Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial.

BACKGROUND: Anaemia affects 46% of pregnancies in Africa; oral iron is recommended by WHO but uptake and adherence are suboptimal. We tested a single dose of a modern intravenous iron formulation, ferric carboxymaltose, for anaemia treatment in Malawian pregnant women. METHODS: In this open-label, individually randomised controlled trial, we enrolled women with a singleton pregnancy of 13-26 weeks' gestation in primary care and outpatient settings across two regions in southern Malawi. Women were eligible if they had capillary haemoglobin of less than 10·0 g/dL and negative malaria rapid diagnostic test. Participants were randomised by sealed envelope 1:1. Assessors for efficacy outcomes (laboratory parameters and birthweight) were masked to intervention; participants and study nurses were not masked. Participants were given ferric carboxymaltose up to 1000 mg (given once at enrolment in an outpatient primary care setting), or standard of care (60 mg elemental iron twice daily for 90 days), along with intermittent preventive malaria treatment. The primary maternal outcome was anaemia at 36 weeks' gestation. The primary neonatal outcome was birthweight. Analyses were performed in the intention-to-treat population for mothers and liveborn neonates, according to their randomisation group. Safety outcomes included incidence of adverse events during infusion and all adverse events from randomisation to 4 weeks' post partum. The trial is registered with ANZCTR, ACTRN12618001268235. The trial has completed follow-up. FINDINGS: Between Nov 12, 2018, and March 2, 2021, 21 258 women were screened, and 862 randomly assigned to ferric carboxymaltose (n=430) or standard of care (n=432). Ferric carboxymaltose did not reduce anaemia prevalence at 36 weeks' gestation compared with standard of care (179 [52%] of 341 in the ferric carboxymaltose group vs 189 [57%] of 333 in the standard of care group; prevalence ratio [PR] 0·92, 95% CI 0·81 to 1·06; p=0·27). Anaemia prevalence was numerically lower in mothers randomly assigned to ferric carboxymaltose compared with standard of care at all timepoints, although significance was only observed at 4 weeks' post-treatment (PR 0·91 [0·85 to 0·97]). Birthweight did not differ between groups (mean difference -3·1 g [-75·0 to 68·9, p=0·93). There were no infusion-related serious adverse events or differences in adverse events by any organ class (including malaria; ≥1 adverse event: ferric carboxymaltose 183 [43%] of 430 vs standard of care 170 [39%] of 432; risk ratio 1·08 [0·92 to 1·27]; p=0·34). INTERPRETATION: In this malaria-endemic sub-Saharan African setting, treatment of anaemic pregnant women with ferric carboxymaltose was safe but did not reduce anaemia prevalence at 36 weeks' gestation or increase birthweight. FUNDING: Bill & Melinda Gates Foundation (INV-010612).

Iron homeostasis governs erythroid phenotype in polycythemia vera.

Polycythemia vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentrations, placing them at risk of life-threatening thrombotic events. Our genome-wide association study of 440 PV cases and 403 351 controls using UK Biobank data showed that single nucleotide polymorphisms in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed overrepresentation of homozygous HFE variants in patients with PV. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of mouse models of PV, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Furthermore, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130-coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

Preanalytic and analytic factors affecting the measurement of haemoglobin concentration: impact on global estimates of anaemia prevalence.

The accuracy of haemoglobin concentration measurements is crucial for deriving global anaemia prevalence estimates and monitoring anaemia reduction strategies. In this analysis, we examined and quantified the factors affecting preanalytic and analytic variation in haemoglobin concentrations. Using cross-sectional data from three field studies (in children, pregnant and nonpregnant women), we examined the difference in haemoglobin concentration between venous-drawn and capillary-drawn blood measured by HemoCue (ie, preanalytic) and modelled how the bias observed may affect anaemia prevalence estimates in population surveys and anaemia public health severity classification across countries. Using data from an international quality assurance programme, we examined differences due to instrumentation from 16 different haematology analyzers (ie, analytic). Results indicated that capillary and venous haemoglobin concentrations are not in agreement (bias +5.7 g/L (limits of agreement (LoA) -11.2, 22.6) in preschool age children; range from -28 g/L to +20 g/L in pregnant women; bias +8.8 g/L (LoA -5.2, 22.9) in non-pregnant women). The bias observed could introduce changes in population survey estimates of anaemia of up to -20.7 percentage points in children and -28.2 percentage points in non-pregnant women after venous adjustment. Analytic variation was minimal and unlikely to influence the diagnosis of anaemia. These findings suggest that global estimates of anaemia prevalence derived from capillary haemoglobin, as they often are, may be inaccurate and lead to erroneous public health severity classification, but that point-of-care, or other, instruments should not introduce variation if properly used.

