The role of metabolomic markers for patients with infectious diseases: implications for risk stratification and therapeutic modulation

Introduction: Metabolomics is a rapidly growing area of research. Metabolomic markers can provide information about the interaction of different organ systems, and thereby improve the understanding of physio-pathological processes, disease risk, prognosis and therapy responsiveness in a variety of diseases.

Areas covered: In this narrative review of recent clinical studies investigating metabolomic markers in adult patients presenting with acute infectious disease, we mainly focused on patients with sepsis and lower respiratory tract infections. Currently, there is a growing body of literature showing that single metabolites from distinct metabolic pathways, as well as more complex metabolomic signatures are associated with disease severity and outcome in patients with systemic infections. These pathways include, among others, metabolomic markers of oxidative stress, steroid hormone and amino acid pathways, and nutritional markers.

Expert commentary: Metabolic profiling has great potential to optimize patient management, to provide new targets for individual therapy and thereby improve survival of patients. At this stage, research mainly focused on the identification of new predictive signatures and less on metabolic determinants to predict treatment response. The transition from observational studies to implementation of novel markers into clinical practice is the next crucial step to prove the usefulness of metabolomic markers in patient care.     

Abdominal infections in patients with acute leukaemia: a prospective study applying ultrasonography and microbiology

A prospective study of 62 chemotherapy-induced neutropenic episodes in patients with acute leukaemia was conducted to determine the incidence and causes of abdominal infections, and to assess the diagnostic value of the combined use of ultrasonography (US) and microbiology. Each patient underwent US of liver, gallbladder and complete bowel before chemotherapy, on days 2-4 after the end of chemotherapy and in cases of fever, diarrhoea or abdominal pain. US was combined with a standardized clinical examination and a broad spectrum of microbiological investigations. From January to August 2001, 243 US examinations were performed. The overall incidence of abdominal infectious diseases was 17.7% (11 out of 62, 95% confidence interval (CI): 9-29%). Four patients (6.5%) developed neutropenic enterocolitis; two of them died, two survived. Bowel wall thickening (BWT) > 4 mm in these four patients ranged from 5.8 to 23.6 mm and was detected only in one patient with mucositis. In three other patients (4.8%) Clostridium difficile, and in one patient (1.6%) Campylobacter jejuni, caused enterocolitis without BWT. Cholecystitis was diagnosed in three patients (4.8%) and hepatic candidiasis was strongly suspected in one patient. Abdominal infections caused by gastroenteritis viruses, cytomegalovirus (CMV) or Cryptosporidium were not observed. We conclude that in neutropenic patients with acute leukaemia receiving chemotherapy: (i) BWT is not a feature of chemotherapy-induced mucositis and should therefore be considered as sign of infectious enterocolitis; (ii) viruses, classic bacterial enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Aeromonas, Vibrio subsp., enterohaemorrhagic Escherichia coli) and Cryptosporidium have a very low incidence; and (iii) abdominal infections may be underestimated when US is not used in every patient with abdominal pain.     

Induction of proliferation of B prolymphocytic leukemia cells by phorbol ester and native or recombinant interferon-gamma

Phorbol ester phorbol myristate acetate (PMA) induces proliferation in nonmalignant human B cells and B cells from a patient with B prolymphocytic leukemia (B-PLL). Mitogen-free T cell-derived conditioned medium acts synergistically with PMA in inducing proliferation of B-PLL cells but does not enhance the PMA-stimulated outgrowth of nonmalignant B cells. Interleukin 2 (IL-2) has no effect on the outgrowth of B-PLL cells, and monoclonal antibodies against the IL-2 receptor do not influence the response to PMA and conditioned medium. Recombinant interferon-gamma (IFN-gamma), in contrast, is a potent enhancer of PMA-induced proliferation of B-PLL cells. With gel filtration techniques and with the use of anti-IFN-gamma antibodies, it is shown that IFN-gamma in the conditioned medium is responsible for the observed increase in B-PLL cell proliferation. Preincubation of B- PLL cells with IFN-gamma induces responsiveness to PMA, whereas IFN- gamma alone had no effect on these cells when pretreated with PMA. The combined data show that, in the presence of PMA, native and recombinant IFN-gamma are growth factors for B cells from a B-PLL patient and that IL-2 is not involved in this process.     

