A woman in her seventies with fever and convulsions. / En kvinne i 70-årene med feber og krampeanfall.

Background: Chagas encephalitis is a rare but severe manifestation of reactivation in patients with chronic Chagas disease. Case presentation: A woman in her seventies who was immunosuppressed after a heart transplant due to Chagas disease was admitted with convulsions, headache and visual disturbances. She developed fever, confusion and repeated convulsions. Pleocytosis was found in spinal fluid. Wet-mount microscopy of spinal fluid revealed motile Trypanosoma cruzi trypomastigotes, and multiple trypomastigotes were seen on a Giemsa-stained smear, confirming reactivation of Chagas disease with meningoencephalitis. Despite benznidazole treatment, she deteriorated, exhibiting pharyngeal paralysis, aphasia and increasing somnolence. Brain CT showed pathology consistent with Chagas encephalitis. Nifurtimox was given as an adjunctive treatment. After a week of treatment, the patient began to improve. She completed 60 days of benznidazole and had regained normal cognitive and neurological function on subsequent follow-up. She had no signs of myocarditis reactivation. Interpretation: Chronic Chagas disease is common among Latin American immigrants in Europe. Reactivation with myocarditis after a heart transplant is well known, while encephalitis is a rare manifestation. We report on a case of Chagas encephalitis in an immunosuppressed patient. Microscopy of parasites in spinal fluid revealed the diagnosis. The WHO provided antiparasitic medications, and despite a severe prognosis, the patient made a full recovery.

A man in his sixties with life-threatening febrile illness after travel abroad. / Ein mann i 60-åra med livstrugande febersjukdom etter utanlandsreise.

Background: African sleeping sickness is a neglected tropical disease seldom seen in European travellers. Case presentation: While working in Eastern Africa, a Norwegian man in his sixties developed weakness and fever. He was prescribed doxycycline after a negative malaria rapid test. On the third day of illness he returned to Norway and was admitted to the hospital upon arrival. On admission he was somnolent with fever, tachypnoea, tachycardia, jaundice, a hyperaemic rash, oliguria and haematuria. Blood tests revealed leukopenia, thrombocytopaenia, renal failure and liver dysfunction. Rapid tests were negative for malaria and dengue. Blood microscopy revealed high parasitaemia with trypanosomes indicating human African sleeping-sickness. He had been bitten by a tsetse fly 11 days prior in an area endemic for Trypanosoma brucei gambiense. However, the clinical picture was consistent with Trypanosoma brucei rhodesiense infection (East African sleeping sickness). Four days after starting treatment with suramin, spinal fluid examination revealed mild mononuclear pleocytosis but no visible parasites. Melarsoprol treatment for possible encephalitis was considered but suramin treatment was continued alone. He improved and remains healthy seven years later. PCR on blood was positive for T. b. rhodesiense. Interpretation: African sleeping sickness can also affect tourists to endemic areas. Onset can be acute, life-threatening and requires treatment with antiparasitic drugs not generally available in Norwegian hospitals.

Complete recovery after fulminant myocarditis in a patient with COVID-19.

The clinical spectrum of Coronavirus disease 2019 (COVID-19) varies from asymptomatic infection to severe disease with multiorgan dysfunction. Cardiovascular involvement is common and in rare cases can lead to serious complications, such as fulminant myocarditis. The clinical course of COVID-19 myocarditis varies from complete recovery to death in rare cases. The pathophysiology of COVID-19-related myocarditis is still unclear but is believed to involve direct viral injury and cardiac damage due to the host's immune response. Guidelines on the management of COVID-19-related myocarditis are yet to be established. We present here the case of a male patient in his early fifties admitted with life-threatening myocarditis in the course of COVID-19 infection who was successfully treated and recovered without any sequelae.

Symptom Burden and Immune Dynamics 6 to 18 Months Following Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2): A Case-control Study.

