Clinical presentation of malaria does not only depend on its causative agent, but also on the innate immunity of the host [4]. In this context, locals often support higher parasitic loads than travelers, and inhabitants of high-transmission areas are less susceptible than those of low-transmission regions. The incubation period is usually a one to two weeks, but may also be considerably longer. This fact should be considered before excluding malaria as a differential diagnosis in patients who report to have traveled to endemic regions.

In general, patients experience flu-like symptoms like malaise, headaches, loss of appetite, myalgia and limb pain as well as nausea and vomiting during the prodromal phase of the disease, which lasts only few days. The sudden onset of high fever, chills, sweats and moderate to severe generalized pain are the hallmarks of PFM, and follow the prodromal phase. Initially, the patient's body temperature rises and decreases in irregular intervals, but after about a week, the temperature curve becomes regular and represents episodes of schizogony and erythrolysis. Most commonly, bouts of fever can be registered in intervals of 24, 36 or 72 hours. In some cases, patients suffer from continuous fever.

Complications may occur at any time. Depending on the compromised organ, patients may develop signs of cardiac, hepatic or renal failure, or central nervous system involvement. With regards to the latter, decreased levels of awareness up to coma, paresis, paralysis or seizures may be observed.

• Splenomegaly

  Two black African immigrants, with no history of recent travel outside France, received a diagnosis of a malignant lymphoproliferative disorder and splenomegaly, and they subsequently underwent splenectomy. [ncbi.nlm.nih.gov]

  The triad of malaria, fever, pallor and splenomegaly were noted in the study group. [alliedacademies.org]

  They present with headache, fever, anemia, splenomegaly, and cyclical fever. [osmosis.org]

• Fever

  We estimate that 35.7% of all self-reported fevers were accompanied by a malaria infection in 2014, but that only 28.0% of those (10.0% of all fevers) were causally attributable to malaria. [ncbi.nlm.nih.gov]

  ·cip·a·rum malaria | \ fal-ˈsip-ə-rəm-, fȯl- \ Medical Definition of falciparum malaria : severe malaria caused by a parasite of the genus Plasmodium (P. falciparum) and marked by irregular recurrence of paroxysms and usually prolonged or continuous fever [merriam-webster.com]

  Benign quartan ( P malariae ) with a fever every 3rd day (e.g., Monday; fever, Tuesday; no fever, Wednesday; no fever, Thursday; fever). 3. [atsu.edu]

• Anemia

  Abstract More than half of all young children and pregnant women are affected by anemia. Although its etiology is multi-factorial, malaria is likely to be a major contributor to chronic anemia in endemic areas. [gov.uk]

  Key words Introduction In sub-Saharan Africa, malaria, hookworm, hemoglobinopathies and nutritional deficiencies may contribute to anemia. 1, 2 Frequently the etiology of anemia is uncertain and many cases are treated as iron deficiency anemia. [haematologica.org]

  Hypotension, convulsions, severe anemia were the main presentations. [ncbi.nlm.nih.gov]

  […] consciousness, respiratory distress, and anemia. [academic.oup.com]

• Chills

  Signs and symptoms of complicated malaria include fever, chills, impaired consciousness, multiple convulsions, deep breathing, respiratory distress, abnormal bleeding, anaemia and jaundice. [sundaymail.co.zw]

  Boctor, M.D., Ph.D., and Joan Uehlinger, M.D. 1 Citing Article Figure 1 A 23-year-old man with sickle cell disease was admitted after reporting fever and chills. He had emigrated from West Africa three months earlier. [nejm.org]

  The major clinical findings of the patient were chills and fever. After examination of thin and thick blood smears prepared from the peripheral blood of the patient, P. falciparum parasites were observed. [ncbi.nlm.nih.gov]

  Then you get: High fever Shaking chills (very bad shivering) Headache, muscle aches, and feeling very sick The fever and chills come and go every couple of days. [msdmanuals.com]

• Pain

  shortess of brath, faintishness), acute limb ischemia (acute limb pain especially during moving, skin discoloration), mesenteric ischmia (abdominal pain), retinal ischemia (visual disturbances). [medicaljoyworks.com]

  Malaria infection is generally characterised by fever, chills, headache, nausea, vomiting, muscle pains and fatigue. Occasionally, the signs and symptoms of malaria may include sweating, chest pains, abdominal pains, and cough. [sundaymail.co.zw]

