Levels of soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-2 in plasma of patients with hemorrhagic fever with renal syndrome, and significance of the changes in level

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral disease characterized by endothelial dysfunction. Vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-2 provide costimulatory signals for the activation of T lymphocytes; these adhesion molecules play key roles in leukocyte adherence and propagation of inflammatory responses. They may be involved in the immunologic response that leads to vascular endothelial cell (VEC) and kidney damage of HFRS patients, and increased levels of soluble (s)VCAM-1 and sICAM-2 in plasma may indicate the severity of HFRS. We examined the presence of sVCAM-1 and sICAM-2 in 52 plasma samples collected from 52 patients. We tested these plasma samples for sVCAM-1 and sICAM-2 by double-antibody sandwich ELISA. We found variable, but persistently elevated, levels of sVCAM-1 and sICAM-2 throughout the various phases and types of the disease, which suggested sVCAM-1 may play an important role in the immunopathological lesions of HFRS and is closely correlated to the severity of HFRS and the degree of kidney damage. sICAM-2 may be associated with the hyperfunctioning of the cellular immune response.     

The Detection of Vascular Endothelial Growth Factor in Serum of Patients with Hemorrhagic Fever with Renal Syndrome

Hemorrhagic fever with renal syndrome (HFRS) is an acute infectious disease characterized by endothelial cell dysfunction, which results in plasma exosmosis, hyperpermeability, and sometimes hemorrhages. As one of the vascular permeability cytokines, vascular endothelial growth factor (VEGF) might mediate the hyperpermeability caused by HFRS. In the present study, the levels of serum VEGF were measured by competitive inhibition ELISA. We found variable but persistently elevated levels of VEGF throughout the various stages and types of HFRS disease, which suggested that the levels of VEGF were closely correlated to the progression of HFRS. Moreover, elevated levels of VEGF have correlation with the severity and degree of kidney damage. Therefore, to study the relationship between levels of VEGF and disease severity of patients with HFRS is helpful to clarify the pathogenesis of HFRS.     

Intensity of platelet beta(3) integrin in patients with hemorrhagic fever with renal syndrome and its correlation with disease severity

beta(3) Integrin has been identified as a cellular receptor for Hantaan virus, which causes hemorrhagic fever with renal syndrome (HFRS). To investigate the relationship between intensity of the platelet membrane beta(3) integrin (CD61) and disease severity, the percentage of CD61-positive platelets and the mean fluorescence intensities (MFI) of platelet CD61 were determined in patients with HFRS by flow cytometry. The intensity levels of CD61 in patients with HFRS were significantly higher than those in the controls and correlated with the clinical phases of the disease. The CD61 intensity at the oliguric phase was inversely correlated with platelet count and serum albumin, and positively correlated with white blood cell count, blood urea nitrogen, serum creatinine, and alanine aminotransferase levels. The results suggest that the intensity levels of platelet CD61 were elevated and associated with clinical phases and disease severity in patients with HFRS, and the intensity of platelet beta(3) integrin in patients with HFRS may be indicative of disease severity.     

Hantavirus infections

Over the past few decades understanding and recognition of hantavirus infection has greatly improved worldwide, but both the amplitude and the magnitude of hantavirus outbreaks have been increasing. Several novel hantaviruses with unknown pathogenic potential have been identified in a variety of insectivore hosts. With the new hosts, new geographical distributions of hantaviruses have also been discovered and several new species were found in Africa. Hantavirus infection in humans can result in two clinical syndromes: haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) caused by Old World and New World hantaviruses, respectively. The clinical presentation of HFRS varies from subclinical, mild, and moderate to severe, depending in part on the causative agent of the disease. In general, HFRS caused by Hantaan virus, Amur virus and Dobrava virus are more severe with mortality rates from 5 to 15%, whereas Seoul virus causes moderate and Puumala virus and Saaremaa virus cause mild forms of disease with mortality rates <1%. The central phenomena behind the pathogenesis of both HFRS and HCPS are increased vascular permeability and acute thrombocytopenia. The pathogenesis is likely to be a complex multifactorial process that includes contributions from immune responses, platelet dysfunction and the deregulation of endothelial cell barrier functions. Also a genetic predisposition, related to HLA type, seems to be important for the severity of the disease. As there is no effective treatment or vaccine approved for use in the USA and Europe, public awareness and precautionary measures are the only ways to minimize the risk of hantavirus disease.     