BACKGROUND: The burden and duration of persistent symptoms after nonsevere coronavirus disease 2019 (COVID-19) remains uncertain. This study aimed to assess postinfection symptom trajectories in home-isolated COVID-19 cases compared with age- and time- matched seronegative controls, and investigate immunological correlates of long COVID. METHODS: A prospective case-control study included home-isolated COVID-19 cases between February 28 and April 4, 2020, and followed for 12 (n = 233) to 18 (n = 149) months, and 189 age-matched severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive controls. We collected clinical data at baseline, 6, 12, and 18 months postinfection, and blood samples at 2, 4, 6, and 12 months for analysis of SARS-CoV-2-specific humoral and cellular responses. RESULTS: Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared with controls, adult cases had a high risk of fatigue (27% excess risk, sex, and comorbidity adjusted odds ratio [aOR] 5.86; 95% confidence interval [CI], 3.27-10.5), memory problems (21% excess risk; aOR 7.42; CI, 3.51-15.67), concentration problems (20% excess risk; aOR 8.88; 95% CI, 3.88-20.35), and dyspnea (10% excess risk; aOR 2.66; 95% CI, 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%; 95% CI, 1.5-21.5; P = .024) and among women (excess risk 18.7%; 95% CI, 4.4-32.9; P = .010). Longitudinal spike immunoglobulin G was significantly associated with dyspnea at 12 months. The spike-specific clonal CD4+ T-cell receptor ß depth was significantly associated with both dyspnea and number of symptoms at 12 months. CONCLUSIONS: This study documents a high burden of persisting symptoms after mild COVID-19 and suggests that infection induced SARS-CoV-2-specific immune responses may influence long-term symptoms.

Fluoroquinolone resistance among fecal extended spectrum ßeta lactamases positive Enterobacterales isolates from children in Dar es Salaam, Tanzania.

BACKGROUND: Fluoroquinolones have been, and continue to be, routinely used for treatment of many bacterial infections. In recent years, most parts of the world have reported an increasing trend of fluoroquinolone resistant (FQR) Gram-negative bacteria. METHODS: A cross-sectional study was conducted between March 2017 and July 2018 among children admitted due to fever to referral hospitals in Dar es Salaam, Tanzania. Rectal swabs were used to screen for carriage of extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-PE). ESBL-PE isolates were tested for quinolone resistance by disk diffusion method. Randomly selected fluroquinolone resistant isolates were characterized by using whole genome sequencing. RESULTS: A total of 142 ESBL-PE archived isolates were tested for fluoroquinolone resistance. Overall phenotypic resistance to ciprofloxacin, levofloxacin and moxifloxacin was found in 68% (97/142). The highest resistance rate was seen among Citrobacter spp. (100%, 5/5), followed by Klebsiella. pneumoniae (76.1%; 35/46), Escherichia coli (65.6%; 42/64) and Enterobacter spp. (31.9%; 15/47). Whole genome sequencing (WGS) was performed on 42 fluoroquinolone resistant-ESBL producing isolates and revealed that 38/42; or 90.5%, of the isolates carried one or more plasmid mediated quinolone resistance (PMQR) genes. The most frequent PMQR genes were aac(6')-lb-cr (74%; 31/42), followed by qnrB1 (40%; 17/42), oqx, qnrB6 and qnS1. Chromosomal mutations in gyrA, parC and parE were detected among 19/42 isolates, and all were in E. coli. Most of the E. coli isolates (17/20) had high MIC values of > 32 µg/ml for fluoroquinolones. In these strains, multiple chromosomal mutations were detected, and all except three strains had additional PMQR genes. Sequence types, ST131 and ST617 predominated among E. coli isolates, while ST607 was more common out of 12 sequence types detected among the K. pneumoniae. Fluoroquinolone resistance genes were mostly associated with the IncF plasmids. CONCLUSION: The ESBL-PE isolates showed high rates of phenotypic resistance towards fluoroquinolones likely mediated by both chromosomal mutations and PMQR genes. Chromosomal mutations with or without the presence of PMQR were associated with high MIC values in these bacteria strains. We also found a diversity of PMQR genes, sequence types, virulence genes, and plasmid located antimicrobial resistance (AMR) genes towards other antimicrobial agents.

Genetic determinants of macrolide and tetracycline resistance in penicillin non-susceptible Streptococcus pneumoniae isolates from people living with HIV in Dar es Salaam, Tanzania.

