[Fever after travel to tropical regions: Malaria and other emergencies]. / Malaria und andere notfallmedizinische relevante Tropenerkrankungen mit dem Leitsymptom Fieber.

BACKGROUND: For people returning from the tropics, malaria is the most common cause of fever. Plasmodium falciparum causes the most common and most dangerous form of malaria, called malignant tertian malaria or falciparum malaria. METHOD: Search and evaluation of the current literature. RESULTS AND CONCLUSION: Over 90 % of all malaria cases and malaria deaths occur in Africa, while the remaining cases are divided between India, Southeast Asia, Oceania, and Latin America. In Germany, between 513 and 613 cases of malaria have been reportet annually over the last 10 years according to the Robert Koch Institute, including 389-541 cases of potentially fatal falciparum malaria (Plasmodium falciparum). All fever patients who have been in to the tropics during the last 4 months must be tested for malaria. However, immigrants from tropical regions might develop malaria even years after their last trip to their former home country. Rapid diagnostic tests are now available-particularly for falciparum malaria. However, the occasional negative or false-positive results are possible. The treatment of malaria depends on the Plasmodium species, the clinical severity, and the region in which the infection was acquired.

Pneumocystis jirovecii colonisation in HIV-positive and HIV-negative subjects in Cameroon.

OBJECTIVE: To determine the prevalence of Pneumocystis pneumonia (PCP), a major opportunistic infection in AIDS patients in Europe and the USA, in Cameroon. MATERIALS AND METHODS: Induced sputum samples from 237 patients without pulmonary symptoms (126 HIV-positive and 111 HIV-negative outpatients) treated at a regional hospital in Cameroon were examined for the prevalence of Pneumocystis jirovecii by specific nested polymerase chain reaction (nPCR) and staining methods. CD4 counts and the history of antiretroviral therapy of the subjects were obtained through the ESOPE database system. RESULTS AND CONCLUSION: Seventy-five of 237 study participants (31.6%) were colonised with Pneumocystis, but none showed active PCP. The Pneumocystis colonisation rate in HIV-positive subjects was more than double that of HIV-negative subjects (42.9% vs. 18.9%, P < 0.001). In the HIV-positive group, the colonisation rate corresponds to the reduction in the CD4 lymphocyte counts. Subjects with CD4 counts >500 cells/µl were colonised at a rate of 20.0%, subjects with CD4 counts between 200 and 500 cells/µl of 42.5%, and subjects with CD4 counts <200 cells/µl of 57.1%. Colonisation with Pneumocystis in Cameroon seems to be comparable to rates found in Western Europe. Prophylactic and therapeutic measures against Pneumocystis should be taken into account in HIV care in western Africa.

Hepatitis B and C: neglected diseases among health care workers in Cameroon.

BACKGROUND: Healthcare workers (HCW) are at risk of acquiring blood-borne viral infections, particularly hepatitis B (HBV), hepatitis C (HCV), and HIV, especially in high endemic regions such as sub-Saharan Africa. METHODS: Sera from 237 hospital workers in Southwest Cameroon were tested for anti-hepatitis B core antigen (anti-HBc), hepatitis B surface antigen (HBsAg), anti-hepatitis B surface antigen (anti-HBs), anti-HCV and (on a voluntary basis) for anti-HIV. Information on pre-study testing for HBV, HCV and HIV and pre-study HBV vaccination status was collected from these individuals. RESULTS: The pre-study testing rate among participating hospital staff for HBV was 23.6% (56/237), for HCV 16% (38/237), and for HIV 91.6% (217/237). The pre-study HBV vaccination rate was 12.3% (29/237). Analysis of anti-HBc revealed that 73.4% (174/237) of the hospital staff had been infected by HBV. Active HBV infection (HBsAg positivity) was detected in 15 participants. Anti-HCV was found in four of 237 participants, HIV antibodies were detected in four of 200 participants tested. CONCLUSION: HBV and HCV are neglected diseases among HCW in sub-Saharan Africa. The vaccination rate against HBV was very low at 12.3%, and therefore anti-HBc testing should be mandatory to identify HCW requiring HBV vaccination. Testing for HBV and routine HBV vaccination for HBV-negative HCW should be strongly enforced in Cameroon.

[Vaccinations in patients with immunodeficiency or immunosuppressive therapy]. / Impfen bei Immundefekten oder medikamentöser Immunsuppression.

