Biomedical subjects
Publications and source records attributed to S M Arend.
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We describe three patients with multifocal osteomyelitis caused by Mycobacterium avium and a family history of one or more first degree family members diagnosed with various clinical presentations of infections with nontuberculous mycobacteria. There was a significant delay in the diagnosis and they had a protracted course of their illness, which responded only slowly to prolonged multi-drug treatment. In one patient, additional treatment with interferon-gamma (IFN-gamma) was necessary. Macrophages of these patients had decreased in vitro responsiveness to IFN-gamma. Genomic sequencing revealed that these patients and their affected family members were heterozygous for a previously described dominant negative mutation in the gene encoding the IFN-gamma binding receptor-1 chain. The clinical presentations of the infections with nontuberculous mycobacteria in these families, with spread limited to skin, bone and lymph nodes, is discussed in the light of the immune mechanisms that are responsible for the clearance of otherwise poorly pathogenic environmental mycobacteria.
The tuberculin skin test (TST) is used for the identification of latent tuberculosis (TB) infection (LTBI) but lacks specificity in Mycobacterium bovis BCG-vaccinated individuals, who constitute an increasing proportion of TB patients and their contacts from regions where TB is endemic. In previous studies, T-cell responses to ESAT-6 and CFP-10, M. tuberculosis-specific antigens that are absent from BCG, were sensitive and specific for detection of active TB. We studied 44 close contacts of a patient with smear-positive pulmonary TB and compared the standard screening procedure for LTBI by TST or chest radiographs with T-cell responses to M. tuberculosis-specific and nonspecific antigens. Peripheral blood mononuclear cells were cocultured with ESAT-6, CFP-10, TB10.4 (each as recombinant antigen and as a mixture of overlapping synthetic peptides), M. tuberculosis sonicate, purified protein derivative (PPD), and short-term culture filtrate, using gamma interferon production as the response measure. LTBI screening was by TST in 36 participants and by chest radiographs in 8 persons. Nineteen contacts were categorized as TST negative, 12 were categorized as TST positive, and 5 had indeterminate TST results. Recombinant antigens and peptide mixtures gave similar results. Responses to TB10.4 were neither sensitive nor specific for LTBI. T-cell responses to ESAT-6 and CFP-10 were less sensitive for detection of LTBI than those to PPD (67 versus 100%) but considerably more specific (100 versus 72%). The specificity of the TST or in vitro responses to PPD will be even less when the proportion of BCG-vaccinated persons among TB contacts evaluated for LTBI increases.
SETTING: Leiden University Medical Center, Leiden, the Netherlands. OBJECTIVE: To illustrate the potential value of a recently developed diagnostic assay for detection of tuberculosis (TB), based on T cell responses to the early secreted antigenic target 6 kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10). These antigens are Mycobacterium tuberculosis specific because they are expressed by M. tuberculosis but absent from M. bovis bacille Calmette-Guérin (BCG) and most environmental mycobacteria. In recent studies, the assay had a high sensitivity and specificity for detection of active TB. DESIGN: We describe five patients with uncommon presentations of tuberculosis, in whom the diagnosis was delayed by negative or conflicting results of diagnostic procedures aimed at detection of M. tuberculosis and an uninformative tuberculin skin test. IFN-gamma production in response to ESAT-6 and CFP-10 by peripheral blood mononuclear cells from these patients was evaluated before and during anti-tuberculosis treatment. RESULTS: In all five patients, IFN-gamma responses to ESAT-6 and/or CFP-10 were above the cut-off level defined in a previous study. During treatment, IFN-gamma responses generally increased. CONCLUSION: These results indicate that T cell responses to M. tuberculosis-specific antigens have potential diagnostic value when TB is suspected and the results of other diagnostic tests are inconclusive, especially in BCG-vaccinated individuals.
