A critical assessment of the association between postnatal toxoplasmosis and epilepsy in immune-competent patients.

While postnatal toxoplasmosis in immune-competent patients is generally considered a self-limiting and mild illness, it has been associated with a variety of more severe clinical manifestations. The causal relation with some manifestations, e.g. myocarditis, has been microbiologically proven, but this is not unequivocally so for other reported associations, such as with epilepsy. We aimed to systematically assess causality between postnatal toxoplasmosis and epilepsy in immune-competent patients. A literature search was performed. The Bradford Hill criteria for causality were used to score selected articles for each component of causality. Using an arbitrary but defined scoring system, the maximal score was 15 points (13 for case reports). Of 704 articles, five case reports or series and five case-control studies were selected. The strongest evidence for a causal relation was provided by two case reports and one case-control study, with a maximal causality score of, respectively, 9/13, 10/13 and 10/15. The remaining studies had a median causality score of 7 (range 5-9). No selection bias was identified, but 6/10 studies contained potential confounders (it was unsure whether the infection was pre- or postnatal acquired, or immunodeficiency was not specifically excluded). Based on the evaluation of the available literature, although scanty and of limited quality, a causal relationship between postnatal toxoplasmosis and epilepsy seems possible. More definite proof requires further research, e.g. by performing Toxoplasma serology in all de novo epilepsy cases.

General practitioner reported incidence of Lyme carditis in the Netherlands.

BACKGROUND: Between 1994 and 2009, incidence rates of general practitioner (GP) consultations for tick bites and erythema migrans, the most common early manifestation of Lyme borreliosis, have increased substantially in the Netherlands. The current article aims to estimate and validate the incidence of GP-reported Lyme carditis in the Netherlands. METHODS: We sent a questionnaire to all GPs in the Netherlands on clinical diagnoses of Lyme borreliosis in 2009 and 2010. To validate and adjust the obtained incidence rate, medical records of cases of Lyme carditis reported by GPs in this incidence survey were reviewed and categorised according to likelihood of the diagnosis of Lyme carditis. RESULTS: Lyme carditis occurred in 0.2 % of all patients with GP-reported Lyme borreliosis. The adjusted annual incidence was six GP-reported cases of Lyme carditis per 10 million inhabitants, i.e. approximately ten cases per year in 2009 and 2010. CONCLUSIONS: We report the first incidence estimate for Lyme carditis in the Netherlands, validated by a systematic review of the medical records. Although Lyme carditis is an uncommon manifestation of Lyme borreliosis, physicians need to be aware of this diagnosis, in particular in countries where the incidence of Lyme borreliosis has increased during the past decades.

Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts.

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-gamma release assays (IGRAs), QuantiFERON-TB Gold In-tube (QFT-GIT) and T-SPOT.TB, and the tuberculin skin test (TST) in immigrants contacts. Immigrant close contacts of sputum smear-positive TB patients were included when aged > or =16 yrs and their TST result was > or =5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease. Of 339 immigrant contacts with TST > or =5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3-5.0%) for TST > or =10 mm, 7/184 = 3.8% (95% CI 1.7-5.9%) for TST > or =15 mm, 5/178 = 2.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3-5.3%) for T-SPOT.TB. Sensitivity was 100%, 88%, 63% and 75%, respectively. The predictive values of QFT-GIT, T-SPOT.TB and TST for progression to TB disease among immigrant close contacts were comparable.

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement.

Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-gamma release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection. In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

Interferon-gamma release assays in immigrant contacts and effect of remote exposure to Mycobacterium tuberculosis.

OBJECTIVE: To assess the association between remote exposure to tuberculosis (TB) and results of the tuberculin skin test (TST), and two interferon-gamma release assays (IGRAs)-QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB-in immigrant contacts of sputum smear-positive TB patients. METHODS: Immigrants aged >or=16 years in close contact with smear-positive TB patients were included. QFT-GIT and T-SPOT.TB were performed if the TST induration size was >or=5 mm. Associations between test results and origin from an endemic country were assessed. RESULTS: Of 433 close contacts, 322 (74%) had TST >or=5 mm, of whom, 282 (88%) had valid test results for all assays. Positive QFT-GIT results were obtained for 152/282 (54%) and positive T-SPOT.TB for 168/282 (60%). After adjustment for age, sex and recent contact, positive IGRA results and TST results >/=10 mm were found to be more frequent among immigrants who originated from Africa, in particular sub-Saharan Africa. CONCLUSION: When IGRAs are used to determine latent TB infection in foreign-born individuals, positive findings not only relate to recent TB infection, but also reflect prior TB exposure in the country of origin. This late reactivity will limit their usefulness in contact investigations among immigrants originating from endemic areas.

