[Kingella kingae septicemia in a patient with coxsackievirus infection]. / Septicémie à Kingella kingae chez une patiente présentant une infection à virus Coxsackie.

Kingella kingae is a gram-negative cocci present in the oral flora ; this organism is difficult to isolate by conventional culture techniques ; it can be detected after longer incubation period (more than 6 days) in blood culture. It is responsible of various infectious diseases, especially in children below 3 years-old where it is a cause of arthritis and osteomyeli tis. It is included in HACEK organisms responsible of 2 to 3 % of all cases of native endocarditis. The case report is the case of a young women with Kingella kingae septicemia in a context of oral lesions from Coxsackie virus infection ; treatment by ciprofloxacine permit a complete resolution of symptoms. Differential diagnosis is made about conditions with oral lesions. This article is an occasion to review literature about this unusual organism and clinical presentation. Improvements in laboratory method will in the future increase incidence and prevalence of infections caused by Kingella kingae.

Le Kingella kingae est un cocci Gram-négatif présent dans la flore buccale ; c'est un organisme qui est difficile à isoler par les techniques de culture conventionnelles ; ainsi, il peut être mis en évidence après des périodes d'incubation plus longues (plus de 6 jours) dans les hémocultures. Il est responsable de diverses pathologies infectieuses, notamment chez l'enfant où il peut occasionner une arthrite ou une ostéomyélite, essentiellement en-dessous de l'âge de 3 ans. Il fait partie des organismes HACEK responsables de 2 à 3 % des endocardites infectieuses. Le cas rapporté dans cet article est celui d'une jeune femme présentant une septicémie à Kingella kingae dans un contexte de lésions buccales dues à une infection par virus Coxsackie ; un traitement antibiotique par ciprofloxacine a permis une résolution complète des symptômes. Cet article est l'occasion d'une revue de la littérature concernant cette présentation clinique et ce germe inhabituels.

Association between protective efficacy of anti-lipopolysaccharide (LPS) antibodies and suppression of LPS-induced tumor necrosis factor alpha and interleukin 6. Comparison of O side chain-specific antibodies with core LPS antibodies.

Two-core LPS antibodies, the rabbit J5 polyclonal antiserum and the human anti-lipid A IgM mAb HA-1A, did not improve the survival of mice challenged with E. coli O111 or P. aeruginosa 3, or with the LPS extracted from them, and did not decrease the incidence of Shwartzman reactions in rabbits challenged with O111 LPS. In contrast, O side chain-specific rabbit antisera were protective in these models. The protection afforded by O side chain-specific antisera against endotoxin lethality was associated with decreased LPS-induced serum TNF and IL-6 levels, whereas core LPS antibodies had no effect on TNF or IL-6 levels. The absence of reduction of LPS-induced cytokines levels by core LPS antibodies suggests that these antibodies are not able to prevent the interactions between LPS and target cells.

Causes of deaths in an oncologic intensive care unit: a clinical and pathological study of 34 autopsies.

We reviewed the charts of the cancer patients admitted in a medical oncology ICU during an 11-month period. Among 330 admissions (55% for a medical complication, 45% for monitoring during administration of an intensive or potentially toxic treatment), 49 patients died and 34 autopsies were performed. Every autopsied case was reviewed by a group of oncologists and pathologists. The direct cause of death was neoplasia itself in only four patients. Six deaths remained unexplained after post mortem examination. In 23.5% of cases, the direct cause of death was a major infection (four aspergillosis, two candidemia, one CMV pneumonia, one acute cholecystitis). Overall, the clinical diagnosis of the immediate cause of death was correct in only 41% of the cases. Lesions of pulmonary edema (PE) were found at autopsy in 68% of the cases. No predictive factors for PE were determined.

High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group.

