Long-term low-dose antibiotics in recalcitrant chronic rhinosinusitis: a retrospective analysis.

INTRODUCTION: In recalcitrant Chronic RhinoSinusitis (CRS) treatment with intranasal corticosteroids, short-term antibiotics and even sinus surgery is frequently insufficient. Long-term low-dose administration of antibiotics has been suggested as a treatment option in these patients. We analysed the outpatient clinic population treated with different long-term low-dose antibiotics at the AMC Amsterdam. PATIENTS AND METHODS: Eligible patients, who were treated with trimethoprim-sulfamethoxazole or macrolides, were retrospectively identified from our outpatient clinic in 2009. The two main outcome measures were sinonasal complaints and nasal endoscopic findings. A 5-point grading scale was used to score the results compared with the pre-treatment situation. This was measured at several time-points during, and after the antibiotic course, and at the end of the follow-up term. RESULTS: Seventy-six patients were included, 53 per cent had asthma and all of them had undergone sinus surgery. Seventy-eight per cent showed improvement of the symptoms, and 84 per cent demonstrated improvement of the sinonasal mucosa at the end of the course. No significant difference was found between the trimethoprim-sulfamethoxazole and macrolide group. DISCUSSION: Long-term low-dose treatment with antibiotics seems to improve CRS symptoms and the appearance of the sinonasal mucosa on nasal endoscopy. However, at this stage, strong conclusions are immature because no placebo-group has been included. Despite increasing use of long-term low-dose treatment of recalcitrant CRS in referral centres, hard clinical evidence is lacking. More research is urgently required.

Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized controlled trial.

BACKGROUND: In persistent chronic rhinosinusitis (CRS), conventional treatment is often insufficient. Long-term, low-dose administration of macrolides has been suggested as a treatment option. The MACS (Macrolides in chronic rhinosinusitis) study is a randomized placebo-controlled trial evaluating the efficacy of azithromycin (AZM) in CRS. METHODS: We describe a group of patients with recalcitrant CRS with and without nasal polyps unresponsive to optimal medical and (in 92% also) surgical treatment. Patients were treated with AZM or placebo. AZM was given for 3 days at 500 mg during the first week, followed by 500 mg per week for the next 11 weeks. Patients were monitored until 3 months post-therapy. The assessments included Sino-Nasal Outcome Test-22 (SNOT-22), a Patient Response Rating Scale, Visual Analogue Scale (VAS), Short Form-36 (SF-36), rigid nasal endoscopy, peak nasal inspiratory flow (PNIF), Sniffin' Sticks smell tests and endoscopically guided middle meatus cultures. RESULTS: Sixty patients with a median age of 49 years were included. Fifty per cent had asthma and 58% had undergone revision sinus surgery. In the SNOT-22, Patient Response Rating Scale, VAS scores and SF-36, no significant difference between the AZM and the placebo groups was demonstrated. Nasal endoscopic findings, PNIF results, smell tests and microbiology showed no relevant significant differences between the groups either. CONCLUSION: At the investigated dose of AZM over 3 months, no significant benefit was found over placebo. Possible reasons could be disease severity in the investigated group, under-dosage of AZM and under-powering of the study. Therefore, more research is urgently required.

Effect of photodynamic therapy on the mechanical strength of healed rodent skin incisions.

A factor that might complicate the use of intraoperative photodynamic therapy (PDT) is a possible adverse effect on normal tissue recovery. In this study, rats with experimental skin incisions received intraoperative PDT (10 mg/kg haematoporphyrin derivative, 180 J/cm(2) laser light), immediately followed by closure. Healing was evaluated by tensile strength assessment of the incisions 21 days after PDT. No significant differences between the PDT-treated group and control groups were found. We therefore concluded that with respect to healing of skin incisions in rats, intraoperative PDT is not contraindicated.

Performance of a light applicator for photodynamic therapy in the oral cavity: calculations and measurements.

Photodynamic therapy (PDT) is an experimental therapy for the treatment of superficial cancer using laser light. In PDT a uniform light distribution is usually required for an optimal therapeutic effect. To irradiate part of the oral cavity uniformly for PDT, two prototype applicators were built, each for a different lower jaw. The applicators made use of the light transmitted through the wall of a cavity of diffusely reflecting material. The radiant exitance of the applicators was measured at 632.8 nm. For the radiant exitance of M of the two applicators, a uniformity ratio, UR = Mmax/Mmin < 2 was found, which was considered reasonable for clinical applications. Calculations predict that the UR can be improved by decreasing the thickness of the cavity wall.