Re-examining ferritin-bound iron: current and developing clinical tools.

Iron is a highly important metal ion cofactor within the human body, necessary for haemoglobin synthesis, and required by a wide range of enzymes for essential metabolic processes. Iron deficiency and overload both pose significant health concerns and are relatively common world-wide health hazards. Effective measurement of total iron stores is a primary tool for both identifying abnormal iron levels and tracking changes in clinical settings. Population based data is also essential for tracking nutritional trends. This review article provides an overview of the strengths and limitations associated with current techniques for diagnosing iron status, which sets a basis to discuss the potential of a new serum marker - ferritin-bound iron - and the improvement it could offer to iron assessment.

High burden of infectious disease and antibiotic use in early life in Australian Aboriginal communities.

OBJECTIVE: To quantify the childhood infectious disease burden and antibiotic use in the Northern Territory's East Arnhem region through synthesis and analysis of historical data resources. METHODS: We combined primary health clinic data originally reported in three separate publications stemming from the East Arnhem Healthy Skin Project (Jan-01 to Sep-07). Common statistical techniques were used to explore the prevalence of infectious conditions and the seasonality of infections, and to measure rates of antibiotic use. RESULTS: There was a high monthly prevalence of respiratory (mean: 32% [95% confidence interval (CI): 20%, 34%]) and skin (mean: 20% [95%CI: 19%, 22%]) infectious syndromes, with upper respiratory tract infections (mean: 29% [95%CI: 27%, 31%]) and skin sores (mean: 15% [95%CI: 14%, 17%]) the most common conditions. Antibiotics were frequently prescribed with 95% (95%CI: 91%, 97%) of children having received at least one antibiotic prescription by their first birthday, and 47% having received six antibiotic prescriptions; skin sores being a key driver. CONCLUSIONS: Early life infections drive high antibiotic prescribing rates in remote Aboriginal communities. Implications for public health: Eliminating skin disease could reduce antibiotic use by almost 20% in children under five years of age in this population.

Role of bone marrow biopsy for fever of unknown origin in the contemporary Australian context.

BACKGROUND: Bone marrow biopsy (BMB) is an accepted investigation in fever of unknown origin (FUO) to uncover haematological malignancies, such as lymphoma, and sometimes infections. With the advance in imaging modalities, such as 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to identify the focus of lymphoma, BMB may not contribute to the diagnosis when there are no other clinical features to suggest an underlying haematological disease. AIM: To investigate the utility of BMB in determining the cause of FUO, when there are no other indications for BMB. METHODS: Medical records of adult patients who had BMB performed for FUO or febrile illness from 1 January 2005 to 31 December 2014 in four metropolitan tertiary hospitals in Melbourne, Australia were reviewed. Patients with other concurrent indications for BMB, known human immunodeficiency virus infection and previously diagnosed connective tissue diseases were excluded. RESULTS: Seventy-three patients were included in the study. Fifty-one patients had a final diagnosis for fever (systemic inflammatory diseases, infective, malignancy or other) while 22 patients had no diagnoses. In only 10 patients (13.7%) did BMB contribute to the diagnosis, finding either malignancy or granulomata. However, all these diagnoses could have been made without BMB. Two patients with diffuse large B-cell lymphoma had normal BMB. FDG-PET was helpful in making a diagnosis in eight (25%) out of 32 patients. CONCLUSION: Performing BMB in patients with FUO and no other haematological abnormalities is of very limited value, and other investigations, such as FDG-PET, may be more likely to help establish a definitive diagnosis.