Low levels of serum vitronectin associated with clinical phases in patients with hemorrhagic fever with renal syndrome

β₃ integrin has been identified as a cellular receptor for Hantaan virus which causes hemorrhagic fever with renal syndrome (HFRS). As one of the ligands of β₃ integrin, vitronectin (VN) may be altered in HFRS. In this study, changes of serum VN levels were determined in 112 patients with HFRS and 30 age- and sex-matched healthy controls by quantitative sandwich enzyme immunoassay. The levels of serum VN were analyzed in patients at various phases of HFRS and with different severity of clinical types. Serum VN levels in patients with HFRS, at all clinical phases except the convalescent phase, were significantly decreased compared with those in the controls (P < 0.01). The serum levels of VN decreased at febrile phase, maintained at the lowest status during hypotensive and oliguric phases, started to increase from polyuric phase and reached almost normal condition till convalescent phase. The levels of serum VN between patients with milder and more severe clinical types showed no significant difference at each phase (P > 0.05). These results suggest that VN level was altered during the course of HFRS and chronological changes of serum levels of VN may correlate with the evolution of the disease.     

上海地区肾综合征出血热尸检肾组织病毒检测

目的：研究上海地区肾综合征出血热（ＨＦＲＳ）尸检病例肾脏组织中病毒ＲＮＡ及抗原的分布及定位，方法：用核酸原位分子杂交方法和细胞免疫组化方法，检测了１７例ＨＦＲＳ尸检肾组织中病毒，结果：１７例肾组织中１５例可检测到病毒ＲＮＡ及抗原，病毒ＲＮＡ主要位于肾组织血管壁，毛细血管内皮细胞脉冲有小球毛细血管内皮细胞，病毒抗原主要分布于肾间质管内皮细胞和血管壁中，部分位于肾曲管上皮细胞，以病毒包涵体样颗粒出现。     

Differential up-regulation of circulating soluble and endothelial cell intercellular adhesion molecule-1 in mice.

Although circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) are frequently used as an indicator of the severity of different immune, inflammatory, or neoplastic diseases, little is known about the factors that govern plasma sICAM-1 concentration and its relationship to the membranous form of ICAM-1 (mICAM-1) expressed on vascular endothelial cells. Plasma sICAM-1 concentration (measured by enzyme-linked immunosorbent assay) and mICAM-1 expression (measured using the dual radiolabeled monoclonal antibody technique) in different vascular beds (eg, lung, small intestine, and spleen) were monitored in wild-type (C57BL) and ICAM-1-deficient mice, before and after administration of tumor necrosis factor (TNF)-alpha. In wild-type mice, TNF-alpha elicited time-dependent increases in lung and intestine mICAM-1 (plateau achieved at 12 hours), with a corresponding increase in plasma sICAM-1 (peaked at 5 hours and then declined). The initial increases in mICAM-1 and pulmonary leukocyte sequestration (measured as lung myeloperoxidase activity) induced by TNF-alpha preceded any detectable elevation in sICAM-1. In ICAM-1-deficient mice, plasma sICAM-1 was reduced by approximately 70%, with > 95% reductions of mICAM-1 in lung and intestine, and > 75% reduction in splenic accumulation of anti-ICAM-1 antibody. Although TNF-alpha doubled plasma sICAM-1 in ICAM-1-deficient mice, mICAM-1 was unaffected in all tissues. Either splenectomy or pretreatment with cycloheximide resulted in an attenuated TNF-induced increase in sICAM-1, without affecting mICAM-1 expression. These findings indicate that plasma sICAM-1 concentration does not accurately reflect the level of ICAM-1 expression on endothelial cells in different vascular beds.     