BACKGROUND: Over one million yearly deaths are attributable to Streptococcus pneumoniae and people living with HIV are particularly vulnerable. Emerging penicillin non-susceptible Streptococcus pneumoniae (PNSP) challenges therapy of pneumococcal disease. The aim of this study was to determine the mechanisms of antibiotic resistance among PNSP isolates by next generation sequencing. METHODS: We assessed 26 PNSP isolates obtained from the nasopharynx from 537 healthy human immunodeficiency virus (HIV) infected adults in Dar es Salaam, Tanzania, participating in the randomized clinical trial CoTrimResist (ClinicalTrials.gov identifier: NCT03087890, registered on 23rd March, 2017). Next generation whole genome sequencing on the Illumina platform was used to identify mechanisms of resistance to antibiotics among PNSP. RESULTS: Fifty percent (13/26) of PNSP were resistant to erythromycin, of these 54% (7/13) and 46% (6/13) had MLSB phenotype and M phenotype respectively. All erythromycin resistant PNSP carried macrolide resistance genes; six isolates had mef(A)-msr(D), five isolates had both erm(B) and mef(A)-msr(D) while two isolates carried erm(B) alone. Isolates harboring the erm(B) gene had increased MIC (> 256 µg/mL) towards macrolides, compared to isolates without erm(B) gene (MIC 4-12 µg/mL) p < 0.001. Using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines, the prevalence of azithromycin resistance was overestimated compared to genetic correlates. Tetracycline resistance was detected in 13/26 (50%) of PNSP and all the 13 isolates harbored the tet(M) gene. All isolates carrying the tet(M) gene and 11/13 isolates with macrolide resistance genes were associated with the mobile genetic element Tn6009 transposon family. Of 26 PNSP isolates, serotype 3 was the most common (6/26), and sequence type ST271 accounted for 15% (4/26). Serotypes 3 and 19 displayed high-level macrolide resistance and frequently carried both macrolide and tetracycline resistance genes. CONCLUSION: The erm(B) and mef(A)-msr(D) were common genes conferring resistance to MLSB in PNSP. Resistance to tetracycline was conferred by the tet(M) gene. Resistance genes were associated with the Tn6009 transposon.

Point-of-Care Influenza Testing Impacts Clinical Decision, Patient Flow, and Length of Stay in Hospitalized Adults.

BACKGROUND: Influenza is difficult to distinguish clinically from other acute respiratory infections. Rapid laboratory diagnosis can help initiate early effective antiviral treatment and isolation. Implementing a novel point-of-care test (POCT) for influenza in the emergency department (ED) could improve treatment and isolation strategies and reduce the length of stay (LOS). METHODS: In a prospective, controlled observational cohort study, we enrolled patients admitted due to acute respiratory illness to 2 public hospitals in Bergen, Norway, one using a rapid POCT for influenza (n = 400), the other (n = 167) using conventional rapid laboratory-based assay. RESULTS: Prevalence of influenza was similar in the 2 hospitals (154/400, 38% vs 38%, 63/167; P = .863). Most patients in both hospitals received antiviral (83% vs 81%; P = .703) and antibiotic treatment (72% vs 62%; P = .149). Isolation was more often initiated in ED in the hospital using POCT (91% vs 80%; P = .025). Diagnosis by POCT was associated with shorter hospital stay; old age, diabetes, cancer, and use of antibiotics, particularly broad-spectrum antibiotics, were associated with prolonged stay. CONCLUSIONS: POCT implementation in ED resulted in improved targeted isolation and shorter LOS. Regardless of POCT use, most influenza patients received antivirals (>80%) and antibiotics (>69%).

Weight gain during treatment course of allogenic hematopoietic stem cell transplantation in patients with hematological malignancies affects treatment outcome.

