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A quantitative ultrastructural study of the liver and the spleen in fatal falciparum malaria
Abstract
We performed a retrospective study of 25 patients who died of severe falciparum malaria in Thailand and Vietnam using electron microscopy. The aims of the study were: to determine if there was any significant association between parasitized red blood cells (PRBC) sequestered in liver and spleen and particular pre-mortem clinical complications, and to compare the degree of parasite load between the liver and spleen within the same patients. PRBC sequestrations in each organ were compared with the pre-mortem parasitemia, to calculate the sequestration index (S.I.). The S.I. showed that the degree of PRBC sequestration in the spleen was higher than the liver (S.I. median = 3.13, 0.87, respectively) (p < 0.05). The results of quantitative ultrastructural study showed a significantly high parasite load in the liver of patients with jaundice, hepatomegaly and liver enzyme elevation (p < 0.05). We found a significant correlation between PRBC sequestration in the liver and a high serum bilirubin level, a high aspartate aminotransferase (AST) level and an increase in the size of the liver (Spearman's correlation coefficient = 0.688, 0.572, 0.736, respectively). Furthermore, a higher parasite load was found in the liver of patients with acute renal failure (ARF) compared to patients without ARF (p < 0.05). These findings suggest that PRBC sequestration in the liver is quantitatively associated with pre-mortem hepatic dysfunction and renal impairment. There was no significant difference between splenomegaly and PRBC sequestration. The size of a palpable spleen was not correlated with parasite load in the spleen. When ultrastructural features were compared between the two reticuloendothelial organs, we found that the spleen had more PRBC and phagocytes than the liver. The spleen of non-cerebral malaria (NCM) patients had more phagocytes than cerebral malaria (CM) patients. This observation reveals that the spleen plays a major role in malaria parasite clearance, and is associated with host defence mechanisms against malaria.
... These numbers then returned to control levels 6 to 8 days post-infection. Subsequent cell trapping experiments showed that peripheral blood lymphocytes were preferentially recruited in the spleen during the initial stages of the infection with Th1 lymphocytes as the main cell type affected [32]. ...
... Immunohistochemical analysis of liver tissue sections from patients may, in the future, provide additional information on lymphocyte trafficking in human SMA. Indeed, studies assessing the importance of the increase in T and B cells traffic to the liver in malaria infection have also provided evidence for a crucial role of the accumulation of leucocytes in the liver to the development of protective immunity during malarial infection [32]. Thus, it is possible that reduced entry of lymphocytes into the spleen may in fact contribute to increase the delivery of committed immunologically competent cells to the liver, where parasite destruction occurs [32]. ...
... Indeed, studies assessing the importance of the increase in T and B cells traffic to the liver in malaria infection have also provided evidence for a crucial role of the accumulation of leucocytes in the liver to the development of protective immunity during malarial infection [32]. Thus, it is possible that reduced entry of lymphocytes into the spleen may in fact contribute to increase the delivery of committed immunologically competent cells to the liver, where parasite destruction occurs [32]. ...
Secondary lymphoid tissues play a major role in the human immune response to P. falciparum infection. Previous studies have shown that acute falciparum malaria is associated with marked perturbations of the cellular immune system characterized by lowered frequency and absolute number of circulating T cell subsets. A temporary relocation of T cells, possibly by infiltration to secondary lymphoid tissue, or their permanent loss through apoptosis, are two proposed explanations for this observation. We conducted the present study to determine the phenotype of lymphocyte subsets that accumulate in the lymph node and spleen during acute stages of falciparum malaria infection in Malawian children, and to test the hypothesis that lymphocytes are relocated to lymphoid tissues during acute infection. We stained tissue sections from children who had died of the two common clinical forms of severe malaria in Malawi, namely severe malarial anemia (SMA, n = 1) and cerebral malaria (CM, n = 3), and used tissue sections from pediatric patients who had died of non-malaria sepsis (n = 2) as controls. Both lymph node and spleen tissue (red pulp) sections from CM patients had higher percentages of T cells (CD4+ and CD8+) compared to the SMA patient. In the latter, we observed a higher percentage of CD20+ B cells in the lymph nodes compared to CM patients, whereas the opposite was observed in the spleen. Both lymph node and spleen sections from CM patients had increased percentages of CD69+ and CD45RO+ cells compared to tissue sections from the SMA patient. These results support the hypothesis that the relocation of lymphocytes to spleen and lymph node may contribute to the pan-lymphopenia observed in acute CM.
... Rapid cellular variations in P. chabaudi malaria-infected spleen are influenced by Fas-mediated apoptotic events [30]. The size of a palpable spleen does not correlate with the parasite load in the spleen [31]. Parasitized RBCs and phagocytes found in the spleen are more numerous than those in the liver [31]. ...
... The size of a palpable spleen does not correlate with the parasite load in the spleen [31]. Parasitized RBCs and phagocytes found in the spleen are more numerous than those in the liver [31]. These previous studies reveal that spleen plays a major role in the clearance of malaria parasites by adopting a host-defense mechanism against malaria [31]. ...
... Parasitized RBCs and phagocytes found in the spleen are more numerous than those in the liver [31]. These previous studies reveal that spleen plays a major role in the clearance of malaria parasites by adopting a host-defense mechanism against malaria [31]. ...
... Histopathological findings have shown that lymphocytes are the predominant cell type in inflammatory infiltrate in the portal tracts and sinusoidal spaces of the liver in patients infected with P. falciparum (Bhalla et al, 2006;Kochar et al, 2003;Viriyavejakul et al, 2014). Livers infected with P. falciparum have pronounced macrophage accumulations (Kochar et al, 2003;Prommano et al, 2005;Viriyavejakul et al, 2014), with hyperplastic characteristics (Prommano et al, 2005) and apoptotic changes (Viriyavejakul et al, 2014). ...
... Histopathological findings have shown that lymphocytes are the predominant cell type in inflammatory infiltrate in the portal tracts and sinusoidal spaces of the liver in patients infected with P. falciparum (Bhalla et al, 2006;Kochar et al, 2003;Viriyavejakul et al, 2014). Livers infected with P. falciparum have pronounced macrophage accumulations (Kochar et al, 2003;Prommano et al, 2005;Viriyavejakul et al, 2014), with hyperplastic characteristics (Prommano et al, 2005) and apoptotic changes (Viriyavejakul et al, 2014). ...
... Macrophage can control malaria parasites through both antibodydependent and independent phagocytosis (Chua et al, 2013;Malaguarnera and Musumeci, 2002) and secretion of soluble cytokines, such as interleukin 1 (IL-1) and TNF (Pichyangkul et al, 1994). A large number of resident macrophages containing hemozoin pigment has been found in the liver tissue of P. falciparum infected patients (Kochar et al, 2003;Prommano et al, 2005;Viriyavejakul et al, 2014). Accumulation of malaria pigment is associated with impairment of macrophage activation and function (Schwarzer et al, 1998). ...
The immune responses against Plasmodiumfalciparum malaria infections are complex and poorly understood. No published studies have yet reported the lymphocyte subsets involved in the human liver tissue of P. falciparum malaria patients. To understand the cellular-mediated immune responses in the liver during malaria infection, we determined the numbers of the various lymphocyte subsets in tissue samples obtained at autopsy from patients who died with P. falciparum malaria infection. All the liver tissue specimens had been stored at the Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Thailand. On the basis of total bilirubin (TB) levels prior to death, patients were divided into 2 groups: those with hyperbilirubinemia [total bilirubin (TB) > or =51.3 micromol/l) (n = 9)] and those without hyperbilirubinemia (TB < 51.3 micromol/l) (n = 12). Normal liver specimens (n = 10) were used as controls. An immunohistochemistry method was used to analyze the types and numbers of lymphocytes (T and B lymphocytes), and Kupffer cells, using specific antibodies against CD3+, CD4+, CD8+, CD20+, and CD68+. Our findings reveal the numbers of T lymphocytes (CD3+ T-cells) and their subsets (CD4+ and CD8+ T-cells) were significantly greater in the portal tracts and sinusoids of liver tissue obtained from P. falciparum malaria cases with hyperbilirubinemia than those without hyperbilirubinemia or controls. CD8+ T-cells were the major lymphocyte subset in the liver tissue of patients with severe falciparum malaria. A significant positive correlation was seen between the numbers of CD4+ and CD8+ T-cells and the liver enzyme levels among P. falciparum malaria patients. The number of CD68+ cells (Kupffer cells) was significantly greater in the liver sinusoids of P. falciparum malaria cases with hyperbilirubinemia than those without hyperbilirubinemia. These findings suggest T-cells, especially CD8+ T-cells and Kupffer cells are an important part of the cellular immune response in the liver tissue of P. falciparum infected patients.
... 19 In postmortem studies on patients infected with P. falciparum, however, the formation of thrombin and fibrin, which is a final result of the hypercoagulable state, is not clearly observed in the spleen. 20,21 For patients who received antimalarial drugs, which induce a non-natural state during treatment, the rare finding of thrombin and fibrin formation might result from a return to normal condition from a hypercoagulable state after administration of antimalarial drugs. 17,22 In contrast with P. falciparum infection, altered thrombostasis and intravascular coagulation have not yet been characterized in P. vivax infection. ...
... 22,26,27 Microvascular endothelial adhesion of P. falciparum-iRBCs appears to develop throughout the body, and distribution of iRBCs and extent of sequestration varies by organ system and is not even uniform within the same organ. 20,21,[28][29][30][31][32] Elevation of TNF-α and IFN-γ/IL-10 and increase in endothelial activation markers such as thrombomodulin, intracellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, and E-selectin are also observed in P. vivax infection. 33,34 Previously, P. vivax was not seen to become sequestered in the deep microvasculature of inner organs. ...
... In postmortem studies, mature P. falciparum-iRBC sequestration is observed in red pulp, suggesting cytoadherence of iRBCs to the sinusoidal endothelium and mechanical retention. 20,21 Malarial parasites express various types of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) that have different adhesive properties and bind to alternative endothelial receptors. 40 This determines the organ in which iRBCs are sequestered and the severity of disease. ...
Splenic infarction is a rare complication of malaria. We report two recent cases of splenic infarction after Plasmodium vivax infection. No systematic review of malaria-induced splenic infarction was available, therefore we conducted a systematic review of the English, French, and Spanish literature in PubMed and KoreaMed for reports of malaria-associated splenic infarction from 1960 to 2012. Of the 40 cases collected on splenic infarction by Plasmodium species, 23 involved P. vivax, 11 Plasmodium falciparum, one Plasmodium ovale, and five a mixed infection of P. vivax and P. falciparum. Of the 40 cases, 2 (5.0%) involved splenectomy and 5 (12.5%) were accompanied by splenic rupture. The median time from symptom onset to diagnosis was 8.5 days (range, 3-90 days). Improved findings after treatment were observed in 8 (88.9%) of 9 patients with splenic infarction on follow-up by computed tomography or ultrasonography. All patients survived after treatment with the exception of one patient with cerebral malaria. Clinicians should consider the possibility of splenic infarction when malaria-infected patients have left upper quadrant pain.
... Different degrees of hepatic dysfunction and jaundice have also been shown to occur in CM patients and are associated with poor prognosis in some studies (53)(54)(55). Although a relationship between liver damage and CM was not found in previous studies with adult patients (56,57), a strong association between increased hemozoin-laden Kupffer cells (a sign of liver inflammation) and CM was recently shown in Malawian children (53). Cerebral edema, a hallmark of ALF, has also been observed in CM patients (4,58). ...
... Reduction in portal venous flow as a consequence of micro-occlusion by pRBC and rosettes, intrahepatic cholestasis due to reticulo-endothelial blockage, hepatic microvilli dysfunction, apoptosis and oxidative stress due to an intense inflammatory response to the parasite are some possibilities (51). In fact, one study showed a significant correlation between the amount of pRBC in the liver and the level of serum bilirubin and the enzyme aspartate transaminase (AST) in adults with severe malaria (57). However, an association between pRBC sequestration in the liver or histologic evidence of hepatocellular damage and CM development was not found in children (53). ...
... The occurrence of CM in patients with mild or without apparent hepatocellular liver damage (53,56,57) and the presence of liver damage in non-CM murine models (56,57,73,74,76,77) indicate that the development of ALF during malaria infection is not the single factor responsible for neuropathology. One may, however, consider that BBB breakdown contributes to the pathogenesis of CM and synergizes with hepatic failure to induce neurological signs and symptoms. ...
... 44 Pigment is predominantly found in macrophages and in intact mature forms. [44][45][46] Increased spleen weight is associated with expansion of both the red and the white pulp. 42 The red pulp is congested with RBCs, 47 and the relative number of macrophages is increased. ...