Revisiting acquired aplastic anaemia: current concepts in diagnosis and management.

Acquired aplastic anaemia is a rare, serious, immunologically mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful attention and investigation, including molecular testing, is required to confirm the diagnosis and exclude other mimicking conditions, such as inherited bone marrow failure syndromes. In a proportion of patients, the disease evolves to myelodysplasia or acute myeloid leukaemia and in some there is an association with paroxysmal nocturnal haemoglobinuria. The disease has a major impact on patient quality of life. Haemopoietic stem/progenitor cell transplantation for eligible patients with an available donor is the only current curative therapy. Other patients may receive immunosuppression, most commonly with anti-thymocyte globulin and cyclosporin. An initial response to immunosuppression is often encouraging, but relapse is common. Supportive care, including management of transfusion requirements and infections, is central to management. Promising new diagnostic tools and emerging therapies will likely transform approaches to this important, chronic and life-threatening condition.

Scabies and risk of skin sores in remote Australian Aboriginal communities: A self-controlled case series study.

BACKGROUND: Skin sores caused by Group A streptococcus (GAS) infection are a major public health problem in remote Aboriginal communities. Skin sores are often associated with scabies, which is evident in scabies intervention programs where a significant reduction of skin sores is seen after focusing solely on scabies control. Our study quantifies the strength of association between skin sores and scabies among Aboriginal children from the East Arnhem region in the Northern Territory. METHODS AND RESULTS: Pre-existing datasets from three published studies, which were conducted as part of the East Arnhem Healthy Skin Project (EAHSP), were analysed. Aboriginal children were followed from birth up to 4.5 years of age. Self-controlled case series design was used to determine the risks, within individuals, of developing skin sores when infected with scabies versus when there was no scabies infection. Participants were 11.9 times more likely to develop skin sores when infected with scabies compared with times when no scabies infection was evident (Incidence Rate Ratio (IRR) 11.9; 95% CI 10.3-13.7; p<0.001), and this was similar across the five Aboriginal communities. Children had lower risk of developing skin sores at age ≤1 year compared to at age >1 year (IRR 0.8; 95% CI 0.7-0.9). CONCLUSION: The association between scabies and skin sores is highly significant and indicates a causal relationship. The public health importance of scabies in northern Australia is underappreciated and a concerted approach is required to recognise and eliminate scabies as an important precursor of skin sores.

Thrombotic microangiopathy associated with intravenous injection of extended-release oxycodone.

We describe the case of a 35-year-old man presenting with thrombotic microangiopathy (TMA) and renal impairment following, as he later disclosed, intravenous injection of oral formulation tamper-resistant extended-release oxycodone hydrochloride (Oxycontin). Recurrent misuse of this agent was associated with relapsing TMA despite treatment with terminal complement inhibitor eculizumab. Cases of TMA have been reported in the USA in association with intravenous misuse of extended-release oxymorphone (Opana ER) after the introduction of a new non-crushable formulation in 2012. There are two reported accounts of TMA associated with tamper-resistant Oxycontin, which became available in Australia in 2014. This is the first documented case in which eculizumab was used. This case illustrates the practical diagnostic challenges in identifying TMA disorders, and the importance of a detailed drug history. It also highlights the need to clarify what role, if any, eculizumab therapy has in cases of drug-associated TMA.

Neurolymphomatosis: MRI and (18) FDG-PET features.

Neurolymphomatosis (NL) is a rare presentation of lymphoma or leukemic infiltration of cranial or peripheral nerves. It is distinct from subarachnoid seeding of lymphoma as well as perineural tumour seen in epidural lymphoma. This rare condition has been reported mainly in oncology literature. Imaging features of solitary nerve involvement mimics, among others, peripheral nerve sheath tumours. We present the MRI and (18) fluorodeoxyglucose positron emission tomography ((18) FDG-PET) features of three cases of NL. MRI demonstrated variable appearances: infiltrative mass displacing neural fascicles, diffuse thickening and enhancement, and thickening of individual neural fascicles. (18) FDG-PET demonstrated avid uptake in all cases, two of which revealed skip lesions of the same nerve. The diagnosis of NL was confirmed by uncomplicated CT-guided biopsy of the affected sciatic nerve in one patient.