BACKGROUND AIMS: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for patients with hematological malignancies; however, allo-HSCT does not come without the cost of treatment-related morbidity and mortality. Early detection of risk factors could be helpful in identifying patients who could benefit from early interventions. Many patients gain weight during the allo-HSCT treatment, although little is known about the impact of weight gain. METHODS: Weight gain in 146 consecutively enrolled adult patients undergoing allo-HSCT was explored. RESULTS: In total, 141 patients (97%) gained weight along the course of allo-HSCT. Median weight increase was 4.8 kg (range 0.0-16.1 kg), with median increase in body weight 6.5% (range 0.0%-30.8%). Maximum weight increase was observed at day +7 (range day -8, +44). Weight gain was associated with increased incidence of acute graft-versus-host disease. Patients with weight gain >10% had a significantly greater 5-year mortality compared with those with lower weight gain (P = 0.031, rank sum test). CONCLUSIONS: Weight gain is a simple variable with the ability to provide prognostic information for patients undergoing allo-HSCT.

Malaria prevalence and performance of diagnostic tests among patients hospitalized with acute undifferentiated fever in Zanzibar.

BACKGROUND: Control efforts in Zanzibar reduced the burden of malaria substantially from 2000 to 2015, but re-emergence of falciparum malaria has been observed lately. This study evaluated the prevalence of malaria and performance of routine diagnostic tests among hospitalized fever patients in a 1.5 years period in 2015 and 2016. METHODS: From March 2015 to October 2016, paediatric and adult patients hospitalized with acute undifferentiated fever at Mnazi Mmoja Hospital, Zanzibar were included. The malaria prevalence, and performance of rapid diagnostic test (RDT) and microscopy, were assessed using polymerase chain reaction (PCR) as gold standard. RESULTS: The malaria prevalence was 9% (63/731). Children under 5 years old had lower malaria prevalence (5%, 14/260) than older children (15%, 20/131, p = 0.001) and persons aged 16 to 30 years (13%, 15/119, p = 0.02), but not different from persons over 30 years old (6%, 14/217, p = 0.7). All cases had Plasmodium falciparum infection, except for one case of Plasmodium ovale. Ten malaria patients had no history of visiting mainland Tanzania. The RDT had a sensitivity of 64% (36/56) and a specificity of 98% (561/575), and microscopy had a sensitivity of 50% (18/36) and  a specificity of 99% (251/254), compared to PCR. The malaria parasitaemia was lower in patients with false negative results on RDT (median 7 × 103 copies/µL, interquartile range [IQR] 2 × 103 - 8 × 104, p = 0.002) and microscopy (median 9 × 103 copies/µL, IQR 8 × 102 - 7 × 104, p = 0.006) compared to those with true positive RDT (median 2 × 105 copies/µL, IQR 3 × 104 - 5 × 105) and microscopy (median 2 × 105 copies/µL, IQR 6 × 104 - 5 × 105). CONCLUSIONS: The study emphasizes that malaria was a frequent cause of febrile illness in hospitalized patients in Zanzibar in the years 2015-2016, particularly among school age children and young adults. We found evidence of autochthonous malaria transmission in Zanzibar. Compared to PCR, both RDT and microscopy had low sensitivity, and false negative results were associated with low parasitaemia. While low parasitaemia identified only by PCR in a semi-immune individual could be coincidental and without clinical relevance, clinicians should be aware of the risk of false negative results on routine tests.

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial.

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

SARS-CoV-2-Specific Neutralizing Antibody Responses in Norwegian Health Care Workers After the First Wave of COVID-19 Pandemic: A Prospective Cohort Study.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, many countries experienced infection in health care workers (HCW) due to overburdened health care systems. Whether infected HCW acquire protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. METHODS: In a Norwegian prospective cohort study, we enrolled 607 HCW before and after the first COVID-19 wave. Exposure history, COVID-19-like symptoms, and serum samples were collected. SARS-CoV-2-specific antibodies were characterized by spike-protein IgG/IgM/IgA enzyme-linked immunosorbent and live-virus neutralization assays. RESULTS: Spike-specific IgG/IgM/IgA antibodies increased after the first wave in HCW with, but not in HCW without, COVID-19 patient exposure. Thirty-two HCW (5.3%) had spike-specific antibodies (11 seroconverted with ≥4-fold increase, 21 were seropositive at baseline). Neutralizing antibodies were found in 11 HCW that seroconverted, of whom 4 (36.4%) were asymptomatic. Ninety-seven HCW were tested by reverse transcriptase polymerase chain reaction (RT-PCR) during follow-up; 8 were positive (7 seroconverted, 1 had undetectable antibodies). CONCLUSIONS: We found increases in SARS-CoV-2 neutralizing antibodies in infected HCW, especially after COVID-19 patient exposure. Our data show a low number of SARS-CoV-2-seropositive HCW in a low-prevalence setting; however, the proportion of seropositivity was higher than RT-PCR positivity, highlighting the importance of antibody testing.

