Search

In the course of the past two decennia, a 3rd route of complement activation (next to the classical and the alternative routes) has been identified: the lectin route in which mannose-binding lectin (MBL) plays an essential role. MBL is produced in the liver. From the phylogenetic and functional points of view, complement activation via MBL falls in between the alternative and the classical routes and combines the advantages of the former (an early response, without the intervention of antibodies) with those of the latter (high specificity). The binding of MBL to the surface of a microorganism results in the activation of two serine proteases (MASP1 and MASP2) that are coupled to MBL. These enzymes can activate C4 and C2 so that, via the MBL route, the C3-convertase of the classical route (C4b2b) is produced long before there are any specific antibodies. The gene for MBL is located on the long arm of chromosome 10 and consists of a promoter gene and 4 exons coding for the protein. The prevalence of mutations in the MBL gene is about 10%, but in Africa South of the Sahara it is as high as 30%. MBL deficiency predisposes both children and adults to all sorts of infectious diseases, chronic diarrhoea, tonsillitis, otitis media, pneumonia, (meningococcal) meningitis, sepsis and osteomyelitis. Remarkably, MBL deficiency may actually be advantageous in some infections, because certain microorganisms use MBL or complement to invade the cell.

The only natural reservoir of Neisseria meningitidis is the human nasopharyngeal mucosa. Depending on age, climate, country, socioeconomic status, and other factors, approximately 10% of the human population harbors meningococci in the nose. However, invasive disease is relatively rare, as it occurs only when the following conditions are fulfilled: (i) contact with a virulent strain, (ii) colonization by that strain, (iii) penetration of the bacterium through the mucosa, and (iv) survival and eventually outgrowth of the meningococcus in the bloodstream. When the meningococcus has reached the bloodstream and specific antibodies are absent, as is the case for young children or after introduction of a new strain in a population, the ultimate outgrowth depends on the efficacy of the innate immune response. Massive outgrowth leads within 12 h to fulminant meningococcal sepsis (FMS), characterized by high intravascular concentrations of endotoxin that set free high concentrations of proinflammatory mediators. These mediators belonging to the complement system, the contact system, the fibrinolytic system, and the cytokine system induce shock and diffuse intravascular coagulation. FMS can be fatal within 24 h, often before signs of meningitis have developed. In spite of the increasing possibilities for treatment in intensive care units, the mortality rate of FMS is still 30%. When the outgrowth of meningococci in the bloodstream is impeded, seeding of bacteria in the subarachnoidal compartment may lead to overt meningitis within 24 to 36 h. With appropriate antibiotics and good clinical surveillance, the mortality rate of this form of invasive disease is 1 to 2%. The overall mortality rate of meningococcal disease can only be reduced when patients without meningitis, i.e., those who may develop FMS, are recognized early. This means that the fundamental nature of the disease as a meningococcus septicemia deserves more attention.

The regulation of tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1beta) production was studied in patients with meningococcal disease. Circulating TNF and IL-1beta normalized within 1 day. TNF mRNA and IL-1beta mRNA in white blood cells decreased over 3-4 days. During the acute stage, TNF and IL-1beta production in stimulated whole blood cultures was down-regulated. After 4-5 days, this production was restored. The down-regulation was unlikely to be caused by circulating IL-6 and IL-10, as these cytokines normalized within 2-3 days. TNF mRNA in stimulated cultures during the acute stage, with down-regulated production, did not differ from that at recovery, with restored production. In contrast, the down-regulated production of IL-1beta was associated with significantly lower IL-1beta mRNA levels. Thus, TNF and IL-1beta production are differentially regulated. Whereas TNF production is regulated posttranscriptionally, IL-1beta production is also regulated at the mRNA level.

