Acknowledgments. Dr Shamdeo Persaud Chief Medical Officer Ministry of Health

Transcription

1 The Ministry of Public Health of Guyana, National Malaria Program and Pan-American Health Organization presents the Malaria Treatment Guideline for health facilities in Guyana updated, MINISTRY OF PUBLIC HEALTH 2015, Georgetown. All rights reserved. This document may be reviewed, summarized, cited, reproduced, or translated freely, in part or in its entirety with credit given to the Ministry of Public Health in Guyana. It cannot be sold or used for commercial purposes. Requests for further information on this publication should contact: National Malaria Control Program of Guyana, Ministry of Public Health in Guyana JUNE 2015.

2 Acknowledgments This version of Malaria treatment Guideline manual was updated by the Ministry of Health in Guyana with support from the Pan-American Health Organization/World Health Organization. We would like to express our gratitude to the Participants in the National Treatment Guidelines Review. For the Technical and Secretarial support the ministry of Health would like to acknowledge either those who reviewed, commented or supported the update and additions of the 2013 Malaria Treatment Guideline. Dr Shamdeo Persaud Chief Medical Officer Ministry of Health

3 TABLE OF CONTENTS Acknowledgments..II Table of context. III-IV Abbreviations.. VI Glossary VII-IX Foreword.X... ABBREVIATIONS ACT AL AS AS+MQ ATM ATM-LUM CI CQ DIC EBT EIR GCS GPHC G6PD HIV/AIDS IM IV MOH MQ NVCS PAHO Pf Pm Pq Pv RAVREDA RBM RDT SP VBD WHO Artemisinin-based combination therapy Artemether-lumefantrine combination Artesunate Artesunate + mefloquine combination Arthemeter Arthemeter-Lumefantrine Confidence interval Chloroquine Disseminated intravascular coagulation Exchange Blood Transfusion Entomological inoculation rate Glasgow coma scale Georgetown Public Hospital Corporation Glucose-6-Phosphate Dehydrogenase Deficiency Human immunodeficiency virus/ Acquired immunodeficiency syndrome Intramuscular Intravenous Ministry of Health Mefloquine National Vector Control Services Pan American Health Organization Plasmodium falciparum Plasmodium malariae Primaquine Plasmodium vivax Amazon Network for Surveillance of Antimalarial Drug Resistance (Spanish acronym). Roll Back Malaria Rapid Diagnostic Test Sulfadoxine pyrimethamine Vector Borne Disease World Health Organization

4 GLOSSARY Acute renal failure (ARF) : Also known as acute kidney failure, is a rapid loss of renal function due to damage to the kidneys, resulting in retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products that are normally excreted by the kidney, patient remains oliguric (<0.4 ml of Urine /kg, per hour). Afebrile: Without fever. Anaemia: A reduction in the quantity of the oxygen-carrying pigment haemoglobin in the blood. Anti-pyretic: A drug such as paracetamol that relieves fever without affecting the causative agent (in this case the parasite). Adequate clinical and parasitological response (ACPR): Absence of parasitaemia on day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure. Artemisinin-based combination therapy (ACT). A combination of artemisinin or one of its derivatives with an antimalarial or antimalarials of a different class. Asexual cycle. The life-cycle of the malaria parasite in host red blood cells (intraerythrocytic development) from merozoite invasion to schizont rupture (merozoite ring stage, trophozoite, schizont, merozoites). Duration approximately 48 hrs in P. falciparum, P. ovale and P. vivax; 72 hrs in P. malariae. Asexual parasitaemia. The presence of asexual parasites in host red blood cells. The level of asexual parasitaemia can be expressed in several different ways: the percentage of infected red blood cells, the number of infected cells per unit volume of blood, the number of parasites seen in one microscopic field in a high-power examination of a thick blood film, or the number of parasites seen per white blood cells in a high-power examination of a thick blood film. Base: The main active part of a drug (see salt). Cerebral malaria. Severe falciparum malaria with coma (Glasgow coma scale <11, Blantyre coma scale <3). Malaria with coma persisting for >30 min after a seizure is considered to be cerebral malaria. Chemoprophylaxis: The protection from, or prevention of, disease by the use of drugs. Cinchonism: Poisoning caused by an overdose of cinchona or the alkaloids quinine, quinidine, or cinchonine derived from it. Combination treatment (CT). A combination of two or more different classes of antimalarial medicines with unrelated mechanisms of action. Cure. Elimination of the symptoms and asexual blood stages of the malaria parasite that caused the patient or carrier to seek treatment.

5 Drug resistance. Reduced susceptibility of the causal agent to a drug. WHO defines resistance to antimalarials as the ability of a parasite strain to survive and/or 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, with the caveat that the form of the drug active against the parasite must be able to gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action. Resistance to antimalarials arises because of the selection of parasites with genetic mutations or gene amplifications that confer reduced susceptibility. Early treatment failure: Danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia; parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature; parasitaemia on day 3 with axillary temperature 37.5 ºC; parasitaemia on day 3 25% of count on day 0. Endemicity: Occurring frequently in a particular region or population Febrile: With an increase in temperature compared with the normal. Febrile convulsions: Convulsions occurring in children aged 6/12-6yrs due to fever caused by infection outside the central nervous system Fever: Arise in body temperature above the normal temperature i.e. above an oral temperature of 37.5 C. G6PD deficiency: G6PD is a critical housekeeping enzyme in red blood cells that intervenes, with no alternative pathways, against oxidative challenge. G6PD deficiency is an inherited genetic disorder, which is associated with some protection against severe P. falciparum malaria infections, but also with increased susceptibility to oxidant haemolysis. In G6PD-deficient patients, a 14-day regimen of primaquine may induce dose dependent haemolysis. Gametocytes. Sexual stages of malaria parasites present in the host red blood cells, which are infective to the anopheline mosquito. Glasgow coma scale: Is a neurological scale that aims to give a reliable, objective way of recording the conscious state of a person for initial as well as subsequent assessment Immunity: All those natural processes which prevent infection, re-infection, or super infection, or which assist in destroying parasites or limiting their multiplication, or which reduce the clinical effects of infection. Heamoglobinuria: Pass urine with blood (Haemoglobin). Hyperlacticaemia: High lactic levels in the blood. Hyperparasitemia: A high density of parasites in the blood, which increase the risk of deterioration to sever malaria (although the risk varies in different endemic areas according to the level of transmission) and of subsequent treatment failure. In this document, the term is used to refer to a parasite density >4 %( ~200,000/µl). Patients with P falciparum parasites densities> 10% and patients with P knowlezi parasite density > do not have evidence of vital organ dysfunction

6 Hyperpyrexia: Temperature over 39.5 C Hypersensitivity: Prone to respond abnormally to the presence of a particular antigen, this may cause a variety of tissue reactions ranging from serum sickness to an allergy. Hypnozoites. Persistent liver stages of P. vivax and P. ovale malaria that remain dormant in host hepatocytes for a fixed interval (3 45 weeks) before maturing to hepatic schizonts. These then burst and release merozoites, which infect red blood cells. Hypnozoites are the source of relapses. Late clinical failure: Danger signs or severe malaria on any day between day 4 and day 28 in the presence of parasitaemia in patients who did not previously meet any of the criteria of early treatment failure; presence of parasitaemia on any day between day 4 and day 28 with axillary temperature 37.5 ºC (or history of fever) in patients who did not previously meet any of the criteria of early treatment failure. Late parasitological failure: Presence of parasitaemia on any day between day 7 and day 28 with axillary temperature < 37.5 ºC in patients who did not previously meet any of the criteria of early treatment failure or late clinical failure. Lumbar puncture: The insertion of a needle into the fluid-filled space of the spinal cord in the lumbar region and the removal of a sample of fluid for examination. Malaria pigment (haemozoin). A dark brown granular pigment formed by malaria parasites as a by-product of haemoglobin catabolism. The pigment is evident in mature trophozoites and schizonts. Merozoites. Parasites released into the host bloodstream when a hepatic or erythrocytic schizont bursts. These then invade the red blood cells. Metabolic acidosis: Is a state in which the blood ph is low (less than 7.35) due to increased production of H+ by the body or the inability of the body to form bicarbonate (HCO3-) in the kidney. Its causes are diverse, and its consequences can be serious, including diarrhoea, coma and death. Together with respiratory acidosis, it is one of the two general types of acidosis. Monotherapy. Antimalarial treatment with a single medicine (either a single active compound or a synergistic combination of two compounds with related mechanism of action). New case. Person with a positive diagnosis for malaria Non-inmune: Having no immunity at all to a particular organism or disease. Opistotonic: (opisthotonus): Neurology; A type of spasm in which the head and heels arch backward in extreme hyperextension and the body forms a reverse bow. Parenteral: The provision of medication into the body by any means other than through the alimentary canal (oral route or rectal), such as by subcutaneous, intramuscular or intravenous injection. Plasmodium. A genus of protozoan invertebrate blood parasites that includes the causal agents of malaria. Plasmodium falciparum, P. malariae, P. ovale and P. vivax cause malaria in humans.