Patients with immunodeficiency and patients under immunosuppressive therapy have an increased risk of infectious diseases. Vaccination strategies are needed to protect them from preventable diseases. The underlying disease and severity of the immune impairment may have influence on indications and contra-indications of vaccines. Inactivated vaccines can be administered safely according to the current recommendations of the Permanent Commission on Vaccinations of the Robert-Koch-Institut in Berlin, Germany (STIKO). Depending on the severity of the immune dysfunction, antibody response to vaccinations varies. Where possible, the antibody response following vaccinations should be tested. Previously, attenuated live vaccines were considered to be strictly contra-indicated in immunocompromised patients. Today, the administration of attenuated live vaccines is thought to be possible, depending on the degree and type of immunodeficiency or immunosuppression of the individual.

[Factitious recurrent septicemia and gastrointestinal corrosive burns]. / Rezidivierende Septikämien und gastrointestinale Verätzung.

HISTORY AND ADMISSION FINDINGS: A 39-year-old woman was admitted for the treatment of recurrent septicemia, corrosive esophageal and gastric mucosal injury, and bloody stools. INVESTIGATIONS: A search of her hospital room provided evidence of a self-inflicted disorder. Bacteremia with typical fecal flora had been caused by self-injected intravenous inoculation of stool and the esophageal ulcers by swallowed vinegar. TREATMENT AND COURSE: The patient was initially treated with meropenem. After initial clinical and psychological stabilization the patient refused further psychiatric or psychosomatic treatment. CONCLUSION: Fluctuating or bizarre symptoms and unusual diagnostic findings may indicate self-inflicted disorders, in which the symptoms of illness are caused by the afflicted person him/herself.

Imaging performance of the hybrid pixel detectors XPAD3-S.

Hybrid pixel detectors, originally developed for tracking particles in high-energy physics experiments, have recently been used in material sciences and macromolecular crystallography. Their capability to count single photons and to apply a threshold on the photon energy suggests that they could be optimal digital x-ray detectors in low energy beams such as for small animal computed tomography (CT). To investigate this issue, we have studied the imaging performance of photon counting hybrid pixel detectors based on the XPAD3-S chip. Two detectors are considered, connected either to a Si or to a CdTe sensor, the latter being of interest for its higher efficiency. Both a standard 'International Electrotechnical Commission' (IEC) mammography beam and a beam used for mouse CT results published in the literature are employed. The detector stability, linearity and noise are investigated as a function of the dose for several imaging exposures ( approximately 0.1-400 microGy). The perfect linearity of both detectors is confirmed, but an increase in internal noise for counting statistics higher than approximately 5000 photons has been found, corresponding to exposures above approximately 110 microGy and approximately 50 microGy for the Si and CdTe sensors, respectively. The noise power spectrum (NPS), the modulation transfer function (MTF) and the detective quantum efficiency (DQE) are then measured for two energy threshold configurations (5 keV and 18 keV) and three doses ( approximately 3, 30 and 300 microGy), in order to obtain a complete estimation of the detector performances. In general, the CdTe sensor shows a clear superiority with a maximal DQE(0) of approximately 1, thanks to its high efficiency ( approximately 100%). The DQE of the Si sensor is more dependent on the radiation quality, due to the energy dependence of its efficiency its maximum is approximately 0.4 with respect to the softer radiation. Finally, we compare the XPAD3-S DQE with published curves of other digital devices in a similar radiation condition. The XPAD3-S/CdTe detector appears to be the best with the highest DQE at low frequency, although some improvements are expected to reduce the increase of noise with the counts statistics and to guarantee a better stability of the detector response.

[Global warming: trailblazer for tropical infections in Germany?]. / Globale Erwärmung: Wegbereiter für tropische Infektionskrankheiten in Deutschland?

Since 1850, the CO (2) content of the atmosphere has increased from 280 to 360 ppm, and the average surface temperature has risen from 14.6 to 15.3 C . A further increase between 1.8 and 4.0 C is expected for the 21st century. Temperate and cold climate zones are affected predominantly, but tropical regions are not spared. At the same time, the world wide climate effects of the "El Niño Southern Oscillation" are amplified. Global warming enhances the growth of tropical pathogens (malarial plasmodia, leishmania, yellow fever virus, dengue virus, West Nile virus, Vibrio cholerae) and vectors (anopheles, aedes, culex, and phlebotomus mosquitos; hard ticks). Global warming may lead to the emergence of diseases which at present are not endemic in Germany, like West Nile fever, Dengue fever, or Leishmaniases, and to enhanced transmission of borreliosis and tick-borne encephalitis. Malaria and cholera, in contrast, are influenced more strongly by socioeconomic factors. Improved surveillance and intensified research on the relationship between climate change and infectious diseases is needed.

