malaria ii

Malaria II

V Term 2008 BatchACMS

Objectives• Natural History of vivax and falciparum Malaria• Factors influencing severity• Clinical presentations of vivax and falciparum

Malaria• Acute and Chronic complications• Diagnosis• Treatment NVBDCP Guidelines 2009 (India)• WHO Guidelines (2010)• Chemoprophylaxis

Recent Publications

Indian Reference

• Malaria Drug Policy (2007). Directorate of National Vector Borne Disease Control Programe. New Delhi. 2007. Available at http://www.nvbdcp.gov.in/Doc/Revised%20drug%20policy.pdf Accessed June 1, 2009

• Status of drug resistance in India. NVBDCP. Available at http://nvbdcp.gov.in/DRUG.html

Indian Guidelines 2009

Definitions: Drug resistance

The World Health Organization (WHO) defines resistance to antimalarials as

• the ability of a parasite strain to survive and/or to multiply despite the administration and absorption of a medicine given in doses equal to or higher than those usually recommended but within the tolerance of the subject, provided drug exposure at the site of action is adequate.

• Resistance to antimalarials arises because of the selection of parasites with genetic mutations or gene amplifications that confer reduced susceptibility.

Definitions

• Relapse. The recurrence of asexual parasitaemia in P. vivax and P. ovale malaria deriving from persisting liver stages.

• Relapse occurs when the blood stage infection has been eliminated but hypnozoites persist in the liver and mature to form hepatic schizonts.

• After variable intervals of weeks to months, the hepatic schizonts burst and liberate merozoites into the bloodstream.

Definitions

• Recurrence. The recurrence of asexual parasitaemia following treatment. This can be caused by a recrudescence, a relapse (in P. vivax and P. ovale infections only) or a new infection.

Definitions

• Recrudescence. The recurrence of asexual parasitaemia after treatment of the infection with the same infection that caused the original illness. This results from incomplete clearance of parasitaemia due to inadequate or ineffective treatment.

• It is, therefore different to a relapse in P. vivax and P. ovale infections, and it differs from a new infection or re-infection (as identified by molecular genotyping in endemic areas).

Definitions

• Severe falciparum malaria: Acute falciparum malaria with signs of severity and/or evidence of vital organ dysfunction.

• Uncomplicated malaria: Symptomatic infection with malaria parasitaemia without signs of severity and/or evidence of vital organ dysfunction

Natural History

• BT Malaria (vivax)- • Incubation period (5 days – 3 months) Davidson 8 to 25 days • Acute Febrile illness-Malarial paroxysms every 48

– 72 hrs for weeks to months• Asymptomatic carrier• Chronicity- antibody response, splenomegaly,

anemia• Reservoir

Natural History

MT Malaria (falciparum)- • Incubation period (3 days to 3 weeks) Davidson 8 to 25 days • Acute febrile syndrome or irregular indolent

febrile illness with several accompaniments• Often rapid progression to complications• Fatal if untreated• NO CHRONICITY

Factors influencing severity of infection

• Pregnancy • Infancy -newborns have some protection from maternal Abs

and fetal Hb)• Semi- Immune/ Non- immune status • Blood groups and Hemoglobinopathies – Sickle Cell Anemia and Thallasemia– Hb S, E, F and C– G6PD Deficiency– Duffy antigen negativity (vivax)– Ovalocytosis

• HIV and Lympho-reticular malignancies• Malnutrition

Clinical Presentation

BT Malaria (P vivax) • Acute Febrile Syndrome- Paroxysms 48 to 72 Hrs• Chills, Rigors, Headache, Prostration, Sweating • Vomiting• Flu Like Illness• Anemia• Mild jaundice• Hepatosplenomegaly• FUO• Urticaria (rare)

Clinical Presentation

MT Malaria (P falciparum)• Irregular fever

Clinical Presentation

MT Malaria (P falciparum)• Irregular fever• Jaundice, hepatosplenomegaly

Clinical Presentation

MT Malaria (P falciparum)• Irregular fever• Jaundice, hepatosplenomegaly• Choleric form: diarrhea vomiting pain

abdomen, dehydration

Clinical Presentation

MT Malaria (P falciparum)• Irregular fever• Jaundice, hepatosplenomegaly• Choleric form: diarrhea vomiting pain

abdomen, dehydration• Dark urine (acute hemolysis)

