“The symptoms of this fever, it is to be regretted, are so various and irregular, in different cases and under different circumstances, that a mere nosological definition of them would afford no precise information and might mislead those it was intended to instruct.” – Boyle, 1831
Malaria most often presents as a non-specific illness and the typical paroxysmal fever may not occur in many. Many patients present with a not-so-typical fever and some with no fever at all. Patients of malaria may also present with many other myriad manifestations that mimic any other systemic illness. Therefore, one has to be careful enough to consider malaria as a diagnostic possibility in several disease conditions. Waiting for the typical paroxysm to ask for a malaria test may result in under-diagnosis or delayed diagnosis, with a potential risk of development of severe malaria; on the other, relying on only fever for a clinical diagnosis and treatment can lead to over-diagnosis and increased cost burden. [2-6]
The clinical course of malaria is influenced by several factors. The variable degrees of antimalarial immunity among people living in the endemic areas, low or non existing immunity among the non-endemic, non-immune population and among returning travelers influences the clinical manifesttaions significantly. Atypical presentation is more common in early infection, falciparum malaria, those who have received malaria chemoprophylaxis, extremes of age[8-10] and pregnancy. Malnutrition, HIV/AIDS, tuberculosis, neoplastic diseases, transplants and immunosuppression and end stage organ disease can also influence the course of malarial illness.[12-18]
Headache is quite common in malaria and may be a presenting feature in some. Most studies have reported the presence of head ache in 50-85% of the patients in falciparum as well as non-falciparum infections.[2,19-21] Headache can be unilateral or bilateral and may mimic migraine, sinusitis etc. At times, headache can be so intense that it may mimic intra-cranial infections or intra-cranial space occupying lesions; occasionally accompanied by neck stiffness, it may further confuse the clinician.[23-25] Although the presence of acute headache with fever is quite characteristic of malaria, particularly in the returning traveler, this alone it is not enough to make a firm diagnosis.[21,26]
Body ache, back ache and joint pains:
These symptoms are fairly common in malaria, either during the febrile illness or prodrome.[2,19-21,25] Muscular pain and stiffness may even be the presenting feature, with slight or no fever. Such patients may have localised muscular pain and tenderness, particularly in the lumbar, intercostals or neck regions. Aching in the eyeballs and pain behind the eyes that is aggravated by movement may be seen in some cases, mimicking viral or leptospiral fevers. Acute enlargement of the spleen, or even splenitis, may cause diffuse or well localized pain in the left upper abdomen or lower, posterior chest wall, mimicking intercostal myalgia or pleurisy.[25,27] Coupled with cough and breathlessness that are sometimes seen in malaria, this pain easily mimics pneumonia.[25,28,29] Recurrence of these symptoms with another bout of malarial infection is not unusual and some patients may report early with these symptoms, with claims of being certain about having malaria again.
Vomiting and diarrhoea:
Vomiting is a common manifestation of malaria and is seen in about 25-35% of patients. Nausea and vomiting can occur during the febrile paroxysm or as a predominant symptom with only low grade fever.[2,19-21,25] Vomiting is also very common among children with malaria and may be associated with higher parasite loads. Most antimalarial drugs, particularly chloroquine, quinine and mefloquine, also induce nausea and vomiting, necessitating repetition of the dose or parenteral administration. Nausea, retching and vomiting can cause immense discomfort to the patient and can interfere with the administration of oral drugs for treating the infection and also can worsen dehydration. Further, the association of headache, with or without neck stiffness, fever and vomiting may mimic acute meningitis; association of acute pain abdomen, vomiting and fever may suggest acute appendicitis or ureteric colic.
Diarrhoea can occur in both falciparum and non-falciparum infections, but tends to be more common and more severe in the former,[2,19,20,25,31] being reported in 5-38% of P. falciparum infections. In most cases, it manifests as simple diarrhea, usually accompanied by colicky abdominal pain of varying severity. This can begin suddenly in association with headache, vomiting and mild or no fever. The stools can be watery (choleraic), or contain blood, mucus and pus, mimicking bacillary dysentery and the frequency may vary from 5 to many times daily or even alternate days.[25,32] Severe diarrhoea indicates complicated malaria and carries higher mortality. Sequestration of red blood cells and ischemia, cytokine activation and intestinal inflammatory response, subsequent capillary leakage and increased gastroduodenal permeability, edema of the submucosa and cellular infiltration of the lamina propria and malabsorption have been identified as the possible mechanisms for diarrhea in P. falciparum infection. Occasionally, rupture of the villi or other mucosal elements can result in gastrointestinal bleeding, more often in the stomach and small intestine than in the colon.
