The fight against Malaria in Malaria-Endemic Countries

Angenommen von der Medizinischen Fakultät der Heinrich-Heine-Universität

  Th he e f fi ig gh ht t a ag ga ai in ns st t M Ma al la ar ri ia a i in n M Ma al la ar ri ia a E En nd de em mi ic c T  

  Co ou un nt tr ri ie es s C  

  Ta ab bl le e o of f C Co on nt te en nt ts s T  

0.  TABLES AND FIGURES  3

1.  LIST OF ABBREVIATIONS  4

1.  LIST OF ABBREVIATIONS  4

2.  INTRODUCTION  6

2.1  HUMAN MALARIA  7

2.1.1  Causative Parasites and their Life Cycle  7

2.1.2  Clinical Signs and Symptoms  10

2.1.2.1  General Clinical Features  10

2.1.2.2  Severe Falciparum Malaria  11

2.1.3  Diagnosis  12

2.1.4  Laboratory Findings  14

2.2  HISTORY  15

2.2.1  History of the Human Malaria Parasites  15

2.2.2  Geographical Malaria History  15

2.2.3  History of Malaria Handling  16

2.3  EPIDEMIOLOGY  17

2.3.1  Malaria Transmission  17

2.3.2  Prevalence and Incidence  18

2.3.3  Endemicity  19

2.3.3.1  Stable Endemic Malaria  20

2.3.3.2  Unstable and Epidemic Malaria  20

2.3.4  Epidemic preparedness prediction and prevention of epidemics  21

2.3.5  Epidemiological information systems  21

2.3.6  Resistance Pattern  22

2.3.7  Travelers  25

2.4  MALARIA IN THE PEDIATRIC POPULATION AND PREGNANT WOMEN  25

2.4.1  Pediatric Population  26

2.4.2  Pregnant Women  27

2.5  MALARIA AS A DISEASE OF THE POOR  28

3.  GLOBAL MALARIA CONTROL STRATEGIES  29

3.1  PREVENTIVE MEASURES  29

3.1.1  History of the Global Malaria Control Strategies  29

3.1.2  General preventative Measures  30

3.1.3  Vector Control  30

3.1.3.1  Insect repellents  30

3.1.3.2  Insecticide treated nets (ITNs)  31

3.1.3.3  Indoor Residual Spraying  32

3.1.3.4  Recommendations  32

3.1.4  Chemo-Prophylaxis  33

3.1.5  Vaccination  34

3.1.6  Other Preventive Measures  35

3.2  CURRENT TREATMENT APPROACHES  35

3.2.1  Benefits and Liabilities of Existing Anti-Malarial Drugs  36

  Magister-Thesis in Public Health  

  Dr Petra Heyen The fight against malaria in malaria-endemic countries  

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3.2.1.1  Quinolines  36

3.2.1.2  Artemisinins  36

3.2.1.3  Antifolates  37

3.2.1.4  Antibiotics  38

3.2.2  Combination Therapy  38

3.3  TREATMENT POLICIES AND PRACTICES  39

3.4  MALARIA PREVENTION AND TREATMENT IN PREGNANT WOMEN  40

4.  GLOBAL PUBLIC INITIATIVES PUBLIC PRIVATE PARTNERSHIPS  43

4.1  WORLD HEALTH ORGANIZATION (WHO)  47

4.1.1  WHO Interactions with NGOs  48

4.1.2  WHO Essential Drugs  49

4.1.3  WHO and the Private Sector Public Private Partnerships (PPPs)  49

4.2  SPECIAL PROGRAM FOR RESEARCH AND TRAINING IN TROPICAL DISEASES (TDR)  51

4.3  MEDICINES FOR MALARIA VENTURE (MMV)  56

4.4  ROLL BACK MALARIA (RBM)  58

4.5  GLOBAL ALLIANCE FOR VACCINES AND IMMUNIZATION (GAVI)  59

4.6  PROGRAM FOR APPROPRIATE TECHNOLOGY IN HEALTH (PATH) AND MALARIA VACCINE  

  INITIATIVE (MVI)  60

4.7  WORLD BANK  62

4.8  BILL MELINDA GATES FOUNDATION AS AN EXAMPLE FOR PRIVATE FOUNDATIONS  63

4.9  DONATION-DISTRIBUTION PARTNERSHIPS  64

5.  HEALTH ECONOMY  66

5.1  MALARIA ASSOCIATED ECONOMIC MEASURES  66

5.2  COSTS OF ANTI-MALARIAL DRUGS  68

5.3  FINANCING OF ANTI-MALARIAL DRUGS  70

5.4  REGULATORY AGENCIES CONTRIBUTIONS  71

5.4.1  Orphan Drugs  71

5.4.2.  Pediatric Laws  73

5.4.3  International Conference on Harmonization of Technical Requirements for Registration of  

  Pharmaceuticals for Human Use (ICH)  74

5.5  PHARMACEUTICAL INDUSTRY  75

5.5.1  Overview on Development of New Drugs  76

5.5.2  Development of New Anti-malarial Drugs  79

5.5.3  Glaxo Smith Kline (GSK)  82

6.  DISCUSSION  84

6.1  THE CHALLENGE OF MALARIA IN ENDEMIC COUNTRIES  84

6.2  ROLE OF THE ENDEMIC COUNTRIES  86

6.3  PUBLIC-PRIVATE PARTNERSHIPS (PPPS)  88

7.  CONCLUSION  90

8.  REFERENCES  91

  Magister-Thesis in Public Health  

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0.  T Ta ab bl le es s a an nd d F Fi ig gu ur re es s  0

