Malaria management pathophysiology clinical features

management of malaria

1. Dr Nabilah Athirah 13.11.2020

2. WHAT IS MALARIA Infection of the red blood cells by the asexual forms of the malaria parasite thus makes malaria a potentially multisystem disease Transmitted by female Anopheles mosquitoes, Malaria is caused by the protozoan parasite Plasmodium. Human malaria is caused by four different species of Plasmodium: P. falciparum, P. malariae , P. ovale and P. vivax. Humans occasionally become infected with Plasmodium species that normally infect animals, such as P. knowlesi .

3. EPIDEMIOLOGY WHO 2019 MALARIA REPORT In 2018, an estimated 228 million cases of malaria occurred worldwide (95% confidence interval [CI]: 206–258 million), compared with 251 million cases in 2010 (95% CI: 231–278 million) and 231 million cases in 2017 (95% CI: 211–259 million). Most malaria cases in 2018 were in the World Health Organization (WHO) African Region (213 million or 93%), followed by the WHO South-East Asia Region with 3.4% of the cases and the WHO Eastern Mediterranean Region with 2.1%. Nineteen countries in sub-Saharan Africa and India carried almost 85% of the global malaria burden. Six countries accounted for more than half of all malaria cases worldwide: Nigeria (25%), the Democratic Republic of the Congo (12%), Uganda (5%), and Côte d’Ivoire, Mozambique and Niger (4% each). The incidence rate of malaria declined globally between 2010 and 2018, from 71 to 57 cases per 1000 population at risk. However, from 2014 to 2018, the rate of change slowed dramatically, reducing to 57 in 2014 and remaining at similar levels through to 2018. The WHO South-East Asia Region continued to see its incidence rate fall – from 17 cases of the disease per 1000 population at risk in 2010 to five cases in 2018 (a 70% decrease).

4. EPIDEMIOLOGY IN MALAYSIA in 2000 12705 0. 55 per 1,000 population DEATH: 35 In 2012 4725 0.16 per 1,000 populations DEATH: 16 in 2016 2302 DEATH: 2

5. L I F E CYCLE

6. PATHOGENESIS

7. Clinical manifestation Incubation period of malaria : average 10–14 days, but may be as short as 7 days or, in exceptional cases, up to 20 years as in P.malariae infection Thus, a febrile illness developing less than 1 week after the first possible exposure is not malaria. Symptoms occur - within 6 weeks of the traveler leaving an endemic area in more than 90% of P. falciparum infections - within 1 year in P. vivax infection - P. knowlesi , symptoms occur 9-12 days after a person has visited or worked in a forested or forest-tinge area.

8. Major manifestation in malaria The expressions of different disease manifestations depend on a variety of factors: host and parasite genetics, rates of infection, coinfection with other organisms and other Plasmodium species, nutritional status, pregnancy, age, and sex. Severe form is caused by P. falciparum Non-specific and similar to the symptoms of a minor systemic viral illness e.g. headache, lassitude, fatigue, abdominal discomfort, muscle and joint aches The most common: intermittent high grades fever a/w chills and rigor (cold stage|| Hot stage || Sweating stage)

9. Imperfect immunity??? Nature of malarial clinical disease depends greatly on the background level of the acquired protective immunity In high-transmission areas, the majority of infections are asymptomatic and infections are acquired repeatedly throughout life. Symptomatic and sometimes fatal malaria occurs in the first few years of life, but, thereafter  asymptomatic. May gradually lost, at least partially, when individuals move out of the endemic areas for long durations

10. Uncomplicated malaria symptomatic malaria without signs of severity or evidence (clinical or laboratory) of vital organ dysfunction.

11. Severe Malaria presence of one or more of the following clinical or laboratory findings classifies the patient as suffering from severe malaria.

12. Major Manifestations of Malaria as Relevant to Pulmonary and Critical Care Medicine Neurological anifestation Neurological manifestations are common, particularly in children, often resulting in cerebral malaria Cerebral malaria – syndrome of which altered sensorium with evidence of malaria infection, could not be attributed to another cause Patient develops an acute febrile illness, headache, and/or vomiting followed by altered sensorium and/or seizure. Convulsions, usually generalized, occur in more than 50% pediatric patients Seizure sometimes are subtle - may manifest as nystagmoid eye movements, irregular breathing, excessive salivation, and conjugate eye deviation.

13. Localizing neurological with a supratentorial lesion are very uncommon – uncommon Brain stem signs – common Signs of mild meningism may be present, but neck rigidity and photophobia are rare manifestations. In adults, papilloedema and retinal exudates are rare 15% of patients have retinal hemorrhage - associated with increased mortality. (CT) scan of the brain - may show cerebral edema sparing of basal ganglia. Cerebrospinal fluid analysis - shows mild pleocytosis and increased proteins.