Clinical Presentation

MT Malaria (P falciparum)• Irregular fever• Jaundice, hepatosplenomegaly• Choleric form: diarrhea vomiting pain

abdomen, dehydration• Dark urine (acute hemolysis)• Renal failure

Clinical Presentation

MT Malaria (P falciparum)• Irregular fever• Jaundice, hepatosplenomegaly• Choleric form: diarrhea vomiting pain abdomen,

dehydration• Dark urine (acute hemolysis)• Oliguria (Renal failure) • Cerebral Malaria- Headache, confusion, abnormal

behaviour, coma, seizures, focal deficits

Clinical Presentation

MT Malaria (P falciparum)• Irregular fever• Jaundice, hepatosplenomegaly• Choleric form: diarrhea vomiting pain abdomen,

dehydration• Dark urine (acute hemolysis)• Renal failure • Cerebral Malaria- Headache, confusion, abnormal

behaviour, coma, seizures, focal deficits• Respiratory symptoms- Variable degree

WHO: Definition of uncomplicated malaria

• Uncomplicated malaria is defined as symptomatic malaria without signs of severity or

• evidence (clinical or laboratory) of vital organ dysfunction.

• The signs and symptoms of uncomplicated malaria are nonspecific. Malaria is, therefore, suspected clinically mostly on the basis of fever or a history of fever.

Severe Malaria

• Evidence (clinical or laboratory) of vital organ dysfunction.

• Usually due to falciparum/ mixed infections

Acute Complications- falciparum• Metabolic acidosis• Hypoglycemia• Peripheral circulatory failure • Blackwater Fever- acute intravascular hemolysis (G6PD,

Quinine, high parasitemia, immune hemolysis

• Cerebral Malaria• Renal failure• Respiratory Failure-ARDS • Hepatitis• DIC

Chronic Complications- vivax• Tropical Splenomegaly Syndrome (HMS)-

Chronic/ repeated P vivax infections Hypergammaglobulinemia, NN anemia/ pancytopenia, splenomegaly & Hepatomegaly.

HMS- Hyper-reactive Malarial Splenomegaly

Chronic Complications- vivax• Tropical Splenomegaly Syndrome (HMS)-

Chronic/ repeated P vivax infections Hypergammaglobulinemia, NN anemia/ pancytopenia, splenomegaly & Hepatomegaly.

• Lump and pain abdomen.•

Chronic Complications- vivax• Tropical Splenomegaly Syndrome (HMS)-

Chronic/ repeated P vivax infections Hypergammaglobulinemia, NN anemia/ pancytopenia, splenomegaly & Hepatomegaly.

• Lump and pain abdomen.• Skin and respiratory infections.

Chronic Complications• Tropical Splenomegaly Syndrome (HMS)-

Chronic/ repeated P vivax infections Hypergammaglobulinemia, NN anemia/ pancytopenia, splenomegaly & Hepatomegaly.

• Lump and pain abdomen. • Skin and respiratory infections. • Death due to sepsis/ lympho-proliferative

malignant transformation

Chronic Complications• Tropical Splenomegaly Syndrome (HMS)- Chronic/

repeated P vivax infections Hypergammaglobulinemia, NN anemia/ pancytopenia, splenomegaly & Hepatomegaly.

• Lump and pain abdomen. Skin and respiratory infections.

• Death due to sepsis/ lympho-proliferative malignant transformation

• Treatment: Antimalarials and supportive therapy

Chronic Complications -Others• TSS• Immune Hemolytic Anemia- Coomb’s Positive• Quartan Malarial Nephropathy- rare• Burkitt’s Lymphoma and EBV infection

Diagnosis• Clinical setting- residence, travel, other cases

Diagnosis• Clinical setting• Presentation

Diagnosis• Clinical setting• Presentation• Exclude other causes-

Diagnosis• Clinical setting• Presentation• Exclude other causes of – Hyperpyrexia- heat stroke, sepsis, drugs, pontine lesion

Diagnosis• Clinical setting• Presentation• Exclude other causes of – Hyperpyrexia- heat stroke, sepsis, drugs, pontine lesion– Acute Febrile Syndrome- Influenza, Viral fevers, Enteric,

Sepsis & Bacteremia, Dengue, Leptospirosis, Rickettsiosis

Diagnosis• Clinical setting• Presentation• Exclude other causes of – Hyperpyrexia- heat stroke, sepsis, drugs, pontine lesion– Acute Febrile Syndrome- Influenza, Viral fevers, Enteric,

