Malaria in Children - Prevention and Management

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Malaria in Children - Prevention and Management Angela Dramowski*, Lisa Frigati, Helena Rabie and Mark Cotton Department of Paediatrics and Child Health, Division of Paediatric Infectious Diseases, Tygerberg Children’s Hospital, Stellenbosch University, South Africa Abstract: Malaria causes a quarter of all childhood deaths in Sub-Saharan Africa. Considerable gains in global malaria control have been achieved in the last decade but coverage of effective interventions remains low in areas of greatest malaria burden. Some countries have achieved reduced malaria related mortality through application of recent advances in malaria prevention and treatment of children. Artemisinin combination therapies (particularly artesunate) are highly efficacious and well-tolerated in children, although several alternative treatments are available. However, the evolution of drug resistance (including emerging resistance to artemisinin derivatives) threatens the success of malaria treatment programmes. This special issue review is aimed at paediatric clinicians in resource-poor settings and provides a summary of recent data from paediatric trials of malaria treatment and prevention interventions.

Keywords: Artesunate, children, malaria, malaria prevention, malaria treatment, plasmodium. GLOBAL BURDEN OF MALARIA Over 40% of the world’s population reside in malariaaffected areas, producing more than 200 million infections and an estimated 655 000 deaths in 2010. Deaths occur primarily among young children in Sub-Saharan Africa (>75%), contributing up to one-fifth of under-five child mortality (U5MR) in the region [1]. Despite renewed political commitment and global funding initiatives, ongoing challenges to malaria control include limited diagnostic capability, restricted treatment options, evolving anti-malarial drug resistance and vector resistance to insecticides. In the last decade however, significant reductions in global malaria burden and mortality have been achieved. Successful interventions include increased coverage of insecticide-treated nets (ITN), indoor residual spraying and increasing availability of effective treatment, particularly artemisinin-based combination therapies (ACT) [2, 3]. In addition, recent advances in intermittent preventive treatment of children (IPTc) hold promise for strengthening malaria control in endemic countries. The ultimate goal of disease eradication through an effective malaria vaccination programme remains elusive. Malaria in humans is caused by five protozoan species of the genus Plasmodium (P falciparum, P vivax, P ovale, P malariae, and P knowlesi). P falciparum is the major driver of global morbidity and mortality however in parts of Asia, P vivax is emerging as the dominant species [4]. Infection with both P vivax and P ovale (rare outside of Africa) are associated with persistent or relapsing disease because of dormancy of hepatic parasites known as hypnozoites. P malariae (although much less common) occurs in most malariaendemic areas. Infection with the zoonosis, P knowlesi occurs in South East Asia and can cause severe malaria or *Address correspondence to this author at the Department of Paediatrics and Child Health, Division of Paediatric Infectious Diseases, Tygerberg Children’s Hospital, Stellenbosch University, South Africa; Tel: 0027219385054; Fax: 0027219385065; E-mails: [email protected]; [email protected] 1871-5265/13 $58.00+.00

death [5]. Mixed infections with P falciparum and P vivax are not uncommon in South East Asia (> 20% when using PCR technology), but more likely represent reactivation of dormant P vivax infections rather that simultaneous inoculation [6]. Data on mixed malaria infections in Africa are limited but co-infection is not uncommonly documented where diagnostic capability exists [7-9]. CLINICAL MANIFESTATIONS OF MALARIA IN CHILDREN Malarial parasites are predominantly introduced to the bloodstream through the bite of an infected female anopheline mosquito. Transplacental infection (resulting in congenital malaria) [11] and transmission via blood transfusion [12] are also well-documented. Clinical presentation and severity of infection is highly dependent on the paediatric host’s level of acquired immunity. Protective immunity to malaria is a product of the pattern and intensity of parasite exposure. Children resident in areas of “stable” malaria transmission (regular, high-level inoculation) acquire immunity early in life. Thus the classical picture of severe malaria predominates in young infants, with older children displaying mild symptoms only. Where inoculation rates fluctuate by season and over time (unstable malaria transmission areas), development of protective immunity is delayed and incomplete, with malaria manifesting as acute, severe disease in both children and adults. In non-immune paediatric travellers with recent or ongoing use of chemoprophylaxis, the clinical presentation of malaria infection may also be less acute and delayed. Infection despite appropriate chemoprophylaxis can occur for multiple reasons, including unpalatability of paediatric formulations, erratic compliance and drug resistance. Under such circumstances, a diagnosis of malaria should be actively excluded even in the presence of multiple negative smears and apparently mild symptomatology.

