R. Van Furth

Aetiology of community-acquired pneumonia: a prospective study among adults requiring admission to hospital.

BACKGROUND--The prevalence of microorganisms causing community-acquired pneumonia in patients who required admission to hospital was investigated and the percentage of cases whose aetiology remained unknown due to the study design and logistical problems estimated. METHODS--Between January 1991 and April 1993 all patients with community-acquired pneumonia admitted to six hospitals were included in the study. Aetiological diagnosis, categorised as definite, probable and possible, was based on the results of routine microbiological and serological tests. RESULTS--Three hundred and thirty four patients with a median age of 65 (range 17-92) years were enrolled in the study. The diagnosis of community-acquired pneumonia was definite in 108 cases, and probable or possible in 73 and 27 cases, respectively, including dual infections. Streptococcus pneumoniae was the predominant pathogen (27%) followed by viruses and Haemophilus influenzae (both about 8%) and Mycoplasma pneumoniae (6%). Chlamydia spp (3%) and Legionella pneumophila (2%) were less frequently detected. No diagnosis was made in 45% of the cases. With adjustment for anti-microbial therapy before admission and for other logistical considerations, it is estimated that the aetiology could have been ascertained in 65% of the cases. CONCLUSIONS--Streptococcus pneumoniae is the most frequently detected cause of community-acquired pneumonia. The inability to detect a micro-organism results mainly from the use of routine diagnostic tests and, to a lesser extent, from logistical problems or the use of antibiotics before admission.

Requirement of extracellular complement and immunoglobulin for intracellular killing of micro-organisms by human monocytes.

The role of serum factors in the intracellular killing of bacteria by monocytes was studied on the basis of an assay independent of phagocytosis. After 3 min of phagocytosis of preopsonized bacteria and removal of noningested bacteria, the monocytes containing bacteria are reincubated for various periods and the number of unkilled bacteria is determined by a microbiological method after lysis of the cells. Evidence that this assay measures the killing of ingested bacteria was provided by scanning electron microscopy, lysostaphin treatment, and the effect on the rate of intracellular killing of inactivated serum lacking specific opsonic activity. Intracellular killing of Staphylococcus aureaus, S. epidermidis, and Escherichia coli by human monocytes does not occur or is low in the absence of serum, and maximal killing is only reached when fresh serum is present; intermediate values are obtained in the presence of heat-inactivated serum. These findings indicate that complement stimulates intracellular killing. Isolated heterogeneous immunoglobulin (Ig)G, pFc fragments of heterogeneous IgG, and both IgG1 and IgG3 stimulate intracellular killing of S. aureaus by monocytes to the same degree as heat-inactivated serum. Sphingomyelinase, which decreases the number of Fc receptors, and neuraminidase, which increases these receptors, respectively, decreased and increased the intracellular killing, whereas anti-monocyte serum completely abolished the stimulation of intracellular killing by inactivated serum. These results prove that interaction of the Fc receptor with the Fc part of IgG is required for the intracellular killing. Inhibition of the activation of complement components via the alternative pathway gave a considerable reduction in the intracellular killing of S. aureaus; impairment of the activation via the classical pathway had no effect. The addition of complement components to heat-inactivated serum showed that intracellular killing is maximal only when C3b is generated. Reduction of the number of C3b receptors in the membrane by trypsin or pronase decreased intracellular killing in the presence of fresh serum; anti-monocyte serum completely abolished the stimulation of intracellular killing by fresh serum. These results lead to the conclusion that intracellular killing is also dependent on the interaction between C3b and its receptor in the membrane.

Pneumococcal polysaccharide vaccines: Indications, efficacy and recommendations

Streptococcus pneumoniae is the primary cause of community-acquired pneumonia, meningitis in adults and otitis media in infants and children and the third cause of meningitis in infants and children. Despite the availability of effective therapeutic agents against this pathogen, mortality has remained high, particularly for infections complicated by bacteremia. For many years, there has been a plea for vaccination. The first steps, using whole bacterial vaccines, were taken during the early decades of this century in the gold mining camps of South Africa, where pneumonia was endemic. The efficacy of purified pneumococcal polysaccharide vaccines has since been demonstrated in young adults, such as gold miners and military recruits, as well as for several other groups at risk, such as institutionalized elderly, patients with sickle cell anemia or those who have undergone a splenectomy, and elderly patients with underlying conditions such as chronic obstructive pulmonary disease and chronic cardiovascular disease, but not in infants and severely immunocompromised patients. Serological studies on the immune response to inoculation of pneumococcal polysaccharide antigens have demonstrated a severely impaired antibody response in the last two groups. Therefore, development of more highly immunogenic vaccines, e.g. by linking pneumococcal polysaccharides or parts of them to protein carriers, should be continued in an attempt to offer adequate protection to those who are insufficiently protected by the current 23-valent polysaccharide vaccine. Opportunities to immunize other patients who are at risk for pneumococcal infection and are capable of responding to the current vaccine should not be missed.