Identification of Hantaan virus-related structures in kidneys of cadavers with haemorrhagic fever with renal syndrome

Summary The etiologic agent of haemorrhagic fever with renal syndrome (HFRS), Hantaan virus, was first isolated in 1976. Since then numerous Hantaan-like viruses have been isolated and five serotypes of Hantavirus have been recognized. Serological studies indicate that these viruses are globally distributed, with each serotype occurring in specific areas. Hantaan virus has been intensively studied antigenically, biochemically, and genetically. However there is still a paucity of information on the pathogenesis of Hantaan virus in the human host.In this paper, we report the detection by thin section immune electron microscopy of the occurrence of numerous dense precipitates, typical inclusion bodies, a surface antigen layer, as well as Hantaan virion-like structures in the kidneys of patients that died during the acute phase of HFRS. These findings may shed some light on understanding the pathogenesis of HFRS in target organs most affected by the disease, such as the kidneys.     

Evaluation of the association of serum levels of hyaluronic acid,sICAM-1, sVCAM-1, and VEGF-A with mortality and prognosis in patients with Crimean-Congo hemorrhagic fever

BackgroundCrimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral hemorrhagic disease. Pathogenesis of the disease has not been well described yet. A well-known pathogenic feature of CCHF virus is its capability to damage endothelium. Increased hyaluronic acid (HA) levels indicate liver sinusoidal endothelial damage. Soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and vascular endothelial growth factor-A (VEGF-A) play a role in the inflammatory process, vascular damage and plasma leakage.ObjectivesTo investigate whether or not there is a relationship between HA, sICAM-1, sVCAM-1 and VEGF-A serum levels and fatality in CCHF.Study designSixty-one patients who were confirmed by RT-PCR and serological tests for CCHF, included in the current study. HA, sICAM-1, sVCAM-1, VEGF-A levels in serum samples were analyzed by ELISA.ResultsThere were statistically significant differences between fatal and non-fatal CCHF patients in terms of HA, sICAM-1, sVCAM-1, and VEGF-A levels. In addition, AST and ALT levels were positively correlated with HA, sICAM-1, sVCAM-1, and VEGF-A levels.ConclusionHA, sICAM-1, sVCAM-1, and VEGF-A levels of the patients that died during hospitalization were statistically significantly higher than the patients that survived, and this finding suggests that the level of these molecules could be used as a prognostic marker in CCHF.     

Clinical and laboratory features and factors predicting disease severity in pediatric patients with hemorrhagic fever with renal syndrome caused by Hantaan virus

The clinical features and factors associated with disease severity in children with hemorrhagic fever with renal syndrome (HFRS) have not been well characterized. This study analyzed the clinical and laboratory factors associated with disease severity in children with HFRS caused by Hantaan virus. Data in pediatric patients with HFRS were retrospectively collected from Xi'an Children's Hospital over a 9-year period. Independent factors associated with disease severity were identified. Nomogram predicting disease severity was constructed based on variables filtered by feature selection. In total, 206 children with HFRS were studied. Fever, digestive tract symptoms, headache, backache, bleeding, and renal injury signs were the common symptoms. Elevated white blood cell, reduced platelet, hematuria, proteinuria, coagulation abnormalities, increased blood urea nitrogen (BUN) and procalcitonin (PCT), decreased estimated glomerular filtration rate and low serum Na⁺, Cl⁻, and Ca²⁺ were the common laboratory findings. In the 206 patients, 21 patients had critical type disease and 4 patients (1.9%) died. Hydrothorax, hypotension and cerebral edema/cerebral herniation at hospital admission were independent clinical characteristics, and neutrophil %, prothrombin activity, PCT, BUN, and Ca²⁺ at hospital admission were independent laboratory factors associated with critical disease. Feature selection identified BUN, PCT and prothrombin time as independent factors related to critical disease. A nomogram integrating BUN and PCT at admission was constructed and calibration showed high accuracy for the probability prediction of critical disease. In conclusion, this study characterized the clinical and laboratory features and constructed a nomogram predicting disease severity in pediatric HFRS, providing references for disease severity evaluation in managing children HFRS.     

Evidence of vascular damage in dengue disease: demonstration of high levels of soluble cell adhesion molecules and circulating endothelial cells.

