Per Engervall

Use of inflammatory markers for early detection of bacteraemia in patients with febrile neutropenia.

The aim of the study was to evaluate the ability of procalcitonin, C-reactive protein, serum amyloid A, interleukin-6 and interleukin-8 to predict bacteraemia during the 2 first d of fever in neutropenic patients. A total of 94 febrile neutropenic episodes in 60 patients were studied. Plasma samples were analysed at 10-h intervals from the onset of fever. Clinical events were categorized into 4 groups: 1) bacteraemia caused by other agents than coagulase-negative staphylococci (non-CNS bacteraemia) (n=21), 2) coagulase-negative staphylococci bacteraemia (n=15), 3) microbiologically or clinically documented infection without bacteraemia (n=26) and 4) fever of unknown origin (n=32). In non-CNS bacteraemia all markers, except for serum amyloid A, showed significantly higher levels compared to patients with fever of unknown origin (p<0.05). For non-CNS bacteraemia the highest negative predictive value was found for procalcitonin (94%), followed by interleukin-6 (89%), C-reactive protein (88%) and interleukin-8 (87%). Procalcitonin, with a cut-off level of 1.4 ng/ml during 10–20 h after fever onset, showed the highest positive predictive value (67%) for a non-CNS bacteraemia. In conclusion, the value of the analysed markers to predict a non-CNS bacteraemia in neutropenic patients was limited due to low sensitivity and positive predictive value. However, procalcitonin, interleukin-6, C-reactive protein, and interleukin-8 could give useful information for the clinician in excluding a non-CNS bacteraemia.

Assessment of systemic inflammation markers to differentiate a stable from a deteriorating clinical course in patients with febrile neutropenia

In this study, we evaluated the predictive values of procalcitonin (PCT), C‐reactive protein (CRP), interleukin‐6 (IL‐6) and serum amyloid A (SAA) for determining the clinical course in febrile neutropenic patients. Daily plasma analyses during the fever course were performed in 101 episodes with fever and chemotherapy‐induced neutropenia (neutrophil count <0.5 × 109/L). Procalcitonin (PCT) and IL‐6 values were significantly higher in febrile episodes in patients who developed complications. Procalcitonin with a cut‐off value of ≤0.4 ng/mL or IL‐6 ≤50 pg/mL 3 d after fever onset indicated daily high negative predictive values (NPVs) (91–100%) for episodes with complications. No marker could predict deterioration; however, daily low plasma concentrations of PCT or IL‐6 during the first 8 d of fever were found to be a good predictor of no subsequent complications in neutropenic patients and therefore to be a helpful tool for limiting anti‐microbial therapy.

A prospective, randomized study comparing cefepime and imipenem-cilastatin in the empirical treatment of febrile neutropenia in patients treated for haematological malignancies

A prospective, open label, randomized, multicentre study was conducted, comparing the efficacy and safety of cefepime with that of imipenem-cilastatin for the management of febrile neutropenia in patients with haematological malignancies. Furthermore, the safety of early discontinuation of antibiotic therapy in patients with fever of undetermined origin (FUO) was assessed. A total of 180 patients with 207 febrile episodes were randomized at start of fever (105 episodes for cefepime and 102 episodes for imipenem). The 2 groups were comparable in terms of age, gender, underlying malignancy, prior transplantation, and presence of central venous catheters. All patients were neutropenic at inclusion with median absolute neutrophil count (ANC) 0.1×109/l(range 0–1×109/l), and ANC ≤0.1×109/l in 77% of included patients. The mean duration of neutropenia, with ANC <0.5×109/l was 6.2 d. Febrile episodes were classified as microbiologically documented infection (47%), FUO (43%), or clinically documented infection (10%). At final evaluation 1–2 weeks after completion of antibiotic therapy, monotherapy success rates were 40% and 51% in the cefepime and imipenem-cilastatin groups respectively (p=0.33). The 4-week overall mortality rate was 5%. Three (2%) of the cefepime treated patients and 4 (3%) of the imipenem-cilastatin treated patients died as a result of infection. Adverse events directly related to antibiotic treatment were uncommon and did not differ between groups. Early discontinuation of antibiotic therapy in 31 patients with FUO 48 h after defervescence was not associated with an increased rate of fever relapse or mortality compared with a subgroup of 29 patients where therapy was continued.