Contribution of granulocytes and monocytes to resistance against experimental disseminatedCandida albicans infection

The aim of the present study was to investigate the contribution of granulocytes and monocytes to resistance against an acute systemic candidal infection in mice. To this end granulocytopenia and monocytopenia were induced by irradiation or treatment with cyclophosphamide, and monocytopenia was obtained by treatment with VP-16. After intravenous injection of 1×104Candida albicans into mice irradiated with 8 GY, the number ofCandida albicans cultured from the kidneys, expressed as the geometric mean of the number of CFU/g tissue, was 5.4×104, 7.1×106 and 5.8×107 on days 1, 3 and 5 of infection respectively (p<0.001 compared to normal mice). The number ofCandida albicans cultured from the liver and spleen was also significantly higher for irradiated animals than for normal mice (p<0.001). For cyclophosphamide-treated mice the number of organisms in the kidney (1.7×104 CFU/g on day 1, 1.9×106 on day 3 and 3.8×106 on day 5 of infection) and spleen was significantly higher (p at least <0.02) than for nomal mice after injection of 1×103Candida albicans. Monocytopenia induced by VP-16 did not result in an increase in the number ofCandida albicans cultured from the kidney or spleen after infection. From these studies it is concluded that granulocytes and not monocytes or exudate macrophages play an important role in resistance againstCandida albicans during the first five days of a systemic infection.

Interaction of povidone-iodine compounds, phagocytic cells, and microorganisms.

The interaction between povidone-iodine, phagocytic cells, and microorganisms was studied. Three preparations of povidone-iodine were investigated: commercially available povidone-iodine solution Betadine, pure high-molecular-weight povidone-iodine as used in Betadine, and a low-molecular-weight povidone-iodine. Low concentrations of povidone-iodine (approximately 0.005%) have considerable activity in vitro. The concentrations used clinically (0.1 to 20%) are toxic for granulocytes and monocytes. Leukocytes reduce the in vitro microbicidal activity of povidone-iodine. No differences of any importance were found between the three preparations of povidone-iodine.

Comparison of the efficacies of amphotericin B, fluconazole, and itraconazole against a systemic Candida albicans infection in normal and neutropenic mice.

We compared the efficacies of the new triazole antifungal drugs fluconazole and itraconazole with that of amphotericin B in vitro and in an animal model of systemic candidiasis in normal and neutropenic mice. Antifungal treatment with fluconazole (2.5 to 20 mg/kg orally twice daily), itraconazole (10 to 40 mg/kg orally twice daily), or amphotericin B (0.1 to 4 mg/kg intraperitoneally once daily) was started 1 day after intravenous injection of 10(4) Candida albicans into normal mice or 10(3) C. albicans into neutropenic mice; the drugs were administered for 2 days. In normal mice the efficacy of treatment, which was assessed on the basis of the number of C. albicans cultured from the kidney, was greater for amphotericin B than for the triazoles. Fluconazole was more potent than itraconazole on the basis of equivalent doses, although itraconazole was more potent on the basis of the amount of free drug that was available. In neutropenic mice amphotericin B was less effective than it was in normal mice, whereas the triazoles were equally effective in normal and neutropenic mice. This was not expected, since in vitro data showed that amphotericin B was highly fungicidal, whereas both fluconazole and itraconazole had only a minimal effect on the growth of C. albicans in vitro.

Characteristics, Origin and Kinetics of Human and Murine Mononuclear Phagocytes

The origin and function of macrophages have generally been studied in what are called free macrophages — i.e., peritoneal or alveolar macrophages obtained mainly from mice but also from rabbits — because suspensions of these cells are not difficult to prepare. In recent years, however, new methods have become available by which the fixed macrophages occurring in the tissues of organs can be obtained by the use of, for instance, enzymatic digestion.

Ciprofloxacin for treatment of malakoplakia

The tumour-like lesions of the rare disease malakoplakia, which consist of macrophages containing undigested coliform bacteria, are often misdiagnosed as a carcinoma. Although an infectious aetiology is likely, no antimicrobial therapy has been successful in the long-term. Since ciprofloxacin penetrates well into macrophages, this drug was given to two patients with advanced malakoplakia (500 mg twice daily). After long-term treatment all granulomatous lesions disappeared. Thus, malakoplakia can be cured by antibiotic treatment.

Effect of lisofylline and pentoxifylline on the bacterial-stimulated production of TNF-alpha, IL-1beta and IL-10 by human leucocytes

The present study concerns the effect of the xanthine derivates lisofylline (LSF) and pentoxifylline (PTX) on the production of pro‐inflammatory cytokines tumour‐necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) and the de‐activating cytokine interleukin‐10 (IL‐10) by human leucocytes during stimulation with lipopolysaccharide (LPS), heat‐killed Gram‐negative bacteria (GNB) or Gram‐positive bacteria (GPB). The production of TNF‐α and IL‐1β by leucocytes stimulated with LPS, Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae was inhibited by both drugs. The production of IL‐10 by leucocytes stimulated with LPS and Hib was inhibited by both xanthine derivates only at 48 hr. However, incubation of leucocytes with S. pneumoniae in the presence of LSF or PTX stimulated the production of IL‐10 about four‐ and twofold at 24 hr and 48 hr, respectively. In all instances, the extent of inhibition or enhancement of cytokine production by LSF or PTX was equal. The divergent effects of xanthine derivates on the IL‐10 production indicate the existence of distinct intracellular pathways depending on whether leucocytes are stimulated by GPB or GNB.

Impaired phagocytosis of Staphylococcus aureus by granulocytes and monocytes of AIDS patients.

In the present study the microbicidal activities of granulocytes and monocytes from AIDS patients (CDC group IV) were assessed and compared with those of healthy controls. The phagocytosis and intracellular killing of Staphylococcus aureus by patient and control cells were measured using a method in which the rate of intracellular killing can be assessed independently of the rate of phagocytosis. Both granulocytes and monocytes of AIDS patients showed a decreased phagocytosis of S. aureus in comparison to phagocytes of healthy individuals. The rates of intracellular killing of S. aureus by granulocytes and monocytes did not differ significantly between these patients with late‐stage HIV infection and controls.