FEASIBILITY OF THE MULTIMODAL SMOKING CESSATION INTERVENTION DURING HOSPITALIZATION WITH SIX-MONTH FOLLOW-UP POST-DISCHARGE: A PILOT STUDY.

The main aim of this pilot project was to introduce multimodal smoking cessation intervention in the hospital setting and to analyze users' satisfaction and efficacy of the intervention within six months post-discharge. Multimodal intervention for smoking cessation was used and it consisted of the "5 A's" model (Ask, Advice, Assess, Assist, Arrange) for behavior change, printed self-help materials for smoking cessation, and telephone counseling (one, three and six months after discharge from the hospital). The main outcome of the study was smoking status at six months. A total of 103 participants were included in this pilot project. At six-month follow-up, 49% of participants self-reported continuous non-smoking. Among the remaining participants, 20 reported smoking reduction, 19 were still smoking, and 16 participants were unable to make contact with. In the logistic regression, among all analyzed variables, only two of them were positively associated with smoking cessation after six months: participants' response that they would like to quit smoking within the next six months (B=4.688; p=0.018) and answering that they did not smoke when they were ill and bed-ridden due to illness (B=3.253; p=0.020). Satisfaction with the intervention was very high; 70% of participants rated the intervention as 'excellent'. Therefore, multimodal smoking cessation intervention can be successfully introduced at hospital setting yielding high smoking abstinence rates at six months post-discharge and high level of user satisfaction. Healthcare workers who work in hospitals should be educated so they can provide such intervention on a regular basis.

Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection.

BACKGROUND: The effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear. METHODS: We conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded. RESULTS: We analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78-.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS. CONCLUSIONS: When patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.

PANDEMIC INFLUENZA A (H1N1) 2009 PRESENTING AS A MILD DISEASE IN CHILDREN IN A CROATIAN CLINICAL CENTRE.

Pandemic influenza A virus (H1N1) 2009 causes a disease that is epidemiologically and clinically not significantly different from seasonal influenza, but there are differences. The aim of the study was to display and compare epidemiological and clinical characteristics of pandemic influenza in children. At Dr. Fran Mihaljevic University Hospital for Infectious Diseases in Zagreb, in the first two seasons, the incidence of pandemic influenza virus A (H1N1) in particular was exhaustively analyzed only in patients with laboratory-confirmed pandemic influenza A virus (H1N1) 2009. In hospitalized children with documented influenza pandemic, moderate form of the disease predominated, which ultimately meant shorter hospital stay and fewer complications. Otitis media was the rarest complication in children in both seasons. In conclusion, children younger than 5 years, especially boys, were vulnerable groups for pandemic influenza, presenting as a mild disease with low mortality and few complications. Most of the affected children with influenza did not have important risk factors such as asthma and obesity, highlighted by other authors as significant risk factors.

Relapsing Bacteraemia due to Corynebacterium striatum in a Patient with Peripheral Arterial Disease.

We describe the first reported case of Corynebacterium striatum (C. striatum) relapsing bacteraemia in a patient with peripheral arterial disease and proven Corynebacterium species colonization of a chronic foot ulcer, focusing on the difficulties in the management of the patient. We conclude that the optimal duration of the antibiotic treatment for relapsing C. striatum bacteraemia from a chronic ulcer should be 6 weeks together with surgical treatment.

Efficacy and safety of moxifloxacin in community acquired pneumonia: a prospective, multicenter, observational study (CAPRIVI).

