Ilija Kuzman

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

BACKGROUND Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each days delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each days delay). INTERPRETATION We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING F Hoffmann-La Roche.

Double Trouble: Hemorrhagic Fever with Renal Syndrome and Leptospirosis

The clinical picture of hemorrhagic fever with renal syndrome can closely mimic that of unicteric leptospirosis and vice versa. This is the first description of dual infection with Dobrava virus and leptospira and alteration of immune parameters in a Croatian soldier.

Electrocardiographic changes in patients with haemorrhagic fever with renal syndrome

The purpose of the study was to assess the incidence, type and dynamics of electrocardiography (ECG) alterations in patients with haemorrhagic fever with renal syndrome (HFRS) according to different stages of the disease. 79 patients hospitalized at the University Hospital for Infectious Diseases in Zagreb during the large HFRS outbreak in Croatia in 2002 were retrospectively analysed. HFRS diagnosis was confirmed by enzyme-linked immunosorbent assay. A 12-lead resting ECG was obtained. 30 (38%) patients had abnormal ECG findings, most frequently in the oliguric stage. Increased levels of urea and creatinine were observed in all patients with abnormal ECG, along with abnormal chest X-ray in nearly 50% of cases. Sinus tachycardia was the most frequent ECG disorder in the febrile stage, and bradycardia in the oliguric stage. During the course of disease, some other ECG disorders were recorded: bundle branch conduction defects, non-specific ventricular repolarization disturbances, supraventricular and ventricular extrasystoles, prolonged QT interval, low voltage of the QRS complexes in standard limb leads, atrioventricular block first-degree, and atrial fibrillation. Myocarditis was present in 3 patients. In conclusion, abnormal ECG was found in more than one-third of HFRS patients with the most common findings during the oliguric stage. All ECG changes were transient.

Electrocardiographic changes and myocarditis in trichinellosis : a retrospective study of 154 patients

Abstract The frequencies of electrocardiographic (ECG) abnormalities and myocarditis were determined, retrospectively, among 154 cases of trichinellosis [101 males and 53 females, with a mean (S.D.) age of 35.60 (14.64) years] who were hospitalized at the University Hospital for Infectious Diseases in Zagreb, Croatia, over a 5-year period. Eighty-seven (56%) of the patients, most of them in the invasive phase of infection with Trichinella spiralis, were found to have abnormalities when examined by 12-lead, resting electrocardiography. The ECG disorder most frequently observed was a non-specific ventricular repolarization disturbance (with ST-T wave changes), followed by bundle-branch conduction disturbances, and sinus tachycardia. The other ECG disorders recorded, during various phases of the infection, were sinus bradycardia, right bundle-branch block, supraventricular and ventricular extrasystoles, low-voltage QRS complexes in standard limb leads, first-degree atrio-ventricular block, and atrial fibrillation. Eighteen (12%) of the patients were identified as cases of myocarditis (13 in the invasive phase and five in the convalescent) and two (1.3%) as cases of myopericarditis. One patient developed acute myocardial infarction 28 days after the onset of disease and died soon thereafter; an autopsy revealed multiple necroses and fibroses of the myocardium and thrombus of a coronary artery. Although ECG abnormalities appear to be a common feature of trichinellosis, especially during the invasive phase of the disease, they are rarely associated with a poor prognosis. A transient, non-specific, ventricular-repolarization disturbance is the abnormality most commonly observed.

Failure of Azithromycin in Treatment of Brill-Zinsser Disease

ABSTRACT Two patients suffering from Brill-Zinsser disease were treated with azithromycin, which did not prove effective. Rickettsia prowazekii, the agent causing Brill-Zinsser disease, cannot be treated with azithromycin. Both patients had epidemiological features consistent with and a clinical course typical of the disease. The diagnosis of Brill-Zinsser disease was serologically confirmed.