  This explains why PFM is associated with symptoms as different as fever, headaches, myalgia, abdominal pain, vomiting and diarrhea. [symptoma.com]

  Uncomplicated malaria is the mild form of malaria which usually causes a fever, with or without headache, tiredness, muscle pains, abdominal pains, nausea, and vomiting. [gov.uk]

  A 45-year-old man presented with a 4-day history of high-grade fever with rigours and a 2-day history of painful bluish black discolouration of extremities (acrocyanosis). [ncbi.nlm.nih.gov]

• Malaise

  A 32-year-old male patient presented with fever, shivering, malaise, and loss of appetite. He had travelled to West Africa. Laboratory findings were as follows: hemoglobin: 8.8 g/dL and anti-HIV: positive. [ncbi.nlm.nih.gov]

  Non specific constitutional symptoms like headache, malaise, myalgia, anorexia These are associated with the fever and occur with the release of inflammatory contents to the circulation with the rupture of erythrocytes. [medicaljoyworks.com]

  […] stage (including shivering) A hot stage (including fever) Fever breaking (sweats and return to normal temperature) Additional symptoms of uncomplicated malaria include nausea, headaches, vomiting, body aches, increased respiratory rate, and general malaise [sphweb.bumc.bu.edu]

  Clinical Manifestation The early symptoms of malaria are nonspecific: malaise, fatigue, headache, abdominal discomfort, and muscle aches. [path.upmc.edu]

  After a prodromal phase marked by flu-like symptoms such as malaise, headaches, loss of appetite, muscle and limb pain as well as nausea and vomiting, PFM patients develop fever. [symptoma.com]

• Cough

  Evidence of pulmonary oedema Shortness of breath, chest pain, cough, wheezing and pink frothy sputum are the main symptoms associated with pulmonary oedema. This also resulting from the pulmonary vessel occlusion with sequestration. [medicaljoyworks.com]

  Occasionally, the signs and symptoms of malaria may include sweating, chest pains, abdominal pains, and cough. Some patients with malaria experience cycles of malaria “attacks”. [sundaymail.co.zw]

  Signs and symptoms Symptoms of malaria may include: fever, which may come and go, or may be constant chills profuse sweating malaise (feeling of unwellness) muscle and joint pain headache confusion nausea loss of appetite diarrhoea abdominal pain cough [sahealth.sa.gov.au]

  Can also have vomiting, headache, chills, abdominal pain, cough, and diarrhea Severe malaria has a mortality of 5% to 30%, even with therapy Diagnostic criteria for severe malaria: Ashley 2018 Most common manifestations of severe malaria affect the brain [coreem.net]

• Vomiting

  Proportion of children with vomiting and diarrhea symptoms was 162 (61.59%) and 94 (35.74%), respectively. Bed net coverage was very limited, with only 76 (28.89%) of the study participants using bed net. [hindawi.com]

  Typical malaria symptoms include fever, chills, fatigue, headache, nausea, and vomiting. In severe cases, it can cause jaundice, seizures, coma, or death. [ncbi.nlm.nih.gov]

  Patients that vomit everything, including anti-malarials, should be managed as severe malaria. [southsudanmedicaljournal.com]

• Nausea

  Typical malaria symptoms include fever, chills, fatigue, headache, nausea, and vomiting. In severe cases, it can cause jaundice, seizures, coma, or death. [ncbi.nlm.nih.gov]

  Uncomplicated malaria is the mild form of malaria which usually causes a fever, with or without headache, tiredness, muscle pains, abdominal pains, nausea, and vomiting. [gov.uk]

  People have a shaking chill, followed by a fever, and may have a headache, body aches, and nausea and may feel tired. [msdmanuals.com]

  10 hours and involves three stages related to changes in body temperature: A cold stage (including shivering) A hot stage (including fever) Fever breaking (sweats and return to normal temperature) Additional symptoms of uncomplicated malaria include nausea [sphweb.bumc.bu.edu]

  Malaria infection is generally characterised by fever, chills, headache, nausea, vomiting, muscle pains and fatigue. Occasionally, the signs and symptoms of malaria may include sweating, chest pains, abdominal pains, and cough. [sundaymail.co.zw]