  Ta ab bl le es s T  

TABLE 1:  CHARACTERISTICS OF PLASMODIUM SPECIES INFECTING HUMANS (SOURCE: 118 )  8

TABLE 2:  SIGNS AND SYMPTOMS OF SEVERE MALARIA IN ADULTS AND CHILDREN (SOURCE: 58 )  26

TABLE 3:  DEATHS ATTRIBUTABLE TO INFECTIOUS DISEASES BY REGION 2001 (SOURCE: 89 )  28

TABLE 4:  OVERVIEW ON DRUGS DEVELOPED BY TDR IN COOPERATION WITH AN INDUSTRIAL PARTNER  

  (SOURCE: 94 )  55

TABLE 5:  PHILANTROPIC DRUG DONATION PROGRAMMES (SOURCE: 57 )  65

TABLE 6:  THE MALARONE DONATION PROGRAMME (SOURCE: HTTP: WWW MALARONEDONATION ORG)  66

TABLE 7:  MANUFACTURER AND CURRENT PRICES FOR ARTESUNATE (600MG) AND ARTESUNATE PLUS  

  AMODIAQUINE BLISTER PRESENTATIONS (SOURCE: 29 )  69

TABLE 8:  COMMITTEE FOR ORPHAN MEDICINAL PRODUCTS (COMP) PUBLIC SUMMARY OF NEGATIVE OPINION  

  FOR THE ORPHAN DRUG DESIGNATION OF LAPDAP (SOURCE: DOCUMENT EMEA COMP 1073 02 REV  1

  LONDON 8 JANUARY 2003)  72

TABLE 9:  ATTRITION RATES FOR THE DIFFERENT PHASES OF DRUG RESEARCH AND DEVELOPMENT (SOURCE:  

  75 )  76

  Fi ig gu ur re es s F  

  FIGURE 1: LIFE CYCLE P FALCIPARUM (SOURCE: 2 )  9

  FIGURE 2: PARASITE LIFE CYCLE AND PATHOGENESIS OF FALCIPARUM MALARIA (SOURCE: NATIONAL CENTER  

  FOR DISEASAE CONTROL HTTP: WWW CDC GOV MALARIA BIOLOGY LIFE CYCLE HTM )  10

  FIGURE 3: SPECIES IDENTIFICATION OF MALARIA PARASITES IN GIEMSA STAINED THICK BLOOD FILMS (SOURCE:  

  58 )  13

  FIGURE 4: APPEARANCE OF P FALCIPARUM PARASITE STAGES IN GIEMSA-STAINED THIN AND THICK BLOOD  

  FILMS (SOURCE: 58 )  14

  FIGURE 5: GLOBAL DISTRIBUTION OF MALARIA (SOURCE: 99 )  18

  FIGURE 6: MORBIDITY AND MORTALITY IN DIFFERENT SETTINGS OF ENDEMICITY (SOURCE: 46 )  20

  FIGURE 7: GLOBAL MALARIA STATUS (SOURCE: 120 )  23

  FIGURE 8: DRUG-RESISTANT MALARIA AND PESTICIDE-RESISTANT MOSQUITOS (SOURCE: 120 )  24

  FIGURE 9: TIMING OF IPT (SOURCE: 114 )  43

  FIGURE 10: OVERVIEW OF MALARIA CO-ORDINATION AND FUNDING ORGANISATIONS (SOURCE: 112 )  44

  FIGURE 11: TDR S COLLABORATIONS WITH THE PHARMACEUTICAL INDUSTRY  

  (SOURCE: HTTP: WWW WHO INT TDR INDEX HTML )  52

  FIGURE 12: TDR BUDGET BY DISEASE 1999 2000 (SOURCE: HTTP: WWW WHO INT TDR INDEX HTML )  53

  FIGURE 13: TDR BUDGET BY RESEARCH AREA 1999 2000 (SOURCE:  

  HTTP: WWW WHO INT TDR INDEX HTML )  53

  FIGURE 14: GRANTS PAID BY THE BILL MELINDA GATES FOUNDATION (SOURCE:  

  HTTP: WWW GATESFOUNDATION ORG DEFAULT HTM)  64

  FIGURE 15: PER CAPITA GOVERNMENT EXPENDITURE ON HEALTH IN AFRICA (SOURCE: 1 )  68

  FIGURE 16: OVERVIEW ON DEVELOPMENT OF NEW DRUGS (SOURCE: 63 )  76

  FIGURE 17: INDUSTRY COSTS AND REVENUES ASSOCIATED WITH PRODUCT DEVELOPMENT (SOURCE: 92 )  78

  FIGURE 18: WORLD PHARMACEUTICAL MARKET 1997 (SOURCE: HTTP: WWW IMS  

  GLOBAL COM INSIGHT REPORT GLOBAL REPORT HTM)  79

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1. . L Li is st t o of f A Ab bb br re ev vi ia at ti io on ns s 1

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ACT AIDS ARDS ARIPO B.C.

CADREAC

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COMP CQ CSP DDT DDW DEET DFID EDM EFPIA EFTA EIR EMEA ESAC GCP GDP GMP GNP GSK GW HIPC HIV IBRD ICC IDA IFPMA IMCI IP IPT Intermittent Preventive Treatment _______________________________________________________________________________ Magister-Thesis in Public Health

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ITN insecticide-treated netting JPMA LICUS MCH MHRA MMV MPS MVI NAI NGO NIH OPD OTC P.