... 42 At the acute phase of fatal infection, uRBC, knob-positive and -negative iRBCs accumulate in the spleen more intensely than in the liver. 45 Typical cytoadherence of mature forms occurs on the luminal side of the sinus endothelium. 45 Electronic microscopy has shown iRBCs containing either morphologically normal parasites or parasite remnants squeezing through interendothelial slits and, possibly, being retained in that position ( Figure 1). ...
... 45 Typical cytoadherence of mature forms occurs on the luminal side of the sinus endothelium. 45 Electronic microscopy has shown iRBCs containing either morphologically normal parasites or parasite remnants squeezing through interendothelial slits and, possibly, being retained in that position ( Figure 1). 42,45 Whether mature forms are phagocytosed predominantly as intact iRBCs or after iRBC lysis is not known. ...
Clinical manifestations of Plasmodium falciparum infection are induced by the asexual stages of the parasite that develop inside red blood cells (RBCs). Because splenic microcirculatory beds filter out altered RBCs, the spleen can innately clear subpopulations of infected or uninfected RBC modified during falciparum malaria. The spleen appears more protective against severe manifestations of malaria in naïve than in immune subjects. The spleen-specific pitting function accounts for a large fraction of parasite clearance in artemisinin-treated patients. RBC loss contributes to malarial anemia, a clinical form associated with subacute progression, frequent splenomegaly, and relatively low parasitemia. Stringent splenic clearance of ring-infected RBCs and uninfected, but parasite-altered, RBCs, may altogether exacerbate anemia and reduce the risks of severe complications associated with high parasite loads, such as cerebral malaria. The age of the patient directly influences the risk of severe manifestations. We hypothesize that coevolution resulting in increased splenic clearance of P. falciparum-altered RBCs in children favors the survival of the host and, ultimately, sustained parasite transmission. This analysis of the RBC-spleen dynamic interactions during P falciparum infection reflects both data and hypotheses, and provides a framework on which a more complete immunologic understanding of malaria pathogenesis may be elaborated.
... Impaired hepatic gluconeogenesis and hepatic lactate clearance have been reported to directly affect blood lactate concentrations, resulting in death-related acidosis in patients with malaria [6]. A positive association between high Plasmodium-infected erythrocyte (pRBC) load of the liver and jaundice, hepatomegaly and elevated liver enzymes has been observed in different malaria patient cohorts [18,19]. Liver dysfunction in these patients is related to other organ dysfunctions and poor outcomes [19,20], suggesting a potential role of the liver in malaria responses. ...
... Compared with the liver stage of the parasite life-cycle, involvement of the liver in the blood stage of the parasite has been overlooked in most studies, and only a few animal and human studies on hepatic pathologies in malaria have been reported [14-16, 21, 22]. Histopathological evidence of the involvement of reactive Kupffer cells, retention of heme pigment, minimal pRBC sequestration and inflammatory responses in the pathogenesis of malaria-induced liver injury has been accumulating [15,18,23,24]. However, systemic identification of molecular events is required to comprehensively demonstrate liver changes and provide a basis for exploring the supportive features of the liver response during infection. ...
Background
The liver is responsible for a range of functions in vertebrates, such as metabolism and immunity. In malaria, the liver plays a crucial role in the interaction between the parasite and host. Although malarial hepatitis is a common clinical complication of severe malaria, other malaria-related liver changes have been overlooked during the blood stage of the parasite life-cycle, in contrast to the many studies that have focused on parasite invasion of and replication in the liver during the hepatic stage of the parasite.
Methods
A rodent model of malaria was established using Plasmodium yoelii strain 17XL, a lethal strain of rodent malaria, for liver transcriptomic profiling.
Results
Differentially expressed messenger RNAs were associated with innate and adaptive immune responses, while differentially expressed long noncoding RNAs were enriched in the regulation of metabolism-related pathways, such as lipid metabolism. The coexpression network showed that host genes were related to cellular transport and tissue remodeling. Hub gene analysis of P. yoelii indicated that ubiquitination genes that were coexpressed with the host were evolutionarily conserved.
Conclusions
Our analysis yielded evidence of activated immune responses, aberrant metabolic processes and tissue remodeling changes in the livers of mice with malaria during the blood stage of the parasite, which provided a systematic outline of liver responses during Plasmodium infection.
Graphical Abstract
... The liver is an important organ involved during the hepatic stage of the malaria parasite's life cycle, where malaria sporozoites develop into merozoites. Previous and current literature has shown that parasites accumulate in many tissues, including the liver, which is one of the sites of greatest parasite tissue sequestration in ECM [43]. Additionally, another study has reported an association between high PRBC load in the livers of malaria patients with jaundice, hepatomegaly and liver enzyme elevation [44]. ...
... It is known that increased inflammation in the liver is associated with elevated levels of aminotransferases enzyme in the serum [95]. Moreover, it has been demonstrated that malaria parasites accumulate in many tissues, including the liver, which is one of the sites of greatest parasite tissue sequestration in ECM [43]. Additionally, another study has reported an association between high PRBC load in the livers of malaria patients with jaundice, hepatomegaly and liver enzyme elevation [44]. ...
... The liver is an important organ involved during the hepatic stage of the malaria parasite's life cycle, where malaria sporozoites develop into merozoites. Previous and current literature has shown that parasites accumulate in many tissues, including the liver, which is one of the sites of greatest parasite tissue sequestration in ECM [43]. Additionally, another study has reported an association between high PRBC load in the livers of malaria patients with jaundice, hepatomegaly and liver enzyme elevation [44]. ...
... It is known that increased inflammation in the liver is associated with elevated levels of aminotransferases enzyme in the serum [95]. Moreover, it has been demonstrated that malaria parasites accumulate in many tissues, including the liver, which is one of the sites of greatest parasite tissue sequestration in ECM [43]. Additionally, another study has reported an association between high PRBC load in the livers of malaria patients with jaundice, hepatomegaly and liver enzyme elevation [44]. ...
In animal model of experimental cerebral malaria (ECM), the genesis of neuropathology is associated with oxidative stress and inflammatory mediators. There is limited progress in the development of new approaches to the treatment of cerebral malaria. Here, we tested whether oral supplementation of Coenzyme Q 10 (CoQ 10 ) would offer protection against oxidative stress and brain associated inflammation following Plasmodium berghei ANKA (PbA) infection in C57BL/6 J mouse model. For this purpose, one group of C57BL/6 mice was used as control; second group of mice were orally supplemented with 200 mg/kg CoQ 10 and then infected with PbA and the third group was PbA infected alone. Clinical, biochemical, immunoblot and immunological features of ECM was monitored. We observed that oral administration of CoQ 10 for 1 month and after PbA infection was able to improve survival, significantly reduced oedema, TNF-α and MIP-1β gene expression in brain samples in PbA infected mice. The result also shows the ability of CoQ 10 to reduce cholesterol and triglycerides lipids, levels of matrix metalloproteinases-9, angiopoietin-2 and angiopoietin-1 in the brain. In addition, CoQ 10 was very effective in decreasing NF-κB phosphorylation. Furthermore, CoQ 10 supplementation abrogated Malondialdehyde, and 8-OHDG and restored cellular glutathione. These results constitute the first demonstration that oral supplementation of CoQ 10 can protect mice against PbA induced oxidative stress and neuro-inflammation usually observed in ECM. Thus, the need to study CoQ 10 as a candidate of antioxidant and immunomodulatory molecule in ECM and testing it in clinical studies either alone or in combination with antimalaria regimens to provide insight into a potential translatable therapy.
... A previous study reported hepatomegaly and altered albumin synthesis in patients with visceral leishmaniasis (Ural et al. 2015). Additionally, patients with fatal falciparum malaria displayed hepatomegaly, jaundice, and ALT elevation (Prommano et al. 2005). An increased number of eosinophils -a common symptom associated with parasite infections -was also observed in the livers of these malaria patients (dos Santos et al. 2009). ...
... Despite recent studies, there is very little information concerning the potential complications of having liver disease and a parasite infection at the same time. A few reports have described hepatomegaly, jaundice, hepatic malfunction, and poor prognoses in patients infected with parasites (Prommano et al. 2005, Ural et al. 2015. However, the aforementioned studies only examined clinical cases of parasites that already show an affinity for infiltrating the liver, such as Plasmodium falciparum and Fasciola hepatica (Nacher et al. 2001, Haseeb et al. 2003. ...
We evaluated the effects of a non-hepatotropic parasite infection (Taenia crassiceps) on the outcome of acetaminophen-induced acute liver failure in mice. Uninfected and T. crassiceps infected mice orally received either 300 mg/kg acetaminophen or water as vehicle (n = 5 per group). Survival analysis, hepatocyte necrosis, alanine aminotransferase (ALT) levels, CYP2E1 protein, interleukin (IL-) 5, and IL-6 were assessed for all groups. All infected mice died within 16 h after exposure to acetaminophen (Tc+APAP group), whereas only one-third of uninfected animals exposed to acetaminophen (APAP group) died. Uninfected (Control group) and infected (Tc group) mice that received the vehicle showed no liver damage. Tc+APAP mice exhibited massive liver necrosis characterised by marked balloning degeneration of hepatocytes and higher serum ALT compared to Control, Tc, and APAP animals. Liver tissue from Tc+APAP mice also displayed increased expression of CYP2E1 protein and higher mRNA and protein levels of IL-5 and IL-6 compared to the other groups. These findings suggest that non-hepatotropic parasite infections may increase mortality following acute liver failure by promoting hepatocyte necrosis via IL-5 and IL-6-dependent CYP2E1 overproduction. This study identifies new potential risk factors associated with severe acute liver failure in patients.
... The mechanisms by which liver damage is induced in human malaria remain unclear. However, a correlation between parasite sequestration in the liver and AST levels has been established (30), suggesting a role for parasites in mediating liver damage in humans. Hepatomegaly is also a common feature of those suffering liver damage during malaria, but at present it is unclear how this is linked to pathology (19,28,30,33,34). ...
... However, a correlation between parasite sequestration in the liver and AST levels has been established (30), suggesting a role for parasites in mediating liver damage in humans. Hepatomegaly is also a common feature of those suffering liver damage during malaria, but at present it is unclear how this is linked to pathology (19,28,30,33,34). It will be of interest to determine whether leukocytes accumulate in the liver during severe human malaria and, if so, whether activated CD8 ϩ T cells are present within the liver in this population. ...
Infection of C57BL/6 mice with Plasmodium berghei ANKA induces a fatal neurological disease commonly referred to as experimental cerebral malaria. The onset of neurological
symptoms and mortality depend on pathogenic CD8+ T cells and elevated parasite burdens in the brain. Here we provide clear evidence of liver damage in this model, which precedes
and is independent of the onset of neurological symptoms. Large numbers of parasite-specific CD8+ T cells accumulated in the liver following P. berghei ANKA infection. However, systemic depletion of these cells at various times during infection, while preventing neurological
symptoms, failed to protect against liver damage or ameliorate it once established. In contrast, rapid, drug-mediated removal
of parasites prevented hepatic injury if administered early and quickly resolved liver damage if administered after the onset
of clinical symptoms. These data indicate that CD8+ T cell-mediated immune pathology occurs in the brain but not the liver, while parasite-dependent pathology occurs in both
organs during P. berghei ANKA infection. Therefore, we show that P. berghei ANKA infection of C57BL/6 mice is a multiorgan disease driven by the accumulation of parasites, which is also characterized
by organ-specific CD8+ T cell-mediated pathology.
... Common histopathological observations of the liver in P. falciparum malaria include the retention of hemozoin pigments, reactive Kupffer cells, and minimal pRBC sequestration (Rupani and Amarapurkar ). An ultrastructural study reported a relationship between high pRBC load in the livers of malaria patients with hepatomegaly, jaundice, and liver enzyme elevation (Prommano et al. 2005). The result on the liver histological section of parasitized mice treated with distilled water (negative control) showed arrays of hepatocytes, portal triad, and averaged sized vessel, inflammatory infiltrates over the parenchyma. ...