Apart from the upper abdominal pain, colicky pain or abdominal discomfort mentioned above, many acute abdominal syndromes have also been reported in malaria, mostly in P. falciparum infections, but some in P. vivax too. These include cases of acute abdominal pain due to enlarged liver and hepatitis, acalculous cholecystitis, acute surgical abdomen, acute pancreatitis and splenic rupture as well as cases mimicking appendicitis, peritonitis and liver abscess.[33-39]
Cough, breathlessness and chest pain:
Pulmonary involvement in malaria, known for more than 200 years, may be encountered in infections with any of the five parasite species.[25,40-42] Respiratory manifestations of malaria can occur anytime during the course of the disease, even a few days after the completion of treatment. They can range from the very commonly reported cough to the more distressing bronchitic, pneumonic and bronchopneumonic syndromes and serious complications like acute lung injury and acute respiratory distress syndrome(ARDS). [25,41,43,44] Acute lung injury and ARDS, once considered to be serious complications of only P. falciparum infection, have by now been reported in infections due to all the five species that cause human malaria, particularly among adults.[41,42] Airflow obstruction, impaired ventilation, impaired gas transfer and increased pulmonary phagocytic activity have been observed in malaria and these changes in the pulmonary function are probably related to the increased inflammatory response and sequestration of the parasites in the pulmonary microvasculature. [41,45,47]
Cough is a very common symptom in all types of malaria, with some studies reporting its occurrence in as high as 63% of cases , with higher incidence in P. vivax (and P. ovale) compared to P. falciparum malaria. It can occur not only in non-immune individuals and returning travellers but also in cases from endemic areas, including children. It tends to be more common among smokers compared to non-smokers. In most cases, cough is dry or minimally productive and is usually self-limiting, lasting up to two weeks.[25,43,45] The frequency of cough is reported to be similar between severe malaria and uncomplicated malaria.
About a third of patients may have tachypnoea at presentation, irrespective of whether they have uncomplicated or severe malaria. It may be related to several factors such as fever, metabolic acidosis and lung injury.[28,45] These patients may also have marginally lower room-air oxygen saturation levels (usually not <95%) at presentation and it generally improves in a week.[28,45] Breathlessness, wheezing, chest pain and haemoptysis have also been reported.[25,46] Although typical consolidations are uncommon, subtle thickening of interlobular septae or overt Interstitial edema and pleural effusion have been reported in malaria.[41,47] The respiratory manifestations of malaria and pneumonia can thus overlap, necessitating a careful consideration of antibacterial therapy.[29,48]
ARDS can develop any time during the course of the infection, at the time of initial presentation or even several days after the treatment, when patients appear to be improving and the parasitaemia has fallen or cleared. ARDS is more common among adults compared to children; pregnant women are particularly at a higher risk. ARDS manifests with cough or chest tightness and abrupt onset of or deterioration of dyspnoea, and the condition may rapidly progress over a few hours to cause life-threatening hypoxia.