Uniform irradiation of irregularly shaped cavities for photodynamic therapy.

It is difficult to achieve a uniform light distribution in irregularly shaped cavities. We have conducted a study on the use of hollow 'integrating' moulds for more uniform light delivery of photodynamic therapy in irregularly shaped cavities such as the oral cavity. Simple geometries such as a cubical box, a sphere, a cylinder and a 'bottle-neck' geometry have been investigated experimentally and the results have been compared with computed light distributions obtained using the 'radiosity method'. A high reflection coefficient of the mould and the best uniform direct irradiance possible on the inside of the mould were found to be important determinants for achieving a uniform light distribution.

Photodynamic destruction of Haemophilus parainfluenzae by endogenously produced porphyrins.

Bacterial resistance against antibiotic treatment is becoming an increasing problem in medicine. Therefore methods to destroy microorganisms by other means are being investigated, one of which is photodynamic therapy (PDT). It has already been shown that a variety of Gram-positive and Gram-negative bacteria can be killed in vitro by PDT using exogenous sensitizers. An alternative method of photosensitizing cells is to stimulate the production of endogenous sensitizers. The purpose of this study was to investigate the bactericidal efficacy of PDT for Haemophilus parainfluenzae with endogenously produced porphyrins, synthesized in the presence of delta-aminolaevulinic acid (delta-ALA). H. parainfluenzae incubated with increasing amounts of delta-ALA showed decreased survival after illumination with 630 nm light. No photodynamic effect on the bacterial viability was found when H. parainfluenzae was grown without added delta-ALA. H. influenzae, grown in the presence of delta-ALA, but not capable of synthesizing porphyrins from delta-ALA, was not affected by PDT. Of the range of incident wavelengths, 617 nm appeared to be the most efficient in killing the bacteria. Spectrophotometry of the bacterial porphyrins demonstrated that the maximum fluorescence occurred at approximately 617 nm, with a much lower peak around 680 nm. We conclude that a substantial killing of H. parainfluenzae by PDT in vitro after endogenous sensitization with delta-ALA can be achieved.

Photodynamic therapy: a promising new modality for the treatment of cancer.

The first reports on photodynamic therapy (PDT) date back to the 1970s. Since then, several thousands of patients, both with early stage and advanced stage solid tumours, have been treated with PDT and many claims have been made regarding its efficacy. Nevertheless, the therapy has not yet found general acceptance by oncologists. Therefore it seems legitimate to ask whether PDT can still be described as "a promising new therapy in the treatment of cancer". Clinically, PDT has been mainly used for bladder cancer, lung cancer and in malignant diseases of the skin and upper aerodigestive tract. The sensitizer used in the photodynamic treatment of most patients is Photofrin, (Photofrin, the commercial name of dihematoporphyrin ether/ester, containing > 80% of the active porphyrin dimers/oligomers (A.M.R. Fisher, A.L. Murphee and C.J. Gomer, Clinical and preclinical photodynamictherapy, Review Series Article, Lasers Surg. Med., 17 (1995) 2-31). It is a complex mixture of porphyrins derived from hematoporphyrin. Although this sensitizer is effective, it is not the most suitable photosensitizer for PDT. Prolonged skin photosensitivity and the relatively low absorbance at 630 nm, a wavelength where tissue penetration of light is not optimal, have been frequently cited as negative aspects hindering general acceptance. A multitude of new sensitizers is currently under evaluation. Most of these "second generation photosensitizers" are chemically pure, absorb light at around 650 nm or greater and induce no or less general skin photosensitivity. Another novel approach is the photosensitization of neoplasms by the induction of endogenous photosensitizers through the application of 5-aminolevulinic acid (ALA). This article addresses the use of PDT in the disciplines mentioned above and attempts to indicate developments of PDT which could be necessary for this therapy to gain a wider acceptance in the various fields.

Photodynamic therapy in AIDS-related cutaneous Kaposi's sarcoma.