Predominance of PVL-negative community-associated methicillin-resistant Staphylococcus aureus sequence type 8 in newly diagnosed HIV-infected adults, Tanzania.

Difficult-to-treat infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are of concern in people living with HIV infection as they are more vulnerable to infection. We aimed to identify molecular characteristics of MRSA colonizing newly diagnosed HIV-infected adults in Tanzania. Individuals newly diagnosed with HIV infection were recruited in Dar es Salaam, Tanzania, from April 2017 to May 2018, as part of the randomized clinical trial CoTrimResist ( ClinicalTrials.gov identifier: NCT03087890). Nasal/nasopharyngeal isolates of Staphylococcus aureus were susceptibility tested by disk diffusion method, and cefoxitin-resistant isolates were characterized by short-reads whole genome sequencing. Four percent (22/537) of patients carried MRSA in the nose/nasopharynx. MRSA isolates were frequently resistant towards gentamicin (95%), ciprofloxacin (91%), and erythromycin (82%) but less often towards trimethoprim-sulfamethoxazole (9%). Seventy-three percent had inducible clindamycin resistance. Erythromycin-resistant isolates harbored ermC (15/18) and LmrS (3/18) resistance genes. Ciprofloxacin resistance was mediated by mutations of the quinolone resistance-determining region (QRDR) sequence in the gyrA (S84L) and parC (S80Y) genes. All isolates belonged to the CC8 and ST8-SCCmecIV MRSA clone. Ninety-five percent of the MRSA isolates were spa-type t1476, and one exhibited spa-type t064. All isolates were negative for Panton-Valentine leucocidin (PVL) and arginine catabolic mobile element (ACME) type 1. All ST8-SCCmecIV-spa-t1476 MRSA clones from Tanzania were unrelated to the globally successful USA300 clone. Carriage of ST8 MRSA (non-USA300) was common among newly diagnosed HIV-infected adults in Tanzania. Frequent co-resistance to non-beta lactam antibiotics limits therapeutic options when infection occurs.

Leishmaniasis in Norway. / Leishmaniasis i Norge.

BACKGROUND: Leishmaniasis is a rare but potentially severe tropical infectious disease, and Norwegian clinicians are generally unfamiliar with its diagnosis and treatment. This study aimed to investigate the number of cases diagnosed, performance of diagnostic methods and treatment of leishmaniasis at five university hospitals in Norway. MATERIAL AND METHOD: The number of cases, diagnosis and treatment of suspected leishmaniasis were registered prospectively in the period March 2014 - September 2017 at the university hospitals of Bergen, Oslo, Stavanger, Trondheim and Tromsø. RESULTS: A total of 13 patients with leishmaniasis were registered in the period. Visceral leishmaniasis was diagnosed in two patients infected in the Mediterranean region, after 7 and 8 weeks with symptoms. The diagnosis was made by serology as well as microscopy and/or polymerase chain reaction tests (PCR) on spleen, blood and bone marrow. Both patients were treated effectively with liposomal amphotericin B. Cutaneous leishmaniasis was diagnosed in 11 patients, and samples from 10 of these tested positive with PCR. Two patients were infected with potentially mucotropic species. Liposomal amphotericin B was the first-line choice for all those who received treatment, but one patient recovered only after local therapy with sodium stibogluconate. INTERPRETATION: Assessment of visceral leishmaniasis was undertaken according to international guidelines. The patients were diagnosed late in the disease course, presumably because the disease is rare and not well known in Norway. Cutaneous leishmaniasis was diagnosed with PCR, but none of the patients received local treatment as the first-line choice, as recommended in suitable cases, presumably because the drugs are not readily available in Norway and many clinicians are unfamiliar with the route of administration with local infiltration.