The purified protein derivative (PPD) skin test has no predictive value for tuberculosis (TB) in Mycobacterium bovis bacillus Calmette-Guérin (BCG)-vaccinated individuals because of cross-reactive responses to nonspecific constituents of PPD. T cell responses to early-secreted antigenic target 6-kDa protein (ESAT-6) and the newly identified culture filtrate protein 10 (CFP-10), 2 proteins specifically expressed by M. tuberculosis (MTB) but not by BCG strains, were evaluated. Most TB patients responded to ESAT-6 (92%) or CFP-10 (89%). A minority of BCG-vaccinated individuals responded to both ESAT-6 and CFP-10, their history being consistent with latent infection with MTB in the presence of protective immunity. No responses were found in PPD-negative controls. The sensitivity and specificity of the assay were 84% and 100%, respectively, at a cutoff of 300 pg of interferon-gamma/mL. These data indicate that ESAT-6 and CFP-10 are promising antigens for highly specific immunodiagnosis of TB, even in BCG-vaccinated individuals.
The early secreted antigenic target 6-kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10) are promising antigens for reliable immunodiagnosis of tuberculosis. Both antigens are encoded by RD1, a genomic region present in all strains of Mycobacterium tuberculosis and M. bovis but lacking in all M. bovis bacillus Calmette-Guérin vaccine strains. Production and purification of recombinant antigens are laborious and costly, precluding rapid and large-scale testing. Aiming to develop alternative diagnostic reagents, we have investigated whether recombinant ESAT-6 (rESAT-6) and recombinant CFP-10 (rCFP-10) can be replaced with corresponding mixtures of overlapping peptides spanning the complete amino acid sequence of each antigen. Proliferation of M. tuberculosis-specific human T-cell lines in response to rESAT-6 and rCFP-10 and that in response to the corresponding peptide mixtures were almost completely correlated (r = 0.96, P < 0.0001 for ESAT-6; r = 0.98, P < 0.0001 for CFP-10). More importantly, the same was found when gamma interferon production by peripheral blood mononuclear cells in response to these stimuli was analyzed (r = 0.89, P < 0.0001 for ESAT-6; r = 0.89, P < 0.0001 for CFP-10). Whole protein antigens and the peptide mixtures resulted in identical sensitivity and specificity for detection of infection with M. tuberculosis. The peptides in each mixture contributing to the overall response varied between individuals with different HLA-DR types. Interestingly, responses to CFP-10 were significantly higher in the presence of HLA-DR15, which is the major subtype of DR2. These results show that mixtures of synthetic overlapping peptides have potency equivalent to that of whole ESAT-6 and CFP-10 for sensitive and specific detection of infection with M. tuberculosis, and peptides have the advantage of faster production at lower cost.
Between January 1996 and May 1997, a four-fold increased rate of isolation of Serratia marcescens was observed amongst patients admitted to the surgical Intensive Care Unit (SICU) of the Leiden University Medical Center compared to the preceding years. Random amplification of polymorphic DNA showed the involvement of genotypically distinct strains, implicating multiple different sources. After improvement of hygienic measures the frequency of isolation of S. marcescens returned to baseline. A case-control study was performed to assess patient-related risk factors for acquisition of S. marcescens. Nineteen cases and 38 controls were included. Hospital- and SICU-stay were significantly longer in case patients than in controls. By univariate analysis, statistically significant differences were found in body weight, the duration of mechanical ventilatory support, the cumulative use of antimicrobial agents, the use of aminoglycosides, parenteral nutrition and tube feeding. The sum of the number of days per invasive device (deep intravenous lines, arterial lines, wound drains and urinary catheters) was higher in cases than in controls (P = 0.08). Categorically, a cumulative number of device-days > 25 was a statistically significant risk factor for acquisition of S. marcescens. Multivariable logistic regression analysis showed that body weight, parenteral feeding and mechanical ventilation were independent predictors of acquisition of S. marcescens. As transmission of S. marcescens appears to be by the hands of personnel, the identified risk factors may act by necessitating an increased frequency and intensity of direct contacts.
