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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.

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.

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.)

Background: In this cross-sectional, international study, we aimed to analyze vector-borne and zoonotic infections (VBZI), which are significant global threats., Method: VBZIs' data between May 20-28, 2018 was collected. The 24 Participatingcountries were classified as lower-middle, upper-middle, and high-income., Results: 382 patients were included. 175(45.8%) were hospitalized, most commonly in Croatia, Egypt, and Romania(P = 0.001). There was a significant difference between distributions of VBZIs according to geographical regions(P < 0.001). Amebiasis, Ancylostomiasis, Blastocystosis, Cryptosporidiosis, Giardiasis, Toxoplasmosis were significantly more common in the Middle-East while Bartonellosis, Borreliosis, Cat Scratch Disease, Hantavirus syndrome, Rickettsiosis, Campylobacteriosis, Salmonellosis in Central/East/South-East Europe; Brucellosis and Echinococcosis in Central/West Asia; Campylobacteriosis, Chikungunya, Tick-borne encephalitis, Visceral Leishmaniasis, Salmonellosis, Toxoplasmosis in the North-Mediterranean; CCHF, Cutaneous Leishmaniasis, Dengue, Malaria, Taeniasis, Salmonellosis in Indian Subcontinent; Lassa Fever in West Africa. There were significant regional differences for viral hemorrhagic fevers(P < 0.001) and tick-borne infections(P < 0.001), and according to economic status for VBZIs(P < 0.001). The prevalences of VBZIs were significantly higher in lower-middle income countries(P = 0.001). The most similar regions were the Indian Subcontinent and the Middle-East, the Indian Subcontinent and the North-Mediterranean, and the Middle-East and North-Mediterranean regions., Conclusions: Regional and socioeconomic heterogeneity still exists for VBZIs. Control and eradication of VBZIs require evidence-based surveillance data, and multidisciplinary efforts., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

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.

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 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.

Aim: To describe the frequency, types, clinical characteristics, diagnostic tools, and outcome of osteoarticular brucellosis., Methods: The study was carried out at the Hospital for Infectious Diseases in Skopje between January 1998 and December 2002. Three hundred and thirty one consecutive patients with brucellosis were enrolled and prospectively assessed according to a previously designed protocol. Brucellosis was diagnosed on the basis of clinical signs, and confirmed by the detection of specific antibodies at significant titers., Results: One hundred and ninety six (59.2%) patients had osteoarticular involvement. Peripheral arthritis was found in 119 (60.7%) patients, followed by sacroiliitis in 60 (30.6%) and spondylitis in 56 (28.6%) of them. In 86 (43.9%) patients, osteoarticular changes were localized in two or more sites. The patients with osteoarticular brucellosis showed more prolonged illness prior to diagnosis and higher erythrocyte sedimentation rate, compared to those without osteoarticular localization. There were no other significant demographic, epidemiological, clinical, and laboratory differences between the two groups. Relapses occurred in 28 (17.5%) and therapeutic failure in 25 (12.8%) patients, 24 of them with spondylitis., Conclusions: Osteoarticular brucellosis was a common form of focal brucellosis and the most unfavorable outcome was seen in patients with spondylitis.