18 Drugs for Non-Severe Falciparum and Malaria Control

Behzad Nadjm 4/9/18

18 Non Falciparum Non Severe

18.0.1 Chloroquine

Initially it was:

  • Cheap
  • Safe
  • Effective

Three day course.

It caused an itch, otherwise no side effects

But resistance developed through 60s (thai:burma),70s (some americas, asia, some africa),80s (all of africa)

Most of this resistance is R1 resistance. So it was effective if combined with S/P

18.0.1.1 S/P

Made by the germans in the 1940s

An adult dose is three stat tablets (single dose!)

A child dose was also stat (1/2 tablet per 10 kg)

Oral and great

It was initially used as chemo-prophylactic, causing SJS in 1:700,000 cases

It also protected you for up to 6 weeks

It acts through folate inhibition

It also is now widely resistant

18.0.1.2 Other

  • Quinine, poor tolerance (tastes horrendous)
  • AModiaquine, interactions with HIV drugs
  • Halofantrine, caused dysrthmias
  • Mefloquine, psychotic reactions
  • Doxycyline, heartburn, photosensitivity
  • Clindamycin, largely in pregnancy used

18.0.2 Artemesia Anua: Artemisin Combination Therapies

They have a wide range of action over the malaria parasite life cycle. Even the small ring forms. early on in the cycle, that quinine doesn’t act on.

Artemisin reduces parasitaemia by around 10,000 fold over a 48 hour period!

But it has a very short half life. Plus some parasites can go into a dormant period when just artemisinin alone, so you will get a recrudesence. So you need a second agent, a long acting second agent, that mops up the tail of parasitaemia. The concern is this style of pharmacokinetics will promote resistance.

There are 5 fully approved ACTS:

  • ALU (artemether lumefantrine)
  • AAQ (artesunate amodiaquine)
  • AMQ (artesunate mefloquine)
  • ASP (artesunate SP)
  • DHA PQ

You pick your ACT based on what resistance exists to the second agent.

The next problem, is it only works as a control mechanism in people who seek medical care with fever, and a big chunk of them dont! Plus not all children receiving antimalarials receive ACT’s

In an attempt to get ACTs/RDTs into the commmunity, WHO have been pushing integrated community case management. Malaria plus diarrhoea, plus pneuomnia, plus malnutrition

18.0.2.1 Avoid

  • Monotheraphy with artemesinin (recrudescence and resistance)
  • Incomplete dosing (people do feel better before they’re better, and stop drugs early)

18.0.2.2 Special Groups

  • Uncomplicated hyperparasitaemia (4-10%)

You should consider a longer course of artemesinin, or IV dosing, with admission

  • Recurrent malaria

If already treated in last 28 days, either retreat with the same ACT, or a second line ACT, or drop back to quinine or clindamycin

Some you shouldn’t give twice in a row

DON’T GET HUNG UP ON ACT’S, IF YOU HAVE THEM, USE THEM. BUT YOU MAY WORK IN A FACILITY THAT DOESN’T HAVE THEM. YOUR OLD DRUGS WILL WORK IN A LOT OF CASES (CHLOROQUINE, CLINDAMYCIN, DOXYCYCLINE, ETC)

18.0.3 Drugs for Malaria Control

This is giving a drug to a population, rather than just symptomatic cases.

You can:

  • Treat symptomatic cases +/- Low dose primaquine (to target gametocytes in a low transmission area)
  • Intermittent preventative treatment - IPT (giving an at risk group - pregnant, children, infants - repeated treatments) - the main one is treating women from third trimester. the other one is giving to children, called “Seasonal Malarial Chemoprophylaxis - SMC”
  • Mass drug administration (giving everyone a repeated dose over time) - cure asymptomatic infections, ongoing chemophrophylaxis. The pool of people with asymptomatic disease are way more likely to spread infection than the people with symptomatic disease.

SMC has a 75% reduction in all malaria and severe malaria episones, with a small improvement in child mortality and anaemia

The other thing that you could do in MDA is give an endectoside (kills endo - worms, and ecto - scabies, mosquitoes parasites). Like ivermectin. It’s now a subject of very large studies on malaria control.

