praziquantel (PZQ), the only drug available for the treatment of schistosomiasis, has limited effect in treating established morbidity. Preschool-age children (PSAC) are not considered to be an at-risk population for severe morbidity. However, the prevalence of periportal fibrosis in PSAC in S. mansoni endemic settings is unknown. METHODS: As part of a phase II clinical trial comparing different dosing regimens of PZQ in children age 12-47 months infected with S. mansoni in Uganda ("praziquantel in preschoolers" trial), we present baseline results assessing liver ultrasound (US) findings as per the WHO Niamey Protocol. RESULTS: A total of 7/347 (2%) PSAC had Image Pattern C with pipe stems and echogenic rings suggestive of periportal fibrosis, 29/347 (8%) had Image Pattern B and 58 (17%) had evidence of periportal thickening There were higher adjusted odds of periportal thickening with older age [odds ratio (OR): 1.04; 95% confidence interval (CI): 1.00-1.07], primary maternal education (OR: 1.04; 95% CI: 1.00-1.07) and being taken to the lake weekly (OR: 3.02; 95% CI: 1.19-7.63). A further 44/347 children (13%) had a rounded caudal liver edge which was associated with high S. mansoni infection intensity (adjusted OR: 3.31; 95% CI: 1.46-7.51). CONCLUSIONS: Incipient schistosomiasis-related liver morbidity was detected in young children enrolled in the praziquantel in preschoolers trial. Adequate age-adjusted reference measurements for liver ultrasound findings in very small children are lacking but urgently needed. Schistosomiasis-related fibrosis may be delayed or averted with early and repeated PZQ treatment.

Interferon beta-1a sc at 25 years: a mainstay in the treatment of multiple sclerosis over the period of one generation.

INTRODUCTION: Interferon beta (IFN beta) preparations are an established group of drugs used for immunomodulation in patients with multiple sclerosis (MS). Subcutaneously (sc) applied interferon beta-1a (IFN beta-1a sc) has been in continuous clinical use for 25 years as a disease-modifying treatment. AREAS COVERED: Based on data published since 2018, we discuss recent insights from analyses of the pivotal trial PRISMS and its long-term extension as well as from newer randomized studies with IFN beta-1a sc as the reference treatment, the use of IFN beta-1a sc across the patient life span and as a bridging therapy, recent data regarding the mechanisms of action, and potential benefits of IFN beta-1a sc regarding vaccine responses. EXPERT OPINION: IFN beta-1a sc paved the way to effective immunomodulatory treatment of MS, enabled meaningful insights into the disease process, and remains a valid therapeutic option in selected vulnerable MS patient groups.

Percutaneous drainage and combined praziquantel-albendazole therapy: a novel approach for the treatment of simple echinococcal liver cysts.

Cystic echinococcosis (CE) is a worldwide helminthic zoonosis causing serious disease in humans. The WHO Informal Working Group on Echinococcosis recommends a stage-specific treatment approach of hepatic CE that facilitates the decision on what therapy option is most appropriate. Percutaneous aspiration, instillation of a scolicide, e.g., ethanol or hypertonic saline, and subsequent re-aspiration (PAIR) have been advocated for treating medium-size unilocular WHO-stage CE1 cysts. PAIR can pose a risk of toxic cholangitis because of spillage of ethanol in the case of a cysto-biliary fistula or of life-threatening hypernatriaemia when hypertonic saline is used. The purpose of our study is to develop an alternative, safe, minimally invasive method to treat CE1 cysts, avoiding the use of toxic topic scolicides.We opt for percutaneous drainage (PD) in four patients: the intrahepatic drainage catheter is placed under CT-fluoroscopy, intracystic fluid is aspirated, and the viability of intracystic echinococcal protoscolices is assessed microscopically. Oral praziquantel (PZQ) is added to albendazole (ABZ) instead of using topical scolicidals.Protoscolices degenerate within 5 to 10 days after PZQ co-medication at a cumulative dosage of 250 to 335 mg/kg, and the cysts collapse. The cysts degenerate, and no sign of spillage nor relapse is observed in the follow-up time of up to 24 months post-intervention.In conclusion, PD combined with oral PZQ under ABZ coverage is preferable to PAIR in patients with unilocular echinococcal cysts.

Diagnosis and management of complicated urogenital schistosomiasis: a systematic review of the literature.

