Jonathan Cohen

Septicaemia caused by viridans streptococci in neutropenic patients with leukaemia.

10 neutropenic leukaemic patients had septicaemia caused by viridans streptococci, organisms not commonly recognised as opportunist pathogens. 1 patient died; in the remainder recovery was generally dependent on an adequate circulating granulocyte count (seven patients) rather than specific antimicrobial therapy. Seven of the infections were caused by Streptococcus mitis, and seven of the eight strains tested were resistant to cotrimoxazole, which the patients had received as prophylaxis against infection. It is suggested that oral ulceration caused by cytotoxic chemotherapy provided a portal of entry for cotrimoxazole-resistant viridans streptococci. The increasing incidence of infections with gram-positive organisms as a complication of neutropenia prompts a reconsideration of current empirical antimicrobial therapy.

Meningococcal septicaemia in a C6-deficient patient and effects of plasma transfusion on lipopolysaccharide release

Patients whose blood is deficient in the terminal component of complement have an increased susceptibility to meningococcal infection. However, mortality from meningococcal infection is lower in these patients than in immunocompetent subjects. We studied a C6-deficient patient with meningococcal sepsis who received fresh frozen plasma (FFP). The patients initial plasma endotoxin, C6, and terminal-complement-complex concentrations were low, but rose sharply after treatment with FFP. Samples of the patients serum taken shortly after admission did not cause endotoxin release from Escherichia coli J5 in vitro, but endotoxin-releasing activity was restored in serum samples taken after infusion of FFP. It is possible that C6-deficient patients have reduced mortality from meningococcal infection because their serum cannot cause acute release of endotoxin from the invading organism and extensive tissue damage is thus avoided.

Raised intracranial pressure and visual complications in AIDS patients with cryptococcal meningitis

The clinical course of cryptococcal meningitis in AIDS shows some important differences from the features of the illness in non-AIDS patients. Complications such as raised intracranial pressure and visual impairment that are recognised in non-AIDS patients may be less frequent in those with AIDS. Persistent intracranial hypertension should be managed actively to prevent visual impairment. In AIDS patients, in whom ventriculo-peritoneal shunts carry additional risks, acetazolamide can be used successfully to lower the CSF pressure and prevent visual loss.

Optimal collection of blood samples for the measurement of tumor necrosis factor α

We have examined how delayed separation of plasma from cells affects the recovery of recombinant human tumor necrosis factor alpha (rhTNF alpha) from whole blood. Storage of heparinized whole blood samples at room temperature for 1 hr results in a significant (p = 0.036) fall in recovery of plasma TNF alpha from 788 +/- 119 pg/mL to 472 +/- 77 pg/mL, measured by specific enzyme-linked immunosorbent assay (ELISA). Storage of whole blood samples at 4 degrees C for 1 hr reduces but does not prevent the fall in recovery of plasma TNF alpha: 725 +/- 82 pg/mL at time 0, 472 +/- 81 pg/mL after 1 hr, p = 0.038. Recovery of bioactive TNF alpha (cytotoxocity for L929 cells) after 1 hr at room temperature is also significantly reduced from 576 +/- 139 pg/mL to 450 +/- 154 pg/mL, p = 0.036. Studies with 125I-rhTNF alpha confirmed the fall in plasma activity and revealed a rapid commensurate increase in 125I-rhTNF alpha activity in the cell fractions. We recommend that clinical samples for the measurement of cytokines should be kept at 4 degrees C and separated rapidly (within half an hour) before storing the plasma at -70 degrees C.

A prospective, randomized comparison of ceftazidime and ciprofloxacin as initial empiric therapy in neutropenic patients with fever

This study developed further clinical experience in using a single agent (monotherapy) as empirical treatment for neutropenic patients with fever, and compared the safety and toxicity of two candidate agents, ceftazidime and ciprofloxacin. A prospective, randomized, single-center efficacy and safety comparison was conducted of intravenous ciprofloxacin, 200 mg every 12 hours, and ceftazidime, 2 g every eight hours, as initial empirical therapy in neutropenic patients with fever. Regimens were modified as necessary, guided by laboratory results and/or the clinical condition. Response was evaluated at 72 hours and at the end of the neutropenia. Toxicity was evaluated by regular clinical examination and laboratory investigations. A total of 43 patients with 51 febrile neutropenic episodes were enrolled into the study and randomly assigned to one of the two regimens. Five episodes were excluded from evaluation of efficacy because of protocol violations, leaving 46 evaluable episodes (21 ciprofloxacin, 25 ceftazidime). The two groups were well matched for risk factors for infection. There were no differences between the two groups in response rates either at 72 hours or at the end of neutropenia, although in the vast majority of patients some modification of the initial therapy was required. No patients died of uncontrolled bacterial infection. Superinfection with gram-positive cocci (often streptococci) was seen primarily in bone marrow transplant recipients who had been randomly assigned to receive ciprofloxacin. This study demonstrated that, in certain circumstances, a single antibiotic can be used successfully as initial empirical therapy in febrile neutropenic patients. In this study, ceftazidime and ciprofloxacin were generally of equal efficacy, but there appeared to be an increased incidence of streptococcal superinfection in bone marrow transplant recipients who received ciprofloxacin.