Clinical evidence suggests that vascular damage plays a key role in the pathophysiology of dengue hemorrhagic fever (DHF). In this study, the authors tested this hypothesis by examining the levels of soluble intercellular adhesion molecule and vascular cell adhesion molecule (sICAM-1 and sVCAM-1), and the presence of circulating endothelial cells (CECs), as evidence of vascular damage, in peripheral blood from DHF patients (n=13). A significant increase in plasma levels of sICAM-1 (n=12) and sVCAM-1 (n=13) was detected by enzyme-linked immunosorbent assay (ELISA) in DHF patients, compared with healthy individuals. Increased numbers of CECs, as detected by the expression of endothelial cell markers (ICAM-1, platelet cell adhesion molecule [PCAM]-1, and CD36) with flow cytometry, were observed in DHF patients (n=4), compared to healthy subjects. The high levels of sICAM-1 and sVCAM-1, together with the presence of CECs in DHF patients, provide further evidence of endothelium damage and activation in DHF patients.     

Infection of Hantaan virus strain AA57 leading to pulmonary disease in laboratory mice

Hantaan virus (HTNV) is a causative agent of hemorrhagic fever with renal syndrome (HFRS). The pathogenesis of HFRS has not been fully elucidated, mainly due to the lack of a suitable animal model. In laboratory mice, HTNV causes encephalitis. However, that symptom is dissimilar to human hantavirus infections. We found that HTNV strain AA57 (isolated from Apodemus agrarius in Far East Russia) caused pulmonary disease in 2-week-old ICR mice. The clinical signs of the infected mice were piloerection, trembling, hunching, labored breathing, and body-weight loss. A large volume of pleural effusion was collected from thoracic cavities of the dead mice. Overall, 45% of the mice inoculated with 3000 focus forming units (FFU) of the virus began to show clinical symptoms at 8 days post-inoculation, and 25% of the inoculated mice died within 3 days of onset of the disease. The morbidity and mortality rates of the mice inoculated with 30-30,000 FFU of HTNV strain AA57 were roughly equivalent. The highest rates of virus positivity (11/12) and the highest titers of HTNV strain AA57 were detected in the lungs of the dead mice, while lower detection rates and viral titers were found in the heart, kidneys, spleen, and brain. Interstitial pneumonia, perivascular edema, hemorrhage, inflammatory infiltration and vascular failure were observed in the lungs of the sick mice. Hantaviral antigens were detected in the lung endothelial cells of the sick mice. The symptoms and pathology of this mouse model resemble those of hantavirus pulmonary syndrome (HPS) and, to a certain extent, those of HFRS. This is the first report that, in laboratory mice, the HFRS-related hantavirus causes a HPS-like disease and shares some symptom similarities with HFRS.     

Genetic determining of the change in VE-cadherin expression and intensified vessel deendothelisation during hemorrhagic fever with renal syndrome

This paper studies the dependence of the level of vascular endothelial cadherin (VE-cadherin) in the blood serum and the degree of endothelial desquamation on the frequency distribution of genotypes and alleles of the polymorphic locus rs1049970 of the VE-cadherin CDH5 gene during hemorrhagic fever with renal syndrome (HFRS) of varying severity. The VE-cadherin concentration statistically significantly drops; the number of circulating endothelial cells increases in the dynamics of HFRS in all degrees of severity of the disease, most significantly, in the severe form with complications. A strong negative correlation is revealed between them. The frequency of occurrence of the homozygous genotype *T/*T is significantly high only in the severe form with complications. It was concluded that there is a correlation between the decrease in the VE-cadherin level in the blood serum and the increase in the vessel endothelial desquamation during moderate to severe and severe uncomplicated HFRS with decreased expression of VE-cadherin on endothelial cells. It may be that missense mutation c.1550T > C of the VE-cadherin gene in the severe form with complications increases the desquamation process of endothelial cells.     

Soluble endothelium-associated adhesion molecules in patients with Graves' disease.