• Abdominal Pain

  shortess of brath, faintishness), acute limb ischemia (acute limb pain especially during moving, skin discoloration), mesenteric ischmia (abdominal pain), retinal ischemia (visual disturbances). [medicaljoyworks.com]

  Uncomplicated malaria is the mild form of malaria which usually causes a fever, with or without headache, tiredness, muscle pains, abdominal pains, nausea, and vomiting. [gov.uk]

  Malaria infection is generally characterised by fever, chills, headache, nausea, vomiting, muscle pains and fatigue. Occasionally, the signs and symptoms of malaria may include sweating, chest pains, abdominal pains, and cough. [sundaymail.co.zw]

  Signs and symptoms Symptoms of malaria may include: fever, which may come and go, or may be constant chills profuse sweating malaise (feeling of unwellness) muscle and joint pain headache confusion nausea loss of appetite diarrhoea abdominal pain cough [sahealth.sa.gov.au]

• Dyspepsia

  Clinical manifestations of malaria were dependent on the age of children: in very young children, early symptoms of intoxication prevailed, dyspepsia, diarrhea, and fever, it had an intermittent character, and there was no typical malarial paroxysm. [hindawi.com]

• Jaundice

  In severe cases, it can cause jaundice, seizures, coma, or death. Jaundice, caused by intravascular hemolysis is a usual complication of malaria, especially in patients with P. falciparum infection. [ncbi.nlm.nih.gov]

  […] particularly to west-Africa should raise suspicion for malaria Clinical Manifestations Average incubation period for Falciparum is 12 days 95% will develop symptoms within 1 month Clinical findings with high likelihood ratios include periodic fevers, jaundice [coreem.net]

  Severe malarial anaemia A haemoglobin concentration Renal impairment (acute kidney injury) Plasma or serum creatinine >265 μM (3 mg/dl) or blood urea >20 mM Jaundice Plasma or serum bilirubin >50 μM (3 mg/dl) together with a parasite count >100 000/μl [severemalaria.org]

  Bleeding and Jaundice Bleeding was present as melena in a small number (2%) of P. falciparum malaria. Jaundice associated with vomiting was a significant symptom in many (16%) patients with fever of 10 days as reported in earlier studies [ 15, 18 ]. [alliedacademies.org]

• Scleral Icterus

  Her physical examination was remarkable for scleral icterus, dry mucous membranes, and tachycardia. [ncbi.nlm.nih.gov]

• Hypotension

  Hypotension, convulsions, severe anemia were the main presentations. [ncbi.nlm.nih.gov]

  […] auscultation Significant bleeding Including recurrent or prolonged bleeding from nose gums or vein puncture sites; haematemesis or melaena Shock Compensated shock is defined as capillary refill ≥3 s or temperature gradient on leg (mid to proximal limb), but no hypotension [severemalaria.org]

  On physical exam, she was afebrile, tachycardic, tachypneic, and hypotensive. [hindawi.com]

  Vasodilation and hypotension occur in response to the high fever. Anemia results following erythrocyte destruction and indirectly from increased phagocytosis of red cells, capillary hemorrhage, thrombosis, and decreased marrow function. [atsu.edu]

• Chest Pain

  Evidence of pulmonary oedema Shortness of breath, chest pain, cough, wheezing and pink frothy sputum are the main symptoms associated with pulmonary oedema. This also resulting from the pulmonary vessel occlusion with sequestration. [medicaljoyworks.com]

  Malaria infection is generally characterised by fever, chills, headache, nausea, vomiting, muscle pains and fatigue. Occasionally, the signs and symptoms of malaria may include sweating, chest pains, abdominal pains, and cough. [sundaymail.co.zw]

  Patient complained that her fevers were associated with headaches, but not chills, rigors, or chest pain. Index of suspicion for malaria was high as patient had recently traveled from an endemic region. [journals.lww.com]

  Chest pain, breathing problems and cough. Diarrhea, nausea and vomiting. As malaria gets worse, it can cause anemia and jaundice (yellowing of the skin and whites of the eyes). [my.clevelandclinic.org]

  If the medication does not reach the stomach, it can irritate the esophagus and cause severe chest pain. [msdmanuals.com]

• Orthostatic Hypotension

  High heartrate, jaundice, pallor, orthostatic hypotension, enlarged liver, and enlarged spleen are also diagnosed.[43] P. falciparum works via sequestration, a distinctive property not shared by few other Plasmodiae. [en.wikipedia.org]