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A 26-year-old man was admitted with abdominal pain, anemia, and hypertension. Ultrasonography and computed tomography revealed a perirenal hematoma. Soon after admission, the patient went into shock, and emergency angiography was performed. Two active bleeding sites were found in the left kidney and were successfully embolized. Also, multiple aneurysms, consistent with the diagnosis of classic polyarteritis nodosa, were seen. After treatment was initiated, the patient recovered fully. When a spontaneous perirenal hematoma is a presenting symptom of classic polyarteritis nodosa, a delay in making the right diagnosis is likely to occur. Angiography not only may provide a quick diagnosis, but it can also be used to perform therapeutic embolization. In patients with classic polyarteritis nodosa and hemorrhage from a ruptured aneurysm, angiography may be a therapeutic alternative to surgery.
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BACKGROUND: The determinators of patient survival after renal transplantation are incompletely known, and conflicting results have been reported. This may have been influenced by time-related changes in patient selection, post-transplantation management and immunosuppressive regimens. This study was performed to evaluate in recipients of a first renal transplant the effect of patient characteristics, transplantation era, and the immunosuppressive regimen on patient survival. METHODS: We used data from the Leiden Renal Transplant Database of all first renal transplantations performed between 1966 and 1994 in Leiden, the Netherlands. The effect of the following parameters on mortality was investigated: era of transplantation, sex, age at transplantation, cause of renal failure, immunosuppressive regimen, type and duration of pretransplantation dialysis, hypertension, diabetes mellitus, and smoking. In addition we analysed the causes of death. Results were expressed as crude mortality rates, relative risks of mortality, and standardized mortality ratios as compared with death rates in the Dutch population. RESULTS: The analysis comprised 86 living donor transplant recipients and 916 cadaver transplant recipients. After adjustment for age and sex, the relative risk of mortality for living donor transplant recipients compared with cadaver transplant recipients was 0.5 (95% CI 0.2 to 1.03, P = 0.06). In first cadaver kidney transplant recipients the risk of first-year mortality improved significantly with time, which coincided with the introduction of cyclosporin. The risk of mortality after the first year was higher in patients aged over 40 years at transplantation, men, smokers, and in the presence of hypertension or diabetes, but the effect of individual factors on mortality was small. We found no effect of the type of pretransplantation dialysis or the duration of pretransplantation haemodialysis on post-transplantation mortality. The standardized mortality ratio for recipients of first renal transplants was 14 times the population average in the first year after transplantation and was still four times in the remaining years. CONCLUSION: In the present study, time-related changes in patient management were responsible for improved patient survival in the first year after transplantation during the study period. Many individual factors contributed moderately to the risk of mortality after the first year. Compared to the general population the mortality rate of renal transplant recipients was significantly higher during the whole follow-up period.
Pneumocystis carinii pneumonia (PCP) is an infection of immunocompromised patients. The purpose of our study was to estimate the risk of PCP in renal transplant recipients in relation to number, timing, and type of rejection treatments and to cytomegalovirus (CMV) infection. In a case-control study, 15 renal transplant recipients with proven PCP were compared with 95 controls. The relative risks of PCP for 1, 2, and > or = 3 rejection treatments vs. no such treatment were 1.7 (95% CI, 0.2-12.5), 4.8 (95% CI, 0.9-25.5), and 9.5 (95% CI, 1.6-56.4). The relative risk of PCP for renal transplant recipients with negative pretransplantation CMV serology was 3.2 (95% CI, 1.0-10.2), and for the combination of recipient-negative and donor-positive pretransplantation CMV serology it was 5.7 (95% CI, 1.4-22.3). The relative risk of PCP for patients with CMV infection was 5.0 (95% CI, 1.6-15.8). The risk of PCP in renal transplant recipients was positively related to the number but not the timing or type of rejection treatments. The risk of PCP was also increased in cases of CMV infection, irrespective of the number of rejection treatments.
