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Background. The aim of this study was to evaluate the ability of severity scoring systems to predict 30-day mortality in patients with severe community-acquired pneumonia.

Introduction. The study aimed to compare the etiologic spectrum of diseases causing fever of unknown origin (FUO) and methods for definitive diagnosis in a tertiary care hospital in the Republic of North Macedonia during two different time periods.

The resurgence of infectious diseases of zoonotic origin observed in recent years imposes a major morbidity/mortality burden worldwide, and also a major economic burden that extends beyond pure medical costs. The resurgence and epidemiology of zoonoses are complex and dynamic, being influenced by varying parameters that can roughly be categorized as human-related, pathogen-related, and climate/environment-related; however, there is significant interplay between these factors. Human-related factors include modern life trends such as ecotourism, increased exposure through hunting or pet owning, and culinary habits, industrialization sequelae such as farming/food chain intensification, globalization of trade, human intrusion into ecosystems and urbanization, significant alterations in political regimes, conflict with accompanying breakdown of public health and surveillance infrastructure, voluntary or involuntary immigration, loosening of border controls, and hierarchy issues in related decision-making, and scientific advances that allow easier detection of zoonotic infections and evolution of novel susceptible immunocompromised populations. Pathogen-related factors include alterations in ecosystems and biodiversity that influence local fauna synthesis, favouring expansion of disease hosts or vectors, pressure for virulence/ resistance selection, and genomic variability. Climate/environment-related factors, either localized or extended, such as El Niño southern oscillation or global warming, may affect host-vector life cycles through varying mechanisms. Emerging issues needing clarification include the development of predictive models for the infectious disease impact of environmental projects, awareness of the risk imposed on immunocompromised populations, recognition of the chronicity burden for certain zoonoses, and the development of different evaluations of the overall stress imposed by a zoonotic infection on a household, and not strictly a person. [ABSTRACT FROM AUTHOR]

Background/Aim. Fewer of unknown origin (FUO) remains amongst the most difficult diagnostic dilemmas in contemporary medicine. The aim of this study was to determine the causes of FUO and to identify the methods of diagnosis in patients with FUO in a tertiary care setting in the Republic of Macedonia. Methods. Retrospectively histories of 123 immunocompetent patients older than 14 years with classical FUO that had been examined at the University Hospital for Infectious Diseases and Febrile Conditions in the city of Skopje, during the period 2006−2012 were evaluated. FUO was defined as axillary fever of ≥ 37.5°C on several occasions, fever duration of more than 21 days and failure to reach the diagnosis after the initial diagnostic workup comprised of several defined basic investigations. Results. Infections were the cause of FUO in 51 (41.5%) of the patients, followed by non-infective inflammatory disorders (NIID) in 28 (22.8%), miscellaneous in 12 (9.7%) and neoplasm in 11 (8.9%) of the patients. Twenty one of the patients (17.1%) remained undiagnosed. The most common causes for FUO were visceral leishmaniasis, abscesses, urinary tract infections, subacute endocarditis, polymyalgia rheumatica and adult onset of Still disease. The final diagnosis was reached with histology in 24 (23.5%), imaging and endoscopic procedures in 21 (20.6%), clinical course and empiric therapy response in 20 (19.6%), serology in 18 (17.6%) and cultures in 16 (15.7%) of the cases. Conclusion. In the Republic of Macedonia infections are the leading cause of FUO, predominately visceral leishmaniasis. In the future in patients with prolonged fever, physicians should think more often of this disease, as well as of the possibility of atypical presentation of the common classical causes of FUO.