BACKGROUND: Community acquired pneumonia (CAP) is a major cause of morbidity, hospitalization, and mortality worldwide. Management of CAP for many patients requires rapid initiation of empirical antibiotic treatment, based on the spectrum of activity of available antimicrobial agents and evidence on local antibiotic resistance. Few data exist on the severity profile and treatment of hospitalized CAP patients in Eastern and Central Europe and the Middle East, in particular on use of moxifloxacin (Avelox®), which is approved in these regions. METHODS: CAPRIVI (Community Acquired Pneumonia: tReatment wIth AVelox® in hospItalized patients) was a prospective observational study in 12 countries: Croatia, France, Hungary, Kazakhstan, Jordan, Kyrgyzstan, Lebanon, Republic of Moldova, Romania, Russia, Ukraine, and Macedonia. Patients aged >18 years were treated with moxifloxacin 400 mg daily following hospitalization with a CAP diagnosis. In addition to efficacy and safety outcomes, data were collected on patient history and disease severity measured by CRB-65 score. RESULTS: 2733 patients were enrolled. A low severity index (i.e., CRB-65 score <2) was reported in 87.5% of CAP patients assessed (n=1847), an unexpectedly high proportion for hospitalized patients. Moxifloxacin administered for a mean of 10.0 days (range: 2.0 to 39.0 days) was highly effective: 96.7% of patients in the efficacy population (n=2152) improved and 93.2% were cured of infection during the study. Severity of infection changed from "moderate" or "severe" in 91.8% of patients at baseline to "no infection" or "mild" in 95.5% at last visit. In the safety population (n=2595), 127 (4.9%) patients had treatment-emergent adverse events (TEAEs) and 40 (1.54%) patients had serious TEAEs; none of these 40 patients died. The safety results were consistent with the known profile of moxifloxacin. CONCLUSIONS: The efficacy and safety profiles of moxifloxacin at the recommended dose of 400 mg daily are characterized in this large observational study of hospitalized CAP patients from Eastern and Central Europe and the Middle East. The high response rate in this study, which included patients with a range of disease severities, suggests that treatment with broader-spectrum drugs such as moxifloxacin is appropriate for patients with CAP who are managed in hospital. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00987792.

Influenza and hepatitis B vaccination coverage among healthcare workers in Croatian hospitals: a series of cross-sectional surveys, 2006-2011.

BACKGROUND: Healthcare workers (HCWs) are at an increased risk of exposure to and transmission of infectious diseases. Vaccination lowers morbidity and mortality of HCWs and their patients. To assess vaccination coverage for influenza and hepatitis B virus (HBV) among HCWs in Croatian hospitals, we conducted yearly nationwide surveys. METHODS: From 2006 to 2011, all 66 Croatian public hospitals, representing 43-60% of all the HCWs in Croatia, were included. Statistical analysis was performed using the Kruskal-Wallis analysis of variance, Dunn's multiple comparison analysis and the chi-square test, as appropriate. RESULTS: The median seasonal influenza vaccination coverage rates in pre-pandemic (2006-2008) seasons were 36%, 25% and 29%, respectively. By occupation, influenza vaccination rates among physicians were 33 ± 21%, 33 ± 22% among graduate nurses, 30 ± 34% among other HCWs, 26 ± 21% among housekeeping and the lowest, 23 ± 17%, among practical nurses (p < 0.01). In 2009-2010 season, seasonal influenza vaccination coverage was 30%, while overall vaccination coverage against pandemic influenza was fewer than 5%. Median vaccination coverage in the post-pandemic seasons of 2010-2011 and 2011-2012 decreased to 15% and 14%, respectively (reduction of 24% and 35%, respectively, p < 0.0001). Meanwhile, the median mandatory HBV vaccination coverage was 98%, albeit with considerable differences according to work setting (range 19-100%) and occupation (range 4-100%). CONCLUSIONS: We found substantial year-on-year variations in seasonal influenza vaccination rates, with reduction in post pandemic influenza seasons. HBV vaccination is satisfactory compared to seasonal influenza vaccination coverage, although substantial variations by occupation and work setting were observed. These findings highlight the need for national strategies that optimize vaccination coverage among HCWs in Croatian hospitals. Further studies are needed to establish the potential role of mandatory vaccination for seasonal influenza.

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

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.

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 Mihaljevic" 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.

[Guidelines on hand hygiene in health care institutions]. / Smjernice za higijenu ruku u zdravstvenim ustanovama.

Healthcare associated infections (HCAI) are huge problem all over the world, and 5-10% of all hospitalized patients will develop infection during hospitalization. From the times of I. P. Semelweiss we know that clean hands are the most important single factor that can decrease the number of HCAI. World Health Organization (WHO) has recognised this problem and developed Guidelines for hand hygiene in healthcare institutions. This also was the reason of developing Croatian national Guidelines. The main goal of the Guidelines was to decrease number of HCAI associated with the hands of healthcare workers. These Guidelines are meant for all healthcare workers and other hospital staff who come to the direct contact with patients. An interdisciplinary team of experts developed these Guidelines using WHO Guidelines, other existing guidelines and literature reviews for hand hygiene. Grades of evidence for specific recommendations were determined using CDC/HICPAC grading system. Categorization is based on existing data, theoretical basis, applicability and economic impact. After a broad discussion in different professional societies, Guidelines were accepted. Guidelines include recommendations for hand hygiene indications, hand hygiene technique, surgical hand preparation, choosing hand hygiene preparations, skin care, nails, glove use, patients and visitors hand hygiene, role of education, as well as role of healthcare institution and role of government. Furthermore, in the Guidelines the concept of "Five moments for hand hygiene" is explained in detail, and main literature data are presented.