PURPOSE AND PATIENTS: We measured the serum concentrations of interleukin-6 (IL-6) in 70 patients with established septic shock caused predominantly by gram-negative bacteria. The aims of the study were to determine whether and for how long IL-6 was detectable in the circulation of these patients, to assess whether IL-6 levels were associated with patients' outcomes, and, finally, to examine the interplay between IL-6, tumor necrosis factor (TNF), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma). RESULTS: IL-6 was detected in 64% of the patients at study entry but in only 18% on Day 1 and 2% on Day 10. Serum levels of IL-6 were higher (median: 3.5 ng/mL, range: less than 0.1 to 305 ng/mL) in patients dying of fulminant septic shock than in those surviving (median: 0.5 ng/mL, range: less than 0.1 to 135 ng/mL; p = 0.003) or in those with a transient reversal of shock but who ultimately died of a relapse of shock (median: less than 0.1 ng/mL, range: less than 0.1 to 12.5 ng/mL; p = 0.005). However, no cutoff values of IL-6 confidently predicted the outcome of an individual patient. The serum concentrations of IL-6 measured at study entry correlated with the duration of survival (r = -0.51, p = 0.004) and with the levels of TNF-alpha (r = 0.53; p less than 0.0001) but not with the levels of either IL-1 beta (r = 0.01, p = 0.90) or IFN-gamma (r = 0.06, p = 0.60). CONCLUSIONS: These results indicate that circulating levels of IL-6 are detectable in a majority of patients with gram-negative septic shock. Concentrations of IL-6 peaked near the onset of shock and rapidly decreased to undetectable levels within approximately 24 hours in most patients. Levels of IL-6 measured at study entry correlated with levels of TNF and with patients' outcomes. Yet, IL-6 does not appear to be a clinically useful laboratory test for predicting the outcome of an individual patient.

Use of the quinolones in the prophylaxis and treatment of granulocytopenic immunocompromised cancer patients.

The potential use of the quinolones in the prophylaxis and treatment of febrile episodes in granulocytopenic patients is reviewed. Of 7 controlled prophylactic studies performed with quinolones, 2 were double-blind and placebo-controlled. The occurrence of fever and mortality due to infection was not reduced with quinolone prophylaxis, although the occurrence of Gram-negative bacteraemia was significantly reduced. The delay to first fever was occasionally increased, and this was associated with a reduction in the number of days with antimicrobial agents. No effect was observed on disseminated fungal infections with quinolone prophylaxis. Breakthrough bacteraemia and subsequent infections were due to resistant organisms, mainly Gram-positive organisms (streptococci, staphylococci). Tolerability and compliance were excellent and were occasionally better than with the classic regimen [nonabsorbable antibiotics and cotrimoxazole (trimethoprim/sulfamethoxazole)]. Six controlled studies dealing with empiric treatment with the quinolones were reviewed. Overall, the results suggested that monotherapy with ciprofloxacin may be used in patients with a good prognosis (short and less severe neutropenia, solid tumours, compliant patients). Combinations with broad spectrum penicillins, netilmicin or teicoplanin seem to be as effective as the classic regimens (a broad spectrum penicillin or cephalosporin plus aminoglycosides), although the number of patients was limited (n = 334). The response rate of Gram-positive bacteraemia was lower with quinolone-containing regimens except for a combination that included teicoplanin.

Systemic and hemodynamic effects of recombinant tumor necrosis factor alpha in isolation perfusion of the limbs.

OBJECTIVE: To describe the systemic effects of high-dose recombinant tumor necrosis factor alpha (rTNF-alpha), recombinant interferon gamma (rIFN-gamma), and melphalan administered through hyperthermic isolation perfusion of the limbs (IPL) in patients with melanoma and malignant soft-tissue tumors. DESIGN: The clinical, hemodynamic, and biologic parameters were recorded after IPL during the postoperative period. SETTING: Surgical intensive care service of a 1,000-bed tertiary university medical center. PATIENTS: Nineteen patients referred to a pluridisciplinary Center for Oncology after relapse of regionally advanced melanoma or soft-tissues tumors, included in a phase 2 therapeutic study. RESULTS: Major systemic and hemodynamic changes were observed after IPL in all patients. Ninety-four percent (17/18) of the evaluable patients presented a shock unresponsive to fluid challenge, requiring the continuous perfusion of vasopressors, inotropic agents, or both. Analysis of hemodynamic data showed two distinctive patterns: a pure distributive shock in nine patients requiring norepinephrine, and a mixed distributive and cardiogenic shock in eight patients requiring vasopressor and inotropic agents. The oxygen parameters were characterized by an increase in both the delivery and the uptake of oxygen, with a prolonged reduced oxygen extraction ratio for most patients. The other observed effects were as follows: transient bilateral or mixed pulmonary infiltrates in all patients; some hematologic disturbances in 83% of patients; infection requiring a modification of the antibiotic prophylaxis in 61% of patients; and some liver toxic reactions in 50% of patients. Very high systemic TNF-alpha serum bioactivity was found in 12 patients for whom serum samples were available, indicating an early and important rTNF-alpha leakage from the IPL. No correlations could be found between the levels of TNF-alpha and the observed systemic effects. Despite the severity of the hemodynamic disturbance, no patient died. CONCLUSION: Major systemic effects, consisting mainly in cardiovascular, respiratory, and hematologic disturbances, were observed in patients after IPL with high-dose of rTNF-alpha. The likely explanation for these observations is an early rTNF-alpha leakage related to inadequate IPL technique. These data show that the iatrogenic administration of high circulating TNF levels lead to a "septic shock-like" syndrome without resulting in lethal organ dysfunction.