Plasmodium parasite causes malaria and affects the biochemical, physiological, and histoarchitecture of the hepatocytes and blood. The resultant effect leads to alterations in the metabolic activities of the liver, erythrocytes, as well as the buffer system. Therefore, we investigated the antiplasmodial activity, histomorphological studies of the hepatocytes and alterations in biochemical parameters in Plasmodium berghei-infected mice administered with the herbal formulation of aqueous extracts of Mangifera indica stem bark and leaves. The plant coarse leaves (250.71 g) and stem bark (509.34 g) were weighed to obtain their ratios, macerated in boiled distilled water (5 L) for 72 h, filtered, and concentrated to obtain the various extracts whereas LD 50 calculation gave 5500.19 mg/kg. The extracts were administered to eleven groups of mice at a dosage of 300 mg/kg whereas artesunate and ACT served as the positive control drugs; the antiplasmodial profiling, biochemical, and histological evaluations followed standard protocols. The schizonticidal activity of the extracts were remarkable; moreover, the histological section of the liver (negative control) had increased deposition of hemozoin, sinusoidal congestions, activation of kupffer cells, and portal tract inflammations; however, the other treatment groups in the study drastically reduced inflammation. The biochemical parameters' results revealed metabolic acidosis mitigation; hypocholesterolemia induction; enhanced hyperproteinemia, as well as hypoglycemia mitigation. The antiplasmodial therapeutic response, and biochemical derangements reversal corroborated with improved hepatocytes histoarchitecture of mice highlights the plant's pharmacological efficacy. (Word counts: 227). Graphical Abstract Keywords Histology · Metabolic acidosis · Hyperprotinemia · Hypoglycemia · Antimalarial · Mangifera indica Abbreviations ACT Artemisinin-based combination therapy WHO World health organization pRBCs Parasitized red blood cells SEM Standard error of mean RBC Red blood cell Hb Hemoglobin LDL Low density lipoprotein
... Common histopathological observations of the liver in P. falciparum malaria include the retention of hemozoin pigments, reactive Kupffer cells, and minimal pRBC sequestration (Rupani and Amarapurkar ). An ultrastructural study reported a relationship between high pRBC load in the livers of malaria patients with hepatomegaly, jaundice, and liver enzyme elevation (Prommano et al. 2005). The result on the liver histological section of parasitized mice treated with distilled water (negative control) showed arrays of hepatocytes, portal triad, and averaged sized vessel, inflammatory infiltrates over the parenchyma. ...
Plasmodium parasite causes malaria and affects the biochemical, physiological, and histoarchitecture of the hepatocytes and blood. The resultant effect leads to alterations in the metabolic activities of the liver, erythrocytes, as well as the buffer system. Therefore, we investigated the antiplasmodial activity, histomorphological studies of the hepatocytes and alterations in biochemical parameters in Plasmodium berghei-infected mice administered with the herbal formulation of aqueous extracts of Mangifera indica stem bark and leaves. The plant coarse leaves (250.71 g) and stem bark (509.34 g) were weighed to obtain their ratios, macerated in boiled distilled water (5 L) for 72 h, filtered, and concentrated to obtain the various extracts whereas LD 50 calculation gave 5500.19 mg/kg. The extracts were administered to eleven groups of mice at a dosage of 300 mg/kg whereas artesunate and ACT served as the positive control drugs; the antiplasmodial profiling, biochemical, and histological evaluations followed standard protocols. The schizonticidal activity of the extracts were remarkable; moreover, the histological section of the liver (negative control) had increased deposition of hemozoin, sinusoidal congestions, activation of kupffer cells, and portal tract inflammations; however, the other treatment groups in the study drastically reduced inflammation. The biochemical parameters' results revealed metabolic acidosis mitigation; hypocholesterolemia induction; enhanced hyperproteinemia, as well as hypoglycemia mitigation. The antiplasmodial therapeutic response, and biochemical derangements reversal corroborated with improved hepatocytes histoarchitecture of mice highlights the plant's pharmacological efficacy. (Word counts: 227). Graphical Abstract Keywords Histology · Metabolic acidosis · Hyperprotinemia · Hypoglycemia · Antimalarial · Mangifera indica Abbreviations ACT Artemisinin-based combination therapy WHO World health organization pRBCs Parasitized red blood cells SEM Standard error of mean RBC Red blood cell Hb Hemoglobin LDL Low density lipoprotein
... Common histopathological observations of the liver in P. falciparum malaria include the retention of hemozoin pigments, reactive Kupffer cells, and minimal pRBC sequestration (Rupani and Amarapurkar ). An ultrastructural study reported a relationship between high pRBC load in the livers of malaria patients with hepatomegaly, jaundice, and liver enzyme elevation (Prommano et al. 2005). The result on the liver histological section of parasitized mice treated with distilled water (negative control) showed arrays of hepatocytes, portal triad, and averaged sized vessel, inflammatory infiltrates over the parenchyma. ...
Plasmodium parasite causes malaria and affects the biochemical, physiological, and histoarchitecture of the hepatocytes and blood. The resultant effect leads to alterations in the metabolic activities of the liver, erythrocytes, as well as the buffer system. Therefore, we investigated the antiplasmodial activity, histomorphological studies of the hepatocytes and alterations in biochemical parameters in Plasmodium berghei-infected mice administered with the herbal formulation of aqueous extracts of Mangifera indica stem bark and leaves. The plant coarse leaves (250.71 g) and stem bark (509.34 g) were weighed to obtain their ratios, macerated in boiled distilled water (5 L) for 72 h, filtered, and concentrated to obtain the various extracts whereas LD50 calculation gave 5500.19 mg/kg. The extracts were administered to eleven groups of mice at a dosage of 300 mg/kg whereas artesunate and ACT served as the positive control drugs; the antiplasmodial profiling, biochemical, and histological evaluations followed standard protocols. The schizonticidal activity of the extracts were remarkable; moreover, the histological section of the liver (negative control) had increased deposition of hemozoin, sinusoidal congestions, activation of kupffer cells, and portal tract inflammations; however, the other treatment groups in the study drastically reduced inflammation. The biochemical parameters’ results revealed metabolic acidosis mitigation; hypocholesterolemia induction; enhanced hyperproteinemia, as well as hypoglycemia mitigation. The antiplasmodial therapeutic response, and biochemical derangements reversal corroborated with improved hepatocytes histoarchitecture of mice highlights the plant’s pharmacological efficacy. (Word counts: 227).
Graphical Abstract
... Damage that occurs in the liver cells can increase the enzymes that work on liver function, especially transaminase enzyme and morphological changes in the appearance of liver [29,30], such as hepatomegaly. Hepatosplenomegaly is a common feature of malarial infection in humans [31] and mice [32] caused by chronic exposure to malarial parasites. However, no enlargement of kidney in malaria infection. ...
Currently, the presence of antimalarial drug resistance has become a major obstacle in the treatment of malaria. To overcome the problem, a series of studies are needed to find new antimalarial drugs from plants. Previously, 90% ethanolic extract of Cassia spectabilis DC (EECS) leaves have been reported to have antimalarial activity in vitro against Plasmodium falciparum and in vivo against Plasmodium berghei ANKA. The research is conducted to find out the toxicity and protective effects of EECS on the liver and kidneys of mice infected with P. berghei ANKA. The acute and subacute toxicity tests were carried out on healthy mice that were given EECS at a dose of 150 mg/kg BW. An antimalarial activity test was carried out at doses of 150 and 200 mg/kg BW in P. berghei-infected mice. Regarding hepatomegaly, further plasma levels of hepatic enzyme were analyzed, as well as histopathological observation of the liver to determine the effect of the extract on liver. The kidney was observed histopathologically as well. The acute toxicity test of EECS showed that there was no mouse died at the highest dose, indicating safe for the mice. The subacute toxicity based on the histology data showed no significant difference in the liver and kidney of mice between the tested group and the healthy group. The histological and enzymatic effect of EECS in mice infected with P. berghei showed the histological and enzymatic effect that improved liver function and the histopathological effect on kidneys with the highest activity at a dose of 200 mg/kg BW compared with the negative control. The results showed the EECS was not toxic in mice and repaired the liver and kidney functions of P. berghei ANKA-infected mice, indicating a good candidate for antimalarial drug development.
... There has been renewed interest in the role of the spleen in both P. vivax and P. falciparum infections (Fernandez-Becerra et al., 2020;Kho et al., 2021) and a similar important role could be expected in P. coatneyi infections. In human P. falciparum infections, it is proposed that sequestration protects the parasite from clearance by avoiding passing through the spleen (Prommano et al., 2005). It has also been noted that, in a splenectomized human infected with P. falciparum, the iRBC examined lacked knobs (Pongponratn et al., 2000) although others reported their retention (Ho et al., 1991). ...
Plasmodium coatneyi has been proposed as an animal model for human Plasmodium falciparum malaria as it appears to replicate many aspects of pathogenesis and clinical symptomology. As part of the ongoing evaluation of the rhesus macaque model of severe malaria, a detailed ultrastructural analysis of the interaction between the parasite and both the host erythrocytes and the microvasculature was undertaken. Tissue (brain, heart and kidney) from splenectomized rhesus macaques and blood from spleen-intact animals infected with P. coatneyi were examined by electron microscopy. In all three tissues, similar interactions (sequestration) between infected red blood cells (iRBC) and blood vessels were observed with evidence of rosette and auto-agglutinate formation. The iRBCs possessed caveolae similar to P. vivax and knob-like structures similar to P. falciparum . However, the knobs often appeared incompletely formed in the splenectomized animals in contrast to the intact knobs exhibited by spleen intact animals. Plasmodium coatneyi infection in the monkey replicates many of the ultrastructural features particularly associated with P. falciparum in humans and as such supports its use as a suitable animal model. However, the possible effect on host–parasite interactions and the pathogenesis of disease due to the use of splenectomized animals needs to be taken into consideration.
... Histopathological observations of the liver in P. falciparum malaria infection incorporate responsive Kupffer cells, the maintenance of the haemozoin color, and insignificant PRBC sequestration 99, 100 . An ultrastructural study showed there to be a relationship between a high PRBCs load in the liver of malaria patients with jaundice, hepatomegaly and liver enzyme elevation 101 . Apoptotic changes occur in various cell systems and include both pathological and physiological changes. ...
Background: Malaria infection is a multisystem pathology with various clinical complications in adults and children. The clinical manifestation originates in humans following the invasion of the erythrocytes by merozoites. Methods: Relevant information and data was collated from scientific databases such as Google Scholar, Science Direct, PubMed, Mendeley, Springer Link and Medline using keywords such as ‘severe malaria infection’, ‘pathophysiology of severe malaria’, ‘complications of severe malaria’, ‘erythrocyte impairment in severe malaria’. Results: Generally, the pathophysiology of severe malaria infection encompasses a succession of stages involving metabolic products of the malaria parasites from haemoglobin digestion, damaged erythrocyte membrane components, actions of the pro- and anti-inflammatory cytokines, and cytoadherence of the malaria parasites to the vascular endothelium as well as sequestration and rosetting. The major complications that are connected with severe malaria infection include acute respiratory distress syndrome, neurologic disorders resulting to cerebral malaria, liver and kidney dysfunction, anaemia and thrombocytopenia as well as fatal placental malaria. Conclusion: The effective management of severe malaria infection involves proper diagnosis, followed by subjection of the patient to suitable antimalarial treatment with the necessary medications depending on the various clinical manifestations of the infection.
... 16 The spleen turns a dark reddish-brown color during infection due to the accumulation of hemozoin in the spleen that is confined mainly in macrophages and intact mature forms of pRBCs. 17,18 The increase in size and weight is associated with cellular expansion in the red and white pulp 16 due to their prominent role during infection. The red pulp is congested with cell phenotype. ...
The spleen is a complex secondary lymphoid organ that plays a crucial role in controlling blood-stage infection with Plasmodium parasites. It is tasked with sensing and removing parasitized RBCs, erythropoiesis, the activation and differentiation of adaptive immune cells, and the development of protective immunity, all in the face of an intense inflammatory environment. This paper describes how these processes are regulated following infection and recognizes the gaps in our current knowledge, highlighting recent insights from human infections and mouse models.
... This enhanced splenic clearance of abnormal and normal RBCs, which lasts for several weeks, may contribute to the partial control of parasite loads. When comparing cerebral malaria with Trends in Parasitology other severe forms (anemia, respiratory distress, acute renal and/or liver failure, shock), postmortem studies also showed that intrasplenic erythrophagocytosis was more frequent in the latter [34]. Splenomegaly is also less frequent in cerebral malaria than in severe malarial anemia, as demonstrated by field studies performed in Uganda and Sudan, and including a total of 1108 children [35][36][37]. ...
The human spleen is an immune sentinel and controls red blood cell (RBC) quality. By mechanically retaining subsets of infected RBCs, the spleen may reduce the pace at which the parasite biomass increases before the adaptive immune response operates. Conversely, the spleen may contribute to malaria pathogenesis, particularly anemia that is associated with splenomegaly. Large spleens may also shelter parasites in chronic carriers. Upon treatment with artemisinins, the spleen clears circulating parasites by pitting and releases 'once-infected' RBCs in circulation. This triggers postartesunate delayed hemolysis and explains the long post-treatment positivity of histidine-rich protein 2 (HRP2)-based dipsticks. Importantly, splenic retention of RBCs also applies to gametocytes, the clearance of which may be enhanced by stiffening them with drugs, a potential way to block malaria transmission.