Mass Drug Administration drugs need to be really safe, cheap, and effective over repeated doses. You worry about resistance (sublethal exposure to agents). So sometimes given in an emergency setting (conflict, etc)

18.1 COTD “5/9/18”

Phil Gothard 05/09/18

18.1.1 Presentation

34y male

9 Days SOB, Fever, Cough

Sabah, UK, Poland

Fever, Tachycardic, Tender LUQ

Neutropaenic, Low Platelets, Raised ALT

18.1.2 Initial Management

IV Ceftriaxone, Oral Doxycycline

18.1.3 DDx

  • Typhoid
  • Malaria
  • Influenza
  • Leptospirosis
  • Scrub Typhus
  • Infective endocarditis

18.1.4 Sabah

Northern Malaysia

Was visiting PhD student in the forest

Staying in a logging camp

Daily river crossing

18.1.5 Later Symptoms

Daily fevers (every 26 hours)

18.1.6 Diagnosis

Malaria knowlesi! (Monkey Malaria)

Treated with primaquine

18.1.7 P knowelsi

First diagnosed in humans in the 60’s

It looks like plasmodium malaria on film

Over half of malaria in malaysia in travellers may be knowelse

Patients do well with low parasitaemia, and badly in high parasitaemia.

In 2013 the main teaching hospital in Sabah saw 150 knowelsi, 150 falciparum (total 380)

In borneo knowelsi causes severe malaria and more common than falciparum.

Malaria with a 1 day cycle

Causes severe disease but not cerebral

“Have you seen a monkey in the last 4 weeks?”

Takes 3-5 days to get severe infection after infection

Gets better with pretty much any antimalarial.

18.2 Post mortem

Brain, microvascular engorgement, and something likesequestration of parasites

But unlike falciparum, no upregulation of ICAM1, so no real sequestration

18.3 Potential Problem

The mosquito covers all of india west coast, as well as most of S. E. Asia. It could break into the periurban population!

18.4 Malaria - “Benign”

Tom 05/09/18

Anopheles mosquitoes, breed in small water puddles, like hoof prints

18.4.1 Forms

P. vivax - Asia and south america

P. ovale - West and Central Africa (there are two distinct strains of ovale: curtisi, wallikeri)

Benign malariaes - parasitaemia never >2% (record for falciparum in London was 77%!)

They usually cause benign disease

Thing that differntiates vivav and ovale from falciparum is that they cause relapsing disease thanks to the hypnozoites

18.4.2 Imported P. vivax, ovale, and malariae

18.4.2.1 Ten years experience at the HTD (retrospective audit)

Vivax 44 indian subcontinent, 25 SE ASia, 4 S America, 3 central america (ASIA AND AMERICAS)

All the ovale seen came from sub saharan africa, most from west africa (AFRICA)

Malariae least common, all those cases came from africa (AFRICA)

18.4.2.2 Trop med audit

Falciparum strongly strongly comes from SSA, rather than asia

18.5 Microscpy

Vivax and falciparum look different trophozoites

Ovale has finbriation at end of red blood cells

18.5.1 Vivax

18.5.1.1 Case Study

56 yr taxi driver. Pakistan, moved to london 20 yrs previously

Went back to pakistan for a family wedding, 6 weeks. No prophylaxis.

Febrile, tachycardic

Blood film showed all stages of vivax

Treated with chloroquine

Respiratory failure (ARDS), requiring intubation. Requiring 5 days intubation.

Left permanently blind in right eye, thanks retinal haemorrhage.

Continued chloroquine, got better. But permanent diability

18.5.2 Malariae

Blood film, classically looks different to vivax and ovale. It has a band form

Least common

Never causes severe disase.

But may persist for decades. Despite there are no hypnozoites! This just grumbles constantly for ages and ages.

Very very rare cause of nephrotic syndrome. <- Remember this for exams.

Was really commonly seen in far-east prisoner of war camps. In singapore.

18.5.3 Treatment of Benign Malaria

P. vivax and ovale: Chloroquinte and Primaquine (primaquine for the hypnozoites)

But primaquine causes haemolysis with people with G6PD deficiency

P. malariae: Chloroquine alone (no hypnozoite needed as no hypnozoites)

Chesson strain of vivax is resistant to chloroquine, does exist in SE Asia but is relatively rare.

Primaquine resistant vivax is much more common. Standard practice in london to eradicate the hypnozoites is to give it twice a day for two weeks, rather than once a day for p. ovale. So in london give the primaquine until you get G6PD deficiency results. You don’t get primaquine resistance for ovale really.

