Clinical manifestations

Malaria is a febrile illness with a wide range of clinical manifestations, from flu like symptoms that may remain undiagnosed to severe malaria with seizures, coma and multiple organ failure.

Most of the clinical manifestations are due to individual immunity response (overproduction of IL, TNF and othen cytokines) that is triggered mainly by the erythrocytic phase of the plasmodium life cycle and the merozoites release in the blood stream (parasitaemia).

Malaria may mimic other diseases and the symptoms may be atypical, fact that, in endemic countries can lead to differential diagnosis dilemmas, while in non endemic countries may confuse the clinicians that are not familiar with the disease.

Malaria disease can be categorized as uncomplicated or severe (complicated).

Uncomplicated malaria

Definition: symptomatic malaria without signs of severity or evidence of vital organ dysfunction.
The manifestations of uncomplicated disease are the following:

Fever
Chills
Headache
Dizziness
Back pain
Myalgia, joint and bone pains
Cough, chest pain
Weakness, prostration
Gastrointestinal disturbances (nausea, vomiting, diarrhea)

The typical but infrequently observed malaria attack consists of three stages:

Cold stage (characterized by feeling of cold and shivering followed by whole body shaking that lasts 15- 60 minutes, cold, dry and pale skin)
Hot stage (high fever up to 40- 41 ^oC that lasts 2- 6 hours, severe headache, palpitations, tachypnoea, flushed and dry skin)
Sweating stage (profuse sweating for 2- 4 hours, feeling of exhaustion)

The total duration is 8- 12 hours. The interval between the fever attacks depends on the erythrocytic cycle length. When a cycle is completed, new merozoites are released and a new fever wave strikes. Table 1 below, shows the type of fever for every plasmodium species:

	Fever type
Plasmodium species	Benign tertian	Malignant tertian	Quartan	Quotidian
P. vivax	X
P. ovale	X
P. falciparum		X
P. malariae			X
P. knowlesi				X

Tertian fever: febrile paroxysms every 48 hours
Quartan fever: febrile paroxysms every 72 hours
Quotidian fever: febrile paroxysms every day

Severe (complicated) malaria

Definition: “the presence, in a patient with falciparum malaria, of clinical manifestations such as^[5]:

Prostration
Hyperpyrexia
Dehydration
Hypotension
Circulatory collapse
Electrolyte imbalances
Hypoglycaemia
Severe anaemia
Spontaneous bleeding
Disseminated Intravascular Coagulation
Haemoblobinuria
Jaundice
Hepatosplenomegaly
Generalized convulsions
Impaired consciousness
Coma
Acidosis
Acute abdominal pain
Acute Respiratory Distress Syndrome
Pulmonary edema
Renal failure

Falciparum malaria complications:

Severe anemia

Severe anemia (Hematocrite: <15%, Hb:< 5g/ dl) is one of the most important causes of malaria deaths, especially in African countries. The mechanisms that lead to severe anemia are the following:

·        Red cells rupture directly by parasites
·        Reticuloendothelial system activation that leads to healthy blood cells destruction
· Reduced flexibility of the infected red blood cells that leads to their destruction
· Dysfunction in erythropoietin production
·        Bone marrow suppression by cytokines

Cerebral malaria

Cerebral malaria is characterized by the presence of unarousable coma and confirmation of falciparum infection while all other possible causes have been excluded. When the merozoites are released in the blood stream (after red blood cells rupture), toxins are also released that make the nearest macrophages secrete Tumor Necrosis Factor (TNF). TNF action leads to adhesive molecules expression on vessel endothelium; thus, platelets aggregate on these molecules (responsible protein: PfEMP-1 of the infected red cells) followed by red cells (infected and uninfected) leading to clots creation. This clots development in cerebral capillaries result in cerebral malaria manifestations. Cerebrospinal Fluid may show mild lymphocytosis , increased protein and lactate concentrations. Possible sings: abnormal behaviour (maniac episodes, acute psychosis), opisthotonos (without meningism signs), generalized convulsions, impairment of consciousness and coma.

Tropical splenomegaly syndrome

Tropical splenomegaly syndrome, known also as hyperreactive malarial splenomegaly, occurs due to abnormal immunological hyper- stimulation of the human body as a result of repeated infections. It is a very rare manifestation that occurs mainly in adults. The predominant symptoms are: abdominal pain, presence of palpable mass, massive weight loss and cachexia. Clinical examination reveals gross splenomegaly and hepatomegaly. Laboratory findings are: normochromic normocytic anemia, reticulocytosis, thrombocytopenia and leucopenia due to hypersplenism, raised polyclonal serum IgM antibodies and cryoglobulins, low C3 levels and rheumatoid factor presence. Most of the times, there is a benign development of the disease but some patients may suffer congestive heart failure due to severe anemia or may be susceptible to respiratory and skin infections.

Non-falciparum malaria complications:

Splenic rupture
Hepatic impairment
Thrombocytopenia
Severe anemia
Quartan fever nefropathy

Vulnerable (sensitive) population groups:

Pregnant women
Children
Elders

Innate resistance to malaria:

Special biologic characteristics can provide protection against malaria.

Sickle cell trait (90% protection)
Thallasaemias (50% protection)
G6PD deficiency (50% protection)
Lack of Duffy antigen