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PATH PhRMA PPP PR PRS R&D RBC RBM SP TB TDR TRIPS TSR UN UNDP UNICEF USD WHA WHO WTO

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2. . I In nt tr ro od du uc ct ti io on n 2

Malaria is a life-threatening parasitic disease transmitted by mosquitoes. It was once thought that the disease came from fetid marshes, hence the name ‘mal aria,’ (bad air). In 1880, scientists discovered the real cause of malaria—a one-cell parasite called plasmodium. Later they discovered that the parasite is transmitted from person to person through the bite of a female Anopheles mosquito, which requires blood to nurture her eggs [84].

Malaria was eliminated from the United States and from most of Europe during the first half of the twentieth century as a result of changes in land use, agricultural practices, house construction and some targeted vector control. The development of the highly effective, residual insecticide Dichloro-Diphenyl-Trichlorethane (DDT) initiated a global eradication program in the 1950s and 1960s which was very successful in many countries such as India, Sri Lanka and the former Soviet Union. However, this success was not sustained because of the costs of the program, the resistance of many communities to repeated spraying of their houses and the emergence of resistance to DDT. Furthermore, with the exception of a few pilot schemes, no sustained effort was made to control malaria in sub-Saharan Africa, the main area of malaria endemicity in the world. The elimination of malaria from most of Europe and from North America and the failure of the global malaria eradication program led to a loss of interest in malaria for a period of about 25 years from the early 1970s to the late 1990s. Only 3 of 1,223 new drugs developed during the period 1975–1996 were anti-malarials [113]. Industry lost interest in the development of insecticides for public health use and support for research on malaria declined. Furthermore, in many malaria-endemic countries, national malaria control programs, established during the colonial period and sustained during the period when elimination of malaria was considered to be an achievable goal, collapsed. Thus, for many years, there was little change in mortality and morbidity from malaria, especially in Africa. Recently, the malaria situation has deteriorated and mortality from malaria is increasing in sub-Saharan Africa [37].

The past five years have seen a pronounced re-awakening of interest in malaria in the richer countries of the world. Statements on the need for greater efforts to control malaria have been made at a number of high-profile political meetings in Africa and in industrialized countries. Research scientists have had an important catalytic role in this process. In 1997, a meeting was held in Dakar, Senegal, attended by most of the small number of scientists undertaking malaria research in Africa and by their sponsors, which established priorities for a multidisciplinary program of research. [37].

At present, about 100 countries or territories in the world are considered malarious, almost half of which are in Africa, south of the Sahara. Although this number is considerably less than it was in the mid-1950s (140 countries or territories), more than 2,400 million of the world’s population are still at risk. The incidence of malaria worldwide is estimated to be 300–500 million clinical cases each year, with about 90% of these occurring in Africa — mostly caused by P. falciparum and secondly by P. vivax . The most important reason for the persistence of malaria in Africa is the presence of the vector Anopheles (A.) gambiae. A. gambiae feeds preferentially on humans and is long-lived, making it particularly effective at transmitting malaria from one person to the next. The entomological inoculation rate (EIR), a measure of the frequency with which an individual is bitten by an infectious mosquito, rarely exceeds 5 per year in Asia or South America. In contrast, EIRs of over 1,000 have been recorded in several parts of sub-Saharan Africa (“Hyperendemicity”). In savannah areas of West Africa, it is not unusual to collect in one room during the course of a single night several hundred mosquitoes of the A. gambiae complex, 1–5% of which are infectious. The task of interrupting transmission in such a situation is daunting [37]. Malaria is thought to kill between 1.1 and 2.7 million people worldwide each year, of whom about 1 million are children under the age of 5 years in Africa. These childhood deaths, resulting mainly from cerebral malaria and anemia, constitute nearly 25% of child mortality in Africa and take more than 2000 young lives _______________________________________________________________________________ Magister-Thesis in Public Health Dr. Petra Heyen „The fight against malaria in malaria-endemic countries“

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every day in the world [1], [37], [99]. or one life every 30 seconds. Case fatality rates of 10–30% have been reported among children referred to hospital with severe malaria, although these rates are even higher in rural and remote areas where patients have restricted access to adequate treatment [94]. In endemic countries, one third of all clinic visits and at least a quarter of all hospital admissions are for malaria [1].

One of the biggest achievements in Public Health is the development of vaccines for polio and other diseases which has been funded publicly [56], and malaria should follow these examples.

Deaths from malaria in countries outside Africa occur principally in non-immune people who become infected with P. falciparum in areas where diagnosis and treatment are not available. One of the greatest challenges facing malaria control worldwide is the spread and intensification of parasite resistance to anti-malarial drugs. The limited number of such drugs has led to increasing difficulties in the development of anti-malarial drug policies and adequate disease management. The challenging task is to overcome resistance and develop safe and effective drugs as well as sustainable preventive measures mainly in young children and pregnant women [94]. As the disease mainly occurs in the poorest populations of the world the pharmaceutical industry in developed countries has little economic interest in the development of anti-malarial drugs (little chance of profits or only break-even point for investment). Therefore, a system of incentives has to be established in order to make drug development in this sector more attractive to the innovative pharmaceutical companies.