BACKGROUND: Currently, there are no standardized guidelines for the diagnosis or management of the complications of urogenital schistosomiasis (UGS). This systematic review of the literature aims to investigate the state of the art in reference to diagnostic approaches and the clinical management of this condition. METHODS: A systematic review of literature published between January 1990 and January 2021 was conducted in the MEDLINE database, scoping for articles regarding diagnostic means or therapeutic options for the complications of UGS, namely obstructive uropathy, bladder cancer, abortion, ectopic pregnancy, infertility, kidney failure, urolithiasis and the need for invasive procedures. Relevant data were then extracted from the articles deemed eligible according to the inclusion criteria. MAIN RESULTS: In total, 3052 articles were identified by the research query, of which 167 articles fulfilling inclusion criteria after title/abstract screening and full-text evaluation were included, 35% on both diagnostic and therapeutic aspects, and 51% on diagnosis and 14% on therapy. Ultrasound was the most frequently tool employed for the diagnosis of UGS complications showing a good performance. Concerning the management of hydronephrosis, the majority of available evidences came from community-based studies where universal treatment with praziquantel was used leading to decrease of prevalence of obstructive uropathy. Concerning studies on surgical procedures, laser endoureterotomy followed by stenting was mostly employed in adult patients leading to a crude cure rate of 60% (43 of 71 patients). In the case of severe hydronephrosis, surgery consisting of ureteral re-implantation showed excellent results with a crude cure rate of 98% (157 cured patients of 160 treated). Concerning bladder cancer, data on 93 patients with a clear diagnosis of UGS-related bladder were available reporting a variable and sometime combined approach based on disease stage. Available data on diagnosis and management of abortion, ectopic pregnancy, infertility, kidney failure, urolithiasis and the need for invasive procedures due to UGS are also presented. CONCLUSIONS: The review produced a complete picture of the diagnostic and therapeutic options currently available for complicated UGS. These results can be useful both for guiding clinicians towards correct management and for tracing the direction of future research.

What do we know about the epidemiology and the management of human echinococcosis in Albania?

Echinococcosis is a life-threatening neglected zoonotic disease. Cystic echinococcosis (CE) due to Echinococcus (E.) granulosus usually involves livestock and dogs; alveolar echinococcosis (AE) due to E. multilocularis involves rodents and canines such as foxes and dogs. Human hosts are infected accidentally via hand to mouth and/or foodborne/waterborne pathways. Albania is deemed to be endemic for cystic echinococcosis (CE), but there is a scarcity of data to confirm this. A systematic literature search was performed in PubMed, Google Scholar, and in other medical sources. Because of the scarcity of existing information, data confirming CE cases were reviewed from the medical hospital records of Albania's largest Hospital, the Mother Teresa University Hospital (UHCMT) Tirana, and from a large private laboratory in Tirana (Pegasus laboratory). A total of eight eligible publications on 540 CE patients were found. Three hundred forty seven additional cases hospitalized in UHCMT from 2011 to 2020 were confirmed, as well as 36 laboratory cases and 10 Albanian cases notified in Germany. Taking all cases into account and considering 162 overlapping cases, 771 cases were documented from 2011 to 2020. The only case reported as AE was most likely a multi-organic CE. Surgery was the most frequent therapy approach used (84.7%). Autochthonous human CE seems to be widespread, and transmission is ongoing in Albania. CE patients in Albania undergo surgery more frequently compared with CE cases in other European countries. In order to establish a realistic estimate of prevalence and incidence of CE in Albania, mandatory notification should be reinforced. Stage-specific therapy can be used in CE to reduce therapy cost and diminish mortality by avoiding surgical overtreatment.

Adherence to Subcutaneous Interferon Beta-1a in Multiple Sclerosis Patients Receiving Periodic Feedback on Drug Use by Discussion of Readouts of Their Rebismart® Injector: Results of the Prospective Cohort Study REBIFLECT.