Sepsis & Bacteremia, Dengue, Leptospirosis, Rickettsiosis

– Fever with splenomegaly

Diagnosis• Clinical setting• Presentation• Exclude other causes of – Hyperpyrexia- heat stroke, sepsis, drugs, pontine lesion– Acute Febrile Syndrome- Influenza, Viral fevers, Enteric,

Sepsis & Bacteremia, Dengue, Leptospirosis, Rickettsiosis

– Fever with splenomegaly– Fever with Anemia / Jaundice

Diagnosis• Clinical setting• Presentation• Exclude other causes of – Hyperpyrexia- heat stroke, sepsis, drugs, pontine lesion– Acute Febrile Syndrome- Influenza, Viral fevers, Enteric,

Sepsis & Bacteremia, Dengue, Leptospirosis, Rickettsiosis

– Fever with splenomegaly– Fever with Anemia / Jaundice– Fever with Cerebral Symptoms – meningitis,

encephalitis

Diagnosis• Clinical setting• Presentation• Exclude other causes of – Hyperpyrexia- heat stroke, sepsis, drugs, pontine lesion– Acute Febrile Syndrome- Influenza, Viral fevers, Enteric,

Sepsis & Bacteremia, Dengue, Leptospirosis, Rickettsiosis

– Fever with splenomegaly– Fever with Anemia / Jaundice– Fever with Cerebral Symptoms – meningitis,

encephalitis– Fever with ARDS

Aims of Early Diagnosis

• Complete cure• Prevention of progression to severe malaria• Prevention of deaths• Interruption of transmission• Minimizing selection and spread of drug

resistance

Diagnostics• Routine

Diagnostics• Routine• Specific

Diagnostics• Routine• Specific• Thick and Thin blood smears- Giemsa /

Wright’s/ Lieshman’s stain stain. view 100 to 200 fields/ 200 wbcs in tail of smear.

Detection & species identificationRelevance ?

Diagnostics• Routine• Specific• Thick and Thin blood smears- Giemsa /

Wright’s/ Lieshman’s stain stain. view 100 to 200 fields/200 wbcs in tail of smear.

Detection & species identificationRelevance ?

Parasitemia: No of parasitized RBCs per 1000 RBCs/ per 200 WBCs. Relevance ?

Diagnostics• Routine• Specific• Thick and Thin blood smears- Giemsa stain /

Wright’s/ Lieshman’s stain. view 100 to 200 fields/ wbcs in tail of smear.

Detection & species identificationRelevance ?

Parasitemia: No of parasitized RBCs per 1000 RBCs/ per 200 WBCs. Calculated as xxx/ micro L Relevance ?

• Antigen Detection- HRP or LDH (RDTs)

Diagnostics• Routine• Specific• Thick and Thin blood smears- Giemsa/ Wright’s/

Lieshman’s stain. view 100 to 200 fields/ wbcs in tail of smear.

Detection & species identificationRelevance ?

Parasitemia: No of parasitized RBCs per 1000 RBCs/ per 200 WBCs. Converted to No/ microL Relevance ?

• Antigen Detection- HRP or LDH (RDTs)• PCR- Resistance testing

The QBC Test, developed by Becton and Dickenson Inc.

• It is a new method for identifying the malarial parasite in the peripheral blood. It involves staining of the centrifuged and compressed red cell layer with acridine orange and its examination under UV light source. It is fast, easy and claimed to be more sensitive than the traditional thick smear examination.

• Not recommended anymore

Peripheral smear QBC

Method Cumbersome Easy Time Longer, 60 - 120 minutes Faster

Sensitivity 5 parasites/µl in thick film and 200 / µl in thin film

Claimed to be more sensitive, at least as good

Specificity Gold standard ? False positives, artifacts may be reported as positive by not-so-well-trained technicians