Monitoring of endotoxin, interleukin-6 and C-reactive protein serum concentrations in neutropenic patients with fever

Abstract: Serum endotoxin, interleukin‐6 (IL‐6) and C‐reactive protein (CRP) were serially determined in 26 patients with hematological malignancies and chemotherapy‐induced neutropenia who developed fever. Endotoxin in serum was detected in 69% of the patients, with the highest values being recorded in patients with gram‐negative (Gr‐) bacteremia. High levels of IL‐6 were found after start of fever, and in 6/9 patients with Gr‐ bacteremia levels exceeded 200 ng/l in samples drawn within the first 72 hours. However, only in 2/17 patients with gram‐positive bacteremias and blood culture‐negative fever episodes did IL‐6 exceed this concentration (p<0.05). High CRP values (exceeding 100 mg/l) did not discriminate between Gr‐ and non‐Gr‐ episodes (7/9 versus 10/17, respectively). In patients with fever at day 3–5 (n = 15), IL‐6 values > 100 ng/l were associated with fever continuing for more than 7 days after start of the episode; contrarily, CRP values did not indicate the persistence of fever. Determination of IL‐6 may be a better test than CRP in monitoring the acute response to infection in the neutropenic patient. A combination of high endotoxin and IL‐6 values may indicate a Gr‐ bacteremia. This could have therapeutic implications before results of blood cultures are obtained.

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Summary. Serum concentrations of tumour necrosis factor alpha (TNF‐α), interleukin‐1 receptor antagonist (IL‐1ra), interferon gamma (IFN‐γ), interleukin‐6 (IL‐6) and interleukin‐10 (IL‐10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram‐negative (Gr−) bacteraemias after 2 h (TNF‐α, IL‐lra and IFN‐γ), 4h (IL‐6) and 6 h (IL‐10), respectively. At time 0 the median TNF‐α value was higher in the Gr− group (80 pg/ml; range 54‐516 pg/ml) as compared to both gram‐positive bacteraemias (Gr+, 14pg/ ml; range 7‐60 pg/ml; P < 0 05) and blood culture negative episodes (BCN, 8pg/ml; range 0‐87pg/ml; P<0 05).

Increased Incidence of Bacteraemia Due to Viridans Streptococci in an Unselected Population of Patients with Acute Myeloid Leukaemia

The aetiology, clinical characteristics and outcome of bacteraemia in patients with acute myeloid leukaemia were studied. All positive blood cultures collected at a haematological ward during 2 7-y periods were evaluated. Altogether, 274 episodes of bacteraemia in 152 patients were recorded, 80 episodes during 1980-86 and 194 during 1990-96. During the 2 periods, trimethoprim-sulfamethoxazol in combination with amikacin was the first-line empirical therapy in patients with neutropaenia and fever. In 1990, antimicrobial prophylaxis with ciprofloxacin and fluconazole was introduced. The incidence of bacteraemia due to viridans streptococci or coagulase-negative staphylococci increased from the first period to the second, whereas the incidence of Enterobacteriaceae decreased. In granulocytopaenic patients during 1990-96, viridans streptococci accounted for 21% of the isolates and in patients treated prophylactically with fluoroquinolone, viridans streptococci accounted for 31%. All viridans streptococci were sensitive to penicillin. At the time of the positive blood cultures, the patients of the second period were granulocytopaenic in 83% of the episodes. The mortality related to septicaemia during the later period was 13% and only 1 of 33 (3%) of the patients with viridans streptococci died. Eight patients (9%) died in relation to septicaemia following curative antileukaemic therapy.The aetiology, clinical characteristics and outcome of bacteraemia in patients with acute myeloid leukaemia were studied. All positive blood cultures collected at a haematological ward during 2 7-y periods were evaluated. Altogether, 274 episodes of bacteraemia in 152 patients were recorded, 80 episodes during 1980-86 and 194 during 1990-96. During the 2 periods, trimethoprim-sulfamethoxazol in combination with amikacin was the first-line empirical therapy in patients with neutropaenia and fever. In 1990, antimicrobial prophylaxis with ciprofloxacin and fluconazole was introduced. The incidence of bacteraemia due to viridans streptococci or coagulase-negative staphylococci increased from the first period to the second, whereas the incidence of Enterobacteriaceae decreased. In granulocytopaenic patients during 1990-96, viridans streptococci accounted for 21% of the isolates and in patients treated prophylactically with fluoroquinolone, viridans streptococci accounted for 31%. All viridans streptococci were sensitive to penicillin. At the time of the positive blood cultures, the patients of the second period were granulocytopaenic in 83% of the episodes. The mortality related to septicaemia during the later period was 13% and only 1 of 33 (3%) of the patients with viridans streptococci died. Eight patients (9%) died in relation to septicaemia following curative antileukaemic therapy.