INTRODUCTION: Consistent treatment adherence is an important determinant of durable response in multiple sclerosis (MS). Published data indicate that adherence to > 80% of prescribed doses may be considered optimal. Feedback of electronic application monitoring data to patients has been considered a promising means to support high adherence. METHODS: The 2-year prospective non-interventional study REBIFLECT conducted at outpatient neurological centers (731 patients at 134 study sites in Germany) investigated whether treatment adherence to subcutaneous (sc) interferon beta-1 injection during a 1-year period is enhanced by regular physician-patient talks reflecting dosing data recorded by the application device in the context of clinical data or disease parameters. Qualitative adherence was defined as number of weeks with properly distributed injections per total number of weeks with prescribed injections. Quantitative adherence was defined as number of administered injections per prescribed injections. RESULTS: Overall median qualitative adherence was 90.5%. Approximately 70% of patients with adherence data available in the respective periods had a qualitative treatment adherence of 80-100%. With a mean of 97.9% quantitative adherence was very high and remained stable in the 2-year observation period. The stability of this effect is demonstrated by the subgroup with just one reflection talk (≥ 100%) and only a slight decrease in the subgroup with more than five reflection talks (97.9%). CONCLUSION: Treatment adherence with the Rebismart® device was generally very high, consistent with other non-interventional studies. The first reflection talk supported by RebiSmart® induces excellent adherence, stabilized by repetition. Reflection to patients of subcutaneous interferon beta-1a treatment monitored by RebiSmart® is recommended to ensure prolonged strong treatment adherence.

Prospective cohort study using ultrasonography of Schistosoma haematobium-infected migrants.

BACKGROUND: Chronic infection with Schistosoma haematobium may lead to serious complications, including bladder carcinoma. Although it is recommended that only bladder masses not regressing within 6 months after praziquantel intake should be investigated invasively, cystoendoscopy is still often performed at diagnosis even in the absence of further signs of concern. No prospective study so far evaluated the evolution of bladder lesions after treatment in case of no risk of reinfection, which could inform case management. METHODS: Adult African migrants with active S. haematobium infection, as assessed by positive urine PCR or microscopy for eggs in urine or bladder biopsy, underwent urinary tract ultrasound at enrolment and at 1, 3, 6, 12 and 24 months after praziquantel treatment. Patients in advanced pregnancy or with known Schistosoma-unrelated chronic pathology of the urinary tract were excluded. RESULTS: Twenty-one patients, aged 18-29 years, participated in the study; ten (47.6%) had bladder masses on ultrasound. Follow-up ≥6 months was completed by 16 (76.2%) patients; ≥12 months by 14 (66.7%) and 24 months by 11 (52.4%). All patients with bladder lesions on enrolment completed a follow-up of ≥6 months. Lesions resolved completely by 6 months in all cases and no new development/re-appearance was observed. CONCLUSIONS: This is the first prospective, long-term follow-up study with ultrasound of patients with urinary schistosomiasis outside endemic areas. Mucosal masses in young patients regressed after treatment without recurrence, supporting the recommendation that invasive procedures should be avoided unless lesions or other symptoms/signs of concern persist for > 6 months. Further studies should assess the evolution of bladder lesions after treatment in larger populations, including older age groups, and, ideally, with parallel assessment of other biomarkers of urinary pathology and of residual S. haematobium active infection.

SARS-CoV-2 Infection, Risk Perception, Behaviour and Preventive Measures at Schools in Berlin, Germany, during the Early Post-Lockdown Phase: A Cross-Sectional Study.

Briefly before the first peak of the COVID-19 pandemic in Berlin, Germany, schools closed in mid-March 2020. Following re-opening, schools resumed operation at a reduced level for nine weeks. During this phase, we aimed at assessing, among students and teachers, infection status, symptoms, individual behaviour, and institutional infection prevention measures. Twenty-four primary and secondary school classes, randomly selected across Berlin, were examined. Oro-nasopharyngeal swabs and capillary blood samples were collected to determine SARS-CoV-2 infection (PCR) and specific IgG (ELISA), respectively. Medical history, household characteristics, leisure activities, fear of infection, risk perception, hand hygiene, facemask wearing, and institutional preventive measures were assessed. Descriptive analysis was performed. Among 535 participants (385 students, 150 staff), one teenager was found to be infected with SARS-CoV-2 (0.2%), and seven individuals exhibited specific IgG (1.3%). Compared to pre-pandemic times, screen time (e.g., TV, gaming, social media) increased, and the majority of primary school students reported reduced physical activity (42.2%). Fear of infection and risk perception were relatively low, acceptance of adapted health behaviors was high. In this post-lockdown period of low SARS-CoV-2 incidence in Berlin, individual and school-level infection prevention measures were largely adhered to. Nevertheless, vigilance and continued preventive measures are essential to cope with future pandemic activity.

