The eye in systemic infection.

Bacterial, fungal, viral, and parasitic pathogens all cause systemic infection and can spread to the eye. Dissemination of pathogens via the bloodstream can lead to direct involvement of the eye. Visual loss is common in bacterial or fungal endophthalmitis, and toxoplasmosis is a major cause of ocular morbidity and poor vision after congenital or acquired infection. Some infections cause intraocular damage by indirect mechanisms (eg, HIV-mediated immunosuppression), leading to opportunistic infections such as cytomegalovirus infection, periocular nerve involvement due to leprosy, and hypersensitivity reactions in tuberculosis. Eye symptoms might indicate the outcome of an underlying infection, such as development of retinal ischaemia in severe malaria, which is associated with a poor prognosis. Successful outcome for patients with ocular infection depends on close collaboration between clinicians identifying and treating underlying disease, specialist ophthalmic review, and ophthalmic interventional skills (when needed).

The wandering eye: eye infection in the returning traveller.

The eye may represent the presenting features of an illness in the returning traveller. In other patients it may serve as a useful marker of severity. Clinicians seeing this group of patients need to have an understanding of the ocular mainfestations of travel related illnesses. The article reviews the features of major imported infections such as malaria, dengue and brucella, in addition to other clinically important conditions that may present to ophthalmologists and travel health specialists.

Syphilis and HIV: a dangerous combination.

HIV and syphilis affect similar patient groups and co-infection is common. All patients presenting with syphilis should be offered HIV testing and all HIV-positive patients should be regularly screened for syphilis. Syphilis agent may enhance the transmission of the other, probably through increased incidence of genital ulcers. Detection and treatment of syphilis can, therefore, help to reduce HIV transmission. Syphilis may present with non-typical features in the HIV-positive patient: there is a higher rate of symptomless primary syphilis and proportionately more HIV-positive patients present with secondary disease. Secondary infection may be more aggressive and there is an increased rate of early neurological and ophthalmic involvement. Diagnosis is generally made with serology but the clinician should be aware of the potential for false-negative serology in both primary and, less commonly, in secondary syphilis. All HIV-positive patients should be treated with a penicillin-based regimen that is adequate for the treatment of neurosyphilis. Relapse of infection is more likely in the HIV-positive patient and careful follow-up is required.

Heart rate response to peptide histidine valine in human subjects is not mediated through beta receptors.

Peptide histidine valine (PHV) is a 42 amino acid polypeptide closely related to the neuropeptides VIP, PHI and PHM. We have performed a placebo-controlled, double-blind study to assess the hypothesis that the cardiovascular response to PHV infusion may be mediated via the sympathetic nervous system. Four subjects received atenolol or matched placebo 90 min prior to a controlled incremental infusion of PHV, with monitoring of heart rate, blood pressure and skin temperature. Following placebo all subjects showed a dose-related increase in heart rate and skin temperature with no effect on blood pressure during PHV infusion. beta-Blockade had no effect on skin temperature response. Pre-treatment with atenolol reduced the resting blood pressure and the maximum heart rate achieved, but did not affect the percentage increase in heart rate during PHV infusion. This suggests that the action of PHV does not involve beta-receptors. The lack of effect of PHV infusion on blood pressure, despite tachycardia and marked cutaneous vasodilatation, implies that PHV has a different effect on the resistance vessels from that of other peptides such as VIP.

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.

Cerebral nocardia abscesses in a patient with AIDS: correlation of magnetic resonance and white cell scanning images with neuropathological findings.

We present a case of cerebral nocardiosis in a patient with AIDS. Space-occupying lesions were identified using magnetic resonance imaging (MRI) and white cell scanning. Nocardia asteroides was isolated from blood cultures. The patient's response to treatment with amikacin, imipenem and ceftriaxone was followed clinically and radiologically. When he died 6 months later, N. asteroides was isolated at post-mortem from a cerebral abscess. Although cerebral infections associated with the infiltration of neutrophils are rare in patients with AIDS, this case demonstrates that indium-labelled neutrophils can be used to identify a brain abscess and monitor its response to antimicrobial therapy.

Anti-endotoxin therapeutic options for the treatment of sepsis.

The identification of lipopolysaccharide binding protein (LBP) and CD14 as key molecules in the cellular response to endotoxin has been a major advance in unravelling the pathophysiological basis of Gram-negative sepsis. Much interest has focused on developing effective anti-endotoxin treatments to abrogate the inflammatory consequences of Gram-negative infection. The therapeutic options can be divided into those aimed at neutralizing or clearing circulating endotoxin, including anti-endotoxin antibodies and endotoxin neutralizing proteins, and those that antagonize the effects of endotoxin on human cells--for example, lipid A analogues. Initial experiences with anti-lipopolysaccharide antibodies have been disappointing but a new generation of anti-endotoxin agents is about to enter clinical trials. Whether these will prove sufficiently effective to reduce the morbidity and mortality of Gram-negative sepsis remains to be seen.

