Primo-invasion malarial fever  After an incubation period lasting from 7 to 20 days up to sometimes several months, the subject suffers a sudden attack of pyrexia, characterized by shivering accompanied by cold sweats, head-aches, sometimes gastrointestinal disorders of the anorexic type, nausea, vomiting, even diarrhea. At this stage, the clinical examination is often normal, the liver and the spleen are not palpable. This fever may persist in a continuous or intermittent mode, interspersed with phases of a 24 hour fever, bringing about a malignant tertian fever. The repetition of the feverish crises, whether due to the permanence of circulating hematozoa or re-infection, brings about fevers of schizogonic reviviscence during which it is frequently possible to observe a splenomegaly: its presence leads to the intervention of the immunity defense mechanisms. During this malarial fever, a blood smear test or a thick film test provides the diagnosis by identifying hematozoa. The parasitic density is between 1,000 and 10,000 HP/µl. 

Atypical aspects 

New clinical forms, or forms forgotten since the appearance of synthetic antimalarial drugs have appeared in recent years with the extension of chemo-resistances. Thus malarial crises have been described with low or nil parasitic density, isolated degradation of the general state of health with asthenia and/or unexplained weight loss, intermittent fevers, isolated or associated blood cytopenia, clinical pictures close to chronic malaria with splenomegaly, hepatomegalia, moderate fever, bi- or tricytopenia and inflammatory  syndrome. In all the atypical forms, the parasitemia is often low, requiring an attentive examination of the blood smear tests, their frequent repetition or recourse to finer identification techniques such as the QBC-test® or the ParaSight®-F. 

 Severe malaria 

It normally occurs in non-immune subjects: children, pregnant women, travelers. 
It comprises several situations: 

The major expression of these severe forms is represented by pernicious malaria, or cerebral malaria. This includes all the neurological manifestations associated with the infection by Plasmodium falciparum: change in awareness, convulsions, drop in vision. Warrell et al. define cerebral malaria as a deep coma in which the patient does not react to nociceptive stimuli, with the exception of the other causes of encephalopathy. Hypoglycemia should in fact be excluded, as well as meningo-encephalitis, eclampsia and metabolic comas. When cerebral malaria is present, its prognosis is frightful, with a high mortality rate (20 % to 30 % depending on the series), even in the best treatment conditions.

Its pathogeny has been better understood in recent years. It causes infected red blood cells to adhere to the vascular endothelial cell surfaces and a cascade of cytokines.

The cytoadherence of the infected red blood cells is based on three elements: 

These different sites of erythrocytic attachment constitute points of immunological anchorage linked to the infected red blood cells by protein ligands. 

Cytokines participate in the pathogeny of severe malaria by intervening in the determinism of the visceral lesions. The TNF-a (Tumor Necrosis Factor alpha) plays an essential role: this cytokine, secreted by the macrophages, may intervene in the pathogeny of the fever and the cerebral edema and its elevation is strictly correlated to the prognosis. In fact, the secretion of TNF-a is integrated in a cytokine cascade which intervenes sooner or later in the pathogeny of severe malaria: Interleukins 1, 2, 3, 10 ; gamma interferon; GMCSF, etc.

This mechanical and immunological conception of the pathophysiology of severe malaria depends in part on parasitic and human factors whose role is essential. The virulence of the strain, the level of chemo-resistance, the capacity of cytoadherence of the parasite are decisive. In the same way, the level of premunition, the genetic factors and the co-infections facilitate the passage from an uncomplicated form to a serious form.   

This entity once corresponded to a picture of acute intravascular hemolysis affecting a non-immune subject residing in a malaria-endemic area, who has already suffered several malarial crises and was taking an irregular chemoprophylaxis with quinine. 

In fact, for more than thirty years, the classical picture of Black water fever was hardly observed and the studies made in Thailand among subjects presenting a hemoglobinuria with a serious malaria attack, have enabled the identification of two groups of patient: those carriers of a deficit in G6PD and undergoing an antimalarial treatment, more particularly primaquine, and those with severe malaria, a massive globular lysis and hyperparasitemia.

More recently, observations of Black water fevers have been reported following random sessions of different amino-alcohols. 

This much too vague a term has been widely and excessively used to designate any splenomegaly in a tropical zone which did not pass etiological tests. English-speakers prefer to use the term hyperreactive malaria splenomegaly.

To retain this diagnosis, it is indispensable for the subject to be exposed to malaria for a long period. It is essentially large children and adults who are concerned. 

Three major diagnostic criteria are required: 

On the biological level, a normochromic, normocytic anemia, leukoneutropenia and thrombocytopenia are observed. Hyperlymphocytosis is sometimes observed, especially in West Africa where the main differential diagnosis is chronic lymphoid splenomegalic leukemia.

Moreover, a very high level of antimalarial antibodies can be detected in these patients by the fluorescent antibody test which suggests earlier and accumulated exposure. 
The complete disappearance of the clinical and biological signs after a prolonged antimalarial treatment is a major argument in favor of a malarial origin of the splenomegaly.   

The malarial crisis is also observed with Plasmodium vivax,  Plasmodium ovale and Plasmodium malariae.

It has the same appearance as Plasmodium falciparum, but the evolution is always benign and spontaneously resolutive. 

The feverish crisis may be repeated following a variable rhythm depending on the plasmodial species: with Plasmodium vivax and Plasmodium ovale, a benign tertiary feverish crisis may be observed with fever spikes on the 1^st, 3^rd, 5^th days, etc. With Plasmodium malariae, fever spikes may be observed on the 1^st, 4^th, 7^th days (etc.), suggesting a 72 hour schizogony of and corresponding to a quartan fever. 

Very specific to Plasmodium vivax and Plasmodium ovale  are the belated relapses, several months or several years after the return from an endemic area. They can be explained by the persistence in the liver of hypnozoites responsible for a secondary erythrocytic schizogony. The very belated relapses, ten or event twenty years later, observed with Plasmodium malariae, can, on the other hand, be explained by the persistence of an erythrocytic schizogony, persisting at too low a rate to reach the patency threshold.

Immunological nephritis may sometimes be encountered in the Plasmodium malariae  malaria. These quartan nephritises are translated by a nephritic syndrome evolving frequently towards renal failure. 

They can be observed especially with subjects, carriers of a voluminous tropical splenomegaly syndrome such as that seen in evolutive visceral malaria and in the hyperreactive malaria splenomegaly. These splenic ruptures are either spontaneous, or provoked by the slightest traumatism. The mechanism of the rupture is either a torsion of the pedicle, or a splenic infarction with a sub-capsular hematoma. Plasmodium vivax is usually responsible; Plasmodium malariae and Plasmodium falciparum are rarely suspected. More recently, spontaneous ruptures have been observed within the context of a chemoresistant Plasmodium falciparum febrile crisis. They may be explained by an acute congestion of a spleen previously fragilized by a prolonged malarial infection.