[A case of autochthonous early summer meningoencephalitis in Mecklenberg-Western Pomerania]. / Ein Fall einer autochthonen Frühsommermeningoenzephalitis (FSME) in Mecklenburg-Vorpommern.

HISTORY: A 61-year-old man was bitten by a tick at Lake Woblitz, near the town of Neustrelitz in former East Germany. Nine days later he saw his general practitioner because of fever and headache. Three weeks after the tick bite he was hospitalized with fever (39.2 degrees C) and mental confusion. Because he had taken a Nile cruise six months earlier, malaria was considered and he was transferred to the department of tropical medicine and infectious diseases of the University of Rostock. INVESTIGATIONS: The patient was somnolent, his speech was slurred, and he had amnesic aphasia, as well as impaired fine motor control, but no meningism, focal signs, pyramidal tract or sensory impairment. Cerebrospinal fluid (CSF) showed mild lymphocytosis (9,400 leukocytes per microL; 89% lymphocytes) and elevated protein concentration (1322 mg/L) with blood brain barrier impairment and intrathecal IgM synthesis. Anti-tick-bite encephalitis (TBE) antibodies (ELISA: IgG and IgM) were present in serum and CSF, and serum immunofluorescence showed an eight-fold titer increase within two weeks. These findings confirm the diagnosis of TBE. Other infections (including those with cross-reacting flaviviruses) were excluded by appropriate antibody testing. THERAPY AND CLINICAL COURSE: There is no specific antiviral treatment for TBE, but on symptomatic therapy the patient recovered fully within four weeks. CONCLUSION: The site of the patient's infection is located 10 km to the west of an old TBE focus, but no TBE virus had been detected there after 1975. The case demonstrates that TBE should be included in the differential diagnosis of meningoencephalitis, even if the patient has not been in an acknowledged TBE endemic area.

Circulating concentrations of cardiac proteins in complicated and uncomplicated Plasmodium falciparum malaria.

In an unmatched case-control study of 63 non-immune European patients with uncomplicated (n = 52) and complicated (n = 11) falciparum malaria, serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), myoglobin, troponin T and creatin kinase-muscle brain were compared. Elevated levels of NT-proBNP and H-FABP indicated myocardial impairment in complicated but not in uncomplicated falciparum malaria. The clinical impact of these findings remains to be evaluated. The pathophysiology of cardiac impairment in complicated falciparum malaria warrants further investigation.

Increased levels of soluble Fas ligand in serum in Plasmodium falciparum malaria.

Levels of soluble Fas ligand (sFasL) in serum were elevated in patients with Plasmodium falciparum malaria and showed a significant decline during disease course. sFasL levels that were elevated before antimalarial treatment began correlated significantly with depressed total lymphocyte and T-cell counts. These data suggest that Fas-induced apoptosis might play a role in malaria-associated lymphopenia.

High levels of inducible nitric oxide synthase mRNA are associated with increased monocyte counts in blood and have a beneficial role in Plasmodium falciparum malaria.

To date, there have been conflicting reports concerning the clinical significance of nitric oxide (NO) in Plasmodium falciparum malaria. Some authors have proposed that NO contributes to the development of severe and complicated malaria, while others have argued that NO has a protective role. To investigate these apparently contradictory reports, reverse transcription-coupled PCR was used to study inducible NO synthase (iNOS) in whole-blood RNA samples from patients with severe and complicated malaria or uncomplicated malaria and from healthy donors. This work produced three principal findings. First, samples of patients with severe and complicated malaria were variably positive, with weak to moderate intensity. Markedly higher iNOS RNA levels were observed in samples of patients with uncomplicated malaria than in patients with severe and complicated malaria. Samples of healthy donors were uniformly negative. Second, since we initially demonstrated iNOS expression in whole-blood RNA samples, we extended our investigations to individual blood cells such as monocytes, lymphocytes, neutrophils, and platelets to identify the cellular source of iNOS. We found that iNOS was expressed predominantly in monocytes. Third, retrospective statistical analysis of monocyte counts clearly demonstrated that patients with uncomplicated malaria had higher monocyte counts at the time of presentation than patients with severe and complicated malaria. Taken together, our findings give room to the interpretation that NO may have a beneficial rather than a deleterious role in falciparum malaria.

Low levels of fibrin-stabilizing factor (factor XIII) in human Plasmodium falciparum malaria: correlation with clinical severity.