Glomerulonephritis preceding late relapse of Hodgkin's disease.

We report a case of focal sclerosing glomerulonephritis which developed 11 years after successful treatment of nodular sclerosing Hodgkin's disease. Hodgkin's disease relapsed 7 months later and responded completely to combination chemotherapy with simultaneous improvement in renal function. This case shows that relapse of Hodgkin's disease may occur after a 10 year interval and furthermore it may preceded by nephrotic syndrome. Renal disease in such cases may not recover until the underlying Hodgkin's disease is treated.

Lipopolysaccharide antagonists.

Bacterial lipopolysaccharide (LPS) is a potent and pleiotropic stimulus of immune cells. LPS has important clinical relevance because it has a direct role in the pathogenesis of Gram-negative bacterial infection. The lipid A moiety of LPS is responsible for the toxic effects of LPS. The identification of structural analogs and precursors of lipid A, which are apparently competitive antagonists of the biological actions of LPS, is strong evidence that the actions of LPS are mediated by a specific LPS receptor or family of receptors. Identification and analysis of these LPS receptors with LPS antagonists should help to define the pathways of cellular activation by LPS and lead to the development of novel anti-LPS strategies in the therapy of bacterial diseases.

Adjunctive therapy for septic shock: a review of experimental approaches.

Septic shock remains a major cause of morbidity and mortality, especially in the intensive care setting. A vast array of treatment strategies is under investigation; despite success in animal models, no effective adjunctive therapy has yet been approved for clinical use. This paper reviews the development of experimental therapies for sepsis and discusses those treatments that show promise for application in humans. Approaches to treatment fall into three broad categories: strategies directed against bacterial components, those directed against host-derived inflammatory mediators, and those designed to limit tissue damage. Because septic shock is a dynamic and evolving condition, different strategies may be needed at different stages in the pathogenesis of sepsis. Through carefully performed trials and thoughtful selection of combination therapy aimed at different points in the pathological process, it may be possible in the future to modify the course of this serious condition.

Neither CD14 nor serum is absolutely necessary for activation of mononuclear phagocytes by bacterial lipopolysaccharide.

The stimulation of mononuclear phagocytes by lipopolysaccharide (LPS) is facilitated by the binding of complexes of LPS and LPS-binding protein to CD14. Although it is clear that CD14 is involved in LPS-induced signaling, other investigators have hypothesized the existence of additional signaling pathways in macrophages. We sought to determine whether CD14-independent pathways of monocyte activation might exist. Washed human mononuclear cells responded with reduced sensitivity to LPS in the absence of serum. Anti-CD14 monoclonal antibody (MAb) inhibited the response to LPS in serum-free conditions, but this was easily reversed at higher concentrations of LPS. We established a human monocytic cell line, designated SFM (derived from THP-1), in serum-free medium to examine LPS responses under defined conditions. Differentiation of SFM cells with 1,25-dihydroxycholecalciferol promoted the expression of abundant cell surface CD14. Differentiated SFM cells responded to LPS despite the complete absence of serum proteins for > 20 generations of growth. LPS stimulation of differentiated SFM cells was inhibited by anti-CD14 MAbs only when serum was present. In contrast to anti-CD14 MAb, the LPS antagonists lipid IVa and Rhodobacter sphaeroides lipid A inhibited monocyte activation under serum-free conditions, implying that these compounds compete with LPS at a site distinct from CD14. Undifferentiated SFM cells (expressing minimal CD14) still responded to LPS in serum-free conditions, and anti-CD14 MAb had little inhibitory effect. The addition of purified LPS-binding protein or human serum promoted a CD14-dependent pathway of monocyte activation by LPS in these cells. We conclude that monocytes do not absolutely require serum proteins to be stimulated by LPS and that CD14-independent LPS signaling pathways exist which are inhibitable by lipid IVa and R. sphaeroides lipid A.

A prospective laboratory-based audit of gentamicin use and therapeutic monitoring.

We report a study investigating the proportion of patients in whom therapeutic serum concentrations of gentamicin are achieved in the early phase of treatment and to determine the underlying reasons for sub-optimal therapy. A laboratory based prospective study of 83 courses of gentamicin was performed (excluding patients receiving renal replacement therapy or with bacterial endocarditis) in a London teaching hospital. Of 83 monitored courses 74 had paired levels tested. Initial trough concentrations were > 2 mg/L in nine (12%) and were < 1 mg/L in 51 (69%) indicating levels were seldom in the toxic range. The first monitored peaks were sub-therapeutic in 58 (78%) courses using a cut-off of 5 mg/L and only seven (9%) were greater than 6 mg/L. Of these seven patients, six had troughs levels of greater than 2 mg/L. Of those with initial levels below 5 mg/L, 33 had further serum levels tested, of which 26 (79%) remained below 5 mg/L. Of those for whom dosing information was available 73% received 80 mg t.d.s. and the mean dose for those for which body weight was known was 3.3 mg/kg/day (S.D. = 0.7). Most patients continued to receive 8-hourly dosing with 80 mg of gentamicin, leading to subtherapeutic peak levels in the majority of cases. In those patients with satisfactory peaks, such dosing frequently leads to elevated troughs. This suggests that such dosing practices should be abandoned and replaced with dosing based on body weight and divided into no more than two daily doses.