Coincidence of familial platelet glycoprotein Ib/IX deficiency (Bernard-Soulier syndrome), idiopathic autoantibody against platelet glycoprotein Ib/IX,familial appearence of antiphospholipid antibodies,and familial factor XII deficiency

Summary The case of an 8-year-old boy with apparently homozygous Bernard-Soulier syndrome (platelet GP Ib/IX complex deficiency) and a transient idiopathic autoantibody against GP Ib/IX is described. He had been diagnosed with chronic autoimmune thrombocytopenia (due to the detection of antiplatelet autoantibodies) before Bernard-Soulier syndrome was proven. Both parents and his brother displayed intermediate deficiency of GP Ib/IX, thus indicating a heterozygote state for Bernard-Soulier syndrome. Alloimmunization as an explanation for the appearance of GP Ib/IX antiplatelet antibodies in the propositus can be excluded. A so-called pseudo Bernard-Soulier syndrome due to selective antibodies was also excluded. Flow cytometric analysis revealed residual expression of 2% GP Ib and 13% GP IX on the propositus' platelets. It seems that the propositus showed an idiopathic autoantibody against a platelet glycoprotein in which he is genetically deficient (but which is not completely lacking). Thus, in patients with untypical behavior upon therapy of autoimmune thrombocytopenia, other differential diagnoses should also be considered even if antiplatelet antibodies are detected. In addition, all family members displayed elevated concentrations of antiphospholipid antibodies. These findings raise the question of a genetic predisposition for the development of autoantibodies. Moreover, an F. XII deficiency was found in all family members except the mother.     

Flottierender Riesenthrombus im offenen Foramen ovale Diagnose mittels transösophagealer Echokardiographie

Zusammenfassung Die Diagnose eines flottierenden Thrombus in einem offenen Foramen ovale wird selten gestellt. Wir berichten über einen Patienten, bei dem aufgrund des dringenden Verdachtes auf eine Pulmonalembolie eine trans?sophageale Echokardiographie (TEE) durchgeführt wurde. Mit Hilfe der TEE konnte der Verdacht der Pulmonalembolie erh?rtet werden. Als überraschungsbefund fand sich jedoch im rechten und linken Vorhof ein langer, wurmf?rmiger, sehr mobiler Thrombus, der im offenen Foramen ovale eingekeilt war. Der Patient wurde aufgrund dieser Diagnose unverzüglich einem chirurgischem Eingriff unterzogen, wobei sich der TEE-Befund best?tigte und ein 19 cm langer Thrombus entfernt wurde. Mit Hilfe der TEE konnte der Riesenthrombus erkannt und einer entsprechenden Therapie zugeführt werden, wodurch Komplikationen, wie das Auftreten einer neuerlichen Pulmonalembolie oder einer paradoxen Embolie, verhindert werden konnten. Eingegangen: 10. August 1998 Akzeptiert: 12. August 1998     

Impact of subclinical hypothyroidism on serum total homocysteine concentrations, the prevalence of coronary heart disease (CHD), and CHD risk factors in the New Mexico Elder Health Survey.

The serum/plasma total homocysteine (tHcy) concentration, now recognized as an independent risk factor for accelerated atherosclerotic disease, is increased in overtly hypothyroid patients, and it decreases with thyroid replacement therapy. Whether or not individuals with subclinical hypothyroidism also increase their tHcy concentrations, and whether this elevation might help to explain the increased prevalence of the atherosclerotic diseases observed in this condition, remains unclear. If individuals with subclinical hypothyroidism have higher tHcy concentrations than euthyroid subjects, there would be added incentive to treat this condition earlier. In this cross-sectional study (New Mexico Elder Health Survey) of a randomly selected sample of Medicare recipients (age > or =65 years), no significant difference in serum tHcy concentrations could be detected between the 112 participants with subclinical hypothyroidism (Groups 2 and 3) and the 643 participants with thyrotropin (TSH) values < or =4.6 microU/mL (Group 1) after adjusting for differences in gender, ethnicity, age, and serum concentrations of folate, vitamin B(12), and creatinine. Only those participants with the highest TSH levels (>10 microU/mL) (Group 3) had a significantly higher prevalence of coronary heart disease (CHD) when compared against Group 1 participants (p = 0.007). No consistent significant differences in the prevalences of CHD or in the CHD risk factors examined were observed when all participants with subclinical hypothyroidism (Groups 2 and 3 combined) were compared against Group 1 participants.     