Options if they have G6PD deficiency:

  • Just give primaquine anyway
  • Give 6 months chloroquine (weekly)
  • Give nothing
  • Give once weekly primaquine for 6 weeks

What do you do if you can’t test for G6PD? Probably don’t give primaquine. You could probably give in africa (less common and less severe), but not in asia (More common and worse)

There is another new drug for the hypnozoite stage, a once a day drug, so theoretically better adherence.

18.6 Severe Malaria Prophylaxis

Baz

18.6.1 What makes falciparum so fatal?

  • Sequestration (schizonts are bigger than RBCs, less flexible to get through, positive electron charge, knobs on the outside : So they get stuck!)
  • Parasitaemia
  • Falciparum invades any red blood cells (vivax restricted to young red cells - reticulocytes, ovale older red cells, knowelsi any red cell)
  • Cytoadherence
  • Transmission intensity (so you get a lot more infections)
  • Multiple erythrocye invasian pathways (falciparum has multiple ways to get into the red blood cell, vivax relies on the duffy antigen to get in)
  • Multiplication rates (falciparum 16, vivax 8, ovale 4 - merozoites from each schizont)
  • Rosetting (parasitised red cell gets surrounded by non parasatised cell, these are stuck together, and get stuck in capillaries)
  • Altered rheology (Both infected and non infected red cells become less “squishy”)

18.6.1.1 Sequestration

Pop of schizonts, releases chemicals causing spike in fever.

These are taken up by macrophage, binding to receptors

Causing macrophages to release TNF alpha

So what’s the important bit? Is it the TNF alpha? Or is it that TNF alpha causes endothelial cells to upregulate ICAM1?

ICAM1 binds to platelet, plus falciparum PfEMP1, causing red cells to get stuck. Schizonts get stuck most, but an immature ring form will also stick (just less). You get activated red cells to clump as well.

18.6.1.2 Other

  • Drug resistance
  • Poverty
  • Access to treatment

18.6.2 Cerebral Malaria

18.6.2.1 Why?

Is it the due to the classical mechanical, cytokine effects?

Is it the acidosis, the status epilepticus, the electrolye abnormalities, coninfection with something else?

Study of 31 children who died of severe cerebral malaria, had no evidence of severe malaria on brain on autopsy!

The thing that characterised whether true cerebral malaria was retinal changes!

18.6.2.2 Retinopathy

  1. Retinal Whitening
  2. Vessel Changes (tortuous, whitening of vessels, tramlining)
  3. Retinal haemorrhages (usually white centered)
  4. Papilloedema

All of these have been seen with opthalmologists with indirect fundoscopy

  • Vessel changes are due to sequestration
  • Whitening caused by oedema
  • Haemorrhages - uncertain mechanism

18.6.2.3 MRI in Malawi

Take large patients with cerebral malaria, select those with retinopathy (262348)

Evidence of oedema, loss of definition, increased ICP

Silting up of veins, causing more oedema

84% of deaths had severe brain swelling.

18.6.3 Acidosis (Respiratory Distress)

Single most important determinant of outcome

Multiple aetiologies in acidosis:

  • Tissue Hypoxia
  • Raised metabolic rate
  • Parasite metabolism

18.6.4 Hypoglycaemia

Most common in children and pregnant women.

Multifactorial:

  • Anorexia
  • Impaired hepatic gluconeogenesis
  • Parasite metabolism

Risk of death in malaria is 50% higher in hypoglycaemia. But the same is true in sepsis! Hypoglycaemia is going to increase your risk of death.

We don’t know if treating hypoglycaemia improves mortality, or whether it’s just a marcker.

18.7 Host Genetics

PfEMP-1 variants determine binding sites

Parasite genetics may affect reproduction

Host genetics (sickle cell, thallasaemia, g6PD) may offer protection

18.7.1 Summary

Severe malaria syndromes have multiple causes, not just malaria

Acidosis and altered conciousness most important determing risk of death

18.8 Malaria Anaemia

Tom Doherty, Jane Crawley 05/09/18

Severe Malaria:

  • Cerebral Malaria (CM)
  • Severe Malarial Anaemia

18.8.1 Severe Malaria Anaemia and introduction

Jointly responsible for the death of 0.5 million children each year.

Children who die from severe anaemia often don’t come anywhere near doctors, as less dramatic presentation, but there’s plenty who die! We probably miss many many kids who die from malaria anaemia

It is common, poorly understood, multifactorial. It is relatively under studied.

