Hyaluronan and procollagen type III aminoterminal peptide in serum and bronchoalveolar lavage fluid from patients with pulmonary fibrosis.

Previous studies of the collagen synthesis markers hyaluronan (hyaluronic acid) (HA) and procollagen type III aminoterminal peptide (PIIINP) in pulmonary fibrosis have reported elevated levels in bronchoalveolar lavage fluid (BALF) and suggested an association with disease activity. The objective of the present study was to evaluate whether HA and PIIINP in BALF and serum (S) correlated with paraclinical markers of disease activity (chest X-ray profusion score, pulmonary function tests (FEV1, FVC, TLC, DLCO)) in patients with pulmonary fibrosis. The material comprised 27 patients with biopsy-proven pulmonary fibrosis (12 cryptogenic and 15 due to connective tissue diseases) and 24 control subjects with normal lung function. BAL was performed in the right middle lobe with 250 ml saline. HA and PIIINP were measured in the cell-free BALF supernatant and in serum. Patients had higher BALF-HA (mean 86 +/- 17 (SEM) micrograms/l) than controls (39 +/- 2 micrograms/l (p < 0.01)), higher BALF-albumin (124 +/- 24 mg/l) than controls (58 +/- 4 mg/l (p < 0.01)) and higher BALF/S-HA ratio (2.4 +/- 0.6) than controls (1.2 +/- 0.6 (p < 0.05)). There were no significant differences respecting BALF-PIIINP, S-HA, or S-PIIINP. Patients (n = 14) with progressive disease had higher BALF-HA, higher BALF-albumin, higher S-PIIINP, and higher S-immunoglobulins than those with stable disease, but the differences did not reach statistical significance. Smokers (n = 18) had lower BALF-HA, lower S-HA, lower S-PIIINP, lower S-immunoglobulins, and higher lung function tests than non-smokers, but the differences did not reach statistical significance. In patients, significantly positive correlations were found between BALF-HA and BALF-albumin, between BALF-PIIINP and BALF-albumin, and a significantly negative correlation between S-PIIINP and TLC. None of the BALF or serum markers correlated with chest X-ray profusion score or any of the other lung function measurements. It is concluded that disease activity may be associated with elevated HA and PIIINP levels. Smoking may influence the immunological processes in pulmonary fibrosis and may be a confounder in studies of these patients.

Glucocorticoids inhibit the synthesis rate of type III collagen, but do not affect the hepatic clearance of its aminoterminal propeptide (PIIINP).

The aminoterminal propeptide of type III procollagen (PIIINP) is a marker of type III collagen metabolism. The serum concentration of PIIINP is increased during inflammation, probably reflecting stimulated biosynthesis of type III collagen. Serum PIIINP decreases during glucocorticoid treatment. This has been interpreted as an inhibited biosynthesis of type III collagen. However, circulating PIIINP is extracted by the liver, and the decrease in serum PIIINP may also be caused by an increased hepatic elimination. In the present study we investigated the influence of intravenous methylprednisolone on the serum PIIINP level in pigs combined with a simultaneous determination of the hepatic extraction of PIIINP. The serum level of PIIINP decreased by approximately 30% within 2 h following glucocorticoid injection (p < 0.01). The initial hepatic extraction ratio of PIIINP was 0.15 (range 0.05-0.33) and neither changed after administration of methylprednisolone nor differ from that of the controls. Injection of methylprednisolone did not influence the gel filtration profile. The results of this study confirm the previous finding of serum PIIINP being decreased following glucocorticoid administration, but disprove the hypothesis that alterations in the liver extraction of PIIINP explain the decrease.

[AIDS in Denmark. 1. Opportunistic infections and malignant diseases. Danish Study Group for HIV infection]. / AIDS i Danmark. 1. Opportunistiske infektioner og maligne sygdomme. Danish Study Group for HIV Infection.

