Etiological spectrum and outcome of fever and inflammation of unknown origin. Does symptom duration matter?

OBJECTIVE: Evidence suggests that the symptom duration may affect the occurrence of certain fever (FUO) and inflammation (IUO) of unknown origin associated conditions. It is unclear if this could potentially guide diagnostic evaluations. We examined the association between symptom duration and diagnostic and prognostic outcomes in FUO/IUO. METHODS: We retrospectively analyzed a cohort of adult patients meeting criteria for FUO/IUO from a tertiary care center in Belgium between 2000 and 2019. The association between symptom duration and outcomes of interest were estimated by Cox proportional hazards models. RESULTS: Among 602 patients who met criteria for FUO/IUO (mean age 54 years, 43% female), 132 (22%) and 68 (11%) had symptoms for 3-12 months and >12 months, respectively. There were no significant differences in diagnosis or all-cause mortality between a symptom duration of <3 months and 3-12 months. In contrast, those who had a symptom duration of >12 months were less likely to receive a final diagnosis (aHR 0.42, 95% CI 0.30-0.60), in particular a diagnosis of infectious disorders (aHR 0.29, 95% CI 0.12-0.74), malignancies (aHR 0.11, 95% CI 0.03-0.46), and miscellaneous conditions (aHR 0.22, 95% CI 0.07-0.71), but no significant differences were seen in noninfectious inflammatory disorders (aHR 0.74, 95% CI 0.48-1.15) or all-cause mortality (aHR 0.55, 95% CI 0.19-1.54). CONCLUSIONS: The symptom duration may be used to guide the diagnostic workup among patients with FUO and IUO, in particular those with longstanding symptoms.

Rheumatic disorders among patients with fever of unknown origin: A systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic literature review and meta-analysis to estimate the proportion of fever of unknown origin (FUO) and inflammation of unknown origin (IUO) cases that are due to rheumatic disorders and the relative frequency of specific entities associated with FUO/IUO. METHODS: We searched PubMed and EMBASE between January 1, 2002, and December 31, 2021, for studies with ≥50 patients reporting on causes of FUO/IUO. The primary outcome was the proportion of FUO/IUO patients with rheumatic disease. Secondary outcomes include the association between study and patient characteristics and the proportion of rheumatic disease in addition to the relative frequency of rheumatic disorders within this group. Proportion estimates were calculated using random-effects models. RESULTS: The included studies represented 16884 patients with FUO/IUO. Rheumatic disease explained 22.2% (95%CI 19.6 - 25.0%) of cases. Adult-onset Still's disease (22.8% [95%CI 18.4-27.9%]), giant cell arteritis (11.4% [95%CI 8.0-16.3%]), and systemic lupus erythematosus (11.1% [95%CI 9.0-13.8%]) were the most frequent disorders. The proportion of rheumatic disorders was significantly higher in high-income countries (25.9% [95%CI 21.5 - 30.8%]) versus middle-income countries (19.5% [95%CI 16.7 - 22.7%]) and in prospective studies (27.0% [95%CI 21.9-32.8%]) versus retrospective studies (20.6% [95%CI 18.1-24.0%]). Multivariable meta-regression analysis demonstrated that rheumatic disease was associated with the fever duration (0.011 [95%CI 0.003-0.021]; P=0.01) and with the fraction of patients with IUO (1.05 [95%CI 0.41-1.68]; P=0.002). CONCLUSION: Rheumatic disorders are a common cause of FUO/IUO. The care of patients with FUO/IUO should involve physicians who are familiar with the diagnostic workup of rheumatic disease.

Mesenteric panniculitis as a presentation of Whipple's disease: case report and review of the literature.

BACKGROUND: Whipple's disease is a rare, multi-organ disease caused by Tropheryma Whipplei. A classic presentation is characterized by arthropathy, diarrhea and weight loss but a broad spectrum of manifestations is possible. We present a case of a patient with mesenteric panniculitis as a manifestation of WD. A comprehensive review of the literature is provided. PATIENT: A 50 year old male presented at the outpatient clinic after an episode of fever and abdominal pain abroad. CT scan showed mesenteric infiltration with associated lymphadenopathies consistent with mesenteric panniculitis. After receiving 6 months of antibiotic therapy abdominal and joint pains improved. CONCLUSION: Clinicians should be aware of Whipple's disease. Mesenteric panniculitis is a rare presentation of this possible lethal infection. The golden standard for diagnosing WD is a PAS positive small bowel biopsy. Adequate antibiotic therapy is the cornerstone of treatment and usually leads to an amelioration of symptoms.