Objectives: The Balkan Peninsula, acting as a crossroad between central Europe and the Middle East, presents diverse ecosystems supporting various tick species capable of transmitting TBDs. This study focuses on Serbia and North Macedonia, both endemic for TBDs, aiming to investigate human-biting ticks' prevalence, TBD prevalence, and major TBPs in blood samples., Patients and Methods: This prospective observational study was conducted in 2022 at two medical centers, involving 45 patients from Novi Sad, Serbia, and 17 patients from Skopje, North Macedonia. All participants had either a tick still attached or had had one removed within the preceding 48 h. The study consisted in clinical evaluations of patients and testing of patient samples and ticks for tick-borne pathogens using a High-Throughput pathogen detection system based on microfluidic real-time PCR. In addition, the study assessed the genetic diversity of the identified pathogens., Results: Ixodes ricinus was the most prevalent tick species, with varying infestation rates across various body parts. Tick species and feeding times differed between Novi Sad and Skopje. TBPs were prevalent, with Rickettsia spp. dominant in Skopje and a mix including Rickettsia aeschlimannii, Rickettsia monacensis, Anaplasma phagocytophilum, and Borrelia afzelii in Novi Sad. Subclinical bacteremia occurred in 8.06% of cases, mostly involving Anaplasma spp. Clinical manifestations, primarily local hypersensitivity reactions, were observed in six patients. Phylogenetic analysis confirmed R. aeschlimannii and R. monacensis identity, highlighting genetic differences in gltA gene sequences., Conclusions: This study sheds light on the prevalence and diversity of TBPs in tick-infested individuals from Serbia and North Macedonia, contributing valuable insights into the epidemiology of TBDs in the Balkan region., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Plasmodium falciparum is the leading cause of imported malaria and the most common cause of death in returning travellers., Aim: To identify the main epidemiological and clinical characteristics of patients with imported falciparum malaria in the Republic of North Macedonia., Material and Methods: Retrospectively analyzed were the epidemiological and clinical features of 34 patients with imported falciparum malaria who were diagnosed and treated at the university clinic for infectious diseases and febrile conditions in Skopje from 2010 to 2022. Malaria diagnosis was based on the microscopic detection of parasites in thick and thin blood smears., Results: All patients were male, with a median age of 36 years and a range of 22-60 years. Of the patients 33 (97.1%) acquired the disease in Sub-Saharan Africa. All patients except one stayed in endemic regions for work/business purposes. Chemoprophylaxis was completely applied in 4 (11.8%) patients. The median time of onset between the symptoms and diagnosis was 4 days, with a range of 1-12 days. Prevailing clinical manifestations were fever, chills, and splenomegaly in 100%, 94%, and 68% of patients, respectively. Severe malaria was noticed in 8 (23.5%) patients. In 5 (14.7%) patients the initial parasitemia was higher than 5%. On admission, thrombocytopenia, hyperbilirubinemia, and elevated alanine aminotransferase were registered in 94%, 58%, and 62% of patients, respectively. Out of the 33 patients with adequate follow-up, the outcome was favorable in 31 (93.9%)., Conclusion: In every febrile traveller returned from Africa, imported falciparum malaria should be an essential part of differential diagnostic considerations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Bacteria of the genus Brucella are facultative intracellular parasites that cause brucellosis, a severe animal and human disease. Recently, a group of taxonomists merged the brucellae with the primarily free-living, phylogenetically related Ochrobactrum spp. in the genus Brucella. This change, founded only on global genomic analysis and the fortuitous isolation of some opportunistic Ochrobactrum spp. from medically compromised patients, has been automatically included in culture collections and databases. We argue that clinical and environmental microbiologists should not accept this nomenclature, and we advise against its use because (i) it was presented without in-depth phylogenetic analyses and did not consider alternative taxonomic solutions; (ii) it was launched without the input of experts in brucellosis or Ochrobactrum ; (iii) it applies a non-consensus genus concept that disregards taxonomically relevant differences in structure, physiology, population structure, core-pangenome assemblies, genome structure, genomic traits, clinical features, treatment, prevention, diagnosis, genus description rules, and, above all, pathogenicity; and (iv) placing these two bacterial groups in the same genus creates risks for veterinarians, medical doctors, clinical laboratories, health authorities, and legislators who deal with brucellosis, a disease that is particularly relevant in low- and middle-income countries. Based on all this information, we urge microbiologists, bacterial collections, genomic databases, journals, and public health boards to keep the Brucella and Ochrobactrum genera separate to avoid further bewilderment and harm., Competing Interests: The authors declare no conflict of interest.

Lyme borreliosis (LB) and tick-borne encephalitis (TBE) are important tick-borne diseases in Europe. This study aimed to investigate the seroreactivity against Borrelia burgdorferi and TBE virus (TBEV) in tick-infested individuals in North Macedonia and Serbia. Serum samples were collected from tick-infested individuals and from healthy individuals in the same regions. Samples were tested for anti- Borrelia IgG reactivity and TBEV-neutralizing antibodies. Results showed higher seroreactivity against Borrelia antigens in patients and healthy donors from Novi Sad compared to those from the Skopje region. However, there was no statistically significant difference between tick-infested patients and healthy donors within each region. No TBEV-neutralizing antibodies were detected in participants from Novi Sad or in the control groups, except for one person from North Macedonia who had a moderate TBEV-neutralizing reaction. The study highlights the need for improved surveillance and diagnostic capabilities for LB and TBE in these regions. It also suggests the potential existence of TBEV foci in North Macedonia. The findings provide a complementary understanding of the LB and TBE epidemiology in the studied regions; however, further research is needed to investigate the presence and distribution of Borrelia spp. and TBEV in ticks to assess the significance of detected seroreactivity.

So far, hematopoietic stem cells (HSC) are considered the source of mature immune cells, the latter being the only ones capable of mounting an immune response. Recent evidence shows HSC can also directly sense cytokines released upon infection/inflammation and pathogen-associated molecular pattern interaction while keeping a long-term memory of previously encountered signals. Direct sensing of danger signals by HSC induces early myeloid commitment, increases myeloid effector cell numbers, and contributes to an efficient immune response. Here, by using specific genetic tools on both the host and pathogen sides, we show that HSC can directly sense B. abortus pathogenic bacteria within the bone marrow via the interaction of the cell surface protein CD150 with the bacterial outer membrane protein Omp25, inducing efficient functional commitment of HSC to the myeloid lineage. This is the first demonstration of direct recognition of a live pathogen by HSC via CD150, which attests to a very early contribution of HSC to immune response., (© 2023 Hysenaj et al.)