7 Pre-erythrocytic development. The life-cycle, generally asymptomatic, of the malaria parasite when it first enters the host. Following inoculation into a human by the female anopheline mosquito, sporozoites invade parenchyma cells in the host liver and multiply within the hepatocytes for 5 12 days, forming hepatic schizonts. These then burst liberating merozoites into the bloodstream, which subsequently invade red blood cells. Pruritus: Itching caused by local irritation of the skin or sometimes nervous disorders. Radical cure. In P. vivax and P. ovale infections, this comprises cure as defined above plus prevention of relapses. Rapid diagnostic test (RDT). An antigen-based stick, cassette or card test for malaria in which a coloured line indicates that plasmodial antigens have been detected. Recheck. A smear done to follow up a patient that has received treatment for a new infection. A recheck is positive when parasites are found on or before day 28. Patients follow up are suggested to be done on days 7, 14, 21 and 28. If positive after day 28, it will be considered a new case. Recrudescence. The recurrence of asexual parasitaemia after treatment of the infection with the same infection that caused the original illness (in endemic areas now defined by molecular genotyping). This results from incomplete clearance of parasitaemia by treatment and is therefore different to a relapse in P. vivax infections. Renewed manifestation of infection believed due to the survival of malaria parasites in the blood. 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. 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 a variable interval of weeks (tropical strains) or months (temperate strains) the hepatic schizonts burst and liberate merozoites into the bloodstream. Resistance: The ability of a parasite to multiply or survive in the presence of concentrations of a drug that normally destroys parasites of the same species or prevents their multiplication. Ring stage. Young usually ring-shaped intra-erythrocytic malaria parasites, before malaria pigment is evident under microscopy. Salt: Any compound of a base and an acid, e.g. Quinine dichloride or quinine sulphate. Schizonts. Mature malaria parasites in host liver cells (hepatic schizonts) or red blood cells (erythrocytic schizonts) that are undergoing nuclear division, process called schizogony. Selection pressure. Resistance to antimalarials emerges and spreads because of the selective survival advantage that resistant parasite have in the presence of antimalarials that they are resistant to. Selection pressure describes the intensity and magnitude of the selection process; the greater the proportion of parasites in a given parasite population exposed to concentrations

8 of an antimalarials that allow proliferation of resistant, but not sensitive parasites, the greater is the selection pressure. Sensitivity: Possessing the ability to respond to a stimulus. Severe anaemia: Haemoglobin concentration of < 5 g/100 ml (haematocrit < 15%). Severe falciparum malaria: Acute falciparum malaria with signs of severity and/or evidence of vital organ dysfunction Shock: Clinical syndrome characterized by inadequate oxygenation and perfusion to supply the body's metabolic needs. There is simply a loss of sufficient blood pressure to generate an adequate pressure gradient to maintain tissue perfusion. This leads to a loss of oxygen supply and the deterioration of energy dependent processes at cellular level and lactic acidosis. Spontaneous bleeding: Haemorrhagic from gums, nose, gastrointestinal tract, etc., and /or substantial laboratory evidence of DIC (Disseminated intra-vascular coagulation) and Coagulopathy. Sporozoites. Motile malaria parasites that are infective to humans, inoculated by a feeding female anopheline mosquito. The sporozoites invade hepatocytes. Steven Johnson Syndrome: An inflammatory condition characterized by fever, large blisters on the skin, and ulceration of the mucous membranes. It may be a severe allergic reaction to certain infections or drugs. Transmission intensity. The intensity of malaria transmission measured by the frequency with which people living in an area are bitten by anopheline mosquitoes carrying sporozoites. This is often expressed as the annual entomological inoculation rate (EIR), which is the number of inoculations of malaria parasites received by one person in one year. Treatment failure: Defined as a failure to achieve the desired therapeutic response after the initiation of therapy. Treatment failure is not synonymous with drug resistance. Trophozoites. Stage of development of the malaria parasites within host red blood cells from the ring stage and before nuclear division. Mature Trophozoites contain visible malaria pigment. Uncomplicated malaria. Symptomatic infection with malaria parasitaemia without signs of severity and/or evidence of vital organ dysfunction.

9 Foreword. Malaria remains a serious public health problem worldwide. It has more than 500 million cases and costs more than $ 1.5 million annually. Historically and today, malaria remains a scourge of the poor and vulnerable. It is an obstacle to achieving the Millennium Development Goals (MDGs) and the initiative to Roll Back Malaria. Guyana has achieved significant progress in the fight against malaria and we believe that the medicines to treat malaria must be well known, managed by health personnel and available to all patients who need them. However, the main problem is often limited access, misuse of those and other medicines. New medicines against malaria are rapidly becoming available and the ability of a country to quickly access to them depends on several prerequisites, including the availability of funds, the ability of human capital and the recognition that behavior, underdevelopment and poverty are the main determinants of disease dynamics. In preparing this guide for the treatment of malaria, we have embarked on the development of one strategy for early diagnosis and treatment for the people of Guyana, in the fight against malaria. This is a review of the first version developed in 2004 with all updated content, adding further complicated treatment guidelines, malaria in pregnancy (complicated and uncomplicated) making it more a complete guide. Working to achieve profound changes in these factors are the essential ingredients for proper treatment, to take control and if possible, elimination of this public health problem. Diagnosis by microscopy and rapid tests are also very important for a successful fight against malaria. Therefore, our strategies must be clearly aimed at making it accessible to a quick diagnosis and treatment, taking advantage of these new tools to break the transmission of this disease. However, in addition to access to these tools, sustainability is critical to controlling and ultimately eliminating this disease. Only if we work in coordination to succeed, we can win! I recommend this guide for the treatment of malaria, urging all to work with commitment and dedication in health posts and hospitals in Guyana, the knowledge contained in this guideline will assist us to achieve our goals and objectives, even in the most remote or inaccessible villages. I want to express gratitude and thanks to all who worked on this document. I urge commitment from all, to provide universal access to prevention services, treatment and care to all people, in particular, those living in the regions of Guyana where malaria is a problem and we must remember that the goal is the elimination of malaria by With regards, Dr. George Aubrey Norton Minister of Public Health, Guyana.

10 1. Introduction The impact of malaria on the health and economic development of human populations is greatest in the tropics and sub-tropics. The World Health Organization (WHO) has estimated that malaria caused an estimated 198 million cases (range, million) and 584,000 deaths in 2013; but malaria is preventable and a curable disease. Most countries in the Americas have adopted the WHO Global Strategy for Malaria Control and the Roll Back Malaria Initiative (RBM) which emphasizes prompt and effective antimalarial treatments as the major means of reducing malaria morbidity and mortality. The ultimate success of this strategy rests on the ability of Ministries of Health to provide antimalarial medicines with proven therapeutic efficacy. Malaria has, over the last 10 years, posed a serious challenge to the public health of people living and working in the hinterlands areas of Guyana. In responding to this challenge, the Government through the Ministry of Health strives to implement comprehensive programs integrated within the primary health delivery system, to achieve the objective of regional and global initiatives in reducing the impact of malaria. The regional initiative through the Amazon Initiative cooperation and RAVREDA has recommended early diagnosis and prompt treatment, continuous surveillance and monitoring of treatment efficacy. The RBM Initiative of the World Health Organization emphasizes the need for better coordinated approaches to malaria management, following approved clinical guidelines and the selective integrated vector control as joint actions to fight malaria. Guyana agreed to adopt and follow the generic recommendations contained in the new WHO Malaria Treatment Guidelines published in 2006 and in 2010, as the base document for the preparation of these national guidelines for malaria management in Guyana. The goal of the National Malaria Control Program is to reduce the social and economic impact of malaria on individual and communities, mitigating the negative contribution of malaria to poverty, thus contributing to national development. Optimizing and building upon the achievements of the previous period and to usher the country towards achieving the RBM and the United Nations Millennium Development Goal targets. The national treatments guidelines, recommended in this new revised version for malaria, are based on evidence compiled by in vivo studies undertaken in Guyana. These guidelines recommend antimalarials which are known to be efficacious and safe and which are unlikely to be affected by resistance in the near future once correctly applied at all levels of the health care system in Guyana. The Manual consist of the following sections: the epidemiological situation of malaria in Guyana updated until 2014, the antimalarial treatment policy, the guidelines for timely diagnosis and adequate doses of the treatment for complicated and uncomplicated malaria and, in unstable and specific populations in special circumstances. The Ministry of Public Health s goal is to provide the best standardized treatment of malaria for the public and private sector in Guyana.

11 2. Global Epidemiological situation The World Malaria Report 2011 summarizes information received from 106 malaria-endemic countries and a range of other sources. It analyses prevention and control measures according to a comprehensive set of indicators, and highlights continued progress towards global malaria targets. This year's report builds primarily on data received from countries for the year The report shows clear progress in the fight against malaria and a decline in estimated malaria cases and deaths. For the first time, the report contains individual profiles for 99 countries with ongoing malaria transmission. During the past decade, malaria incidence and mortality rates have been cut in all regions of the world, according to the World Malaria Report In 2010, there were an estimated 216 million cases of malaria in 106 endemic countries and territories in the world. An estimated 81% percent of these cases and 91% of deaths occurred in the WHO African Region. Globally, 86% of the victims were children under 5 years of age. There were an estimated malaria deaths in 2010, which is lower than the year before. While this 5% year-on-year decline represents significant progress, the mortality figures are still disconcertingly high for a disease that is entirely preventable and treatable. The impact of malaria on the health and economic development of the human population is the greatest in the tropics and sub-tropics. According to the World Malaria Report 2010, malaria continues to be prevalent in these 106 countries of the tropical and semitropical world, with 35 countries in central Africa bearing the highest burden of cases and deaths. Compared to a century earlier, the area of malaria risk has reduced from 53% to 27% of the Earth s land surface and the number of countries exposed to some level of malaria risk has fallen from 140 to 106. In 2007, 2.37 billion people were estimated as being at risk of P. falciparum malaria worldwide, with 26% located in the WHO AFRO region compared to 62% in the combined SEARO-WPRO regions. Of this total population at risk, about 42% or almost 1 billion people lived under extremely low malaria risk. 2.1 Malaria- a deadly disease Malaria is a potentially deadly tropical disease characterized by cyclical bouts of fever with muscle stiffness, shaking (rigors) and sweating. It is caused by a tiny parasite, genus Plasmodium, that is transmitted by the female anopheline mosquito, genus Anopheles, when she feeds on blood as a meal, to develop her eggs. Humans are generally host to four species of malaria parasites: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. However, reports from the forested regions of South-East Asia and particularly the Island of Borneo suggested increased human infections with the monkey malaria parasite P. knowlesi. P. falciparum causes the most dangerous complications, such as cerebral malaria. It is the species that is most virulent and potentially lethal to humans. Human malaria parasites only develop in anopheline mosquitoes. The parasites move to the salivary glands of the mosquito and are injected into a human host by the feeding insect. The rush hour contact with mosquitoes and malaria infection is between 5 pm to 5 am. Malaria can also be acquired from an infected blood transfusion. Signs and symptoms

12 Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia caused by hemolysis, hemoglobinuria (blood in urine), retinal damage, and convulsions. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. vivax and P. ovale infections, and every three days for P. malariae. P. falciparum can have recurrent fever every hours or a less pronounced and almost continuous fever. Malaria has been found to cause cognitive impairments, especially in children. For reasons that are poorly understood, but that may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage. Widespread anaemia, caused by malaria during a period of rapid brain development, also produces direct brain damage. Cerebral malaria, to which children are more vulnerable, is associated with retinal whitening. 2.2 Malaria control in Guyana The Republic of Guyana is bordered by the Atlantic Ocean to the north, Suriname to the east, Venezuela on the west and Brazil to the south-west. Most of Guyana s interior is classified as parts of the Amazon Basin. With a land area of approximately 214,000 square kilometers, it is divided into ten administrative regions (Regions 1 to 10) and four geographical regions; the interior savannahs, the highland region, the hilly sand and clay area and the low coastal plain. Based on the 2012 National Census, Guyana has a total population of 747,884; most of it, 89%, lives in the coastal areas in regions 2, 3, 4, 5, 6 &10. The hinterland regions (1, 7, 8 and 9) have a total of 81,623 which represents 10.9% of the country s population. The National Malaria Eradication Programme began in the 1950 s and by 1974 the number of cases of malaria had decreased from thirty-two thousand to seventy two cases in the entire country. Malaria was eliminated from the highly populated coastal area. With the decrease in morbidity and mortality associated with the disease and the oil crisis in the late 1970 s, malaria expenditure was reduced, resulting in a resurgence of the disease reaching a peak of more than 84,000 cases in 1995, mostly in the hinterland Regions 7, 8 and 9. The national program was restructured in the late 1980s to a control program with emphasis on early detection and treatment in the hinterland regions; along with strengthen capacity for central supervision and management. Following these changes, there was a subsequent decrease in the number of cases until 1999 with a total of 27,283 cases and maintained until 2004 at an average of 25,900 cases annually. Reported new cases were further reduced during the period 2006 to 2009 following a spike in 2005 with almost 40,000 cases reported with more people ventured further into the high risk malaria endemic areas to seek gold. During the period 2006 to 2009, with renewed efforts supported by the Global Fund for control by prompt diagnosis and treatment of all cases and the promotion of LLINs, the number of reported cases decreased to an average of 14,500 cases annually in the period mentioned above. However, once again in 2010, the escalating demand for gold on the global market lead to increases in mining activities in the hinterland region, causing the reported number of cases to increase to more than 31,000 in 2012 and 2013 (Figure 1).