2.1 Human Malaria

2.1.1 Causative Parasites and their Life Cycle

Malaria is a protozoan disease transmitted by the bite of Anopheles mosquitoes. It is the most important parasitic disease in humans. Four species of the genus Plasmodium infect humans:

• P. falciparum

• P. malariae

• P. vivax

• P. ovale.

Recently, a fifth species has been found to be causative for human malaria: P. knowlesi which was previously thought to be infective in long-tailed macaque monkeys only. Obviously, P. knowlesi infections have been wrongly diagnosed as P. malariae malaria. Further work is needed to determine whether human P. knowlesi infections are acquired from macaque monkeys or whether a host switch to human beings has occured [107].

Among the four well-known species of human malaria, P. falciparum stands out as the most malignant form and the only one where severe complications such as cerebral malaria, severe anemia, renal failure and pulmonary affection are frequently seen. Some features, important for disease severity and pathogenesis, separate P. falciparum from the other human malarias: the ability to invade erythrocytes of all ages causing very high parasitemias, enhanced growth and the capacity to adhere to vascular endothelium through the process of sequestration. The infected erythrocyte can adhere to the endothelium and to uninfected erythrocytes via parasite-derived proteins expressed on the surface of the infected erythrocyte. This enables the parasite to avoid clearance by the immune system in the spleen. The adherence causes a considerable obstruction to tissue perfusion. The destruction of the red blood cells is an inevitable part of falciparum malaria [42], [64].

Genetic differences between individuals regarding the immune response mounted by the host are also of great significance for bringing about severe disease. Many hypotheses have been formulated _______________________________________________________________________________ Magister-Thesis in Public Health Dr. Petra Heyen „The fight against malaria in malaria-endemic countries“ Page 7

to explain the pathology behind severe falciparum malaria, no final mechanistic explanation has yet been found [42].

Infection with P. vivax and P. ovale, can cause disease relapse as parasites can rest in the liver for several months up to four years after a person is bitten by a mosquito [112], [118].

TABLE 1: CHARACTERISTICS OF PLASMODIUM SPECIES INFECTING HUMANS (SOURCE: [118])

Human infection begins when a female anopheline mosquito, the disease vector, inoculates sporozoites from its salivatory glands during a blood meal. A vector in general is an animal that transmits a pathogen, or something that causes a disease, to another animal. Mosquitoes are the only vectors for malaria, but only 60 out of the 380 species of anopheline mosquitoes can host malaria-causing plasmodium. Three-fifths of the female anopholes mosquitoes, like their sisters of other lines, are dependent on blood meals to feed their maturing eggs. While sipping blood, a plasmodium-infected female mosquito injects thread-shaped, infectious agents called sporozoites into her human host. Sporozoites circulate for a time (less than 5 minutes) and then enter the parenchymal cells of the liver to hide out from the immune system (intrahepatic or pre-erythrocytic merogony). Here, they live for one to two weeks, multiplying asexually to produce thousands of offspring. The swollen liver cell bursts, discharging invasive merozoites into the bloodstream an event that initiates the symptomatic stage of the infection. In P. vivax and P. ovale infections, a proportion of the intrahepatic forms do not divide immediately but remain dormant for months before reproduction starts. These “sleeping forms” or hypnozoites are the cause of the relapses that characterize infection with these two species. Later, hypnozoites mature to reinvade other liver cells, where they continue to produce more merozoites, causing recurring bouts with malaria. Interestingly, the most deadly species, P. falciparum, does not produce these hypnozoites. Merozoites enter red blood cells to feed on the blood. They reproduce asexually to form more merozoites, which invade other red blood cells. This cycle continues unless stopped by the body’s defenses or medicine. While in the red blood cells, some merozoites mature into male and female gametocytes that are long-lived and not associated with illness. Upon release, these do not enter the red blood cells, but circulate awaiting transfer to the mosquito host. The female mosquito takes her _______________________________________________________________________________ Magister-Thesis in Public Health Dr. Petra Heyen „The fight against malaria in malaria-endemic countries“

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blood meal and simultaneously sucks up some of the gametocytes. In the mosquito’s stomach, the male gametocyte (sperm) and the female gametocyte (egg) fuse and form a zygote. This stage matures to form an ookinete, which penetrates and encysts in the mosquito’s gut wall. The resulting oocyst expands by asexual division until it bursts to liberate thousands of sporozoites. The sporozoites migrate to the salivary glands of the mosquito for their journey into a human host. The disease in humans is attributable to the direct effects of red cell invasion and destruction and the host’s reaction to this process [2]. Figure 1 diagrams the life cycle Plasmodium falciparum [2].