• Tachycardia

  Her physical examination was remarkable for scleral icterus, dry mucous membranes, and tachycardia. [ncbi.nlm.nih.gov]

  The temperature of nonimmune individuals and children often rises above 400C with tachycardia and sometime delirium. In patients with uncomplicated malaria, physical findings include fever, malaise, mild anemia, and (in some cases) palpable spleen. [path.upmc.edu]

  At hospital admission, the patient had a temperature of 39°C, a slight tachycardia, paraesthesia of the lower lip, and splenomegaly. The rest of the findings of the examination were normal, without focal signs of infection. [academic.oup.com]

  Its clinical features are similar to other changes observed in severe malaria, such as anxiety, dyspnea, tachycardia, diaphoresis, coma and generalized seizures.(34) In some patients, a deterioration in consciousness may be the only sign.(1) Metabolic [scielo.br]

• Myalgia

  Non specific constitutional symptoms like headache, malaise, myalgia, anorexia These are associated with the fever and occur with the release of inflammatory contents to the circulation with the rupture of erythrocytes. [medicaljoyworks.com]

  This explains why PFM is associated with symptoms as different as fever, headaches, myalgia, abdominal pain, vomiting and diarrhea. [symptoma.com]

  Also symptoms like headache, myalgia, cough, breathlessness, nausea, bleeding tendencies, dark colored / decreased urine output and altered sensorium / convulsions were enquired. [alliedacademies.org]

  These symptoms include chills, headache, myalgias, and malaise, and they occur in a cyclic pattern. The parasite may also cause jaundice and anemia due to the lysis of the RBCs. [emedicine.medscape.com]

  Blog - Case of the Week 558 [Accessed 13 September 2019]) 51 year old man with severe Plasmodium falciparum infection mimicking acute myocardial infarction (Mala J 2014;13:341) A patient with recent travel to southern Africa presented with fever and myalgias [pathologyoutlines.com]

• Back Pain

  History: talked about having minor injury, hurt lower back, pain there bothering him. Some anemia (normochromic), basic hem/chem/urine/liver nothing remarkable. Physical exam, nothing remarkable. HIV negative. [microbe.tv]

  The patient was an 18-year-old man who was admitted to Örebro Hospital (Örebro, Sweden) with a 3-day history of chest, stomach, and back pain and recurrent episodes of sweating and fever. [academic.oup.com]

• Arthralgia

  Clinical symptoms include the following: Headache (noted in virtually all patients with malaria) Cough Fatigue Malaise Shaking chills Arthralgia Myalgia Paroxysm of fever, shaking chills, and sweats (every 48 or 72 hours, depending on species) Less common [emedicine.medscape.com]

• Kidney Failure

  Patients with severe falciparum malaria may develop liver and kidney failure, convulsions, and coma. [stanfordhealthcare.org]

  If left untreated, uncomplicated malaria can develop into severe malaria with kidney failure, breathing difficulties, fitting, unconsciousness, and eventually death. [gov.uk]

  Severe malaria refers to cases that progress to hemolysis, which can result in severe anemia, hyperparasitemia, abnormal blood coagulation, acute kidney failure, hypoglycemia, and metabolic acidosis. [sphweb.bumc.bu.edu]

  failure Liver failure Pulmonary oedema Cerebral malaria, producing coma Death. [betterhealth.vic.gov.au]

  As the infection continues, you may get: Falciparum malaria also causes other symptoms depending on what organs are affected: Brain: Headache, confusion, coma, death Lungs: Trouble breathing Kidneys: Dark urine, kidney failure Pregnant women may have [msdmanuals.com]

• Headache

  Typical malaria symptoms include fever, chills, fatigue, headache, nausea, and vomiting. In severe cases, it can cause jaundice, seizures, coma, or death. [ncbi.nlm.nih.gov]

  Malaria is an infection characterised by fever, shivering, chills, generally feeling unwell, headache and sweats, but it can present as a respiratory or gastrointestinal illness. [betterhealth.vic.gov.au]

  They present with headache, fever, anemia, splenomegaly, and cyclical fever. [osmosis.org]

  People have a shaking chill, followed by a fever, and may have a headache, body aches, and nausea and may feel tired. [msdmanuals.com]

