Pediatric malaria : current issues in dx and trt

Malaria is a common cause of child mortality globally

Severe malaria is more common in children less than 5 years of age, and it generally presents as cerebral malaria, severe malarial anemia, respiratory distress, and/or acute renal failure.

The migrant population  makes it endemic as well as resistance prone

Uncomplicated malaria is generally treated with artemisinin combination therapy and severe malaria is generally treated with parenteral artesunate.

Artemisinin resistance, mutant parasites that escape detection by rapid diagnostic tests, andinsecticide-resistant mosquitoes complicate the treatment, diagnosis, and prevention

What is the aetiology?

Most infections and deaths owing to malaria are caused by Plasmodium falciparum, the predominant parasite species in Africa.

Other Plasmodium species that can cause malaria include Plasmodium vivax, Plasmodium ovale (of which there are 2 congenic species P ovale wallekeri and P ovale curtisi),1 Plasmodium malariae, Plasmodium knowlesi, and Plasmodium simium.2

These parasites are transmitted to humans through the bite of the female Anopheles mosquito, which acts as the disease vector.

Do all develop symptoms?

CLINICAL MANIFESTATIONS

Symptomsa ndseverity are affected by age and immune status as well as level of parasitemia.

Nonimmune individuals such as individuals who are born in nonendemic countries or immigrants who have been living outside of endemic home countries periods longer than 6 months are at higher risk of severe disease than semi-immune individuals.

Symptoms of uncomplicated malaria infection are nonspecific and include headache, fatigue, and myalgia, followed by fever, chills, sweats, and malaise.

The disease may progress to severe malaria, which usually manifests with 1 or more of the following syndromes: cerebral malaria (coma and convulsions), severe anemia, respiratory distress, or acute renal failure.1

 

What is severe malaria?

Clinical features of severe malaria •impaired consciousness (including unrousable coma);

•prostration, i.e. generalized weakness so that the patient is unable to sit, stand or walk without assistance;

•multiple convulsions: more than two episodes within 24h;

•deep breathing and respiratory distress (acidotic breathing); •acute pulmonary oedema and acute respiratory distress syndrome;

•circulatory collapse or shock, systolic blood pressure < 80mm Hg in adults and < 50mm Hg in children;

•acute kidney injury; •clinical jaundice plus evidence of other vital organ dysfunction; and •abnormal bleeding.

Lab

Laboratory and other findings •hypoglycaemia (< 2.2mmol/l or < 40mg/dl);

•metabolic acidosis (plasma bicarbonate < 15mmol/l);

•severe normocytic anaemia (haemoglobin < 5g/dl, packed cell volume < 15% in children; <7g/dl, packed cell volume < 20% in adults); •haemoglobinuria;

•hyperlactataemia (lactate > 5mmol/l); •renal impairment (serum creatinine > 265μmol/l); and

•pulmonary oedema (radiological).

 

How to dx?

 

Themain3diagnosticmodalities currently in usearemicroscopy ofperipheral blood smears, mRDTs, and polymerase chain reaction (PCR).

Microscopy

Microscopy is an accurate and inexpensive means of diagnosing malaria that allows for species determination and estimation of parasite density through light microscopic visualization of Giemsa-stained peripheral thin and thick blood smears.16,17 A diagnosis of malaria should not be excluded on the basis of a single negative smear; instead, if the initial is negative, smears should be repeated at 12- and 24-hour intervals until there are 3 negative smears.

Malaria Rapid Diagnostic Tests

Malaria RDTs are monoclonal antibody tests used to detect Plasmodium-specific antigens in blood samples, such as P falciparum histidine-rich protein-2 (HRP-2), panplasmodium parasite lactate dehydrogenase, and pan-plasmodium aldolase.16,17

They are accurate and cost effective, and unlike microscopy, mRDTs are easy to use even by untrained personnel. The sensitivity of mRDTs may be compromised by inadequate handling and storage before use.16

Recently, deletion of the Pfhrp2/3 genes has been detected in some P falciparum strains, which encodes HRP-2, the target of the most widely used mRDTs globally.18 This deletion may lead to falsenegative mRDTs,17 which could have important implications in malaria-endemic areas for missed diagnoses. I

Polymerase Chain Reaction

PCR isthemostsensitive andspecific diagnostic modality for malaria.16,17 It allows for species determination even at low levels of parasite density (1–5 parasites/mLof blood) compared with microscopy and mRDTs (50–100 parasites/mL of blood).16,20–22 PCR is a very useful tool for the detection of mutations associated with drug resistance. Many PCR methods can be used to detect malaria, including conventional, nested, real-time, droplet digital, and isothermal PCR.16,17 Despite the many advantages associated with PCR detection, the accompanying costs are often prohibitive in many endemic regions.17

 

What is the treatment?