FIGURE 1: LIFE CYCLE P. FALCIPARUM (SOURCE: [2])

_______________________________________________________________________________ Magister-Thesis in Public Health Dr. Petra Heyen „The fight against malaria in malaria-endemic countries“

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FIGURE 2: PARASITE LIFE CYCLE AND PATHOGENESIS OF FALCIPARUM MALARIA. (SOURCE: NATIONAL CENTER FOR DISEASAE CONTROL, [HTTP://WWW.CDC.GOV/MALARIA/BIOLOGY/LIFE_CYCLE.HTM]) THE MALARIA PARASITE LIFE CYCLE INVOLVES TWO HOSTS. DURING ^{A BLOOD MEAL, A MALARIA-INFECTED FEMALE} ANOPHELES MOSQUITO INOCULATES SPOROZOITES INTO THE HUMAN HOST . SPOROZOITES INFECT LIVER CELLS AND MATURE INTO SCHIZONTS , WHICH RUPTURE AND RELEASE MEROZOITES . (OF NOTE, IN P. VIVAX AND P. ^{OVALE A DORMANT STAGE} [HYPNOZOITES] CAN PERSIST IN THE LIVER AND CAUSE RELAPSES BY INVADING THE BLOODSTREAM WEEKS, OR EVEN YEARS LATER.) AFTER THIS INITIAL REPLICATION IN THE LIVER (EXO-ERYTHROCYTIC SCHIZOGONY ), THE PARASITES UNDERGO ASEXUAL MULTIPLICATION IN THE ERYTHROCYTES (ERYTHROCYTIC SCHIZOGONY ). MEROZOITES INFECT RED BLOOD CELLS . THE RING STAGE TROPHOZOITES MATURE INTO SCHIZONTS, WHICH RUPTURE RELEASING MEROZOITES . SOME PARASITES DIFFERENTIATE INTO SEXUAL ERYTHROCYTIC STAGES (GAMETOCYTES) . BLOOD STAGE PARASITES ARE RESPONSIBLE FOR THE CLINICAL MANIFESTATIONS OF THE DISEASE. THE GAMETOCYTES, MALE (MICROGAMETOCYTES) ^{AND FEMALE} (MACROGAMETOCYTES), ARE INGESTED BY AN ANOPHELES MOSQUITO DURING A BLOOD MEAL . THE PARASITES’ MULTIPLICATION IN THE MOSQUITO IS KNOWN AS THE SPOROGONIC CYCLE . WHILE ^{IN THE MOSQUITO'S STOMACH, THE MICROGAMETES PENETRATE THE MACROGAMETES GENERATING ZYGOTES} . THE ZYGOTES IN TURN BECOME MOTILE AND ELONGATED (OOKINETES) WHICH INVADE THE MIDGUT WALL OF THE MOSQUITO WHERE THEY DEVELOP INTO OOCYSTS . THE OOCYSTS GROW, RUPTURE, AND RELEASE SPOROZOITES , ^{WHICH MAKE THEIR WAY TO THE MOSQUITO'S SALIVARY GLANDS.} INOCULATION OF THE SPOROZOITES INTO A NEW HUMAN HOST PERPETUATES THE MALARIA LIFE CYCLE.

2.1.2 Clinical Signs and Symptoms

2.1.2.1 General Clinical Features

Malaria begins as a flu-like illness with non-specific symptoms such as malaise, headache, fatigue, abdominal discomfort and muscle aches 8-30 days after infection. Typical cycles of fever, shaking chills and drenching sweats may then develop. As the untreated infection becomes synchronised the fever becomes periodic with pyrexial spikes every one or three days associated with chills or rigors. Synchronization occurs earlier with P. vivax and P. ovale than with P. falciparum (coincidence with parasite multiplication and destruction of red blood cells [RBC]). The untreated infection continues for weeks or months in the non-immune patients, but only P. falciparum _______________________________________________________________________________ Magister-Thesis in Public Health Dr. Petra Heyen „The fight against malaria in malaria-endemic countries“

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produces fulminant disease in untreated patients. The classic malarial paroxysms in which fever spikes, chills and rigors (tremors induced by chills) occur at regular intervals are rare. The rigors are more common with P. vivax and P. ovale than with P. falciparum. More often, the fever is irregular at first; in non-immune adults or children nausea, vomiting and orthostatic hypotension are common. Most patients with uncomplicated acute infections have few abnormal physical findings other than mild anemia and in some cases a palpable spleen [118], [119].

2.1.2.2 Severe Falciparum Malaria

Severe falciparum malaria is defined by the presence of asexual blood stage parasites in the blood plus one or more of a list of clinical features including neurological impairment, pronounced anemia, hypoglycemia, acidosis, hyperlactatemia, circulatory collapse, multi-organ failure and coagulopathies [42].

Severe malaria can mimic many other diseases that are also common in malarious countries. The most important of these are all types of meningitis, typhoid fever and septicemia. Other differential diagnoses include influenza, dengue and other arbovirus infections, hepatitis, leptospirosis, the relapsing fevers, haemorrhagic fevers, scrub typhus, all types of viral encephalitis (including rabies), gastroenteritis and, in Africa, trypanosomiasis. In pregnant women, malaria must be distinguished from sepsis arising in the uterus, urinary tract or breast. In children, convulsions due to malaria must be differentiated from febrile convulsions. In the latter, coma usually does not last for more than half an hour, although some children do not regain full consciousness until 30–60 minutes after the ictal phase [58].

Severe malaria is a disorder that affects several organs although the most marked manifestations may seem to involve a single organ such as the brain [64].

Coma is a characteristic feature of severe cerebral falciparum malaria and despite treatment associated with a mortality of approximately 20% in adults and 15% in children. The onset of coma may be gradual or sudden following a convulsion. Approximately 15% of patients have retinal hemorrhages. Anemia and jaundice are common. Generalized convulsions are common in children with cerebral malaria and in about half of adults. Seizures are associated with high temperatures. Approximately 10% of children who survive cerebral malaria particularly those with hypoglycemia, severe anemia, repeated seizures and deep coma have persistent neurologic deficits. Residual deficits are rare in adults [118]. In many pediatric patients with cerebral malaria coma seems to be a response to overwhelming metabolic stress rather than a primary problem in the brain. Such children are often profoundly acidotic and may regain consciousness remarkably quickly after appropriate resuscitation, suggesting that cerebral malaria in this instance can not be a consequence of the classical histological picture [64].