To examine the distribution of AIDS-defining illnesses among Danish AIDS patients, data on 687 AIDS patients diagnosed in the period from 1980 to 1990 (93% of all reported cases in the period) were collected. The most frequent AIDS-defining illness was Pneumocystis carinii pneumonia followed by candida oesophagitis and Kaposis sarcoma. The proportion of homo/bisexual men presenting with Kaposis sarcoma as the initial AIDS-defining illness declined over time. Patients with extrapulmonary tuberculosis had higher CD4 cell counts than patients presenting with other illnesses. Cytomegalovirus chorioretinitis and atypical mycobacteriosis were seen more frequently after the time of the AIDS diagnosis, and a low CD4 cell count at time of the AIDS diagnosis was a significant predictor for the development of these opportunistic infections during follow-up. Danish AIDS patients present with a wide spectrum of HIV-related illnesses, reflecting their exposure to opportunistic microorganisms and the degree of immune deficiency. The pattern of HIV-related illnesses is changing over time, and therefore continuous surveillance is needed to optimize therapeutic and prophylactic regimens.

[AIDS in Denmark. 2. Survival after the diagnosis of AIDS. Danish Study Group for HIV infection]. / AIDS i Danmark. 2. Overlevelse efter AIDS-diagnosen. Danish Study Group for HIV Infection.

The survival pattern was studied for 687 Danish AIDS patients (93% of notified cases in the study period) who were diagnosed with AIDS during the period from 1980 to 1990. The median survival was 17 months. Factors significantly associated with a shortened survival were transfusion-acquired HIV infection, age > 40 years, year of diagnosis before 1987, and the presence of either disseminated infection with Mycobacterium avium-complex, Cytomegalovirus chorioretinitis or malignant lymphoma at time of the AIDS diagnosis. There was also a significant association between survival and CD4 cell count at time of AIDS diagnosis. Patients who had CD4 cell counts above 200 x 10(6)/l had twice as long a survival as patients who had CD4 cell counts less than 50 x 10(6)/l. The prognosis of Danish AIDS patients remains poor. The most important determinant of survival time appears to be the degree of immune deficiency at time of diagnosis.

Hyaluronan and procollagen type III aminoterminal peptide in serum and bronchoalveolar lavage fluid in patients with pulmonary sarcoidosis.

The aim of this study was to evaluate whether markers of collagen synthesis, hyaluronan (HA) and procollagen type III aminoterminal peptide (PIIINP) in bronchoalveolar lavage fluid (BALF) and serum (S) were correlated to paraclinical markers of disease activity (S-ACE, S-IgG S-IgA S-calcium, chest X-ray (CXR) profusion score, pulmonary function tests (FEV1, FVC, TLC, DLCO)) in pulmonary sarcoidosis. The material comprised 48 patients with biopsy proven sarcoidosis (35 male, 13 female, median age 31 years) and 24 controls (16 male, 8 female, median age 60 years). BAL was performed in the right middle lobe with 250 ml saline. Patients had higher BALF-HA, mean 88 +/- 13 (SEM) micrograms/l, than controls, 39 +/- 2 micrograms/l (p < 0.01), higher BALF-albumin, 121 +/- 13 mg/l, than controls 58 +/- 4 mg/l (p < 0.01), and higher BALF/S-HA ratio, 3.35 +/- 0.51, than controls, 1.23 +/- 0.60 (p < 0.01). There were no significant differences for S-HA, BALF-PIIINP, or S-PIIINP. In patients significant correlations were found between BALF-HA, S-HA, and BALF-albumin; between S-HA and S-ACE; between BALF/S-HA and BALF-albumin; between CXR profusion score and S-HA, S-ACE, S-IgG, S-IgA, FEV1, FVC, TLC and DLCO. The results indicate that measurement of S-HA, BALF-HA, and BALF-albumin may be of value in the monitoring of disease in pulmonary sarcoidosis.

The prognosis of patients with alcoholic liver disease. An international randomized, placebo-controlled trial on the effect of malotilate on survival.