Species identification

Accurate, gold standard Difficult to impossible

Cost Inexpensive Costly equipment and consumabl

Acceptability 100% Not so

Availability Everywhere Limited

Other Accidentally can detect filariasis

Treatment

• Supportive• Antipyretics• Fluids• Dextrose

• Specific

Antimalarials

vivax Malaria

• Chloroquine 25 mg base/kg bw divided over 3 days, combined with primaquine 0.25 mg base/kg bw, taken with food once daily for 14 days is the treatment of choice for chloroquine-sensitive infections. In Oceania and South-East Asia the dose of primaquine should be 0.5 mg/kg bw.[

vivax Malaria• Chloroquine – total 25mg/Kg over 3 days• +• Primaquine – 15 mg/ day X 14 days

vivax Malaria• Chloroquine – total 25mg/Kg (BASE)• Day 1 -10 mg/kg (600 mg) 4• Day 2 -10 mg/kg (600 mg) 4• Day 3 -5 mg/kg (300 mg) 2

Earlier-• Day 1- 10 mg/kg (600 mg) 4• +12 hrs -5 mg/kg (300 mg) 2• +24 hrs- 5 mg/kg (300 mg) 2• +36 hrs- 5 mg/kg (300 mg) 2

WHO 2010: vivax Malaria• For chloroquine-resistant vivax malaria,

Amodiaquine (30 mg base/kg divided over 3 days as 10 mg/kg bw single daily doses) + primaquine should be given.

• Where ACT has been adopted as the first-line treatment for P. falciparum malaria, it may also be used for P. vivax malaria in combination with primaquine for radical cure.

• Artesunate + sulfadoxine-pyrimethamine is the exception as it will not be effective against P. vivax in many places.

Other Choices - vivax

• Q + Tetra/ Doxy/ Clinda• ACT• Mefloquine

Uncomplicated falciparum: NVBDCP

• Treatment of P. falciparum cases• The treatment of P. falciparum malaria is based

on areas identified as chloroquine resistant/ sensitive as listed in annexure.

• Artemisinin Combination Therapy (ACT) should be given in resistant areas whereas chloroquine can be used in sensitive areas. ACT should be given only to confirmed P. falciparum cases found positive by microscopy or RDT.

Severe Malaria

• Severe manifestations can develop in P. falciparum infection over a span of time as short as 12 – 24 hours and may lead to death, if not treated promptly and adequately. Severe malaria is characterized by one or more of the following features:

• • Impaired consciousness/coma• • Repeated generalized convulsions• • Renal failure (Serum Creatinine >3 mg/dl)• • Jaundice (Serum Bilirubin >3 mg/dl)• • Severe anaemia (Hb <5 g/dl)• • Pulmonary oedema/acute respiratory distress

syndrome

Severe Malaria

• • Hypoglycaemia (Plasma Glucose <40 mg/dl)• • Metabolic acidosis• • Circulatory collapse/shock (Systolic BP <80 mm

Hg, <70 mm• Hg in children)• • Abnormal bleeding and DIC Haemoglobinuria• • Hyperthermia (Temperature >104o F)• • Hyperparasitaemia (>5% parasitized RBCs in low

endemic and• >10% in hyperendemic areas)

Severe Malaria• Requirements for management of complications• For management of severe malaria, health facilities should• be equipped with the following:• • Parenteral antimalarials, antibiotics, anticonvulsants,• antipyretics• • Intravenous infusion equipment and fluids• • Special nursing for patients in coma• • Blood transfusion• • Well-equipped laboratory• • Oxygen• If these items are not available, the patient must be referred

without delay to a facility, where they are available.

Severe Malaria: Treatment• Parenteral artemisinin derivatives or quinine should

be used irrespective of chloroquine sensitivity• • Artesunate: 2.4 mg/kg i.v. or i.m. given on

admission (time=0), then at 12 hours and 24 hours, then once a day (Care should be taken to dilute artesunate powder in 5% Sodium bi-carbonate provided in the pack).

• • Artemether: 3.2 mg/kg i.m. given on admission then 1.6 mg/kg per day.

• • ab Arteether: 150 mg daily i.m. for 3 days in adults only (not recommended for children).

Severe Malaria: Treatment

• Quinine: 20 mg quinine salt/kg on admission (i.v. infusion in 5% dextrose/dextrose saline over a period of 4 hours)

• followed by maintenance dose of 10 mg/kg 8 hourly; infusion rate should not exceed 5 mg/kg per hour.

• Loading dose of 20 mg/kg should not be given, if the patient has already received quinine.

• NEVER GIVE BOLUS INJECTION OF QUININE.• If parenteral quinine therapy needs to be continued

beyond 48 hours, dose should be reduced to 7 mg/kg 8 hourly.