Efficacy and safety of canakinumab treatment in schnitzler syndrome: A systematic literature review.

BACKGROUND: Schnitzler syndrome is a rare autoinflammatory disorder characterized by chronic urticarial rash and a monoclonal gammopathy, accompanied by intermittent fever, bone pain, and arthralgia or arthritis. Canakinumab is a fully human monoclonal anti-interleukin-1ß (IL-1ß) antibody proven to be effective in IL-1 driven autoinflammatory disorders. METHODS: We systematically searched PubMed and Embase to include all types of studies on canakinumab treatment in Schnitzler syndrome published until March 16, 2020. RESULTS: Since 2011, 7 publications have been reported on canakinumab treatment in 34 patients with Schnitzler syndrome. The cumulative follow-up was 253 months, and 5 studies had a follow-up duration of 12 months or more. A complete response during treatment was reported in 58.6% of patients; all other patients had a partial response. Two hundred and seven adverse events were reported in 23 patients. Infection (n = 79) was the most common adverse event. One patient died from sepsis due to atypical mycobacterial infection. CONCLUSION: Based on the results of the current systematic review, canakinumab is an effective long-term treatment with a favorable safety profile in patients with Schnitzler syndrome.

Genomewide copy number alteration screening of circulating plasma DNA: potential for the detection of incipient tumors.

Background: Early cancer diagnosis might improve survival rates. As circulating tumor DNA (ctDNA) carries cancer-specific modifications, it has great potential as a noninvasive biomarker for detection of incipient tumors. Patients and methods: We collected cell-free DNA (cfDNA) samples of 1002 elderly without a prior malignancy, carried out whole-genome massive parallel sequencing and scrutinized the mapped sequences for the presence of (sub)chromosomal copy number alterations (CNAs) predictive for a malignancy. When imbalances were detected, 6-monthly clinical follow-up was carried out. Results: In 3% of participants chromosomal imbalances were detected. Follow-up analyses, including whole-body MRI screening, confirmed the presence of five hematologic malignancies: one Hodgkin lymphoma (HL), stage II; three non-HL (type chronic lymphocytic leukemia, Rai I-Binet A; type SLL, stage III; type mucosa-associated lymphoid tissue, stage I) and one myelodysplastic syndrome with excess blasts, stage II. The CNAs detected in cfDNA were tumor-specific. Furthermore, one case was identified with monoclonal B-cell lymphocytosis, a potential precursor of B-cell malignancy. In 24 additional individuals, CNAs were identified but no cancer diagnosis was made. For 9 of them, the aberrant cfDNA profile originated from peripheral blood cells. For 15 others the origin of aberrations in cfDNA remains undetermined. Conclusion(s): Genomewide profiling of cfDNA in apparently healthy individuals enables the detection of incipient hematologic malignancies as well as clonal mosaicism with unknown clinical significance. CNA screening of cellular DNA of peripheral blood in elderly has established that clonal mosaicism for these chromosomal anomalies predicts a 5- to 10-fold enhanced risk of a subsequent cancer. We demonstrate that cfDNA screening detects CNAs, which are not only derived from peripheral blood, but even more from other tissues. Since the clinical relevance of clonal mosaics in other tissues remains unknown, long-term follow-up is warranted. Taken together, this study demonstrates that genomewide cfDNA analysis has potential as an unbiased screening approach for hematological malignancies and premalignant conditions.

There is no benefit in routinely monitoring ANCA titres in patients with granulomatosis with polyangiitis.

OBJECTIVES: To analyse the link between antineutrophil cytoplasmic antibody (ANCA) levels and risk of relapse in patients with granulomatosis with polyangiitis (GPA), as the clinical benefit of monitoring ANCA levels is uncertain. METHODS: A retrospective analysis was made of all charts available from 43 patients diagnosed with GPA, fulfilling The American College of Rheumatology 1990 criteria, and followed between 1994 and 2012 at a general internal medicine department of a university hospital. Clinical and biochemical data (i.e. anti-proteinase 3 (PR3) levels) were collected and correlated. RESULTS: 43 relapses occurred in 25 patients (58.1% of 43 patients). When blood samples are routinely taken at a follow-up visit (i.e. low pre-test probability, ± 5.5%) in the GPA-population, a 75%-increase in the PR3-level or its reappearance has only limited positive predictive value (PPV 15.0% and 22.5% respectively) for predicting relapse. Adversely, when clinical suspicion of relapse is high (i.e. high pre-test probability, for example 50%), an increase of 75% or reappearance of PR3 makes relapse even more likely (PPV 77.5%, 81.6% respectively). Conversely, a high negative predictive value (NPV) of 99.3% and a negative likelihood ratio (LR-) of 0.12 suggest that, in the absence of PR3, relapse is unlikely if patients had detectable ANCAs at diagnosis. CONCLUSIONS: Routine ANCA monitoring in patients diagnosed with GPA has limited value. However, targeted determination of ANCA levels may be useful if a relapse is clinically suspected (i.e. high pre-test probability).

