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.

Neuropsychiatric Derangement by Polycythemia Vera: A Case Report of an Unexpected Disease Presentation and Review of the Literature.

Cerebral infarction as well as other thromboses, headaches, and visual complaints are well-known symptoms of polycythemia vera. However, chorea and neuropsychiatric disturbances are less recognized consequences of this chronic disease. Whereas chorea is a rare but acknowledged symptom of polycythemia vera, neuropsychiatric symptoms have only sporadically been reported. We depict 2 patients with an unusual presentation of polycythemia vera. Our first patient presented with right-sided hemiballism and psychosis, and the second patient had a long diagnostic trajectory of unexplained chorea. In both cases diagnosis of JAK2 positive polycythemia vera was established, and in both cases remarkable recovery occurred after the initiation of phlebotomies. The underlying pathophysiology of these symptoms has not been clearly elucidated. Because of the unfamiliarity of the link between especially neuropsychiatric symptoms and polycythemia, current reported numbers are probably an underestimation. Benefit of treatment appears to be large. We seek to create more awareness among physicians about this phenomenon.

SARS-CoV-2-Induced Multisystem Inflammatory Syndrome in a Young Adult: Case Report.

We describe a case of a previous healthy 20-year-old male athlete who presented with an atypical clinical profile with multiorgan involvement within five weeks after confirmed SARS-CoV-2 infection, suggestive for multisystem inflammatory syndrome (MIS); MIS is a rare, potentially life-threatening complication associated with SARS-CoV-2. MIS shares similar clinical features compatible with several overlapping lifethreatening hyperinflammatory syndromes, such as incomplete Kawasaki Disease (KD) and toxic shock syndrome (TSS) associated to a cytokine storm suggestive of a macrophage activation syndrome (MAS) without fulfilling the criteria for hemophagocytic lymphohistiocytosis (HLH), that may create a great challenge to distinguish between them. MIS should promptly be considered and treated, as uncontrolled MIS has a high mortality. In MIS cardiac involvement, heart failure may present as an additional problem, especially because volume loading is advised in accordance with proposed therapy. Carefully monitoring of the respiratory and cardiac status in response of resuscitation is therefore warranted.

Rituximab-PECC induction followed by 90 Y-ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT: results from a phase II HOVON study.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after, or ineligible for, autologous stem cell transplantation (ASCT) have a dismal prognosis. This phase II study evaluated treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by radio-immunotherapy consolidation with 90 Y-ibritumomab tiuxetan in responsive patients. Primary endpoints were failure-free survival (FFS) and incidence of grade ≥3 adverse events from start of 90 Y-ibritumomab tiuxetan. The overall response rate after R-PECC was 50%. Twenty-nine of 31 responsive patients proceeded to 90 Y-ibritumomab tiuxetan. Five out of 15 partial remission patients converted to complete remission after 90 Y-ibritumomab tiuxetan. One-year FFS and overall survival (OS) from start of 90 Y-ibritumomab tiuxetan was 52% (95% confidence interval [CI], 33-68%) and 62% (95% CI, 42-77%), respectively. One-year FFS and OS from start of R-PECC was 28% (95% CI, 17-39%) and 49% (95% CI, 36-61%), respectively. Toxicities of R-PECC and 90 Y-ibritumomab tiuxetan were mainly haematological. In conclusion, for relapsed DLBCL patients the largely oral R-PECC regimen achieves promising response rates, combined with an acceptable safety profile. Consolidation with 90 Y-ibritumomab tiuxetan resulted in long-term response durations in approximately one third of the patients that received it.

Coxiella burnetii in non-Hodgkin lymphoma tissue samples: Innocent until proven otherwise?