13 P. vivax is currently the most frequent malaria species in Guyana (53% of the cases in 2014). Approximately 97% of the cases are among persons who, either, reside permanently, or are itinerant workers in Regions 1, 7, 8, 9, where mining and logging form the predominant source of income. The large itinerant population consists mainly of male adults, among whom the majority of cases occur. Persons of all age groups are at risk depending on their behavior pattern. There is risk of transmission in remote areas; there is no evidence of sustained transmission occurring along the coastal area, which includes the capital city of Georgetown (Regions 2, 3, 6 and 10). 2.3 Disease management at the different levels of the health care delivery system Health services in Guyana are delivered by a five level system based on the primary health care system outlined in the Alma Ata declaration of 1974 for health for all. The entry point in hinterland communities is the health posts, but most parts of the coastal area is served by primary health centres managed by medical doctors and Medex (Medical Extension Officer). Those entry points are supported by a referral network of district hospitals offering in and out patient care, and regional hospitals offering more specialized services. The fifth level of the system consist of the national referral hospital (Georgetown Public Hospital Corporation) and other specialized facilities. Disease management varies in complexity and specificity according to the different levels of the referral system of the health care network in Guyana. At the entry points of the system the emphasis is on preventative services and basic malaria diagnosis and treatment. District and regional hospitals serve as management sites for more critical and complicated cases. The national referral hospital in Georgetown provides critical care and treatment for cerebral malaria and complicated malaria. The central malaria clinic serves as a diagnostic and treatment site, and a training hub. Many of the mobile populations access essential diagnostic and treatment services for malaria at this facility. 2.4 Interventions

14 Several strategies of intervention are used in the malaria control in Guyana, these include: prompt and reliable case management, integrated vector control, comprehensive epidemiological surveillance, decentralization and integration of the malaria program into the PHC service, and information, education, communication (IEC) with community participation. Early diagnosis, prompt and appropriate treatment allows for effective management of the disease. The diagnosis of malaria is based on clinical suspicion confirmed by the detection of parasites in the peripheral blood. Prompt and accurate diagnosis in endemic areas is important for the most vulnerable groups in the targeted population (young children, pregnant mothers and the immunological naïve population). These vulnerable groups are at increased risk for complications unless diagnosed early and adequately treated. Accurate diagnosis will reduce unnecessary treatment and improve the management of other illnesses that are also characterized by febrile attacks. Thus accurate malaria diagnosis is important for the prognosis of patients with febrile illness. Parasitological diagnosis has the following advantages: 1. Improved patient care in parasite positive patients. 2. Identification of parasite negative patients in whom other diagnosis must be sought. 3. Prevention of unnecessary use of anti-malarial. 4. Confirmation of treatment failure. In the mining areas, easy access to medicines which are not recommended by the Ministry of Health is a problem for the malaria control in Guyana. The indiscriminate use of these drugs which can suppress clinical symptoms (for a period of time) makes it difficult to detect cases by diagnosis and could lend to widespread resistance. 3. Antimalarial treatment policy 3.1 Historical outline of anti-malarial treatment policies in Guyana Since 1940 the treatment protocols have varied for the treatment of P. falciparum, as shown below. Table 1 Chronological review of malaria treatment regimen in Guyana PERIOD BLOOD SCHIZONTICIDALS TISSUE/GAMETOCYTOCIDALS Chloroquine 25 mg/kg over 3 days Primaquine 0.75 mg/kg as a single dose Sulfadoxine 25 mg/kg + Pyrimethamine 1.25 mg/kg Quinine10 mg/kg over 3 days + Tetracycline 5 mg/kg over 7 days 1980 Quinine10 mg/kg over 7 days + Tetracycline 5 mg/kg over 7 days 1980 Quinine10 mg/kg over 3 days + Sulfadoxine 25 mg/kg + Pyrimethamine 1.25 mg/kg on day 4 single dose Quinine 10 mg/kg for 7 days Primaquine 0.75 mg/kg on day 4 single dose

15 Quinine 10 mg/kg for 5 days + on day 6 Primaquine 0.75 mg/kg on day 6 Sulfadoxine 25 mg/kg + Pyrimethamine 1.25 mg/kg Quinine 10 mg/kg For 7 days Primaquine 0.75 mg/kg on day one Mefloquine 25 mg/kg over 2 days Primaquine 0.75 mg/kg on day one 2004 Co-artem twice daily for 3 days Primaquine 0.75 mg/kg with presence of gametocytes on day one 2006 Artesunate + Mefloquine Co-artem twice daily for 3 days present Source MOH (this is compiled base on historical data). Primaquine 0.75 mg/kg as a single 3.2 Therapeutic efficacy of antimalarials medicines As in the rest of the Amazon region, P. falciparum malaria in Guyana is resistant to chloroquine and sulfadoxine-pyrimethamine. In 2004, Guyana s antimalarial treatment policy changed and introduced the use of therapeutic combinations with artemisinin derivatives as first line treatment for uncomplicated P. falciparum malaria. In 2004, under the Amazon Network for Surveillance of Antimalarials Drug Resistance (Spanish acronym La Red Amazónica de Vigilancia de la Resistencia de los Antimaláricos ) (RAVREDA), the Ministry of Health initiated in-vivo studies to provide the required evidencebase information to revise the national antimalarials treatment policy. Arthemether/lumefantrine (Coartem ) was evaluated and proposed as the first line treatment for P. falciparum malaria. Mefloquine and Artesunate as a combination therapy was assessed and suggested as the second-line treatment. The results of both studies revealed that both therapies demonstrated significant antimalarial responses to falciparum malaria Assessment of Artemether /Lumefantrine (Coartem ) /in vivo study The efficacy and safety of the six-dose regimen of arthemether + lumefantrine (Co-artem, Novartis) was assessed on 73 patients according to the standard in-vivo study for Guyana adopted from WHO standard protocol for in-vivo study (2004). A total of 72 patients were enrolled. All the patients completed treatment and 65 of them ended the 28-day follow-up period, only one was lost to follow-up. Co-artem induced rapid clearance of parasites with 88.9% on day 2 and 100% on day 3. The 28-day cure rate was 100% (Adequate Clinical and Parasitological Responses). In 2007/2008 another clinical study was conducted to evaluate the efficacy of arthemetherlumefantrine treatment in Guyana. In this new study 90 patients were included. Blood smears and blood filter papers were collected during a 28 day follow-up and external microscopic quality control (QC) data showed that no therapeutic failure had occurred after arthemetherlumefantrine treatment. This was confirmed after PCR correction and genotyping.

16 3.2.2 Mefloquine vs Mefloquine with Artesunate The Efficacy and Safety of Monotherapy Mefloquine against Mefloquine with Artesunate as the treatment of acute, uncomplicated Plasmodium falciparum malaria infections in Mahdia, was assessed on 86 patients for each arm of the standard in-vivo study WHO protocol in In the Mefloquine arm (25mg/kg), 86 patients were enrolled, 3 (3.4 %) were lost to follow up and 1 (1.2 %) was a withdrawal. From the 82 patients remaining, 79 (96.3%) had an adequate clinical/parasitological response, 2 (2.4%) presented as early treatment failure and 1 (1.2%) as late treatment failure. In the Mefloquine with Artesunate arm (25mg/kg in 2 days dose /12mg/kg in 3 days), 86 patients were enrolled and 4 (4.6%) were lost to follow up. From 82 patients remaining in the study, 81 (98.8%) presented adequate clinical and parasitological responses and 1 (1.2%) as a late parasitological failure. These results confirmed the excellent efficacy and safety of the 6-dose regimen of artemetherlumefantrine for the treatment of P. falciparum malaria in Guyana and the mefloquine and mefloquine with artesunate as a second line. Further, to demonstrate adherence problems with this 3-day treatment of Co-artem, health awareness and education is a necessary component (3) in Guyana. 4. Diagnosis Prompt and accurate diagnosis of malaria is part of effective disease management and will, if implemented effectively, help to reduce unnecessary use of antimalarials. High sensitivity and specificity of malaria diagnosis is important in all settings, to allow for prompt treatment, while reducing unnecessary treatment with antimalarials and improving differential diagnosis of febrile illness. The diagnosis of malaria is based on clinical criteria (clinical diagnosis) confirmed by the detection of parasites in the blood (parasitological or confirmatory diagnosis). There is the need to always weigh the risk of withholding antimalarials treatment from a patient with malaria against the risk associated with antimalarial treatment when given to a patient who does not have malaria. The first symptoms of malaria are nonspecific and similar to the symptoms of a minor systemic viral illness. They comprise: headache, fatigue, abdominal discomfort and muscle and joint aches, followed by fever, chills, perspiration, anorexia, vomiting and worsening malaise. Infection with P. vivax, more than with other species, can be associated with well-defined malarial paroxysms, in which fever spikes, chills and rigors occur at regular intervals. 4.1 Parasitological diagnosis The introduction of ACTs has increased the urgency of improving the specificity of malaria diagnosis. The relatively high cost of these medicines makes waste through unnecessary treatment of patients without parasitaemia unsustainable. In addition to cost savings, parasitological diagnosis has the following advantages:

17 1. Improved patient care in parasite-positive patients owing to greater certainty that the patient has malaria; 2. Identification of parasite-negative patients in whom another diagnosis must be sought; 3. Prevention of unnecessary exposure to antimalarials, thereby reducing side-effects, drug interactions and selection pressure; 4. Improved health information; 5. Confirmation of treatment failures; 6. Avoid inappropriate use of medicines. The two methods in use for parasitological diagnosis are light microscopy and rapid diagnostic tests (RDTs). The diagnostic gold standard is the use of quality assured light microscopic examination of the peripheral blood smears (thick and thin) to identify the parasite and characterize the species by well-trained staff. RDTs for detection of parasite antigen are generally more expensive, but the prices of some of these products have recently decreased to an extent that makes their deployment cost-effective in some settings. Their sensitivity and specificity are variable, and their vulnerability to high temperatures and humidity is an important constraint. These concerns make it important for the Ministry of Public Health to follow a thorough process to select the correct RDT to be used in the country. RDTs make it possible to expand the use of confirmatory diagnosis, mainly in difficult to reach areas, where microscopy is not available. Deployment of the RDTs, as well as of microscopy, must be accompanied by quality assurance Selective use of RDTs Microscopy is the gold standard method for malaria diagnosis according to WHO. Microscopy has further advantages in that it can be used for speciation and quantification of parasites, and identification of other causes of fever. The choice for a Rapid Diagnostic Test will depend on the following circumstances (Figure Z): Unavailability of skills: in few health facilities, the skills for microscopy are not available, either the microscopes or a skilled microscopist. In these places, RDT will be the only method used for malaria diagnostic. The routine quality of positive RDTs will be done by collecting samples on slides from the patients that will be evaluated by a Quality Control Officer. Case management at the community level: this is a new strategic line (Malaria National Strategic Plan ) adopted by the country in which rapid malaria diagnostic tests will be performed by volunteers (in mining and logging settings). Case-load of suspected cases at the facility level: when the case load is high (more than XXX slides per microscopist in a day), the surplus number of patients will be tested for malaria using RDTs Patients seen in extra-hours at the facility level: the normal working day starts at 8:00 AM to 4:00 PM. All patients seen out of this interval will be tested with RDTs. During holidays, RDTs will also be the main method to test patients for malaria. Figure Z

18 5. Treatment Policy 5.1 Policy recommendation in Guyana Parasitological confirmation of the diagnosis of malaria is recommended before administration of antimalarial medicine. This is vital also to differentiate between the different species of Plasmodium so as to allow for the correct treatment Treatment objectives The objective of treating uncomplicated malaria is to cure the infection. This is important as it will help prevent progression to severe. Cure means eradication from the body of the infection that caused the illness; it is necessary to follow patients long enough to document cure. The public health goal of treatment is to reduce transmission by reducing the infectious reservoir. An equally important objective of treatment is to prevent the emergence and spread of resistance to antimalarials. Tolerability, the adverse effect profile and the speed of therapeutic response are also important considerations. 5.3 Treatment recommendation for Guyana Uncomplicated falciparum infection: first-line treatment Uncomplicated falciparum infection: second line treatment.

19 a. First line: Artemether -lumefantrine (Coartem ) AL (3 days) + Primaquine (as a single dose) b. Second line: Artesunate + Mefloquine AS (3 days) + MQ (2 days) + Primaquine (as a single dose) b. (i) Alternate second line (choice 1): Quinine + clindamycin or doxycycline or tetracycline+ Primaquine (as a single dose) b. (ii) Alternate second line (choice 2) : Artesunate + clindamycin + Primaquine (as a single dose) Treatment of uncomplicated vivax malaria a. First line: Chloroquine (3 days) + Primaquine (14 days) b. Second Line: Coartem (3 days) + Primaquine (14 days) Treatment of uncomplicated malariae malaria a. Chloroquine (3 days) + Primaquine ( 7 days) Treatment of mixed infections First Line a. Falciparum + vivax: artemether - lumefantrine (Coartem) + Primaquine (14 days) b. Falciparum + malariae: artemether - lumefantrine (Coartem) + Primaquine (7 days) c. Vivax + malariae: chloroquine (3 days) + Primaquine (14 days) d. Falciparum + vivax + malariae: artemether - lumefantrine (Coartem) + Primaquine (14 days) Second Line a. Falciparum + vivax: artemether - lumefantrine (Coartem) + chloroquine (3 days) + Primaquine (14 days) 5. 4 Doses of treatment of uncomplicated malaria in Guyana Falciparum infection- First-line treatment: Arthemether + lumefantrine (Coartem ) with a single dose of Primaquine. This is currently available as co-formulated tablets containing 20 mg of artemether and 120 mg of lumefantrine marketed as Coartem. The total recommended treatment is a 6-dose regimen of arthemether+lumefantrine twice a day for 3 days (see table 2). Lumefantrine absorption is enhanced by co-administration with fat. Low blood levels, with resultant treatment failure, could potentially result from inadequate fat intake, and so it is essential that patients or careers are informed of the need to take this ACT with milk or fatcontaining food, particularly on the second and third days of treatment. Day 1 Day 2 Day 3 ACT ACT ACT

20 Primaquine (PQ) Table 2 Artemether-lumefantrine (Coartem ) dosage Age (in years) No. of tablets at approximate timing of dosing Body weight(kg) 0 h 8 h 24 h 36 h 48 h 60 h < > >34 Table 2.1 Primaquine Treatment for P. falciparum cases Age Dose Weight <6 mths kg 6-11 mths ½ tab (7.5 mg) kg 1-2 yrs ½ tab (7.5 mg) kg 3-6 yrs 1 tab (15 mg) kg 7-11 yrs 2 tabs (30 mg) kg yrs 3 tabs (45 mg) kg >15 yrs 3tabs (45 mg) 50> kg = 0.75mg/kg body weight as a single dose on day one Falciparum infection: second-line treatment a. Indications for second line treatment: Treatment failure or recrudescence with the first line treatment - this is defined as reappearance of symptoms and /or parasites on rechecks within 28 days of the onset of treatment (Note: reappearance of symptoms and /or parasites after 28 days of onset of initial treatment should be considered a new infection and re-treated with the first line medicine - Coartem). Allergy to first line medicine. Non- tolerability of the first line medicine. Unavailability of the first line treatment. b. The recommended second line treatment for uncomplicated falciparum malaria is: Artesunate + mefloquine + single dose of Primaquine. b. (i) Alternate second line treatment (choice 1): Quinine + tetracycline or doxyclycline or clindamycin + a single dose of Primaquine. b. (ii) Alternate second line treatment (choice 2): Artesunate + Clindamycin + a single dose of Primaquine. Mefloquine with Artesunate This is currently available as separate scored tablets containing 50 mg of artesunate and 250 mg base of mefloquine, respectively. Co-formulated tablets are under development but are not available at present. The total recommended treatment is 4 mg/kg of artesunate given once a day for 3 days and 25 mg base/kg of mefloquine usually split over 2 or 3 days.

21 To reduce acute vomiting and optimize absorption, the 25 mg/kg dose is usually split and given either as 15 mg/kg (usually on the second day) followed by 10 mg/kg one day later. Mefloquine is associated with an increased incidence of nausea, vomiting, dizziness, dysphoria and sleep disturbance in clinical trials, but these are seldom debilitating and in general, where this ACT has been deployed, it has been well tolerated. Table 3 Mefloquine and Artesunate dosage Age Dose in mg (Number of tablets) Artesunate (50mg ) Mefloquine (250mg) Day 1 Day 2 Day 3 Day 1 Day 2 Day months 25 (½) 25 (½) 25 (½) (½) (1) 50 (1) 50 (1) (1) (2) 100 (2) 100 (2) (2) 250 (1) >13 years 200 (4) 200 (4) 200 (4) (4) 500 (2) Table 3.1 Primaquine Treatment for P. falciparum cases Age Dose Weight < 6 months kg 6-11 months ½ tab (7.5 mg) kg 1-2 years ½ tab (7.5 mg) kg 3-6 years 1 tab (15 mg) kg 7-11 years 2 tabs (30 mg) kg years 3 tabs (45 mg) kg >15 years 3 tabs (45 mg) 50 > kg = 0.75/kg body weight as a single dose on day one Alternate second Line treatment for uncomplicated falciparum malaria (Choice 1) Quinine Sulphate 300mg tab Age Morning Midday Afternoon < 1 year ¼ (75 mg) ¼ (75 mg) ¼ (75 mg) 1-2 years ½ (150 mg) ½ (150 mg) ½ (150 mg) 3-6 years ½ (150 mg) 1 (300 mg) ½ (150 mg) 7-11 years 1 (300 mg) 1 (300 mg) 1 (300 mg) years 1 (300 mg) 2 (600 mg) 1 (300 mg) >15 years 2 (600 mg) 2 (600 mg) 2 (600 mg) PLUS Tetracycline 4mg/kg four times a day Or Doxycycline 3.5mg/kg once a day Or Clindamycin 10mg/kg twice a day N.B. Any of these combinations should be given for seven days. PLUS single dose of Primaquine Age Dose Weight

22 < 6 months kg 6-11 months ½ tab (7.5mg) kg 1-2 years ½ tab (7.5mg) kg 3-6 years 1 tab (15mg) kg 7-11 years 2 tabs (30mg) kg years 3 tabs (45mg) kg >15 years 3tabs (45mg) 50 > kg = 0.75/kg body weight as a single dose on day one Alternate Second Line treatment for uncomplicated falciparum malaria (Choice2) Artesunate (50mg tab) Age Dose in mg (Number of tablets) Day 1 Day 2 Day months 25 (½) 25 (½) 25 (½) (1) 50 (1) 50 (1) (2) 100 (2) 100 (2) >13 years 200 (4) 200 (4) 200 (4) PLUS Clindamycin 10mg/kg twice a day PLUS Single dose of Primaquine (as follows) Age Dose Weight < 6 months kg 6-11 months ½ tab (7.5 mg) kg 1-2 years ½ tab (7.5 mg) kg 3-6 years 1 tab (15 mg) kg 7-11 years 2 tabs (30 mg) kg years 3 tabs (45 mg) kg >15 years 3 tabs (45 mg) 50 > kg = 0.75/kg body weight as a single dose on day one Treatment of P. vivax malaria The recommended first line drug for the treatment of vivax in Guyana remains chloroquine and Primaquine, to achieve radical cure. Chloroquine is given at a dose of 25mg/kg (base) over 3 days. A detail of the dosing schedule is given in table 4 below: D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14 CQ CQ CQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ Table 4 Chloroquine dosage (150mg base / tablet) Age in Weight Duration in Days of chloroquine treatment years in Kg Day 1 Day 2 Day3 < 6 months <6 ¼ ¼ ¼ 6-11 months 6-10 ½ ½ ½ ½ ½