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Fig. (1). P falciparum endemicity, classified by levels of risk, within the limits of stable malaria transmission. Areas shown in light pink are those at the lowest levels of risk, where annual average infection prevalence in 2-10 year olds (PfPR2-10) is lower than 5%. Areas shown in red are those at intermediate risk, where PfPR2-10 is higher than 5% but less than 40%. Areas shown in dark red are those at the highest levels of risk, where PfPR2-10 is likely to exceed 40%. Source: Malaria Atlas Project [10].

Classical symptoms of malaria are non-specific and may closely resemble viral illness. Common symptoms include high fever, sweats, rigors, headache, vomiting, abdominal pain, myalgia and loss of appetite. With delay in appropriate therapy, a cyclical pattern of fever and rigors may develop, with the frequency of paroxysms dependant on the infecting plasmodial species. Distinct clinical phenotypes of severe malaria are described (cerebral malaria, respiratory distress, severe anaemia and hypoglycaemia), although many of these features may present simultaneously [13]. The manifestations of severe malaria are shown in Table 1. In addition, severe malaria may be clinically indistinguishable from severe sepsis (multi-organ dysfunction is common in both conditions). Concomitant bacterial sepsis (particularly gramnegative sepsis) is a well-recognised occurrence in African children [14, 15]. Malaria in pregnancy may result in preterm delivery, low birth weight, stillbirth or congenital malaria. Congenital malaria can occur with any plasmodial species infection and affects around 10% of infants born to non-immune mothers in endemic areas [16]. Symptoms usually begin within 2 months of birth, with non-specific complaints of poor feeding, fever, gastro-intestinal upset and irritability. Hepatosplenomegaly, pallor and jaundice are the most common

physical signs. Therapy directed at the appropriate plasmodial species effects cure. Hyper-reactive malarial syndrome (HMS) [also known as tropical splenomegaly syndrome] is thought to be precipitated by chronic exposure to malaria, with persistent immune stimulation producing high concentrations of total serum IgM. Haematological findings in such patients include anaemia, reticulocytosis and less commonly, thrombocytopaenia and neutropaenia. Lifelong antimalarial treatment is advocated for HMS patients resident in endemic areas [16]. DIAGNOSIS OF MALARIA – CONSIDERATIONS IN CHILDREN The World Health Organisation (WHO) recommends prompt parasitological diagnosis of malaria using rapid diagnostic tests (RDTs) or blood film microscopy [13] because clinical algorithms are insensitive for diagnosis of paediatric malaria [17]. Laboratory confirmation is considered essential to avoid over-treatment (which exacerbates drug resistance) and to promote investigation for alternative causes of fever in parasite-negative children. Presumptive treatment of children with compatible symptoms should be reserved only for areas without access to RDTs or microscopy. In such set-

Malaria in Children - Prevention and Management

Table 1.

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Manifestations of severe malaria in children [13, 31].

Clinical Features

Laboratory Features

Decreased level of consciousness (GCS* < 11/15)

Severe anaemia (Hb < 5g/dl)

Severe weakness

Plasma glucose 10mmol/l

Compensated shock (capillary refill >3 seconds)

Acidosis (pH 4% or > 100 000/ul)

Visible jaundice

Asexual parasitaemia > 10%

Macroscopic haematuria * GCS = Glasgow Coma Scale.

