Thiamin deficiency and uncomplicated falciparum malaria in Laos

OBJECTIVE: Thiamin deficiency complicates severe Plasmodium falciparum malaria in Thailand and may contribute to acidosis. We therefore estimated the frequency of biochemical thiamin deficiency in patients presenting with uncomplicated falciparum malaria in southern Laos. METHODS: Red cell transketolase activation coefficients (alpha) were measured in 310 patients presenting with uncomplicated falciparum malaria and 42 days after starting treatment. RESULTS: Twelve per cent of patients had biochemical evidence of severe deficiency (alpha values >1.31) at presentation, declining to 3% 42 days later. CONCLUSION: Thiamin deficiency was common in Lao patients admitted with uncomplicated P. falciparum infection and was reduced following treatment of malaria and multivitamin supplementation. The role of this preventable and treatable disorder in malaria and other acute infections, and the incidence of beriberi in rural Laos, needs further investigation.     

Lactic acidosis caused by thiamine deficiency in a pregnant alcoholic patient

BACKGROUND: Metabolic acidosis from accumulation of lactic acid is a relatively common condition, whereas its causation by thiamine deficiency is not. METHODS: We studied a pregnant alcoholic patient who presented with hyperemesis and a high anion gap acidosis. RESULTS: Lactic acidosis and thiamine deficiency were confirmed. The patient's symptoms and acidosis resolved with thiamine administration. CONCLUSIONS: Lactic acidosis caused by thiamine deficiency must be suspected when pregnant patients at risk for thiamine deficiency present with a high anion gap acidosis. A large dose of thiamine must be administered immediately.     

Platelet-induced autoagglutination of Plasmodium falciparum-infected red blood cells and disease severity in Thailand

The relationship of the platelet-mediated autoagglutination of Plasmodium falciparum-infected red blood cells (IRBCs) to disease severity was investigated in 182 Thai patients with falciparum malaria; it was evident in 43% of uncomplicated malaria (n=63), 41% of severe malaria (n=104), and 100% of cerebral malaria (n=15; P=.001) isolates. The median (range) number of IRBCs in agglutinates per 1000 IRBCs was significantly higher in cerebral malaria (6 [3-42]) than in severe (0 [0-52]) and uncomplicated (0 [0-24]) malaria (P=.01). In multivariate analyses, high parasitemia and cerebral malaria were associated independently with parasite agglutination.     

Severe lactic acidosis and thiamine deficiency during total parenteral nutrition--case report

We encountered a case of total parenteral nutrition-associated lactic acidosis that did not respond to sodium bicarbonate or other conventional emergency treatments. He was characterized by minimal food intake before surgery, delayed gastric emptying after pylorus-preserving pancreatoduodenectomy due to pancreas head cancer and long-term total parenteral nutrition without food intake and vitamin supplements after surgery. After thiamine administration, the patient very quickly recovered with dramatic reestablishment of the acid-base balance. We emphasize the need to supplement total parenteral nutrition with thiamine-containing vitamins for the patients whose food intake does not meet nutritional requirements and to intravenously replenish using high-dose thiamine simultaneously with the manifestation of signs and symptoms of severe lactic acidosis with unknown cause. In conclusion, thiamine deficiency should be included in the differential diagnosis of lactic acidosis for the patients who received total parenteral nutrition without food intake and vitamin supplements.     