Interferon-gamma release assays during follow-up of tuberculin skin test-positive contacts.

SETTING: Following a large-scale contact investigation, individuals with a positive tuberculin skin test (TST) result were offered preventive tuberculosis treatment. OBJECTIVE: To investigate the effect of isoniazid (INH) treatment and the effect of time on interferon gamma release assay (IGRA) results during follow-up. DESIGN: TST-positive subjects (n = 122) detected during the large-scale contact investigation were included in the study. Blood was obtained every 6 months over 2 years to perform both tests. RESULTS: Preventive INH treatment was completed by 36 of the 122 (29.5%) subjects, 71 (58.2%) were followed up with 6-monthly X-ray screening and 15 (12.3%) did not complete INH treatment. The overall percentage of individuals with a positive result remained stable during the 2 years, at approximately 45-50%, but individual responses varied over time. The majority of initially low IGRA results remained below the cut-off value, initially high IGRA results remained positive, while initially intermediate IGRA results were followed by more dynamic patterns. CONCLUSION: This study showed a highly variable pattern of IGRA responses over time and suggests limited value for their use during follow-up of latently infected individuals. However, the significance of different kinetic patterns observed among subjects with intermediate initial IGRA results warrants further study.

Rifampin levels in daily practice: the accuracy of a single measurement.

BACKGROUND: Measurement of rifampin levels is not part of routine practice. However, low levels are associated with failure of tuberculosis treatment. The clinical relevance of serum levels in daily practice is unclear. The objective was to evaluate rifampin serum concentrations and factors associated with insufficient concentrations. METHODS: Patients with at least one rifampin concentration drawn 3 hours after intake (C3) between 2005 and 2014 were included. Data on demographic and clinical characteristics were collected, including side effects and dose adjustments. Two different criteria were used to define adequate concentrations (criterion 1: C3 a nd C 6 ≥ 3 mg/l; criterion 2: C3 or C6 ≥ 5 mg/l). RESULTS: Of 63 patients, 66% and 76% had a sufficient level according to criterion 1 or 2, respectively. C3 exceeded C6 in most patients, while a late maximum was significantly associated with diabetes mellitus (p = 0.003). A dose adjustment was made in 19% of cases, more frequently in patients with insufficient levels (p = 0.02) or with ≥ 2 side effects (p = 0.03). CONCLUSION: Rifampin levels varied but were mostly adequate and a single measurement at 3 hours after intake provided the required information in most cases, indicating that full AUC0-24 measurements could be limited to specific situations.

Diagnostic imaging of hepatic tuberculosis: case series.

BACKGROUND: Hepatic tuberculosis (TB) shows non-specific symptoms, and liver imaging may provide diagnostic clues. Here we describe a series of patients with hepatic TB showing characteristic radiological findings. METHODS: Single-centre retrospective evaluation of patients with hepatic TB diagnosed over a period of 16 years who underwent ultrasound, computed tomography (CT) and/or magnetic resonance imaging (MRI). Hepatic lesions were classified as miliary, nodular, serohepatic or cholangitis. RESULTS: Of 14 patients with hepatic TB, five were co-infected with the human immunodeficiency virus. All patients had additional extrahepatic TB localisations. An interferon-gamma release assay was performed in 11/14 patients, ultrasound and CT were available for all patients and MRI for four. Observed patterns were miliary (n = 6) with multiple nodules < 2 cm; nodular (n = 5), characterised by a variable number of nodules (2-7 cm); and serohepatic (n = 3), with multiple nodular subcapsular lesions with a thin, smooth wall. Shared findings were hypoechoic lesions on ultrasound, hypodense lesions with ring enhancement on CT, while MRI lesions were hypointense on T1- and hyperintense on T2-weighted images. CONCLUSIONS: Ultrasound, CT and MRI can independently contribute to detection of hepatic TB. While a miliary pattern or calcifications are characteristic, no pattern is completely pathognomonic and the diagnosis depends on microbiological evidence. Particularly in risk groups, characteristic radiological findings may prompt targeted diagnostic work-up.

Donor-derived tuberculosis via orthotopic liver transplantation.