Other Drugs and Combinations

• Numerous

Drugs unsafe in pregnancy

• Sulfadoxine-Pyremethamine• Doxycycline/ Tetracycline• Primaquine

Treatment Follow- up

• In all cases of malaria, follow-up MP tests should be done on the 6th and 28th days after treatment.

• The 6th day smear is done to assess clearance of parasitemia

• 28th day smear is done to identify resistance in vivax and recrudescence in falciparum.

World Malaria Report 2009

• RDT Rapid diagnostic test• SPR Slide positivity rate• API Annual parasite incidence• IRS Indoor residual spraying• IPT Intermittent preventive treatment• ACT Artemisinin-based combination therapy • ITN Insecticide-treated nets• LLIN Long-lasting insecticidal nets

Abbreviations of antimalarial medicines

• AQ Amodiaquine• AL Artemether-

lumefantrine• AM Artemether• ART Artemisinin• AS Artesunate• CL Clindamycin• CQ Chloroquine• D Doxycycline• DHA Dihydroartemisinin

• MQ Mefloquine• NQ Naphroquine• PG Proguanil• PPQ Piperaquine• PQ Primaquine• PYR Pyronaridine• QN Quinine• SP Sulfadoxine-

pyrimethamine• T Tetracycline

WHO: Main objectives of Antimalarial Treatment Policy

1. To reduce morbidity and mortality by• ensuring rapid, complete cure of the infection

and thus preventing the progression of uncomplicated malaria to severe, potentially fatal disease

• malaria-related anaemia and, during pregnancy• the negative impact of malaria on the fetus

2. To curtail the transmission of malaria by reducing the parasite reservoir of infection and infectivity.

WHO recommendations for diagnosis and treatment of malaria

• Prompt parasitological confirmation by microscopy or alternatively by rapid diagnostic tests (RDTs) is recommended for all patients with suspected malaria before treatment is started.

• Treatment solely on the basis of clinical suspicion should be considered only when a parasitological diagnosis is not accessible.

Uncomplicated Cases

• Uncomplicated falciparum malaria should be treated with Artemesinin - based combination therapy (ACT).

• Vivax malaria should be treated with Chloroquine where it is effective or an appropriate ACT in areas where P vivax resistance to Chloroquine has been documented.

• Both Chloroquine and ACT should be combined with Primaquine for 14 days in the treatment of P vivax malaria for the prevention of relapses, subject to considering the risk of hemolysis in patients with G6 PD Deficiency.

Five ACTs are currently recommended for use

• Artemether – Lumifantrine• Artesunate – Amodiaquine• Artesunate - Mefloquine • Artesunate – Sulfadoxine- Pyremethamine• Dihydroartemisinin- Pipraquine

• The choice of ACT should be based on the efficacy of the combination in the country or area of intended use

The National Vector Borne Disease Control Programme (NVBDCP)

• While the WHO recommends Artemether-lumefantrine in areas of multidrug resistance such as South-East Asia, the NVBDCP does not recommend this ACT for use anywhere in India.[1,2]

• Therefore, this ACT, now widely marketed in India by the private pharma, need not be used to treat malaria in India.

Avoid Monotherapy

• Artemesinin derivatives should not be used as monotherapies for the treatment of uncomplicated malaria as this will promote resistance to this important class of antimalarials.

Public Health Measure: Eliminate Gametes

• A single dose of Primaquine to be added as an anti – gametocyte medicine to ACT treatment of P falciparum malaria, particularly as a component of elimination / pre- elimination programme is recommended provided the risk of hemolysis in G6PD deficient patients is considered

Severe Malaria

• Severe malaria should be treated with a parenteral artemesinin derivative or quinine

• to be followed by a complete course of an effective ACT as soon as the patient can take oral medications.

• When IV/ IM treatment is not feasible , e.g. peripheral health posts, patients should receive pre- referral treatment with an artemesinin suppository and be transferred to a health facility capable of providing definitive treatment with parenteral antimalarial medicines.

Resource Poor Settings

• In settings with limited health facility access, diagnosis and treatment should be provided at community level through a programme of community case management (home – based management) of malaria.

• Furthermore, in light of evidence of resistance to artemisinins, WHO urges more strongly the continued routine monitoring of therapeutic efficacy of antimalarial medicines and halting the use of all monotherapies for the treatment of uncomplicated malaria.

Chemoprophylaxis

• Several factors to be considered