Background: Maternal, fetal, and neonatal complications of brucellosis in pregnant women are probably higher than those in the general population. This comparative study aimed to survey the mentioned complications in pregnant women with positive and negative Brucella serologic tests., Study Design: This is a prospective cohort study., Methods: In this study, 2160 pregnant women residing in the rural area of Hamadan province were screened for Brucella infection by agglutination test. Then, 106 (4.90%) pregnant women with a positive test (exposed group) were compared with 210 subjects (non-exposed group) who were randomly selected from more than 2000 pregnant women with a negative serological test in terms of maternal, fetal, and neonatal outcomes from October 2018 to March 2020. Data were analyzed by SPSS 20 software at a 95% confidence level., Results: The mean age of mothers in both exposed and unexposed groups was 27.84±6.13 and 38.71±6.85 years, respectively. Past medical history of brucellosis, animal contact, and the consumption of unpasteurized dairy products were reported to be 14 (13.2%), 63 (59.4%), and 82 (77.4%), respectively, in the exposed group. The mentioned measures were 3 (1.5%), 109 (51.9%), and 54 (26.9%) in the unexposed group, respectively. Among exposed and unexposed groups, the incidence of abortion was 9 (8.6%) and 5 (2.4%) with P =0.005, intrauterine fetal death was 2 (1.9%) and zero with P =0.211, low birth weight was 10 (10.6%) and 7 (3.4%) with P =0.012, and premature birth was 15 (15.2%) and 18 (8.8%) with P =0.066, respectively., Conclusion: Brucella infection in pregnant women appears to be associated with the risk of miscarriage, low birth weight, and premature birth., (© 2023 The Author(s); Published by Hamadan University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Objectives: Brucellosis is a ubiquitous emergent bacterial zoonotic disease causing significant human morbidity in Bosnia and Herzegovina. So far, a high rate of resistant Brucella has been found worldwide. This study prospectively analysed the rates of resistance among human Brucella melitensis strains isolated in Bosnia and Herzegovina., Methods: This study included 108 B. melitensis isolates from 209 patients diagnosed at five medical centres in Bosnia and Herzegovina. The resistance profiles of the B. melitensis isolates for the 13 most commonly used antimicrobials were studied in standard Brucella broth (BB) and cation-adjusted Mueller-Hinton broth (CAMHB) supplemented with 4% lysed horse blood or 5% defibrinated sheep blood., Results: Of the 209 patients, B. melitensis blood cultures were positive for 111 (53.1%). Among the 108 isolates investigated, 91 (84.3%) were resistant to trimethoprim-sulfamethoxazole on BB, but not on either CAMHB. Nearly all isolates (>90%) were resistant to azithromycin on BB and both CAMHBs., Conclusion: We observed a high rate of B. melitensis resistance to azithromycin. The high rate of resistance to trimethoprim-sulfamethoxazole that we observed was related to BB, so an alternative broth should be used, such as the enriched CAMHBs in this study, for evaluating resistance to trimethoprim-sulfamethoxazole. Whole-genome sequencing studies are needed to understand the development of antimicrobial resistance in B. melitensis strains isolated from humans., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Prompt and adequate treatment of human brucellosis continues to be the most important strategy in its management, as eradication of animal brucellosis is not possible so far, and there is no adequate vaccine for humans. The goal of antibrucellar treatment is to alleviate and shorten the symptomatic period and reduce complications, relapses, and chronicity. Contemporary trends in the treatment of human brucellosis are postulated on the ability of Brucellae to persist in host macrophages through the inhibition of phagolysosome fusion and to survive for prolonged periods intracellularly without restricting basic cellular functions. As a result of this and despite satisfactory antibiotic treatment, relapses and therapeutical failures are inevitable to a certain degree. The current principles for the treatment of brucellosis advocate for a long enough treatment duration combined with antimicrobial regimens that possess activity in the intracellular acidic environment. In the future, other antimicrobial agents, immunomodulation, decrease in the intracellular acidic environment, or development of agents that would act on well-defined molecular bacterial targets, might be incorporated to improve the therapeutical effects., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Introduction: Brucellosis, the most common zoonosis globally, is considered a major public health problem., Objective: A retrospective study was carried out over 21 years (1998-2018) to determine the epidemiological features of human brucellosis in the province of El-Oued (south-eastern Algeria)., Results: 1,832 confirmed cases of human brucellosis were reported during the study period, with an average incidence rate of around 12.26 cases per 100,000 inhabitants. The annual distribution of the incidence was characterized by an increasing trend and a strong fluctuation ; its values ranged between 2.27 and 24.96 per 100,000 inhabitants. The monthly distribution showed that the highest incidence rates were recorded from mid-February to July, with a peak of 2.74 cases per 100,000 inhabitants in April.Human brucellosis has affected all municipalities. The highest incidence rate was observed in border municipalities such as Ben Guecha and Oum Tiour (89.76 and 66.14 per inhabitants, respectively).The incidence in the male population was higher than that of the female at 14.63 versus 9.83 per 100,000 inhabitants, respectively, noting that it increases with age. Individuals over 65 years are the most at risk, with an incidence rate of 22.32 per 100,000 inhabitants., Conclusion: Along with strengthening preventive measures in the population, eliminating brucellosis in animals is the most effective method to protect humans against infection.

Cat scratch disease (CSD) is the main clinical manifestation caused by Bartonella henselae in immuno-competent patients. The bacterium is transmitted to humans from cats via scratches or bites. In this case report, we are presenting to our knowledge the first etiologically confirmed case of CSD in our country. Here we describe the case of a previously healthy adult female patient presenting with fever and axillar lymphadenopathy over 1-month period. She underwent numerous clinical and paraclinical investigations for potential etiologies associated with lymphadenopathy and fever. Finally, serological testing for B.henselae was performed with titers for IgG 1:1024 and 1:160 for IgM, which confirmed the diagnosis. Five-day treatment with azithromycin resulted with good clinical response and complete recovery. We proved that CSD is a reality in our country and this report should raise awareness in medical doctors, especially infectious disease specialist. Also, CSD should be included in differential diagnosis in patients with fever of unkown origin (FUO), who are presenting with regional lymphadenopathy, with or without history of cat contact.