Hypoglycemia is associated with a poor prognosis. It has been reported to be of major prognostic significance in malaria-infected children in Malawi and the most serious complication of childhood falciparum malaria in The Gambia predicting the highest mortality of all categories in a group of 604 patients. Children and pregnant women are at special risk. Hypoglycemia results from failure of hepatic gluconeogenesis and increased consumption of glucose by the host and the parasites [18], [118].

Anaerobic glycolysis occurs in tissues where sequestered parasitized erythrocytes interfere with microcirculatory flow. This phenomenon, together with hypotension and a failure of hepatic lactate clearance causes lactic acidosis. Hyperventilation is the consequence, prognosis is poor [118].

Adult respiratory distress syndrome (ARDS) may develop in adults with severe falciparum malaria even after several days of anti-malarial treatment and clearance of parasites. The pathogenesis is unclear, the mortality rate over 80% [118].

_______________________________________________________________________________ Magister-Thesis in Public Health Dr. Petra Heyen „The fight against malaria in malaria-endemic countries“ Page 11

Renal impairment is common among adults with severe falciparum malaria but rare among children. Renal failure is associated with high mortality, the pathogenesis is unclear [118].

Anemia is caused by direct destruction of the erythrocytes when the parasites (merozoites) are released, by accelerated destruction and removal of red cells by the spleen and by suppression of the bone marrow with ineffective erythropoiesis. Anemia can develop rapidly and transfusion is often required. Anemia is a particular problem in children. In some patients with P. falciparum malaria massive hemolysis causes hemoglobinemia, black urine and renal failure (blackwater fever) [118].

2.1.3 Diagnosis

The diagnosis of malaria rests on the demonstration of the asexual forms of the parasite in peripheral blood films stained preferably with Giemsa. Both, thin and thick blood smears should be made with great care on clean slides. In thin smear, the level of parasitemia is expressed as the number of parasitized erythrocytes per 1000 red bloods cells and this figure is converted to the number per microliter of blood. Interpretation of thick film results (based on evaluation of white blood cells) is more difficult and requires a lot of experience [118]. Nevertheless, thick films are more useful than thin films in the detection of a low-density malaria parasitaemia. Facilities and equipment for microscopic examination of blood films can be easily set up in the side-room of a clinic or ward, and films can be read by trained personnel on site. This reduces the delay that commonly occurs when samples must be sent to a distant laboratory [58].

The relation between the level of parasitemia and the prognosis is complex; patients with excess of 10 ⁵ per microliter are more likely to die. However, nonimmune patients may die with relatively low parasite densities, and partially immune persons may tolerate relatively high levels with minor symptoms [118].

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FIGURE 3: SPECIES IDENTIFICATION OF MALARIA PARASITES IN GIEMSA STAINED THICK BLOOD FILMS (SOURCE: [58])

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FIGURE 4: APPEARANCE OF P. FALCIPARUM PARASITE STAGES IN GIEMSA-STAINED THIN AND THICK BLOOD FILMS (SOURCE: [58])

2.1.4 Laboratory Findings

Normochromic, normocytic anemia is the rule. The leukocyte count is low to normal. The platelet count is usually moderately reduced (to about 100.000 per microliter). In severe infections, the prothrombin and partial prothrombin times may be prolonged and thrombocytopenia may be severe. In severe falciparum malaria, metabolic acidosis may be present with low plasma concentrations of glucose, sodium, bicarbonate, calcium, phosphate, albumin; elevated plasma levels of lactate, blood urea nitrogen, creatinine, urate, muscle and liver enzymes and conjugated and unconjugated bilirubin. Hypergammaglobulinemia is usual in immune and semi-immune patients. In cerebral malaria, the white blood count often varies between 9000 and 11000 per microliter but can be higher than 20000 per microliter, the differential count is usually normal [118].

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2.2 History

2.2.1 History of the Human Malaria Parasites

P. malariae is a natural parasite of African great apes and humans in Africa. It is found in no other Old World primate species within or outside Africa. As a parasite of the ancestor of both humans and African great apes, ancestral P. malariae would have continued to parasitise and cross-infect both host lineages as they diverged around five million years ago. P. malariae survives under tropical and temperate transmission conditions and is adopted to endemicity in sparse and mobile human populations [16]. P. ovale is a strictly warm-climate parasite. Today it is found commonly throughout tropical Africa and in very limited distribution elsewhere in the tropics [16]. P.falciparum and P. vivax each have a close biological relative which is a parasite of African great apes, an argument that speaks in favour of the African origins of both species [16].

Outside Africa, the female mosquito vectors of malaria are zoophilic rather than anthropophilic. In the endemic areas of Africa, 80% to 100% of the vector bites are anthropophilic. This is the most important factor for the stability and the intensity of malaria transmission in Africa today [16].

2.2.2 Geographical Malaria History

Malaria seems to have been known in China for almost 5000 years and in Northern India for 3500 years. Sumerian and Egyptian texts date from 3000 to 4000 years ago. In 323 B.C. beyond Mesopotamia Alexander the Great is said to have died of malaria. Malaria seems not to have reached Italy until the second century B.C. By the beginning of the Christian era, malaria was wide-spread around the shores of the Mediterranean, central and south-east Asia, China, Korea, Japan. In the Middle Ages, malaria began to spread in northern Europe [16].