23 ½ 1 ½ Primaquine is given at a dose of 0.25mg/kg daily for 14 days. Table 4.1 below gives the dosing schedule. Primaquine for 14 days should be given as per prescribed guidelines only. Table 4.1 daily dosing for Primaquine for 14 days Age Daily dose (15mg tablets) Daily dose (7.5mg tablets) < 6months Nil Nil 6-11 months ¼ ⅓ 1-2 years ¼ ½ 3-6 years ½ years 1 1½ years 1 1⅔ 15 years 1 2 Second Line P. vivax treatment Artemether-lumefantrine (Coartem ) dosage Age (in No. of tablets at approximate timing of dosing Body years) 0 h 8 h 24 h 36 h 48 h 60 h weight(kg) < > > 34 PLUS Daily dosing for Primaquine (as follows) for 14 days Age in years Daily dose (15mg tablets) Daily dose (7.5mg tablets) < 6 months Nil Nil 6-11 months ¼ ⅓ 1-2 ¼ ½ 3-6 ½ ½ ⅔ Treatment of P. malariae malaria Infections caused by this species are considered to be generally sensitive to chloroquine. Experience indicates that P. malariae is also susceptible to amodiaquine, mefloquine and the artemisinin derivatives. Their susceptibility to antifolate antimalarials such as sulfadoxinepyrimethamine is less certain. The recommended treatment for P. malariae is the standard regimen of chloroquine and primaquine. Chloroquine dosis is of 25mg/kg (base) divided over three days; primaquine is given at 0.25mg/kg daily for seven days.

24 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 CQ CQ CQ PQ PQ PQ PQ PQ PQ PQ Table 5 Chloroquine dosage (150mg base/tablet) Age in years Weight in Kg Duration in Days of chloroquine treatment Day 1 Day 2 Day3 <6 months < 6 ¼ ¼ ¼ 6-11 months 6-10 ½ ½ ½ ½ ½ ½ 1 ½ PLUS Primaquine for 7 days. Dosing as follows in table 5.1 below Table 5.1 Daily dosing for Primaquine Age in years Daily dose (15mg tablets) Daily dose (7.5mg tablets) < 6 months Nil Nil 6-11 months ¼ ⅓ 1-2 ¼ ½ 3-6 ½ ½ ⅔ Treatment for mixed infections Mixed malaria infections are common and usually underestimated by routine microscopy. ACTs are effective against all malaria species and are the treatment of choice. Radical treatment with Primaquine should be given along with ACT s. Table 6 treatment of mixed infections To review the doses of each medicine used for the treatment of mixed infections; see tables above. Falciparum + malariae: artemether - lumefantrine (Coartem) + Primaquine (7 days) table # 2 & 5.1 Vivax + malariae: chloroquine (3 days) + Primaquine ( 14 days) 4 & 4.1 Falciparum + vivax + malariae: artemether - lumefantrine (Coartem) + Primaquine (14 days) Falciparum + vivax: artemether - lumefantrine (Coartem) + Primaquine (14 days) 2 & & Treatment of severe P. falciparum malaria

25 6.1 Definition Severe P. falciparum malaria In a patient with P. falciparum asexual parasitaemia and no other obvious cause of detected symptoms, with the presence of one or more of the following (Table 6.1 below) clinical and/or laboratory features, the patient is diagnosed as suffering from severe falciparum malaria. Severe falciparum malaria is defined as an acute falciparum infection with signs of severity and/or evidence of vital organ dysfunction. Table 6.1 Clinical and laboratory findings for Severe Falciparum malaria Clinical findings: - Impaired consciousness or coma,(hallucinations, disorientation in time place or person) Prostration, i.e. generalized weakness so that the patient is unable walk or sit up without Assistance Failure to feed (unable to swallow) Multiple convulsions more than two episodes in 24 hrs Deep slow breathing, respiratory distress (acidotic breathing) Circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults and < 50 mm Hg in children Clinical jaundice plus evidence of other vital organ dysfunction Haemoglobinuria (as distinct to haematuria) Abnormal spontaneous bleeding (blood-shots in conjunctiva or about body) Pulmonary oedema (radiological or clinical observation). Laboratory findings: Test values in severe malaria Hypoglycaemia (blood glucose < 40 mg/dl or < 2.2 mmol/l) Metabolic acidosis (plasma bicarbonate < 15 mmol/l) Severe normocytic anaemia (Hb < 7 g/dl; Packed Cell Volume (PCV) < 15%) Haemoglobinuria, Hyperparasitaemia (> 2%/ /μl in low intensity transmission areas or > 5 %. In local settings a qualitative parasite count of +++ ( 3 plus ) or greater with or without gametocytaemia. Normal test values 80 to 120 mg/dl 19 to 25 meq/liter Hyperlactataemia (lactate > 5 mmol/l) mmol/l Renal impairment (serum creatinine > 265 μmol/l or > 3mg/dL). Male (M) Hb = g/dl; PCV = % Female (F) Hb = g/dl; PCV % Normally, hemoglobin does not appear in the urine. Parasite does not appear in the smear. F= 0.5 to 1.0 mg/dl (about μmol/l) M= 0.7 to 1.2 mg/dl ( μmol/l)

26 To Note: Severe malaria is caused by Plasmodium falciparum infection and usually occurs as a result of delay in treating an uncomplicated attack of falciparum malaria. Sometimes, however, especially in children, severe malaria may develop very rapidly. i Recognizing and promptly treating uncomplicated P. falciparum malaria is therefore of vital importance. In non-transmission, and low-transmission areas, the risk is greatest among travelers returning with undiagnosed malaria infection from any area where P. falciparum transmission occurs. 6.2 Treatment objectives The most important objective is to prevent the patient from dying. Secondary objectives include prevention of disabilities and prevention of recrudescence. In the treatment of severe malaria in pregnancy, saving the life of the mother should be the primary objective. The mortality of untreated severe malaria (particularly cerebral malaria) is thought to approach 100%. With prompt, effective antimalarial treatment and supportive care, the mortality falls to 15 20% overall; although within the broad definition there are syndromes associated with lower mortality rates (e.g. severe anaemia) and others with higher (e.g. metabolic acidosis). Death from severe malaria often occurs within hours of admission to hospital or clinic, so it is essential that therapeutic concentrations of highly effective antimalarials are achieved as soon as possible. The management of severe malaria comprises four main areas: 1. Clinical assessment of the patient. 2. Specific antimalarial treatment. 3. Adjunctive therapy. 4. Supportive care Clinical assessment of the patient Severe malaria is a medical emergency; it is thus important to have an extensive and prompt medical history to determine the patient s condition and set the diagnosis or suspicion of severe falciparum malaria. An open airway should be secured in unconscious patients and breathing and circulation (blood pressure) assessed. The patient should be weighed or body weight estimated, so that medicines, including antimalarials and fluids, can be given accordingly. An intravenous cannula should be inserted (for fluid therapy) and immediate measurements of blood glucose (stick test), haematocrite/haemoglobin, parasitaemia and, mainly in adults, renal function should be taken. A detailed clinical examination should be conducted, including a record of the coma score. Several coma scores have been advocated. The Glasgow coma scale is suitable for adults, and the simple Blantyre modification or children s Glasgow coma scale are easily performed in children. Unconscious patients should have a lumbar puncture for cerebrospinal fluid analysis to exclude bacterial meningitis. If facilities are available, arterial or capillary blood ph and gases (the plasma bicarbonate or venous lactate level) should be measured in patients who are i Management of severe malaria: a practical handbook. 2nd edition. WHO

27 unconscious, hyperventilating or in shock as the degree of acidosis is an important determinant of outcome. Blood should be taken for cross-match, full blood count, platelet count, clotting studies, blood culture and full biochemistry (wherever possible). The assessment of fluid balance is critical in severe malaria. Respiratory distress, in particular with acidotic breathing in severely anaemic children, often indicates hypovolaemia and requires prompt re-hydration and, where indicated, blood transfusion Differential diagnosis The differential diagnosis of fever in a severely ill patient is broad. Coma and fever may result from meningo-encephalitis or malaria. To note are the following: Cerebral malaria is not associated with signs of meningeal irritation (neck stiffness, photophobia or Kerning s sign), but the patient may be opistotonic. As untreated bacterial meningitis is almost invariably fatal, a diagnostic lumbar puncture should be performed to exclude this condition. There is also considerable clinical overlap between septicaemia, pneumonia and severe malaria and these conditions may coexist. In malaria endemic areas, particularly where parasitaemia is common in the young age group, it is often impossible to rule out septicaemia in a shocked or severely ill, obtund child. Where possible, blood should always be taken on admission for culture and, if there is any doubt about the diagnosis, empirical antibiotic treatment should be started immediately along with antimalarial treatment. Other differential diagnoses that should also be considered include enteric fever, salmonella sepsis/septicaemia, dengue fever, leptospirosis, acute hepatitis, acute pyelonephritis, pneumonia or bronchopneumonia, pyogenic processes (abscesses), etc Specific antimalarial treatment It is essential that effective, parenteral (or rectal) antimalarial treatment in full doses be given promptly in severe malaria. Two classes of medicines are available for the parenteral treatment of severe malaria: The cinchona alkaloids (quinine and quinidine) or The artemisinin derivatives (artesunate, artemether and artemotil). Parenteral chloroquine is no longer recommended for the treatment of severe malaria, because of widespread resistance. Intramuscularly, sulfadoxine-pyrimethamine is also not recommended Pre-referral treatment options The risk of death from severe malaria is greatest in the first 24 hrs, yet, in most malaria endemic countries, the transit time between referral and arrival at health facilities able to administer intravenous treatment is usually prolonged; this delays the commencement of appropriate antimalarial treatment. As during this time the patient may deteriorate or die, it is recommended that patients be treated with the first dose of one of the recommended treatments before referral (unless the referral time is less than 6 hrs.). The following are options for pre-referral treatment: Artesunate IM (single dose) and refer ASAP Artemether IM (if artesunate is not available)