tings, a presumptive malaria diagnosis should be based on a history of fever in the previous 24 hours and anaemia (palmar pallor is the most reliable clinical sign) [13, 18]. Parasite visualisation via microscopy remains the diagnostic gold standard for malaria, and can in addition identify plasmodial species and establish percentage parasitaemia. However, the need for skilled microscopists and equipment limits its utility in most malaria-endemic settings. RDTs are easy-to-use, point-of-care immunochromatographic tests that provide an effective diagnostic alternative for children in areas without laboratory access [19, 20]. Currently available RDTs have a high detection rate (even at low parasite levels) but false negatives can occur. Causes of false negative RDTs include: very low density parasitaemia; symptoms and signs preceding detectable parasite proliferation (especially in nonimmune infants/young children); test failure owing to improper storage conditions; the prozone effect [21] or parasite genetic variation [22, 23]. Despite therapy, RDTs may remain positive for up to three weeks after elimination of malaria parasites and thus cannot be used to determine treatment response. In children with new onset of febrile illness within this time frame, three possibilities should be considered: recrudescence of malaria infection; treatment failure (both diagnosed by blood smear) or an alternative cause of the fever. GENERAL MANAGEMENT OF MALARIA AND SEVERE MALARIA Organ dysfunction and subsequent clinical manifestations of malaria are the result of red cell sequestration, coagulopathy and ischaemia induced by cytokine release and increased vascular adherence of parasitized erythrocytes. In children without clinical features of severe falciparum malaria, close clinical observation and oral antimalarial therapy is possible. Intravenous antimalarial therapy is indicated for children with severe disease (see Table 2) or inability to tolerate oral medication. With delayed or ineffective therapy for P falciparum infection, progression to severe malaria may occur within hours. Even with optimal treatment, case fatality rates usually exceed 10% [13]. Early presentation to healthcare, rapid diagnosis and prompt, effective pharmacological and supportive treatment are crucial. In addition, careful clinical assessment should occur with triage or referral of children

with severe or complicated disease requiring intensive care. Severity of malaria is often underestimated in children. Decreased level of consciousness and respiratory distress predict a poor prognosis and may be useful tools for rapid clinical triage [24, 25]. Table 2. outlines WHO’s general recommendations for treatment of severe malaria [13], with adaptations and additional evidence for paediatric practice [26-30]. PHARMACOLOGICAL TREATMENT OF P FALCIPARUM MALARIA The dramatic reduction in severe malaria mortality achieved by parenteral artesunate (SEAQUAMAT [31] and AQUAMAT [32] trials) has intensified social and political pressure to provide rapid and equitable access to this welltolerated, highly effective treatment. Among African children with severe malaria, artesunate achieved a relative reduction in mortality of 22.5% (95% CI 8.1-36.9%) versus quinine, and is now the recommended first-line treatment for severe malaria in children. Episodes of post-treatment hypoglycaemia were significantly fewer among children treated with artesunate [32]. In areas where artesunate is unavailable, parenteral quinine remains the treatment of choice for severe malaria. Parenteral antimalarials are recommended for a minimum of 24 hours, followed by a full treatment course of a second antimalarial agent, so as to minimise development of drug resistance [13]. Alternatives to artesunate and quinine therapy include intramuscular artemether, but absorption may be erratic [33]. Rectal artemether is safe and effective in the absence of intravenous access [34]. Table 3 lists medications used, indications and precautions for antimalarial drugs. Management guidelines for mixed malarial infections and non-falciparum malaria in children are available from WHO [13]. New artemisinin combination therapies (ACT’s) are available including dihydroartemisinin-piperaquine (DHAPPQ) and artesunate-pyronaridine. DHA-PPQ is safe and highly effective against P falciparum and asexual stages of P vivax and is recommended by WHO as an option for firstline treatment of uncomplicated malaria [35,36]. Similarly, pooled data from 6 clinical trials has demonstrated safety and efficacy of artesunate-pyronaridine, with suggestion that it should be included as a first-line treatment option for uncomplicated falciparum malaria [37]. A new class of antimalarials (artemisinin-aminoquinoline hybrids) with potent


Table 2.

Dramowski et al.

Clinical management of severe malaria in children.

Manifestation/Complication

Management Recommendation

Severe malaria (including: coma/lethargy/seizures/inability to feed/respiratory distress)

General supportive care should be instituted in all cases. This includes: •

full dose parenteral antimalarial treatment (see Table 3)

•

if no intravenous access, use rectal (preferred) or intramuscular route

•

maintenance of airway patency, administration of face mask oxygen

•

glucose monitoring

•

fever management (paracetamol)

•

careful fluid management, urine output monitoring

•

haemoglobin and parasite counts every 12-24 hours

•

referral to the next care level where appropriate

Hypoglycaemia

Correct blood glucose < 2.2 mmol/l, maintenance glucose-containing fluids

Severe anaemia

Transfuse with screened packed red blood cells

Convulsions/cerebral malaria

Maintain airway, check blood glucose, terminate seizures with parenteral or rectal anticonvulsant. Prophylactic use of anti-convulsants in cerebral malaria is not recommended [26, 27]. Mannitol is not routinely recommended [28].