From mid-19 ^th century onward malaria disappeared from Europe mainly due to cheap and widespread availability of quinine although at the beginning of the 20 ^th century large areas of Europe and Northern America were still affected (e.g. Mediterranean and Balkan countries, England, Netherlands, much of central Europe and southern Russia). By the early 1950s malaria had largely disappeared from North America and almost all of Europe [16], [106].

In Central America and the Caribbean successful vector control via DDT was performed. In South America, malaria was observed only locally, but the situation became complicated due to the resistance of the parasites (mainly P. falciparum) to chloroquine (CQ).

In Asia, many successful campaigns against malaria were performed due to the high burden of illness (mainly DDT for vector control) [16].

From a European perspective, malaria has long been a formidable problem for the colonizing powers in their dependencies in the tropics, but in times of war the disease has assumed overwhelming importance. In the first world war, malaria was a major problem in several regions of Europe including the Balkans and troops had to be persuaded to take appropriate prophylactic measures. In the second world war, the principal impact was felt in the Far Eastern theatre particularly in the jungles of South-East Asia as well as in malarious areas of Europe and North Africa [21]. By the time of the Korean war 1950-1953, malaria had assumed less military importance. This is partly because the prevalent form of malaria in the Korean peninsula is the incapacitating, but usually not-lethal P. vivax, but also because new potent prophylactic agents had become available. During the American involvement in Vietnam (1964 – 1973) malaria forced itself back on the agenda partly due to the incidence of malaria among American forces (390,000 sick days lost to malaria) but also due to the emergence of P. falciparum strains that were resistant to available drugs [38].

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2.2.3 History of Malaria Handling

As early as in the sixth century B.C.: the Greeks and the Romans were aware of the association between fever and warm-wet climate as well as stagnant waters and swamps [36], [69]. This awareness led to the drainage interventions aimed at improving the health of the nearby population and increasing agricultural production [36]. Later, other communities throughout much of Europe took up deliberate drainage activities focussing on improvements in public health. Not so long ago, malaria was a summer-time risk in Denmark [69]. With the discovery of the role of mosquitoes as the vector of malaria in India in 1897 first specific interventions to control malaria were introduced. Some of the major environmental-management interventions come from the construction of the Panama Canal and the drying of the Pontine marshes in Italy where land filling and drainage played an important role. In the second half of the 20th century, chemical-based vector control became the dominating strategy (e.g. DDT), and engineering-based interventions like draining, one of the oldest and best documented methods, lost their importance. The renewed interest in environmentalmanagement approaches for the control of malaria is mainly due to

• The rapid development of resistance to the insecticides by mosquitoes

• The increasing cost of developing new chemicals

• Logistic constraints involved in the operation of chemical-vector programs.

In terms of curative treatment, quinine has been used for malaria prophylaxis and therapy for more than 350 years [12], and up to the first world war it had no serious rivals. Since malaria could be treated successfully with quinine and the drug was easily available from the bark of the Chinchona tree there was little pressure for the development of alternatives. During the first world war acute shortage of quinine occured since most of the world’s supply came from Dutch and British plantations in the East. Germany found itself cut off from the world supply of quinine and developed synthetic drugs the first being plasmoquine (later called pamaquine). In retrospect, plasmoquine was hardly a major breakthrough as it proved to be much less effective against human malaria (especially P. falciparum) and turned out to be more toxic than had been hoped. One advantage is that it killed malaria gametocytes and prevented relapse in P. vivax malaria [38].

In recent strategies, the WHO has advocated the use of a multitude of interventions in the control of malaria environmental control measures as well as chemically-based vector control as well as drugs to treat malaria. Some disagreement between the engineering side focusing on preventive measures and the curative medically trained professionals over resource prioritization existed in the 20 ^th century. It is evident that the interventions are of a site-specific nature. Without detailed ecological knowledge of the local vector and the epidemiology of the disease any intervention will be a shot in the dark or may potentially do more harm than good [51]. These efforts however led to a decrease of malaria prevalence: today it is 1/10 or less of what it used to be at its height. For case fatality the same figure holds true. With the main exceptions of Europe and North America up to subtropical countries, elsewhere in the world, mainly in the tropical regions, the mid-20 ^th century goal of malaria eradication was never realized. The achievement was an unprecedented reduction in morbidity and mortality [16]. After malaria had been eradicated in the above mentioned regions, it became almost wholly a disease of the tropics, particularly in Africa [102]. The malaria problems in Africa were and are of a different type from those confronted anywhere else as the stability and intensity of malaria transmission present huge problems. National malaria control organizations were operational in many African countries by the 1950s. The WHO goal of “malaria eradication” failed in Africa and has been abandoned [16] as it became evident that global eradication was not feasible (particularly due to the vector resistance to DDT and the parasite resistance to CQ and other low-cost first-line drugs [102]). Today the “malaria control programs” are state of the art [16].

Other reasons for abandoning the campaign may have been geopolitical and based on the fact that malaria control had been achieved in the southern USA, southern Europe, southern regions of the

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Soviet Union, much of Latin America and large parts of Asia. In mid 1970s, the USA had withdrawn from Vietnam so that the US military evinced a sharply reduced concern for malaria control. The major pharmaceutical companies neglected malaria drug discovery or vaccine research because the travelers’ market was small and still handled by existing medicines. Impoverished African countries were not on the geopolitical radar screen [102].