The targeting and recruitment of inflammatory cells to vascular endothelium in Graves' disease (GD) is mediated by intercellular adhesion molecule-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1). We have studied serum levels of soluble ICAM-1 (sICAM-1), soluble ELAM-1 (sELAM-1), and soluble VCAM-1 (sVCAM-1) in patients with GD (n = 21) and in patients with iodine-deficient goitre (IDG) (n = 23). The serum levels of sICAM-1 were markedly elevated in patients with GD before treatment with thiamazole (median 560 ng/ml versus 185 ng/ml in patients with IDG). In addition, elevated serum concentrations of sELAM-1 (median 85 ng/ml versus 33 ng/ml, respectively) and sVCAM-1 (median 42 ng/ml versus 15 ng/ml, respectively) were observed in patients with GD (P < 0.01 for all). The serum levels of sELAM-1 and sVCAM-1 dropped significantly after initiation of therapy and were within the normal range after 4, and 8 weeks of therapy, respectively. Serum levels of sICAM-1 were elevated even after 8 weeks of therapy. Serum levels of sVACM-1 and sICAM-1 correlated with the serum concentrations of anti-thyroid-stimulating hormone (TSH)-receptor antibodies (TSHR-R) (n = 21; r = 0.929 and r = 0.810, respectively) and anti-thyroid peroxidase antibodies (TPO-Ab) (n = 21; r = 0.673 and r = 0.750, respectively). However, no correlation between sELAM-1 and TPO-Ab, TSHR-R, and anti-thyroglobulin antibodies (Tg-Ab), respectively, could be found. In addition to thyroid hormones and autoantibodies, serum concentrations of sELAM-1 and sVCAM-1, but not sICAM-1, could be useful as clinical markers for disease activity.     

The detection of sLFA-3 in plasma of patients with hemorrhagic fever with renal syndrome

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral disease characterized by endothelial dysfunction. The cellular immune response, especially the virus-specific CD8+ T lymphocytes, is known to attack vascular endothelial cells (VEC) and to contribute to the diffuse damage and penetrability increasing of VEC. Lymphocyte function associated antigen 3 (LFA-3) is expressed on T lymphocytes and VEC, which is contributed to the activation of T lymphocytes. The expression of LFA-3 on the activated T lymphocytes and VEC is highly increased, which can exfoliate into plasma to increase the level of soluble LFA-3 (sLFA-3) in plasma. So the change of sLFA-3 levels is correlated with the activation of T lymphocytes. In this study we detected the levels of sLFA-3 in plasma of patients with HFRS. We examined the levels of sLFA-3 in plasma samples collected from 53 HFRS patients by double antibody sandwich ELISA. We found variable, but persistently elevated levels of sLFA-3 throughout the various phases and types of the HFRS disease, which suggest that sLFA-3 levels have correlation with disease stages. Moreover, elevated sLFA-3 levels are closely correlated to the severity of HFRS and the degree of kidney damage.     

Immune responses to inactivated vaccine in people naturally infected with hantaviruses

An inactivated Hantaan virus vaccine for hemorrhagic fever with renal syndrome (HFRS) was given by injection to 15 people who were naturally infected with either Hantaan or Seoul viruses. Immunofluorescent antibody (IFA), reversed passive hemagglutination inhibition (RPHI), hemagglutination inhibition (HI), and neutralization antibody (NA) assays were used to measure the antibody titers of the vaccinated people before and after three doses of vaccine. The results indicated that IFA and RPHI antibody titers were boosted significantly (P < 0.05) after the vaccination. Either Hantaan or Seoul virus could induce two-way cross-reactive neutralization antibody responses in humans. After HTNV vaccine immunization, the NA titers of people with natural infection increased significantly (P < 0.05) to both Hantaan and Seoul viruses, while the relative dominance between these two type responses was still similar to that of natural infection. It is worthwhile to studying the procedure further to inoculate two different virus vaccines for improving the cross-protective effect. © 1996 Wiley-Liss, Inc.     

Puumala and Dobrava viruses cause hemorrhagic fever with renal syndrome in Bosnia-Herzegovina: Evidence of highly cross-neutralizing antibody responses in early patient sera