28 Quinine IM (if artesunate and artemether are not available) Rectal artesunate (where IM artesunate is not available for young children of less than 6 years of age, the use of rectal Artesunate (10 mg/kg bw) has been shown to reduce the risk of death and permanent disability). ii (Specific treatment) Artemisinin derivatives Various artemisinin derivatives have been used in the treatment of severe malaria, including artemether, artemisinin (rectal), artemotil and artesunate. Artesunate offers several programmatic advantages over quinine in terms of not requiring rate controlled infusion or cardiac monitoring. Intravenous Artesunate should be used in preference to quinine for the treatment of severe P. falciparum malaria in adults. iii Artesunate Artesunate is dispensed as a powder of artesunic acid. This is dissolved in sodium bicarbonate (5%) to form sodium artesunate. The solution is then diluted in approximately 5 ml of 5% dextrose and given by intravenous injection or by intramuscular injection to the anterior thigh. The solution should be prepared freshly for each administration and should not be stored. Artesunate has preferable Pharmacokinetic properties to artemether or artemotil, as it is watersoluble and can be given either by intravenous or intramuscular injection. There are rectal formulations of artesunate, artemether, artemisinin and dihydro-artemisinin. Artesunate (2.4 mg/kg bw IV or IM) is given on admission (time = 0), then at 12 and 24 hours. From the second day, once dose a day is the recommended treatment. Children weighing less than 20kg should receive a higher parenteral dose of Artesunate (3mg/kg bw IV or IM on admission, at 12 and 24 hours, then once a day) to ensure equivalent drug exposure (v). The artesunate suppository should be administered rectally with a dosis of 10 mg/kg body weight, single dose, as soon as the presumptive diagnosis of severe malaria is made. If an artesunate suppository is expelled from the rectum within 30 min of insertion, a second suppository should be inserted and, especially in young children, the buttocks should be held together for 10 min to ensure retention of the rectal dose of artesunate Artemether Artemether and quinine are acceptable alternatives if parenteral artesunate is not available. Artemether and artemotil are formulated in oil and are only to be administered by intramuscular -IM- injection (not suitable for intravenous- IV- administration). They are both absorbed erratically, particularly in very severely ill patients. Artemether dosis used is 3.2 mg/kg bw IM given on admission then 1.6 mg/kg BW per day. Presentations are available in 2 ml vials 40 mg/ml, in coconut or peanut oil Quinine Quinine treatment for severe malaria was established before modern clinical trial methods were developed. Several salts of quinine have been formulated for parenteral use, but the dihydrochloride is the most widely used. The maintenance dose of quinine (10 mg salt/kg Body weight) is administered at 8 hour intervals; starting 8 hours after the first dose. Pharmacokinetic modeling studies suggest that a loading dose of quinine (i.e. 20 mg salt/kg body weight twice the maintenance dose) reduces the time needed to reach therapeutic plasma concentrations. If ii Guidelines for the treatment of malaria 2nd edition WHO iii Guidelines for the treatment of malaria 2nd edition WHO

29 there is no improvement in the patient s condition within 48 hrs, the dose should be reduced by one third, i.e. to 10mg salt/kg bw every 12 hrs Intravenous (IV) route In Guyana, parenteral (IV) quinine is usually available as Quinine Dihydrochloride 300 mg/ml in 2 ml vials (600 mgs base salt). Rapid administration of quinine is unsafe. Each dose of parenteral quinine must be administered as a slow, rate controlled infusion (usually diluted in 5% dextrose and infused over 4 hours). The infusion rate should not exceed 5 mg salt/kg body weight per hour. Dosage for a 60kg patient is usually 1(one) vial 8 hourly by slow IV infusion diluted in 5% Dextrose over 4 hours, to avoid quinine induced hypoglycaemia. Quinine must never be given by intravenous bolus injection, as lethal hypotension may result Intramuscular (IM) route (in exceptional circumstances) Undiluted quinine dihydrochloride at a concentration of 300 mg/ml is acidic (ph 2) and painful when given by intramuscular injection, so it is best either formulated or diluted to concentrations of mg/ml for intramuscular injection Quinidine Quinidine commonly causes hypotension and concentration-dependent prolongation of ventricular depolarization (QT prolongation). Quinidine is thus considered more toxic than quinine and should only be used if no other effective parenteral drugs are available. Electrocardiography monitoring and frequent assessment of vital signs are required if Quinidine is used. iv Follow-up treatment Following initial parenteral treatment, once the patient can tolerate oral therapy, it is essential to continue and complete treatment with an effective oral antimalarial using a full course of an effective ACT. This may be artemether plus lumefantrine or dihydroartemisinin plus piperaquine, or artesunate plus clindamycin or doxycycline. Doxycycline is preferred to other tetracyclines because it can be given once daily, and does not accumulate in renal failure. Other follow-up treatment options include quinine plus clindamycin or doxycycline. As treatment with doxycycline only starts when the patient has recovered sufficiently, the 7-day doxycycline course finishes after the quinine, artemether or artesunate course. To note that clindamycin is a better option compared with doxycycline in children and pregnant women, as doxycycline cannot be given to these groups. Regimens containing mefloquine should be avoided if the patient presented initially with impaired consciousness. This is because of an increased incidence of neuropsychiatry complications associated with mefloquine following cerebral malaria. Any combination used as follow up treatment, the one dose primaquine should always be used as per the guidelines of P falciparum malaria. The current recommendation from experts opinion is that, before starting the oral follow-up treatment of severe malaria, parenteral antimalarials should have been given for a minimum of 24 hours once started (irrespective of the patient s ability to tolerate oral medication earlier) or until the patient is about to tolerate oral medication. iv, v Guidelines for the treatment of malaria 2 nd & 3 rd edition WHO

30 6.2.3 Additional aspects of therapy and management Adjustment of dosing in renal failure or hepatic dysfunction The dosage of artemisinin derivatives does not need adjustment in vital organ dysfunction. However, quinine and quinidine levels may accumulate in severe vital organ dysfunction. If the patient remains in acute renal failure or has hepatic dysfunction, then the dose of these drugs should be reduced by one third (to 10mg salt/kg bw every 12 hours) after 48 hrs. Dosage adjustments are not necessary if patients are receiving either hemodialysis or hemofiltration Immediate clinical management of severe manifestations and complications of P. falciparum malaria a Coma (cerebral malaria) Hyperpyrexia Hypoglycemia Convulsions Severe anemia Acute pulmonary edema c Acute renal failure Spontaneous bleeding and Coagulopathy Metabolic acidosis Shock Maintain airway; place patient on his or her side; exclude other treatable causes of coma (e.g. hypoglycemia, bacterial meningitis); avoid harmful ancillary treatment, such as corticosteroids, heparin and adrenaline; intubate if necessary. Administer tepid sponging, fanning, a cooling blanket and antipyretic drugs. Paracetamol is preferred over more nephrotoxic drugs (e.g. NSAIDs b ) Correct hypoglycemia with glucose containing infusion and maintain on check blood glucose. Maintain airways; treat promptly with intravenous or rectal diazepam or intramuscular paraldehyde. Check blood glucose. Transfuse with screened fresh whole blood. Prop patient up at an angle of 45, give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory pressure/ continuous positive airway pressure in life-threatening hypoxemia. Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal failure add hemofiltration or hemodialysis or if unavailable, peritoneal dialysis. Transfuse with screened fresh whole blood and cryoprecipitate, fresh frozen plasma or platelets, if available; give vitamin K injection. Exclude or treat hypoglycemia, hypovolemia and septicemia. If severe, add hemofiltration or hemodialysis. Suspect septicemia, take blood for cultures; give parenteral broadspectrum antimicrobials, correct hemodynamic disturbances. a It is assumed that appropriate antimalarial treatment would have been started in all cases. b Non-steroidal anti-inflammatory drugs. c Prevent by avoiding excess hydration Supportive management Patients with severe malaria require intensive nursing care, preferably in an intensive care unit where possible. Clinical observations and adjustments in therapy should be made as frequently as possible. The supportive management should include: Monitoring of vital signs, coma score, and urine output, as well as blood glucose every four hours, if possible, particularly in unconscious patients.

31 Fluid requirements should be assessed individually. Adults with severe malaria are very vulnerable to fluid overload. Children, on the other hand, are more likely to be dehydrated. The fluid regimen must also be tailored around infusion of the antimalarial drugs. Central venous pressure should be maintained at 0 5 cm. If available, hemofiltration (dialysis) should be started early for acute renal failure and severe metabolic acidosis, which are unresponsive to re-hydration. If blood glucose is < 2.2 mmol/l (40 mg/dl), then hypoglycemia should be treated immediately ( g/kg body weight of glucose IV (50% Dextrose diluted in 5% Dextrose or Dextro-Saline)). Hypoglycemia should be suspected in any patient who deteriorates suddenly. Patients with severe malaria with clinically significant disseminated intra-vascular coagulation should be given fresh whole blood transfusions and vitamin K. Patients with secondary pneumonia or with clear evidence of aspiration should be given empirical treatment with a third-generation cephalosporin, or the appropriate antibiotic of known sensitivity in that locality. In children with persistent fever despite parasite clearance, other possible causes of fever should be excluded. These include a systemic Salmonella infection and urinary tract infections, especially in catheterized patients. However, in most cases of persistent fever, no other pathogen is identified after parasite clearance. Antibiotic treatments should then be based on culture and sensitivity results, or, if not available, consider local antibiotic sensitivity patterns Fluid therapy The degree of fluid depletion varies considerably in patients with severe malaria. Thus, it is not possible to give general recommendations on fluid replacement. Each patient must be individually assessed and fluid resuscitation based on estimated deficit. In high-transmission settings, children commonly present with severe anemia and hyperventilation (sometimes termed respiratory distress ) resulting from severe metabolic acidosis and anemia; they should be treated by blood transfusion. In general, children tolerate rapid fluid resuscitation better than adults; they are less likely to develop pulmonary edema. In adults, there is a very thin dividing line between over-hydration, which may produce pulmonary edema, and under-hydration contributing to shock, worsening acidosis and renal impairment. Careful and frequent evaluations of the jugular venous pressure, peripheral perfusion, venous filling, skin turgor and urine output should be made. Where the nursing facilities permit, a central venous catheter should be inserted and the central venous pressure measured directly (target 0 5 cm H2O) Treatments not recommended Several other supportive strategies and interventions have been used in severe malaria patients to further reduce the mortality, but very few are supported by evidence of benefit and many have proved harmful. The following products are not recommended for the treatment of severe malaria: Heparin, prostacyclin, desferoxamine, pentoxifylline, low molecular weight dextran, urea, high-dose corticosteroids, acetylsalicylic acid, deferoxamine, anti-tumor necrosis factor antibody, cyclosporin, dichloroacetate, adrenaline and hyper immune serum. In addition, the use of corticosteroids increases the risk of gastrointestinal bleeding and seizures, and has been associated with prolonged coma resolution times when compared with placebos.