PURPOSE: Coxiella burnetii has been suggested as a potential cause of B-cell non-Hodgkin lymphoma (B-NHL), as C. burnetii was detected in B-NHL tissues. To further investigate this potential relationship, we hypothesized that among subjects previously exposed to C. burnetii, the bacterium is more frequently detectable in tissues of patients with B-NHL (cases) compared to patients without B-NHL (controls). METHODS: We aimed to evaluate this hypothesis by assessing the presence of C. burnetii with polymerase chain reaction (PCR), immunofluorescence staining (IF) and fluorescent in-situ hybridization (FISH). Eligible patients were those previously exposed to C. burnetii. RESULTS: Samples were available for 13 cases and 16 controls. C. burnetii was demonstrated in tissues of 8/29 patients in total (28%), with either PCR, IF or FISH: in 5/13 cases (38%) and 3/16 controls (19%), p = 0.41. Negative and positive control samples were all negative and positive appropriately for all three diagnostic methods. CONCLUSIONS: In patients previously exposed to C. burnetii the bacterium was detected in tissue samples from subjects with and without B-NHL, without significant differences in the proportion positive samples. Therefore, we conclude that detection of C. burnetii in tissues of patients previously exposed to C. burnetii is a non-specific finding.

Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis.

Infection remains one of the most prominent complications after cytotoxic treatment for cancer. The connection between neutropenia and both infections and fever has long been designated as 'febrile neutropenia', but treatment with antimicrobial agents and haematopoietic growth factors has failed to significantly reduce its incidence. Moreover, emerging antimicrobial resistance is becoming a concern that necessitates the judicious use of available antimicrobial agents. In addition to neutropenia, patients who receive cytotoxic therapy experience mucosal barrier injury (MBI) or 'mucositis'. MBI creates a port-de-entrée for resident micro-organisms to cause blood stream infections and contributes directly to the occurrence of fever by disrupting the highly regulated host-microbe interactions, which, even in the absence of an infection, can result in strong inflammatory reactions. Indeed, MBI has been shown to be a pivotal factor in the occurrence of inflammatory complications after cytotoxic therapy. Hence, the concept 'febrile neutropenia' alone may no longer suffice and a new concept 'febrile mucositis' should be recognized as the two are at least complementary. This review we summarizes the existing evidence for both paradigms and proposes new therapeutic approaches to tackle the perturbed host-microbe interactions arising from cytotoxic therapy-induced tissue damage in order to reduce fever in neutropenic patients with cancer.

Intestinal damage determines the inflammatory response and early complications in patients receiving conditioning for a stem cell transplantation.

BACKGROUND: Stem cell transplantation (SCT) is still complicated by the occurrence of fever and inflammatory complications attributed to neutropenia and subsequent infectious complications. The role of mucosal barrier injury (MBI) of the intestinal tract therein has received little attention. METHODS: We performed a retrospective analysis in 163 SCT recipients of which data had been collected prospectively on intestinal damage (citrulline), inflammation (C-reactive protein), and neutrophil count. Six different conditioning regimens were studied; 5 myeloablative (MA) and 1 non-myeloablative (NMA). Linear mixed model multivariate and AUC analyses were used to define the role of intestinal damage in post-SCT inflammation. We also studied the relationship between the degree of intestinal damage and the occurrence of early post-SCT complications. RESULTS: In the 5 MA regimen there was a striking pattern of inflammatory response that coincided with the occurrence of severe intestinal damage. This contrasted with a modest inflammatory response seen in the NMA regimen in which intestinal damage was limited. With linear mixed model analysis the degree of intestinal damage was shown the most important determinant of the inflammatory response, and both neutropenia and bacteremia had only a minor impact. AUC analysis revealed a strong correlation between citrulline and CRP (Pearson correlation r = 0.96). Intestinal damage was associated with the occurrence of bacteremia and acute lung injury, and influenced the kinetics of acute graft-versus-host disease. CONCLUSION: The degree of intestinal damage after myeloablative conditioning appeared to be the most important determined the inflammatory response following SCT, and was associated with inflammatory complications. Studies should explore ways to ameliorate cytotoxic therapy-induced intestinal damage in order to reduce complications associated with myeloablative conditioning therapy.