In 39 patients with acute meningococcal infections, the plasma concentrations of tumor necrosis factor-alpha (TNF) and its soluble receptors (sRs) TNFsR-p55 and TNFsR-p75 were measured from admission till recovery. At admission, patients with shock had significantly higher TNF, TNFsR-p55, and TNFsR-p75 values than patients without shock. In addition, during the first 24 hours, patients with shock had higher TNFsR-p75 to TNFsR-p55 ratios, indicating that in shock the increase of TNFsR-p75 exceeds that of TNFsR-p55. TNF measured more than 12 hours after admission failed to differentiate between shock and nonshock because TNF concentrations normalized within 12-24 hours. However, because concentrations of TNFsRs remained elevated for 5-6 days, at that time plasma TNFsRs still differentiated between shock and nonshock. Plasma exchange or whole blood exchange (PEBE), performed in 20 patients with shock, accelerated the decrease of plasma TNFsRs. However, because of a rebound after each PEBE session, the overall half-lives of both TNFsRs were not affected by PEBE.

Objective: To determine the value of the platelet count at admission for the assessment of the severity of disease in acute meningococcal infections., Design: Retrospective and prospective, descriptive patient study., Setting: University Hospital Intensive Care Unit (ICU)., Patients: All patients (n = 92) with acute meningococcal disease from 1985 to 1997, who arrived at the ICU within 12 h after hospital admission and had more than one platelet count during the first 12 h., Measurements and Results: After admission, platelets dropped in 95% of the patients. At admission, 2/41 (5%) of the non-hypotensive patients and 13/51 (25%) of the hypotensive patients had platelets fewer than 100 x 10(9)/l. During the following 12 h, these percentages increased to 15% and 71%, respectively. Fatalities had, at admission, a median platelet count of 111 x 10(9)/l (range, 19-302 x 10(9)/l), whereas the nadir, occurring at median 7.0 h (range, 1.3-12 h), was 31 x 10(9)/l (range, 12-67 x 10(9)/l). Plasma TNF, measured shortly after admission, correlated better with the platelet nadir (r = -0.65, p < 0.0001) than with the platelet count at admission. Similarly, serum lactate correlated better with the platelet nadir., Conclusions: As platelets drop after admission, the use of the platelet count at admission for the assessment of the prognosis in acute meningococcal disease may be misleading. Frequently repeated platelet counts are a better tool for evaluating the severity of disease.

Secretion of cytokines by monocytes has been implicated in the pathogenesis of dialysis-related morbidity. Cytokine generation is presumed to take place in two steps: induction of mRNA transcription for cytokines by C5a and direct membrane contact, followed by lipopolysaccharide (LPS)-induced translation of mRNA (priming/second signal theory, Kidney Int 37: 85-93, 1990). However, the in vitro conditions on which this theory was based differed markedly from clinical dialysis. To test this postulate for routine hemodialysis, 13 patients were studied cross-over with high-flux cuprammonium (CU), cellulose triacetate (CTA), and polysulfon dialyzers, using standard bicarbonate dialysate, as well as CTA with filtered dialysate (fCTA). Besides leukocytes, C3a, C5a, and limulus amebocyte lysate reactivity, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-1RA, soluble TNF receptors, and IL-1 beta mRNA were assessed. Only during dialysis with CU did C5a increase significantly (561 to 8185 ng/ml, P < 0.001). Endotoxin content of standard bicarbonate was higher than filtered dialysate (median, 24.3 and < 5 pg/ml respectively, P = 0.002), whereas limulus amebocyte lysate reactivity was not detected in the blood, except in the case of CU. TNF-alpha levels were elevated before, and remained stable during, dialysis, independent of the modality used. IL-1 beta, IL-6, and mRNA coding for IL-1 beta could not be demonstrated. IL-1RA and soluble TNF receptors (p55/p75) were markedly elevated compared with normal control subjects, but showed no differences between fCTA and CTA. To summarize, no evidence was found for production and release of cytokines by monocytes during clinical high-flux bicarbonate hemodialysis, neither with complement-activating membranes nor with unfiltered dialysate. Therefore, this study sheds some doubt on the relevance of the "priming/second signal" theory for clinical practice. The data presented suggest that reluctance to prescribe the use of high-flux dialyzers, as advocated in many reports, may not be warranted.