Heterotopic abdominal heart transplantation: a pilot study

The increasingly severe shortage of donor hearts has prompted a liberalization of what is considered an acceptable donor heart. The use of marginally acceptable organs has increased in recent years. Although these marginal donors have proved effective, there still remains a tremendous shortage of donors to treat the large number of patients who are candidates for cardiac transplantation. Further use of marginal donors is limited by the requirement to assume immediate and full support of the circulation. New strategies are required to increase donor organ use even further. The authors developed a model of heterotopic abdominal heart transplant (HAHT) to investigate the possibility of using marginal donor hearts to expand the donor pool for cardiac transplantation. The authors' goal was to show that HAHT was technically feasible and could potentially function as auxiliary circulatory support in the setting of low cardiac output. The hemodynamic and metabolic consequences of a HAHT were investigated in a pilot study that provides proof of concept and lays the groundwork for future investigations.     

Intravascular ultrasound-guided creation of re-entry sites to improve intermittent claudication in patients with aortic dissection.

PURPOSE: To report percutaneous fenestration of aortic dissection flaps to relieve distal ischemia using a novel intravascular ultrasound (IVUS)-guided fenestration device. CASE REPORTS: Two men (47 and 62 years of age) with aortic dissection and intermittent claudication had percutaneous ultrasound-guided fenestration performed under local anesthesia. Using an ipsilateral transfemoral approach, the intimal flap was punctured under real-time IVUS guidance using a needle-catheter combination through which a guidewire was placed across the dissection flap into the false lumen. The fenestration was achieved using balloon catheters of increasing diameter introduced over the guidewire. Stenting of the re-entry was performed in 1 patient to equalize pressure across the dissection membrane in both lumens. The procedures were performed successfully and without complications. In both patients, ankle-brachial indexes improved from 0.76 to 1.07 and from 0.8 to 1.1, respectively. Both patients were without claudication at the 3- and 6-month follow-up examination. CONCLUSION: Percutaneous intravascular ultrasound-guided fenestration and stenting at the level of the iliac artery in aortic dissection patients with claudication is a technically feasible and safe procedure and relieves symptoms.     

Prevalence of proteinuria/microalbuminuria in an elderly urban, biethnic community

Introduction. The purpose of this study was to compare the prevalences of urinary abnormalities, notably proteinuria and microalbuminuria, in a randomly selected, biethnic population of Hispanic and nonHispanic white males and females and to determine the effects of diabetes, hypertension, and coronary heart disease on these prevalence rates. Methods. A survey of health and health related issues was conducted on 883 volunteers, mean age 74.1 years, selected randomly from the Medicare rolls of Bernallilo County (Albuquerque), New Mexico. The sample consisted of nearly equal numbers of Hispanic and nonHispanic white males and females. A dipstick urinalysis and test for microalbuminuria was performed on a clean void, untimed urine sample as a part of a 4-hour interview/examination. Results. Of the 696 participants with complete databases, 10.5% had 1+ or greater proteinuria (30 mg/dL or more) by convential urinalysis dipstick and 19.8% had microalbuminuria (50 mg/L or more) by Micral Chemstrip® methodology. Participants with diabetes mellitus (Odds Ratio (OR) 2.54, Confidence Interval (CI) 1.71–3.76, p < 0.001), and/or hypertension (OR 2.09, 95% CI 1.46–3.01, p < 0.001) were more likely to have microalbuminuria than participants without either of these conditions. After adjusting for the presence of diabetes and hypertension, there was a trend toward an increased prevalence of coronary heart disease (OR 1.23, 95% CI 0.84–1.81 p = 0.28) in those with microalbuminuria, but this did not reach levels of statistical significance. Conclusions. Hispanics, even after adjusting for a higher prevalence of diabetes, and for small differences in prevalences of hypertension and coronary heart disease, had more microalbuminuria than nonHispanic whites, and males had more microalbuminuria than females.