Malaria anaemia is treated rather badly.

Is malaria an infectious disease? (we know there’s an infection) is it an immunological disease? (but there’s also an immune response)

Repeated exposure to malaria get an acquired immunity. Is that an anti-disease immunity (probably initially)? Or an anti-parasite immunity (probably later)?

This immunity is dependent on the prevalence, and the EIR. We see different

18.8.2 Anaemia Demographics

There is a physiological drob in Hb in the first 2-3 months of life, that’s normal.

In Malaria endemic environments (50% exposure to malaria), this drop continues to fall over the first year, reaching it’s lowest point at ten months.

At least 80% of children at ten months are anaemia, 1/3 of all children at ten months have an Hb of <8

18.8.3 Sub Optimal Malaria Treatment

  • People may not be able to afford a full course of anti malarial therapy
  • Treatments may be over the counter, and may not be effective

18.8.4 Definition

Anaemia in the presence of evidence of malaria (asexual parasites - active infection, or only gametocytes - so cleared infection, malaria pigment in WBC - haemozoin, hb broken down by parasite, dots seen within a white blood cell, evidence of infection within the last few weeks)

Hb < 11 mild anaemia Hb < 8 moderate Hb < 5 severe

Children can present with Hb of 3 and 4, who don’t appear very sick at all.

This anaemia is normally normochromic and normocytic.

The pathophysiology is due to:

  • haemolysis, both of infected and uninfected red blood cells (don’t know why)
  • dyserythropoeisis - is that due to TNF-alpha, or IL-10 perhaps?
  • hypersplenism
  • erythrophagocytosis

18.8.5 Acute Malarial Anaemia

  • Acute Febrile Episode
  • Rapid Fall in Hb, maximal at 48-72 hours
  • Fall in Hb Directly proportional to parasitaemia
  • Most seen with p. falciparum

18.8.5.1 Anaemia in FEAST

Large RCT of fluid resuscitation

3000 hospitalised children age 2 months to 12 years

Kids admitted with fever + coma or resp distress + one or more signs of impaired perfusion

Of those children about 60% had falciparum 75% had hb < 10 1/3 had hb <5

About 45% were transfused 29% of hb < 5 were transfused more than once

29% of Hb was < 5: Of 103 children who were severely anaemic children who were not transfused, half died, (90% of those were within first 2 hours of admission)

18.8.6 Chronic Malaria Anaemia

More likely to be important than acute, and more likely to kill you.

Less likely to be febrile, these children have developed “anti-disease” immunity

They classically present with weakness, malaise, CCF (ultimately, but some debate about that last point)

It has an impact on cognition and learning. As well as huge mortality it also has dramatic morbidity.

Parasitaemia is generally low or even absent.

Associated with some degree of immunity and sup optimal treatment.

18.8.7 Acute On Chronic

This may be what kills the child!

Their Hb zig zags down all the way to a fatal range.

18.8.8 Clinical Signs

  • Pale
  • Pale conjunctiva
  • Palmor pallor
  • Splenomegaly
  • Lactic Acidosis (Deep breathing)
  • Respiratory Distress
  • Ultimately evidence of cardiac failure (hepatosplenomegaly, gallop rhythm, increased JVP)

18.8.9 Management

18.8.9.1 Transfusion

18.8.9.1.1 Transfusion Quickly?

Is there really cardiac failure in severe malarial anaemia?

A study of 24 children, 16 had hb <5 plus respiratory distress.

All had low CVP on admission. Mean lactate was high

Profoundly acidoric (-13, to -30)

All were treated with rapid transfusion, no diuretics. 10ml/kg over 1 hour, 10mls/kf over two hours.

CVP doesn’t rise in response. Suggesting not cardiac failure.

Some do have cardiac failure, but majority have hypotension cause of shock

18.8.9.2 Other transfusion plans

  • Effective anti malarial drugs: Follow the national guidelines
  • Transfusion

18.8.10 Iron and the Acute Phase Response:

Iron decreases in the acute phase response to all infections! So serum transferrin will go down, and the ferritin will go up.

So iron studies are very difficult to interpret in the acute infection

Key paper: The adverse effect of iron repletion on the course of certain infections. BMJ 1978. The murray family. Iron supplemention of somali nomads apparently increased the incidence of malaria.