We present a case of donor-derived tuberculosis after liver transplantation, in which the donor origin of the Mycobacterium tuberculosis isolate was made most likely by DNA fingerprinting. Screening for latent tuberculosis of transplant donors originating from high endemic areas with an ex-vivo interferon-gamma release assay should be considered.

Risk factors of acute hepatic failure during antituberculosis treatment: two cases and literature review.

Hepatotoxicity is a well-known side effect of antituberculosis treatment (ATT). If not recognised in time, drug-induced hepatitis can develop, which may rapidly progress to acute liver failure. We describe two patients with acute hepatic failure caused by ATT, whose pretreatment liver function had been normal. Both patients successfully underwent liver transplantation. Possible risk factors predisposing towards ATT-induced hepatic failure were evaluated, and at least four risk factors were present in these patients. Although available guidelines do not advocate routine monitoring of liver function during ATT unless baseline values are elevated or in the case of pre-existent liver disease, this is nevertheless common practice. Liver function should always be measured in patients who develop symptoms during ATT, and rising liver function parameters should prompt immediate action to prevent the occurrence of liver failure. This report underscores that regular monitoring of liver function parameters and adherence to guidelines is especially important in patients with risk factors for ATT-induced liver disease. An evaluation of chronic viral hepatitis in risk groups before starting ATT could be worthwhile.

Pneumocystis carinii pneumonia in patients without AIDS, 1980 through 1993. An analysis of 78 cases.

BACKGROUND: Pneumocystis carinii pneumonia (PCP) occurs in immunocompromised patients without the acquired immunodeficiency syndrome (AIDS). There has been an increasing yearly number of cases of PCP in our patients without AIDS. OBJECTIVE: To determine the nature of the underlying disorder and previous immunosuppressive treatment in patients with PCP without AIDS. METHOD: A study of the charts of 78 such patients admitted to our hospital from 1980 through 1993. RESULTS: The number of PCP cases per year increased during the period studied. All patients had an underlying disorder, either hematologic malignancy (49%), solid organ tumor (4%), vasculitis or other immunologic disorder (22%), or they had undergone renal transplantation (17%) or bone marrow transplantation (9%). Previous immunosuppressive medication consisted of prednisone or other corticosteroids in 72 (92%) of 78 patients, cytotoxic drugs in 55 (71%) of 78 patients, both in 50 (64%) of 78 patients, and none in one patient. Quantification of previous corticosteroid treatment showed a large variability among patients. The overall mortality rate for patients was 35% (27/78). Mortality was significantly higher in patients with a concomitant pulmonary infection (P = .01), an underlying disorder other than that which resulted in renal transplantation (P = .03), mechanical ventilation (P < .001), previous chemotherapy (P = .04), as well as previous cyclophosphamide treatment (P = .01). A trend toward a higher mortality in patients with previous corticosteroid use was detected (P = .06). CONCLUSION: Pneumocystis carinii pneumonia may complicate a variety of immunocompromised states, with considerable mortality. Pneumocystis carinii pneumonia occurred at all levels of immunosuppression; no threshold level could be defined.

Embolization of a ruptured aneurysm in classic polyarteritis nodosa presenting as perirenal hematoma.

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.

[Two patients with tuberculous pleurisy]. / Pleuritis tuberculosa bij 2 patiënten.

Tuberculous pleurisy was diagnosed in two patients, a 21-year-old Somali woman and a 19-year-old Surinam man. The first patient suffered from a paradoxical (immunological) reaction and the other had an infectious reaction. Both patients recovered after treatment with tuberculostatic agents and pleural drainage. The pathophysiology of the paradoxical reaction is still largely unclear. Culture continues to be the gold standard in diagnosing tuberculous pleuritis but, in many cases, bacteriological confirmation is not obtained. The (probable) diagnosis is then often made on the basis of a combination of the patient's history, estimation of the risk, physical examination, radiology and histology, and on the basis of a (trial) treatment with tuberculostatic agents. In the diagnostic process, a PCR on the Mycobacterium tuberculosis complex can be helpful. The routine determination of adenosine deaminase and interferon gamma in patients with tuberculous pleurisy is not useful in low-incidence countries such as The Netherlands. The measurement of the in-vitro T-cell reactivity against M. tuberculosis-specific antigens may be of more value in the future. The pharmacotherapy of tuberculous pleurisy is the same as that of pulmonary tuberculosis. Rinsing the pleural cavity is recommended in the case of an infectious reaction. Drainage of pleural fluid is indicated in the case of a paradoxical reaction if there are mechanical difficulties.