A man in his 80s with arthritis and persistent fever. / En mann i 80-årene med leddgikt og vedvarende feber.

BACKGROUND: Febrile illness is a common clinical problem and frequently caused by bacterial and viral infections. When blood cultures are negative and symptoms persist despite empirical antibiotic treatment, clinicians must consider other differential diagnoses including malignancy, rheumatologic disease and parasitic infections. CASE PRESENTATION: A Norwegian male in his eighties experienced febrile illness during a stay in Southern Spain. Upon return to Norway, he was hospitalized with fever, weight-loss, enlarged spleen, pancytopenia and hypergammaglobulinemia. After failing to respond to broad-spectrum antibiotics and antifungals, he was diagnosed with visceral leishmaniasis and Leishmania infantum was confirmed by PCR and sequencing of spleen biopsy and blood. INTERPRETATION: With increasing migration and tourism, doctors in non-endemic countries should be familiar with visceral leishmaniasis.

Delivery strategies for malaria chemoprevention with monthly dihydroartemisinin-piperaquine for the post-discharge management of severe anaemia in children aged less than 5 years old in Malawi: a protocol for a cluster randomized trial.

BACKGROUND: Children initially hospitalized with severe anaemia in Africa are at high risk of readmission or death within 6 months after discharge. No intervention strategy specifically protects children during the post-discharge period. Recent evidence from Malawi shows that 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment with artemether-lumefantrine in children with severe malarial anaemia prevented 31% of deaths and readmissions. While a confirmatory multi-centre trial for PMC with dihydroartemisinin-piperaquine is on going in Kenya and Uganda, there is a need to design and evaluate an effective delivery strategy for this promising intervention. METHODS: This is a cluster-randomized trial with 5 arms, each representing a unique PMC delivery strategy. Convalescent children aged less than 5 years and weighing more than 5 kg admitted with severe anaemia and clinically stable are included. All eligible children will receive dihydroartemisinin-piperaquine at 2, 6 and 10 weeks after discharge either: 1) in the community without an SMS reminder; 2) in the community with an SMS reminder; 3) in the community with a community health worker reminder; 4) at the hospital with an SMS reminder; or 5) at the hospital without an SMS reminder. For community-based strategies (1, 2 and 3), mothers will be given all the PMC doses at the time of discharge while for hospital-based strategies (4 and 5) mothers will be required to visit the hospital each month. Each arm will consist of 25 clusters with an average of 3 children per cluster giving approximately 75 children and will be followed up for 15 weeks. The primary outcome measure is uptake of complete courses of PMC drugs. DISCUSSION: The proposed study will help to identify the most effective, cost-effective, acceptable and feasible strategy for delivering malaria chemoprevention for post-discharge management of severe anaemia in under-five children in the Malawian context. This information is important for policy decision in the quest for new strategies for malaria control in children in similar contexts. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02721420 . Protocol registered on 29 March 2016.The study was not retrospectively registered but there was a delay between date of submission and the date it first became available on the registry.

Introducing post-discharge malaria chemoprevention (PMC) for management of severe anemia in Malawian children: a qualitative study of community health workers' perceptions and motivation.

BACKGROUND: Severe malarial anaemia is one of the leading causes of paediatric hospital admissions in Malawi. Post-discharge malaria chemoprevention (PMC) is the intermittent administration of full treatment courses of antimalarial to children recovering from severe anaemia and findings suggest that this intervention significantly reduces readmissions and deaths in these children. Community delivery of health interventions utilizing community health workers (CHWs) has been successful in some programmes and not very positive in others. In Malawi, there is an on-going cluster randomised trial that aims to find the optimum strategy for delivery of dihydroartemesinin-piperaquine (DHP) for PMC in children with severe anaemia. Our qualitative study aimed to explore the feasibility of utilizing CHWs also known as health surveillance assistants (HSAs) to remind caregivers to administer PMC medication in the existing Malawian health system. METHODS: Between December 2016 and March 2018, 20 individual in-depth-interviews (IDIs) and 2 focus group discussions (FGDs) were conducted with 39 HSAs who had the responsibility of conducting home visits to remind caregivers of children who were prescribed PMC medication in the trial. All interviews were conducted in the local language, transcribed verbatim, and translated into English. The transcripts were uploaded to NVIVO 11 and analysed using the thematic framework analysis method. RESULTS: Although intrinsic motivation was reportedly high, adherence to the required number of home visits was very poor with only 10 HSAs reporting full adherence. Positive factors for adherence were the knowledge and perception of the effectiveness of PMC and the recognition from the community as well as health system. Poor training, lack of supervision, high workload, as well as technical and structural difficulties; were reported barriers to adherence by the HSAs. CONCLUSIONS: Post-discharge malaria chemoprevention with DHP is perceived as a positive approach to manage children recovering from severe anaemia by HSAs in Malawi. However, adherence to home visit reminders was very poor and the involvement of HSAs in a scale up of this intervention may pose a challenge in the existing Malawian health system. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02721420 . The trial was registered on 26 March 2016.