More recent paper from Pemba (Tanzania) in 2006, Lancet. Effects of routine prophylactic supplementation with iron and folic acid, on admission to hospital and mortality in preschool children. In a high malaria transmission setting. RCT iron supplementation. Iron supplemented groups were 12% more likely to die and 11% more likely to be admitted to hospital. This was after the trial was stopped early (24000 patients).

The take home message is that iron supplementation is potentially good in an iron deficient population, but onle when malaria transmission is well controlled. Else you make things worse!

Severe anaemia in Malawian children. Calis et al. NEJM. 2008. 381 preschool children who were severely anaemic (<5). 750 children who were >5 but < 8. They looked to see what illnesses they could find in this cohort. Most strongly associated with anaemia was bacteraemia, hookworm, vit a deficiency, g6pd, malaria, b12, HIV (from strongest positively predictive to least, but still predictive). Factors that werent asscoiated were folate, sickle cell, iron deficiency, parvovires, IL-10:TNF ratio. There are multiple causes of severe anaemia, but iron and folate were not prominent. In the presence of malaria, alternative or additional causes of severe should be considered.

18.8.11 Malaria in Pregnancy

  • Iron deficient mothers
  • Mothers with HIV
  • Mothers with malaria

These children are being born with v low starting stores of iron. Then they have a diet with little iron. Then they get a helminth infection.

So if it’s multifactorial cause, maybe we need a multifactorial prevention strategy. Insecticides, deworming, reduce mother to child transmission, iron supplementation(when no malaria), quality ACTs for malaria

18.8.12 Summary

  • Not simple
  • Common
  • Not recgonsised
  • Under studied
  • Sig morbidity and mortality
  • Blood is life saving, but often not available

18.9 Hyper Reactive Malarial Splenomegaly Syndrome - HMS (Tropical Splenomegaly Syndrome - TSS)

  • V poorly understood
  • immunological reaction to falciparum reaction
  • causes massive splenomegaly
  • there’s a negative blood film, so no evidence of active malaria
  • there is a strongly positive malaria serology (IFAT)
  • and a marked elevated IgM
  • liver biopsies - lymphocytic infiltrates
  • pancytopaenia
  • classically occurs more in older women (in their 20’s) in west africa
  • not a new phenomenon, occuring in the 1920s

Treatments:

Long term anti-malarial prophylaxis, chloroquine (weekly) and proguanil (daily). For 6 months. Treated as an outpatient.

These treatments are not based on any trial data.

This condition is v rare. 7 cases seen in london over a decade. Evidence of recent/ongoing infection seeen in 4, not seen in 3. Hypersplenism doesn’t get better in those without evidence of infection.

18.9.1 Case Study

34 yr man, moved from nigeria to UK 4 years prior.

Described a dragging sensation in the LUQ. Had hypersplenism and petechiae in moth

Was anaemia and thrombocytopaenic.

Malaria film negative. Malaria IFAT and ELISA were positive, suggesting infection at some time.

Haemotologists thought he had myelofibrosis and recommended splenectomy.

18.10 Invasive bacterial disease and malaria

Baz

13 years with severe anaemia

Hypogylcaemic.

HRP 2 RDT positive

18.10.1 DDx

  • Falciparum
  • Bacterial infection

18.10.2 Epidemiology

Studies throughout Africa for 26 years. 38000 patients with fever. 60% paeds. 1/10 had a positive blood culture

The bugs that caused this, from most common to least.

  • S. typhi
  • Non typhoidal salmonella
    1. pneumo
  • brucella
    1. aureus
    1. coli
  • Hib
  • TB

Most of the s. typhi and all of the brucella all came from north africa. And the TB was incomplete.

18.10.3 Non Typhoidal Salmonella

18.10.3.1 Epidemiology

OVer 2000 serovars, 4 of these cause enteric fever (the ones that cause), all the rest cause Non typhoidal salmonella.

They are all intracellular

They cause 4 clinical syndromes

  • Asymptomattic
  • Diarrhoeal
  • Focal suppurative infection (osteomyelitis in sickle cell patients, aortitis in people with atheroma)
  • Primary bacteraemic disease (without there being another clear focus) They shed in stool, they don’t stay in gallbladder like typhoid

S typhimurium s enteritidis.

Possibly human to human spread. Probably not food borne or zoonosis.