Rotavirus is highly contagious factor with dominant feces-oral transmission. Because it is stable in external environment, transmission clusters are possible by close contact, ingestion of contaminated water or food or contact with contaminated surfaces. It survives within hours and days on hands and contaminated surfaces. This makes it the most common enteric and nosocomial pathogen in the world, especially in early childhood. In addition to the rapid dehydration with pronounced electrolyte disturbances, numerous extraintestinal possibilities have been recorded in the clinical picture, which emphasizes the need for prevention of this disease.In the period from 1.02.2018 to 31.01.2020 at the Clinic for Infectious diseases were treated 1060 patients with diarrheal disease, of which 502 children (47.36%). Rotavirus etiology was confirmed in 23.30% of the children. According to the protocols, laboratory and biochemical investigations were done to all 117 children, with tracking parameters and their dynamics of admission and discharge from the hospital. Most of the children, 84 (82.0 6%) are from urban areas, with a more confirmed epidemiological survey of 59 (42.00%). The average age of the children was 8 months, with a small percentage of children on maternal food (breastfed 25, i.e. 21.37%), with high febrile admission in 99% of children with an average temperature of 38.5oC and an average febrile duration of 4 days, with an average of 7 (+ 2.49) of stools and 5 (+ 2.12) of vomiting. There was a significant difference in hematocrit, leukocyte, electrolyte, glycaemia, and CRP values on admission and discharge. There was predominant isonatremic dehydration, and the compensatory mechanisms followed by the values of the electrolytes ABS, Ph, BE showed a tendency to maintain within the physiological limits. The clinical picture of extraintestinal manifestations included bronchitis, mesenteric lymphadenitis, upper respiratory infections and rash.Rotavirus infection is a serious health and economic problem in our country, so it needs continuous prevention and monitoring in order to reduce the incidence, and thus the need for hospitalization and cure of rotavirus disease.

Human brucellosis during pregnancy is characterized by significantly less pronounced adverse obstetric outcomes than in animals, but with remarkably more adverse obstetric outcomes when compared to healthy pregnant women. Seroprevalence of brucellosis in pregnancy and cumulative incidence of brucellosis cases per 1000 delivered obstetrical discharges in endemic regions were reported to be 1.5-12.2% and 0.42-3.3, respectively. Depending on the region, the frequency of pregnant women in the cohorts of patients with brucellosis was from 1.5% to 16.9%. The most common and the most dramatic unfavorable outcomes during brucellosis in pregnancy are the obstetric ones, manifested as abortions (2.5-54.5%), intrauterine fetal death (0-20.6%), or preterm deliveries (1.2-28.6%), depending on the stage of pregnancy. Other unfavorable outcomes due to brucellosis are addressed to infant (congenital/neonatal brucellosis, low birth weight, development delay, or even death), the clinical course of disease in mother, and delivery team exposure. When diagnosed in pregnant women, brucellosis should be treated as soon as possible. Early administration of adequate therapy significantly reduces the frequency of adverse outcomes. Rifampicin in combination with trimethoprim-sulfamethoxazole for 6 weeks is the most commonly used and recommended regimen, although monotherapies with each of these two drugs are also widely used while waiting for the results from prospective randomized therapeutic trials. As no effective human vaccine exists, screening of pregnant women and education of all women of childbearing age about brucellosis should be compulsory preventive measures in endemic regions.

Background: Brucellosis is endemic in Iran with a higher level of endemicity in western areas, including the Hamadan province. This study aims to define the seroprevalence of brucellosis and it,s risk factors in general the population of Famenin, Hamadan province, in western Iran., Methods: This survey was conducted on 2367 participants in Famenin and its villages from September to November 2016. After receiving written consent from subjects, demographic information was obtained through questionnaires and 10cc blood samples were taken from the participants. Blood samples were sent to the Core facility of Hamadan University of Medical Sciences and were tested using Wright and 2ME kits (Pasteur Institute, Iran) for serological detection of brucellosis. The seroprevalence of brucellosis was reported as percentage with 95% confidence interval (CI)., Results: Totally, 2367 individuals with the mean age (SD) of 34.6 (20.9) (range: 2 to 95) years were enrolled. Of these, 1060 (44.8%) were men and 1610 (68.0%) lived in rural areas. The seroprevalence of brucellosis according to the Wright titer (equal to or greater than 1:80) was 6.6% (95% CI: 5.62%, 7.66%). The corresponding prevalence based on 2ME titers (equal to or greater than 1:40) in subjects with positive Wright test was 37.2% (95% CI: 29.5%, 44.84%). We saw a significant association between the incidence of brucellosis and occupation ( P < 0.001) and type of contact with livestock ( P = 0.009) as two important risk factors., Conclusion: The seroprevalence of brucellosis in Famenin population was considerable. Contact with livestock, animal husbandry, farming and history of brucellosis were risk factors for brucellosis infection., (© 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Different outcomes of brucellosis in pregnancy regarding the fetus/neonate and the mother are described. Medical records of five pregnant women with brucellosis were retrospectively analyzed. Patients were treated in several departments of infectious diseases in the Republic of Macedonia between 1995 and 2009. The diagnosis of brucellosis was based on clinical findings compatible with the disease supported by detection of specific antibodies. Pregnancy outcomes in patients were as follows: spontaneous abortion, intrauterine fetal death, premature delivery in two cases (one with twin pregnancy) and term delivery. One of the women experienced relapse. Follow-up results of neonates showed no infection and their normal growth and development. Brucellosis, especially if acquired in early pregnancy, can have an impact on pregnancy outcome. In endemic regions, in pregnant women with persisting fever and unspecific manifestations one should always have in mind brucellosis. In these areas, cases with unexplained spontaneous abortion, intrauterine fetal death and premature delivery should also be investigated for brucellosis.