Comprehensive Analysis of Prevalence, Epidemiologic Characteristics, and Clinical Characteristics of Monoinfection and Coinfection in Diarrheal Diseases in Children in Tanzania.

The role of interactions between intestinal pathogens in diarrheal disease is uncertain. From August 2010 to July 2011, we collected stool samples from 723 children admitted with diarrhea (cases) to 3 major hospitals in Dar es Salaam, Tanzania, and from 564 nondiarrheic children (controls). We analyzed the samples for 17 pathogens and assessed interactions between coinfections in additive and multiplicative models. At least one pathogen was detected in 86.9% of the cases and 62.8%, of the controls. Prevalence of coinfections was 58.1% in cases and 40.4% in controls. Rotavirus, norovirus genogroup II, Cryptosporidium, and Shigella species/enteroinvasive Escherichia coli were significantly associated with diarrhea both as monoinfections and as coinfections. In the multiplicative interaction model, we found 2 significant positive interactions: rotavirus + Giardia (odds ratio (OR) = 23.91, 95% confidence interval (CI): 1.21, 470.14) and norovirus GII + enteroaggregative E. coli (OR = 3.06, 95% CI: 1.17, 7.98). One significant negative interaction was found between norovirus GII + typical enteropathogenic E. coli (OR = 0.09, 95% CI: 0.01, 0.95). In multivariate analysis, risk factors for death were presence of blood in stool and severe dehydration. In conclusion, coinfections are frequent, and the pathogenicity of each organism appears to be enhanced by some coinfections and weakened by others. Severity of diarrhea was not affected by coinfections.

Thoracic aorta calcification but not inflammation is associated with increased cardiovascular disease risk: results of the CAMONA study.

PURPOSE: Arterial inflammation and vascular calcification are regarded as early prognostic markers of cardiovascular disease (CVD). In this study we investigated the relationship between CVD risk and arterial inflammation (18F-FDG PET/CT imaging), vascular calcification metabolism (Na18F PET/CT imaging), and vascular calcium burden (CT imaging) of the thoracic aorta in a population at low CVD risk. METHODS: Study participants underwent blood pressure measurements, blood analyses, and 18F-FDG and Na18F PET/CT imaging. In addition, the 10-year risk for development of CVD, based on the Framingham risk score (FRS), was estimated. CVD risk was compared across quartiles of thoracic aorta 18F-FDG uptake, Na18F uptake, and calcium burden on CT. RESULTS: A total of 139 subjects (52 % men, mean age 49 years, age range 21 - 75 years, median FRS 6 %) were evaluated. CVD risk was, on average, 3.7 times higher among subjects with thoracic aorta Na18F uptake in the highest quartile compared with those in the lowest quartile of the distribution (15.5 % vs. 4.2 %; P < 0.001). CVD risk was on average, 3.7 times higher among subjects with a thoracic aorta calcium burden on CT in the highest quartile compared with those in the lowest two quartiles of the distribution (18.0 % vs. 4.9 %; P < 0.001). CVD risk was similar in subjects in all quartiles of thoracic aorta 18F-FDG uptake. CONCLUSION: Our findings indicate that an unfavourable CVD risk profile is associated with marked increases in vascular calcification metabolism and vascular calcium burden of the thoracic aorta, but not with arterial inflammation.