Jaundice, hepatomegaly, hepatic encephalopathy:
Jaundice is not an uncommon manifestation of malaria, reported in 2.5-62% of cases in different studies, in both falciparum and non-falciparum infections. Several factors have been blamed for the causation of jaundice in malaria viz., intravascular hemolysis of parasitized RBCs and possibly non-parasitised RBCs, hepatic dysfunction and malarial ‘hepatitis’, microangiopathic hemolysis associated with DIC, G6PD deficiency related hemolysis, drug induced haemolysis (quinine etc.,) or co-existing conditions like septicemic hepatitis, acute viral hepatitis or underlying chronic hepatitis.[49,50] Jaundice tends to be more common among adults compared to children and in infections due to P. falciparum compared to non-falciparum species. Most patients tend to have unconjugated hyperbilirubinemia with a serum bilirubin of <3mg/dL[49,50] and it resolves with successful antimalaria treatment. According to the WHO, serum bilirubin of ≥3 mg/dL may be associated with other manifestations of severe malaria. Conjugated hyperbilirubinemia, as high as 50mg/dL, can also occur in malaria and has been attributed to hepatocellular dysfunction, reticulo-endothelial blockage and disturbance of hepatocyte microvilli leading to impairment of bilirubin transport and bile stasis and renal failure compromising bilirubin excretion.[50,52] Mild elevation in the serum levels of the liver enzyme alanine aminotranferase (ALT) is also common in malaria.[49,53] Hepatomegaly, sometimes tender, has been reported in 4-42% of cases and tends to be more common in P. falciparum infection.[25,53,54]
Cases of ‘malarial hepatitis’ (or ‘hepatopathy’) and hepatic encephalopathy, once thought to be rare or non-existent, have been reported increasingly in the recent years in P. falciparum infection. Hepatic dysfunction has been attributed to compromised intrahepatic blood flow due to cytoadherence of the parasitized RBCs to the sinusoidal endothelium. Histopathological changes like hepatocyte necrosis, cholestasis, bile stasis, granulomatous lesions and malarial nodules have been reported. In P. falciparum malaria, more than three fold elevation in serum ALT levels, absence of any other possible cause for hepatic dysfunction and response to antimalaria treatment would qualify for a diagnosis of malarial hepatopathy which is indicative of severe falciparum infection.[50,52] Some cases of hepatic encephalopathy have also been reported in P. falciparum infection, characterized by asterexis, deranged psychometric tests, deranged mental state examination, increased arterial blood ammonia level and EEG changes suggestive of encephalopathy. Although there have been some reports of fulminant hepatitic failure in malaria, these are not supported by histopathological evidence for severe liver disease.
Thus, with manifestations such as fever, vomiting, abdominal pain, jaundice, hepatomegaly and elevation of serum bilirubin and transaminases, malaria easily mimics common infections in the tropics such as viral hepatitis, leptospirosis etc., and anyone presenting with these manifestations must therefore be tested for malaria.
Some patients of malaria may present with dizziness or vertigo, with or without fever and this can develop even post-treatment. Drugs like chloroquine, quinine, mefloquine or halofantrine can also cause dizziness, vertigo and tinnitus.[55,56]
Altered behaviour, acute psychosis
Patients of malaria may present with altered behaviour, mood changes, hallucinosis or even acute psychosis characterized by aggressive behaviour, poor sleep and mixed affective and schizophreniform symptoms, with or without fever. In some of these cases, malaria may be detected accidentally and the symptoms improve completely with anti malarial therapy. Altered behaviour and psychosis in malaria can be due to severe disease, high grade fever or drugs. Although more often reported in P. falciparum infections, psychosis can also occur in non-falciparum infections. In some, it may occur after weeks of treatment, suggesting a possibility of immune-mediated pathogenesis. Antimalarial drugs like chloroquine, quinine, mefloquine and halofantrine can also cause restlessness, hallucinations, confusion, delirium or even frank psychosis.[57-70]
Altered sensorium, convulsions and coma
Patients with severe malaria, mostly due to P. falciparum, but possibly due to non-falciparum infections as well, may present with altered sensorium and/or generalised convulsions that can rapidly deteriorate into deep coma. Severe infection, hypoglycemia, imbalance of fluid, electrolytes and acid-bases, hyperpyrexia may all contribute to these problems. Drugs like chloroquine, quinine, mefloquine and halofantrine may also trigger convulsions. Malaria should be considered a possibility in all cases of acute neuropsychiatric syndromes and differential diagnoses in such situations include acute encephalitis, meningitis, metabolic encephalopathy etc. Papilloedema, features of raised intracranial tension, neck stiffness and focal deficits should prompt a consideration of other possibilities, even if the blood smear shows the presence of malaria.[42,65,71-76]
Weakness, Fatigue and Prostration
Generalised weakness and prostration are fairly common manifestations in malaria. Severe prostration usually signifies complicated malaria and is more often seen in children and the elderly. Anemia, hypotension (algid malaria) and dehydration are commonly associated with weakness and prostration.[20,77,78]
Passage of dark, reddish or blackish urine may be reported by patients of malaria on rare occasions. Most such cases are due to intravascular hemolysis and resulting hemoglobinuria. Rarely, acute glomerulonephritis due to malaria can result in the passage of high coloured urine.[79-82]
There are anecdotal reports in malaria of stroke, vertibro basilar insufficiency, acute coronary syndrome, cerebellar syndrome, Guillain Barre syndrome, sudden loss of vision due to cortical blindness or retrobulbar neuritis, puffiness of lids, pruritic and urticarial rash, angioedema, anaphylaxis, relative bradycardia, postural hypotension, hemophagocytic syndrome etc. These only add to the diverse array of clinical manifestations of malaria, pressing the need for a simple test for malaria parasites in all such cases, especially in areas with malaria transmission and in symptomatic travelers returning from such areas.[83-103]
Anemia is a common complication in malarial infection. Even though both P. falciparum and P. vivax induce anemia, it is a bigger problem with the former. In endemic areas, malarial anemia is more common and severe in young children (1-3 years) and pregnant women and is responsible for approximately a third of the deaths associated with P. falciparum infection. It can also occur in malaria among the non-immune population. Severe prostration is a common accompanying symptom in these patients. [104-107]
Acute anemia can also occur following massive intravascular hemolysis, either due to the infection itself as in cases of Blackwater fever reported from endemic areas or due to oxidant stress following treatment with primaquine in cases with G6PD deficiency. Such cases usually have high fever with rigors, abdominal pain, jaundice, hepatosplenomegaly, vomiting, and renal failure (especially in adults).