Treatment of a giant hepatic echinococcal cyst with percutaneous drainage and in vivo assessment of the protoscolicidal effect of praziquantel.

Therapy choices for cystic echinococcisis (CE) are stage-specific: surgical, minimally invasive, medical or observation without intervention. PAIR (percutaneous aspiration, instillation of a scolicide, and re-aspiration) has been considered the treatment of choice for uncomplicated echinococcal liver cysts. However, PAIR carries the risk of toxic cholangitis or hypernatremia and that the cyst frequently refills with bile after withdrawing the catheter. We treated a patient with a giant CE 1 liver cyst with puncture drainage (PD) under albendazole coverage. Drainage enabled us to monitor the morphology of protoscolices under praziquantel (PZQ) co-medication. Protoscolices degenerated within 5 days of PZQ 50 mg/kg/d. The cyst cavity solidified with no evidence of reactivation or secondary spread. Percutaneous treatments can replace surgery in a significant number or cases with hepatic CE. PD allows to assess microscopically the viability of protoscolices under co-medication with PZQ-albendazole and to avoid the instillation of topical scolicides.

Diagnosis and clinical management of hepatosplenic schistosomiasis: A scoping review of the literature.

BACKGROUND: Hepatosplenic schistosomiasis (HSS) is a disease caused by chronic infection with Schistosma spp. parasites residing in the mesenteric plexus; portal hypertension causing gastrointestinal bleeding is the most dangerous complication of this condition. HSS requires complex clinical management, but no specific guidelines exist. We aimed to provide a comprehensive picture of consolidated findings and knowledge gaps on the diagnosis and treatment of HSS. METHODOLOGY/PRINCIPAL FINDINGS: We reviewed relevant original publications including patients with HSS with no coinfections, published in the past 40 years, identified through MEDLINE and EMBASE databases. Treatment with praziquantel and HSS-associated pulmonary hypertension were not investigated. Of the included 60 publications, 13 focused on diagnostic aspects, 45 on therapeutic aspects, and 2 on both aspects. Results were summarized using effect direction plots. The most common diagnostic approaches to stratify patients based on the risk of variceal bleeding included the use of ultrasonography and platelet counts; on the contrary, evaluation and use of noninvasive tools to guide the choice of therapeutic interventions are lacking. Publications on therapeutic aspects included treatment with beta-blockers, local management of esophageal varices, surgical procedures, and transjugular intrahepatic portosystemic shunt. Overall, treatment approaches and measured outcomes were heterogeneous, and data on interventions for primary prevention of gastrointestinal bleeding and on the long-term follow-up after interventions were lacking. CONCLUSIONS: Most interventions have been developed on the basis of individual groups' experiences and almost never rigorously compared; furthermore, there is a lack of data regarding which parameters can guide the choice of intervention. These results highlight a dramatic need for the implementation of rigorous prospective studies with long-term follow-up in different settings to fill such fundamental gaps, still present for a disease affecting millions of patients worldwide.

Suitability of current typing procedures to identify epidemiologically linked human Giardia duodenalis isolates.

BACKGROUND: Giardia duodenalis is a leading cause of gastroenteritis worldwide. Humans are mainly infected by two different subtypes, i.e., assemblage A and B. Genotyping is hampered by allelic sequence heterozygosity (ASH) mainly in assemblage B, and by occurrence of mixed infections. Here we assessed the suitability of current genotyping protocols of G. duodenalis for epidemiological applications such as molecular tracing of transmission chains. METHODOLOGY/PRINCIPAL FINDINGS: Two G. duodenalis isolate collections, from an outpatient tropical medicine clinic and from several primary care laboratories, were characterized by assemblage-specific qPCR (TIF, CATH gene loci) and a common multi locus sequence typing (MLST; TPI, BG, GDH gene loci). Assemblage A isolates were further typed at additional loci (HCMP22547, CID1, RHP26, HCMP6372, DIS3, NEK15411). Of 175/202 (86.6%) patients the G. duodenalis assemblage could be identified: Assemblages A 25/175 (14.3%), B 115/175 (65.7%) and A+B mixed 35/175 (20.0%). By incorporating allelic sequence heterozygosity in the analysis, the three marker MLST correctly identified 6/9 (66,7%) and 4/5 (80.0%) consecutive samples from chronic assemblage B infections in the two collections, respectively, and identified a cluster of five independent patients carrying assemblage B parasites of identical MLST type. Extended MLST for assemblage A altogether identified 5/6 (83,3%) consecutive samples from chronic assemblage A infections and 15 novel genotypes. Based on the observed A+B mixed infections it is estimated that only 75% and 50% of assemblage A or B only cases represent single strain infections, respectively. We demonstrate that typing results are consistent with this prediction. CONCLUSIONS/SIGNIFICANCE: Typing of assemblage A and B isolates with resolution for epidemiological applications is possible but requires separate genotyping protocols. The high frequency of multiple infections and their impact on typing results are findings with immediate consequences for result interpretation in this field.

