Is it too expensive to fight cancer? Analysis of incremental costs and benefits of the Croatian National Plan Against Cancer.

This cost-effectiveness study analyses the expected impacts of activities proposed by the Croatian National Plan Against Cancer (NPAC) on cancer incidence and survival rates, as related to their respective costs. We evaluated the impact of the NPAC on two main outcomes, namely, reduced incidence and the improved survival of cancer patients, expressed as life years gained (LYGs), which enabled the calculation of incremental cost-effectiveness ratios (ICERs) in the form of cost per LYG. In the analysis of costs, we considered both the direct costs of NPAC activities as well as the wider indirect societal costs of cancer, thus permitting the calculation of the ICER both from the narrower national health insurer's perspective (accounting only for the direct costs) and the wider societal perspective (accounting both for the direct and indirect costs). We estimated that on average, for all patients benefiting from the implementation of the NPAC in Croatia, an additional LYG would be yielded at the additional cost of €1.021 (societal perspective). The NPAC can, for some sites, even be considered a dominant intervention due to the negative cost/LYG ratio, meaning that it generates additional LYGs while at the same time, reducing total societal costs. Taking a narrower health insurer's perspective (i.e., accounting only for the direct costs), the NPAC produces an additional LYG at an additional cost of €1.408. Both cost per LYG estimates can be considered cost-effective investment options.

Mycobacterium shimoidei-cavitary pulmonary disease with favorable outcome.

We report a case of cavitary pulmonary disease caused by Mycobacterium shimoidei in 67-year-old female with history of asthma. Even though susceptibility testing was not available, choice of treatment regimen (streptomycin, rifampicin, ethambutol, and clarithromycin), based on a few cases with favorable outcome reported in the literature, resulted with an excellent clinical, microbiological, and radiological response. This is the first report of pulmonary disease caused by M. shimoidei, but also the first ever isolation of M. shimoidei in Croatia.

Mycobacterium marinum Infection of the Hand in an Immunocompromised Aquarium Hobbyist.

M. marinum, a nontuberculous mycobacterium, is a rare human pathogen widely distributed in the aquatic environment. In the previous century, epidemics took place due to inadequately chlorinated swimming pool water. Nowadays the majority of infections are acquired through contact of previously damaged skin with contaminated fish tank water. We present a case of M. marinum infection of the hand in an aquarium hobbyist which stayed unrecognized for 2 years. After confirming the correct diagnosis, the patient was successfully treated with a regiment containing clarithromycin and rifampicin. The aim of this paper is to raise the awareness of the possibility of M. marinum infection when encountered with non-healing nodular/verrucous/ulcerative lesions of the extremities.

Neglected disease in mentally ill patients: Major tuberculosis outbreak in a psychiatric hospital.

As tuberculosis incidence decreases, the possibility of overlooking the disease increases, especially in vulnerable populations. We describe here a major tuberculosis outbreak among mentally ill patients in Croatia, focusing on 1 regional hospital where most patients were hospitalized. The outbreak emphasizes the vulnerability of mentally ill patients to tuberculosis infection and the complexity of infection control measures in psychiatric institutions. The awareness of tuberculosis in these settings should be maintained to interrupt prolonged exposure and avoid unnecessary infection.

Successful Treatment of Disseminated Bacillus Calmette-Guérin Disease in an HIV-Infected Child with a Linezolid-Containing Regimen.

Upon HIV infection diagnosis, an 8-month-old boy was transferred for evaluation of worsening respiratory distress requiring mechanical ventilation. Pneumocystis jirovecii pneumonia (PCP) was diagnosed; the boy also had a nonhealing ulcer at the site of vaccination with Statens Serum Institut (Danish strain) Bacillus Calmette-Guérin (BCG) vaccine and associated axillary lymphadenopathy. PCP treatment resulted in weaning from mechanical ventilation. Antimycobacterial treatment was immediately attempted but was discontinued because of hepatotoxicity. Over several months, he developed splenic lesions and then disseminated skin and cystic bone lesions. M. bovis was repeatedly cultured from both skin and bone lesions despite various multidrug antimycobacterial regimens which included linezolid. Eventually, treatment with a regimen of rifabutin, isoniazid, ethambutol, and linezolid led to definitive cure. Clinicians should consider a linezolid-containing regimen for treatment of severe disseminated BCG infection, especially if other drug regimens have failed. Although drug toxicity is a particular concern for young children, this patient received linezolid for 13 months without serious toxicity. This case also highlights the need for universal screening among pregnant women to prevent vertical transmission of HIV. Finally, routine immunization with BCG vaccine at birth should be questioned in countries with low and declining burden of tuberculosis.