Background: Patients with hepatitis Be antigen-negative chronic hepatitis B (HBeAg-negative CHB), and patients' inactive carriers (IC) have similar laboratory and serologic characteristics and are not always easy to distinguish., Aim: To characterise hepatitis Be antigen (HBeAg) negative chronic hepatitis B cohort based on their laboratory and virology evaluations at one point of time., Methods: A prospective non-randomized study was conducted on 109 patients with HBeAg negative chronic hepatitis B treated as outpatients at the Clinic for Infectious Diseases and Febrile Conditions. All patients underwent laboratory and serology testing, quantification of HBV DNA and HBs antigen (qHBsAg)., Results: A group of 56 patients were inactive carriers (IC), and 53 patients had HBeAg-negative CHB (AH). The mean values of ALT, HBV DNA and qHBsAg in IC were 29.13 U/L; 727.95 IU/ml and 2753.73 IU/ml respectively. In the AH group, the mean values of ALT, HBV DNA and quantitative HBsAg were 50.45 U/L; 7237363.98 IU/ml and 12556.06 IU/ml respectively. The serum value of ALT was more influenced by qHBsAg than HBV DNA in both IC and AH groups (R = 0.22 vs R = 0.15) (p > 0.05)., Conclusion: patients with inactive and active HBeAg-negative CHB have similar laboratory and serology profile. It is necessary to combine analysis of ALT, HBV DNA and qHBsAg for better discrimination between patient's IC and patient with HBeAg-negative CHB.

Our study assesses the influence of illness duration before establishing the diagnosis of brucellosis and initiating therapy on patients' main clinical characteristics and outcome in an endemic area. The medical files of 297 patients with brucellosis were retrospectively analysed. They were divided into four groups according to illness duration before initiating therapy: <10 days; 11-30 days; 31-90 days; and >90 days. There were significant differences in the occurrences of fever ( P  = 0.019), focal forms ( P  = 0.026), spondylitis ( P  = 0.034) and therapeutic failures ( P  = 0.006) between the groups. Duration of >30 days before treatment initiation is responsible for more serious clinical presentation and outcome, whereas illness duration of >90 days further worsens the clinical progression in human brucellosis.

Brucellosis in pregnant women is reported to be associated with obstetric complications (OCs), and adequate data for human brucellosis during pregnancy are largely lacking. We performed this multicenter retrospective cross-sectional study to evaluate the epidemiology, clinical course, treatment responses, and outcomes of brucellosis among pregnant women. The study period comprised a 14-year period from January 2002 to December 2015. All consecutive pregnant women diagnosed with brucellosis in 23 participating hospitals were included. Epidemiological, clinical, laboratory, therapeutic, and outcome data along with the assessment data of the neonate were collected using a standardized questionnaire. Data of 242 patients were analyzed. The OC rate was 14.0% (34/242) in the cohort. Of the 242 women, 219 (90.5%) delivered at term, 3 (1.2%) had preterm delivery, 15 (6.2%) aborted, and 5 (2.1%) had intrauterine fetal demise. Seventeen (7.0%) of the newborns were considered as low birth weight. Spontaneous abortion (6.1%) was the commonest complication. There were no maternal or neonatal deaths and pertinent sequelae or complications were not detected in the newborns. Splenomegaly (p = 0.019), nausea and/or vomiting (p < 0.001), vaginal bleeding (p < 0.001), anemia (blood hemoglobin < 11 g/dL; p < 0.001), high level of serum aspartate aminotransferase (> 41 IU/L; p = 0.025), oligohydramnios on ultrasonography (p = 0.0002), history of taking medication other than Brucella treatment during pregnancy (p = 0.027), and Brucella bacteremia (p = 0.029) were the significant factors associated with OCs. We recommend that pregnant women with OC or with fever should be investigated for brucellosis if they live in or have traveled to an endemic area.

Background: Liver biopsy for evaluation of liver fibrosis has several adverse effects, for which reason noninvasive tests have been developed., Aim: To evaluate the usefulness of noninvasive biomarkers, qHBsAg and HBV DNA levels in predicting liver fibrosis in patients with hepatitis Be antigen (HBeAg) negative chronic hepatitis B (CHB)., Material and Methods: This prospective study included 50 patients with HBeAg negative CHB. All patients underwent laboratory and serology testing, quantification of HBV DNA and HBs antigen. The liver stiffness was measured with elastography. The patients were analysed for APRI and FIB-4, quantitative hepatitis Bs antigen and HBV DNA., Results: Logistic regression analysis showed that greatest significance in predicting liver fibrosis has FIB-4 (Wald = 3.24, P = 0.07), followed by HBV DNA ≥ 2 000 IU/ml ≤ 20 000 IU/ml (Wald = 2.86, P = 0.09), qHBsAg (Wald = 2.17, P = 0.14), HBV DNA > 20 000 IU/ml (Wald = 0.58, P = 0.45), APRI (Wald = 0.04, P = 0.84)., Conclusion: the FIB-4 index has the greatest value in predicting liver fibrosis while APRI has the lowest; the more advanced liver disease is associated with lower serum level of quantitative HBs antigen. Combination of noninvasive blood biomarkers and imaging tests can provide better diagnostic accuracy and exclude the need for liver biopsy.