Malarial retinopathy in Bangladeshi adults

To establish if assessment of malarial retinopathy in adult malaria using ophthalmoscopy by non-ophthalmologists has clinical and prognostic significance, 210 Bangladeshi adults were assessed by both direct and indirect ophthalmoscopy; 20 of 20 healthy subjects and 20 of 20 patients with vivax malaria showed no retinal changes, whereas in patients with falciparum malaria, indirect ophthalmoscopy revealed malarial retinopathy (predominantly retinal hemorrhages) in 18 of 21 (86%) fatal, 31 of 75 (41%) cerebral, 16 of 64 (25%) non-cerebral but severe, and 1 of 31 (3%) uncomplicated cases. Direct ophthalmoscopy missed retinopathy in one of these cases and found fewer retinal hemorrhages (mean difference = 3.09; 95% confidence interval = 1.50-4.68; P < 0.0001). Severity of retinopathy increased with severity of disease (P for trend < 0.0001), and renal failure, acidosis, and moderate/severe retinopathy were independent predictors of mortality by both ophthalmoscopic techniques. Direct ophthalmoscopy by non-ophthalmologists is an important clinical tool to aid diagnosis and prognosis in adults with severe malaria, and indirect ophthalmoscopy by non-ophthalmologists, although more sensitive, provides minimal additional prognostic information.     

Cytoadherence in paediatric malaria: ABO blood group,CD36, and ICAM1 expression and severe Plasmodium falciparum infection

As a leading cause of childhood mortality worldwide, selection pressure by Plasmodium falciparum continues to shape the human genome. Severe disturbances within the microcirculation result from the adhesion of infected erythrocytes to host receptors on monocytes, platelets, and endothelium. In this prospective study, we compared expression of all major host cytoadhesion receptors among Ugandan children presenting with uncomplicated malaria (n = 1078) versus children with severe malaria (n = 855), including cerebral malaria (n = 174), severe anaemia (n = 522), and lactic acidosis (n = 154). We report a significant survival advantage attributed to blood group O and increased monocyte expression of CD36 and ICAM1 (CD54). The high case fatality rate syndromes of cerebral malaria and lactic acidosis were associated with high platelet CD36 expression and thrombocytopenia, and severe malaria anaemia was characterized by low ICAM1 expression. In a logistic regression model of disease severity, odds ratios for the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were greater than that of sickle haemoglobin. Host genetic adaptations to Plasmodium falciparum suggest new potential malaria treatment strategies.     

Association of intraleukocytic Plasmodium falciparum malaria pigment with disease severity, clinical manifestations, and prognosis in severe malaria

Peripheral parasite density of Plasmodium falciparum is used as an indicator of malaria disease severity, but does not quantify central sequestration, which is important in the pathogenesis of severe disease. Malaria pigment, recognizable within the cytoplasm of phagocytic cells by light microscopy may represent a peripheral marker for parasite biomass. One hundred seventy-two index cases of severe malaria and 172 healthy age-, residence-, and ethnicity-matched controls with uncomplicated malaria in Bandiagara, Mali were analyzed prospectively for presence of malaria pigment. The presence of polymorphonuclear cell (PMN) and monocyte pigment was strongly associated with severe disease compared with uncomplicated malaria. Total PMN pigment burden in children with severe malaria was higher in those with cerebral manifestations and with combined cerebral manifestations and severe anemia (hemoglobin < or = 5 g/dL) but was not associated with hyperparasitemia (> 500,000 asexual forms/mm3). Additionally, pigmented PMNs/mm3 was associated with a fatal outcome in patients with severe malaria. This study validates the presence of malaria pigment in monocytes and neutrophils as a marker for disease severity, and demonstrates that pigmented neutrophils are associated with cerebral malaria and with death in children with severe malaria.     

Lung injury in uncomplicated and severe falciparum malaria: a longitudinal study in papua, Indonesia

BACKGROUND: In patients with severe malaria, acute respiratory distress syndrome usually develops after the start of drug treatment and is a major cause of death. Its pathogenesis is not well understood. METHODS: Respiratory symptom, spirometry, and gas transfer analyses were performed longitudinally in adults in Papua, Indonesia, with uncomplicated (n=50) and severe (n=30) falciparum malaria; normal values were derived from 109 control subjects. Gas transfer was partitioned into its alveolar-capillary membrane (D(M)) and pulmonary vascular (Vc) components, to characterize the site of impaired gas transfer. RESULTS: Cough was frequent in both patients with uncomplicated malaria (50%) and those with severe malaria (30%) and resolved by day 14. Reduced midexpiratory flow indicated obstruction of the small airways. Gas transfer was significantly impaired in patients with severe malaria. D(M) was reduced in patients with severe malaria but not in those with uncomplicated malaria and only returned to normal levels after 2 weeks. In patients with uncomplicated malaria, Vc was reduced at presentation but improved thereafter. In patients with severe malaria, Vc decreased with treatment and was lowest at day 7. CONCLUSIONS: Our results suggest that pulmonary vascular occlusion occurs in both patients with uncomplicated malaria and those with severe malaria, likely from sequestration of both red blood cells (RBCs) and white blood cells. There was also impaired alveolar-capillary membrane function in patients with severe malaria but not in those with uncomplicated malaria. Persistent impairment long after clearance of parasitized RBCs suggests prolonged posttreatment inflammatory alveolar-capillary injury.     