Clinic attendances during the first 12 months of life for Aboriginal children in five remote communities of northern Australia.

BACKGROUND: The vast majority (>75%) of Aboriginal people in the Northern Territory (NT) live in remote or very remote locations. Children in these communities have high attendance rates at local Primary Health Care (PHC) centres but there is a paucity of studies documenting the reason and frequency of attendance. Such data can be used to help guide public health policy and practice. METHODS AND FINDINGS: Clinic presentations during the first year of life were reviewed for 320 children born from 1 January 2001-31 December 2006. Data collected included reason for infectious presentation, antibiotic prescription and referral to hospital. The median number of presentations per child in the first year of life was 21 (IQR 15-29) with multiple reasons for presentation. The most prominent infectious presentations per child during the first year of life were upper respiratory tract infections (median 6, IQR 3-10); diarrhoea (median 3, IQR 1-5); ear disease (median 3, IQR 1-5); lower respiratory tract infection (median 3, IQR 2-5); scabies (median 3, IQR 1-5); and skin sores (median 3, IQR 2-5). CONCLUSIONS: Infectious diseases of childhood are strongly linked with poverty, poor living conditions and overcrowding. The data reported in our study were collected through manual review, however many remote communities now have established electronic health record systems, use the Key Performance Indicator System and are engaged in CQI (continuous quality improvement) processes. Building on these recent initiatives, there is an opportunity to incorporate routine monitoring of a range of infectious conditions (we suggest diarrhoea, LRTI, scabies and skin sores) using both the age at first presentation and the median number of presentations per child during the first year of life as potential indicators of progress in addressing health inequities in remote communities.

Skin disease in the first two years of life in Aboriginal children in East Arnhem Land.

BACKGROUND: The most common skin infections affecting children in remote Aboriginal communities are scabies and impetigo. Group A streptococcal skin infections are linked to the high rates of heart and renal disease occurring in Aboriginal Australians. METHODS: A retrospective review of medical records was conducted in a primary health care centre in the East Arnhem region of the Northern Territory. Data was collected from all presentations to the clinic in the first 2 years of life for 99 children born between 2001 and 2005 as a component of the East Arnhem Regional Healthy Skin Project. RESULTS: The median number of presentations to the clinic in the first 2 years of life was 32. Skin disease was recorded in 22% of all presentations. By 1 year of age 82% of children had presented to the clinic with their first episode of impetigo and 68% with their first episode of scabies. Antibiotics were administered to 49% of children with impetigo. CONCLUSION: Skin infections are a major reason for presentation to primary health clinics and contribute to the high disease burden experienced by children in the first 2 years of life. This high frequency of presentation provides multiple opportunities for intervention and monitoring.

Disease burden and health-care clinic attendances for young children in remote aboriginal communities of northern Australia.

OBJECTIVE: To determine the frequency of presentations and infectious-disease burden at primary health care (PHC) services in young children in two remote Aboriginal communities in tropical northern Australia. METHODS: Children born after 1 January 2001, who were resident at 30 September 2005 and for whom consent was obtained, were studied. Clinic records were reviewed for all presentations between 1 January 2002 and 30 September 2005. Data collected included reason for presentation (if infectious), antibiotic prescription and referral to hospital. FINDINGS: There were 7273 clinic presentations for 174 children aged 0-4.75 years, 55% of whom were male. The median presentation rate per child per year was 16 (23 in the first year of life). Upper-respiratory-tract infections (32%) and skin infections (18%) were the most common infectious reasons for presentation. First presentations for scabies and skin sores peaked at the age of 2 months. By 1 year of age, 63% and 69% of children had presented with scabies and skin sores, respectively. CONCLUSION: These Aboriginal children average about two visits per month to PHC centres during their first year of life. This high rate is testament to the disease burden, the willingness of Aboriginal people to use health services and the high workload experienced by these health services. Scabies and skin sores remain significant health problems, with this study describing a previously undocumented burden of these conditions commencing within the first few months of life. Appropriate prevention and treatment strategies should encompass early infancy to reduce the high burden of infectious diseases in this population.