Aim: To analyze the impact of measures undertaken to control brucellosis in the Republic of Macedonia on demographic, epidemiological and clinical characteristics of the disease in humans., Methods: Demographic, epidemiological and clinical characteristics of 340 patients with brucellosis were retrospectively analyzed. Patients were treated at the University Clinic of Infectious Diseases in Skopje during three time periods: 1989-1990 when no national strategy for disease control existed, 2000-2001 when some activities for control were performed and 2011-2014 when an organized and financially supported strategy was accomplished., Results: A drastic decrease of the number of cases of human brucellosis during the last period when compared to the first two ones (3.9 and 3.3 times lower, respectively) was evident. Patients from the third period were significantly older, with median age 41 years (range 4-73) vs. 31 years (3-77) and 34 years (1-74), respectively (p = .013). There were more males (86.6 vs. 73.6% and 63.2%, respectively, p = .002) and the disease was more often acquired professionally (80.6 vs. 60.1% and 59.2%, respectively, p = .006). Fewer patients from the third period had elevated body temperature either as a symptom (50.7 vs. 73.6% and 69.6%, respectively, p = .003), or as a sign (35.8 vs. 55.4% and 56.8%, respectively, p = .011) and less often exhibited focal forms (40.3 vs. 56.8% and 64.0%, respectively, p = .007)., Conclusion: The national strategy for brucellosis control, which included vaccination of small ruminants, resulted in a decrease of human brucellosis cases in the Republic of Macedonia and there was a tendency to milder disease manifestations.

Background/purpose: To present clinical and laboratory features, treatment options, and outcome in patients with brucellar testicular infection and to compare them with analogous in brucellar patients without testicular involvement., Methods: Thirty four brucellar patients with testicular infection treated in two general hospitals in the Republic of Macedonia, during the period 1998-2009, were retrospectively analyzed. Their clinical and laboratory characteristics were compared with analogous in 364 male brucellar patients without testicular infection, who were treated at the same hospitals during the same time period., Results: Brucellar testicular infection was evident in 34 (8.5%) out of 398 male patients with brucellosis. The median age of the patients was 46.5 years. In all patients testicular involvement was presented as an acute form with a median duration of 5 days (range, 2-14 days) prior to diagnosis. Twenty-three of the patients had at least one other simultaneous focal infection. After starting with the treatment testicular infection lasted a median 10 days, range 7-21 days. Brucellar patients with testicular infection when compared with other brucellar patients more frequently manifested fever (97% vs. 61%), concomitant spondylitis (32% vs. 16%), and urinary system involvement (12% vs. 2%). Also, the relapse rate in patients with testicular involvement was significantly higher (24% vs. 9%)., Conclusion: In endemic regions brucellosis should be taken into consideration in any patient with testicular infection. Brucellar testicular involvement is usually characterized with a severe acute clinical presentation and a high percentage of relapses which entails the need of timely recognition and proper treatment duration of at least 60 days., (Copyright © 2016. Published by Elsevier B.V.)

The aim of the study was to determine the main demographic, epidemiological, clinical characteristics, and outcome in patients with various types of brucellar monoarticular involvement. Retrospectively, we analyzed medical histories of 331 patients with brucellar monoarticular involvement who were treated at the infectious diseases departments in Prilep, Shtip, and Veles, Republic of Macedonia, during the period 1990-2012. Their data were compared accordingly to the affected joint (sacroiliac, hip, knee, ankle, wrist, and shoulder).Patients with shoulder arthritis were significantly the oldest (mean ± standard deviation [SD] 46.0 ± 14.5 years) whereas sacroiliitis and hip arthritis were present predominantly in younger patients (mean ± SD 28.7 ± 14.1 and 28.3 ± 18.3 years, respectively) (p = 0.014). Shoulder arthritis duration was significantly the longest (mean ± SD 24.5 ± 12.4 days), and wrist arthritis duration was significantly the shortest (mean ± SD 4.1 ± 2.5 days) (p < 0.001), before establishing the diagnosis of brucellosis. With appropriate treatment, the need for restitution of the joint impairment was significantly longer when sacroiliitis and hip arthritis were present (mean ± SD 32.8 ± 23.0 and 24.6 ± 12.5 days, respectively) (p < 0.001). The relapses were noted in 14.5, 14, 16.5, 5.5, 6, and 5.5 % of the patients with sacroiliitis, hip-, shoulder-, knee-, ankle-. and wrist arthritis, respectively. In endemic areas, brucellosis should be included in the differential diagnostic consideration in patients with monoarticular involvement. Knee-, ankle-, and wrist arthritis seem to be more benign and with appropriate treatment result in short duration and satisfactory outcome. On the other hand, the involvement of sacroiliac, hip-, and shoulder joint deserves more serious approach due to longer arthritis duration and higher frequency of relapses.