Severe malaria in Cameroonian children: correlation between plasma levels of three soluble inducible adhesion molecules and TNF-alpha

Plasma levels of three soluble inducible adhesion molecules, namely: intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and endothelial leucocyte adhesion molecule-1 (sELAM-1) or sE-selectin and the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-alpha) were measured in well-defined clinical groups of children with severe and uncomplicated malaria. The goal of the study was to investigate the role of these molecules in immunopathogenic processes associated with severe malaria in Cameroonian children. Results showed significantly increased plasma concentrations of sICAM-1, sVCAM-1 and sE-selectin in children with severe malaria compared to those with uncomplicated malaria and healthy children (P<0.001). TNF-alpha levels increased significantly in children with severe malaria, approximately 2-folds compared to those with uncomplicated malaria and about 3-folds compared to healthy children (P<0.001). More importantly, levels of TNF-alpha strongly correlated with those of the three adhesion molecules and were significantly associated with increased risk of death (P=0.03). In addition, children who died from severe malaria showed higher mean levels of all measured factors compared to those who recovered, with significant differences observed with sICAM-1 (P<0.001) and sE-selectin (P=0.002). Furthermore, children with severe malarial anemia relative to those without, showed significantly elevated levels of the three soluble molecules; and sICAM-1 was significantly associated with increased risk of severe anemia. Taken together, these results confirm the role of TNF-alpha and the three adhesion molecules in pathogenic processes associated with severe malaria in children, and suggest an association between sICAM-1 and severe malarial anemia.     

Parasite multiplication potential and the severity of Falciparum malaria

The multiplication rates and invasiveness of Plasmodium falciparum parasites isolated from adult Thai patients hospitalized with uncomplicated malaria (n=34) were compared with those from persons with severe malaria (n=42). To simulate severe malaria and control for host effects, the in vitro cultures were adjusted to 1% parasitemia and used the same red blood cell donor. P. falciparum isolates from persons with severe malaria had initial cycle multiplication rates in vitro that were 3-fold higher than those from uncomplicated malaria (median [95% confidence interval], 8.3 [7. 1-10.5] vs. 2.8 [1.7-3.9]; P=.001). Parasites causing severe malaria exhibited unrestricted red blood cell invasion, whereas those from uncomplicated malaria were restricted to a geometric mean of 40 (31%-53%) of red blood cells. P. falciparum parasites causing severe malaria were less selective and multiplied more at high parasitemias than those causing uncomplicated malaria.     

Seizure disorders among relatives of Kenyan children with severe falciparum malaria

PURPOSE: The cause of seizures in children with falciparum malaria is unclear. In malaria endemic areas, children who develop severe falciparum malaria with seizures may have a genetically higher risk of epilepsy or febrile seizures. We used the history of seizures in relatives of children previously admitted with malaria to determine if there is evidence for a familial predisposition of seizures in children admitted with malaria and seizures or cerebral malaria. METHODS: Family history of seizures were obtained from the parents/guardians of 81 children (35 children previously admitted with severe malaria and 46 children matched for age who had not been admitted with severe malaria). Data were collected on frequency, duration, age of onset, presence of fever and causes of seizures. RESULTS: The prevalence of seizures in the relatives of children not admitted with severe malaria was 4.3%, of whom 2.2% had a history of seizures compatible with febrile seizures, and 1.1% with epilepsy. Overall the odds ratio (OR) for relations of children admitted with malaria, to have a seizure disorder was 1.41 [95% confidence interval (CI) 1.06-1.88]. There was a significant risk of the relatives dying if they had epilepsy [relative risk 1.88 (95% CI 1.11-3.19)], but not for other seizure disorders (i.e. febrile, single or unclassifiable seizures). CONCLUSION: Relatives of children admitted with severe falciparum malaria are more likely to have a seizure disorder compared with controls, but it is unclear if this is because of a genetic propensity or caused by exogenous factors such as malaria.     