In 1979 a WHO definition made clear that the control of the vectors must not have “adverse effects on the quality of human environment”. Early permanent modifications of the environment would have been categorized today as influencing ecosystems such as wetlands or mangrove swamps. In the early 20 ^th century, the implications for the natural environment were never given much attention. Emphasis was on costing of interventions (direct costs of malaria as well as the wider economic cost of the malaria burden to production systems or society features). Many of the environment interventions could be designed to have additional economic benefits over and above disease reduction as the experimentation with alternate wet and dry irrigation in rice cultivation [115] and the secondary benefit of drainage activities resulting from land reclamation or increased agricultural productivity [39] have shown [51].

2.3 Epidemiology

2.3.1 Malaria Transmission

The malaria burden is not evenly distributed. The global pattern of malarial transmission suggests a disease centered in the tropics, but with a reach into subtropical regions in five continents. Regions where malaria occurs are, of course, restricted to those inhabited by the anopheline mosquito. Attempts to eliminate or at least suppress the disease have been an important public health story through much of the last century. For details see section 2.2.3. At malaria’s furthest reaches, in temperate zones characterized by strong seasonality and cold winters, these attempts have been successful. Beyond any other factors, this reflects the fact that the base case reproduction rate of malaria (parasite and vector) is considerably lower in temperate regions than in the tropics, so that moderately intensive efforts at vector control and case management can lead to elimination of the disease. The remarkably high transmission rates in sub-Saharan Africa also reflect the particular capacity of Africa’s main vector mosquitoes, the Anopheles gambiae complex of species, with their remarkable tendency towards human biting (anthropophily). For details see section 2.1. These climatic patterns reflect the natural history of the disease. The malaria parasite is transmitted to the female Anopheles mosquito from an infected individual when it takes a blood meal as a prelude to the reproductive process. The parasite develops within the mosquito before it becomes infectious to other individuals in the course of subsequent blood meals. For details of the reproduction cycle see section 2.1.1. The period required for that life-cycle change increases as the ambient temperature declines, and given the life span of the mosquito, transmission becomes much less likely when the temperature falls below 18°C. Moreover, malaria parasites cease development completely at temperatures below 16 °C, and many species of vector mosquitoes suspend biting activity at very low temperatures, further reducing the stability of malaria transmission in temperate regions.

Although other climatic features such as rainfall and humidity also affect the stability of transmission, seasonal temperature variation is a predominant factor in explaining the geographical distribution of the disease. Cold winters and moderate temperatures in summer facilitated effective elimination of malaria infection from much of the temperate zone. In tropical regions, exposure to mosquitoes may be perennial and frequently includes several contacts with infected vector mosquitoes each night. Such inoculation rates, combined with the long duration of parasite survival in the mosquito, rapidly saturate local human populations, resulting in universal prevalence and superinfection. This stable pattern of transmission resists amelioration, and vector control efforts that succeed in temperate zones have repeatedly failed to eradicate the parasite from tropical and subtropical regions, although control is possible [99].

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FIGURE 5: GLOBAL DISTRIBUTION OF MALARIA (SOURCE: [99])

THE CHANGING GLOBAL DISTRIBUTION OF MALARIA RISK FROM 1946 TO 1994 SHOWS A DISEASE BURDEN THAT IS INCREASINGLY BEING CONFINED TO TROPICAL REGIONS. THE ^{CHANGING GLOBAL PATTERN OF MALARIA TRANSMISSION FROM} 1946 TO 1994 ILLUSTRATES THE SUCCESS OF ANTI-MALARIAL EFFORTS IN THE MORE TEMPERATE REGIONS OF THE WORLD AND THE INCREASED CONCENTRATION OF DISEASE BURDEN IN THE TROPICS (SOURCE: [99])

2.3.2 Prevalence and Incidence

This section is mainly taken from the incidence and prevalence database, status February 2004 [44] and WHO fact sheet no 94, revised October 1998 [122]. Further quotations are indicated.

There have been several attempts to quantify malaria’s importance epidemiologically during the last decade with increasing interest in controlling malaria through strengthened national and local health care systems. Estimates have remained for the most part close to the often quoted figure of 1 million deaths and the number of cases and infections has varied from 300 to 500 million. Most importantly, there has been a general consensus that about 90% of all cases occur in Africa, although the basis for this assumption has not been clear. Relatively few reports of economic toll due to malaria have been published. About 93% of the 550 million people living in Africa are at risk of malaria.

A recent study shows that in the 1990s 26% of the more than 1500 children born in 1990 in rural western Kenya died over a four-year period. Neonatal and infant mortality were 32 per 1000 and 176 per 1000 live births respectively. In Africa, malaria-attributable death rates have been reported as high as 25% to 30% for children under the age of 5 years. These rates, based often on the change in mortality following intervention projects drop below 5% in children over age of 5 years in areas of stable endemicity. If these figures can be generalized up to 25% or more of all African children born in malarious areas will die from malaria. Malaria’s burden reflects the variability in the microepidemiology of the disease and the availability and effectiveness of control measures throughout the continent.

Malaria-related effects on pregnant women, their fetuses and newborns comprise an extremely large and often hidden burden. Malaria causes up to 15% of maternal anemia and some 35% of low

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