... Without exception, all patients tested positive for malaria antibodies showed positive α-FP in circulation. The plausible rationale is, infected mosquitoes introduce uninucleate sporozoites into the human host, which rapidly invade hepatic parenchymal cells, resulting in jaundice and slight decrease in serum's Alb together with elevated liver AST and ALT [25]. This supports our contention of malaria's pathology; that is, sporozoitesinduced hepatic inflammation leads to necrosis and regeneration upon regression of the inflammatory response. ...
... Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License knob positive and negative iRBC accumulated in spleen (Prommano et al, 2005, Imbert et al, 2010) Moreover, P. falciparum infection causes cerebral malaria; a neurological disorder found in African countries. Generally, according to previous reports, children are the most vulnerable to the brain injury which can even lead to coma, caused by neurological disruption infected by P. falciparum parasite (Henry et al, 2012). ...
... Histopathological examination of liver biopsies of severe malaria patients showed that dilated sinusoids, parasitized red blood cell (pRBC) sequestration within hepatic sinusoids and adhesion of pRBCs to sinusoidal endothelial cells, and the retention of malaria pigment, accompanied with hepatocyte swelling and necrosis, host macrophage infiltration and focal centrilobular hepatic necrosis [1,[4][5][6]. It is reported that the degree of jaundice, hepatomegaly and liver enzyme abnormalities correlates with the overall parasite load in the body, and the sequestration of pRBCs in the liver was quantitatively associated with liver weight, serum bilirubin and AST levels [7]. ...
Hepatic dysfunction is one of the clinical features in severe malaria. However, the mechanism of hepatic injury during malaria is still unknown. Myeloid-related protein (MRP) 14 is abundantly expressed by myeloid cells and involved in various inflammatory diseases. We previously reported that serum MRP14 is elevated in mice infected with Plasmodium berghei ANKA. In order to verify whether extracellular MRP14 is involved in the pathology of hepatic injury during rodent malaria, we intravenously administrated recombinant MRP14 (rMRP14) to mice infected with P. berghei ANKA. The administration of rMRP14 did not affect parasite number or hematocrit. On the other hand, the hepatic injury was exacerbated in rMRP14-treated mice, and their serum concentration of hepatic enzymes increased significantly more than PBS-treated controls. Immunohistochemical analysis of the liver showed that more MRP14⁺ macrophages accumulated in rMRP14-treated mice than PBS-treated controls after infection. The administration of rMRP14 also promotes the up-regulation of pro-inflammatory molecules in the liver, such as iNOS, IL-1β, IL-12, and TNF-α. Even in the absence of Plasmodium infection, administration of rMRP14 could induce the accumulation of MRP14⁺ macrophages and up-regulation of the pro-inflammatory molecules in the liver of naïve mice. The results indicate that MRP14 promotes the accumulation of MRP14⁺ cells and the up-regulation of pro-inflammatory molecules and NO, which amplify inflammatory cascade leading to hepatic injury. In conclusion, MRP14 is a one of key molecules for liver inflammation during rodent malaria.
... The liver is one of the main organs damaged by blood stage Plasmodium species, inducing jaundice, hepatomegaly and liver enzyme elevation 32,33 . Therefore, we investigated the protective effect of Ext-Ts in the liver under PbA infection. ...
Increased resistance to the first-line treatment against P. falciparum malaria, artemisinin-based combination therapies, has been reported. Here, we tested the effect of crude ethanolic extract of the fungus Trichoderma stromaticum (Ext-Ts) on the growth of P. falciparum NF54 in infected human red blood cells (ihRBCs) and its anti-malarial and anti-inflammatory properties in a mouse model of experimental cerebral malaria. For this purpose, ihRBCs were treated with Ext-Ts and analysed for parasitaemia; C57BL/6 mice were infected with P. berghei ANKA (PbA), treated daily with Ext-Ts, and clinical, biochemical, histological and immunological features of the disease were monitored. It was observed that Ext-Ts presented a dose-dependent ability to control P. falciparum in ihRBCs. In addition, it was demonstrated that Ext-Ts treatment of PbA-infected mice was able to increase survival, prevent neurological signs and decrease parasitaemia at the beginning of infection. These effects were associated with systemically decreased levels of lipids and IFN-γ, ICAM-1, VCAM-1 and CCR5 cerebral expression, preserving blood brain barrier integrity and attenuating the inflammatory lesions in the brain, liver and lungs. These results suggest that Ext-Ts could be a source of immunomodulatory and antimalarial compounds that could improve the treatment of cerebral malaria.
... Eventos locales: principalmente la activación endotelial (expresión de receptores y producción de citocinas), citoadherencia, secuestro de GRP, respuesta inflamatoria, obstrucción vascular y vasoconstricción 7,26,29,30 (fig. 2). ...
La malaria o paludismo, enfermedad causada por protozoos parásitos de género Plasmodium , se considera un gran problema de salud pública mundial por sus elevadas tasas de morbimortalidad. Las manifestaciones clínicas de esta infección van desde un síndrome febril agudo hasta un cuadro de malaria complicada que afecta órganos específicos, pudiendo progresar a una falla multisistémica que comprometa la vida del paciente. En la malaria, el riñón es un órgano susceptible de daño por mecanismos fisiopatológicos directos del plasmodio como el secuestro de glóbulos rojos parasitados, la obstrucción de la microcirculación y la activación del sistema inmune; además, por efectos indirectos hematológicos, hepáticos y metabólicos. La lesión renal en malaria se ha informado en Colombia hasta en el 31% de los pacientes con malaria grave; incluye la lesión renal aguda y el síndrome nefrótico, cada uno con manifestaciones clínicas, implicaciones terapéuticas y factores pronósticos propios. La lesión renal aguda es la condición más frecuente y puede llevar a una acidosis metabólica grave, daño renal crónico e incluso, cuando hace parte de una falla multiorgánica, asociarse con mortalidad que alcanza tasas de entre 40 y 50%. Un mejor entendimiento de la fisiopatología de la lesión renal en la malaria permitirá reconocer las manifestaciones clínicas para hacer un diagnóstico temprano e iniciar un tratamiento oportuno, con los beneficios que esto conlleva para la evolución y pronóstico del paciente.
... Common histopathological findings of the liver in P. falciparum malaria include reactive Kupffer cells, retention of haemozoin pigment and minimal PRBC sequestration (Whitten et al., 2011;Rupani and Amaraparkar, 2009). An ultra-structural study reported an association between high PRBC load in the liver of malaria pigments with jaundice, hepatomegaly and liver enzyme elevation (Prommano et al., 2005). Experimental prophylaxis malaria in figure 1 group A (placebo treated and infected) had prominent cellular derangements and distortions signs of severe infection and diffuse inflammation which without prolong treatment can lead to mortality. ...
... ≥3 times enlarged), and clearance function increases [59][60][61][62][63][64][65][66]. Pathology studies of fatal human malaria which [38] have examined the spleen show marked accumulation of parasitized erythrocytes of all stages [1,2,20,50,[67][68][69][70][71]. Similar findings are reported in primate malaria [72]. ...
Following anti-malarial drug treatment asexual malaria parasite killing and clearance appear to be first order processes. Damaged malaria parasites in circulating erythrocytes are removed from the circulation mainly by the spleen. Splenic clearance functions increase markedly in acute malaria. Either the entire infected erythrocytes are removed because of their reduced deformability or increased antibody binding or, for the artemisinins which act on young ring stage parasites, splenic pitting of drug-damaged parasites is an important mechanism of clearance. The once-infected erythrocytes returned to the circulation have shortened survival. This contributes to post-artesunate haemolysis that may follow recovery in non-immune hyperparasitaemic patients. As the parasites mature Plasmodium vivax-infected erythrocytes become more deformable, whereas Plasmodium falciparum-infected erythrocytes become less deformable, but they escape splenic filtration by sequestering in venules and capillaries. Sequestered parasites are killed in situ by anti-malarial drugs and then disintegrate to be cleared by phagocytic leukocytes. After treatment with artemisinin derivatives some asexual parasites become temporarily dormant within their infected erythrocytes, and these may regrow after anti-malarial drug concentrations decline. Artemisinin resistance in P. falciparum reflects reduced ring stage susceptibility and manifests as slow parasite clearance. This is best assessed from the slope of the log-linear phase of parasitaemia reduction and is commonly measured as a parasite clearance half-life. Pharmacokinetic-pharmacodynamic modelling of anti-malarial drug effects on parasite clearance has proved useful in predicting therapeutic responses and in dose-optimization.
... The clinical-pathologic features of liver infected by P. falciparum include reactive Kupffer cells, retention of hemozoin pigment, and minimal levels of PRBC sequestration (40,41). A high load of hepatomegaly, PRBC and elevated levels of liver enzymes are also observed in malaria patients (42). Earlier studies confirmed that liver pathology, such as the induction of inflammation, leads to important changes in intervillous fibrin deposition (43), infarction regulation and cellular apoptosis in liver tissues, which affects the organ's function. ...
Malaria is one of the most widespread and serious parasitic diseases worldwide. Currently available antimalarial drugs have side effects, and many strains of Plasmodia have developed resistance to such drugs. The present review examines the use of annexins (ANXs) and of natural peptides from snake venom as a new class of anti-malarial agents, with the key property of reducing inflammation. Severe cases of malaria manifest elevated serum levels of liver enzymes, inflammation, fibrin deposition, apoptosis, and reduction in peripheral CD8+ T cells. The annexin-A1/5 (ANXA-1/5) proteins trigger inflammation via increased expression of diverse cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin- (IL-10), however, by shielding microbial phospholipids they prevent injury via damage-associated molecular patterns (DAMPs). Here, we also review an in silico -based bioengineering approach that may allow for a better design, synthesis and characterization of novel peptides from snake venom as a more effective approach for treatment due to their improved antimalarial activity.
... Genistein has an influence on the reduction of malaria infection rate on day 7 (Fig. S1). However, the size of palpable spleen does not indicate parasitic load in the spleen (Prommano et al., 2005 ). Bioluminescent imaging of transgenic luciferase-expressing parasites was reported to provide a non-invasive approach in the monitoring of parasite growth in organs (Miller et al., 2013). ...
Spleen traps malaria-infected red blood cells, thereby leading to splenomegaly. Splenomegaly induces impairment in splenic function, i.e., rupture. Therefore, splenomegaly inhibition is required to protect the spleen. In our previous study, genistein was found to have an influence on malaria-induced splenomegaly. However, the effect of genistein in malaria-induced splenomegaly, especially on the function of spleen, has not been fully investigated. In this study, hematoxylin and eosin (H&E) staining images show that genistein partially prevents malaria-induced architectural disruption of spleen. In addition, genistein decreases transgenic Plasmodium parasites accumulation in the spleen. Genistein treatment can protect splenic function from impairment caused by malaria infection. To examine the functions of malaria-infected spleen, we employed single-photon emission computed tomography/computed tomography (SPECT/CT) technology. Red blood cells are specifically radiolabeled with Technetium-99m pertechnetate ((99m)TcO4(-)) and trapped inside the spleen. The standardized uptake values (SUVs) in the spleen of infected mice are higher than those of naive and genistein-treated mice. However, genistein reduces the malaria-induced trapping capacity of spleen for heat-damaged radiolabeled RBCs, while exhibiting a protective effect against malaria. Considering these results, we suggested that genistein could be effectively used in combination therapy for malaria-induced splenic impairment.
... The malaria pigments accumulation in the liver tissues also clarifies the hepatic dysfunction during P. berghei ANKA infection. Additionally, the parasites sequestration in the liver microvasculature correlates with the increase in liver enzymes, aspartate transaminase (AST), indicating parasites role in mediating hepatic dysfunction (42,43). ...
Background: Interleukin 18 (IL-18) exerts pleiotropic roles in many inflammatory-related diseases including parasitic infection. Previous studies have demonstrated the promising therapeutic potential of modulating IL-18 bioactivity in various pathological conditions. However, its involvement during malaria infection has yet to be established. In this study, we demonstrated the effect of modulating IL-18 on the histopathological conditions of malaria infected mice.
Methods:
Plasmodium berghei ANKA infection in male ICR mice was used as a model for malaria infection. Modulation of IL-18 release was carried out by treatment of malarial mice with recombinant mouse IL-18 (rmIL-18) and recombinant mouse IL-18 Fc chimera (rmIL-18Fc) intravenously. Histopathological study and analysis were performed on major organs including brain, liver, spleen, lungs and kidney.
Results: Treatment with rmIL-18Fc resulted in significant improvements on the histopathological conditions of the organs in malaria-infected mice.
Conclusion: IL-18 is an important mediator of malaria pathogenesis and targeting IL-18 could prove beneficial in malaria-infected host.