Tackling fever and inflammation of unknown origin: the do's and don'ts.

Fever and inflammation of unknown origin continue to challenge the clinician. The differential diagnosis is broad and potential diagnostic pitfalls abound. To guide the approach, the authors discuss the do's and don'ts.

Mortality in patients presenting with fever of unknown origin.

BACKGROUND: Few data exist on the contemporary prognosis of patients presenting with fever of unknown origin (FUO). METHODS: The data of 436 adult immunocompetent patients presenting with FUO between 2000 and 2010 and followed for at least 6 months were analyzed, with a focus on FUO-related deaths. The following variables were assessed in survivors and non-survivors: age, underlying diagnosis, and, in a nested case-control design, fever periodicity, selected laboratory parameters (including peripheral blood counts, enzymes, and inflammatory markers) and organomegaly. RESULTS: Thirty FUO-related deaths occurred (6·9%). Malignancy accounted for 11% of fevers but for 60% of deaths. Especially non-Hodgkin lymphoma carried a disproportionally high death toll. In the non-malignant categories, fatality rates were below 6%. All patients discharged without diagnosis in spite of ample investigations (n = 164) survived. Besides malignancy, age, continuous (as opposed to episodic) fever, anaemia, leucopenia, LDH levels, and hepatomegaly were associated with mortality. CONCLUSIONS: Fatality rates of FUO have continuously declined over the past decades. Malignancy, including lymphoma, remains a cardinal cause of death. Patients with FUO discharged without diagnosis survive.

Fever in HIV-infected patients: less frequent but still complex.

Fever was a common symptom in patients with Human Immunodeficiency Virus (HIV) infection in the early phases of the epidemic. Fever of Unknown Origin (FUO) was frequent in HIV-patients and conditions causing FUO were often opportunistic conditions. The HIV-epidemic continues to expand, but access to effective antiretroviral therapy is also expanding, resulting in a growing number of HIV-infected patients less likely to be severely immunocompromised and less likely to present opportunistic conditions. Yet part of newly diagnosed patients continue to present with advanced HIV-infection and are still at high risk of opportunistic conditions. This epidemiological evolution strongly influences the spectrum of conditions causing fever and FUO in HIV-patients. While some patients with HIV-associated fever and FUO may still be suffering from opportunistic conditions classically associated with HIV-related FUO, many others will have causes of fever that are similar to the non-HIV-infected population or to classical FUO. Strategies for diagnosis and treatment of fever and its causes in HIV-infected patients need to take into account this evolution.

Lymph node biopsies in a general internal medicine department: algorithm or individualized decision-making?

BACKGROUND: Lymphadenopathy (LA) imposes a diagnostic challenge in internal medicine. Exclusion of malignancy is the primary concern. METHODS: A retrospective case series, including 40 adult patients from the general internal medicine department who underwent lymph node biopsy (LNB) at a single university hospital. Demographics, clinical data and histopathological diagnoses were registered. By means of the latest medical record, we obtained a final diagnosis for each patient and subsequently searched for variables correlated with malignancy. Follow-up was at least one year in 95% of cases. RESULTS: The prevalence of malignancy was 58%. Older age (p = 0.02) was significantly correlated with malignancy. The presence of painful lymphadenopathy at clinical examination (p = 0.02) was significantly associated with a benign outcome. No single or combination of baseline variables satisfactorily excluded malignancy. Histopathological analysis correctly predicted malignancy in 93% of cases. In two cases, an initial diagnosis of benign non-specific lymphadenopathy was reversed to non-Hodgkin lymphoma. In one case the pathological diagnosis was inconclusive. CONCLUSION: Rather than following a universal algorithm to determine the need for LNB in patients with LA, we call for individualized decision-making in each case, carefully appreciating all available information. Additionally, one should keep in mind that false-negative results occur due to sampling errors. Therefore, a minimal number of cases should end with a final diagnosis of benign non-specific lymphadenopathy. Intensive, multidisciplinary cooperation with surgeon and pathologist is needed. Moreover, clinical follow-up should be at least one year.

The haemophagocytic syndrome.