The aim of this study was to examine the effect of malotilate on survival in patients with alcoholic liver disease and to determine prognostic variables for survival. Four hundred and seven patients with alcoholic liver diseases, from seven European liver units, entered a randomized placebo-controlled, double-blind trial: 140 patients received malotilate 1500 mg/day, 133 patients received 750 mg/day, and 134 patients received placebo. The patients were included in the study over a period of 3 1/2 years, and the study was closed 1 year after the entry of the last patient. Eighty-four patients died (35, 19, 30 patients in groups 1500 mg/day, 750 mg/day, and placebo, respectively). Survival was slightly better in the 750 mg/day group than in the two other treatment groups, when tested by conventional log-rank tests (p = 0.06). However, a treatment effect was supported by a highly significant (p = 0.006) non-proportionality of the death intensity in patients receiving 750 mg/day against those receiving either 1500 mg/day or placebo. Prognostic variables for survival were evaluated using the multiple Cox regression analysis of clinical and laboratory variables and with or without liver histology variables, as determined at entry into the study. The analysis was stratified for the three treatment regimens. In the analysis including liver histology variables, independent significant prognostic variables were: years of high alcohol intake, prothrombin index, alkaline phosphatases, creatinine, immunoglobulin M, white blood cell count, and liver cell steatosis. In the analysis without liver histology variables, prognostic variables were: years of high alcohol intake, prothrombin index, alkaline phosphatases, creatinine, and immunoglobulin M.

Oral candidiasis and immune status of HIV-infected patients.

A total of 84 HIV-infected homosexual men having either normal oral mucosa (NOM), erythematous candidiasis (EC) or pseudomembranous candidiasis (PsC) were included in the study. The patients were evaluated by median number of peripheral CD4+ cells, CD8+ cells and by lymphocyte function assessed by poke-weed mitogen test. There was a significant difference between CD4+ counts among patients with the two subtypes of candidiasis (95% CI of median difference: 10-240/mm3; P = 0.03), but not for pokeweed mitogen response. Survival analysis showed that after 2 y there was no significant difference in development of AIDS between patients with EC and PsC (P = 0.29). If patients with both types of oral candidiasis were pooled and compared with patients with NOM, a significant difference in development of AIDS was found (P = 0.04). It is concluded that HIV-infected patients with oral candidiasis of any subtype (EC or PsC) are significantly more immune suppressed and show a faster development of AIDS than HIV-infected patients with NOM. However, in this cohort, EC and PsC are of equal importance as predictors for immune suppression and AIDS development.

Serum type III procollagen peptide in patients with Pneumocystis carinii infection. The Copenhagen-Amsterdam PCP-Prednisolone Study Group.

Inflammation may play a central role in the pathogenesis of HIV-related Pneumocystis carinii pneumonia (PCP). Serum levels of the amino-terminal propeptide of Type III procollagen (PIIINP) reflect inflammatory activity in granulation tissue and in chronic rheumatic and liver disorders. To investigate changes in PIIINP serum levels during an episode of HIV-related PCP, consecutive serum samples were taken from 48 HIV-infected patients with PCP in a randomized, placebo-controlled study of the effect of adjunctive methylprednisolone therapy (26 in corticosteroid [CS] group and 22 in control group). All patients were treated with co-trimoxazole. In the control group, PIIINP serum levels at day of initiation of therapy (Day 0) were significantly higher in patients requiring mechanical ventilation and/or dying during the course of the pneumonia, and serum levels of PIIINP higher than 5 ng/ml were associated with a higher mortality than levels below 5 ng/ml. The level of PIIINP increased from Day 0 to Day 5. There was a significant correlation between changes in PIIINP levels and changes in the alveolar-arterial oxygen gradient from Day 0 to Day 5. In the CS group, the PIIINP levels decreased while steroid was administered. At Days 21 to 28 there were no difference in the levels of PIIINP between the two groups. PIIINP serum levels may predict the clinical outcome of PCP. The antimicrobial therapy may exacerbate the inflammatory reaction in HIV-related PCP, leading to respiratory failure. CS prevents this increased inflammatory activity.