The occurrence of hemorrhagic fever with renal syndrome in southern parts of Bosnia and Herzegovina.

Bosnia and Herzegovina (B&H) has been known as an endemic region for hemorrhagic fever with renal syndrome (HFRS) for over 50 years. Multiple epidemics of this disease have been registered so far, especially in endemic parts of Central and Northeastern Bosnia, as well as the Sarajevo region. Seroepidemiological investigations demonstrate naturalization of Hantaviruses and their wide spread in B&H. However, there are no studies from the southern areas of B&H, and endemic foci of this disease are unknown. The aim of this study was to determine the distribution and serologic prevalence of Hantavirus infections by testing for specific IgG antibodies against hantaviruses in the population of Herzegovina. This study included two groups of participants. The target group consisted of 300 participants from exposed professional and population groups, and control group included 100 educators with lower exposure to HFRS. Identification of specific IgG antibodies against hantaviruses in 16 participants confirmed an initial assumption about the presence of Hantavirus infections in the region of interest. Seroprevalence of 5% was registered in the "exposed" and 1% in the "unexposed" group. Simultaneous circulation of Puumala (PUU) and Dobrava (DOB) viruses was discovered. The frequency of positive antibody results was higher in the population above 50 years of age, and three times more prevalent in men then at women. The highest proportion of exposed participants (80%) was registered in the municipalities which geographically belong to high or mountainous Herzegovina.

Imported case of nephropathia epidemica--a case report.

A 41-year-oldpatient was hospitalized in hypotensive phase of nephropathia epidemica. The diagnosis was confirmed by serology. It is highly likely that the patient was exposed to infected aerosol of bank voles in endemic area of Sweden. The disease clinically manifested with fever, headache, abdominal and back pain, vision disturbances. Pathologic laboratory findings included thrombocytopenia, leukocytosis, increased values of C-reactive protein, blood urea and creatinine, abnormal chest X-ray and transient electrocardiogram abnormalities.

Gamma-glutamyltransferase activity and total antioxidant status in serum and platelets of patients with community-acquired pneumonia.

BACKGROUND: We undertook this study to analyze serum and platelet gamma-glutamyltransferase (GGT) activity and total antioxidant status (TAS) concentration during the course of pneumonia and to compare them between patients with normal platelet count and those who developed reactive thrombocytosis. METHODS: Platelet count, GGT activity and TAS concentration in serum (S) and platelet (Plt) isolates were measured in 60 patients with community-acquired pneumonia (CAP) on admission and at discharge. RESULTS: At the end of treatment, platelet count increased significantly from the value recorded on admission. By the end of treatment, 42% of patients developed reactive thrombocytosis. Serum and platelet GGT activity was higher, whereas (S)TAS was significantly lower in CAP patients than in control subjects. On admission, (Plt)TAS was significantly higher in CAP patients as compared with control subjects; at discharge, (Plt)TAS was lower in comparison with either patient admission and control subjects. GGT activity and TAS concentration in serum and platelet isolate on admission did not differ significantly between patients with and without thrombocytosis. At discharge, (S)GGT activity showed no significant changes, whereas (Plt)GGT decreased significantly in patients with thrombocytosis as compared with those without thrombocytosis. In patients with thrombocytosis, (S)TAS concentration showed no significant difference, whereas (Plt)TAS concentration measured at discharge was significantly lower in patients with thrombocytosis as compared to those with normal platelet count. CONCLUSIONS: The pattern of changes in (Plt)GGT catalytic activity and TAS concentration might be indicative of a certain role of thrombocytosis during treatment in patients with CAP. Further investigations are necessary to clarify these changes.

Different features of influenza A H1N1pdm09 virus infection among adults in 2009/10 and 2010/11.