Objective: To describe the main epidemiological, clinical, and laboratory features, treatment options and outcome in children with brucellosis., Methods: Retrospectively evaluated data were obtained from 317 pediatric patients with brucellosis that were treated at the University Clinic for Infectious Diseases and Febrile Conditions in Skopje, during the period from 1989 to 2011. The medical records and follow-up protocols were used for evaluation., Results: Childhood brucellosis composed 317 (18.7%) of 1691 patients with brucellosis. The patients were median 9 years old, ranging from 7 months to 14 years, and 201 (63.4%) were males. Family history was present in 197 (62.1%), and direct contact with animals occurred in 140 (44.2%) of the children. The dominant manifestations were fever in 248 (78.2%), joint pain in 228 (71.9%) and hepatomegaly in 216 (68.1%). Organ affection was present in 206 (65.0%) of the patients. One hundred and six (33.4%) of the patients were treated with combination composed of two, and 211 (66.6%) with three antimicrobial agents. Relapses were registered in 21 (6.6%), and therapeutic failures in 3 (0.9%) of the children., Conclusions: In endemic regions childhood brucellosis represents a significant part of human cases. Wide spectrum of clinical manifestations, frequent affection of various organ systems and possibility of relapses show that brucellosis could be a serious disease in this age group. The presence of fever, joint pain, sweating, and affection of various systems in children from endemic regions should alert pediatricians for the possibility of brucellosis., (Copyright © 2015 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.)

Cervical lymph nodes (CLN) are the first lymph nodes encountered by material taking the oral route. To study their role in orally acquired infections, we analyzed 307 patients of up to 14 years treated in the university clinic of Skopje, Macedonia, for brucellosis, a zoonotic bacterial disease frequently acquired by ingestion of contaminated dairy products. From these children, 36% had lymphadenopathy. Among orally infected children, lymphadenopathy with CLN being the only lymph nodes affected was significantly more frequent as compared to those infected by contact with animals (83% vs. 63%), suggesting a possible involvement of CLN during orally acquired human brucellosis. Using a murine model where bacteria are delivered into the oral cavity, we show that Brucella quickly and selectively colonize the CLN where they proliferate and persist over long periods of time for up to 50 days post-infection. A similar efficient though less specific drainage to CLN was found for Brucella, Salmonella typhimurium and fluorescent microspheres delivered by gavage, a pathway likely representing a mixed infection mode of intragastric and oral infection, suggesting a central pathway of drained material. Microspheres as well as bacteria drained to CLN predominately reside in cells expressing CD68 and no or low levels of CD11c. Even though no systemic response could be detected, Brucella induced a locally restricted inflammatory reaction with increased expression levels of interferon γ, interleukin (IL)-6, IL-12, granzyme B and a delayed induction of Nos2. Inflammation led to pronounced lymphadenopathy, infiltration of macrophages/monocytes expressing high levels of major histocompatibility complex II and to formation of epitheloid granulomas. Together, these results highlight the role of CLN in oral infections as both, an initial and efficient trap for bacterial invaders and as possible reservoir for chronic pathogens. They likewise cast a new light on the significance of oral routes for means of vaccination.

Brucellosis is still endemic in many countries in the world, however, having a significantly higher incidence in developing countries. As consequence of travel, risk for children from non-endemic areas would be considerable when visiting developing countries. Then, the purpose of this review is to provide, after a bibliographical search, an update on the main aspects of this disease in the traveler children. For the general practitioner, but particularly for travel medicine practitioner and pediatricians, these clinicoepidemiological considerations should be taken in mind in the differential diagnosis when assessing children returning from travel to brucellosis endemic areas.

Aim: To describe the main clinical and laboratory characteristics, frequency and distribution of osteoarticular involvement, therapeutic options and outcome in children with osteoarticular brucellosis., Methods: This descriptive study includes 133 pediatric patients with osteoarticular brucellosis who were treated at the University Clinic for Infectious Diseases and Febrile Conditions in Skopje, Republic of Macedonia, during the period between 1989 and 2011. Brucellosis was presumptively diagnosed on the basis of clinical signs and confirmed by the detection of specific antibodies at significant titers., Results: The median age of patients was 9 years (range, 2-14 years) and 63.9% were males. Family history of brucellosis was present in 54.1%. The dominant clinical symptoms were arthralgia and fever in 77.4% and 73.7%, respectively, and the dominant sign was hepatomegaly in 73.7% of patients. The main laboratory abnormalities were elevated C-reactive protein (81.0%) and circulating immunocomplexes (80.7%). In 71.4% of patients, the osteoarticular involvement was monoarticular. Hip arthritis was present in 49.6%, followed by the knee in 30.1%. Various therapeutic regimens with a duration of 6 weeks were used. In 87 patients during a follow-up of at least 6 months, relapse occurred in 13.8%., Conclusions: Osteoarticular involvement is frequent in children with brucellosis. It is most often manifested with monoarthritis of the large weight-bearing joints. Brucellosis should be included in the differential diagnosis of childhood arthritis in endemic countries, especially in the presence of family history, contact with infected animals or ingestion of unpasteurized food products, fever and hepatomegaly.

