Allergic bronchopulmonary aspergillosis: the hunt for a diagnostic serological marker in cystic fibrosis patients

The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis patients remains challenging, mainly owing to overlapping symptoms of the underlying lung disease with clinical symptoms of ABPA. In addition, a varying mixture of diagnostic criteria, including clinical status, radiological findings and immunological measurements, has led to confusion and differing recommendations. In order to help simplify as well as standardize the diagnostic criteria for ABPA, different serological markers have been evaluated in the last 20 years and their usefulness has been assessed in many clinical studies. This review presents current diagnostic criteria of ABPA, with a special focus on serum markers supporting the diagnosis and explains why the hunt for a serological marker for ABPA is still ongoing.

Clinical presentation of celiac disease and the diagnostic accuracy of serologic markers in children

There has been growing recognition of a changing clinical presentation of celiac disease (CD), with the manifestation of milder symptoms. Serologic testing is widely used to screen patients with suspected CD and populations at risk. The aim of this retrospective analysis was to evaluate the clinical presentation of CD in childhood, assess the diagnostic value of serologic tests, and investigate the impact of IgA deficiency on diagnostic accuracy. We evaluated 206 consecutive children with suspected CD on the basis of clinical symptoms and positive serology results. Ninety-four (46%) had biopsy-proven CD. The median age at diagnosis of CD was 6.8 years; 15% of the children were <2 years of age. There was a higher incidence of CD in girls (p = 0.003). Iron deficiency and intestinal complaints were more frequent in children with CD than those without CD (61% vs. 33%, p = 0.0001 and 71% vs. 55%, p = 0.02, respectively), while failure to thrive was less common (35% vs. 53%, p = 0.02). The sensitivity of IgA tissue transglutaminase (IgA-tTG) was 0.98 when including all children and 1.00 after excluding children with selective IgA deficiency. The specificity of IgA-tTG was 0.73 using the recommended cut-off value of 20 IU, and this improved to 0.94 when using a higher cut-off value of 100 IU. All children with CD and relative IgA deficiency (IgA levels that are measurable but below the age reference [n = 8]) had elevated IgA-tTG. In conclusion, CD is frequently diagnosed in school-age children with relatively mild symptoms. The absence of intestinal symptoms does not preclude the diagnosis of CD; many children with CD do not report intestinal symptoms. While the sensitivity of IgA-tTG is excellent, its specificity is insufficient for the diagnostic confirmation of a disease requiring life-long dietary restrictions. Children with negative IgA-tTG and decreased but measurable IgA values are unlikely to have CD.

Carcinoma ex pleomorphic adenoma: diagnostic difficulty and outcome

OBJECTIVE: To analyze a series of carcinoma ex pleomorphic adenoma (CXPA) and to assess the diagnostic difficulties. STUDY DESIGN: The clinical presentation of 24 CXPAs was compared with 300 pleomorphic adenomas (PAs). Furthermore, pathohistological findings and follow-up results of CXPAs were evaluated. RESULTS: Eight of 24 (33%) CXPAs versus 41 of 300 (14%) PAs were localized in the deep lobe (P < 0.05). Forty-two percent of CXPAs versus 6 percent of PAs, respectively, were greater than 4 cm (P < 0.05). The sensitivity in detecting CXPA by fine-needle aspiration cytology (FNAC) was 47 percent. The tumor was known to be malignant preoperatively in 10 (42%) patients. Six of 24 (25%) patients with CXPA developed a tumor recurrence. The overall 5-year survival rate of CXPA was 76 percent. CONCLUSION: CXPAs are difficult to identify preoperatively. FNAC has a low accuracy and sensitivity. CXPAs versus PAs are significantly more frequently localized in the deep lobe and are significantly greater in size.

The diagnostic value of a treadmill test in predicting lumbar spinal stenosis

Lumbar spinal stenosis is a frequent indication for spinal surgery. The predictive quality of treadmill testing and MRI for diagnostic verification is not yet clearly defined. Aim of the current study was to assess correlations between treadmill testing and MRI findings in the lumbar spine. Twenty-five patients with lumbar spinal stenosis were prospectively examined. Treadmill tests were performed and the area of the dural sac and neuroforamina was examined with MRI for the narrowest spinal segment. VAS and ODI were used for clinical assessment. The median age of the patients was 67 years. In the narrowest spinal segment the median area of the dural sac was 91 mm(2). The median ODI was 66 per cent. The median walking distance in the treadmill test was 70 m. The distance reached in the treadmill test correlated with the area of the dural sac (Spearman's rho = 0.53) and ODI (rho = -0.51), but not with the area of the neuroforamina and VAS. The distance reached in the treadmill test predicts the grade of stenosis in MRI but has a limited diagnostic importance for the level of clinical symptoms in lumbar spinal stenosis.