INTRODUCTION: Influenza A H1N1pdm09 virus infection causes an epidemiologically and clinically severe disease mostly characterized by pneumonia, resulting in a high mortality rate. The purpose of this study was to investigate and compare epidemiological and clinical characteristics of influenza A H1N1pdm09 virus infection in patients hospitalized during the pandemic (2009/10) and post-pandemic seasons (2010/11). METHODOLOGY: The data of patients with laboratory-confirmed influenza A H1N1pdm09 virus infection hospitalized and treated at the University Hospital for Infectious Diseases Dr. Fran Mihaljevic in Zagreb, Croatia in the first two seasons of appearance were analyzed. RESULTS: Compared to the pandemic season, in the post-pandemic season, patients were hospitalized longer, had higher values of inflammatory parameters, and were more often treated with antibiotics. The total number of risk factors in patients did not vary significantly between the two seasons. In the pandemic season, a significantly higher number of obese patients and patients with chronic lung disease was observed, whereas in the post-pandemic season, a statistically significant number of patients presented with symptoms of chronic cardiac and neuromuscular diseases. Primary viral pneumonia was frequently registered in younger adults during the pandemic season, whereas in the post-pandemic season, there were more cases of bacterial pneumonia. CONCLUSIONS: During the pandemic season, the influenza A H1N1pdm09 virus infection caused a severe disease with rare bacterial complications, especially in adult patients. The common characteristics of the influenza A H1N1pdm09 virus were lost in the post-pandemic season, assuming the shape and characteristics of the seasonal influenza A virus.

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

BACKGROUND: 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. METHODS: A worldwide meta-analysis of individual participant data from 20 634 hospitalised patients with laboratory-confirmed A(H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) 'pandemic influenza'. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. RESULTS: Of 20 634 included participants, 5978 (29·0%) had IRP; conversely, 3349 (16·2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0·83 (95% CI 0·64-1·06; P = 0·136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0·72 (0·44-1·17; P = 0·180)] or likelihood of requiring ventilatory support [adj. OR = 1·17 (0·71-1·92; P = 0·537)], but early treatment versus later significantly reduced mortality [adj. OR = 0·70 (0·55-0·88; P = 0·003)] and likelihood of requiring ventilatory support [adj. OR = 0·68 (0·54-0·85; P = 0·001)]. CONCLUSIONS: Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support.

[Laboratory findings in patients with hemorrhagic fever with renal syndrome]. / Analiza laboratorijskih nalaza u bolesnika s hemoragijskom vrucicom s bubreznim sindromom.

AIM: To examine the frequency and distribution of hematologic and biochemical laboratory findings in 94 patients with hemorrhagic fever with renal syndrome (HFRS) in the epidemic year 2002. PATIENTS AND METHODS: The following laboratory findings were retrospectively analyzed: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, hematocrit, leukocyte count and differential percentage (segmented neutrophils, band neutrophils, atypical lymphocytes), platelet count, coagulation tests, blood urea nitrogen (BUN), creatinine, urine, potassium, bilirubin (BIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GT), alkaline phosphatase (ALP), and serum protein electrophoresis. The study included 94 HFRS patients treated at the Dr Fran Mihaljevic University Hospital for Infectious Diseases in Zagreb during 2002. RESULTS: ESR increase, mostly mild to moderate, was found in 86.2% of study patients. Increased CRP was recorded in 98.9% of study patients, however, one-fourth had CRP higher than 100 mg/L. Leukocytosis was recorded in 38.3% (10.1 +/- 4.2 x 10(9)/L), thrombocytopenia in 89.4% patients (68.2 +/- 48.3 x 10(9)/L), and severe thrombocytopenia (x 10(9)/L) in six patients. Three patients had abnormal coagulation tests. Increased values of BUN and creatinine were recorded in more than a half of patients, while only four patients had mild hyperkalemia. Only three patinets required hemodialysis. Mildly to moderately increased values of aminotransferases (AST, ALT, GT) were observed in more than 2/3; hypoalbuminaemia in nearly 1/3, and elevated alpha-2 fraction in more than 2/3 of patients. The majority of patients had pathologic urine findings. First laboratory abnormalities were usually found between day 5 and 7 of the disease (increased CRP level, thrombocytopenia, leukocytosis, and elevation of hemoglobin and hematocrit). Biochemical abnormalities(elevation of cratinine and urea, increased levels of aminotransferases) usually occurred at the beginning of the second week, and ESR increase in the second week of disease. CONCLUSION: The majority of our patients had laboratory findings characteristic of HFRS. Thrombocytopenia and increased level of CRP were the most common laboratory findings during the first week of the disease. Renal and liver impairment occurred at the beginning of the second week of the disease.

[Efficacy of moxifloxacin in the treatment of respiratory tract infections: the Croatian post-marketing study]. / Ucinkovitost moksifloksacina u lijecenju respiratornih infekcija: hrvatsko postmarketinsko istrazivanje.