Bacteraemia caused by non-aeruginosa Pseudomonas species in a cancer centre.

Fifty-one episodes of bacteraemia due to Pseudomonas species other than Pseudomonas aeruginosa occurring between 1980 and 1990 in a Belgian cancer centre were reviewed. This corresponded to an incidence of 0.62/1000 admissions, or 1.5% of all bacteraemic episodes. Twenty-nine episodes, each with several positive blood culture sets were considered clinically significant, including six patients belonging to a well-documented outbreak of pseudobacteraemia with Xanthomonas maltophilia and associated with contaminated blood sampling tubes. The respiratory tract was the source in six (20.7%), an infected intravenous catheter in 10 (34.5%) and the source was unknown in seven (24.1%). Seven patients died from infection (24.1%). Twenty-three episodes with a single positive blood culture set were considered clinically not significant, although four of them were considered significant by the Centers for Disease Control (CDC) criteria because of the presence of symptoms and specific antibiotic treatment being administered. None of the patients with a single isolate died from infection despite the fact that 17 of 22 did not receive an effective antimicrobial agent. All isolates were susceptible to co-trimoxazole.

[Efficacy of the tumor necrosis factor-alpha (rTNF-alpha) associated with interferon-gamma and chemotherapy in extracorporeal circulation in the limb in inoperable malignant melanoma, soft tissue sarcoma and epidermoid carcinoma. A 4-year experience]. / Efficacité du facteur de nécrose tumorale-alpha (rTNF-alpha) associé à l'interféron-gamma et à la chimiothérapie en circulation extracorporelle du membre isolé dans le mélanome malin, les sarcomes des tissus mous et les carcinomes épidermoïdes inopérables. Expérience de 4 années.

The authors review their experience of 4 years with isolated limb perfusion for the application of high dose TNF-alpha associated to IFN-gamma and melphalan for the treatment of regionally advanced tumours such as malignant melanoma, soft tissue sarcoma and epidermoid carcinoma. In malignant melanoma, the complete remission rate reaches 91%. In irresectable soft tissue sarcoma, this treatment when used as a neoadjuvant treatment saves the limb from amputation in 87.5% of the cases. Similar results are obtained for epidermoid carcinoma. With the regional application of high doses of TNF-alpha associated to chemotherapy and IFN-gamma, it has been possible to validate the concept of a strategy based on a dual targeting, that is the selective impact of the intratumoral vessels by TNF-alpha and of the tumour cells by chemotherapy. This approach appears to be the treatment of choice for locally advanced tumours of the limbs. However, as a single therapy, this procedure should be considered in melanoma as an induction therapy, and in sarcoma, as a preoperative treatment.

[Prevention using pefloxacin of infections in cancer patients with granulocytopenia]. / Prévention par la péfloxacine des infections chez les malades cancéreux granulocytopéniques.

The practical procedures of digestive tract decontamination and prophylaxis of bacterial infection in granulocytopenic patients are debated. Fluoroquinolones are active against Gram-negative bacilli and have few side-effects. Pefloxacin was administered prophylactically to patients with cancer and granulocytopenia. None of them developed Gram-negative septicaemia, but 2 cases of streptococcal septicaemia were observed. The drug was well tolerated by all patients except one. Studies are currently in progress to try to reduce the incidence of septicaemia caused by Gram-positive cocci, using pefloxacin combined with penicillin.

[Prevention of bacterial infections using ciprofloxacin in granulocytopenic patients with cancer]. / Prophylaxie des infections bactériennes par la ciprofloxacine chez les patients cancéreux granulocytopnéiques.

The optimal approach to reduce bacterial infections in granulocytopenic patients is still controversial. Recently, fluoroquinolones have been developed and real progress has been achieved in the prevention of Gram negative bacilli septicemia. This study reports our experience with ciprofloxacin and shows the excellent tolerance of ciprofloxacin by our patients as well as promising data for the reduction of Gram negative bacilli infection. However, practical modalities to prevent infection caused by Gram positive cocci remain to be defined.