For evaluating the role of photodynamic therapy (PDT) in the local treatment of acquired immune deficiency syndrome (AIDS)-related cutaneous Kaposi's sarcoma (KS), nine treatments were performed in eight human immunodeficiency virus-positive homosexual men. The patients received 2 mg Photofrin/kg and either 120 J/cm2 (n = 5) or 70 J/cm2 (n = 4) laser light (630 nm). A total of 83 lesions were evaluable for response with a follow-up of 3-8 months. The overall response rates by patient for all treated lesions were 50-100% (120 J/cm2) and 83.3-90.3% (70 J/cm2), with a median duration of 3 months (range, 2-6 months). Tumors located at the head had higher response rates than those at the trunk or extremities (p = 0.005 and p - 0.015 respectively). The size of the KS showed a negative relationship with the probability of complete response (p = 0.047). Local and general side effects occurred, including pain, blisters, temperature increase, muscle stiffness, and severe edema. The cosmetic result was unsatisfactory because of a high prevalence of scars and long-lasting hyperpigmentation. Although the response rates of PDT are high, light dose of 70-120 J/cm2 cannot be recommended in the treatment of cutaneous KS in combination with 2 mg/kg Photofrin because of severe side effects and unsatisfactory cosmetic result.

Temperature response of biological materials to pulsed non-ablative CO2 laser irradiation.

This paper presents surface temperature responses of various tissue phantoms and in vitro and in vivo biological materials in air to non-ablative pulsed CO2 laser irradiation, measured with a thermocamera. We studied cooling off behavior of the materials after a laser pulse, to come to an understanding of heat accumulation and related thermal damage during (super) pulsed CO2 laser irradiation. The experiments show a very slow decay of temperatures in the longer time regime. This behavior is well predicted by a simple model for one-dimensional heat flow that considers the CO2 laser radiation as producing a heat flux on the material surface. The critical pulse repetition frequency for which temperature accumulation is sufficiently low is estimated at about 5 Hz. Although we have not investigated the ablative situation, our results suggest that very low pulse frequencies in microsurgical procedures may be recommended.

Male-female differences in the cytotoxic activity of human monocytes in vitro.

The cytotoxic activity of human monocytes towards anti-D-sensitized Rh(D)-positive red cells in vitro was studied in relation to the age and sex of healthy monocyte donors. It was found that cytotoxic activity of monocytes from young females (age range 18-40 years) was significantly less than that of monocytes from age-matched males, irrespective of the use of oral contraceptives. No such difference was found between monocytes from older males and females (age range 43-63 years). The cytotoxic activity of monocytes from the two latter groups of donors was similar to that of young males. In the presence of cytochalasin B, which enhances the cytotoxic activity of monocytes, no male-female difference was detected, indicating that the maximal cytotoxic capacity of monocytes from young females is similar to that of monocytes from young males. We have previously presented evidence that the cytotoxic activity of monocytes is mediated by lysosomal enzymes released by these cells. These present data suggest that the reduction in cytotoxic activity of monocytes from young females might be a result of a reduced lysosomal enzyme release which is possibly related to the in vivo action of female sex hormones. However, we were not able to detect an inhibitory effect of oestrogens and progestagens on cytotoxic activity of monocytes from males in vitro.

Quantitative aspects of the destruction of red cells sensitized with IgG1 autoantibodies: an application of flow cytofluorometry.

The purpose of this study was to determine whether quantitative or qualitative factors are of major importance in the destruction of red cells sensitized with incomplete warm autoantibodies of subclass IgG1. To that end, the relative amount of igG1 antibody present on the red cells of patients with autoantibodies of this subclass only, was measured by means of continuous flow cytofluorometry. This method appeared to give an idea of the amount of antibody on red cells and was reproducible. The intensity of the fluorescence of patient's red cells, measured after incubation with a FITC-labelled anti-IgG1, was compared with the presence or absence of signs of increased haemolysis in vivo and the cytotoxic activity of normal monocytes towards these red cells in vitro. It appearedthat it was predominantly the amount of IgG1 autoantibody that determined whether or not these antibodies induced haemolysis in vivo or cytotoxicity of monocytes in vitro. This was also true with methyldopa-induced IgG1 autoantibodies.

Destruction of IgG-sensitized erythrocytes by human blood monocytes: modulation of inhibition by IgG.