A Snapshot of Drug-Resistant M. tuberculosis Strains in Croatia.

Tuberculosis caused by resistant M. tuberculosis strains poses a serious threat as it requires prolonged and costly treatment and has high mortality rate. In order to investigate resistance to antituberculous drugs in Croatia, we analysed all resistant M. tuberculosis strains isolated from patients' samples in period 2010-2014 (1 strain per patient). Out of 2384 M. tuberculosis strains, we identified 88 (3.69 %) resistant strains. The analysis included resistance patterns, resistance conferring mutations and, according to MIRU-VNTR analysis, clustering and global lineages distribution. Relatively high number of strains was monoresistant, especially to isoniazid, while there were only six multiresistant strains. Among 59 strains with any pattern that includes resistance to isoniazid, a total of 22 (37.29 %) had resistance conferring mutation in katG gene (S315T), 23 (38.98 %) in inhA promoter region (C-15T) and 14 (23.73 %) had none of these mutations. The observed clustering rate of resistant strains was 28.41 %, and the most common global lineage was Euro-American (75 %).

[Which tuberculin skin test hyperreactive child should be treated with -our experience]. / KOJIM PPD-HIPERREAKTORIMA TREBA DATI PROFILAKSU - NASA ISKUSTVA.

Since persons with latent tuberculosis infection (LTBI) represent a huge reservoir of potential tuberculosis (TB) disease, accurate diagnosis and treatment of LTBI is essential for TB control and eradication. The aim was to assess the diagnostic value of determination of interferon-gamma release assay in school children with hyperreactive tuberculin skin test (TST) reaction. A total of 120 BCG-vaccinated children were investigated due to a hyperreactive TST results. The QuantiFERON-TB Gold In-Tube test (QFT-GIT) was performed. Fifteen children (12.5%) had positive QFT-GIT and 105 (87.5%) children had negative QFT-GIT. There was no statistically significant difference in TST reaction (21.5 mm u QFT+ vs. 20.9 mm u QFT-group, p=0.458). The children with positive QFT-GIT had a statistically higher level of interferon-gamma (IFN-γ) than children with negative QFT-GIT. There were no statistically significant differences in concentrations of IFN-y either basic or upon stimulation with mitogen phytohemagglutinin. After isoniazid prophylaxis QFT-GIT remained positive in two children (p=0.019). In a difficult procedure for diagnosing LTBI in BCG-vaccinated children determination of IFN-γ could be the key factor in making decision whether to use preventive therapy or not.

Discordance Between Tuberculin Skin Test and Interferon-γ Release Assay in Children Younger Than 5 Years Who Have Been Vaccinated With Bacillus Calmette-Guérin.

BACKGROUND: Interferon-γ release assays (IGRAs) offer the possibility of improved detection of latent tuberculosis infection (LTBI). OBJECTIVE: To analyze discordant tuberculin skin testing (TST) and IGRA results in ethnic Croatian children as old as 5 years for whom there is documented exposure to an adult with active tuberculosis (TB) and who have been vaccinated with Bacillus Calmette-Guérin. METHODS: In specimens from our cohort individuals, we tested the performances of the QuantiFERON-TB Gold In-Tube (QFT-GIT) test and TST and analyzed discordant results. RESULTS: At the TST cutoff value of 10 mm or greater, the estimated prevalence of M. tuberculosis infection was 18.1% (31/171) using TST and 15.2% (26/171) using QFT-GIT. The results of these 2 tests showed an overall concordance of 87.7%. There was no evidence that subjects' age correlated with discordant results. CONCLUSIONS: The reasons for discordant results in young children are still unclear, which highlights the importance of further longitudinal studies to better understand the interpretation and any possible clinical implications of the results of these tests.

Inventory study of non-tuberculous mycobacteria in the European Union.

BACKGROUND: Since non-tuberculous mycobacteria (NTM) disease is not notifiable in most European Union (EU) and European Economic Area (EEA) countries, the epidemiological situation of the >150 NTM species is largely unknown. We aimed to collect data on the frequency of NTM detection and NTM species types in EU/EEA countries. METHODS: Officially nominated national tuberculosis reference laboratories of all EU/EEA countries were asked to provide information on: laboratory routines for detection and identification of NTM, including drug sensitivity testing (DST) methods; data on the number and type of NTM species identified; coverage and completeness of the provided data on NTM; type and number of human specimens tested for NTM; and number of specimens tested for Mycobacterium tuberculosis complex and NTM. This information was summarized and the main results are described. RESULTS: In total, 99 different NTM species were identified with M. avium, M. gordonae, M. xenopi , M. intracellulare, and M. fortuitum identified most frequently. Seven percent of the NTM species could not be identified. NTM was cultured from between 0.4-2.0% of the specimens (data from four countries). The laboratories use culturing methods optimised for M. tuberculosis complex. Identification is mainly carried out by a commercial line probe assay supplemented with sequencing. Most laboratories carried out DST for rapid growers and only at the explicit clinical request for slow growers. CONCLUSION: It is likely that the prevalence of NTM is underestimated because diagnostic procedures are not optimized specifically for NTM and isolates may not be referred to the national reference laboratory for identification. Due to the diagnostic challenges and the need to establish the clinical relevance of NTM, we recommend that countries should concentrate detection and identification in only few laboratories.