Interleukin-1beta (IL-1beta) is considered an important mediator in the pathogenesis of septic shock or bacterial meningitis. Its activity is specifically modulated by IL-1 receptor antagonist (IL-1Ra) and IL-1 soluble receptor type II (IL-1sRII). We now describe the time-course of IL-1beta and these modulating agents in 59 patients with acute meningococcal infections, the prototype human disease of acute endotoxin exposure. Plasma IL-1beta was increased only in severe shock and normalized within 12 to 24 hours, indicating that patients were admitted in an early stage of cytokine activation. Increased IL-1beta values in cerebrospinal fluid (CSF) were confined to patients with meningitis. Plasma IL-1Ra was elevated in both shock and nonshock patients, extremely high values being measured in severe shock. High concentrations of IL-1Ra in CSF were found in meningitis. Plasma IL-1Ra peaked shortly after IL-1beta and decreased steeply in 1 to 2 days, followed by sustained moderately elevated levels in shock patients. Interestingly, IL-1sRII showed a completely different pattern. At admission, both nonshock and shock patients manifested a similar moderate increase of plasma IL-1sRII. However, during recovery plasma IL-1sRII further increased reaching maximal concentrations 3 to 5 days after admission, 1 to 2 days after normalization of IL-1Ra. In shock patients this increase was more prominent than in nonshock patients. It is hypothesized that this increase in plasma IL-1sRII can be explained by a synergistic effect of dexamethasone and endotoxin. A second interesting observation was that, unlike the pattern in plasma, IL-1sRII levels in CSF paralleled those of IL-1beta and IL-1Ra. This suggests different modulation of IL-1beta activity in the subarachnoid space and the plasma compartment. We conclude that: (1) During the early stage of meningococcal infections IL-1Ra modulates IL-1 activity, whereas during recovery IL-1sRII may be more important. (2) Modulation in CSF and in the plasma compartment are differentially regulated.

A 19-years-old Turkish woman had recurrent attacks of abdominal pain. She underwent numerous diagnostic procedures and an appendectomy. In addition, imminent pethidine addiction developed. It was only after the patient presented with a swollen painless wrist, some years later, that the correct diagnosis was made: C1 esterase inhibitor deficiency. Early recognition may prevent a prolonged course and is mandatory as the disease is potentially life-threatening.

Objectives: To determine the pattern of the soluble interleukin (IL)-6 receptor during acute meningococcal infections and recovery phase, and to measure the effect of plasma or whole blood exchange on the plasma concentrations of these mediators., Design: Prospective, descriptive patient study., Setting: University hospital intensive care unit., Patients: Patients with bacteriologically proven meningococcal infections were entered in the study. Three group were formed: a) patients with meningitis without shock (group A); b) patients with meningitis and shock (group B); and c) patients with shock only (group C)., Interventions: Part (n = 9) of the patients with shock underwent plasma or whole blood exchange., Measurements and Main Results: Serum concentrations of interleukin-6 and soluble IL-6 receptors were determined sequentially during the acute and recovery phases. Peak concentrations of IL-6 were highest in group C, followed by group B and group A. Soluble IL-6 receptor concentrations showed an opposite pattern and were all below normal. Soluble IL-6 receptor concentrations were negatively correlated with the IL-6 concentrations. During recovery, IL-6 rapidly decreased and soluble IL-6 receptors increased to supranormal concentrations, after which concentrations returned to normal. Plasma or whole blood exchange did not significantly influence IL-6 concentrations but did increase the soluble IL-6 receptor concentration directly after an exchange session followed by a rapid decrease., Conclusions: Soluble IL-6 receptor concentrations are low in acute meningococcal infections. Plasma or whole blood exchange temporarily increases these concentrations. It needs to be determined whether the effect of this therapy is beneficial to the patient.