Hypovolaemia and/or shock

Fluid replacement, inotropic support and prophylactic parenteral broad-spectrum antibiotics should be administered. Fluid boluses (whether saline or colloid-based) are associated with increased mortality [29].

Coagulopathy

Transfuse with screened fresh frozen plasma and platelets, vitamin K injection.

Acute pulmonary oedema

Uncommon in children, nurse at 45 degree angle, administer oxygen, diuretics and stop intravenous fluids. Intubate and provide positive end-expiratory pressure.

Acute renal failure

Uncommon in children < 8 years; exclude pre-renal causes, maintain fluid balance, in established renal failure consider haemodialysis. Although considered a controversial adjunctive therapy, exchange transfusion may be beneficial in certain circumstances [30].

in vivo antimalarial activity in mice will enter clinical trials in 2013 [38]. A problem with both new and existing antimalarial drugs is the limited pharmacokinetic data from children. Dosing is often extrapolated from adult data, in some instances leading to sub-therapeutic drug levels and increased risk of treatment failure and drug resistance [39, 40]. In addition to obtaining paediatric pharmacokinetic data, priority should be given to development of drug formulations that are palatable, tolerable and feasible to give orally. Other special populations, such as children suffering from HIV or malnutrition, should be included when testing new antimalarial drugs [41]. A recent Ugandan study reported an interesting finding, of particular relevance to populations affected by both malaria and HIV. A 41% reduction in malaria incidence was achieved in young HIV-infected children commenced on Lopinivir/ritonavir (LPV/r) based antiretroviral regimens following presentation with malaria and artemetherlumefantrine treatment [42]. However it remains to be seen if this finding can be translated into a practical recommendation in malaria/HIV affected regions. Poor quality and counterfeit medication in many parts of Africa present a further challenge to malaria treatment programmes, and compounds the problem of antimalarial drug resistance [43, 44]. Additional causes of drug resistance include indiscriminate use of antimalarials for generic management of febrile episodes and failure to complete a full

course of treatment. Development of drug resistance can be delayed by combining agents with different mechanisms of action, appropriate dosing regimens and ensuring treatment course completion [13]. Ongoing monitoring for development of resistance to antimalarial agents is critical to ensure that effective drugs are prescribed. Updated information on the emergence and spread of antimalarial drug resistance is available online [45]. Resistance to artemisinin derivatives has already been detected in South East Asia [46-48]. CHEMOPROPHYLAXIS FOR PAEDIATRIC TRAVELLERS TO MALARIA-ENDEMIC AREAS Children visiting malarious areas (whether as travellers or returning immigrants from non-endemic areas) are at increased risk for malaria. Parents should be well-informed of the risks of malaria in young children and the need for strict adherence to malarial prophylaxis and bite prevention methods (avoid going outdoors before dawn/after dusk, wear long-sleeved clothing, use insecticide-treated bed nets/ screens, apply insect repellent [DEET-based repellants {N,N-diethyl-m-toluamide} concentrations under 30% are safe for infants over 2 months of age). Several options for chemoprophylaxis are available for infants as young as 6 months of age and regularly updated advice on international travel recommendations is available online at: http://apps.who.int/tools/geoserver/www/ith/index.html and http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3infectious-diseases-related-to-travel/malaria.htm.


Table 3.

Mode/area of action Paediatric dose Indication

307

Antimalarial drugs.