Adjunctive corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS: a randomized European multicenter open label study.

Fifty-nine human immunodeficiency virus type-1-infected patients with a microscopically proven first episode of moderate to severe Pneumocystis carinii pneumonia (PCP) were enrolled into a randomized European multicenter study. The effect of adjunctive corticosteroid (CS) therapy was assessed on (a) survival to discharge, (b) need for mechanical ventilation, and (c) survival at day 90. CS was given within 24 h of standard therapy as intravenous methylprednisolone 2 mg/kg body weight daily for 10 days. All patients received cotrimoxazole as standard treatment. Inclusion criteria were a PaO2 less than 9.0 kPa (67.5 mm Hg) and/or a PaCO2 less than 4.0 kPa (30.0 mm Hg) while breathing room air. During the acute episode of PCP, 9 (31%) of the 29 control patients died versus 3 (10%) of the 30 CS patients; p = 0.01. Mechanical ventilation was necessary in 15 patients; 12 (41%) in the control group and 3 (10%) in the CS group; p = 0.01. The 90-day survival was 69% in controls versus 87% in CS patients; p = 0.07. Based on these data we conclude that adjunctive CS therapy for moderate to severe PCP in AIDS patients reduces the acute mortality and the need for mechanical ventilation.

Hepatic extraction of the aminoterminal propeptide of type III procollagen before and after bile duct ligation in pigs.

The aminoterminal propeptide of type III procollagen is extracted from the circulation by the liver, and PIIINP is found in bile. This study was performed in order to investigate whether biliary excretion contributes substantially to the hepatic extraction of circulating PIIINP. Hepatic extraction before and during a 4-h period after ligation of the common bile duct was assessed from serum PIIINP concentrations in a systemic artery, the portal vein and a hepatic vein of seven healthy anaesthetized pigs. Seven sham-operated anaesthetized pigs served as controls. Ligation of the bile duct did not cause a decrease in the hepatic extraction ratio of circulating PIIINP. The PIIINP serum levels of the cholestatic pigs and of the controls were similar throughout the investigation period. The PIIINP concentrations in bile were only 10% of the corresponding serum values. Gel filtration of sera showed that the lower PIIINP concentration in the hepatic vein, as compared to the artery and the portal vein was due to a selective decrease in the concentration of the intact propeptide. The study shows that biliary excretion does not contribute significantly to the hepatic extraction of circulating PIIINP in the normal liver. Furthermore, the hepatic extraction of circulating PIIINP preferentially affects the intact propeptide, rather than the somewhat larger PIIINP related molecule in serum.

[3 cases of visceral leishmaniasis, one in a HIV-positive man]. / Tre tilfaelde af visceral leishmaniasis: det ene hos en HIV-positiv mand.

Three cases of visceral leishmaniasis (kala-azar) are presented. One of these was in a 43-year-old patient with AIDS who was infected in Southern Spain. Another was in a man aged 25 years infected in West Africa. These cases are the first two adults to be reported in Denmark. The third case was an 18 month old previously healthy boy, infected in Southern Spain. The symptomtology, diagnosis and treatment of the disease are discussed and it is stressed that serological diagnostic tests have limited value in HIV positive patients.

Splanchnic and renal extraction of circulating type III procollagen aminoterminal propeptide in patients with normal liver function and in patients with alcoholic cirrhosis.