Pneumonia caused by Mycobacterium kansasii in a series of patients without recognised immune defect.

The clinical and epidemiological characteristics of 17 patients diagnosed with Mycobacterium kansasii pneumonia within a limited geographical region over a period of 10 years are described. An in-depth evaluation of the innate and adaptive immune systems was performed for five available patients. A comparison was made of the genetic fingerprint patterns of the isolates obtained by restriction fragment length polymorphism (RFLP) analysis, with the major polymorphic tandem repeat (MPTR) as a probe. Predisposing factors consisted of smoking, airway abnormalities, substance abuse, diabetes or poor general condition, but in two patients no risk factor was identified. In the five patients tested, no abnormalities or deficiencies were detected in the innate or adaptive type-1 immunity. All M. kansasii isolates had identical MPTR RFLP patterns, although no epidemiological connection could be established, and these were identical to those of clinical isolates from Australian patients. These data do not support the theory that defects in the innate or adaptive type-1 immunity have a role in the pathogenesis of invasive M. kansasii infections. The identical fingerprint patterns of the isolates suggested the existence of a virulent strain of M. kansasii.

Uncommon presentations of tuberculosis: the potential value of a novel diagnostic assay based on the Mycobacterium tuberculosis-specific antigens ESAT-6 and CFP-10.

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.

Is there evidence for recommending silver-coated urinary catheters in guidelines?

We evaluated the available literature on effectiveness of silver-coated versus uncoated catheters for the prevention of urinary tract infections in catheterized patients stratified by sex, systemic antibiotic use, renal function and duration of catheterization. Controlled clinical trials, randomized clinical trials and systematic reviews/meta-analysis were identified by a search strategy in Medline (1966-August 2001) and in the Cochrane Controlled Trials Register. Keywords were urinary catheterization, silver and infection. Trials using silver-coated catheters in the treatment group and uncoated catheters in the control group, with bacteriuria as the outcome measure, were selected. The quality of the methods used of all selected publications was assessed by using a quality assessment scale for randomized clinical trials. In addition we looked critically at subject-specific aspects. Data from the original publications were used to calculate the overall relative risk of bacteriuria in patients with silver-coated versus uncoated catheters, as well as the effect in subgroups. Thirteen trials and one meta-analysis were identified. Seven reports satisfied the selection criteria with only one achieving a high-quality score. Confounding variables were not considered in any trial. Additional studies with a high standard of internal quality and careful specification of the clinical question with regard to subject-specific critical points are necessary to decide whether the use of silver-coated catheters can be recommended.

Risk factors for acquisition of Serratia marcescens in a surgical intensive care unit.

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.

TNF-alpha blockade and tuberculosis: better look before you leap.

According to several reports, the risk of active tuberculosis in patients who are latently infected with Mycobacterium tuberculosis is increased after treatment with tumour necrosis factor alpha (TNF)-blocking agents. These drugs have demonstrated effectiveness and are increasingly being used for treatment of several inflammatory diseases, including rheumatoid arthritis and Crohn's disease. Specialists prescribing TNF-blocking agents should be aware of the risk of tuberculosis and other infections, the unusual and severe clinical presentations and the available preventive measures. In this review, we will weigh currently available data on the risk of infection with intracellular pathogens and in particular tuberculosis in patients treated with TNF-blocking agents, discuss the role of TNF in the pathogenesis of tuberculosis and describe the risk profile of this complication. Awaiting further consensus protocols, a provisional flow chart is presented that is based on dinical parameters to provide a logical framework to reduce and minimise the risk of tuberculosis during TNF blockade.

Repeatedly negative tuberculin skin tests followed by active tuberculosis in an immunocompetent individual.

We describe a woman who was repeatedly tuberculin (PPD) skin test negative after exposure to smear-positive tuberculosis (TB), but developed active TB with a positive skin test 7 years later. Molecular epidemiologic evidence is presented that the infection was contracted 7 years previously from the original source case. PPD skin testing is subject to many technical and biological variables and this report underscores that this tool can fail to detect latent TB infection in some cases. The causes of false-negative and false-positive PPD skin test results are reviewed.

Extraskeletal localization of 99mTc-labeled bone-seeking tracers in bone scintigraphy.

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.