14. Pulmonary manifestation Pulmonary manifestations are common in children, pregnant women, and travelers with malaria vary from tachypnea and asymptomatic respiratory alkalosis to acute respiratory failure Acute lung injury (ALI) and ARDS occur in 3% to 30% of patients with severe malaria and has been described with P falciparum/P vivax and P ovale . P regnant women - prone to developing pulmonary oedema Pathophysiology: Increased alveolar capillary permeability leading to intravascular fluid loss into the lung

15. Acute kidney injury Malarial acute renal failure (MARF) complicates 1% to 4.5% of native population of endemic areas & can be seen in up to 25% to 30% of nonimmune population Mainly occurs with P falciparum and P malariae , rarely with P vivax Malarial acute renal failure in falciparum malaria is mostly due to acute tubular necrosis (ATN) Attributed to hypoxaemia hyperparasitemia , hyperbilirubinemia, intravascular coagulation, hemolysis, rhabdomyolysis, severe pyrexia, and sepsis presence of renal failure is a poor prognostic associated with high mortality

16. Metabolic Complication Hypoglycaemia potential mechanisms include impaired hepatic gluconeogenesis, metabolic demands of parasite and increased glucose consumption because of fever, infection, and anaerobic glycolysis Glycogen reserves are depleted in children and pregnant women predisposing them to severe hypoglycemia. 2. Acidosis pathophysiological mechanism responsible for acidosis is lactic acidosis Contributing factors include anemia, hypovolemia and shock, interference of microcirculatory flow, impaired hepatic and renal function

17. Hematological abnormalities 1. Anemia – Haemolysis / dyserythropoesis * ‘‘Blackwater fever - a rapid and massive intravascular hemolysis of parasitized and nonparasatized red blood cells results in hemoglobinuria and acute onset anemia. It is accompanied with high fever, hepatic involvement, and is often fatal. 2. Thrombocytopenia - attributable to sequestration in the spleen or increased consumption secondary to activation of coagulation system Disseminated intravascular coagulation (DIC) with the presence of bleeding is reported in 5% to 10% of severe malaria cases (1% of all cases)

18. Gastrointestinal and Hepatic Complications Hepatic involvement, defined as raised serum bilirubin levels 6 mg% and prothombin time >4 compared to controls, Hyperbilirubinemia - contributed to hemolysis and hepatic parenchymal involvement AST &(ALT) were raised almost 2-fold in 98% cases & nearly 3-fold elevation of alkaline phosphatase was observed in 80% cases Malarial hepatitis can have an acute fulminant presentation with coma, renal failure, very high bilirubin levels, and hemorrhagic manifestations. Hepatic dysfunction contributes to hypoglycemia, lactic acidosis, and impaired drug metabolism.

19. Diagnosis Prompt and accurate diagnosis of malaria is part of effective disease management. The diagnosis of malaria is based on clinical suspicion and on the detection of parasites in the Once Plasmodium is detected, the BFMP test should be done daily during hospital stay, weekly tests x 4 during follow-up for all species and additional monthly tests x 11 during follow-up for P.vivax

20. Investigating suspected malaria

21. BFMP Microscopic examination of both thick and thin film remains the gold standard for confirmation of malaria thick film is more sensitive for detecting malaria parasites thin film helps in parasite species identification

22. Quantitative malaria - can assist the doctor to assess the disease severity, monitor response to treatment and the patient’s progress

23. PCR PCR for confirmation and species determination is indicated in certain situation such as: • With clinical symptoms of malaria but no malaria parasite seen in BFMP • Mortality cases • Cases having microscopic appearance of P.malariae

24. Rapid Diagnostic Test (RDT) Rapid Diagnostic Tests are based on the detection of circulating parasite antigens can be supplementary when malaria diagnosis is being performed by relatively inexperienced staff Histidine rich protein 2 Plasmodium lactase dehydrogenase Pan – specific adolase No commercially available RDTs have been sufficiently sensitive overall for P.knowlesi , thus a negative pLDH -RDT or aldolase-based RDT does not exclude the diagnosis of knowlesi malaria.

25. Treatment At early stage of malaria infection - prompt and effective treatment is given If ineffective medicines are given or if treatment is delayed, especially in P.knowlesi and P. falciparum malaria, the parasite burden continues to increase every 24 or 48 hours, severe malaria and even death may ensue. WHO recommends the use of Artemisinin Combination Therapy (ACT) as the standard treatment for malaria and discourages the prescription of monotherapy or sub-standard ACT as this will promote resistant plasmodium.