Pineal parenchymal tumor of intermediate differentiation: diagnostic pitfalls and discussion of treatment options of a rare tumor entity

Tumors of the pineal region are uncommon, comprising approximately 0.4-1% of all intracranial tumors in adults in European and American series. Histopathologically, they are a very heterogeneous group of tumors. Of genuine pineal tumors, pineal parenchymal tumors of intermediate differentiation (PPTIDs) are the least frequently found type. In this paper, we report on the case of a patient with an unexpected and difficult-to-diagnose PPTID. A 2.2 x 2.2-cm midline mass within the posterior part of the third ventricle with consecutive obstructive hydrocephalus was found in a 44-year-old man presenting with diplopia and gait disturbances. There was no clear connection of the tumor to the pineal gland. Differential diagnosis included all intraventricular and midline tumors, therefore a biopsy was taken. Preliminary histopathological diagnosis was germinoma or primitive neuroectodermal tumor, and the tissue sample was reexamined by a referential neuropathological institute. Final diagnosis was PPTID. The tumor was then resected through a transventricular/transchoroidal approach. Histopathological examination of tumor specimen confirmed the diagnosis of a PPTID. Postoperatively, the patient received gamma-knife radiosurgery. At 1-year follow-up, there are no signs of tumor regrowth. Diagnosis of pineal parenchymal tumors in general and PPTIDs in particular can be troublesome. Their histopathological features are still being defined, as is the biological behavior of the different tumor entities. Thus, treatment options including surgery, radiation therapy, and chemotherapy remain controversial. We recommend surgical removal of PPTID, preferably in toto whenever the size of the tumor permits that kind of excision.

Graphical presentation of diagnostic information

BACKGROUND: Graphical displays of results allow researchers to summarise and communicate the key findings of their study. Diagnostic information should be presented in an easily interpretable way, which conveys both test characteristics (diagnostic accuracy) and the potential for use in clinical practice (predictive value). METHODS: We discuss the types of graphical display commonly encountered in primary diagnostic accuracy studies and systematic reviews of such studies, and systematically review the use of graphical displays in recent diagnostic primary studies and systematic reviews. RESULTS: We identified 57 primary studies and 49 systematic reviews. Fifty-six percent of primary studies and 53% of systematic reviews used graphical displays to present results. Dot-plot or box-and- whisker plots were the most commonly used graph in primary studies and were included in 22 (39%) studies. ROC plots were the most common type of plot included in systematic reviews and were included in 22 (45%) reviews. One primary study and five systematic reviews included a probability-modifying plot. CONCLUSION: Graphical displays are currently underused in primary diagnostic accuracy studies and systematic reviews of such studies. Diagnostic accuracy studies need to include multiple types of graphic in order to provide both a detailed overview of the results (diagnostic accuracy) and to communicate information that can be used to inform clinical practice (predictive value). Work is required to improve graphical displays, to better communicate the utility of a test in clinical practice and the implications of test results for individual patients.

An empirical comparison of methods for meta-analysis of diagnostic accuracy showed hierarchical models are necessary

OBJECTIVE: Meta-analysis of studies of the accuracy of diagnostic tests currently uses a variety of methods. Statistically rigorous hierarchical models require expertise and sophisticated software. We assessed whether any of the simpler methods can in practice give adequately accurate and reliable results. STUDY DESIGN AND SETTING: We reviewed six methods for meta-analysis of diagnostic accuracy: four simple commonly used methods (simple pooling, separate random-effects meta-analyses of sensitivity and specificity, separate meta-analyses of positive and negative likelihood ratios, and the Littenberg-Moses summary receiver operating characteristic [ROC] curve) and two more statistically rigorous approaches using hierarchical models (bivariate random-effects meta-analysis and hierarchical summary ROC curve analysis). We applied the methods to data from a sample of eight systematic reviews chosen to illustrate a variety of patterns of results. RESULTS: In each meta-analysis, there was substantial heterogeneity between the results of different studies. Simple pooling of results gave misleading summary estimates of sensitivity and specificity in some meta-analyses, and the Littenberg-Moses method produced summary ROC curves that diverged from those produced by more rigorous methods in some situations. CONCLUSION: The closely related hierarchical summary ROC curve or bivariate models should be used as the standard method for meta-analysis of diagnostic accuracy.

Identification of novel mutations in X-linked retinitis pigmentosa families and implications for diagnostic testing