• Seizure

  […] may precipitate some seizures, most seizures occur when the rectal temperatures are less than 38.0 o C. 61 By comparison with simple febrile seizures, the seizures in malaria are often recurrent, and 84% of the seizures are complex, most often with a [jnnp.bmj.com]

  In severe cases, it can cause jaundice, seizures, coma, or death. Jaundice, caused by intravascular hemolysis is a usual complication of malaria, especially in patients with P. falciparum infection. [ncbi.nlm.nih.gov]

  Features of hypoglycaemia Patient will present will symptoms like faintishness, sweating and development of seizures. With the excessive usage for cell turnover leads to hypoglycaemia. [medicaljoyworks.com]

  It can also cause severe psychologic side effects and seizures in people with a seizure disorder (epilepsy), and affect the heart. [msdmanuals.com]

  It consists of A cold stage (sensation of cold, shivering) A hot stage (fever, headaches, vomiting; seizures in young children); and Finally a sweating stage (sweats, return to normal temperature, tiredness). [cdc.gov]

• Confusion

  The detection of IgG and IgM antibodies in serum and cerebrospinal fluid (CSF) against multiple viruses and bacteria reflected a non-specific polyclonal B cell activation and was more confusing than helpful for diagnostic decisions. [ncbi.nlm.nih.gov]

  The condition is characterized by extremely grave systemic symptoms, mild jaundice, mental confusion, enlarged spleen and liver, increased respiratory rate, edema, GI symptoms, and anemia. [medical-dictionary.thefreedictionary.com]

  Evidence of cerebral malaria There will be confusion, drowsiness, coma, seizures, body weakness and sensory loss. Cerebral malaria is one of life threatening complication associated with plasmodium falciparum malaria. [medicaljoyworks.com]

  Criteria for severe malaria: ≥ 1 of the following in a patient with proven malaria [16][19][21] Clinical findings General: prostration CNS: hallucinations, confusion, impaired consciousness, seizures, coma Cardiac: shock (e.g., hypotension, capillary [amboss.com]

  Malaria causes fever, chills, sweating, a general feeling of illness (malaise), and sometimes diarrhea, abdominal pain, respiratory distress, confusion, and seizures. [msdmanuals.com]

• Lethargy

  Easy fatiguability, lethargy and shortness of breath With the excessive premature destruction of erythrocytes, patient will develop anaemia13]. [medicaljoyworks.com]

  Manifestations can resemble those of neonatal sepsis, including fever and nonspecific symptoms of poor appetite, irritability, and lethargy. [meddean.luc.edu]

  The symptoms are a history of high fever, plus at least one of the following:- Prostration (inability to sit), altered consciousness lethargy or coma Breathing difficulties Severe anaemia Generalized convulsions/fits Inability to drink/vomiting Dark and [vikaspedia.in]

  […] list of clinical features associated with severe malaria is shown in Table 1 - Diagnostic criteria for severe P. falciparum malaria.[13][18] Children Children are more likely to present with non-specific and gastrointestinal symptoms such as fever, lethargy [ncbi.nlm.nih.gov]

• Reduced Consciousness

  CM is diagnosed in a patient with P. falciparum identified on a peripheral blood smear, with one or more neurological symptoms including reduced consciousness, coma (Blantyre coma score ≤ 2) and seizures, where other potential causes have been ruled out [tandfonline.com]

Paroxysmal fever in a patient who reports to have lived in or traveled to endemic regions is highly suspicious of malaria. In contrast, PFM may not be on the list of differential diagnoses during the prodromal phase of the disease or during the first days after onset of fever. In any case, it is of utmost importance to diagnose P. falciparum infections as early as possible in order to avoid life-threatening complications [8].

Several rapid and sensitive diagnostic tests are available today [9]:

• Microscopic examination of blood smears is still considered the gold standard. This diagnostic measure is readily available in every part of the world, is sensitive and cheap. Erythrolysis precedes this analysis and allows for quantifying parasitic loads. Of note, this technique is also applied to assess parasite clearance and response to therapy.
• Rapid diagnostic tests rely on the presence of antigens in the blood of infected individuals. They are of low cost and are even more easily applicable than microscopic tests. However, they do not allow for a quantification of parasitemia. Test results may remain positive for several days even if effective treatment is provided.
• Molecular biological tests may be applied to detect parasitic nucleic acids. In detail, polymerase chain reaction (PCR), real-time PCR and reverse transcriptase PCR protocols have been established as very sensitive diagnostic measures. Despite their high sensitivity, their applicability is limited by relatively high costs and the need for sophisticated equipment.