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Organic nitrates exert their effect by direct inhibition of vascular tone, resulting in decreased myocardial oxygen demand and improved oxygen supply. Less well known is the effect of nitrates on blood rheology. To evaluate the haemodiluting effect of intravenous nitroglycerin we studied 70 consecutive patients admitted to our coronary care unit. The study group consisted of 51 patients with acute chest pain who were treated with nitroglycerin intravenously in a dose between 1 and 5 mg.h-1 during the first 24 h of admission; 19 patients without this treatment were used as controls. In the study group, values of haemoglobin, haematocrit, serum protein and serum albumin, as indirect parameters of haemodilution, all decreased significantly within 24 h, irrespective of the final diagnosis. Similar values were found in the control group. The mean decrease in the haemoglobin value was 0.92 (SD = 0.55) mmol.l-1 vs controls -0.05 (SD = 0.48) mmol.l-1, P < 0.05; the mean decrease in haematocrit was 0.047 (SD = 0.032) vs controls 0.000 (SD = 0.023), P < 0.05. Similar decreases were found in serum protein and albumin values. It is concluded that intravenous nitroglycerin causes a significant decrease in haemoglobin and haematocrit values within 24 h of administration. This altered hemorheologic state may, besides the well known direct vascular effects of nitroglycerin, contribute to the protective effect of nitroglycerin in acute myocardial ischaemia. The effects of nitroglycerin, and the possible mechanisms underlying the decrease in haemoglobin and haematocrit values, will be discussed.
In this article clinical examples of extraskeletal localization of technetium-99m (99mTc)-labeled diphosphonate are described. In several of these cases this finding was relevant for clinical decision-making. 99mTc-labeled diphosphonates have been used for skeletal imaging since 1971, and from 1973 on many reports of extraskeletal localizations of these agents have been published. This visualization can be due to (1) an abnormality of the excretory route of 99mTc-labeled diphosphonate or (2) increased uptake in pathologically altered tissues and organs. The latter has been recorded in a multitude of disease processes, such as ischaemic injury, inflammatory processes, benign or malignant neoplasms, non-skeletal metastases, malignant pleuritis, scars, radiation injury and amyloidosis. Although the precise mechanism of extraskeletal uptake of 99mTc-labeled diphosphonate remains uncertain, binding of this radiopharmaceutical to calcium-containing compounds is thought to play a critical role.
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A 47-year old man presented with general malaise, pain in several joints and muscles, lymphadenopathy, livedo reticularis, an elevated sedimentation rate and mild pancytopenia. A positive ANF, anticardiolipin antibodies and circulating immune complexes raised suspicion of an autoimmune disease. A perivascular infiltrate in muscle and fascia was found, but a specific diagnosis could not be made. The patient appeared to be infected with the human immunodeficiency virus (HIV) type I, with the cellular immunity already decreased. During treatment with zidovudine the symptoms and signs diminished, suggesting a causal relation between the HIV infection and this clinical presentation. The rheumatic manifestations and autoimmune phenomena with which HIV infection can be associated are discussed.
Toxic shock syndrome (TSS) is a well-defined clinical syndrome attributed to certain exotoxins produced by Staphylococcus aureus. The acute episode is often characterized by a toxic encephalopathy, possibly caused by direct neurotoxicity of these exotoxins, although this mechanism has never been proven. We describe a patient who developed TSS, meningitis and cauda equina syndrome simultaneously several days after lumbar laminectomy. A space-occupying lesion was excluded. Enterotoxin C-producing S. aureus was cultured from the surgical wound and the cerebrospinal fluid (CSF). The patient recovered from TSS but remained partially paralyzed. Presumably the cauda equina syndrome was caused by neurotoxic effects of the intrathecally produced S. aureus exotoxins. This case provides evidence for the neurotoxic effects of TSS-associated S. aureus exotoxins.