No data on whether brucellar meningitis or meningoencephalitis can be treated with oral antibiotics or whether an intravenous extended-spectrum cephalosporin, namely, ceftriaxone, which does not accumulate in phagocytes, should be added to the regimen exist in the literature. The aim of a study conducted in Istanbul, Turkey, was to compare the efficacy and tolerability of ceftriaxone-based antibiotic treatment regimens with those of an oral treatment protocol in patients with these conditions. This retrospective study enrolled 215 adult patients in 28 health care institutions from four different countries. The first protocol (P1) comprised ceftriaxone, rifampin, and doxycycline. The second protocol (P2) consisted of trimethoprim-sulfamethoxazole, rifampin, and doxycycline. In the third protocol (P3), the patients started with P1 and transferred to P2 when ceftriaxone was stopped. The treatment period was shorter with the regimens which included ceftriaxone (4.40 ± 2.47 months in P1, 6.52 ± 4.15 months in P2, and 5.18 ± 2.27 months in P3) (P = 0.002). In seven patients, therapy was modified due to antibiotic side effects. When these cases were excluded, therapeutic failure did not differ significantly between ceftriaxone-based regimens (n = 5/166, 3.0%) and the oral therapy (n = 4/42, 9.5%) (P = 0.084). The efficacy of the ceftriaxone-based regimens was found to be better (n = 6/166 [3.6%] versus n = 6/42 [14.3%]; P = 0.017) when a composite negative outcome (CNO; relapse plus therapeutic failure) was considered. Accordingly, CNO was greatest in P2 (14.3%, n = 6/42) compared to P1 (2.6%, n = 3/117) and P3 (6.1%, n = 3/49) (P = 0.020). Seemingly, ceftriaxone-based regimens are more successful and require shorter therapy than the oral treatment protocol.

The dynamic of Brucellacapt titers was evaluated in 104 patients with brucellosis with favorable outcome and in 28 patients with persistent illness duration, during the follow-up period of 15 months. In patients with favorable outcome, a permanently decreasing tendency of Brucellacapt titers was evident. Titers< or =1/320 were noted in 27% and 90% of the patients, at the end of the 4th and 15th month, respectively. In patients with persistent disease, persistence or slow titre regression during the entire follow-up period was evident. Four and 15 months of the treatment, titers of 1/320 were registered in 4%, and 14%, respectively, and in no one less than 1/320. The evaluation of Brucellacapt titres between recovered and patients with persistent illness showed significant difference at the 3rd month after beginning of treatment. The evolution of Brucellacapt titers over time proves to be a handy indicator of brucellosis activity when combined with clinical parameters., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Aim: To present our 10-year clinical experience with brucellosis patients at the University Clinic for Infectious Diseases and Febrile Conditions in Skopje, Republic of Macedonia., Methods: A total of 550 patients with brucellosis treated between 1998 and 2007 were retrospectively assessed for their demographic, epidemiological, and clinical characteristics and outcomes., Results: Of the 550 patients, 395 (72%) were male. The median age was 34.5 years (range, 1-82). Direct contact with infected animals was recorded in 333 (61%) patients and positive family history in 310 (56%). The most frequently seen symptoms were arthralgia (438, 80%), fever (419, 76%), and sweating (394, 72%). The most common signs were fever and hepatomegaly, which were verified in 357 (65%) and 273 (50%) patients, respectively. Focal brucellosis was found in 362 patients (66%) and osteoarticular in 299 (54%). Therapeutic failures were registered in 37 (6.7%) patients. Of the 453 (82%) patients who completed a follow-up period of at least 6 months, relapses occurred in 60 (13%)., Conclusion: Due to non-specific clinical manifestation and laboratory parameters, brucellosis should be considered one of the differential diagnoses of any patient suffering from obscure involvement of various organs in a brucellosis-endemic region. High percentage of relapses and therapeutic failures in spite of the use of currently recommended therapeutic regimens indicates the seriousness of this zoonosis and the need to control it.

The aim of the study was to determine the evolution and outcome of human brucellosis in an endemic region in relation to time interval. Retrospective analysis was employed to compare demographic, epidemiological, clinical, laboratory features and the outcome of patients with brucellosis, treated at University Department of Infectious Diseases in Skopje during two different periods of time. A series of 159 patients were studied in the first (1990-1991) and 138 in the second (2003-2005) study period. Patients treated in the second period were older (34.6+/-20.9 vs. 30.0+/-17.7 years; P=0.041) and acquired brucellosis less frequently on ingestion of incriminated food (34.8% vs. 47.2%; P=0.031). Focal forms were more evident in the second period (66.7% vs. 50.3%; P=0.004), mainly due to osteoarticular localization. Post-treatment follow up was more efficient in the second group (76.1% vs. 61%; P=0.005). There was no difference according to disease outcome in spite of different therapeutic trials during the two study periods. In conclusion, the established differences showed an improvement in the understanding of the disease by the general population as well as upgrading of some aspects considering medical activities. Nevertheless, this endemic region still lacks the most important measure, i.e. development and implementation of an appropriate national program for efficient control of the disease.

Objective: The aim of this study was to describe some demographic, clinical and laboratory characteristics, and to evaluate the outcome, in patients with brucellosis in an endemic area in the Balkan Peninsula, and to reveal the differences between patients with and without occupational exposure., Methods: The study was carried out at the Clinic for Infectious Diseases in Skopje over a period of seven years. Four hundred and eighteen patients with brucellosis were enrolled and classified into two groups: patients with (251) and without (167) occupational exposure., Results: Two hundred and twenty-eight (54.5%) of the patients had a positive family history. The most common clinical manifestations were arthralgia (81.8%), sweating (71.5%), localized disease (67.7%) and subjective fever (68.4%), whereas elevated values of C-reactive protein (78.9%) and circulating immune complexes (75.8%) were the most frequent laboratory abnormalities. Relapses and therapeutic failure were registered in 16.2% and 10.4%, respectively. Male gender, positive family history and arthralgia were more prevalent in those with occupational exposure, while pediatric age, fever and anemia were inversely correlated with occupational exposure., Conclusions: Human brucellosis is a serious problem in the Republic of Macedonia presenting with a high percentage of localized forms, relapses and therapeutic failures. The risk factor for acquiring the disease had no influence on the outcome.