26. Presumptive treatment For those in endemic area with classical symptoms of malaria in whom a blood film was taken but result not available due to domestic issues ex in pt live in remote area// risks of defaulting follow up Treatmen shold be based on the predominant species in that area

27. Classification of antimalarial drug

28. MANAGEMENT OF MALARIA IN PAEDIATRICS The treatment regimen for pediatric patients is the same as for adults except that the drug dose is adjusted according to the weight of the patient. In addition, drug such as doxycyline is contra-indicated in children less than eight years old. Primaquine should be given to pediatric patients only after they have been screened for G6PD deficiency

29. MANAGEMENT OF SEVERE AND COMPLICATED MALARIA All malaria patients should be admitted. In exceptional cases where this is not possible, uncomplicated malaria can be managed at out-patient clinics with close monitoring. However, for patients with the following features, admission is mandatory in patients with manifestations of severe/ complicated malaria patients who cannot tolerate orally patients with high parasitaemia (>100 000/ μl ) [> 20,000/ μl for P.knowlesi patients with G6PD deficiency all pregnant mothers with acute malaria patients with severe malnutrition g. children

30. Referral to hospitals with specialists These patients should be referred to hospitals with specialists for further management: all patients with severe and complicated malaria immuno-compromised patients with significant co-morbidities e.g. hepatic or renal dysfunction pregnant mothers All patients diagnosed as malaria or suspected malaria should be admitted. In situations where this is not possible, they should be treated and followed-up daily by a doctor or assistant medical officer

31. Criteria for referral to the High Dependency Unit (HDU) or Intensive Care Unit (ICU) Patient with features of severe malaria, All patients with complicated malaria should be referred to the Physician on call. An early referral to intensivist should be made for further evaluation and management. If the patient cannot be transferred, then the patient should be monitored closely in the district hospital in close consultation with the physician

32. General Management for Severe Malaria Take a complete History and physical examination which includes Glasgow Coma Scale (GCS), presence of neck stiffness, Blood pressure, Pulse rate, Respiratory rate & examine the fundi as well. Send the following investigations:

33. Admit to ICU/ HDU Prompt administration of antimalarial drug -IV Artesunate (2.4 mg/kg) stat or IV Quinine if IV Artesunate is not available (and IM, if no IV access) - at least 24 hours before switching to an oral formulation Keep closed monitoring – GCS/ vital sign / I/O Give fluids just enough to maintain the circulation and correct dehydration. Rapid fluid boluses are contraindicated in severe malaria resuscitation Dehydration should be managed cautiously and ideally guided by urine output - output goal of > 1ml/kg body weight per hour unless the patient has anuric renal failure or pulmonary oedema , for which fluid management should be tailored to the needs of the patient and reassessed frequently

34. If GCS is reduced, look for other causes such as meningitis. A lumbar puncture may then be indicated and antibiotics instituted. There is considerable clinical overlap between septicaemia , pneumonia and severe malaria, and these conditions may coexist .If secondary infections are suspected, then start the patient on a broad spectrum IV antibiotic such as Ceftriaxone 2g OD ( after a septic workout is done) Monitor for clinical and parasitological therapeutic response – parasite count and clinically High fever can be managed by tepid sponging and Paracetamol.

35. Discharge criteria: the patients can be discharged once they are clinically well with two negative BFMP slides within 48 hours. Follow up: Patients should be followed up weekly for a month. Thereafter, follow up for those infected with P. vivax infection should be followed up monthly for one year

36. Management of complications of malaria

37. Adjunctive Therapy Adjunctive therapy is defined as any additional therapy that modifies physiologic processes caused by malaria.

38. Modulate the immune response to P. falciparum (dexamethasone, intravenous immunoglobulin, monoclonal antibodies to TNF- α, pentoxifylline and curdlan sulfate)* Reduce iron burden (iron chelation with desferrioxamine or deferipone ) Reduce oxidative stress (N-acetylcysteine [NAC]) Counteract the prothrombotic state and prevents the formation of rosettes of infected red blood cells (RBCs) (heparin and aspirin) Reduce parasitemia (EBT) Expand volume and potentially decrease acidosis (albumin) Decrease intracranial pressure and cerebral edema (mannitol and dexamethasone) Prevent seizure activity (prophylactic phenobarbital)

39. Exchange blood transfusion (EBT) The rationale for EBT has been variously proposed as Removing infected red blood cells from the circulation and, therefore, lowering the parasite burden Reducing rapidly both the antigen load and the burden of parasite-derived toxins and toxic mediators Replacing the rigid unparasitized and parasitized red cells by more deformable cells and, therefore, reducing microcirculatory obstruction.