... Although the relative contribution of sequestration to pathogenesis remains contentious, sequestration in multiple organs including the brain, kidney, liver, heart, lung and skin has been observed at post-mortem of patients who died of severe malaria (Pongponratn et al. 2003;Silamut et al. 1999;Nguansangiam et al. 2007;Prommano et al. 2005;MacPherson et al. 1985), and sequestration in the placenta is the defining characteristic of parasites that cause malaria in pregnancy (Bray and Sinden 1979). Cerebral malaria (CM) is the malaria syndrome with the highest mortality with a case fatality rate of up to 18 %. ...
Plasmodium falciparum is the protozoan parasite that causes most malaria-associated morbidity and mortality in humans with over 500,000 deaths annually. The disease symptoms are associated with repeated cycles of invasion and asexual multiplication inside red blood cells of the parasite. Partial, non-sterile immunity to P. falciparum malaria develops only after repeated infections and continuous exposure. The successful evasion of the human immune system relies on the large repertoire of antigenically diverse parasite proteins displayed on the red blood cell surface and on the merozoite membrane where they are exposed to the human immune system. Expression switching of these polymorphic proteins between asexual parasite generations provides an efficient mechanismto adapt to the changing environment in the host and to maintain chronic infection. This chapter discusses antigenic diversity and variation in themalaria parasite and our current understanding of the molecular mechanisms that direct the expression of these proteins.
... The spleen of non-CM patients has more phagocytes than that of CM patients. This observation reveals that the spleen plays a major role in malarial parasite clearance and is associated with host defense mechanisms against malaria [59]. The adhesion of parasitized red blood cells to spleen endothelial cells induces caspase activation, oxidative stress and apoptosis [60]. ...
To investigate the involvement of systemic oxidative stress in the pathogenesis of murine cerebral malaria, mice were infected with the Plasmodium berghei (P. berghei) ANKA 6653 strain. Serum tryptophan (Trp), kynurenine and urinary biopterin, liver, brain, spleen and serum superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) and nitrite and nitrate (NOx) levels were measured on day 7 post-inoculation. Our data showed a significant decrease in SOD and an increase in GPx activity and MDA level in all the examined biological materials (p<0.05), except spleen. Conversely, GPx activities in spleen were depleted, while SOD and MDA levels remained unchanged. Increased MDA levels might indicate increased peroxynitrite production, lipid peroxidation and oxidative stress. Also, elevated urinary biopterin, which was accompanied by increased NOx (p<0.05), may support the inhibition of Trp degradation (p>0.05). The excessive NO synthesis in P. berghei infection may be related to the up-regulation of inducible NO synthase, which was in accordance with the increased biopterin excretion. Thus, the large quantities of released toxic redox active radicals attack cell membranes and induce lipid peroxidation. Although P. berghei infection did not demonstrate systemic Trp degradation and related indoleamine-2,3-dioxygenase activity, it may cause multi-organ failure and death, owing to host-derived severe oxidative stress.
... The plasma Total Bile Acids could be used to determine liver dysfunction which could be found in plasmodium infection as the pathophysiology of malaria involves liver. Liver dysfunction was however found to be more in plasmodium infected subjects than the control and in the test subjects before treatment than after treatment considering the significant alterations in the value of plasma total bile acids [33,34]. Levels of TBA rise in many liver diseases, for example hepatitis and liver sclerosis [22]. ...
Background to the Study: Pathophysiology of Plasmodium infection and the metabolism of the phytochemicals of raw liquid extract of Vernonia amygdalina used in the traditional treatment of Plasmodium spp infection in Saki-East Local Government area of Oyo state -Nigeria involve the hepatocytes, which could bring about biochemical alterations in the plasma level of albumin, fibrinogen, Lactate dehydrogenase (LDH) and Total Bile Acids (TBA). Aim and Objective: This work was designed to determine the effect of the raw extract of Vernonia amygdalina used in the treatment of Plasmodium spp infection on acute phase protein (albumin, fibrinogen), Total bile acids and Lactate dehydrogenase. Materials and Method: Forty five 45 (72.6%) that were HIV, HBsAg and anti-HCV seronagative female-23 (51.1%); male-22 (48.9%) aged 21-48 years were recruited and studied out of the sixty two (62) patients infected with Plasmodium spp based on the exclusion and inclusion criteria from 5 herbal homes in Saki-East Local government area of Oyo-state-Nigeria. Giemsa-thick film staining technique was used for Plasmodium detection including estimation of plasmodium parasite density and Viral immunochemical serology for anti-HIV, anti-HCV and HBsAg was carried out in the 62 subjects initially recruited was determined by ELIZA and Immunoblotting. These tests were also employed in recruiting the normal control subjects (n=50). Plasma albumin, fibrinogen, Total Bile Acids and Lactate dehydrogenase were analyzed in the control and Plasmodium infected subjects before and after treatment with the raw extract of Vernonia amygdalina . Results: There was a significantly lower mean values of fibrinogen, LDH, Parasite density in the control Plasmodium non-infected subjects (264±10.6 mg/dl; 253 ±13.1 U/L; 0 µL) than the values (438±10.1 mg/dl; 302±18 U/L; 490±10.0 /µL) obtained in the plasmodium infected subjects before treatment with p Conclusion : There was a significant biochemical alterations in the concentration of plasma acute phase proteins (fibrinogen, albumin), Lactate dehydrogenase, Total Bile acids and parasite density in Plasmodium infected patients before the traditional treatment with extract of Vernonia amygdalina which was restored almost to normal after the treatment supporting the use of Vernonia amygdalina as an effective anti-plasmodia agent. The result obtained also revealed the immunochemical status of the Plasmodium infected patients as: 17.7% (11) out of the 62 Plasmodium infected patients were tested positive to HIV, HBsAg or anti-HCV which include: 9.7% (6) HIV, 4.8% (3) HBV and 3.2% (2) HCV.
... It was recently hypothesized that development of ALF in malaria patients may lead to accumulation of ammonia and other neurotoxins, which then enter the brain aided by blood brain barrier (BBB) breakdown and ultimately cause neurological damage and manifestation of CM (Martins and Daniel-Ribeiro, 2013). However, several studies indicates that parasite-induced liver dysfunction is not a common occurrence in P. falciparum malaria (Anand et al., 1992;Murthy et al., 1998;Nacher et al., 2001;Mazumder et al., 2002;Mohanty et al., 2004;Prommano et al., 2005;Kochar et al., 2010;Whitten et al., 2011). Therefore, it is conceivable that sequestered parasites in the brain vasculature known to produce large amounts of ammonia as a catabolic by-product, may disrupt normal brain ammonia metabolism leading to local accumulation of ammonia. ...
Cerebral malaria (CM) is the most severe complication associated with Plasmodium falciparum infection. The exact pathogenic mechanisms leading to the development of CM remains poorly understood while the mortality rates remain high. Several potential mechanisms including mechanical obstruction of brain microvasculature, inflammation, oxidative stress, cerebral energy defects, and hemostatic dysfunction have been suggested to play a role in CM pathogenesis. However, these proposed mechanisms, even when considered together, do not fully explain the pathogenesis and clinicopathological features of human CM. This necessitates consideration of alternative pathogenic mechanisms. P. falciparum generates substantial amounts of ammonia as a catabolic by-product, but lacks detoxification mechanisms. Whether this parasite-derived ammonia plays a pathogenic role in CM is presently unknown, despite its potential to cause localized brain ammonia elevation and subsequent neurotoxic effects. This article therefore, explores and proposes a potential role of parasite-derived ammonia in the pathogenesis and neuropathology of CM. A consideration of parasite-derived ammonia as a factor in CM pathogenesis provides plausible explanations of the various features observed in CM patients including how a largely intravascular parasite can cause neuronal dysfunction. It also provides a framework for rational development and testing of novel drugs targeting the parasite's ammonia handling.
... studied quantitatively by others across several organs [11][12][13][14]. ...
Children in sub-Saharan Africa continue to suffer from and succumb to cerebral malaria despite efforts to control or eliminate the causative agent, P falciparum. We present a quantitative histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs sampled from a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi on pediatric cerebral malaria patients and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in cerebral malaria and in other parasitemic patients. Within cases of histologically defined cerebral malaria which includes a "sequestration only" phenotype (CM1) and a "sequestration with extravascular pathology" phenotype (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin (CM2). A striking histological finding overall is the marked sequestration of parasitized erythrocytes across most organs in patients with fatal cerebral malaria, supporting the hypothesis that the disease is, in part, a result of a high level of total body parasite sequestration.
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... Eventos locales: principalmente la activación endotelial (expresión de receptores y producción de citocinas), citoadherencia, secuestro de GRP, respuesta inflamatoria, obstrucción vascular y vasoconstricción 7,26,29,30 (fig. 2). ...
Malaria, a parasitic disease caused by protozoa of the genus Plasmodium, is currently considered a public health problem due to its high rates of morbidity and mortality. The clinical picture of malaria is diverse, ranging from classical febrile illness to severe malaria, which affects various organs and becomes a multisystem organ dysfunction. The kidney is an organ susceptible to damage from the plasmodia by direct pathophysiological mechanisms such as the sequestration of parasitized red blood cells, obstruction of microcirculation and immune system activation, and by indirect hematological, hepatic and metabolic causes. In Colombia, renal lesions have been reported in up to 31% of patients with severe malaria. This complication in malaria can appears as an acute renal injury or as a nephrotic syndrome, each one having different symptoms, therapeutical approach and prognosis. Acute kidney injury is the most common and can cause severe metabolic acidosis, chronic renal failure or in the presence of multiorgan dysfunction may be associated with high mortality rates (40-50%). We need to improve our knowledge about the phisiopathology of renal impairment during malaria in order to obtain early clinical diagnosis and to achieve better treatment outcomes.
... Common histopathological findings of the liver in P. falciparum malaria include reactive Kupffer cells, retention of haemozoin pigment and minimal PRBC sequestration [4,5]. An ultrastructural study reported an association between high PRBC load in the livers of malaria patients with jaundice, hepatomegaly and liver enzyme elevation [6]. ...
Liver involvement in severe Plasmodium falciparum infection is commonly a significant cause of morbidity and mortality among humans. The clinical presentation of jaundice often reflects a certain degree of liver damage. This study investigated the liver pathology of severe P. falciparum malaria as well as the regulation and occurrence of apoptosis in cellular components of formalin-fixed, paraffin-embedded liver tissues.
The liver tissues used in the study came from patients who died from P. falciparum malaria with hyperbilirubinaemia (total bilirubin (TB) >= 51.3 mumol/L or 3 mg/dl) (12 cases), P. falciparum malaria without hyperbilirubinaemia (TB < 51.3 mumol/L) (10 cases); and patients who died due to accidents, whose liver histology was normal (the control group) (10 cases). The histopathology of the liver tissue was studied by routine histology method. Caspase-3 and nuclear factor kappa B (NF-kappaB) p65 expressions were determined using immunohistochemistry.
The severity of liver histopathology, occurrence of apoptosis and NF-kappaB p65 activation in P. falciparum malaria were associated with higher TB level. Significant correlations were found between NF-kappaB p65 expression and apoptosis in Kupffer cells and lymphocytes in the portal tracts.
Hyperplastic Kupffer cells and portal tract inflammation are two main features found in the liver tissues of severe P. falciparum malaria cases. In addition, NF-kappaB is associated with Kupffer cells and lymphocyte apoptosis in severe P. falciparum malaria.
... This effect might protect organs (e.g. liver, lung, and kidney) whose dysfunction contributes to severity of malaria [123][124][125][126]. ...
The role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood.
We undertook testing Tempol-a superoxide dismutase (SOD) mimetic and pleiotropic intracellular antioxidant-in cells relevant to malaria pathogenesis in the context of coagulation and inflammation. Tempol was also tested in a murine model of CM induced by Plasmodium berghei Anka infection. Tempol was found to prevent transcription and functional expression of procoagulant tissue factor in endothelial cells (ECs) stimulated by lipopolysaccharide (LPS). This effect was accompanied by inhibition of IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) production. Tempol also attenuated platelet aggregation and human promyelocytic leukemia HL60 cells oxidative burst. In dendritic cells, Tempol inhibited LPS-induced production of TNF-α, IL-6, and IL-12p70, downregulated expression of co-stimulatory molecules, and prevented antigen-dependent lymphocyte proliferation. Notably, Tempol (20 mg/kg) partially increased the survival of mice with CM. Mechanistically, treated mice had lowered plasma levels of MCP-1, suggesting that Tempol downmodulates EC function and vascular inflammation. Tempol also diminished blood brain barrier permeability associated with CM when started at day 4 post infection but not at day 1, suggesting that ROS production is tightly regulated. Other antioxidants-such as α-phenyl N-tertiary-butyl nitrone (PBN; a spin trap), MnTe-2-PyP and MnTBAP (Mn-phorphyrin), Mitoquinone (MitoQ) and Mitotempo (mitochondrial antioxidants), M30 (an iron chelator), and epigallocatechin gallate (EGCG; polyphenol from green tea) did not improve survival. By contrast, these compounds (except PBN) inhibited Plasmodium falciparum growth in culture with different IC50s. Knockout mice for SOD1 or phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (gp91(phox-/-)) or mice treated with inhibitors of SOD (diethyldithiocarbamate) or NADPH oxidase (diphenyleneiodonium) did not show protection or exacerbation for CM.