• Hypoglycemia

  Hypoglycemia (low blood glucose). [cdc.gov]

  Pregnant women have a three-fold higher risk of developing severe malaria compared to nonpregnant women, as well as the risk of severe complications such as pulmonary edema, placental infarction, and hypoglycemia [4]. [hindawi.com]

  Other complications of P falciparum infection include the following: Seizures - Secondary to either hypoglycemia or cerebral malaria Renal failure - As many as 30% of nonimmune adults infected with P falciparum suffer acute renal failure Hypoglycemia [medscape.com]

  However, this response may also induce complications, such as severe anemia, hypoglycemia and cerebral malaria. [infectiousdiseaseadvisor.com]

  The pathophysiology of adult hypoglycemia is usually associated with hyperinsulinemia, which may result from pancreatic cell stimulation and Plasmodium spp-derived factors. Hypoglycemia is difficult to detect. [scielo.br]

• Leukopenia

  Fever (100%), splenomegaly (86.7%), hepatomegaly (26.7%), leukopenia (13.3%), thrombocytopenia (80%), elevated liver function tests (40%), and increased serum creatinine levels (13.3%) were found in the patients. [ncbi.nlm.nih.gov]

  CBC: Changes in multiple parameters may occur. [23] Hemolytic anemia: ↓ Hb, ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes Thrombocytopenia Leukocytosis or leukopenia are uncommon except in severe disease. [amboss.com]

  Results consistent with the diagnosis Complete blood count often shows mild normochromic normocytic anemia, thrombocytopenia, and leukopenia. Erythrocyte sedimentation rate and C-reactive protein (CRP) levels are generally elevated. [infectiousdiseaseadvisor.com]

• Hemoglobin Decreased

  These are divided into structural hemoglobinopathies, produced by the simple substitution of amino acids in the α and β chains of hemoglobin and thalassemic syndromes, which are manifested by the total or partial decrease in the synthesis of a globin [intechopen.com]

• Plasmodium Falciparum

  Cytoadherence and sequestration in Plasmodium falciparum: Defining the ties that bind. Microbes Infect. 2003;5:897-909. 7. Urban BC, Roberts DJ. [revistabiomedica.org]

  Five species of Plasmodium (single-celled parasites) can infect humans and cause illness: Plasmodium falciparum (or P. falciparum) Plasmodium malariae (or P. malariae) Plasmodium vivax (or P. vivax) Plasmodium ovale (or P. ovale) Plasmodium knowlesi [stanfordhealthcare.org]

  Plasmodium falciparum malaria falciparum m. Medical dictionary. 2011. [medicine.academic.ru]

  To save this word, you'll need to log in. fal·cip·a·rum malaria | \ fal-ˈsi-pə-rəm- \ Definition of falciparum malaria : extremely severe malaria caused by a sporozoan parasite (Plasmodium falciparum) First Known Use of falciparum malaria 1940, in the [merriam-webster.com]

  B50.0 - Plasmodium falciparum malaria with cerebral complications B50.8 - Other severe and complicated Plasmodium falciparum malaria B50.9 - Plasmodium falciparum malaria, unspecified Map to ⑨ B50.9 converts approximately to ICD-9-CM: 084.0 - Falciparum [unboundmedicine.com]

PFM treatment consists in antiparasitic therapy and possibly additional measures that remedy complications like anemia, acidosis, hypoglycemia and seizures.

According to the most recent guidelines published by the World Health Organization [10]. , the following regimens are indicated in case of uncomplicated malaria:

• artemether and lumefantrine
• artesunate and amodiaquine
• artesunate and mefloquine
• artesunate and sulfadoxine–pyrimethamine
• dihydroartemisinin and piperaquine

Such treatment should be administered for three days.

In case the disease cannot be cured this way, artesunate may instead be combined with tetracycline antibiotics or doxycycline or clindamycin. Alternatively, quinine may be applied in combination with either of those antibiotics. These second-line treatments are to be administered for seven days.

Patients suffering from severe malaria are essentially treated the same way, but they should receive their drugs intravenously until they are able to tolerate oral medication.

