Plasmodium falciparum malaria is the most severe form of the parasitic disease, malaria. Its causative agent, the protozoan Plasmodium falciparum, is transmitted by mosquitoes pertaining to the genus Anopheles.
Clinical presentation of malaria does not only depend on its causative agent, but also on the innate immunity of the host . 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.
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 .
Several rapid and sensitive diagnostic tests are available today :
According to the most recent guidelines published by the World Health Organization . , the following regimens are indicated in case of uncomplicated malaria:
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 .
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 . 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 . 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.
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  . 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 , 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 .
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 .
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 . 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:
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  . 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 . 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.