Plasmodium falciparum malaria is associated with procoagulant activity but not with thromboembolism. We measured coagulation factor XIII, i.e., fibrin-stabilizing factor, in 45 patients with falciparum malaria over time. Of these, 22 had organ complications. The factor XIII antigen (subunits A and B) and plasma activity levels were abnormally low in those with falciparum malaria. They increased during antiparasitic therapy. In 14 of 22 patients with complications, but in no patient with mild disease (P < 0.001), subunit A and activity was < 50%. The factor X.III levels were inversely correlated with clinical severity, parasitemia, and human neutrophil elastase (HNE), but not with thrombin-antithrombin III levels. Thus, low factor XIII levels may reflect proteolysis by HNE, rather than procoagulant activity. One could speculate that factor XIII degradation in severe malaria prevents thromboembolism. On the other hand, factor XIII deficiency might reduce protection of the vascular endothelium against HNE and reactive oxygen species, which would promote organ damage.

Supportive pentoxifylline in falciparum malaria: no effect on tumor necrosis factor alpha levels or clinical outcome: a prospective, randomized, placebo-controlled study.

Pentoxifylline (POF) may suppress overproduction of tumor necrosis factor alpha (TNF alpha), which is thought to contribute to complications of human falciparum malaria. However, POF is believed to improve impaired capillary blood flow, which can be impaired in falciparum malaria. To test whether POF affects TNF alpha serum levels or other variables in this disease, we administered POF (20 mg/kg/day intravenously in 150 ml of saline for five days) randomized versus placebo (150 ml of saline without POF) in addition to standard antimalarial therapy. After recruitment of 51 patients with Plasmodium falciparum malaria, those receiving POF had more nausea and abdominal discomfort than the placebo group, as expected. Eleven of 27 patients receiving POF and three of 24 patients receiving placebo requested termination of the study medication (P < 0.05). Pentoxifylline did not change the decrease of TNF alpha levels or affect the clinical course in a significant way. Since POF failed to improve the clinical situation or to impact numerous laboratory parameters (including TNF alpha, thrombin-antithrombin III, thrombomodulin, and human neutrophil elastase), the study was terminated earlier than planned. While this study does not specifically address cerebral complications of malaria, the results suggest that POF is not useful as a routine adjunct to the standard therapy of falciparum malaria.

Sera from patients with falciparum malaria induce substance P gene expression in cultured human brain microvascular endothelial cells.

Substance P is a pluripotent neuropeptide capable of inducing neurogenic inflammation, immunoregulation, and vasodilatation. In an effort to contribute to the understanding of the pathophysiology of cerebral malaria, we have evaluated the effects of sera obtained from patients suffering from severe or mild malaria and from a healthy donor with no previous history of exposure to malaria on the expression of the substance P gene by cultured human brain microvascular endothelial cells (HBMEC) and human umbilical-vein endothelial cells. PCR, Southern blotting, hybridization with an internal probe, and densitometry demonstrated that treatment of HBMEC with sera from patients with severe malaria caused remarkably increased expression of the substance P gene. In HBMEC, substance P was not significantly influenced by serum from a healthy donor. Substance P was expressed at almost undetectable levels in untreated HBMEC. Treatment of cultured human umbilical-vein endothelial cells with the same sera produced no signal. The influence of different sera on the expression of substance P by HBMEC suggests that substance P expression may be involved in events leading to the development of severe malaria.

Comparison of spiral CT scan and arteriography for evaluation of renal and visceral arteries.

Renal and visceral artery images obtained concurrently with spiral CT and conventional arteriography were compared for 32 patients. Indications for imaging were occlusive disease (n = 12), aneurysmal disease (n = 9), and renal or visceral artery disease (n = 11). Conventional arteriography enabled visualization of 64 renal arteries and 15 accessory renal arteries. Lateral aortograms obtained in 15 patients enabled visualization of 14 superior mesenteric (SMA) and 14 celiac arteries. Spiral CT enabled visualization of 60 renal arteries, 12 accessory renal arteries, 27 SMAs, and 22 celiac arteries. Calcification or a disparity in timing of contrast material injection and scanning prevented visualization of the celiac artery in 10 patients and the SMA in four patients. With conventional arteriography as the standard for comparison, spiral CT had a sensitivity of 67% and a specificity of 95% for depiction of at least 75% stenosis in the main renal artery. By means of the Pearson correlation coefficient, significant correlation (p < 0.001) was confirmed between spiral CT and arteriography for evaluation of stenosis of the main renal artery, SMA, and celiac artery. This early experience suggests that spiral CT may be useful in evaluation of renal and visceral arteries and their relationship to aortic disease.

Antiparasitic treatment of patients with P. falciparum malaria reduces the ability of patient serum to induce tissue factor by decreasing NF-kappa B activation.