Affects children and HIV infection

COmmon in areas where malaria transmission is high. It is non specific presentation, mimicking malaria or pneumonia. Resistant to cheap antibiotics But if you reduce malaria you will reduce cases of NTS

18.10.3.2 Children

Most common 6 months to 3 years

Associated with anaemia, malaria, rainy seasons

Also associated with malnutrition and HIV

18.10.3.3 NTS and Malaria

NTS is related to malaria. When malaria goes down, so does NTS. Is that a causative relationship or not.

A cohort of children with sickle cell trait, in 1999 at a time with lot of malaria admissions if you had sickle cell trait, your odds of admission with bacterial disease were half of those without sickle cell trait. Over time the amount of malaria was falling, and the protective effect of sickle cell trait vanished. In lots of malaria, sickle cell protects against bacterial disease, in little malaria, no longer an advantage of sickle cell

18.10.3.4 Clinical Aspects

Study for sick children in hospital in Tanzania, in a high malaria transmission rate, with access to: rapid tests, glucose, cultures, lactate, pulse oximetry. In the lab blood culture interpretation.

The aim was to identify what came into hospital. P. falciparum accounted for 76 patients, invasive bacterial disease 35 patients. IBD had higher mortality than malaria. IBD plus falciparum malaria was higher mortality than malaria alone.

NTS was 47% of all bacteraemia

RDT positive slide negative was associated with bacterial disease. As was young age, hypoglycaemia, hepatomegaly, and anaemia. So how can you tell the difference between bacterial sepsis versus malaria

NTS was the commonest isolate even in children with “clinical pneumonia”

One third of NTS had slide positive malaria. A further 40% had RDT positive, slide negative - recently cleared.

NTS was NOT associated with diarrhoea.

Meningitis was well described.

18.10.3.4.1 Treat

Inherently resistant to penicillins as intracellular.

Gentamicin should work as abx, but doesn’t work as it doesnt really get into cells

Resistant increasing to amox, cotrimoxazole, chloramphenicol, ceftriaxone, quinolones (plus problems to quinolones)

There aren’t any easy answers to how to fix this. It’s starting to become a real problem in sub saharan africa.

Antimicrobial reistance increaseing in general in SSA. Generally gram negatives are becoming resistant in SSAs (ESBL, E. coli, klebsiella)

18.10.3.4.2 Why NTS plus malaria

Maybe:

Progressive haemolyisis in malaria results in a sustained release of free haem into the blood stream. This free haem induces an enzyme called haem-oxygenase (as haem is toxic to use). This same enxyme stops neutrophils killing intracellular organisms.

All the free haem also results in mobilisation of immature neutrophils that aren’t really that good.

So there’s impaired killing of salmonella.

So this process only really works in high prevelance areas, where there are repeated cases of malaria.

18.11 Severe Malaria

Tom and Baz 06/09/18

EVERY DEATH FROM MALARIA IS A WHOLLY AVOIDABLE TRAGEDY

18.11.0.1 Case Report

11 Mo girl. Three at fever, convulsions, vomiting. Rr up. Not hypoxic. Not tachycardia. Pale. Responsive to voice.

Breathing fast and hard. Acidosis.

If a chest caves in deep breathing, think chest wall unable to expand, think pus sticking, think pneumonia.

Severe malaria plus acidosis, reduced gcs, anaemia. So predicted mortality 35%

Received quinine, got better.

18.11.0.1.1 When is it safe to lumbar puncture a child?

-Not when posturing -Not when reduced GCS on admn

18.11.0.2 Do you give abx in this context?

Probably in child in high transmission setting

Prob not in adult in low transmission

18.11.0.2.1 Adjunctive Treatments

Steroids?

Dex increased mortality due to GI bleeding and bacterial sepsis

Heparin?

Would thinning the blood help w sequestration? No! It increased mortality from bleeding

Anti-TNF monoclonal antibodies? No

Oxpentifyline? No

Aspirin/mannitol/NAC? No

These trials were all done on patients with cerebral malaria as per WHO GUIDANCE, so some may not have had actual cerebral malaria!

Desferrioxamine? No

Phenobarbitone, as prophylactic.

18.11.1 SEIZURES

status epilepticus in this:

ABC

IV access

IV diazepam Or Rectal diazepam DOSES ON SLIDES

Phenobarbitone. Is cheap and effective in Africa and well absorbed IM

would prophylactic phenobarbitone help? No! It reduces seizures but doubles mortality! The hypothesis is that reducing respiratory drive with these drugs would increase acidosis, as they would rely on respiratory drive to counter acidosis.