Enumeration of Haemagglutinin‐specific CD8+ T Cells after Influenza Vaccination Using MHC Class I Peptide Tetramers

With emergence of MHC class I tetramers loaded with CD8+ T‐cell viral epitopes, it is possible to study virus‐specific CD8 cells in humans during infection and after vaccination. MHC class I tetramers was used to detect the frequency of haemagglutinin (HA)‐specific T cells in 26 healthy influenza‐vaccinated humans. Peripheral blood was collected before, and 7, 14 and 28 days after vaccination. Four‐colour flow cytometry was used for monitoring of vaccine induced T‐cell response. In 15 donors, two‐ to fivefold increase in frequency of HA‐specific T cells was observed 7 days after vaccination. In addition, in 12 of these donors, this increase was accompanied with fourfold increase of H1N1 antibody titre. The increase in frequency of HA‐specific CD8+/IFN‐γ+ cells was low and peaked 28 days after vaccination in three of the six donors tested. Frequencies of HA‐specific CD8+ T cells and antibody titre returned to prevaccination values 1 year after vaccination. Subunit influenza vaccines have the ability to induce HA‐specific CD8+ cells. As the immune response to this vaccine decreased significantly after 1 year, our results confirm the importance of annual immunization for adequate protection.

Liver involvement during influenza infection: perspective on the 2009 influenza pandemic

Please cite this paper as: Papic et al. (2011) Liver involvement during influenza infection: perspective on the 2009 influenza pandemic. Influenza and Other Respiratory Viruses 6(3), e2–e5.

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

The impact of neuraminidase inhibitors (NAIs) on influenza‐related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection.

Mycoplasma pneumoniae in adult community-acquired pneumonia increases matrix metalloproteinase-9 serum level and induces its gene expression in peripheral blood mononuclear cells

Summary Background The objective of this study was to assess the concentration of metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) in peripheral circulation and their mRNA expression in peripheral blood mononuclear cells (PBMCs) in patients with CAP caused by M. pneumoniae. Material/Methods We prospectively analyzed MMPs in 40 hospitalized patients with M. pneumoniae CAP on admission, and in the convalescent phase. Twenty healthy men were used as controls. Quantitative real-time PCR and ELISA tests were used. Results MMP-9 mRNA expression in PBMCs was increased in the acute phase of illness compared to the control group as well as in convalescent phase in which case it was statistically significant (Mann-Whitney; p=0.028). The same was found for MMP-9 plasma levels (Mann-Whitney test; p<0.001; p=0.001). Circulating MMP-2 concentration in acute patients was significantly lower than in the control group and convalescent phase (Mann-Whitney test; p=0.012; p=0.001), while no MMP-2 mRNA expression was found in PBMCs. The plasma level of MMP-9 correlated with leukocyte count in peripheral circulation (r=0.67, p<0.001). Conclusions We conclude that M. pneumoniae in adult CAP induces activity of MMP-9 in peripheral blood circulation.

Electrocardiographic changes in hospitalized patients with leptospirosis over a 10-year period.

Summary Background The aim of this study was to investigate the incidence and type of ECG changes in patients with leptospirosis regardless of clinical evidence of cardiac involvement. Material/Methods A total of 97 patients with serologically confirmed leptospirosis treated at the University Hospital for Infectious Diseases „Dr. Fran Mihaljević‟ in Zagreb, Croatia, were included in this retrospective study. A 12-lead resting ECG was routinely performed in the first 2 days after hospital admission. Thorough past and current medical history was obtained, and careful physical examination and laboratory tests were performed. Results Abnormal ECG findings were found in 56 of 97 (58%) patients. Patients with abnormal ECG had significantly elevated values of bilirubin and alanine aminotransferase, lower values of potassium and lower number of platelets, as well as more frequently recorded abnormal chest x-ray. Non-specific ventricular repolarization disturbances were the most common abnormal ECG finding. Other recorded ECG abnormalities were sinus tachycardia, right branch conduction disturbances, low voltage of the QRS complex in standard limb leads, supraventricular and ventricular extrasystoles, intraventricular conduction disturbances, atrioventricular block first-degree and atrial fibrillation. Myopericarditis was identified in 4 patients. Regardless of ECG changes, the most commonly detected infection was with Leptospira interrogans serovar Australis, Leptospira interrogans serovar Saxkoebing and Leptospira kirschneri serovar Grippotyphosa. Conclusions The ECG abnormalities are common at the beginning of disease and are possibly caused by the direct effect of leptospires or are the non-specific result of a febrile infection and metabolic and electrolyte abnormalities. New studies are required for better understanding of the mechanism of ECG alterations in leptospirosis.