Two man presented with recurrent venous thrombosis. One of them also suffered from arterial thrombosis and aneurysm. Additional history-taking revealed that both suffered from recurrent oral and/or genital ulcers, erythema nodosum and iritis. Consequently a diagnosis of 'angio-Behçet syndrome' was made. Related to the clinical observations in these patients, we discuss the complications and the management of angio-Behçet syndrome. Treatment includes anticoagulants and immunosuppressive drugs.

We investigated whether a 6-h endurance run changes cytokine plasma concentrations and lipopolysaccharides (LPS) stimulated ex vivo production of cytokines in a whole blood culture of 19 well-trained athletes. The average distance covered was 65.1 +/- 8.64 (SD) km. At the end of the exercise, the mean plasma concentration of interleukin-1-receptor agonist (IL-1ra), which was 188 pg/ml 24 h before finish, increased to 886 pg/ml (P < 0.0005). The mean plasma interleukin-6 concentration increased from 18.5 +/- 4.2 to 71.5 +/- 33.3 pg/ml (P < 0.0001). The increase of neutrophils correlated with the increase of IL-1ra concentrations (r = 0.58, P < 0.005). We could not detect an effect of exercise on plasma concentrations of interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha). The ex vivo LPS-stimulated production of IL-1 beta in athletes 24 h before the run was significantly higher than in sedentary controls. Exercise induced a decrease of LPS-stimulated production of IL-1 beta and TNF-alpha, whereas production of IL-1ra was unchanged. These results show that prolonged exercise elicits a selective downregulation of the proinflammatory cytokine production and upregulation of the cytokines IL-1ra and interleukin-6.

Pro- and antiinflammatory cytokines and mediators were measured in 39 patients with acute life-threatening meningococcal infections classified into 3 groups: A, meningitis without shock (n = 20); B, meningitis with shock (n = 9); and C, shock without meningitis (n = 10). The plasma concentrations of proinflammatory endotoxin, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8 and antiinflammatory cytokines and mediators IL-1 receptor antagonist, IL-10, and soluble TNF receptors p55 and p75 were strongly associated with this classification; the highest concentrations were in group C. IL-4 was not measurable. IL-1 beta was increased only in rapidly fatal cases. In addition, cerebrospinal fluid (CSF) was analyzed in 21 patients for TNF-alpha and its soluble receptors. In CSF, these compounds were mainly increased in group A, reflecting an intrathecal compartmentalized cytokine production. It is concluded that both pro- and antiinflammatory mediators are simultaneously increased and are strongly associated with a classification based on simple clinical parameters.

The hyperimmunoglobulinemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent febrile attacks with abdominal distress, joint involvement (arthralgias/arthritis), headache, skin lesions, and an elevated serum IgD level (> 100 U/mL). This familial disorder has been diagnosed in 59 patients, mainly from Europe. The pathogenesis of this febrile disorder is unknown, but attacks are joined by an acute-phase response. Because this response is considered to be mediated by cytokines, we measured the acute-phase proteins C-reactive protein (CRP) and soluble type-II phospholipase A2 (PLA2) together with circulating concentrations and ex vivo production of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) and the inhibitory compounds IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF receptors p55 (sTNFr p55) and p75 (sTNFr p75) in 22 patients with the hyper-IgD syndrome during attacks and remission. Serum CRP and PLA2 concentrations were elevated during attacks (mean, 213 mg/L and 1,452 ng/mL, respectively) and decreased between attacks. Plasma concentrations of IL-1 alpha, IL-1 beta, or IL-10 were not increased during attacks. TNF alpha concentrations were slightly, but significantly, higher with attacks (104 v 117 pg/mL). Circulating IL-6 values increased with attacks (19.7 v 147.9 pg/mL) and correlated with CRP and PLA2 values during the febrile attacks. The values of the antiinflammatory compounds IL-1ra, sTNFr p55, and sTNFr p75 were significantly higher with attacks than between attacks, and there was a significant positive correlation between each. The ex-vivo production of TNF alpha, IL-1 beta, and IL-1ra was significantly higher with attacks, suggesting that the monocytes/macrophages were already primed in vivo to produce increased amounts of these cytokines. These findings point to an activation of the cytokine network, and this suggests that these inflammatory mediators may contribute to the symptoms of the hyper-IgD syndrome.