PURPOSE: The goal of this study was to identify mutations in X-chromosomal genes associated with retinitis pigmentosa (RP) in patients from Germany, The Netherlands, Denmark, and Switzerland. METHODS: In addition to all coding exons of RP2, exons 1 through 15, 9a, ORF15, 15a and 15b of RPGR were screened for mutations. PCR products were amplified from genomic DNA extracted from blood samples and analyzed by direct sequencing. In one family with apparently dominant inheritance of RP, linkage analysis identified an interval on the X chromosome containing RPGR, and mutation screening revealed a pathogenic variant in this gene. Patients of this family were examined clinically and by X-inactivation studies. RESULTS: This study included 141 RP families with possible X-chromosomal inheritance. In total, we identified 46 families with pathogenic sequence alterations in RPGR and RP2, of which 17 mutations have not been described previously. Two of the novel mutations represent the most 3'-terminal pathogenic sequence variants in RPGR and RP2 reported to date. In exon ORF15 of RPGR, we found eight novel and 14 known mutations. All lead to a disruption of open reading frame. Of the families with suggested X-chromosomal inheritance, 35% showed mutations in ORF15. In addition, we found five novel mutations in other exons of RPGR and four in RP2. Deletions in ORF15 of RPGR were identified in three families in which female carriers showed variable manifestation of the phenotype. Furthermore, an ORF15 mutation was found in an RP patient who additionally carries a 6.4 kbp deletion downstream of the coding region of exon ORF15. We did not identify mutations in 39 sporadic male cases from Switzerland. CONCLUSIONS: RPGR mutations were confirmed to be the most frequent cause of RP in families with an X-chromosomal inheritance pattern. We propose a screening strategy to provide molecular diagnostics in these families.

[Chronic diarrhea: etiologies and diagnostic evaluation]

Chronic diarrhea is defined as a decrease in fecal consistency lasting for four or more weeks. A myriad of disorders are associated with chronic diarrhea. In developed countries, chronic diarrhea is mostly caused by non-infectious diseases. There are four pathogenic mechanisms leading to chronic diarrhea: osmotic diarrhea, secretory diarrhea, inflammatory diarrhea, and dysmotility. Overlaps between these mechanisms are possible. A 72-hour fecal collection as well as the fasting test are important diagnostic tools to identify the underlying pathomechanism. The identification of the pathomechanism narrows down the possible etiologies of chronic diarrhea and allows therefore a cost-saving diagnostic workup. The endoscopy is well established in the workup of chronic diarrhea. This article gives an overview about the main causes and mechanisms leading to chronic diarrhea and proposes an algorithm for the diagnostic evalution.

Value of a novel Neisseria meningitidis--specific polymerase chain reaction assay in skin biopsy specimens as a diagnostic tool in chronic meningococcemia

BACKGROUND: Chronic meningococcemia (CM) is a diagnostic challenge. Skin lesions are frequent but in most cases nonspecific. Polymerase chain reaction (PCR)-based diagnosis has been validated in blood and cerebrospinal fluid for acute Neisseria meningitidis infection, in patients in whom routine microbiologic tests have failed to isolate the bacteria. In 2 patients with CM, we established the diagnosis by a newly developed PCR-based approach performed on skin biopsy specimens. OBSERVATIONS: Two patients presented with fever together with systemic and cutaneous manifestations suggestive of CM. Although findings from blood cultures remained negative, we were able to identify N meningitidis in the skin lesions by a newly developed PCR assay. In 1 patient, an N meningitidis strain of the same serogroup was also isolated from a throat swab specimen. Both patients rapidly improved after appropriate antibiotherapy. CONCLUSIONS: To our knowledge, we report the first cases of CM diagnosed by PCR testing on skin biopsy specimens. It is noteworthy that, although N meningitidis-specific PCR is highly sensitive in blood and cerebrospinal fluid in acute infections, our observations underscore the usefulness of PCR performed on skin lesions for the diagnosis of chronic N meningitidis infections. Whenever possible, this approach should be systematically employed in patients for whom N meningitidis infection cannot be confirmed by routine microbiologic investigations.

Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine

BACKGROUND: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. METHODS/DESIGN: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians. DISCUSSION: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.

[Implementation of a routine gradual psycho-diagnostic programme in somatic rehabilitation centres - results of a pilot study]

STUDY AIM: A pilot study was conducted to implement and evaluate a routine gradual psycho-diagnostic programme to improve diagnostics and treatment of mental disorders in somatic rehabilitation centres. First of all, implementation strategies were acquired in trainings together with psychologists and physicians. The psycho-diagnostic programme consists of a screening instrument (PHQ-9) designed to permit time-effective detection of comorbid mental disorders. Besides evaluation of the training, the aim of the study was to analyze the extent to which it is possible to implement the routine gradual psycho-diagnostic programme in practice. Additionally, it was intended to identify beneficial and obstructive conditions for implementation. METHODOLOGY: The pilot study was conducted in two orthopaedic and one cardiological rehabilitation centre. The training was evaluated directly after its completion using a questionnaire. Three months after its implementation, the introduction of the psycho-diagnostic programme was evaluated using interviews with n=11 physicians and psychologists. RESULTS: The training was rated positively by the participants . Implementation of the entire gradual psycho-diagnostic programme was possible in one centre and to some degree in the other two. Beneficial for implementation were a frank organisational climate, sufficient time resources, and physicians' biopsychosocial understanding of disease. A dismissive attitude towards psycho-diagnostics, little communication between staff members, little perceived advantage for one's own work and fear to stigmatise patients by psychiatric diagnoses were obstructive. CONCLUSION: Essential for a successful implementation are sufficient time and personal resources, a motivation for change in staff and centre management, and a positive attitude regarding psycho-diagnostics in clinic staff. Furthermore, flexibility in implementation strategies and the opportunity to participate in the implementation process are important.