32 Blood transfusion Severe malaria is associated with rapid development of anemia as infected and uninfected erythrocytes are hemolyzed and/or removed from the circulation by the spleen. Ideally fresh cross-matched blood should be transfused. However, in most settings cross-matched, virus-free blood is in short supply. As with fluid resuscitation, there have not been enough studies to provide strong evidence-based recommendations on the indications for transfusion, so the recommendations given here are based on expert opinion. In high-transmission settings, blood transfusion is generally recommended for children with a hemoglobin level of < 5 g/100ml (hematocrit < 15%). In low-transmission settings, a threshold of 20% (hemoglobin 7 g/100 ml) is recommended. However, these general recommendations still need to be tailored to the individual, as the pathological consequences of rapid development of anemia are worse than those of chronic or acute anemia where there has been adaptation and a compensatory right shift in the oxygen dissociation curve Exchange blood transfusion There have been many anecdotal reports and several series claiming benefit for exchange blood transfusion (EBT) in severe malaria but no comparative trials, and there is no consensus on whether it reduces mortality or how it might work. Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved, or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of EBT Use of anticonvulsants The treatment of convulsions in cerebral malaria with intravenous (or, if this is not possible, rectal) benzodiazepines or intramuscular paraldehyde is similar to that for repeated seizures from any cause. A 20 mg/kg dose of Phenobarbital should not be given without respiratory support, but whether a lower dose would be effective and safer, or whether if ventilation is given, mortality would not be increased is not known. In the absence of further information, prophylactic anticonvulsants are not recommended Concomitant use of antibiotics The threshold for administering antibiotic treatment should be low in severe malaria. Septicemia and severe malaria are associated and there is a diagnostic overlap, particularly in children. Unexplained deterioration may result from a supervening bacterial infection. Although enteric bacteria (notably Salmonella) have predominated in most trial series, a variety of bacteria have been cultured from the blood of patients diagnosed as having severe malaria; so broad- spectrum antibiotic treatment should be given initially until a bacterial infection is excluded. 7. Additional aspects of clinical management 7.1 Can the patient take oral medications? Some patients cannot tolerate oral treatment, and will require parenteral or rectal administration for 1 2 days until they can swallow and retain oral medication reliably. Although such patients may not show signs of severity, they should receive the same antimalarial dose regimens as for severe malaria. 7.2 Does the patient have very high parasitaemia (hyperparasitaemia) a?

33 Some patients may have no signs of severity but on examination of the blood film are found to have very high parasitaemia. The risks associated with high parasitaemia vary depending on the age of the patient and on transmission intensity. Thus cut-off values and definitions of hyperparasitaemia also vary. Patients with high parasitaemia are at an increased risk of treatment failure and of developing severe malaria, and therefore have an increased risk of dying. These patients can be treated with the oral ACTs recommended for uncomplicated malaria. However, they require close monitoring to ensure that the drugs are retained and that signs of severity do not develop, and they may require a longer course of treatment to ensure cure. a In Guyana hyperparasitemia means +++ (3 plus) and above. 7.3 Use of antipyretics (management of fever) Fever is a cardinal feature of malaria, and is associated with constitutional symptoms of lassitude, weakness, headache, anorexia and often nausea. In young children, high fevers are associated with vomiting, inclusive of medication, and seizures. Fever treatment is with antipyretics and, if necessary, tepid sponging. Care should be taken to ensure that the water is not too cool as, paradoxically, this may raise the core temperature by inducing cutaneous vasoconstriction. Paracetamol (acetaminophen) 15 mg/kg every 4 hours is widely used; it is safe and well tolerated given orally or as a suppository. Ibuprofen (5 mg/kg) has been used successfully as an alternative in malaria and other childhood fevers, although there is less experience with this compound; however, acetylsalicylic acid (aspirin) should not be used in children because of the risks of Reye s syndrome. There has been some concern that antipyretics might attenuate the host defense against malaria, as their use is associated with delayed parasite clearance. However, this appears to result from delaying cyto-adherence, which is likely to be beneficial. There is no reason to withhold antipyretics in malaria. 7.4 Use of antiemetic Vomiting is common in acute malaria and may be severe. Antiemetic are widely used, although there have been no studies of their efficacy in malaria, and no comparisons between different antiemetic compounds. 7.5 Management of seizures Generalized seizures are more common in children with falciparum malaria than in those with the other malarias. This suggests an overlap between the cerebral pathology resulting from malaria and febrile convulsions. Sometimes these seizures are the prodrome (a symptom indicating the onset of a disease) of cerebral malaria. If the seizure is ongoing, the airway should be maintained and anticonvulsants given. If it has stopped and the core temperature is above 38.5 ºC the child should be treated as indicated in section There is no evidence that prophylactic anticonvulsants are beneficial in otherwise uncomplicated malaria. 7.6 Incorrect approaches to treatment A potentially dangerous practice is to give only the first dose of the treatment course for patients with suspected but unconfirmed malaria, with the intention of giving full treatment if the diagnosis is eventually confirmed. This practice is not recommended; if malaria is suspected and the decision to treat is made, then a full effective treatment is required whether the diagnosis is confirmed by a test. Except for artemether + lumefantrine, the partner medicines of all other ACTs have been previously used as monotherapies, and continue to be available as such in many countries. Their

34 continued use as monotherapies can potentially compromise the value of ACTs by selecting for drug resistance. The withdrawal of artemisinin and other monotherapies is recommended. 8. Treatment of malaria in specific populations and special situations 8.1 Treatment of malaria in pregnancy Pregnant women with acute malaria are a high-risk group, and must receive prompt and effective treatment with antimalarials. Malaria in pregnancy is associated with low birth weight, fetal death, premature labor, anemia and, increased risk of severe malaria. Women in the second and third trimesters of pregnancy are more likely to develop severe malaria than other adults and this is often complicated by pulmonary edema and hypoglycemia. Maternal mortality from severe malaria is approximately 50%, which is higher than in non-pregnant adults. Therefore, all pregnant women living in malaria endemic areas in Guyana should have a malaria smear, at each antenatal check-up, and if positive, start treatment with antimalarials promptly. Also, all pregnant women who present with a fever, who are from or have visited a malaria endemic area, require a malaria smear and treatment if the smear is positive. As malaria in pregnancy can rapidly progress from uncomplicated to severe, with devastating consequences, all women with malaria in pregnancy should be reviewed by a MEDEX or a doctor. If the woman first presents to a health post, the Community Health Worker (CHW) should commence oral therapy immediately and refer her to the health centre where she can be seen by a MEDEX or a doctor. After assessment, and recommended observation, the MEDEX or the doctor can seek expert obstetric advice. If severe malaria is suspected all pregnant women should start treatment with parenteral antimalarials and be transferred to Georgetown Public Hospital immediately. Parenteral artesunate is preferred over quinine in the second and third trimesters, because quinine is associated with recurrent hypoglycemia. In the first trimester, the risk of hypoglycemia is lower and the uncertainties over the safety of the Artemisinin derivatives are greater. However, weighing these risks against the evidence that artesunate reduces the risk of death from severe malaria, treatment must not be delayed. If any one of the drugs artesunate, artemether or quinine is available, then it should be started immediately. Obstetric advice should be sought at an early stage, the pediatricians alerted, and blood glucose checked frequently. Hypoglycemia should be expected, and it is often recurrent if the patient is receiving quinine. Severe malaria may also present immediately following delivery. Postpartum bacterial infection is a common complication in these cases. There is insufficient information on the safety and efficacy of most antimalarials in pregnancy, particularly for exposure in the first trimester, and so treatment recommendations are different to those for non-pregnant adults. Organogenesis occurs mainly in the first trimester and this is therefore the time of greatest concern for potential teratogenicity; the antimalarials available in Guyana that are considered safe in the first trimester of pregnancy are quinine, chloroquine, and clindamycin. Of these, quinine remains the most effective and can be used in all trimesters of pregnancy including the first trimester. While there is insufficient evidence to ensure the safety of artemisinin derivatives during 1 st trimester, registers of pregnancies inadvertently receiving ACT during the 1 st trimester have not demonstrated increased risk thus far. Therefore, inadvertent exposure to antimalarials is not an indication for termination of the pregnancy. Moreover, artemisinin derivatives are recommended in the 1 st trimester, after treatment failure with quinine. Increasing experience with artemisinin derivatives during the 2 nd and 3 rd trimesters have not demonstrated adverse effects on the mother or the fetus and they are now routinely used. Given the disadvantages of

35 quinine, i.e. the long course of treatment, and the increased risk of hypoglycemia in the second and third trimesters, ACTs are now recommended as 1 st line treatment for these trimesters. There is insufficient evidence to base the choice of a combination partner for the ACTs in pregnancy. Clindamycin is considered safe, but both drugs (clindamycin and the artemisinin partner) must be given for 7 days. Primaquine and the tetracyclines SHOULD NOT be used in pregnancy Treatment of uncomplicated & severe P. falciparum malaria in pregnancy The severity of a patient s condition and their prognosis is dependent on several clinical parameters. Assessing these parameters determines their status as uncomplicated malaria or complicated/severe malaria, which in turn determines the appropriate treatment algorithm. The table below summarizes the clinical and laboratory features of complicated or severe malaria. Clinical findings: - Impaired consciousness or coma,(hallucinations, disorientation in time place or person) Prostration, i.e. generalized weakness so that the patient is unable walk or sit up without Assistance Failure to feed ( unable to swallow ) Multiple convulsions more than two episodes in 24 hrs Deep slow breathing, respiratory distress (acidotic breathing) Circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults and < 50 mm Hg in children Clinical jaundice plus evidence of other vital organ dysfunction Haemoglobinuria (as distinct to haematuria) Abnormal spontaneous bleeding (blood-shots in conjunctiva or about body) Pulmonary oedema (radiological or clinical observation). Test values in severe malaria Laboratory findings: Normal test values Hypoglycaemia (blood glucose < 40 mg/dl) 80 to 120 mg/dl Metabolic acidosis (plasma bicarbonate < 15 mmol/l) Severe normocytic anaemia (Hb < 7 g/dl; Packed Cell Volume (PCV) < 15%) 19 to 25 meq/liter Male (M) Hb = g/dl; PCV = % Female (F) Hb = g/dl; PCV % Normally, hemoglobin does not appear in the Haemoglobinuria, urine. Hyperparasitaemia (> 2%/ /μl in low Parasite does not appear in the smear. intensity transmission areas or > 5 %.

