Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial.

BACKGROUND: Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. METHODS: This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 109/L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60-84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329. FINDINGS: Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52-65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI -1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3-5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections. INTERPRETATION: Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating. FUNDING: The Netherlands Organisation for Health Research and Development and Fonds NutsOhra.

[Recurrent isolated angioedema as a result of acquired C1 inhibitor deficiency]. / Geïsoleerd angio-oedeem door verworven C1-esteraseremmerdeficiëntie.

Isolated angioedema may be the presenting symptom of acquired C1 inhibitor (C1-INH) deficiency. C1-INH deficiency is associated with lymphoproliferative disorders. Treatment of the underlying disease can result in a complete reversal of clinical and complement abnormalities. We describe a 41-year-old woman who was referred to our emergency department with recurrent episodes of isolated angioedema. Initially, her angioedema was linked to the use of angiotensin receptor blockers. However, after discontinuation of this drug angioedema recurred. Additional investigations revealed the presence of acquired C1-INH deficiency caused by an indolent non-Hodgkin's lymphoma. Treatment with rituximab resulted in complete clinical and biochemical remission of the acquired angioedema.

[Patients with superior vena cava syndrome: pitfalls in recognition]. / Patiënten met het vena-cava-superiorsyndroom: valkuilen bij de herkenning.

Superior vena cava syndrome (SVCS) may be the presenting sign of malignancy. SVCS may be difficult to recognize due to its usual slow development or possible temporary regression. We discuss the pitfalls in recognizing SVCS by presenting two cases. In a 45-year-old man, facial swelling diminished after he was administered intraarticular steroids to treat brachialgia. During the same period, collateral veins appeared on his chest wall. Only a few weeks later he was diagnosed with SVCS due to lung cancer. A 31-year-old man with a swollen face was treated with glucocorticoids, allegedly for an allergic reaction. When symptoms recurred after one week, it was discovered that SVCS was caused by lymphoma. These cases illustrate that the first manifestations of SVCS may be subtle and that development of collaterals or the use of glucocorticoids may relieve symptoms. Importantly, late diagnosis of SVCS results in delay of treatment of the underlying cause, which is often malignant.

[Castleman's disease, a fatal cause of lymph node enlargement and fever]. / De ziekte van Castleman: een fatale oorzaak van lymfkliervergroting en koorts.

A 71-year old Turkish man with fever, night sweats and generalized lymphadenopathy was diagnosed as having multicentric Castleman's disease. This is a rare and often fatal cause of lymph node enlargement and fever. Histological investigation confirms the diagnosis, but the morphological features closely resemble reactive lymphadenopathy or lymphoma. Infection with human herpes virus 8 is associated with Castleman's disease, in both hiv-positive and hiv-negative patients. An interleukin-6 mediated immune response against HHV-8 seems to play an important role in the pathogenesis of the multicentric form of Castleman's disease. The disease is usually rapidly progressive, but can have a milder course. There is no standard treatment: usually systemic chemotherapy in combination with steroids is applied..Recently, promising results have been obtained using rituximab and anti-IL-6-receptor antibodies.

Anaplastic large-cell lymphoma in women with breast implants.

CONTEXT: Recently, we identified 2 patients with anaplastic large T-cell lymphoma (ALCL) negative for tyrosine kinase anaplastic lymphoma kinase (ALK-negative) in the fibrous capsule of silicone breast prostheses, placed for cosmetic reasons. Similar cases have been reported in the literature. Although an increased risk of ALCL in patients with breast prostheses has been speculated, no studies have been conducted so far. OBJECTIVE: To determine whether ALCL risk is associated with breast prostheses. DESIGN: A search for all patients with lymphoma in the breast diagnosed in The Netherlands between 1990 and 2006 was performed through the population-based nationwide pathology database. Subsequently, we performed an individually matched case-control study. Conditional logistic regression analysis was performed to estimate the relative risk of ALCL associated with breast prostheses. SETTING AND PATIENTS: Eleven patients with breast ALCL were identified in the registry. For each case patient with ALCL in the breast, we selected 1 to 5 controls with other lymphomas in the breast, matched on age and year of diagnosis. For all cases and controls (n = 35), pathological and clinical information was obtained with special emphasis on the presence of a breast prosthesis. MAIN OUTCOME MEASURE: Association between breast implants and ALCL of the breast. RESULTS: The 11 patients with ALCL of the breast were diagnosed between 1994 and 2006 at a median age of 40 years (range, 24-68 years). In 5 of these patients, bilateral silicone breast prostheses had been placed 1 to 23 years before diagnosis. All received prostheses for cosmetic reasons. Lymphoma classes of 35 eligible control patients were 12 diffuse large B-cell lymphomas, including 1 T-cell rich B-cell lymphoma; 5 Burkitt lymphomas; 10 mucosa-associated lymphoid tissue-type lymphoma; 3 follicular lymphomas; 3 peripheral T-cell lymphomas; and 2 indolent B-cell lymphomas, unclassified. One of 35 control patients had a breast implant placed before diagnosis of lymphoma. The odds ratio for ALCL associated with breast prostheses was 18.2 (95% confidence interval, 2.1-156.8). CONCLUSIONS: These preliminary findings suggest an association between silicone breast prostheses and ALCL, although the absolute risk is exceedingly low due to the rare occurrence of ALCL of the breast (11 cases in The Netherlands in 17 years). These findings require confirmation in other studies.

T/NK cell lymphoma presenting as a "blocked nose".

We present the case of a 63-year-old Caucasian male who complained of persistent rhinitis and sinusitis accompanied by a total left-sided nasal blockage. The diagnosis nasal T/NK cell lymphoma was established by histopathological investigation. This case was diagnosed as stage IE lymphoma as no other sites were involved. The patient was treated with CHOP (cyclophosfamide, doxorubicin, vincristin and prednisone) chemotherapy and involved-field radiotherapy. The nasal T/NK cell lymphoma is a rare malignancy, which is known to have an extremely aggressive and destructive course. The mainstay of treatment is locoregional radiotherapy combined with chemotherapy, depending on disease stage. A high index of clinical suspicion is imperative to ensure early diagnosis and ultimately improve disease outcome.

A novel (Leu183Pro-)mutation in the HFE-gene co-inherited with the Cys282Tyr mutation in two unrelated Dutch hemochromatosis patients.

We describe a novel heterozygous mutation in exon 3 of the HFE-gene that was co-inherited with Cys282Tyr in two unrelated Dutch men both presenting a classical form of hereditary hemochromatosis. Heterozygosity for this mutation was also found in one out of 100 healthy controls of Dutch descent. This c.548T>C mutation converts a leucine to a proline residue at position 183 in the alpha2-helix of the HFE-protein (Leu183Pro). Standard bioinformatics analysis shows that the mutation is likely to disturb the HFE interaction with TfR1. This disrupting role of the mutation in the iron regulatory pathway is further corroborated by the familial co-occurrence of the observed compound heterozygosity with increased serum iron parameters. Haplotype analysis strongly suggests that this novel mutation arose from a common ancestor in the distant past. These findings may have implications for HFE-testing of iron overloaded heterozygous Cys282Tyr-patients of Northern European origin and their relatives.