It’s still a good drug for those who need it, those with repeated seizures.

In Britain, Malaria is a notifiable disease. In 2000 every case was reported. 2050 cases. 16 deaths. (1500 falciparum) all deaths were falciparum, so ~1% chance of dying.

15 of 16 deaths were ssa

13 were Caucasian, 2 were Nigerian that lost immunity.

In 2016 1600 cases. 6 deaths. Same pattern of falciparum, vivax, ovale, malariae.

Patients w severe malaria can get v sick. With decreased gcs in 60 of patients that required ICU, in day one of admn. Adults generally get falciparum and get AKI with it.

ARDS is a particularly worrying and poor prognostic sign with adults with severe disease, doesn’t really seem to happen in kids

Impaired gcs and aki early. ARDS occurs later.

AKI always seem to improve, if the patient survives.

Most adult icu deaths seem to be ICU complications, unable to get off ventilator.

18.12 THE COCK UP THEORY OF MALARIA

in large parts of Africa there are huge changes, the worlds top ten growing economies are in sub Saharan Africa.

However these positive changes are occur in urban areas. But malaria occurs in ritual areas

These are the kids who are dying in malaria

Due to lack of access to health care, it’s a geopolitical failing, a lack of access to good drugs. Either inadequate or fake!

A recent Nigerian study showed that 60% of drugs bought over counter were counterfeit!

Late presentation. Miss diagnosis.

Inappropriate over enthusiastic children.

Usually something has gone wrong.

5-10% of cerebral malaria recoveries, will have significant neurological sequelae. Hemiparesis. Blindness. Etc.

So you’ve got an entirely preventable, easily treatable disease, that still can carry a 30% of death and a 10% of disability.

But what causes sequestration? Is it cytokines, parasite factors, or human factors ?

Very simplistically, sequestration in brain = cerebral,

In studies of malaria in SSA, children have a 20% chance of dying in cerebral malaria.

18.12.1 PREGNANCY

Immunity is reduced in pregnancy.

Primagravidae more affected than later pregnancies.

This is due to new proteins only expressed on placenta, so you haven’t developed immunity to parasites that target this!

Parasitisation of placenta is common! And they might not be seen on films or RDTS

HIV Positive women are also affected, they aren’t protected in their later pregnancies.

In placental infection, you are more likely to get anaemia and low birth weight baby

Foetus complications are foetal loss and premature delivery, secondary to fever.

Does quinine induce labour? Maybe but that’s not worse than malaria so treat anyway.

Severe malaria can occur with not high parasitaemia.

18.13 Cerebral Malaria

If you have young child with cerebral signs and a positive blood film, do they have cerebral malaria? Usually but not always.

Take 5 children with loss of consciousness and positive film. They all need antimalarial drugs! BUT DON’T SWITCH OFF!

  • One of them might have febrile seizures!
  • One of them might be in status epilepticus!
  • One of them maight be hypoglycaemic!
  • One of them might be due to profound acidosis!

18.13.1 Treating Cerebral Malaria

Do what you can, use artemesinin if you can, but if you don’t, use quinine, do what you can

18.13.1.1 Parenteral Quinine

Quinine is the most widely used drug for malaria in sub saharan africa

Always give a loading dose of 20mg/kg. Either deep IM, or 4 hrly IV infusion.

IV infusions can kill children through volume. Unless you’re working in a setting that can monitor IV fluids properly, it may be more appropriate to give this loading dose through a deep IM injection. Half the dose given in each thigh. A fast infusion of quinine can also act as a negative cardiac inotrope.

10mg/kg either 8-12 hourly

Switch to oral when you can. Children get better quickly! Often after a couple of doses you’ll see improvement and waking up.

So then you can switch to orals, and at that point you should give a second drug in addition

18.13.1.1.1 SE’s
  • Hypotension
  • Hypoglycaemia
  • Arrhythmias

In older patients, with any risk of ischaemic heart disease, quinine is risky!

18.13.1.2 Artesunate

18.13.1.2.1 SEAQUAMAT

IV artesunate vs quinine, first trial was in 4 countries SE asia, over ~1500 adults enrolled. Adults had a larger proportion of adults still alive when receiving artesunate. NNT for artesunate versus quinine was 14.

There were some issues with this trial. It was in asia, in adults, what about quinine resistance. Practical lack of access of artesunate

18.13.1.2.2 AQUAMAT: Same trial but in africa

9 countries.