Type B lactic acidosis as a severe metabolic complication in lymphoma and leukemia: a case series from a single institution and literature review

Type B lactic acidosis is a rare complication of hematologic malignancies. The exact mechanism of this process is not well understood. Because caregivers may not be aware of the association of type B lactic acidosis with hematologic malignancies, it may go unrecognized as a cause of acidosis in these patients. We report the cases of 7 patients with type B lactic acidosis who were cared for by members of the Brown Medical School Hematology/Oncology Division. Of the 7 patients reported, 5 had lymphomas and 2 had chronic lymphocytic leukemia. One of the lymphomas was a T-cell lymphoma. Of the patients we were able to evaluate, there did not seem to be a unique cluster of differentiation marker in association with type B lactic acidosis. We also review 14 additional cases, most reported since 2001. From our review of the literature, we suggest that a deficiency of thiamine or riboflavin may play a more pivotal role than previously recognized in the development of type B lactic acidosis associated with malignancy. Further investigation should be undertaken to learn if thiamine or riboflavin replacement might be useful in treating this disorder.     

Distinctive acid-base pattern in Wernicke's encephalopathy

Wernicke's encephalopathy may result in severe morbidity and possible mortality when unrecognized. We report a distinctive acid-base pattern that has not been associated with this syndrome. This is a case series of patients with Wernicke's encephalopathy who had an arterial blood gas measurement performed on initial presentation. Exclusion criteria were patients with an unclear diagnosis of Wernicke's encephalopathy and those for whom no arterial blood gas measurement was performed. Four patients with Wernicke's encephalopathy were included in the analysis. All 4 patients exhibited an anion-gap (primary) metabolic acidosis, accompanied by a primary respiratory alkalosis. Three of 4 patients exhibited a significant lactic acidosis. None of the patients had any competing diagnoses or dysfunction to account for this acid-base pattern. Patients with Wernicke's encephalopathy may exhibit a distinctive acid-base pattern consisting of a primary metabolic acidosis in conjunction with a primary respiratory alkalosis. Observation of this acid-base disturbance should prompt clinicians to consider thiamine deficiency disorders as a possible cause.     

A preliminary study of thiamine status in northeastern Thai children with acute diarrhea

This study is a preliminary determination of thiamine status in children with diarrhea and metabolic acidosis admitted to hospital. Children with diarrhea (N = 14; age 2 m-6 yr) were divided into 2 groups according to anion gap type; group 1 (21.4%) with a normal anion gap (5.5 +/- 5.2 mmol/l) and group 2 (78.6%) with a wide anion gap (21.2 +/- 5.2 mmol/l). Blood was taken on the day of admission to determine thiamine and lactate levels. Sixty-six point seven percent of patients in group 1 had a normal lactate level (1.5 +/- 0.8 mmol/l) and 33.3% had a high lactate level (2.2 mmol/l); none had thiamine deficiency (TPPE < 20%). High lactate (3.5 +/- 1.4 mmol/l) was found in 54.5% of group 2 and thiamine deficiency was observed in 18.2% of this group. In conclusion, no thiamine deficiency was noted in patients with normal anion gap, but thiamine deficiency was not uncommon in patients with a wide anion gap, regardless of lactic acidosis.     