Hantavirus infection was diagnosed serologically by μ-capture IgM and IgG ELISAs in hemorrhagic fever with renal syndrome (HFRS) patients admitted to Tuzla Hospital, Bosnia-Herzegovina. The results indicated that more than one hantavirus caused the outbreak. To address the question of which hantavirus serotypes were involved, sequentially drawn sera were analyzed by focus reduction neutralization test (FRNT) for antibodies against Puumala, Hantaan, Dobrava, and Seoul hantaviruses. The data revealed that acute- or early convalescent-phase sera, even when drawn as late as 3 weeks after the onset of disease, could not be used for typing of the causative hantavirus; a significant number of these samples showed similar reactivity of neutralizing antibodies to several different hantavirus serotypes. Moreover, although several acute-phase sera showed the highest FRNT titer to Hantaan virus, convalescent sera from these patients in all cases showed high specificity for Puumala or Dobrava viruses. This phenomenon, interpreted as a cross-neutralizing primary antibody response, makes several earlier reports concerning causative agents of HFRS questionable. Serological examination of small rodents trapped in the endemic area identified Puumala- and Dobrava-like virus infections. RT-PCR and sequencing of rodent lung samples identified Dobrava virus in one yellow-necked field mouse (Apodemus flavicollis). Cross-FRNT data, using polyclonal rabbit antibodies, clearly confirmed Dobrava virus as a unique hantavirus serotype. In conclusion, the results revealed that both Puumala- and Dobrava-like viruses caused HFRS in Bosnia-Herzegovina, whereas no signs of Hantaan or Seoul virus involvement were found. J. Med. Virol. 53:51–59, 1997. © 1997 Wiley-Liss, Inc.     

The role of Hantaan virus serotypes in the etiology of hemorrhagic fever with renal syndrome in the Far East of the USSR

The employment of two serological tests (indirect fluorescence antibody technique and neutralization test) demonstrated the leading role of Hantaan virus serotype 1 strains isolated from field mice in the pattern of the incidence of hemorrhagic fever with renal syndrome (HFRS). Proofs of the etiological importance of strains of serotypes 3 and 5 occurring in brown rats and Cl. rufocanus were obtained. No data on any association of human HFRS cases with strains of serotype 4 isolated from reed voles could be demonstrated.     

Differential up-regulation of circulating soluble selectins and endothelial adhesion molecules in Sicilian patients with Boutonneuse fever.

In 150 patients with Boutonneuse fever (BF), caused by Rickettsia conorii, we studied the plasma levels of soluble L-selectin (sL-selectin), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1) and E-selectin (sE-selectin) in various phases of disease to clarify their role in disease evolution. Results indicate that during the acute phase of BF there is a significant increase in the serum levels of sL-selectin, sE-selectin, sVCAM-1 and sICAM-1. sL-selectin and sVCAM-1 returned to normal levels in the third week of disease, whereas sE-selectin and sICAM-1 persisted at significantly high levels even after the third week. The secretion of these soluble CAMs in BF is mainly the result of leucocyte expression and endothelial cell activation, but secretion also appears to mediate anti-inflammatory activities, moderating leucocyte adhesion and reducing in particular lymphocyte and monocyte infiltration. Only sL-selectin serum levels were found to correlate with the acute phase of infection characterized by fever.     

Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity.

Fatal Plasmodium falciparum malaria is accompanied by systemic endothelial activation. To study endothelial activation directly during malaria and sepsis in vivo, the expression of cell adhesion molecules on dermal microvascular endothelium was examined in skin biopsies and correlated with plasma levels of soluble (circulating) ICAM-1, E-selectin, and VCAM-1 and the cytokine tumor necrosis factor (TNF)-alpha. Skin biopsies were obtained from 61 cases of severe malaria, 42 cases of uncomplicated malaria, 10 cases of severe systemic sepsis, and 17 uninfected controls. Systemic endothelial activation, represented by the up-regulation of inducible cell adhesion molecules (CAMs) on endothelium and increased levels of soluble CAMs (sCAMs), were seen in both severe and uncomplicated malaria and sepsis when compared with uninfected controls. Plasma levels of sICAM-1, sVCAM-1, and sE-selectin correlated positively with the severity of malaria whereas TNF-alpha was raised nonspecifically in malaria and sepsis. Immunohistochemical evidence of endothelial activation in skin biopsies did not correlate with sCAM levels or disease severity. This indicates a background of systemic endothelial activation, which occurs in both mild and severe malaria and sepsis. The levels of sCAMs in malaria are thus not an accurate reflection of endothelial cell expression of CAMs in a particular vascular bed, and other factors must influence their levels during disease.