The haemophagocytic syndrome or haemophagocytic lymphohistiocytosis (HLH) is a syndrome encompassing a heterogeneous group of disorders characterized by a persistent activation of benign macrophages, leading to uncontrolled secretion of cytokines and phagocytosis of blood cells. The syndrome can be primary due to mutations in different genes crucially involved in lymphocyte cytotoxicity and secondary in association with infectious, autoimmune or malignant disorders. In most cases HLH displays an aggressive disease course with a high fatality rate without treatment. Early recognition of the syndrome and prompt initiation of appropriate treatment, in most cases consisting of immunochemotherapy, are mandatory to ensure long-term survival.

An unusual cause of syndrome of inappropriate antidiuretic hormone secretion.

A 22-year-old woman was admitted to intensive care with severe hyponatraemia. She suffered from lower abdominal pain, vomiting and irritability since one week. Physical findings showed euvolemia and an altered mental status with severe agitation and slurred speech. Abdominal examination was painful but there were no signs of peritonitis. Laboratory data were compatible with the diagnosis of syndrome of inappropriate secretion of antidiuretic hormone. Since patient was in a premenstrual phase, recently started to take an oral contraceptive and since no abnormalities were seen on an abdominal CT scan, the presentation was considered suggestive of an acute porphyria attack. A urinary sample indicated markedly increased levels of delta-aminolevulinic acid, porphobilinogen and uroporphyrin. A low activity of the porphobilinogen deaminase enzyme confirmed the diagnosis of acute intermittent porphyria. The present case demonstrates the need for a high level of suspicion in order to diagnose this disorder in unexplained syndrome of inappropriate antidiuretic hormone secretion and prevent life-threatening complications.

Nosocomial infective endocarditis: should the definition be extended to 6 months after discharge.

Because the microbiology and patient population of infective endocarditis (IE) have evolved, the traditional definition of nosocomial IE may require revision. The question of whether this definition should be extended to 6 months after discharge was explored, and a high rate of episodes with nosocomial pathogens (coagulase-negative staphylococci) and a low rate of episodes with community pathogens (streptococci) in the extended nosocomial group were found. Therefore, modification of the traditional definition is proposed, distinguishing between early (as traditionally described) and late nosocomial IE (IE in association with a significant invasive procedure performed during a hospitalization between 8 weeks and 6 months before the onset of symptoms).

Relationship between fluorodeoxyglucose uptake in the large vessels and late aortic diameter in giant cell arteritis.

OBJECTIVE: GCA carries an increased risk of developing thoracic aortic aneurysms. Previous work with fluorodeoxyglucose (FDG)-PET has shown that the aorta is frequently involved in this type of vasculitis. We wanted to investigate whether there is a correlation between the extent of vascular FDG uptake during the acute phase of GCA and the aortic diameter at late follow-up. METHODS: All patients with biopsy-proven GCA who ever underwent an FDG-PET scan in our centre were asked to undergo a CT scan of the aorta. The diameter of the aorta was measured at six different levels (ascending aorta, aortic arch, descending aorta, abdominal suprarenal, juxtarenal and infrarenal aorta) and the volumes of the thoracic and of the abdominal aorta were calculated. RESULTS: Forty-six patients agreed to participate (32 females, 14 males). A mean of 46.7 +/- 29.9 months elapsed between diagnosis and CT scan. All aortic dimensions were significantly smaller in women than in men, except for the diameter of the ascending aorta. Patients who had an increased FDG uptake in the aorta at diagnosis of GCA, had a significantly larger diameter of the ascending aorta (P = 0.025) and descending aorta (P = 0.044) and a significantly larger volume of the thoracic aorta (P = 0.029). In multivariate analysis, FDG uptake at the thoracic aorta was associated with late volume of the thoracic aorta (P = 0.039). CONCLUSION: GCA-patients with increased FDG uptake in the aorta may be more prone to develop thoracic aortic dilatation than GCA patients without this sign of aortic involvement.

Living donor kidney transplantation: analysis of the first 40 cases performed in UZ Leuven.

Living donation kidney transplantation has been popular worldwide to try to increase the donor pool. In Belgium, the rate of living donation kidney transplantation has been traditionally relatively low compared to other countries. This is--in part--due to the relatively higher cadaveric organ offer that is available in Belgium (around 25 donors per million inhabitants), compared to other countries. However, the increasing waiting times on cadaveric waiting list and the superiority of the results of live donation versus cadaveric kidney transplantation have led to a reappraisal of this strategy. In our center a living donation kidney transplant programme was started in 1997. Since then 40 cases of live donation kidney transplantation have been performed and are reported herein.