36 In local settings a qualitative parasite count of +++ ( 3 plus ) or greater with or without gametocytaemia. Hyperlactataemia (lactate > 5 mmol/l) mmol/l Renal impairment (serum-creatinine > 265 μmol/l). F= 0.5 to 1.0 mg/dl (about μmol/l) M= 0.7 to 1.2 mg/dl ( μmol/l) For quick reference, an easier distinction might be the following table: Uncomplicated malaria in pregnancy Fever Shivers/ chills/ rigors Headaches Muscle& joint pains Nausea or vomiting False labour pains Severe malaria Signs of uncomplicated malaria + one or more of the following: dizziness breathlessness or difficulty breathing sleepy, drowsy or coma confusion fits (seizures) jaundice (yellow skin & eyes) severe dehydration Treatment of uncomplicated P. falciparum malaria in Pregnancy Uncomplicated falciparum malaria can be treated with oral medication. The choice of drug is dependent on the gestational age of the pregnancy to reduce the risk of teratogenicity. Table 7 Treatment for pregnant women with falciparum infection by trimester TREATMENT OF UNCOMPLICATED MALARIA: 1 ST TRIMESTER: QUININE 600mg orally, three times daily (or 450mg if <50kg) for 7 days PLUS CLINDAMYCIN 450mg orally, three times daily (or 300mg if <50kg) for 7 days 2 ND & 3 RD TRIMESTER: Age (in years) No. of tablets at approximate timing of dosing Body weight(kg) 0 h 8 h 24 h 36 h 48 h 60 h

37 > >34 *Coartem tab: 20mg artemether + 120mg lumefantrine. **Adult dose (>35kg) = 4 tabs Treatment of severe or complicated falciparum malaria in pregnancy Complicated falciparum malaria is an emergency. Treatment should be given according to the severity and associated complications, best resolved by the treating physicians and meticulous nursing care. Table 7.1 Treatment of complicated malaria in pregnancy 1 ST TRIMESTER TREATMENT OF SEVERE/COMPLICATED MALARIA : QUININE 600mg IV in 5% Dextrose over 4hrs, every 8 hrs (10mg/kg, max 700mg) Should not exceed 5mg salt/kg over 4hr body weight per hr PLUS CLINDAMYCIN 600mg IV, every 12 hours (10mg/kg) Should not exceed 1.2g in a single dose PARENTERAL ANTIMALARIALS for a minimum of 24 hours & until well enough to tolerate oral medication, then switch to oral quinine & clindamycin for a total of 7 days. 2 ND & 3 RD TRIMESTER ARTEMETHER 160mg IM loading dose ; followed by 80mg IM daily (3.2mg/kg BW/day IM) (1.6mg/kg BW/day IM) OR QUININE 600mg IV in 5% Dextrose, over 4hrs, every 8 hrs(10mg/kg, max 700mg) PLUS CLINDAMYCIN 600mg IV, every 12 hours (10mg/kg) PARENTERAL ANTIMALARIALS for a minimum of 24hours & until well enough to tolerate oral medication, then switch to Coartem for minimum of 3 days. NB: Quinine, should never be given undiluted IV. It is usually diluted in 5% dextrose to prevent hypoglycaemia. A loading dose of Quinine is no longer given, as evidence suggests no improvement in outcome. Doses are calculated at 10 mg/ kg given 8 hourly and the infusion rate should not exceed 5 mg/kg per hour. The parenteral treatment should be given for a minimum of 24 hours and once the patient tolerates oral therapy, oral Quinine and Clindamycin, should be given to complete 7 days of treatment. Intravenous quinine should be administered at the recommended dosage for the first 48 hours even if acute renal failure (ARF) or severe jaundice is present. If there is no clinical improvement after 48 hours of parenteral therapy, the maintenance dose of parenteral quinine should be reduced by one third.

38 All patients receiving IV quinine should be monitored for hypoglycaemia. As the risk of hypoglycaemia also increases in the 2 nd & 3 rd trimesters of pregnancy, women receiving IV quinine at this time should be monitored particularly carefully with RBS checked every 3-4 hours Treatment options for P. vivax & P. malariae Chloroquine 25mg/kg divided over 3 days is the recommended treatment in pregnancy. Primaquine is contraindicated in pregnancy and should be withheld until after delivery. All women with malaria in pregnancy should be scheduled for a follow up visit for malaria review, postpartum. Treatment of the blood stage: Table 8 Number of tablets of Chloroquine 150 mg base to be given daily Age in years Duration in Days Day 1 Day 2 Day Only clinically vivax infections that have been confirmed microscopically should be treated. Radical Cure: In women who are pregnant or breastfeeding, consider weekly chemoprophylaxis with chloroquine until delivery and breastfeeding are completed, then on the basis of G6PD status, treat with primaquine to prevent future relapse. 8.2 Lactating women The amounts of antimalarials that enter breast milk and are therefore likely to be consumed by the breast-feeding infant are relatively small. Tetracycline is contraindicated because of their effect on the infant s bone s and teeth. Primaquine should not be given to lactating women due to the risk of hemolysis in breast-feeding infants with G6PD deficiency. The treatment of lactating women is the same as that of non-pregnant women (see Table 4.1) once their breast fed infants have been checked for G6PD deficiency. In patients known to be G6PD deficient, primaquine may be considered at a dose of 0.75mg base/kg bw once a week for 8 wks. The decision to give or withhold primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services. (vi) If G6PD testing is not available, a decision to prescribe or withhold primaquine should be based on the balance of the probability and benefits of preventing relapse against the risks of primaquine-induced haemolytic anaemia. This depends on the population prevalence of G6PD deficiency, the severity of the prevalent genotypes and on the capacity of health services to identify and manage primaquine-induced haemolytic reactions. (vii)

39 8.3 Treatment of malaria in under 5kg (6 months) It is essential to refer all such infants to health facilities where comprehensive investigations can be undertaken to adequately rule out possible differentials of fever, as malaria is not a common cause of fever in this age group. Even where malaria is the cause of the fever, this can co-exist with other potentially serious bacterial infections, which should be adequately diagnosed and treated. Treat infants weighing < 5kg with uncomplicated P. falciparum malaria with an ACT at the same mg/kg bw target dose as for children weighing 5kg. However, Quinine (10mg base/kg three times daily for 7 days) with Clindamycin (7 mg per oral (PO), or 10 mg / kg IV, every 12 hours) can also be used. If PO isn t possible and the referral center is at least 6 hours away, give 1 dose of artemeter per rectum (10 mg/ kg). vi, vii Guideline for the treatment of malaria- 3 rd edition WHO (2015) 8.4 People living with HIV or other high risk groups for Malaria Worsening HIV-related immunosuppression may lead to more severe manifestations of malaria. In HIV-infected pregnant women, the adverse effects of placental malaria on birth weight are increased. In stable endemic areas, HIV-infected patients with partial immunity to malaria may suffer more frequent and higher density infections; while in areas of unstable transmission, HIV infection is associated with an increased risk of severe malaria and malariarelated deaths. There is limited information at present on how HIV infection modifies the therapeutic responses to ACTs or on interactions between antimalarial medicines and antiretroviral. The most significant interactions seem to be the additional risk of hepatotoxicity with Efavirenz and anaemia with Zidovudine. Early studies with less effective regimens suggested that increasing HIV-related immunosuppression was associated with decreased treatment response, increased parasite burdens and reduced host immunity. Both of them are now known to occur with HIV infection. Therefore as with all high risk groups early detection and prompt treatment with effective antimalarials is required to prevent progression to severe malaria. 8.5 Other conditions Other groups at high risk of acquiring malaria and developing severe malaria include the elderly, people with severe malnutrition and immunocompromised people for whatever reason, e.g., uncontrolled diabetes. For all these groups prompt diagnosis and treatment is recommended to prevent progression to severe disease. (Guidelines for the treatment of malaria 2 nd & 3 rd edition WHO).

40 FLOWCHART FOR TREATMENT OF MALARIA IN PREGNANCY DOES SHE HAVE ANY OF THE FOLLOWING SIGNS OR RESULTS. impaired consciousness generalised weakness -unable to walk or sit without assistance failure to feed multiple convulsions (>2 in 24hs) respiratory distress shock sbp<70mmhg jaundice coke coloured urine black water fever abnormal spontaneous bleeding pulmonary oedema (on xray) hypoglycaemia (RBS <40mg/dL) metabolic acidosis (bicarb<15mmol/l, lactate>5mmol/l) severe anaemia (Hb<5g/dL) renal impairment (Cr>265umol/L) haemoglobinuria hyperparasitaemia (>2% or +++). YES NO COMPLICATED OR SEVERE MALARIA REQUIRES PARENTERAL THERAPY & ADMISSION TO HDU/ICU UNCOMPLICATED MALARIA FOR ORAL THERAPY ON THE WARD IS SHE < 12 WEEKS GESTATION YES NO YES NO 1 ST TRIMESTER QUININE 600mg IV in 5% Dextrose over 2hrs tid PLUS CLINDAMYCIN 600mg IV tid for minimum 24 hours & tolerating orals, then change to oral quinine & clindamycin for a total of 7 days 1 ST TRIMESTER QUININE po 600mg po tid (or 450mg if <50kg) PLUS CLINDAMYCIN po 450mg po tid (or 300mg if <50kg) For a total of 7 days 2 ND & 3 RD TRIMESTER 2 ND & 3 RD TRIMESTER ARTEMETHER 160mg IMI stat followed by 80mg daily OR QUININE 600mg IV in 5% Dextrose over 2hrs, tid PLUS CLINDAMYCIN 600mg IV, tid COARTEM tabs (20/120) Day 1-4 tabs po stat & in 8 hrs Day 2 & 3-4 tabs mane & nocte after minimum 24hrs & able to tolerate oral medication Fig. 1

41 Simplified Flow Chart of Treatment for Malaria in Pregnancy Uncomplicated malaria in pregnancy Fever Shivers/ chills/ rigors Headaches Muscle& joint pains Nausea or vomiting False labour pains Severe malaria Signs of uncomplicated malaria + one or more of the following: dizziness breathlessness or difficulty breathing sleepy, drowsy or coma confusion fits (seizures) jaundice (yellow skin & eyes) severe dehydration Uncomplicated Symptoms Complicated Symptoms Patient <14 weeks Gestation YES NO 1 st Trimester Quinine 600mg PO TID x 7/7 + Clindamycin 450mg PO BD x 7/7 Second Line Artesunate 2mg/kg PO OD x 7/7 + Clindamycin 10mg/kg PO BD 7/7 2 ND and 3 rd Trimester Coartem 4 tabs PO BD x 3/7 1 st Trimester Quinine 600mg incorporated in 5% Dextrose Saline over 4 hours TID x 7/7 + Clindamycin 600mg IV BD x 7/7 2 nd and 3 rd Trimester Artemeter 160mg IM stat then 80mg OD x 3/7 Or Quinine + Clindamycin for seven days is safe in all trimesters