IL-6 and other biomarkers as predictors of severity in COVID-19.

OBJECTIVE: Cytokine release syndrome is suggested to be the most important mechanism triggering acute respiratory distress syndrome and end organ damage in COVID-19. The severity of disease may be measured by different biomarkers. METHODS: We studied markers of inflammation and coagulation as recorded in 29 patients on admission to the hospital in order to identify markers of severe COVID-19 and need of ICU. RESULTS: Patients who were eventually admitted to ICU displayed significantly higher serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin. No statistical differences were found between the groups in median levels of lymphocytes, D-dimer or ferritin. CONCLUSIONS: IL-6 and CRP were the strongest predictors of severity in hospitalized patients with COVID-19.

Utility of C-reactive protein in assessing the disease severity and complications of community-acquired pneumonia.

Previous studies on the usefulness of C-reactive protein (CRP) in patients with community-acquired pneumonia (CAP) have yielded somewhat inconsistent results. Our aim was to assess the value of CRP in estimating the severity and complications of CAP. CRP levels during the first 5 days of hospitalization were measured in 384 adult patients with CAP, and the data were evaluated using comprehensive statistical analyses. Significantly higher CRP levels on admission were detected in Pneumonia Severity Index (PSI) classes III-V than in classes I and II (p <0.001). An increment of 50 mg/L CRP on admission was associated with a 1.22-fold odds for a patient to be in PSI classes III-V as compared with classes I and II (OR 1.22, 95% CI 1.11-1.34; p <0.001). CRP levels were significantly higher in bacteraemic pneumonia than in non-bacteraemic pneumonia (p <0.001). An increment of 50 mg/L CRP was associated with a 1.67-fold odds for a patient to be bacteraemic (OR 1.67, 95% CI 1.46-1.92; p <0.001). CRP levels >100 mg/L on day 4 after the admission were significantly associated with complications (p <0.01). There was a trend for an association between the level of CRP on admission and the time to reach clinical stability (p <0.01). In conclusion, CRP may be valuable for revealing the development of complications in CAP. It may also be useful to assess the disease severity, thus being complementary to the assessment of the PSI. In our patients, high CRP levels were associated with a failure to reach clinical stability.

Infective endocarditis in a Finnish teaching hospital: a study on 326 episodes treated during 1980-2004.

OBJECTIVES: To evaluate potential changes of infective endocarditis (IE) in patients treated in a Finnish teaching hospital during the past 25 years. PATIENTS: 326 episodes of IE in 303 patients treated during 1980-2004 were evaluated for clinical characteristics and their changes over time. RESULTS: The mean age of the patients increased with time (from 47.2 to 54.5 years, p = 0.003). Twenty-five (7.7%) episodes were associated with intravenous drug use (IVDU), with a significant increase of these episodes after 1996 (from 0 to 19 (20%), p < 0.001). Viridans streptococci were the most common causative agents of IE during 1980-1994, but after that Staphylococcus aureus was the most common pathogen (p = 0.015). The proportion of IE of the aortic valve decreased during the study (from 30 (49%) to 26 (27%), whereas the proportions of mitral (11 (18%) to 33 (35%) and tricuspid valve IE (0 to 13 (14%) increased correspondingly (p = 0.001). This was mainly due to more patients with IVDU. Chronic dialysis for renal failure as an underlying condition increased over time (from 0 to 7 (7.4%), p = 0.015) but no other predisposing conditions changed. Complications such as neurological manifestations and heart failure did not change in frequency, but the incidence of lung emboli increased (from 0% to 10.5%, p < 0.001); 83% of these emboli occurred in patients with IVDU. The proportion of patients requiring surgical treatment and mortality due to IE did not change. CONCLUSIONS: During these 25 years, the causative agents, affected valves and complications of IE changed to some degree. These changes were mainly attributed to the increase of IVDU-associated IE. Except for the increase in age, the clinical presentation and outcome in non-addicts remained substantially unchanged.

Bronchoalveolar lavage in immunocompromised patients with haematological malignancy--value of new microbiological methods.