Concentrations of interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), and soluble tumor necrosis factor receptor (sTNFR) p55 and p75 were measured in 25 patients with sepsis syndrome. Sequential blood samples were drawn from patients during a 7-h period. IL-6 concentrations were 34-763,000 pg/mL; they were higher in nonsurvivors than survivors, but the difference was not statistically significant. In septic patients, the median sIL-6R concentration was significantly lower than in 19 healthy volunteers (43 vs. 80 ng/mL). sIL-6R concentrations in survivors were not significantly different than those in nonsurvivors. There was a negative correlation between IL-6 and sIL-6R in septic patients (r = -.72). In patients with moderately impaired renal function, sIL-6R levels were not affected, but the concentrations of sTNFRs were significantly higher.

Circulating concentrations of tumor necrosis factor-alpha (TNF), interleukin (IL)-1 beta, IL-6, IL-1 receptor antagonist (IL-1ra), and soluble TNF receptors p55 (sTNFr-55) and p75 (sTNFr-75) and ex vivo production of TNF, IL-1, IL-6, and IL-1ra using a whole blood culture system were measured during the acute and convalescent stages of meningococcal infection. Circulating TNF and IL-1 were below detection level, whereas IL-6 and IL-1ra, sTNFr-55, and sTNFr-75 were increased at admission. The ex vivo production of proinflammatory cytokines TNF, IL-1, and IL-6 was suppressed at admission and restored gradually during recovery. On the contrary, the production of the antiinflammatory IL-1ra was increased at admission. The elevated concentrations of both IL-1ra and sTNFr early in the course of infection suggest a regulatory role for these antiinflammatory compounds. The observed down-regulation of the ex vivo production of TNF, IL-1, and IL-6 and up-regulation of the production of IL-1ra in the acute stage may indicate a protective regulation mechanism.

Tumour necrosis factor-alpha (TNF) and interleukin-1 beta (IL-1 beta) are the central mediators in the genesis of sepsis. The proinflammatory effects of these cytokines are counteracted in vivo by natural inhibitors. Soluble TNF receptors (sTNFR) are shed upon inflammatory stimuli such as IL-1 beta and TNF itself. Circulating TNF can be complexed by these receptors, thus preventing TNF from binding to effector cells. The binding of IL-1 beta to its receptor can be blocked by high concentrations of interleukin-1 receptor antagonist (IL-1Ra), which is produced and released upon nearly the same stimuli as IL-1 beta. This review presents some aspects of the kinetic behaviour of native sTNFR and of the production of native IL-1Ra during severe infections. It appears that in fulminant septicaemia, the plasma concentration of TNF is increased only transiently, during the very early stage of the infection. The concentration of sTNFR, in contrast, remains elevated much longer, probably due to a slower clearance. During the acute stage of severe infectious diseases, peripheral blood cells cannot be stimulated to produce IL-1 beta. The production of IL-1 Ra, in contrast, is not affected. Thus, the kinetic behaviour and regulation of TNF and IL-1 beta, is different from that of their antiinflammatory counterparts.