Results with Tempol suggest that intracellular ROS contribute, in part, to CM pathogenesis. Therapeutic targeting of intracellular ROS in CM is discussed.
... P. falciparum-infected erythrocytes adhere to microvascular endothelium in a process known as sequestration, which allows them to avoid being removed in the spleen. This is favoured by other processes, such as a reduction of red cell deformability, rosetting of noninfected erythrocytes around the infected erythrocytes, platelet-mediated aggregation of infected erythrocytes [37][38][39][40][41]. Sequestration is seen especially in the small venules of vital organs (brain -predominantly in white matter, heart, lung, liver, kidneys, eyes) [42,43]. Sequestering of the erythrocytes in areas with low oxygen tension may favour survival of the parasites. ...
In this position paper, the European Society for Clinical Microbiology and Infectious Diseases, Study Group on Clinical Parasitology, summarizes main issues regarding the management of imported malaria cases. Malaria is a rare diagnosis in Europe, but it is a medical emergency. A travel history is the key to suspecting malaria and is mandatory in patients with fever. There are no specific clinical signs or symptoms of malaria although fever is seen in almost all non-immune patients. Migrants from malaria endemic areas may have few symptoms.
Malaria diagnostics should be performed immediately on suspicion of malaria and the gold- standard is microscopy of Giemsa-stained thick and thin blood films. A Rapid Diagnostic Test (RDT) may be used as an initial screening tool, but does not replace urgent microscopy which should be done in parallel. Delays in microscopy, however, should not lead to delayed initiation of appropriate treatment. Patients diagnosed with malaria should usually be hospitalized. If outpatient management is preferred, as is the practice in some European centres, patients must usually be followed closely (at least daily) until clinical and parasitological cure. Treatment of uncomplicated Plasmodium falciparum malaria is either with oral artemisinin combination therapy (ACT) or with the combination atovaquone/proguanil. Two forms of ACT are available in Europe: artemether/lumefantrine and dihydroartemisinin/piperaquine. ACT is also effective against Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi, but these species can be treated with chloroquine. Treatment of persistent liver forms in P. vivax and P. ovale with primaquine is indicated after excluding glucose 6 phosphate dehydrogenase deficiency. There are modified schedules and drug options for the treatment of malaria in special patient groups, such as children and pregnant women. The potential for drug interactions and the role of food in the absorption of anti-malarials are important considerations in the choice of treatment.
Complicated malaria is treated with intravenous artesunate resulting in a much more rapid decrease in parasite density compared to quinine. Patients treated with intravenous artesunate should be closely monitored for haemolysis for four weeks after treatment. There is a concern in some countries about the lack of artesunate produced according to Good Manufacturing Practice (GMP).
... Four of the 26 patients examined had no visible sequestration in the rectal microcirculation. The absence of sequestration on a limited examination of the rectal mucosa does not preclude sequestration elsewhere in the body [24][25][26][27][28]. Furthermore, 3 of these 4 patients had their OPS assessments >14 hours after their first dose of artesunate, and in both this study and previous in vitro studies, the amount of sequestration decreased as the interval from starting artesunate increased [23]. ...
Sequestration of parasitized erythrocytes in the microcirculation is considered the central pathophysiological process in severe falciparum malaria. Hypovolemia with reduced oxygen delivery and microvascular obstruction have different implications for patient management; however, their relative contributions to disease severity are uncertain.
Adult patients (n = 28) with severe Plasmodium falciparum malaria were enrolled in a prospective hemodynamic study. Volume status and oxygen delivery were assessed using transpulmonary thermodilution. Microvascular sequestration was measured using orthogonal polarized spectroscopy.
Duration of therapy before study enrollment was correlated with the amount of directly visualized and quantitated microvascular sequestration (P = .03). The amount of sequestration correlated with plasma lactate (r(s )= 0.55; P = .003) and disease severity (r(s )= 0.41; P = .04). In patients who had received artesunate for <10 hours, sequestration was higher in fatal cases than in survivors: median (range) 45% (32-50) vs 15% (0-40); P = .03). Parasite biomass estimated from plasma P. falciparum histidine-rich protein 2 correlated positively with disease severity (r(s )= 0.48; P = .01) and was significantly higher in patients who died (P = .046). There was no relationship between oxygen delivery and disease severity (P = .64) or outcome (P = .74).
Vital organ dysfunction in severe malaria results primarily from sequestration of parasitized erythrocytes in the microvasculature rather than reduction in circulating blood volume and oxygen delivery.
... In 1974, Littman described a single patient with hereditary spherocytosis who developed severe anaemia secondary to vivax malaria. A relapse five months later after a splenectomy did not cause anaemia suggesting that the spleen was the primary site of red blood cell removal (though the effect of strain specific immunity could not be excluded)[134]In vitro phagocytosis of uninfected RBC[71]Accumulation & phagocytosis of infected & uninfected RBC in the spleen[74]& bone marrow[66]Phagocytosis of infected & uninfected RBC in the spleen[75]& bone marrow[76]Nuclear abnormalities of erythroblasts more frequent in children with chronic infection[66,68,69]0.23-15.1% of erythroblasts with marked nuclear abnormalities in 6 of 9 adults with acute infection[76]Phagocytosis of erythroblasts (also in falciparum malaria)[69]Decreased cellularity at acute stage in 3/11 adults[77]Rare observations of parasitized erythroblasts[78,79]. Not seen in 9 adults[76]No data in children or in severe anaemia. ...
Plasmodium vivax threatens nearly half the world's population and is a significant impediment to achievement of the millennium development goals. It is an important, but incompletely understood, cause of anaemia. This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia. Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent. Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells. Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion. Anaemia can be averted by early and effective anti-malarial treatment.
Free heme in plasma acts as a prooxidant; thus, it is bound to hemopexin and eliminated by the liver. High iron content in the liver can support Plasmodium growth and cause oxidative liver injury. Inversely, the withholding of excessive iron can inhibit this growth and protect the liver against malaria infection. This study examined the effects of a deferiprone-resveratrol (DFP-RVT) hybrid on malaria parasites and its relevant hepatoprotective properties. Mice were infected with P. berghei, gavage DFP-RVT, deferiprone (DFP), and pyrimethamine (PYR) for 8 consecutive days. Blood and liver parameters were then evaluated. The presence of blood-stage parasites was determined using the microscopic Giemsa staining method. Subsequently, plasma liver enzymes, heme, and concentrations of thiobarbituric acid-reactive substances (TBARS) were determined. The liver tissue was examined pathologically and heme and TBARS concentrations were then quantified. The results indicate that the suppression potency against P. berghei growth occurred as follows: PYR > DFP-RVT hybrid > DFP. Importantly, DFP-RVT significantly improved RBC size, restored alanine aminotransferase and alkaline activities, and increased heme and TBARS concentrations. The compound also reduced the liver weight index, heme, and TBARS concentrations significantly when compared to mice that were untreated. Our findings support the contention that the hepatoprotective effect of DFP-RVT is associated with parasite burden, iron depletion, and lipid peroxidation in the host.
Malaria is a significant cause of morbidity and mortality throughout the world, and environmental changes are likely to increase its importance in the coming years. Diagnosing this disease is difficult and requires a high index of suspicion, especially in non-endemic countries. Critical care providers play a major role in treating severe malaria and its complications, which has management particularities that might not be readily apparent. Fluid resuscitation should be carefully tailored to avoid complications, and dysperfusion seems more related to degree of parasitemia than hypovolemia. Antimalarial agents are effective, but resistance is growing. Complications can be found in nearly every organ, including cerebral malaria, acute respiratory distress syndrome, and acute kidney injury. As such, a critical care unit is frequently required for organ support when they appear. Superimposed infections are not infrequent. Despite all of this, mortality is encouragingly low with a timely diagnosis and access to appropriate treatment.
Background/aims:
Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver's response to malarial infection.
Methods:
Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot.
Results:
Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1β, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-β, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin β4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice.
Conclusion:
Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.
This prospective study assessed the incidence, clinical profile and outcome of malarial hepatopathy and its association with other complications in patients with malaria, proved by peripheral blood smear examination and rapid malaria test. Hyperbilirubinemia (Serum bilirubin>3mg/dL) with>3-fold rise in serum aminotransferases in absence of a different explanation for such derangement was considered as malarial hepatopathy. Of 134 (falciparum-81, vivax-48 and mixed falciparum and vivax-5) malaria cases, hyperbilirubinemia occurred in 41.04%. Serum aspartate aminotransferase (AST) was raised>3-fold in 17.16% and serum alanine aminotransferase (ALT) in 4.47% cases. Malarial hepatopathy was observed in 4.47% (falciparum-5 and vivax malaria-1) cases, but had insignificant association with the type of malaria (p=0.532). Serum bilirubin, AST and ALT levels were higher while age was lower overall (p<0.05 each) and in falciparum malaria cases with hepatopathy than without hepatopathy (p<0.05 each). Malarial hepatopathy was associated with a higher incidence of cerebral malaria, shock, hyponatremia, acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation overall (p<0.05 each) and in falciparum malaria (p<0.05 each) and acute kidney injury only in overall malaria (p<0.05). Malarial hepatopathy had significant association with duration of hospitalization, parasite clearance time, fever clearance time and jaundice clearance time overall (p<0.05 each) and in falciparum (p<0.05 each) but not vivax malaria (p>0.05 each). Mortality occurred in 1(20%) case of falciparum-induced hepatopathy with an overall mortality of 16.66%. ARDS (p=0.003) and shock (p=0.026) were independently associated with malarial hepatopathy overall while only ARDS with falciparum-induced hepatopathy. Thus, hepatocellular dysfunction is common in malaria but that qualifying as malarial hepatopathy is not common. Malarial hepatopathy is likely to occur in presence of other malarial complications. It is an epiphenomenon in severe malaria and indicative of severe disease. Establishing a particular association with malaria or mortality would require a larger case-control study of severe malaria.
Malaria is a major international public health problem causing around 500 million infections worldwide and approximately one million deaths every year. Transmission occurs in large areas of Africa, central and South America, the Caribbean, Asia, eastern Europe and the South Pacific. Malaria is a rare diagnosis in Europe, the US and other developed countries, but it is a medical emergency. A travel history or living in endemic areas are the key to suspecting malaria, and this is a priority in patients with fever. There is no specific clinical symptomatology and immigrants from endemic regions might have mild symptoms. The diagnosis must be performed quickly on suspicion. Rapid diagnostic tests (RDTs) should be performed but the gold standard is microscopy.
Egypt, whose soil germinated the first civilization, monotheism, refined ethics and culture of sharing the abundance of extracted natural resources among its populace became the crucible proliferating de-novo genotypes of organic and moral maladies. The enigma is these mutations are synchronized by several factors, namely; failing medical health, if there is any, abundant filth, cultural bankruptcy, over population, dogmatic militarism, societal deprivation and characterization, etc. These domineering ingredients fossilized Egypt as of 1952 coup in an irrevocable national apoptosis, together with the crippled social justice and imbalanced distribution of wealth among Egyptians, rates of bacterial and viral evolution to second generation resistant to known medical interventions are expected to exponentially accelerate. Therefore, it deemed essential to elaborate on pollution and psychosis-induced inflammations and grievous crimes evoked by dogmatic cults at the breeding source, e.g., ghettos and sporadic locations of the homeless in Cairo, Alexandria and Upper Egyptian villages. While this second generation of viral and bacterial diseases could labor plagues threatening the precariously maintained so-called social fabric of Middle Eastern countries, that are uniquely segregating its populace according to their dogmatic affiliations and soaked into intolerance, it would definitely compromise the integrity of the expensively managed medical care system of developed countries.
To characterize adult patients with acute lung injury complicating severe imported Plasmodium falciparum malaria.
Retrospective study of patients with severe P falciparum malaria admitted to the medical ICU of a university hospital infectious diseases department.
Forty adults with complicated malaria, with (group 1, 12 patients) or without (group 2, 28 patients) acute lung injury.