Splanchnic and renal extraction of circulating aminoterminal propeptide of type III procollagen and related antigens were studied in 12 patients with normal liver function and in 19 patients with alcoholic cirrhosis during catheterization. Type III procollagen peptide in serum was measured in two assays: the Type III Procollagen Peptide Radioimmunoassay Kit, a new assay that selectively determines the intact propeptide (and larger type III propeptide-holding antigens) and the Type III procollagen Fab assay that measures both the intact propeptide and the smaller fragments that quantitatively dominate in serum. A significant decrease in the concentration of the intact propeptide between the artery and the hepatic vein was found in the group with normal liver function (p less than 0.01) and in patients with cirrhosis (p less than 0.01). In patients with cirrhosis, however, the splanchnic extraction ratio of the intact propeptide (median = 0.04, range = -0.03 to 0.16) was significantly lower than in patients with normal liver function (median = 0.17, range = 0.05 to 0.36, p less than 0.01). The concentration of the intact propeptide in the hepatic vein was positively correlated to hepatic pressure (n = 18, r = 0.51, p less than 0.05) and inversely correlated to indocyanine green clearance (n = 15, r = -0.61, p less than 0.05). No splanchnic extraction could be demonstrated in the Type III propeptide Fab assay. A significant renal extraction was found in the Fab assay, but not in Type III Procollagen Peptide Radioimmunoassay Kit.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum aminoterminal type III procollagen peptide reflects repair after acute myocardial infarction.

In 16 patients with acute myocardial infarction and in 15 controls, procollagen type III aminoterminal peptide in serum (PIIINP) was measured consecutively. Serum PIIINP was increased on the second to third postinfarction day (p less than 0.01) and remained elevated for more than 4 months. Peak values were observed on the third to seventh postinfarction day. The individual peak changes were correlated to infarction size calculated from serum CK-MB and serum lactate dehydrogenase (p = 0.60, p = 0.02). The changes in distribution of PIIINP-related antigens in serum after gel chromatography were similar to changes observed during wound healing in humans. PIIINP is cleaved off procollagen type III during the biosynthesis of type III collagen, which characterizes the early stages of repair and inflammation. Our findings suggest that serum PIIINP reflects the repair processes and scar formation following acute myocardial infarction. The serum PIIINP alterations in acute myocardial infarction differ essentially from the changes in myocardial enzymes reflecting myocardial injury. Serum PIIINP may therefore provide new and clinically relevant information on the healing of myocardial infarction.

Procollagen type III aminoterminal peptide in serum in idiopathic myelofibrosis and allied conditions: relation to disease activity and effect of chemotherapy.

The serum concentration of the aminoterminal propeptide of type III procollagen (PIIINP) was measured serially in patients with idiopathic myelofibrosis and other myeloproliferative syndromes. Two different assays were applied, the RIA-gnost assay (Hoechst, Frankfurt, FRG) and a new equilibrium RIA for the N-terminal propeptide of human type III procollagen (Farmos Diagnostica, Oulu, Finland). A positive correlation was found between the results obtained by the two RIA's (rho = 0.90, P less than 0.001). The highest propeptide levels were recorded in patients with idiopathic myelofibrosis, particularly in those with active disease. Elevated serum PIIINP levels decreased during treatment with various cytotoxic drugs, including intensive chemotherapy. By contrast, serum PIIINP was unchanged or increased in patients undergoing interferon alpha-2b therapy. Gel filtration of sera on Sephacryl S-300 column (Pharmacia, Sweden) showed that smaller PIIINP related peptides dominated in healthy subjects and in osteomyelosclerosis with stable disease. Conversely, the relative proportion of intact propeptide increased in accelerating disease stages and acute myelofibrosis. In conclusion, the present study implicates serum PIIINP as a useful indicator of disease activity in idiopathic myelofibrosis. The propeptide also appears to be a sensitive sero-marker of chemotherapy effect on fibrogenesis related to clonal myeloproliferation. Finally, the propeptide is suggested as an early predictor of relapse during cytotoxic therapy.

Hepatic and renal extraction of circulating type III procollagen amino-terminal propeptide and hyaluronan in pig.