Monotherapies are generally not recommended to avoid the development of resistances.

Their may be regional differences regarding the effectivity of determined treatment options. For instance, dihydroartemisinin plus piperaquine has been proven superior to artemether plus lumefantrine in Africa, while both treatments seem to be equally effective in Asia [11].

PFM is a life-threatening disease and accounts for the vast majority of malaria-related deaths. The single most important risk factor for a poor outcome is the delay of treatment [8]. Unfortunately, areas of high prevalence of P. falciparum often coincide with regions of low levels of economic development. Access to medical attention in general and effective therapeutics in particular is often restricted. This fact further underlines the importance of prevention and indeed, it has been estimated that mortality rates have been diminished by more than 50% during the last decades thanks to the implementation of corresponding measures.

Signs of organ failure as well as involvement of the central nervous system, severe anemia and high parasitemia (hemoglobin levels below 5 g/dl and more than 250,000 parasites/µl), acidosis, hypoglycemia and shock are unfavorable prognostic factors. With regards to parasitemia, the value given applies to regions of high prevalence of malaria. In contrast, much lower burdens may result lethal in geographic areas of lower prevalence.

The protozoan parasite P. falciparum is the etiologic agent of PFM; it is transmitted by female mosquitoes of the genus Anopheles. An infection occurs upon injection of P. falciparum sporozoites into the patient's circulation during an insect bite.

A mosquito may ingest gametocytes, i.e., sexual-stage parasites, while feeding on an infected human [5]. Inside the insect's gut, gametocytes pass distinct developmental stages, form zygotes which turn into oocysts, and the latter eventually release sporozoites that migrate into the mosquito's salivary glands. As has been mentioned above, these sporozoites are infectious and give rise to PFM upon transmission.

Additionally, malaria may be acquired by receiving transfusions of blood products obtained from infected donors. In fact, malaria is still one of the most common transfusion-transmitted diseases [6].

Although numbers regarding the annual incidence of PFM range from 200 to more than 450 million cases, they coincide in PFM being a very common infectious disease [1] [5]. Malaria-related mortality is almost exclusively associated with infections with P. falciparum, and it has been estimated that up to a million PFM patients die each year.

With regards to the geographical distribution of the disease, malaria may only be acquired within the distribution range of Anopheles spp. PFM is currently considered to be endemic to 87 countries in tropical and subtropical Africa, the Indian Subcontinent, Southeast Asia, Central America and norther South America. Corresponding maps are available elsewhere [1], but it should be noted that distribution ranges of carriers and pathogens may change over time and that, for clinical purposes, updated information should be consulted whenever possible. Today, highest burdens are encountered in the Democratic Republic of the Congo, Nigeria, India and Myanmar. Here, almost 1.5 billion people are at risk of contracting the disease.

Upon transmission of haploid sporozoites during an insect bite, the latter reach the patient's liver and invade hepatocytes. Here, they grow and divide, thereby forming several thousands of haploid merozoites. Subsequently, merozoites exit hepatocytes, return to circulation and infect erythrocytes. In red blood cells, merozoites multiply by formation of mature schizonts and schizogony. This process involves the destruction of infected erythrocytes and gives rise to many new merozoites able to invade further red blood cells. In PFM patients, erythrolysis occurs repeatedly after reproduction cycles lasting one to three days, and is accompanied by bouts of fever. This rise in body temperature is provoked by the release of toxins during cell lysis and the ensuing activation of pro-inflammatory cascades. During such a bout of fever, pro-inflammatory cytokines and other mediators such as interleukin-1β, tumor necrosis factor-α and reactive oxygen species are released in great amounts by activated macrophages, leukocytes and endothelial cells [7].

Since virtually all tissues of the human body directly depend on blood supply, erythrolysis and pro-inflammatory events may occur in multiple organs. Excess release of the aforementioned mediators interferes with the function of the central nervous system, the cardiovascular system and several internal organs. This explains why PFM is associated with symptoms as different as fever, headaches, myalgia, abdominal pain, vomiting and diarrhea.

Of note, in some infected erythrocytes, merozoites develop into sexual forms of the parasite, namely into gametocytes. These gametocytes are ingested by mosquitoes biting the patients and give rise to the above described part of the parasite's life cycle that takes place in the insect.