Response to splenectomy is durable after a certain point in time in adult patients with chronic immune thrombocytopenic purpura

Abstract:  Splenectomy may lead to a good response in 60–80% of adult patients with corticosteroid refractory idiopathic thrombocytopenic purpura (ITP) but, the long‐term response to splenectomy still remains less well defined. We assessed the long‐term efficacy and safety of splenectomy in adult patients with chronic ITP. A cohort of 59 splenectomised ITP patients (M/F = 25/34; median age 39 yr; range 14–75) were followed up for a median of 18 yr (range 2–32). No life‐threatening surgical complications were observed. The overall response rate was 78% with 59% complete remission (CR) and 19% partial remission (PR). CR and PR patients were younger than non‐responding patients at time of diagnosis (median age: 36 yr vs 48 yr, P = 0.03) and at splenectomy (median age: 38 yr vs 51 yr, P = 0.02). Among the 46 responding patients, eventually 17 had relapse. No disease progression occurred after 12.1 and 7.3 yr for patients in CR or PR, respectively. One case of fatal septicaemia was recorded. We conclude that splenctomy is an effective and safe treatment in adult patients with chronic ITP failing to respond to corticosteroid treatment and importantly, our findings support the view that response to splenectomy is durable after a certain point in time.

Liposomal Amphotericin B and Surgery in the Successful Treatment of Invasive Pulmonary Mucormycosis in a Patient with Acute T-Lymphoblastic Leukemia

Pulmonary mucormycosis is a usually fatal opportunistic infection in immunocompromised patients. We describe the first case of an adult patient with hematological malignancy and profound neutropenia to survive a disseminated pulmonary Rhizomucor pusillus infection. Early diagnostic procedures combined with high doses of liposomal amphotericin B and surgical resection may have contributed to the successful outcome.Pulmonary mucormycosis is a usually fatal opportunistic infection in immunocompromised patients. We describe the first case of an adult patient with hematological malignancy and profound neutropenia to survive a disseminated pulmonary Rhizomucor pusillus infection. Early diagnostic procedures combined with high doses of liposomal amphotericin B and surgical resection may have contributed to the successful outcome.

Trimethoprim-sulfamethoxazole plus amikacin versus ceftazidime monotherapy as empirical treatment in patients with neutropenia and fever.

In a prospective randomized comparison, 217 episodes of fever (oral temperature > 38.5 degrees C on 1, or 38.0 degrees C on 2 occasions with a minimum interval of 4 h between recordings) during neutropenia (neutrophil count < 0.5 x 10(9)/I), patients were empirically treated with trimethoprim-sulfamethoxazole plus amikacin (TMP/SMZ plus AMI) or ceftazidime. Successful antibiotic treatment was defined as eradication of all signs, symptoms and microbiological evidence of infection on the primary therapy alone. The overall success rate did not differ between the 2 treatment groups: 31/102 (30%; 21-39%, 95% confidence interval, CI) for TMP/SMZ plus AMI and 41/115 (36%; 27-44%) for ceftazidime (difference 0.06 +/- 0.13, 95% CI). The corresponding numbers for documented infections were 12/50 (24%; 12-36%) and 14/60 (23%; 12-35%), respectively (difference 0.01 +/- 0.16). One patient in the TMP/SMZ plus AMI group and 2 patients in the ceftazidime group died from Gram-negative bacteraemias within 72 h. No other early deaths were observed. Antibiotics were changed due to adverse events in 2 episodes of each treatment group. In conclusion, this study demonstrates that TMP/SMZ plus AMI combination is comparable (i.e. a difference of < 20%) to ceftazidime monotherapy with regard to efficacy and safety in haematological patients with severe neutropenia. Both regimens require frequent modifications, particularly in bacteraemic fever episodes. However, in centres with a low frequency of isolation of Pseudomonas and especially of multi-resistent Pseudomonas strains, TMP/SMZ plus AMI offers an inexpensive alternative for the empirical treatment of febrile neutropenia.

Increase of monocytes predicts mobilization of peripheral stem and progenitor cells after chemotherapy followed by G‐CSF administration

Abstract: Mobilization of primitive haematopoietic cells to the peripheral blood was studied in 25 patients with haematological malignancies. The optimal level of peripheral stem cells (PSC), defined by their surface expression of CD34, was significantly higher after mobilization with G‐CSF, either following chemotherapy or alone (median: 123 × 106/l and 143 × 106/l of CD34+ cells respectively) than without administration of G‐CSF subsequent to chemotherapy (median: 27 × 106/l of CD34+ cells). An individual variation in when optimal mobilization of CD34+ cells and myeloid progenitors occurs after chemotherapy and G‐CSF administration was noted (median: day 12, range 7–24 days), which makes it difficult to predict when PSC collections in a given patient should be performed. In this study, chemotherapy followed by G‐CSF administration resulted in a short lasting (2–3 days) peak appearance of CD34+ cells that could predicted by a 2‐fold increase in absolute numbers of monocytes, as compared to the previous day. After the peak level of CD34+ cells in the blood was reached, no further increase in monocytes was seen. The identification of an increase in monocytes, to be used as a predictive variable for when optimal mobilization of PSC will occur in a given patient, may be particularly useful in the individual timing of PSC collections from non‐hospitalized patients.