PURPOSE: To assess the usefulness of new culture-independent microbiological methods to analyse bronchoalveolar lavage (BAL) fluid from haematological patients with clinical pneumonia. PATIENTS AND METHODS: Results of 135 BALs from 122 disease episodes in 99 patients treated between 1996 and 2002 were retrospectively analysed. Forty-three patients had undergone haematopoietic stem cell transplantation and 56 patients had been treated with conventional chemotherapy for haematological malignancy. In addition to conventional microbiological methods, polymerase chain reaction (PCR) tests for Pneumocystis carinii, cytomegalovirus (CMV), Legionella sp., mycobacterium, Mycoplasma pneumoniae, and Chlamydia pneumoniae and the Aspergillus antigen test were performed. RESULTS: Three (2.2%) quantitative and four (3.0%) special bacterial cultures gave an aetiological diagnosis. A respiratory virus was isolated in 10 episodes (8.2%). The diagnostic yield increased to 35.6% (48 of 135) by other methods. The P. carinii PCR test was positive in 21 of 24 patients with P. carinii pneumonia, being the only microbiological indication of P. carinii in four cases. The CMV PCR test was positive in 18 patients, but in 14 patients the clinical significance of the finding remained unproven. The Aspergillus antigen test was positive in seven of nine patients with aspergillosis, being the only microbiological indication of Aspergillus in three cases. The result of BAL indicated commencement of specific antimicrobial treatment in 27 episodes (22.1%). CONCLUSION: The contribution of new culture-independent methods to the total diagnostic yield was of note. Among these methods, the P. carinii PCR and Aspergillus antigen tests proved the most valuable, while the CMV PCR test was not clinically useful.

Parainfluenza virus type 3 infections in a hematology unit.

Parainfluenza virus type 3 (PIV3) is associated with a high mortality rate in BMT recipients with lower respiratory tract infections. We describe nine patients with hematological malignancies (five having undergone either allogeneic or autologous stem cell transplantation) identified as having PIV3 infection during a 2-month period in a Hematology Unit. Four patients with infiltrates on chest radiograph received intravenous ribavirin therapy; all survived. The infection was community-acquired in two patients, while nosocomial origin of the disease was evident, or presumed, in the remaining seven. The policy implemented to control the spread of PIV3 was as follows: (1) nasopharyngeal samples for antigen detection were obtained from all patients presenting with respiratory symptoms; (2) all diagnosed (or suspected) PIV3-positive hematological patients were nursed following contact isolation precautions, preferably in the Infectious Diseases Unit; and (3) staff were given further education on hospital hygiene. Our experience shows that it may be possible to avoid mortality for PIV3 lower respiratory tract infection in immunocompromised patients by early commencement of intravenous ribavirin. It is also possible, even without closing the ward, to contain nosocomial spread of PIV3 by implementing systematic nasopharyngeal sampling for rapid diagnostics, and by strict adherence to cohorting and contact isolation precautions.

Increased serum neutral endopeptidase activity in acute renal allograft rejection.

Neutral endopeptidase (EC 3.4.24.11; NEP), originally isolated from renal tubular brush border, is a cell surface peptidase identical to the CD10 antigen (or CALLA; common acute lymphoblastic leukemia antigen) in lymphoid cells. We studied the serum NEP levels daily after transplantation (Tx) in 19 renal allograft recipients. The NEP activity was determined with a two-step enzymatic assay utilizing a fluorogenic substrate (Suc-Ala-Ala-Phe-AMC; see text) and related to clinical signs of graft rejection, to signs of immunoactivation in transplant fine-needle aspiration biopsy (FNAB) specimens, to renal function, and to serum levels of C-reactive protein. The serum NEP levels remained normal (peak level 10.3 +/- 1.8 micrograms/l on days 6-9 after Tx, initial level after Tx 7.3 +/- 1.4 micrograms/1 on day 2; mean values +/- SEM) in patients who neither showed clinical signs of rejection nor had findings of immunoactivation in FNAB samples. On the contrary, the serum NEP levels rose clearly in patients developing acute rejection verified clinically and in FNAB samples (peak value 90.4 +/- 18.7 micrograms/l on days 6-9 post-Tx; p < 0.001 compared with patients without sings of immunoactivation) and even in patients having immunoactivation in FNAB without clinical evidence of rejection (108.2 +/- 22.4 micrograms/l, p < 0.001). Serum NEP peak appeared 2-3 days before clinical diagnosis of rejection and a positive findings in FNAB samples. Serum NEP increments did not correlate with changes in serum creatinine, delayed onset of renal excretory function, blood leukocyte count, C-reactive protein level, or infections. Thus, the serum NEP activity was shown to increase after renal allotransplantation associated with early phases of immunoactivation and development of acute graft rejection. Because of the limited number of patients studied, the clinical implications of these preliminary observations for kidney transplant monitoring clearly need confirmation in larger studies.

Inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes.

Synthesis of angiotensin-converting enzyme is induced during its chronic inhibition. Like angiotensin-converting enzyme, neutral endopeptidase (EC 3.4.24.11) is a plasma membrane peptidase. We studied changes of the two enzymes in lung, kidney and serum in a coronary ligation model of experimental congestive heart failure, and during chronic inhibition of the enzymes. Coronary-ligated rats (n = 19) and sham-operated controls (n = 18) were given SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine], a specific neutral endopeptidase inhibitor (n = 13), captopril (n = 12), or vehicle (n = 12) for 4 days, and exsanguinated. Pulmonary angiotensin-converting enzyme was induced both by captopril (52% compared to vehicle) and by SCH 34826 (21%). Serum angiotensin-converting enzyme was induced by captopril (44%). Neutral endopeptidase was induced in lung by captopril (73%), and in kidney by SCH 38426 (32%). Compared to controls, the relative heart weight of rats with heart failure was increased by 29%, and the plasma level of atrial natriuretic peptide elevated by 74%, but enzyme activities were not different. We conclude that, in the rat, separate inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes, and that the induction varies in different tissues. Alterations in the substrates of the two enzymes, e.g. in bradykinin, might cause these changes.

Endothelin-1 is expressed and released by a human endothelial hybrid cell line (EA.hy 926).

A permanent vascular endothelial cell line, EA.hy 926, was shown to express endothelin-1 (ET-1) mRNA and to secrete big ET-1 and ET-1 into culture medium. The concentration of both big ET-1 and ET-1 was significantly increased in EA.hy 926 culture medium by phosphoramidon, a metalloproteinase inhibitor, suggesting that phosphoramidon sensitive protease(s) may be responsible for the degradation of ET-1 and big ET-1. EA.hy 926 cells responded to various regulators of ET-1 similarly as primary human vascular endothelial cells. The production of ET-1 was increased by thrombin and decreased by vasodilators such as atrial natriuretic peptide, brain natriuretic peptide and nitroprusside, and by 8-bromo cyclic GMP and papaverine. This continuous human endothelial hybrid cell line could facilitate studies of regulation of ET-1 production in human endothelial cells, which in primary cultures have limited replication potential.

Evaluation of the double antibody-solid phase radioimmunoassay technique in plasma LH and FSH and urinary LH measurements.

Double antibody-solid phase (DASP) radioimmunoassay methods for plasma LH and FSH and urinary LH were developed and carefully evaluated as to their reliability and practicability. The peptide hormones were iodinated enzymatically with immobilized lactoperoxidase which resulted in pure and stable products of unchanged immunoreactivity. The sensitivities of these assay methods are 0.02, 0.17 and 0.20 mIU/tube for plasma LH (MRC 68/40) and FSH (MRC 68/39) and urinary LH (IRP-HMG, urinary), respectively. Interassay coefficients of variation obtained over a 6-18 month period were 14.2, 14.7 and 12.8%, respectively. The latter values for plasma LH and FSH assays were obtained from one level pool samples, and the value for urinary LH is the mean of those obtained from two pools of different levels. Plasma reference values for LH and FSH obtained using these methods are about 1.8-2.9 times higher than those cited for other types of radioimmunoassay. However, the values obtained for LH in urine are similar to those reported in the literature. It is suggested that the DASP technique is less influenced by interference from plasma proteins and because of this gives plasma values closer to the true ones. It is concluded that the methods are well suited for use as routine clinical assays in laboratories with a high work load.