In this study, we investigated and analysed clinical efficacy and tolerability of moxifloxacin, a new quinolone antibiotic, for the outpatient treatment of bacterial respiratory infections--acute exacerbation of chronic obstructive pulmonary disease (AE-COPD), pneumonia and acute sinusitis. The study was post-marketing and observational, and was conducted after the registration and listing of moxifloxacin in commercial distribution in Croatia. A total of 84 physicians throughout Croatia participated in this study that included 440 patients, 231 with clinically confirmed diagnosis of AE-COPD, 103 with pneumonia and 46 with acute sinusitis. According to physicians, evaluation, 96.8% of the patients were cured. The improvement was recorded on the average after 3.2 days and cure after 6.4 days from the beginning of treatment. Adverse events (48 side effects) were recorded in 40 patients, most commonly suffering from milder gastrointestinal symptoms (nausea, diarrhoea). Serious adverse events were not recorded (phototoxicity, severe hepatic impairment, cardiotoxicity). Moxifloxacin tolerability and patient compliance during treatment were rated as excellent in three-quarters of the patients. Physicians stated they would again prescribe moxifloxacin in 415 or 94.3% of the patients.

[Clinical picture of hemorrhagic fever with renal syndrome in Croatia]. / Klinicka slika hemoragijske vrucice s bubreznim sindromom u Hrvatskoj.

Among many viral hemorrhagic fevers, only hemorrhagic fever with renal syndrome (HFRS) occurs in Croatia. HFRS is a natural focus zoonosis with sudden onset, characterized by high fever and other clinical symptoms, renal insufficiency and hemorrhages. In Croatia, HFRS is caused by two types of hantaviruses--Puumala (PUU) and Dobrava (DOB). The basic pathologic and patophysiologic disorder in HFRS is capillary damage (vasculitis). Incubation of HFRS has not been precisely determined, it is most frequently around two weeks. The disease onset is usually abrupt. At the beginning, general symptoms include high fever and myalgias, especially in the lumbar region, and abdominal pain, as well as strong headaches, malaise and nausea, and often vomiting or diarrhea. In half of the patients respiratory symptoms occur. Later on, some patients may experience hypotension, oliguria and other signs of renal failure, and apart from petechial, severe hemorrhages may also occur in other organs. During typical clinical presentation of the disease, some characteristic symptoms are clearly distinguished in particular stages of the disease. Therefore, the course of HFRS is usually divided into five distinct stages (febrile, hypotensive, oliguric, polyuric and convalescent). Such a course of the disease is more commonly present in case of DOB virus than PUU virus infection. The febrile stage with sudden onset usually lasts from 3 to 7 days, when thrombocytopenia and hemoconcentration, as well as albuminuria and hematuria are almost always recorded. The hypotensive stage lasts from one to 2 days on an average and is characterized by lower blood pressure and signs of renal failure. The oliguric stage usually starts at the beginning of the second week of the disease, when extensive hemorrhage may occur and urea and creatinine reach their highest values. The oliguric stage is followed by the polyuric stage which can last for up to two weeks, and is characterized by excretion of a large quantity of urine of low specific gravity (up to 15 liters during 24 hours). The convalescence (convalescent stage) is slower, may last for several weeks or months, but usually resolves without complications. During the infection caused by PUU virus, the course of disease is usually milder with only two stages. The first one is febrile, followed by the second stage with renal symptoms, and rare and mild hemorrhagic manifestations. This type of disease is mostly encountered during epidemics. The mortality in severe cases of the disease (DOB virus) is 5% to 10%, whereas in PUU virus infection it is less than 1%.

[Hemorrhagic fever with renal syndrome in Croatia--historical review]. / Hemoragijska vrucica s bubreznim sindromom u Hrvatskoj--povijesni pregled.