[Erythema nodosum and AIDS]. / Erythema nodosum und AIDS.

We report on a patient with AIDS who developed erythema nodosum, an association that has not previously been reported. Extensive clinical and laboratory investigations disclosed no obvious origin of erythema nodosum apart from HIV infection with disseminated Kaposi sarcoma.

High serum levels of TNF-alpha after its administration for isolation perfusion of the limb.

In a phase II study, 18 patients with locally spreading melanoma or sarcoma of lower limb were treated by isolation perfusion (ILP) with hyperthermia and local infusion of high dose of recombinant human tumor necrosis factor alpha (rHuTNF-alpha) (4 mg). Bioactive TNF-alpha and interleukin 6 (IL-6) serum levels were measured serially. In the limb, TNF-alpha rapidly reached a plateau at 2 mu/ml, while IL-6 appeared later and progressively increased until the end of ILP. In the systemic circulation TNF-alpha rose up to a median concentration of 31 ng/ml after 1 hour, then decreased and became negligible after 6 hours. IL-6 peaked only after 5 hours after start of ILP (median: 36.7 ng/ml). In patients with substantial leakage towards systemic circulation, both cytokines peaked higher and earlier as compared with patients with minimal leakage. No correlation was found between cytokine levels and severity of side effects which in all cases were reversible. We conclude that high dose TNF-alpha infusion in ILP results in extremely high levels of bioactive TNF-alpha in the systemic circulation without irreversible side effect, and provokes a delayed blood release of large amounts of IL-6; there was a correlation between leakage from the limb during procedure and the magnitude of systemic cytokines levels.

Circulating concentrations of interleukin-6 in cancer patients and their pathogenic role in tumor-induced hypercalcemia.

Circulating interleukin-6 (IL-6) concentrations correlate with disease activity in severe inflammatory conditions, in sepsis and in some hematological malignancies. On the other hand, IL-6 is a potent stimulator of osteoclastogenesis and has been implicated as a contributory factor in the genesis of osteopenic conditions. We measured circulating IL-6 levels by a sensitive (detection limit of 10 U/ml) and specific bioassay in 103 patients with advanced cancer, including 41 with tumor-induced hypercalcemia before any specific hypocalcemic therapy. We related IL-6 concentrations to clinical features and to biochemical parameters of bone metabolism, including blood Ca, Ca2+, Pi, intact parathyroid hormone, parathyroid hormone-related protein, osteocalcin, 1,25-(OH)2-vitamin D and, as markers of bone resorption, the fasting urinary excretion of calcium (Ca/creatinine) and hydroxyproline. IL-6 levels were increased, i.e. detectable, in 23% of the patients, 8/41 (20%) hypercalcemic and 16/62 (26%) normocalcemic patients (NS); the distribution of the values was similar in the two groups. The presence of increased IL-6 concentrations was not related to any clinical characteristic, notably not to the survival nor to the existence of bone metastases, whether in hypercalcemic or normocalcemic patients; e.g., only 3/12 (25%) hypercalcemic subjects without bone metastases had elevated IL-6 levels. We found no significant correlations between IL-6 concentrations and any of the biochemical parameters studied. Hypercalcemic subjects with increased IL-6 had higher urinary Ca/creatinine levels than patients with normal IL-6 levels (P < 0.005) but this was not the case in normocalcemic subjects. Mean concentrations of inflammatory or other bone metabolism markers were not significantly different between patients with normal or with elevated IL-6 levels. In summary, circulating IL-6 levels were increased in 23% of 103 patients with advanced cancer, but the frequency of increased IL-6 concentrations was not related to the presence of hypercalcemia or to any marker of calcium metabolism or bone turnover. The pathogenic importance of circulating IL-6 in patients with solid tumors remains to be demonstrated and our data indicate that increased circulating levels of IL-6, possibly reflecting the activation of the immune system, only contribute in a minor way to the osteolytic process in patients with tumor-induced hypercalcemia.

Blood inflammatory response to inhaled endotoxin in normal subjects.