Cutaneous leishmaniasis in refugees from Syria: complex cases in Berlin 2015-2020.

BACKGROUND: The Syrian conflict has led to a dramatic increase of Old World cutaneous leishmaniasis (CL), triggered by continuous population displacements, disrupted control programmes, poor shelter and sanitation. METHODS: A retrospective patient record study was conducted at the Institute of Tropical Medicine and International Health in Berlin. Records of all refugees from Syria treated for CL between January 2015 and March 2020 were reviewed. RESULTS: Twenty refugees from Syria were treated. Seventeen refugees (85%) had complex lesions, mainly due to previous therapy failure or localization on the face. A long disease duration (50% > 1 year), pronounced facial scarring (20%), recurrences (20%), or worsening of existing lesions (20%) were observed. Nine patients (45%) had been pretreated in Syria. Complete remission was achieved in 10 of 16 patients (63%) treated with perilesional antimony. Eight patients (40%) required systemic treatment, thereof four (20%) repeated systemic treatment. Eight patients (40%) reported a delay of therapy ≥3 months in Germany, thereof one patient with a delay of 12 months and one patient with a delay of 32 months. CONCLUSION: Between 2015 and 2020, Syrian refugees presented with severe morbidities of CL frequently requiring systemic and even consecutive systemic treatments. We assume a combination of socioeconomic and environmental factors associated with the ongoing Syrian conflict and migration to be responsible for the complex clinical presentations in this case series. More attention should be drawn to the situation of Syrian refugees with CL in countries where they are displaced to.

Cystic echinococcosis, review and illustration of non-hepatic manifestations.

Cystic echinococcosis (CE) or hydatidosis (hydatid cysts), is an infection with a wide spectrum of manifestations, from asymptomatic infection to fatal disease. Ultrasound (US) allows screening, diagnosis, differential diagnosis, treatment guidance and follow-up of CE under many circumstances. Hydatid cysts are predominantly observed in the liver but many other organs can be involved. As part of a series of publications, herewith we present a review describing the characteristic imaging features of the broad variety of organs which can be involved.

Cystic and alveolar echinococcosis of the hepatobiliary tract - the role of new imaging techniques for improved diagnosis.

Cystic echinococcosis (CE) or hydatidosis (hydatid cysts) is an infection with a wide spectrum of manifestations, from symptomatic infection to fatal disease. Ultrasound (US) allows screening, diagnosis, differential diagnosis, treatment guidance and follow-up of CE under many circumstances. Hydatid cysts are predominantly observed in the liver. Herewith we present a review to demonstrate established and innovative imaging features of CE of the hepatobiliary tract.

Can we be sure that the human Plasmodium exoerythrocytic developmental stages occur exclusively in the liver?

The development cycle of the malaria parasite, Plasmodium sp., in humans takes place after an infected female Anopheles mosquito injects motile infective forms called sporozoites into the bloodstream. Sporozoites migrate via blood vessels to the liver. This pre-erythrocytic tissue stage is widely accepted to occur in humans exclusively in the liver, contrary to avian malaria where this may occur also in other parenchymatous organs. This concept is based on research conducted by English researchers Henry Shortt and P.C.C. Garnham in the late 1940s. Although Italian researchers as, e.g., Giulio Raffaele, additionally claimed the presence of the parasites in the bone marrow, this is not well acknowledged. So, the question remains whether there exists also a tissue life cycle stage in humans.