The in vitro interaction between monocytes and erythrocytes sensitized with non-complement binding IgG antibodies (i.e. the Rh antibody anti-D:EAIgG anti-D) is completely inhibited by low concentrations of IgG (E.G. 30--100 microgram/ml). However, the interaction between monocytes and erythrocytes sensitized with IgG anti-A (EAIgG anti-A) is not inhibited by IgG. The findings presented in this paper indicate that this difference is probably due to the difference in the number of IgG antibody molecules per EAIgG. Thus, the higher the number of IgG antibody molecules per EAIgG, the less the interaction between EAIgG and monocytes is inhibited by IgG. A second factor which proved to have a strong influence on inhibition by IgG was the number of EAIgG per monocyte. When the number of EAIgG per monocyte was increased from 1 to 32, the percentage of inhibition by a fixed amount of IgG (50 microgram/ml) decreased significantly. This in vitro effect is only evident when relatively weakly sensitized erythrocytes are used and, in vivo, destruction of these weakly sensitized red cells (e.g. EAIgG anti-D) is confined to the spleen. Since a considerable haemoconcentration occurs in this organ, it is conceivable that a high EAIgG:macrophage ratio is accomplished. The latter data are an indication that this high ratio may allow interaction between weakly sensitized erythrocytes and splenic macrophages despite the presence, in vivo, of a high concentration of IgG, and that, in this way, in the spleen, the inhibitory effect of IgG is overcome.

The role of adherence to human mononuclear phagocytes in the destruction of red cells sensitized with non-complement binding IgG antibodies.

In patients with IgG incomplete non-complement binding warm autoantibodies, the subclass composition of the antibodies was studied in relation to the occurrence of increased haemolysis in vivo and the adherence of the patients red cells to peripheral blood monocytes (PBM) in vitro. The presence of IgG3 autoantibodies was almost always accompanied by haemolytic anaemia, but the presence of IgG1 autoantibodies only in some patients but not in others. IgG2 and IgG4 autoantibodies were not associated with increased red cell destruction. A relation identical to that between subclass composition and increased haemolysis was found between subclass composition and adherence of the patients erythrocytes to PBM and thus a strong correlation between positive adherence in vitro and increased red cell destruction in vivo. These results support an important role of adherence to mononuclear phagocytic cells in the destruction of red cells sensitized with non-complement binding IgG antibodies. Strong indications were found that IgG1 autoantibodies are of two kinds, only one of which causes adherence to phagocytes and thus increased red cell destruction.

IgG4 autoantibodies against erythrocytes, without increased haemolysis: a case report.

A patient is described who, notwithstanding a strongly positive direct antiglobulin test with anti-IgG serum, apparently did not suffer from haemolytic anaemia. The survival of the patient's red cells, measured with 51Cr, was only slightly decreased. In vitro, the sensitized cells of the patient showed only a minimal tendency to adhere to monocytes. The patient's spleen functioned normally, since 51Cr-labelled donor erythrocytes, either sensitized with IgG-anti-D or damaged by heating, were eliminated rapidly from the circulation and sequestered in the spleen. These apparently contradictory findings could be explained by the fact that the patient's red cells were sensitized with autoantibodies, mainly belonging to the IgG4 subclass. Only weak IgG1 and IgG3 autoantibodies were detectable. Since previously the patient had suffered from a severe haemolytic anaemia, it is postulated that a switch has occurred from 'active' to 'inactive' IgG autoantibodies, perhaps induced by prednisone therapy.

[Immunological damage to erythrocytes]. / Immunologische Schädigung der Erythrozyten

The mechanisms by which red cells are destroyed under the influence of antibodies with different immunochemical and biological characteristics are described. It is shown that the interaction of antibody with the red cell per se does not lead to a disturbance of red cell function. Activation of the whole complement system leads to direct lysis of the erythrocyte (complement hemolysis). The fixation of red cells coated with activated C3:C3 receptors on phagocytic cells is another mechanism which leads to red cell destruction. The hypothesis that adherence to the Fc-receptors of phagocytic cells is essential for the destruction of red cells under the influence of noncomplement-binding antibodies is discussed. Arguments in favour of this theory are correlation between the subclass of IgG red cell autoantibodies and the absence or presence of increased hemolysis in the patient and a correlation between the degree to which red cells of patients with this kind of antibody adhere to monocytes in vitro and the degree of hemolysis in the patient. It is shown by in vitro experiments how this adherence process can take place in vivo in the presence of normal plasma IgG although the latter completely inhibits the adherence phenomenon in vitro.