Artesunate

Drug Interactions


Artemether +lumefantrine

Quinine

Chloroquine

Amodiaquine

Sulfadoxine + Pyrimethamine

Doxycycline

Clindamycin

Primaquine

Inhibits an essential calcium adenosine triphosphatase; Activity against asexual parasites and gametocytes

Artemether: same as artesunate; Lumefantrine: acts on erythrocytic stages

Acts mainly on mature trophozoites, does not prevent sequestration or further development of circulating ring stages of p.falciparum; Does not kill p.falciparum gametocytes or effect preerythrocytic stages

Interferes with parasite haem detoxification; Acts on trophozoite stage (erythrocytic)

Interferes with parasite haem detoxification; Same as choloroquine

Sulfadoxine: Competitive inhibitor of dihydropteroate synthase (enzyme that incorporates paminobenzoic acid in the synthesis of folic acid) Pyrimethamine: inhibits plasmodial dihydrofolate reductase Slow acting schizontiicide; Some action against preerythrocytic forms; Inhibits sporozoite development in mosquito

Inhibitors of amino acyl-tRNA during protein synthesis;acts on erythrocytic stages

Inhibits early stages of protien synthesis; acts on erythrocytic stages

Unknown; Effective against intrahepatic forms; Gametocidal against p.falciparu m and some asexual stages

2.4mg/kg IV at 0,12,24 hours and daily thereafter until tolerating oral medication (give at least 3 IV doses) Can be given PR before referral if no IM or IV access to IM or IV

5-15kg: 1 tablet 15-25kg: 2 tablets 25-35kg: 3 tablets 35-65kg: 4 tablets Taken orallyrepeated after 8 hours and then twice daily for the following two days (3 day course of 6 doses)

Loading dose:20mg/kg over 4 hours, then 10mg/kg over 4 hours 8hourly (started 8 hours after initial loading dose)

25mg/kg over 3 days: 10mg/kg then 5mg/kg given at 6,24 and 48 hours after the first dose

10mg/kg daily for 3 days orally

25mg/kg and 12.5mg/kg as a single dose

2mg/kg daily Only in children > 8 years

< 8years: 10mg/kg 12hourly for 7 days

0.3mg/kg daily for 14-21 daily

Severe malaria, as part of ACT for uncomplicated malaria

uncomplicated falciparum malaria or continuation of treatment of severe malaria

Severe malaria

Not recommended for P falciparum (resistance), can be used to treat nonfalciparum if sensitive

Used in conjunction with artemesinin, no longer recommended alone for falciparum (resistance)

No longer recommended for p falciparum ( resistance)

Only for prophylaxis or cotreatment in severe malaria

Only for prophylaxis or cotreatment in severe malaria

For radical cure of P ovale, malariae or vivax

None known

CYP3A inhibitors: amiodarone, atazanavir,itraco nazole, ritonavir, voriconazole CYP2D6 substrates: flecainide,amitry ptiline

Antacids: (decreased absorption of oral quinine), anticoagulants, increased levels of anticonvulsants; mefloquine (seizures), Efavirenz/nevira pine, protease inhibitors, erythromycin, cimetidine, rifampicin

Antacids, cimetidine, cotrimoxazole, mefloquine

Limited data

May exacerbate bone marrow suppression if given with: cotrimoxazole, methotrexate, phenytoin. Increased risk of hepatotoxicity with benzodiazepines

Antacids and iron may affect absorption. Metabolism enhanced by carbamazepine, phenytoin, phenobarbitone, rifampicin

May enhance effect of drugs with neuromuscular blocking activity

Do not combine with drugs with increased risk of haemolysis or bone marrow supression


Dramowski et al.

(Table 3) Contd….

GIT disturbances, dizziness

Contraindications

Common side effects

Artesunate

Table 4.

Artemether +lumefantrine

Quinine

sleep disorders, headache, dizziness, palpitations, anorexia, GIT disturbances, cough, pruritis, rash, arthralgia, myalgia, asthenia, fatigue

cinchonism, severe toxicity: coma, visual /auditory loss, cardiovascular effects, hypoglycaemia (more common in children), haemolysis in G6PD

Prolonged QT syndrome, hypersensitivity to artemether or lumefantrine, hypokalaemia, hypomagnesaemia

Hypersensitivity to quinine, tinnitus, optic neuritis, haemolysis, history of thrombocytopaenia Caution: G6PD, renal impairment (reduce dose)