Uncomplicated Malaria caused by P falciparum The WHOguidelines for treatment of uncomplicated malaria recommend oral artemisinin combination therapy

Uncomplicated Malaria caused by P vivax and Other Species

The WHO guidelines recommend oral chloroquine for the treatment of chloroquinesensitive P vivax.9 Primaquine, which targets the hypnozoite stage of P vivax, must be prescribed in addition to chloroquine as a radical cure.9

 

Severe Malaria

Thecurrent WHO guidelinesrecommend parenteral artesunate for the treatment of severe malaria.27 In several large, randomized, controlled trials in Asia and Africa among children and adults, a head-to-head comparison of quinine and artesunate demonstrated improved survival with artesunate.

 

Postartesunate Delayed Hemolysis

Parenteral artesunate has an excellent safety profile, with lower incidence of hypoglycemia, new seizures, and development of coma during treatment than quinine.30,33 Nonetheless, a recently described adverse event among patients receiving artesunate is postartesunate delayed hemolysis (PADH), which occurs well after parasite clearanceandresolution of clinical symptoms34,35 and involves a distinct mechanism of hemolytic anemia.36

 

Emerging Artemisinin Resistance

Malaria control efforts are increasingly threatened by antimalarial drug resistance. P falciparum resistance to current first-line ACT drugs has been detected in multiple Asian countries in the Greater Mekong subregion.3 Cambodia has seen the greatest prevalence of drug resistance, with high rates of treatment failure for ACTs.3 Resistance is manifested initially by a phenotype of delayed parasite clearance.46 Genetic determinants of resistance include mutations in the propeller domain of the Pfkelch13 gene.47–50 Resistance to ACT partner drugs (eg, mefloquine and piperaquine) has also been detected, and high rates to ACT failure have now been reported from Cambodia, Thailand, and Vietnam.4

 

PREVENTION

In malaria-endemic regions, vector control is the main mode of malaria prevention and is achieved primarily using insecticide-treated bed nets (ITNs) or indoor residual spraying (IRS).

Case management of infected individuals, which includes prompt diagnosis andtreatmentofinfections, is another component ofmalaria control andtheprevention of onward transmission. In some areas, chemoprevention using a variety of strategies (eg, mass drug administration, seasonal malaria chemoprophylaxis, or intermittent preventative treatment) has been used.

A new vaccine against malaria is being pilot tested in 3 countries as a possible addition to the armamentarium of prevention strategies.

 

Vaccine

The leading malaria vaccine candidate is known as RTS,S/AS01 vaccine (Mosquirix). This vaccine targets the P falciparum circumsporozoite protein.5

Recombinant circumsporozoite protein epitopes (represented by the letters “R” and “T”) are fused to the hepatitis B surface antigen and expressed together with free hepatitis B surface antigen (represented by the letter “S”).54

The resulting proteins (RTS,S) self-assemble into virus-like particles.55 RTS,S is formulated with an adjuvant system (AS01).55

The RTS,S/AS01 vaccine is the first malaria vaccine shown to provide partial protection against malaria in young children.56 Phase III trials of the RTS,S/AS01 conducted at 11 centers in sub-Saharan Africa enrolled at total of 15,459 participants in 2 age groups (infants aged 6–12 weeks and children aged 5–17 months).56

The vaccine efficacy against clinical malaria was 20% in infants and 35% in children over 32 months of follow-up.56 In a 7-year follow-up study, vaccine efficacy waned over time.57 In particular, negative efficacy (higher clinical infection rates in the vaccine group relative to the placebo group) were seenduring thefifth year among children in areas with high malaria exposure.57

Given its modest vaccine efficacy, the WHO considers RTS,S/ AS01 as a potential complementary tool in combatting the global malaria burden.58

Malaria prevention  for travellers

 

All travelers should be counseled on mosquito precautions. Physical barriers include long-sleeved shirts, full-length pants, and other full-coverage garments, especially at dusk, when Anopheles mosquitoes are most likely to feed.12 Insect repellents may be used, with the following considerations for efficacy and safety in children. Topical repellents that contain 10% to 30% DEET or 20%icaridin are effective against Anopheles bites when applied properly.12 Safe and protective concentrations of DEET vary by age: children aged 6 months to 2 years should use 10% DEET no more than once daily; children aged 2 to 12 should use 10% DEET no more than thrice daily; and adults andchildrengreaterthan12yearsofageshoulduse30%DEETevery6hours.60

The20%icaridinis safeandeffective for all ages except children less than 6 months of age. Mosquito nets should be used in place of topical repellents for children less than 6 months of age.

Antimalarial drugs are highly effective at preventing severe malaria, but they require strict adherence to the dosing regimen.12

All antimalarial drug regimens should begin before departure to assess tolerability. For individuals traveling to Pfalciparum chloroquine-resistant zones (most of the world), atovaquone–proguanil, doxycycline, or mefloquine all provide adequate protection

About Dr. Jayaprakash

Asst. Prof. of Pediatrics, ICH. Institute of Child Health. Gov. Medical College Kottayam. Kerala, India.

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