Splenomegaly is a common sign of malaria infection due to any species; however, its absence does not rule out malaria. Filled with red cells containing mature and growing parasites, spleen rapidly enlarges in acute malaria and feels soft. After repeated exposure, spleen becomes larger and firm to hard owing to fibrosis. A massive enlargement of the spleen, termed as hyperreactive malarial splenomegaly(HMS), is seen in about 10% of the residents living in malarious areas like Africa, SE Asia, Srilanka and some parts of India. It is commonly seen in older children and young adults; however, a few cases in young children have also been reported. An aberrant immune response to recurrent malarial infection resulting in polyclonal B cell activation by an unidentified malaria mitogen, unregulated production of immunoglobulin M, cryoglobulins and autoantibodies and reticuloendothelial cell hyperplasia are believed to cause HMS. It is often accompanied by lassitude, fever, weight loss and hepatomegaly. Rarely, cases with HMS can develop acute haemolysis, severe anemia and fever, which may be even fatal, and this has been termed as fulminant tropical splenomegaly syndrome.[108-113]
Complications such as splenitis, splenic infarction, abscess, haematoma formation, rupture, hypersplenism, ectopic spleen, torsion or cyst formation have also been reported. Rupture of the enlarged spleen, particularly in P. vivax malaria, manifests with acute abdominal pain, hypotension and anemia. Splenic infarction can occur very rarely in P. falciparum as well as P. vivax infections, manifesting with left upper abdominal pain that may radiate to the left shoulder.[114-120]
Certain unique retinal changes, first described in children with cerebral malaria, have now been validated as specific signs of cerebral malaria in both children and adults. Malarial retinopathy consists of retinal whitening affecting the macula, white or orange discoloration of retinal vessels in the peripheral fundus, retinal hemorrhages and papilledema; the first two of these abnormalities are specific to malaria, not seen in other ocular or systemic conditions. These changes are related to microvascular obstruction of severe falciparum malaria and correlate with disease severity and coma.[121,122]
Malaria not only manifests with many symptoms that are non-specific and akin to any infective disease, but also can increase the susceptibility to other bacterial infections, particularly in severe disease, pregnancy and children. Respiratory tract infections, urinary tract infections (following catheterization) and bacterial septicemia can occur in patients of malaria. Non-typhoidal Salmonella bacteremia can occur, particularly in children, probably due to the deranged gut wall defences due to sequestration of parasitized red cells in the splanchnic circulation that allow the enteric bacteria to gain access into the circulation. Considerable overlap between the manifestations of severe malaria and infections like pneumonia and meningitis can make the diagnosis and treatment difficult. Other mosquito borne diseases common in the tropics may also co-exist with malaria and rarely, opportunistic infections like Cryptococcal meningitis have also been reported. [29,48,123-127]
Thus, malaria can manifest with myriad symptoms and signs. Although atypical manifestations are more often reported in P. falciparum infections, no malaria can be an exception. Considering the fact that malaria is a multi-system disease, many of the above mentioned clinical features can occur in various combinations. Therefore, the treating clinician should be alert to the possibility of malaria in any clinical situation, particularly in the malaria endemic areas and while treating symptomatic travelers returning from malarious areas. A simple blood test to look for malaria parasites can be life saving.
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