Objectives: To evaluate the usefulness of Gram staining and culture of skin lesions in patients with acute meningococcal infections., Design: Retrospective study., Setting: Community hospital and intensive care unit of a teaching hospital., Subjects: 51 patients admitted from 1989 to 1993 with proved meningococcal infections and microbiological examination of specimens from skin lesions., Interventions: Needle aspiration of a skin lesion before start of antibiotic treatment in 26 patients in the community hospital; punch biopsy of skin lesion after start of antibiotic treatment in 25 patients in the teaching hospital., Main Outcome Measures: Detection of meningococci by Gram staining of specimens from skin lesions according to category of infection (meningococcaemia, meningitis, meningitis with shock, or septic shock without meningitis)., Results: Bacteria were detected in the specimen from haemorrhagic skin lesions by culture or Gram staining, or both in 32 (63%) patients. The sensitivity of the Gram stain was 51% and did not differ significantly from its sensitivity in detecting bacteria in cerebrospinal fluid. In meningococcal sepsis, however, a Gram stained skin lesion was significantly more sensitive (72%) than Gram stained cerebrospinal fluid (22%). In patients with meningitis skin lesions gave positive results on staining more often if shock was present. The results for punch biopsy specimens were not affected by antibiotics as Gram staining gave positive results up to 45 hours after the start of treatment and culture gave positive results up to 13 hours., Conclusion: Microbiological examination of skin lesions is informative, especially in patients with sepsis and inconclusive results from cerebrospinal fluid, and may provide a diagnosis in such patients within 45 minutes. It differentiates well between meningitis with and without haemodynamic complications, and the result is not affected by previous antibiotic treatment.

To investigate the wishes and ideas about length of working week, part-time work, length of career and future kind of establishment, a questionnaire was sent to all Dutch registrars of internal medicine. In the opinion of more than 70 percent of the registrars, the length of a full-time working week of an internist should be less than 50 hours. Of all registrars (62% men and 38% women), 68% would decide in favour of part-time work if the length of a full-time working week of an internist were to remain at about 68 hours (common length of a working week of Dutch internists nowadays). 33% would still like to work part-time when the length of a full-time working week became as they desired (about 47 hours). The preferred length of their career was for most registrars less than 30 years. The majority preferred a tenure to a position in a partnership. In conclusion, the wishes about the future of the registrars of internal medicine differ markedly from the current situation.

The present study describes the effect of plasma exchange or whole blood exchange (PEBE) on the survival rate among patients with fulminant meningococcal sepsis and on the level of circulating endotoxin. Since 1989 all patients with meningococcal disease and hypotension who were admitted to our intensive care unit were treated with PEBE. Results for our patients were compared with those for a historical control group conventionally treated between 1984 and 1989 (n = 10; mortality rate, 60%); the expected mortality rate, which was based on the Niklasson prognostic score and was calculated for seven patients in this control group, was 73%. A total of 15 patients were treated with PEBE, three (20%) of whom died, whereas the prognostic score (calculated for 14 patients) for this group was 62%. In two of the fatal cases, PEBE was started after a delay of greater than or equal to 40 hours. In the remaining 13 patients, PEBE was started within 5-30 hours after the first hospital admission. The mortality rate among this group was 8% (one of 13 patients); this rate was significantly different from that among the control group (P = .025). For seven patients treated with PEBE, plasma endotoxin concentrations were sequentially measured. The overall half-life (+/- SEM) of endotoxin was 181 +/- 18 minutes. This is approximately the same as reported values for patients who were not treated with PEBE. It is concluded that early initiation of PEBE may improve the rate of survival among patients with meningococcal infection and hypotension but that the mechanism of the beneficial effect is most likely not based on the elimination of endotoxin.

Constrictive pericarditis is a slowly progressive disabling disease. The diagnosis is easily overlooked because of the striking extracardial signs and symptoms such as abdominal discomfort, general fatigue, cachexia, ascites and oedema. We describe 7 patients with these symptoms in whom the diagnosis was missed during 0.5-17 years. The decisive clue for correct diagnosis appeared to be the raised central venous pressure. This proves the importance of an accurate physical examination. Other findings were: ascites (7/7), hepatomegaly (7/7), oedema (6/7), narrow pulse pressure (less than or equal to 35 mmHg) (5/7), ECG abnormalities (7/7) and pericardial calcifications on the chest X-ray (5/7). In addition we found slightly raised liver enzymes and a protein-losing enteropathy leading to low serum protein levels. These abnormalities are all explained by the alterations in haemodynamics and lymph flow. The only curative therapy is surgical decortication of the heart.