Patients with acute lung injury had a higher simplified acute physiology score on admission (24.2 +/- 3.2 vs 13.7 +/- 0.7 in group 2, p < 0.0001) and a longer time interval to adequate antimalarial therapy (8.8 +/- 2.5 vs 4.9 +/- 0.6 days in group 2, p = 0.046). Of the nine group 1 patients given mechanical ventilation, eight had a PaO2/FIO2 < or = 200 mm Hg. Two patients with moderate hypoxemia received oxygen through a nasal tube and one received continuous positive airway pressure via a face mask. Acute renal failure, unrousable coma, metabolic acidosis, and shock were significantly more common among group 1 patients. The number of complications of malaria was significantly higher in patients with acute lung injury (4.7 +/- 0.5 vs 1.6 +/- 0.1 in group 2, p < 0.0001). Five patients, including four with acute lung injury, had evidence of bacterial infection (pneumonia or primary bacteremia) at ICU admission. Four patients with acute lung injury died (33%) vs one patient without acute lung injury (4%, p = 0.022).
Acute lung injury is more likely to occur in patients with extremely severe, multisystemic P falciparum malaria. In patients with acute lung injury and septic shock, bacterial coinfection should be suspected and treated empirically since it contributes substantially to early mortality.
As liver can be an important target organ in malaria, we performed an ultrastructural study of hepatic alterations in the final stage of Plasmodium berghei infection in mice. Significant hepatocyte abnormalities were found. An elevated number of cells showed mitochondria with a high electron-dense matrix and multiple changes in shape and size, alterations in the structure of Golgi complex, swelling and disorganisation of both rough and smooth-surfaced endoplasmic reticulum, differently shaped peroxisome nucleoids, and disappearance of glycogen granules. In other areas the hepatocytes were significantly altered with diminished microvilli and exhibited myelin-like figures, autophagic vacuoles, abundant lipid droplets, and swollen mitochondria in their cytoplasm. Necrotic and atrophied hepatocytes with scarce microvilli in the Disse space and biliary canaliculi could be seen. Parasitised red blood cells and parasite debris were found inside degenerated hepatocytes. Alterations were also noticed in microvasculature, including thickened endothelial cells with swollen mitochondria, lysosomes and autophagic vacuoles in their cytoplasm. Our results demonstrate that hepatocyte damage is an important finding associated with the advanced stages of P. berghei malarial infection, which may lead to liver dysfunction in this disease.
Studies were conducted to determine how malaria parasites are cleared from the blood after antimalarial treatment. Neither
artesunate nor quinine decreased parasitized red cell deformability or increased antibody binding. In acute falciparum malaria,
ring-infected erythrocyte surface antigen (RESA) was observed in erythrocytes without malaria parasites (RESA-red blood cell
[RBC]), indicating prior parasitization. In uncomplicated malaria, RESA-RBC numbers increased significantly (P = .002) within 24 h of starting artesunate but rose much more slowly (7 days) after quinine treatment. In severe malaria,
RESA-RBC increased significantly (P = .001) within hours of starting artesunate but not with quinine treatment (P = .43). RESA-RBCs were not produced after drug treatment of malaria parasite cultures in vitro. Rapid malaria parasite clearance
after treatment with artemisinin derivatives results mainly from the extraction of drug-affected parasites from host erythrocytes—presumably
by the spleen. This explains why the fall in hematocrit after treatment of hyperparasitemia is often less than that predicted
from loss of parasitized cells.
We describe severe hepatic dysfunction associated with an attack of falciparum malaria in six Sri Lankan patients. Clinicians working in areas endemic for malaria should be made aware of this unusual complication.
The role of the spleen during Plasmodium falciparum malaria in humans is unclear. In Thailand, malaria transmission is low and splenomegaly is rarer than in high transmission areas. We compared the prevalence of splenomegaly between 52 cerebral malaria patients and 191 patients without complications despite a high parasite biomass. We also measured concentrations of reactive nitrogen intermediates (RNIs) in a fraction of these cases recruited in 1998 (24 cerebral malaria and 56 controls). Splenomegaly was significantly associated with cerebral malaria (adjusted odds ratio = 2.07 [95% confidence interval = 1-4.2]; P = 0.048). There was a linear trend for this association (P = 0.0003). After adjusting for potential confounders, concentrations of RNIs were significantly lower in the presence of splenomegaly (P = 0.01). These results suggest that in humans, as in animal models, the spleen may be involved in the pathogenesis of cerebral malaria. The relationship between RNI concentrations and the spleen suggest that nitric oxide may have a regulating role in the complex physiology of the spleen during malaria.
We conducted a case record study comparing liver tests abnormalities in 20 malaria-related acute renal failure cases without cerebral malaria, 52 cerebral malaria cases without other organ impairment, 189 cases of nonsevere malaria associated with a high parasite burden, and 131 cases of mild Plasmodiumfalciparum malaria. Jaundice and hepatomegaly were significantly associated with renal failure (adjusted odds ratio [AOR], 3.3, 95% confidence interval [CI], 1.3-8.6, P = 0.01; and AOR, 1.7 95% CI, 1.13-2.4, P = 0.01) but not with cerebral malaria (AOR, 1, 95% CI, 0.5-2, P = 0.8; and AOR, 1.08, 95% CI, 0.8-1.8, P = 0.5). Patients with acute renal failure were significantly older and had increased liver abnormalities compared with other groups. Although an increase in the proportion of mature schizonts over ring forms was significantly associated with cerebral malaria, it did not seem to have affected acute renal failure. These results suggested that cytoadherence was not the main determinant for renal failure and that jaundice itself may have potentiated the effects of hypovolemia.
In acute malaria, red blood cells (RBCs) that have been parasitized, but no longer contain a malaria parasite, are found in
the circulation (ring-infected erythrocyte surface antigen [RESA]-RBCs). These are thought to arise by splenic removal of
dead or damaged intraerythrocytic parasites and return of the intact RBCs to the circulation. In a study of 5 patients with
acute falciparum malaria who had previously undergone splenectomy, it was found that none of these 5 patients had any circulating
RESA-RBCs, in contrast to the uniform finding of RESA-RBCs in all patients with acute malaria and intact spleens. Parasite
clearance after artesunate treatment was markedly prolonged, although the parasites appeared to be dead and could not be cultured
ex vivo. These observations confirm the central role of the spleen in the clearance of parasitized RBCs after antimalarial
treatment with an artemisinin derivative. Current criteria for high-grade antimalarial drug resistance that are based on changes
in parasitemia are not appropriate for asplenic patients.
According to the WHO, signs of hepatic dysfunction are unusual, and hepatic encephalopathy is never seen in malaria. However, in recent years, isolated cases have been reported from different parts of world.
To identify the evidence for hepatocyte dysfunction and/or encephalopathy in jaundiced patients with falciparum malaria.
Prospective observational study.
We studied 86 adult patients of both sexes who had malaria with jaundice (serum bilirubin > 3 mg%). The main outcome measures were: flapping tremor, deranged psychometric test, level of consciousness, serum bilirubin level, serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, blood ammonia level, viral markers for hepatitis, ultrasonography of liver and gall bladder and electroencephalography (EEG).
The range of serum bilirubin was 3-48.2 mg% (mean +/- SD 10.44 +/- 8.71 mg%). The ranges of AST and ALT levels were 40-1120 IU/l (294.47 +/- 250.67 IU/l) and 40-1245 IU/l (371.12 +/- 296.76 IU/l), respectively. Evidence of hepatic encephalopathy was seen in 15 patients. Asterexis was observed in 9 patients, impaired psychometric tests in 12 and altered mental state in 13. Arterial blood ammonia level was 120-427 meq/l (310 +/- 98.39 meq/l). EEG findings included presence of large bilateral synchronous slow waves, pseudo burst suppression and triphasic waves. Four patients died due to multiple organ dysfunction; the others made rapid recoveries.
There is strong evidence of hepatocyte dysfunction and hepatic encephalopathy in some of these patients, with no obvious non-malarial explanation. Current guidelines may need to be revised.
Cerebral malaria (CM) is a major cause of death in severe Plasmodium falciparum malaria. We present quantitative electron microscopic findings of the neuropathologic features in a prospective clinicopathologic study of 65 patients who died of severe malaria in Thailand and Vietnam. Sequestration of parasitized red blood cells (PRBCs) in cerebral microvessels was significantly higher in the brains of patients with CM compared with those with non-cerebral malaria (NCM) in all parts of the brain (cerebrum, cerebellum, and medulla oblongata). There was a hierarchy of sequestration with more in the cerebrum and cerebellum than the brain stem. When cerebral sequestration was compared with the peripheral parasitemia pre mortem, there were 26.6 times more PRBCs in the brain microvasculature than in the peripheral blood. The sequestration index was significantly higher in CM patients (median = 50.7) than in NCM patients (median = 6.9) (P = 0.042). The degree of sequestration of P. falciparum-infected erythrocytes in cerebral microvessels is quantitatively associated with pre-mortem coma.
Thirty-nine falciparum malaria autopsy cases from the Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand were divided into two groups that had had either cerebral malaria (CM) or non-cerebral malaria (NCM). We then studied significant pathological differences between these groups in order to investigate the correlation between parasitized erythrocyte (PRBC) sequestration in small blood vessels in the brain, heart, lungs and small intestines. We found that the percentage of PRBC sequestration in the organs which we studied was higher in the CM patients than in the NCM patients. The difference of PRBC sequestration among the organs of two groups was significant (P < 0.05). In the CM group, the average percentage of PRBC sequestration in the brain was significantly higher than in the heart, lungs and small intestines (P < 0.05). No statistically significant difference was found between PRBC sequestration in the brains, hearts, lungs and small intestines in the NCM group (P > 0.05). Our study indicates that severity of malaria in the CM patients depends on PRBC sequestration, especially in the brain. A combination of functional disturbances of the other organs, in addition to the cerebral pathology, may augment the severity of the disease.
The hepatic manifestations were studied in 65 patients having uncomplicated primary attacks of vivax and falciparum malaria. Hepatomegaly due to a "non-specific reactive hepatitis" occurred in 57% of cases. Jaundice occurred in 15% of patients and was invariably associated with hepatomegaly. The clinical syndromes of jaundice and hepatomegaly in uncomplicated primary attacks of malaria have to be distinguished from those related to disorders like viral hepatitis, hepatic amoebiasis, typhoid hepatitis, infectious mononucleosis and Q fever. The causes for the jaundice and the pathogenesis for the hepatic lesions have been discussed.
Liver function tests were performed in 165 hospitalized patients suffering from P. falciparum malaria with complications. Serum bilirubin was found increased in 33 patients, and 22 of them had unconjugated hyperbilirubinaemia. Serum alanine aminotransferase was increased in 5 patients, but only to mild to moderate levels. Serum alkaline phosphatase was increased in 11 patients, gamma-glutamyl transpeptidase in 3 patients. Serum total protein and albumin were significantly decreased but these were considered more as indicator of acute phase response. Liver cell necrosis was observed in one patient, and oedema and mononuclear cell infiltration in two patients. Though hepatomegaly and mild elevation of enzymes can be observed in a significant proportion of patients, involvement of liver leading to acute hepatitis or liver cell necrosis is a relatively uncommon complication in P. falciparum malaria.
Blockage of the cerebral microvasculature by Plasmodium falciparum-infected erythrocytes appears to be the principal cause of human cerebral malaria. Knobs which appear on the membrane of the infected erythrocytes adhere to the endothelium, causing the obstruction of cerebral microvessels. Protein molecules such as CD36, thrombospondin, and intercellular adhesion molecule-1, which are present on the membrane of endothelial cells, may act as receptors for the attachment of knobs of P. falciparum-infected erythrocytes. Each of these candidate host molecules for infected-cell recognition and attachment are expressed in microvessels of the human brain. The presence of HRP1 and HRP2 in the cerebral microvessels of cerebral malaria patients may indicate the involvement of knob proteins in the pathogenesis of cerebral malaria. Owl monkeys infected with P. falciparum do not develop cerebral malaria. There is no blockage of cerebral microvessels by infected erythrocytes and knob proteins are absent. These findings support the contention that cerebral microvessel blockage and the presence of knob proteins are the probable causes of cerebral malaria.
Based on the cerebral malaria coma scale, 39 falciparum malaria autopsy cases from the Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand were divided into two groups of patients that had either cerebral malaria or non-cerebral malaria. We then studied significant pathological differences, such as parasitized erythrocyte (PRBC) sequestration, ring hemorrhages and cerebral edema, between these two groups in order to investigate the correlation between the clinical coma scale and pathological findings. Patients with a coma grade of 2 and higher were designated as having cerebral malaria, and had erythrocyte PRBC sequestration in cerebral microvessels. Ninety four percent (94%) of cerebral microvessels showed PRBC sequestration when quantitatively analyzed. On the other hand, only 13% of cerebral microvessels showed sequestration in non-cerebral malaria patients with a coma grade of 1 and lower, although some degree of PRBC sequestration was found in 50% of these patients. Our study, therefore, clearly demonstrated that the degree of the PRBC sequestration in cerebral microvessels appeared to correlate closely with the clinical coma scale.