Serum from patients with P. falciparum malaria at day 1 (pretherapy) induces tissue factor (TF) in cultured endothelial cells. TF induction depends on de novo transcription as shown in Nuclear Run On assays. Electrophoretic mobility shift assays demonstrated binding of AP-1 and NF-kappa B/Rel proteins to their recognition sites in the TF promotor. After therapy (day 28), stimulation of TF antigen by patient serum is reduced by 70%. When serum obtained before and after therapy was compared, a decrease of NF-kappa B activation was evident. Activation of NF-kappa B-like proteins was in part dependent on TNF alpha in patient serum, since a TNF alpha neutralizing antibody reduced induction of TF transcription and translation and induction of NF-kappa B-like proteins. Induction of TF activity was suppressed by pDTC, an inhibitor of NF-kappa B activation. When different promotor constructs of the TF gene were tested, induction was dependent upon the presence of the intact NF-kappa B-like binding site in the TF promotor. A mutant with deleted NF-kappa B, but intact AP-1 sites was not inducible. Mutation of the AP-1 sites did not prevent induction, but reduced inducibility by pretherapy serum. Therefore, NF-kappa B/Rel proteins are responsible for induction of TF transcription by pretherapy serum, but AP-1 is needed for highest inducibility. The effect of antiparasitic therapy on the induction of TF by serum from patients with complicated P. falciparum malaria is dependent on a therapy-mediated loss of activation of NF-kappa B-like proteins in post-treatment patient serum.

Elevated thrombomodulin plasma levels as a result of endothelial involvement in plasmodium falciparum malaria.

We used thrombomodulin (TM) to assess the participation of the vascular endothelium in human Plasmodium falciparum (P.F.) malaria. Before therapy TM plasma levels were elevated in P.F. malaria and fell to normal values during therapy. Parasitemia, TNF alpha, elastase and TAT levels correlated directly with TM. Elevated TM levels can not be explained by increased synthesis, since incubating HUVEC with pretherapy serum of patients with P.F. malaria, but not reconvalescence serum, suppressed TM transcription. This was partially prevented by adding a TNF alpha neutralizing antibody to patient serum before incubation with HUVEC. However, TNF alpha does not release TM from cultured HUVEC in vitro. Coincubation of HUVEC with pretherapy serum together with neutrophils resulted in endothelial cell destruction, which could be partly prevented by a TNF alpha neutralizing antibody. Hence the increase of TM during P.F. malaria might reflect the concerted action of cytokines and neutrophils on HUVEC.

Inappropriate secretion of antidiuretic hormone and hyponatremia in severe falciparum malaria.

Overhydration can contribute to fatal complications of falciparum malaria, even though renal function may be normal. In this context, the role of inappropriate secretion of antidiuretic hormone (ADH) has been controversial. Therefore, we have analyzed ADH serum concentrations together with serum osmolality and sodium levels in serum and urine of 17 consecutively studied patients with severe falciparum malaria. Serum sodium levels were low in 13 of 17 patients upon admission and returned to normal levels during antiparasitic therapy. Urine sodium levels were low in seven of 13 patients before treatment and increased during therapy. Urine sodium concentrations were high, however, in the remaining six patients. Serum osmolality was lower in these six patients than in the other seven hyponatremic patients (P < 0.002). In relation to serum osmolality, ADH levels were inappropriately high in these six patients, which confirms the presence of inappropriate secretion of ADH. Serum creatinine levels were not higher in these six patients than in those without inappropriate secretion of ADH. Inappropriate secretion of ADH seemed to be a major cause of hyponatremia, since other factors that could lead to this condition were not found in these six patients. In conclusion, we have shown, that human falciparum malaria can be associated with inappropriate secretion of ADH.

Vascular origin of Kaposi's sarcoma. Expression of leukocyte adhesion molecule-1, thrombomodulin, and tissue factor.

We studied seven cases of Kaposi's sarcomas (KS) obtained from patients with AIDS and one KS from a patient without HIV infection. Antigen expression was studied by immunocytochemistry and mRNA expression by in situ hybridisation. The markers tested were endothelial leukocyte adhesion molecule-1, thrombomodulin, and tissue factor. In all tumors (AIDS and non-AIDS associated) these markers reacted positive, indicating transcription and translation of these genes in KS. The synthesis and expression of tissue factor and thrombomodulin suggests that KS is a tumor that has tissue factor-mediated thrombin formation under the control of thrombomodulin. The expression of thrombomodulin and endothelial leukocyte adhesion molecule-1 provides evidence for the vascular origin of KS.