In general, any measure aiming at the prevention of insect bites contributes to reducing the individual risk of contracting malaria. However, neither travelers nor locals are able to completely prevent exposure to Anopheles spp. and thus, additional measures are required to prevent PFM. People who are traveling to endemic regions are recommended to prophylactically take antimalarials like chloroquine or mefloquine, or to carry stand-by medication in order to immediately initiate treatment in case an infection is suspected. Distinct compounds are available for chemoprophylaxis and the decision for or against a certain drug should be based on the current knowledge regarding resistances. Moreover, contraindications may exist for children, pregnant or lactating women. For instance, only chloroquine is approved for use in pregnant women, but there are endemic regions with high rates of resistance to this drug. Consequently, pregnant patients are recommended to avoid visiting such areas.

In endemic regions, programs aiming at larval source management have been implemented to hinder mosquito reproduction. These programs comprise measures to reduce the availability of water bodies for larval development, to introduce predators of Anopheles spp., and to kill larvae by use of larvicides [12].

Malaria is a parasitic disease that continues to be a major public health concern, particularly in tropical and subtropical regions. In total, more than 300 million malaria cases are registered annually and about one million people die each year from this disease [1]. There are distinct forms of malaria that differ with regards to their respective etiologic agents and disease severity. In detail, the following forms of malaria are distinguished:

• Plasmodium falciparum malaria (PFM)
• Plasmodium vivax malaria
• Plasmodium ovale malaria
• Plasmodium malariae malaria
• Plasmodium knowlesi malaria

PFM is triggered by infection with Plasmodium falciparum (P. falciparum). Because PFM is the most severe form of the disease, it is also referred to as malignant malaria. In contrast, all other forms of malaria are generally termed benign malaria. PFM accounts for the vast majority of malaria cases worldwide, but there are considerable geographical differences regarding the ratio of malignant and benign cases [2] [3]. Mortality is almost exclusively seen in PFM patients.

Patients infected with P. falciparum may develop uncomplicated or complicated malaria. The latter is diagnosed when the affected individual shows signs of organ failure, e.g., severe functional impairment of the central nervous system, heart, liver or kidneys. Such symptoms are often associated with high parasitemia. It is currently assumed that host-pathogen interactions are affected by numerous environmental factors, and that disease severity is the result of the entirety of these influences. For instance, thalassemia and other forms of hemoglobinopathy confer partial resistance against PFM and are thus highly prevalent in areas of malaria transmission [4]. People living in geographical regions of lower prevalence of malaria as well as those traveling to endemic areas are therefore more susceptible to the disease.

Treatment of PFM primarily consists in the administration of antimalarials, but patients suffering from complicated malaria often require additional therapies aiming at an improvement of organ function.

Malaria is a parasitic disease caused by infection with protozoans of the genus Plasmodium. There are distinct species, e.g., Plasmodium falciparum and Plasmodium vivax, which are all transmitted by mosquitoes of the genus Anopheles, but that provoke disorders of varying severity. The most severe form of malaria is triggered by infection with Plasmodium falciparum and is consequently called Plasmodium falciparum malaria (PFM).

It has been estimated that about 2.5 billion people are at risk of contracting PFM, and these people are mainly living in subtropical and tropical regions of Africa, America and Asia. Particularly high prevalence rates have been reported in the Democratic Republic of the Congo, Nigeria, India and Myanmar. While locals may dispose of a partial immunity against PFM, this does not apply to travelers who are generally considered to be highly susceptible to the disease.

Symptom onset typically occurs within two weeks after exposure to the parasite. After a prodromal phase marked by flu-like symptoms such as malaise, headaches, loss of appetite, muscle and limb pain as well as nausea and vomiting, PFM patients develop fever. Initially, their body temperature may rise in irregular intervals, but within a week of illness, regular patterns become recognizable: Bouts of fever are experienced in intervals of one to three days and thus correspond to the reproductive cycle of parasites. Fever is usually accompanied by chills, sweats and generalized pain. PFM patients may develop complications involving brain, heart, liver and kidney function at any time, and this is why PFM is considered a life-threatening disease.

Fortunately, patients generally respond well to therapy. Primarily, antimalarial drugs are administered to kill the parasites. Additional treatment may be required in case of organ compromise. Lethal outcomes are often related to delayed medical attention.

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