Reduced levels of transforming growth factor-beta1, interleukin-12 and increased migration inhibitory factor are associated with severe malaria

In the present study, we investigated plasma levels of interleukin (IL)-12 and transforming growth factor (TGF-beta1) in malaria patients as these two cytokines regulate the balance between pro- and anti-inflammatory cytokines. We compared plasma IL-12 and TGF-beta1 levels in groups of malaria patients categorized as uncomplicated, severe, cerebral and placental malaria. Both TGF-beta1 and IL-12 levels were significantly reduced in peripheral plasma of adults with severe and cerebral malaria as well as in plasma of Tanzanian children with cerebral malaria (P<0.05). Similar results were observed with both placental and peripheral plasma of pregnant women who were infected with Plasmodium falciparum. IL-18, a cytokine known to be critical for the induction of IFN-gamma along with IL-1, was produced more in uncomplicated adult patients than in aparasitimic healthy controls (P<0.05). However, IL-18 response rate declined as the symptoms of the disease became more severe suggesting that the IL-18 response may be impaired with increased malaria severity. Together, the results of the three cytokines support the notion that imbalance between pro- and anti-inflammatory cytokines may contribute to the development of severe malaria infection. With malaria infection during pregnancy, we demonstrated that macrophage migration inhibitory factor (MIF) levels in infected placental plasma were significantly higher than those in the paired peripheral plasma (P<0.05). MIF, therefore, may play an important role in the local immune response to placental P. falciparum infection.     

Thiaminmangel als Ursache für eine schwere Lactazidose im Erwachsenenalter

Thiamine deficiency may be the cause of severe lactacidosis. The clinical picture may be characterized by acute hemodynamic instability and heart failure with secondary organ dysfunction, like acute Beri-Beri in infants. Thiamine deficiency should be considered in cases of severe lactic acidosis without any other known cause. The treatment with thiamine is safe, effective and shows a fast response. High-risk factors for thiamine deficiency are malnutrition, maldigestion, alcoholism and liver disorders. Four case reports will be presented in this article.     

Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production

Nitric oxide (NO) production and mononuclear cell NO synthase 2 (NOS2) expression are high in healthy Tanzanian children but low in those with cerebral malaria. Factors that downregulate NOS2 also diminish factors involved in cellular uptake and biosynthesis of L-arginine, the substrate for NO synthesis. We therefore postulated that L-arginine concentrations would be low in individuals with cerebral malaria. We measured concentrations of L-arginine in cryopreserved plasma samples from Tanzanian children with and without malaria. L-arginine concentrations were low in individuals with cerebral malaria (mean 46 micromol/L, SD 14), intermediate in those with uncomplicated malaria (70 micromol/L, 20), and within the normal range in healthy controls (122 micromol/L, 22; p<0.0001). Analysis by logistic regression showed that hypoargininaemia was significantly associated with cerebral malaria case-fatality. Hypoargininaemia may contribute to limited NO production in children with cerebral malaria and to severe disease.     

Serum antibody levels to glycosylphosphatidylinositols in specimens derived from matched Malian children with severe or uncomplicated Plasmodium falciparum malaria and healthy controls

Neutralizing antibodies to glycosylphosphatidylinositols (GPIs), which are Plasmodium falciparum surface protein anchor molecules implicated in malaria pathogenesis, are thought to protect against symptomatic malaria. Index cases of severe malaria in Malian children 3 months to 14 years of age were matched by age and residence to uncomplicated malaria and healthy controls. Serum antibodies to GPI (IgM and IgG) were measured at the time of severe malaria and after the malaria transmission season. The mean optical density values for IgM and IgG antibodies were higher in children with severe or uncomplicated malaria compared with healthy controls. Similarly, higher percentages of children with IgM and IgG antibodies to GPI were observed in the severe malaria group compared with matched healthy controls. IgG antibody levels to GPI were highest among children with cerebral malaria and children who died. The IgG antibody levels to GPI peaked during periods of malaria transmission and decreased after malaria transmission ended. A direct correlation between age and parasitemia and IgG antibodies to GPI was observed. In summary, higher levels of IgM and IgG antibodies to GPI in young children were associated with disease severity and were short-lived.