Previously we have reported that in asthmatics an inhalation of 20 micrograms lipopolysaccharide (LPS) produces a bronchial obstruction associated with an inflammatory blood response. The aim of the present study was to evaluate this response in normal subjects. Eight normal non-atopic subjects were challenged by inhalation of a solution containing 20 micrograms LPS (from Escherichia coli 026:B6) a week after bronchial challenge with control solution. The lung function response was evaluated by the changes in forced expiratory volume in one second (FEV1), in specific conductance and in airway resistance while the blood inflammatory response was evaluated by serial measures of total white blood cells (WBC) and polymorphonuclear neutrophils (PMN) count, luminol enhanced-chemiluminescence (luminol-CL, as a marker of the PMN degree of activation), C-reactive protein (CRP), haptoglobin, complement fraction C3, tumour necrosis factor-alpha (TNF-alpha) and adrenocorticotropic hormone (ACTH). No response in lung function was observed for 6 h after the LPS inhalation. The count in WBC and PMN increased 300 (P < 0.01) and 360 (P < 0.01) min after the LPS challenge associated with an increase in the level of luminol-CL (P < 0.001). This rise in luminol-CL level was significant at 120 min (P < 0.05) before any change in the PMN count. After 24 and 48 h the acute-phase protein CRP raised significantly (P < 0.01), the other proteins C3 and haptoglobin being unchanged. A slight increase in ACTH was observed 240 and 360 min (P < 0.05) after the LPS challenge while the TNF alpha detectable level was not modified.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic release of soluble TNF receptors after high-dose TNF in isolated limb perfusion.

Isolated limb perfusion (ILP) with high dose tumour necrosis factor (TNF), interferon gamma and melphalan (TIM) is an efficient treatment for patients with regionally advanced melanoma and sarcoma. In 44 patients, we determined the kinetics of soluble TNF receptors (sTNF-RI and RII) plasma concentrations, and correlated them with systemic TNF and interleukin 6 (IL-6) levels and shock. Seven patients treated conventionally by ILP without cytokine served as controls. Elevated levels of both sTNF-Rs were observed within 30 min after beginning of the TIM-ILP. A first peak of sTNF-Rs levels was observed 3 h after ILP and was followed by a rapid decrease reaching a nadir at 12-14 h post ILP. This first peak was followed by a second, long-lasting elevation of both sTNF-Rs levels persisting for 4 to 5 days after TIM-ILP. Patients treated by ILP without TNF/interferon gamma (IFN-gamma) had no detectable increase in either sTNF-Rs or in circulating TNF, demonstrating that the release of TNF-Rs was dependent upon the administration of TNF/IFN-gamma. High plasma levels of TNF and IL-6 were observed in patients that had more than 5% leakage during the TIM-ILP, but no significant correlation between TNF levels and the peak values of both sTNF-Rs was observed. The levels of TNF and IL-6 were, however, significantly related to each other. TNF systemic levels, but not sTNF-Rs concentrations, correlated significantly with the severity of the shock observed after TIM-ILP. Patients in which sTNF-RII concentration was in excess over circulating TNF, had no shock or grade I shock only, suggesting that sTNF-RII may play a protective, although limited, role in inhibiting activity of circulating TNF.

Meropenem versus ceftazidime as empirical monotherapy for febrile neutropenic cancer patients.

A total of 101 cancer patients with 121 febrile neutropenia episodes were randomised to receive empirical treatment with i.v. meropenem (1g/8 h) or ceftazidime (2 g/8 h). After 3 days, 89% of patients were on unmodified therapy in the meropenem group, compared with 83% in the ceftazidime group. Of the evaluable episodes (n = 106), the success rate with unmodified empirical therapy until the end of the treatment course was slightly higher with meropenem than with ceftazidime (48% vs 38%, P=0.39). Furthermore, initial success with further infections was observed in 22% of episodes treated with meropenem and in 13% of episodes treated with ceftazidime. Glycopeptides were used as first modification in 28% and 39% of meropenem and ceftazidime recipients, respectively. Both treatments were well tolerated and there were no reports of drug-related nausea/vomiting or seizures. No significant differences in response rate or in tolerability were observed when analysing only the first febrile episodes. In conclusion, meropenem seems to be as efficacious and well tolerated as ceftazidime and may be associated with a lesser requirement for the addition of glycopeptides.

About two cases of Mycobacterium simiae infection in AIDS: review of the pathogenicity.

Mycobacterium simiae is an ubiquitous species rarely involved as a cause of human infection. Its pathogenicity remains therefore unclear and controversial. Disseminated infections with M. simiae occur rarely and only 7 cases have been reported in patients with acquired immunodeficiency syndrome (AIDS). At least, two were mixed infections caused by M. simiae and M. avium-intracellulare. We report the case of two AIDS patients presenting with pure M. simiae infections: one was a disseminated infection and the other a pulmonary infection. Epidemiology and pathogenicity of M. simiae in pulmonary, extra-pulmonary and disseminated infections are reviewed.