Detection of CTX-M-15 beta-lactamases in Enterobacteriaceae causing hospital- and community-acquired urinary tract infections as early as 2004, in Dar es Salaam, Tanzania.

BACKGROUND: The spread of Extended Spectrum ß-lactamases (ESBLs) among Enterobacteriaceae and other Gram-Negative pathogens in the community and hospitals represents a major challenge to combat infections. We conducted a study to assess the prevalence and genetic makeup of ESBL-type resistance in bacterial isolates causing community- and hospital-acquired urinary tract infections. METHODS: A total of 172 isolates of Enterobacteriaceae were collected in Dar es Salaam, Tanzania, from patients who met criteria of community and hospital-acquired urinary tract infections. We used E-test ESBL strips to test for ESBL-phenotype and PCR and sequencing for detection of ESBL genes. RESULTS: Overall 23.8% (41/172) of all isolates were ESBL-producers. ESBL-producers were more frequently isolated from hospital-acquired infections (32%, 27/84 than from community-acquired infections (16%, 14/88, p < 0.05). ESBL-producers showed high rate of resistance to ciprofloxacin (85.5%), doxycycline (90.2%), gentamicin (80.5%), nalidixic acid (84.5%), and trimethoprim-sulfamethoxazole (85.4%). Furthermore, 95% of ESBL-producers were multi-drug resistant compared to 69% of non-ESBL-producers (p < 0.05). The distribution of ESBL genes were as follows: 29/32 (90.6%) bla CTX-M-15, two bla SHV-12, and one had both bla CTX-M-15 and bla SHV-12. Of 29 isolates carrying bla CTX-M-15, 69% (20/29) and 31% (9/29) were hospital and community, respectively. Bla SHV-12 genotypes were only detected in hospital-acquired infections. CONCLUSION: bla CTX-M-15 is a predominant gene conferring ESBL-production in Enterobacteriaceae causing both hospital- and community-acquired infections in Tanzania.

Acute undifferentiated fever in India: a multicentre study of aetiology and diagnostic accuracy.

BACKGROUND: The objectives of this study were to determine the proportion of malaria, bacteraemia, scrub typhus, leptospirosis, chikungunya and dengue among hospitalized patients with acute undifferentiated fever in India, and to describe the performance of standard diagnostic methods. METHODS: During April 2011-November 2012, 1564 patients aged ≥5 years with febrile illness for 2-14 days were consecutively included in an observational study at seven community hospitals in six states in India. Malaria microscopy, blood culture, Dengue rapid NS1 antigen and IgM Combo test, Leptospira IgM ELISA, Scrub typhus IgM ELISA and Chikungunya IgM ELISA were routinely performed at the hospitals. Second line testing, Dengue IgM capture ELISA (MAC-ELISA), Scrub typhus immunofluorescence (IFA), Leptospira Microscopic Agglutination Test (MAT), malaria PCR and malaria immunochromatographic rapid diagnostic test (RDT) Parahit Total™ were performed at the coordinating centre. Convalescence samples were not available. Case definitions were as follows: Leptospirosis: Positive ELISA and positive MAT. Scrub typhus: Positive ELISA and positive IFA. Dengue: Positive RDT and/or positive MAC-ELISA. Chikungunya: Positive ELISA. Bacteraemia: Growth in blood culture excluding those defined as contaminants. Malaria: Positive genus-specific PCR. RESULTS: Malaria was diagnosed in 17% (268/1564) and among these 54% had P. falciparum. Dengue was diagnosed in 16% (244/1564). Bacteraemia was found in 8% (124/1564), and among these Salmonella typhi or S. paratyphi constituted 35%. Scrub typhus was diagnosed in 10%, leptospirosis in 7% and chikungunya in 6%. Fulfilling more than one case definition was common, most frequent in chikungunya where 26% (25/98) also had positive dengue test. CONCLUSIONS: Malaria and dengue were the most common causes of fever in this study. A high overlap between case definitions probably reflects high prevalence of prior infections, cross reactivity and subclinical infections, rather than high prevalence of coinfections. Low accuracy of routine diagnostic tests should be taken into consideration when approaching the patient with acute undifferentiated fever in India.