ANTIBODY TITRES TO A ROUGH-MUTANT STRAIN OF ESCHERICHIA COLI IN PATIENTS UNDERGOING ALLOGENEIC BONE-MARROW TRANSPLANTATION: Evidence of a Protective Effect Against Graft-versus-host Disease

Much clinical and experimental evidence suggests that infection and graft-versus-host disease (GvHD) are commonly associated as complications of bone-marrow transplantation (BMT). A likely basis for this association is the gram-negative faecal flora,the origin of many septicaemias and a source of bacterial endotoxin, which has potent immunostimulatory effects. A rough-mutant strain, Escherichia coli J5, has only core determinants in its endotoxin,and antibodies to E coli J5 protect animals and human beings from the consequences of septic shock. Naturally occurring antibodies to E coli J5 (anti-endotoxin) were assayed in serum from patients undergoing BMT, healthy controls, and patients with obstructive jaundice. BMT recipients had significantly lower titres than the other two groups. Furthermore, the titre of IgM class anti-J5 antibody was significantly associated with protection from GvHD.

Invasive aspergillosis: clinical and pathological features of a new animal model

A new animal model of invasive aspergillosis is described in which female New Zealand White rabbits were immunosuppressed with corticosteroids and cyclophosphamide and were given an intratracheal inoculation of 4 x 10(4) conidia of Aspergillus fumigatus. Thirteen of 15 animals survived during a 10-day-period of observation. Most had clinical signs of a respiratory infection (dyspnoea) and at autopsy there was macroscopic and microscopic evidence of invasive pulmonary aspergillosis. Six control animals (infected but not immunosuppressed) showed no such signs. The extent of hyphal invasion was assessed histologically and quantified by calculating the number of colony forming units (c.f.u.) g-1 of tissue: in the experimental group the mean c.f.u. value for the lungs was 1.25 x 10(3) compared to 73.3 c.f.u. g-1 of lung for the control group (P = 0.003). The infection was also quantified by a whole lung chitin assay: in the experimental group the mean chitin content (expressed as a glucosamine equivalent) was 3.05 micrograms g-1 lung tissue compared to a 0.53 micrograms g-1 lung tissue for the control group (P = 0.01). We conclude that this model of invasive aspergillosis in rabbits reflects closely the pathological features of the disease in man and that it may prove useful for studies of the pathogenesis and the treatment of invasive aspergillosis.

Pituitary apoplexy secondary to an underlying abscess

An unusual case of pituitary apoplexy in a patient with pituitary abscess is described. The patient was found to have underlying chronic lymphocytic leukaemia and an associated hypogammaglobinaemia is postulated as being the predisposing cause for infection.

Management of septic shock

Septic shock due to bacterial and other infections remains an increasing cause of hospital mortality and morbidity. Early recognition and prompt management with diagnostic evaluation, antimicrobial therapy, surgery when indicated and advanced life support undoubtedly saves many lives. Once treatment has been instituted, careful and frequent monitoring is required to optimise therapy and detect complications at an early stage. However, once shock and organ failure have become established the mortality remains high and has changed little in the last few years despite improvements in intensive management. A variety of other approaches to treatment are under investigation but as yet there are insufficient data to recommend their use.

Do monoclonal antibodies and anticytokines still have a future in infectious diseases

The continuing high mortality of septic shock has prompted a major effort by the research community to identify novel therapeutic targets. These targets can be conveniently grouped into (1) those derived from microbial components or products; (2) inflammatory mediators; and (3) effector molecules. Many of the experimental, so-called adjunctive agents developed have been monoclonal antibodies or anticytokine molecules of various kinds, and some have progressed into clinical trial. Unfortunately, these trials have failed to show unequivocal survival benefit for patients in shock, prompting a reappraisal of our approach to these agents. In this article, we discuss the possible reasons for these failures: (1) the targets are wrong; (2) the agents are inappropriate; or (3) the trial design is flawed. It would be premature to conclude that adjunctive agents have no future in the therapy of sepsis, but identifying the correct agent, and perhaps more importantly, the correct target population, is going to be more difficult than was at first believed.