Hepatic and renal clearance of the amino-terminal propeptide of type III procollagen (PIIINP) and of the glycosaminoglycan, hyaluronan (HA) were investigated in a catheterization study of seven healthy anesthetized pigs. Two assays were used, in order to distinguish between the metabolism of different PIIINP-related antigens. One was the PIIINP RIA Kit, which measures the intact propeptide. The other was the PIIINP Fab assay, in which the antibody has an equal affinity to the intact propeptide and to smaller fragments, of which the latter constitutes most of the antigenic activity in serum. Hepatic and gastrointestinal extraction were evaluated from measurements of serum concentrations in the artery, the portal vein and the hepatic vein. We found a significant hepatic extraction of the intact propeptide (extraction ratio 0.14) and of HA (extraction ratio 0.23), but not of smaller PIIINP fragments. No gastrointestinal extraction of any of the tested substances could be demonstrated. Only smaller PIIINP fragments (such as the col 1 fragment) were extracted by the kidneys (the extraction ratio in the PIIINP Fab assay was 0.19). The renal extraction ratio of HA was 0.14. The amounts of PIIINP fragments and of HA extracted by the kidneys were 50- and 3-times the amounts found in urine, respectively, indicating that the col 1 fragment and HA are degraded in the kidneys in addition to urinary excretion. Our results suggest a dynamic turnover of connective tissue-related components with a fast catabolism of circulating components in liver and kidneys.

Serum aminoterminal type III procollagen peptide. Relation to biosynthesis of collagen type III in experimentally induced granulation tissue in rats.

Serum aminoterminal type III procollagen peptide was measured in rats during the development of granulation tissue induced by subcutaneous implantation of viscose cellulose sponges. Active collagen type III synthesis in granulation tissue during the first three weeks was accompanied by an increase in serum propeptide level. A positive correlation was observed between the increase in serum propeptide level on the one hand and the increase in granulation tissue collagen type III content and the in vitro formation of tissue 3H-hydroxyproline on the other hand. In some animals the serum propeptide level remained low, despite biochemical signs of collagen synthesis, indicating variations in the release into serum and/or the metabolism of circulating propeptide. The increase in propeptide antigen concentration was mainly due to an elevated content of material with molecular weight equal to or twice that of the propeptide. A minor fraction of the propeptide remained attached to the interstitial collagen fibres in the granulation tissue. The correlation between the serum propeptide level and the biosynthesis of collagen at the site of the focal fibroproliferative process suggests that the serum propeptide level may be a valuable indicator of fibrogenesis and thereby of disease activity in fibrotic conditions.

Collagen type IV and procollagen type III during granulation tissue formation: a serological, biochemical, immunohistochemical and morphometrical study on the viscose cellulose sponge rat model.

The serum concentrations of collagen type IV,7S, collagen type IV,nc1, and aminoterminal type III procollagen peptide immunoreactive components were measured by means of specific radioimmunoassays during development of granulation tissue in rats. The results were compared with tissue deposition of basement membranes and interstitial collagens in the granulation as measured morphometrically. A parallel sequential pattern in tissue deposition of collagen types III and IV, and serum increase of collagen types III- and IV-related fragments, was observed. Serum collagen type IV was less sensitive as a marker for development of granulation tissue than the serum procollagen type III N-peptide. This was in accordance with a low collagen type IV/interstitial collagen ratio in the granulation tissue. However, a cross-sectional study showed that serum collagens types IV,7S and IV,nc1 may be useful as early quantitative indicators of granulation tissue formation. Simultaneously, measurement of collagen type IV- and procollagen type III N-peptide-related antigens in serum provides a differentiated reflection of the dynamic matrix processes in developing granulation tissue.

Fibronectin as predictor of cirrhosis in men who abuse alcohol.

In a study of 142 male alcohol abusers without evidence of cirrhosis the presence of intralobular fibronectin in the liver was investigated in relation to the subsequent development of the disease. All 142 initial biopsy samples showed preserved architecture. During a follow up period of 10-13 years 23 patients (16%) developed cirrhosis. Twelve of 110 patients with normal or slightly increased amounts of parenchymal fibronectin in the initial biopsy specimen developed cirrhosis, whereas eight out of 27 patients with moderately increased amounts and three out of five with significantly increased amounts later developed the disease (p less than 0.005). Semiquantitative assessment of the amount of parenchymal fibronectin at an early stage of alcoholic liver disease is of definite predictive value for the development of cirrhosis.