The splenic response in lethal 17XL Plasmodium yoelii murine malaria is vigorous, displaying marked phagocytosis, erythropoiesis, lymphopoiesis, plasmacytopoiesis, and, from day 3 of infection, increasing levels of parasitized erythrocytes. There is also a pronounced response of newly characterized fibroblastic stromal cells which branch and fuse with one another, forming extensive, complex, irregular, syncytial membranous sheets which provide a variety of barriers. Hence, I term these barrier cells (BC), and their fusion results in barrier-forming complexes (BFC). BC form adherent surfaces, trapping parasitized erythrocytes and monocytes-macrophages, facilitating phagocytosis. They envelop single plasma cells, erythrocytes, erythroblasts, lymphocytes, reticulocytes, monocytes-macrophages, or clusters of them. They surround blood vessels, forming blood-spleen barriers. They are insinuated into the circumferential reticulum at the periphery of white pulp, isolating white pulp. They form channels in red pulp, directing blood flow. They are associated with collagen. There appear to be several sources of BC. They may originate by activation of established reticular cells which form the filtration beds, by activation of reticular cells covering the pulp surface of capsule and trabeculae, and as a major source in this malaria, from circulating progenitors entering the splenic pulp from the vasculature. In non-lethal malaria, these barrier systems protect splenic reticulocytes from parasitization. In the lethal 17XL malaria they do not, and there follows a considerable increase in parasitization in the spleen with a corresponding increase in active macrophages. Large-scale parasitization and parasite recycling through the great stores of splenic reticulocytes in the lethal malaria, and the failure of parasitization of these splenic reticulocytes reserves on the non-lethal malaria, suggests that the actions of the spleen aggravate the lethal malaria and ameliorate the non-lethal. This is supported by the finding that non-lethal malaria is aggravated and lethal malaria ameliorated by splenectomy.
The clearance of autologous red cells sensitized with an IgG anti-D has been studied in patients during and after an attack of P. falciparum malaria, and in 11 uninfected control subjects. In most patients with P. falciparum malaria there was evidence of increased clearance of sensitized red cells, compared to controls.
Clearance half-times of IgG sensitized red cells were significantly decreased (P < 0.01) in 16 patients with acute falciparum malaria (median 21 min, range 11–53 min) compared to 11 control subjects (median 37 min, range 20–60 min). This difference was independent of the degree of IgG sensitization of red cells. In patients with acute falciparum malaria, clearance half-times were positively correlated with venous haematocrit (P < 0.05). In 11 patients studied between 1 and 9 weeks after the attack, clearance half-times (median 17 min, range 11–56 min) were also significantly decreased compared to controls (P < 0.01). In the majority of acute and convalescent patients, there was further evidence for early destruction of an additional substantial proportion of sensitized red cells.
Our data indicate that in most patients with uncomplicated P. falciparum malaria, IgG sensitized red cells are rapidly removed from the peripheral circulation by the spleen, and that rapid clearance persists during recovery.
The ultrastructure of the spleen of a patient who died of natural infection of Plasmodium falciparum was studied with emphasis on phagocytosis. Parasitized erythrocytes were shown to interact with the heterogenous populations of phagocytic cells. Phagocytosis occurred predominantly in macrophages than endothelial cells and immature forms of parasites were preferentially phagocytosed. Splenic trapping, pitting and destruction of both infected and noninfected erythrocytes were demonstrated. Other forms of interaction between phagocytic cells and parasitized erythrocytes observed include complex interdigitation, association of loose and tight phagosomes, and preferential sites of adherence, the significance of which need further investigation.
Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated 51Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes [mean +/- SD] vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than did the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.
An ultrastructural study was undertaken of the spleen of 13 year-old-boy who died of falciparum malaria. The spleen revealed the following: both parasitized and non-parasitized erythrocytes are phagocytosed in large numbers by macrophages, littoral and reticular cells. Blood congestion and trapping of parasitized erythrocytes are commonly seen in splenic sinusoids and cords. Erythrocytes forming rosette structure around immuno-presenting cells is observed. The results of this study provide evidence that the mechanisms underlying splenic host defence in malaria include both immunological and non-immunological interaction with erythrocytes. Splenic trapping of parasitized erythrocytes is an important defence mechanism and the phagocytosis of erythrocytes probably accounts for anaemia.
For investigation of the pathogenesis of cerebral malaria, immediate postmortem samples from brain and other tissues of patients dying with Plasmodium falciparum malaria, with (CM) or without (NCM) cerebral malaria, were processed for electron microscopy. Counts of parasitized erythrocytes (PRBCs) in cerebral and other vessels showed that the proportion of PRBCs was higher in CM than in NCM, and also that the proportion of PRBCs was higher in the brain than in other organs examined in both CM and NCM. Cerebral vessels from CM patients were more tightly packed with RBCs than those from NCM patients, but there was no significant difference in the amount or degree of endothelial damage or numbers of vessels with endothelial pseudopodia. Fibrillar (fibrin) deposits were present in a small proportion of vessels, but no thrombosis was present. There was neither acute nor chronic inflammation, and leukocytes were absent within or outside cerebral vessels. There was no immune complex deposition in cerebral vessels. Parasites in cerebral vessels were mainly trophozoites or schizonts. Occasional RBC remnants following parasite release were seen. Some parasites were degenerate, resembling crisis forms. PRBCs adhered to endothelium via surface knobs. It is concluded that there is no evidence for an inflammatory or immune pathogenesis for human cerebral malaria and that the clinical effects probably relate to anoxia and the metabolic activities of the parasites.
Three patients were described in whom falciparum malaria was accompanied by severe jaundice, renal failure due to tubular necrosis, and anaemia without overt intravascular haemolysis. Treatment with antimalarial drugs and peritoneal dialysis was successful in 2, but the third patient died from a bleeding peptic ulcer which complicated his illness. The renal failure and other manifestations of the P. falciparum infection are considered in the light of a common toxic factor.
To demonstrate the liver profile abnormalities in jaundiced falciparum malaria patients and to determine whether jaundice was associated with other complications in falciparum malaria, 390 patients with acute falciparum malaria were studied. 124 patients were jaundiced and the others were non-jaundiced. Hyperbilirubinemia (total serum bilirubin 3 to 64 mg/dl) was found in jaundiced patients predominantly as unconjugated bilirubin. Asparatate amino-transferase and alanine minotransferase were significantly higher in jaundiced patients (p < 0.01). There was a slight decrease of serum albumin in jaundiced malaria. The complications in jaundiced patients included cerebral malaria (n = 10), acute renal failure (n = 12), pulmonary edema (n = 3), shock (n = 3), and other severe malarial complications (n = 43). Jaundice was associated with cerebral malaria (p < 0.05), acute renal failure (p < 0.01), and hyperparasitemia (p < 0.01). After successful treatment, liver profile returned to normal within a few weeks. We found that jaundiced malaria patients had transient liver profile impairment which indicated predominantly hemolysis rather than liver damage; complications were more frequent in jaundiced patients.
The characteristics of hepatomegaly in acute falciparum malaria were studied in 114 children presenting consecutively with the disease. Hepatomegaly was more common than splenomegaly and was significantly more frequent in younger than in older children. In children with hepatomegaly at presentation, there was an equal sex distribution, a negative correlation between liver size and age, and a positive correlation between liver enlargement and the reported duration of symptoms at presentation. Symptoms attributable directly to liver involvement were relatively uncommon. There was no correlation between liver and spleen size, presenting core temperature, or peripheral parasite density. Tender hepatomegaly and tender splenomegaly were rare during the acute illness; tenderness resolved within 72 h after commencement of antimalarial therapy. Complete resolution of hepatomegaly occurred in 41% of children after recovery from the acute illness (by days 7 or 14), varying degrees of resolution occurred in 48% and no reduction or an increase in liver size occurred in the remainder. In children with hepatomegaly who failed to clear parasitaemia by days 7 or 14, persistent hepatomegaly was common. These results suggest that hepatomegaly, like splenomegaly, may be assessed as a possible malariometric index of the intensity of transmission in children in an endemic area.
Renal and systemic hemodynamics, plasma arginine vasopressin, plasma renin activity, plasma norepinephrine, blood volume and water loading test were studied in 10 patients with falciparum malaria without renal failure. Six patients responded to water load normally, while 4 patients had a decreased response to water load. The patients with a normal water load response had normal renal and systemic hemodynamics and a normal hormonal profile. The patients with a decreased response to water load had hyponatremia, hypervolemia, high cardiac index, low systemic vascular resistance, high plasma arginine vasopressin, high plasma renin activity, high plasma norepinephrine, low creatinine and p-aminohippurate clearances, low urine sodium and high urine osmolality. They had a lower mean arterial pressure during the acute phase of the disease than during the recovery phase. The findings suggest that a decreased response to water load is due to peripheral vasodilatation which results in a decreased effective blood volume leading to the release of vasopressin and norepinephrine, increased renin activity and decreased renal hemodynamics.
Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (Plasmodium falciparum, 49; P. vivax, 1). Malaria parasites were sequestered in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the P. vivax case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1, VCAM-1, E-selectin, and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (P < 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0-90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0-36.2%). All developmental stages of P. falciparum are sequestered in the brain in severe malaria.
The clinical characteristics and the kinetics of the disposition of the hepatomegaly associated with acute, uncomplicated Plasmodium falciparum malaria were investigated in 162 children in an endemic area of Nigeria. Hepatomegaly was significantly more common in the younger than in the older children. Complete resolution occurred in 48% following antimalarial chemotherapy. In the children in whom hepatomegaly did not resolve, a reduction in liver size of < 17% by the time parasitaemia was cleared (usually on day 3) was associated with non-resolution of hepatomegaly by days 7 or 14 of follow-up. An increase in liver size to at least 125% of the baseline value by day 4 or 5 was associated with a lack of therapeutic response, providing the child involved was aged < 5 years. In the children who had complete clearance of parasitaemia and resolution of hepatomegaly, there was no significant relationship between the parasitaemia-derived conventional indices of therapeutic response [i.e. time to clearance of 50% (PC50) or 90% (PC90) of the parasitaemia, and the parasite-clearance time (PCT)] and the corresponding parameters derived from measurement of liver size [i.e. time for resolution of 50% (HR50) or 90% (HR90) of the hepatomegaly and the hepatomegaly-resolution time (HRT)] in the same patients. However, as the HR50:PC50, HR90:PC90 and HRT:PCT ratios were similar (range = 1.6-2.1), the liver parameters may have therapeutic application. In the children with drug-sensitive P. falciparum infections and in whom hepatomegaly completely resolved, the area produced by plotting liver size against time (i.e. the area under the curve of hepatomegaly v. time, or AUChp) increased in proportion to the liver size below the costal margin (P = 0.02, from analysis of variance), but there was no significant difference in the half-lives of hepatomegaly (t1/2hp) or in the ratios of liver size to AUChp, indicating that the kinetics of the resolution of hepatomegaly were linear in the range examined. Comparison of the kinetic indices of hepatomegaly and parasitaemia showed that, although the half-lives of parasitaemia and hepatomegaly and the corresponding clearance values were similar, there was no correlation between these parameters among those in whom hepatomegaly completely resolved and parasitaemia completely cleared. These results indicate that routine clinical measurement of the liver size in children with hepatomegaly during acute, uncomplicated, P. falciparum malaria may have some use in evaluating and monitoring the therapeutic responses of infections. The resolution of hepatomegaly, a reflection of pathological changes, lags behind clearance of parasitaemia in children with P. falciparum malaria, and supports the use of the liver 'rate' as a malariometric index for assessing the intensity of transmission in endemic areas.
Malaria continues to be a major problem in tropical countries. To study the clinical features and complications of malaria in a tertiary care hospital in south India, records of 183 patients were analysed. Among 86 patients with P. falciparum and mixed infection, 24 (28 per cent) had cerebral malaria and 32 (37 per cent) had hyperbilirubinemia. Twenty-three out of 32 (72 per cent) patients with jaundice had direct hyperbilirubinemia and elevated liver enzymes suggesting hepatocellular damage. Mortality of the order of 10 per cent was seen only in P. falciparum malaria. High incidence of hepatic involvement and hepatorenal failure were the unusual features observed in the study.
Liver involvement in cerebral malaria
- P Wilairatana
- E Pongponratn
- M Riganti
- S Vanaphan
- S Looareesuwan
Wilairatana P, Pongponratn E, Riganti M, Vanaphan S,
Looareesuwan S. Liver involvement in cerebral
malaria. Mahidol Univ J 1996; 3: 11-3.
Severe falciparum malaria
WHO. Severe falciparum malaria. Trans R Soc Trop
Med Hyg 2000; 94 (suppl 1): S 1/1-74.