Chloroquine

Sulfadoxine + Pyrimethamine

Doxycycline

Clindamycin

Primaquine

Pruritis, risk of agranulocytosis

GIT disturbances, skin rash, photosensitivity, leucopaenia, thrombocytopaenia,megaloblastic anaemia, hepatitis, oliguria/anuria

GIT disturbances, oesophageal ulceration, apthous ulcers

diarrhoea, pseudomembranous colitis, unpleasant taste in mouth

haemolytic anaemia, leukopaenia, agranulocytosis, GIT disturbance, methaemoglobinaemia

Should not be given to infants less than 6 weeks

Should not be given to infants less than 6 weeks

Children < 8 years

Amodiaquine

GIT disturbances, skin rash, pruritis, headaches, vertigo, blurred vision

G6PD deficiency

Drugs used for malarial prophylaxis in children.

Paediatric dosage

Atovaquone and Proguanil

Mefloquine

Paediatric formulation: 62.5mg A + 25mg proguanil hydrochloride.

5-20kg: 62.5mg

11-20kg: one tablet 21-30: 2 tablets 31-40kg: 3 tablets Indinivar (decreased concentration) Co-trimoxazole

Drug interactions

Rifampicin Warfarin Zidovudine

Side-effects

Common: GIT disturbances, stomatitis, mouth ulcers, skin rash, hair loss, anaemia, neutropaenia, hyponatraemia, elevated liver enzymes and amylase, headache, insomnia, angioedema.

Contraindications

Doxycycline

21-30kg: 125mg 31-45kg: 187.5mg >45kg: 250mg Possible increase in arrythmias if given with other cardiovascular drugs e.g. blockers, Ca channel blockers. Risk of convulsions if given with chloroquine or quinine. Increased concentration when co-administered with ampicillin

2mg/kg daily Only in children > 8 years

Antacids and iron may affect absorption. Metabolism may be enhanced by carbamazepine, phenytoin, phenobarbitone and rifampicin

Common: GIT disturbances, headache, dizziness, dysphoria, sleep disorders, neuropsychiatric disturbances, seizures.

Common: GIT disturbances, oesophageal ulceration, apthous ulcers.

Not with halofantrine

Children < 8 years

ADVANCES IN MALARIA PREVENTION STRATEGIES FOR CHILDREN RESIDENT IN ENDEMIC AREAS Intermittent Preventive Treatment in Children Several differing malaria prevention strategies are available, but the role and efficacy of the various interventions remains controversial. In areas with narrow seasonal trans-

Clindamycin

< 8 years: 10mg/kg 12hourly for 7 days

May enhance effect of drugs with neuromuscular blocking activity

Common: Diarrhoea, pseudomembranous colitis, unpleasant taste in mouth

mission where sulfadoxine-pyrimethamine (SP) remains efficacious (only the Sahel countries), seasonal malaria chemoprevention (SMC) using SP-amodiaquine is practised. In areas with moderate to high transmission, IPTi entails administration of a single dose of SP at scheduled immunisation visits. IPTc entails giving a full therapeutic course of an anti-malarial drug to pre-school children at regular intervals


during the transmission season (whether known to be currently infected or not) [49]. Two recently published meta-analyses of seven IPTc trials in West Africa, showed protective efficacy of IPTc between 75% [50] and 82% [51] against clinical malaria episodes (including severe disease) during the malaria transmission season. Using a combination of two drugs with extended half-lives achieved highest protective efficacy; ACT showed no efficacy advantage. Pooled data from additional studies suggested that IPTc reduced overall mortality among children 3-59 months of age by over 50%. No serious adverse events were documented and no impact on development of drug-resistance was noted after short-term therapy. Only 3 studies examined the effect of IPTc on malaria transmission in the season following the intervention, but found only slight increases in disease incidence among IPTc recipients. Coverage of Insecticide-treated Nets (ITN’s)


CONCLUSIONS In the last decade multiple advances in malaria treatment and prevention have achieved significant gains in global malaria control. However coverage of effective interventions remains lowest in parts of Sub-Saharan Africa where malaria still accounts for a quarter of all childhood deaths. Intensified political commitment and international financial support for malaria control in high burden areas is needed. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES [1]

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Received: October 23, 2012

Revised: March 20, 2013

Accepted: March 20, 2013

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