Hemorrhagic fever with renal syndrome (HFRS) has been known from ancient times as a disease with many names, which raised great interest during the Korean war (1951-1954), occurring as a large epidemic (Korean hemorrhagic fever). Therefore, the subsequently discovered causative agent was named after the Hantaan River which runs along the 38th parallel and divides North Korea from South Korea. A similar disease was described in 1934 in Scandinavian countries (epidemic nephrosonephritis or nephropathy). During the Second World War, the disease was also registered as wartime nephritis in several European south-eastern countries. Since 1982, similar clinical manifestations of the disease, differently named in various parts of the world, have been assigned one unique name--hemorrhagic fever with renal syndrome, as recommended by the World Health Organization. In Croatia, the first patient with HFRS was diagnosed in 1952 and the paper describing the case was published in 1954 (Radosevic and Mohacek). Since then, the disease has been regularly occurring in our country, especially in sporadic form, with only two smaller epidemics recorded until 1995. The first epidemic with 14 forestry workers involved occurred in 1967 at the Plitvice Lakes, and the second with the same number of soldiers in 1989 around the Pieso-Airport near Zagreb. Simultaneously, in 1967 and 1989 two large-scale epidemics of HFRS occurred in Bosnia and Herzegovina with 144 cases each. Until the first large epidemic of HFRS in Croatia during the Croatian War in 1995, occurring at several localities (Mala Kapela, Dinara mountain, west Slavonia), it was considered that there were only several natural foci of the disease in Croatia (around Ogulin and Slunj, Plitvice Lakes, Zagreb surroundings). A total of 125 cases were reported to the Croatian National Institute of Public Health in 1995. Fifty patients, 45 of them soldiers, were hospitalized at Dr. Fran Mihaljevic University Hospital for infectious Diseases in Zagreb. In the same year, the largest epidemic also occurred in Bosnia and Herzegovina with more than 300 cases. During the almost 50-year experience in HFRS surveillance, we have noticed two different clinical manifestations of the disease. The milder type of illness without hemorrhage is more common than the severe type with hemorrhages and extensive renal insufficiency. After the virus discovery and introduction of serologic testing, two causative agents have been detected during the 1970s and 1980s--Vranica and Fojnica, that were later serotyped as Puumala and Dobrava viruses.

[Grading the severity of disease in patients with Puumala or Dobrava virus infections from 1995 to 2000 in Croatia]. / Stupnjevanje tezine klinicke slike u bolesnika s Puumala ili Dobrava virusnom infekcijom u razdoblju od 1995. do 2000. godine u Hrvatskoj.

AIM: The aim of our study was to evaluate the proposed Croatian scale for grading the disease severity in patients with hemorrhagic fever with renal syndrome (HFRS). The aim was also to determine whether the infection with Dobrava virus (DOBV) in Croatia was associated with a more severe illness than the infection with Puumala virus (PUUV). PATIENTS AND METHODS: To evaluate the scale, case records of 62 HFRS patients hospitalized at the University Hospital for Infectious Diseases in Zagreb from 1995 till 2000 were reviewed. ELISA IgM and IgG tests were used for the detection of specific IgM and IgG antibodies to PUUV or DOBV. DISCUSSION: HFRS caused by hantaviruses is a zoonotic disease spread worldwide, posing a major public health problem of global dimensions. Recent epidemiologic studies show that almost all parts of Croatia are endemic regions for two hantaviruses, Puumala and Dobrava. The disease severity ranges from subclinical infection to severe illness with fatal outcome. Clinical picture is predominated by fever, myalgia, vomiting, hemorrhagic manifestation, visual impairment and kidney affection. There is still a lack of knowledge concerning all the parameters involved in the disease severity. Besides the type of virus and genetic material, host genes are also associated with the variable clinical course. HLA alleles B8, DR3, and DQ2 are strongly associated with severe outcome of PUUV infection, white HLA B27 allele is associated with a mild course. Whether similar genetic factors also operate in DOBV infection remains to be determined. Recently, a Croatian scale for grading the disease severity was proposed. The disease severity is graded by a scoring system (points attributed to specific clinical symptoms and laboratory findings) as 1--mild, 2--moderate, 3--severe, and 4--very severe. We found 60% of HFRS patients to be infected with PUUV and 40% with DOBV. In our study, 65% of patients infected with PUUV had mild, and 24% moderate disease. Severe and very severe disease was recorded in 11% of PUUV infected patients. In contrast, only 44% of patients infected with DOBV had mild disease, whereas 40% of patients showed a moderate clinical picture. Severe and very severe clinical picture was recorded in 16% of patients with DOBV infection. Statistical analysis showed a significant number of pa (p < 0.01) with PUUV infection to have mild disease, whereas a significant number of HFRS patients infected with DOBV had moderate (p < 0.01) and severe or very severe (p < 0.01) disease. CONCLUSION: Our results clearly indicate that in Croatia DOBV infection is associated with a more severe disease than PUUV infection. However, we confirmed previous findings that even PUUV infection could lead to a severe disease. Our initial experience in the evaluation of the proposed grading scale for disease severity demonstrated the proposed Croatian scale to be a useful tool in grading disease severity in patients infected with PUUV or DOBV. Moreover, the proposed scale may also prove highly useful for the prognostic purpose.