So same as SEAQUAMAT.

Children average age was 3 years, and they were very sick.

Children again had greater survival in artesunate versus quinine. 11% mortality in quinine. 8% in artesunate. NNT for artesunate 22.5

18.13.1.2.3 Access

So the lack of access to artesunate is now the issue. One drug is better

18.13.1.3 Follow on therapy

ACT’s are the main thing used for follow on therapy, you need something

18.13.1.3.1 SE’s
  • Initially 1st trimester pregnancy concerns. But now we think the benefits outweigh the risks.
  • Late haemolysis

The concerns with ACT’s and 1st trimester pregancy are also now thought not well founded

18.13.1.3.2 Rectal Artesunate

There was an improvement in mortality through giving rectal artesunate. In a situation where the IV form would be delayed for > 6 hours, there was an advantage.

18.13.2 Haemolysis in Artemesinins

18.13.2.1 Case Report

London, 32 yr old, caucasian, affluent. 4 months in Togo, no phrophylaxis

Day -15: febrile and unwell, blood film +ve p. falciparum. I/M Artemether for three dats and oral ACTs

Day -13: more anaemic

Day -10: transeferred to Lome. Blood film negative. Hb 7!. Took over counter ofloxacin

Day 0: Attended HTD. Blood film negative. Hb 4.1 gm/dL!

Eventual diagnosis was haemolysis secondary to artemisinin therapy

18.13.2.2 Post Treatment Haemolysis in Hyperparasitaemic falciparum malaria

Quinine versus Artesunate. Doesnt seem to be any problem in children in Africa.

Artesunate kills off a ring form, and then the spleen takes out the whole cell. If it’s just a ring form the spleen can take out the parasite and leave the red cell. This leaves an unstable red cell that haemolyses later. This doesn’t seem to happen in children

18.13.3 Artesunate Resistance

Starting to happen in Cambodia and Thailand

In thaland, a study showed rapid clearance of parasites. But in Cambodia the time to clearance was taking longer. So more delayed clearance rather than true resistance resistance.

With artemisinin, we don’t know genetic markers yet so rely on clinical studies, that are slow and resource intensive.

Delayed clearance is spreading through asia.Not being seen in africa in 2014 study.

Some genetic markers are starting to emerge. But not simple, you can have the marker and no delayed clearance.

So at the moment we think we’re ok, but for how long?

18.13.4 Dirty Laundry - Spot the Cock Ups!

  • Arthur
  • 56 yr male
  • Working in Sierra Leone, Security
  • Well
  • No anti-malarial prophylaxis

Fevere, headache, vomiting, diarrhoea

Seen and given unknown “treatment” at local health centre

Got transferred by boat, to Choithram hospital

RDT positive for P. falciparum

Given I/V quinine 1.2gm in hotel room

Deteriorated

Contacted company insurers to work out transfer

Insurance wanted transfer to Dakar. Family wanted transfer to London.

Flown to london via miliatary air ambulance

Jaundice/Dry/Clear Lungs/ Hepatosplenomegaly

Hb 9.8 WCC 6 Plts 20

Na 18 Urea 42

Bili 295 ALT 157 Alb 17

CRP 73

D Dimer 6340

Still had falciparum trophiozoites

PH 7

Chest x rays - l zone consolidation

Was started on haemofiltration in ICU Then ventilated, hypotensive, requiring inotropes Trialed pacing,

Cultures all negative. HIV negative. ECG normal.

Died later that day cardiogenic shock.

Pathology reports of CYTOKINE STORM.

18.13.5 Simple Things that make a huge difference in Severe Malaria in Children in Resource Poor Settings

  • Hypogylcaemia
  • Hydration
  • Consider Blood Transfustion
  • Correct acidosis - blood?
  • Consider broad spectrum abx (in a high prevalence setting, you should prescribe!
  • ?Anti-pyretics
  • Lumbar Puncture
  • Control Fits - Diazepam
  • Give Artesunate when available

The management of malaria is not difficult! It is not high tech

18.13.6 The Cock Up

GET THE FEATURES FROM THE SLIDES ON MOODLE

18.13.7 SUMMARY

  • medical emergency
  • acts should be first choice
  • do what you can to contain resistance (avoid monotherapy, long enough courses)
  • cases should be managed in the most sophisticated available setting
  • no anyone with a positive blood film has only malaria
  • most cases do make a full recovery