Lipopolysaccharide-induced stimulation of CD11b/CD18 expression on neutrophils. Evidence of specific receptor-based response and inhibition by lipid A-based antagonists.

Gram-negative bacterial septicemia is a common clinical syndrome resulting, in part, from the activation of phagocytic leukocytes by LPS. By using flow cytometry, we have characterized LPS-induced expression of the beta 2 integrin CD11b/CD18. After exposure to Salmonella minnesota R595 LPS, expression of neutrophil CD11b/CD18 is rapidly upregulated, beginning within 5 min and achieving a peak fluorescence (typically two- to threefold over base line) by 30 min. The increase in CD11b/CD18 expression was similar in kinetics and magnitude to that produced by FMLP, PMA, and human rTNF-alpha. Concentrations of LPS necessary to stimulate a response were as low as 1 ng/ml of R595 LPS; a maximal response was observed between 30 and 100 ng/ml. The upregulation of CD11b/CD18 due to LPS was not interrupted by protein synthesis inhibitors. A group of glucosamine disaccharide lipid A-like molecules: Rhodobacter sphaeroides lipid A, lipid IVA, KDO2IVA, and deacylated LPS were able to block the stimulatory effect of LPS. This inhibition was specific for the actions of LPS as stimulation of polymorphonuclear leukocytes (PMN) by FMLP, human rTNF alpha, PMA, and rewarming were not altered by the disaccharide inhibitors. PMN which were exposed to the specific disaccharide LPS antagonists and then washed, were refractory to stimulation by LPS. The monosaccharide lipid A precursor lipid X also blocked stimulation of neutrophils by LPS, although with a 100-fold reduction in potency. Unlike the disaccharide inhibitors, PMN exposed to lipid X were still responsive to LPS stimulation after washing. The PMN response to LPS was less sensitive in the absence of serum, although upregulation of CD11b/CD18 could still be seen using higher concentrations of LPS. Monoclonal antibody directed against CD14 (clone 3C10), also specifically inhibited LPS induced PMN CD11b/CD18 expression both in the presence and absence of serum. These findings support the hypothesis that LPS stimulates neutrophils by interacting with specific cellular receptors.

The anti-lipid A monoclonal antibody E5 binds to rough gram-negative bacteria, fixes C3, and facilitates binding of bacterial immune complexes to both erythrocytes and monocytes.

Treatment of patients with septic shock using monoclonal antibodies (mAbs) to endotoxin is still controversial. Clinical trials of E5, one of the mAbs directed against the lipid A moiety of lipopolysaccharide (LPS), are currently in progress. The mechanisms of action of this, and other antibodies under clinical evaluation, are, however, poorly understood. In this study we examined in vitro the ways in which E5 interacted with Gram-negative bacteria, complement, erythrocytes and monocytes. By fluorescence-activated cell sorter (FACS) analysis we showed direct, dose-dependent binding of E5 to Escherichia coli (E. coli) and Salmonella minnesota (S. minnesota). Antibody binding to S. minnesota was enhanced by treatment with the beta-lactam antibiotic amoxycillin, but not by treatment with the aminoglycoside gentamicin. Immune complexes formed between E5 and both species of Gram-negative bacteria activated both classical and alternative complement pathways, but only in the case of S. minnesota did this facilitate binding to erythrocyte CR1 and monocyte CR3. Bacterial C3b and iC3b fixation by E5 was quantified using specific mAbs. These observations suggest that E5 may enhance bacterial clearance in several ways: (1) by facilitating direct complement fixation; (2) by facilitating the binding of opsonized bacteria to cells of the mononuclear phagocyte system; (3) by enabling bacteria to bind to erythrocyte CR1 (CD35), allowing safe carriage in the circulation to the fixed macrophages of the liver and spleen; (4) by acting synergistically with beta-lactam antibiotics.

Treatment of adenoviral pneumonitis with intravenous ribavirin and immunoglobulin.

A 67 year old woman developed a severe adenoviral pneumonitis whilst receiving immunosuppressive therapy. She showed clinical and radiological evidence of a response to treatment with nebulised and intravenous ribavirin and intravenous pooled normal human immunoglobulin. To our knowledge this is the first time that such a therapeutic approach has been used in the treatment of a condition which normally carries a very high mortality.