First insights into the molecular epidemiology of tuberculosis in Croatia during a three-year period, 2009 to 2011.

BACKGROUND: Mycobacterium tuberculosis still represents a serious cause of morbidity and mortality worldwide. The aim of this study was to determine the transmission rate and genetic lineages of M. tuberculosis circulating in Croatia during a 3-y period, between 2009 and 2011. METHODS: A total of 1587 M. tuberculosis strains (1 strain per tuberculosis patient) isolated in Croatia from 2009 to 2011 were genotyped using 15-locus mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) analysis. RESULTS: The majority of tested isolates (66.73%) belonged to the Euro-American global lineage. The most prevalent sub-lineages were Haarlem (48.64%), followed by S (6.05%), Cameroon (3.72%), and Latin American-Mediterranean (3.4%). Among the total 1587 tested isolates, 996 (63%) were included in 1 of 236 clusters. The cluster size ranged from 2 (114 clusters) to 45 (1 cluster) patients, the mean cluster size being 4.2. These results indicate that 47.83% of tuberculosis cases during the period analyzed were the result of recent transmission. CONCLUSIONS: The most prevalent global lineage in Croatia is Euro-American (sub-lineages Haarlem, S, Cameroon, and Latin American-Mediterranean). The high clustering rate and high medium clustering size of 4.2 tuberculosis cases could indicate a possible failure in interrupting the transmission of infection and points to the need for improvements in national and local tuberculosis control activities. This is the first study describing the molecular epidemiology of tuberculosis in Croatia.

The role of interferon-gamma release assay in tuberculosis control.

Tuberculosis is still one of the major global public health threats. Countries with low incidence must focus on exhausting the reservoir of future cases by preventing reactivation. Therefore, it is important to identify and effectively treat those individuals who have latent tuberculosis infection and who may develop active disease. The tuberculin skin test has been the standard for detection of immune response against M. tuberculosis since the beginning of the 20th century. The new millennium has brought advancement in the diagnosis of latent tuberculosis infection. The name of the new blood test is interferon-gamma release assay (IGRA). Croatia is a middle-incidence country with a long decreasing trend and developed tuberculosis control. To reach low incidence and finally eliminate tuberculosis, its tuberculosis programme needs a more aggressive approach that would include intensive contact investigation and treatment of persons with latent tuberculosis infection. This article discusses the current uses of IGRA and its role in tuberculosis control.

Epidemiological patterns of tuberculosis in Croatia in the period 1996-2005.

The last comprehensive publication on tuberculosis in Croatia and the earliest impact of war, besides the yearly routine reports, was done in 1996 in Croatian. We were, therefore, interested to explore incidence trends and to highlight the early post-war tuberculosis epidemiological patterns in the next ten years period (1996-2005). A retrospective analysis of epidemiological data on all registered tuberculosis cases in Croatia searching the databases of 21 Croatian Public Health Institutes and the National Tuberculosis Registry was made. During the study period, the total tuberculosis incidence rates in Croatia dropped from 45 to 25.8/100 000 inhabitants. The average highest age-specific rates were recorded in the age group > or = 65 years being in decrease in all age groups. Paediatric cases (0-14 years) represented 4.5% of all cases. Tuberculosis cases among males were recorded in 64% cases, and 83.6% were indigenous population. Tuberculosis was bacteriologically confirmed in 67.7% cases. A low proportion of drug resistance (3.3%) was recorded. During 1985-2005, 56 tuberculosis cases among 242 AIDS cases were reported. Tuberculosis mortality showed a decreasing trend (p < 0.001). However, tuberculosis has still had the highest mortality rates among infectious diseases in Croatia. Despite the War chain of events and tuberculosis programmatic changes, tuberculosis incidence rates in Croatia have been decreasing but they are still far away from national target, incidence rate of 10/100 000 declared in 1998 and much higher than in European Union and Western Europe. Tuberculosis among children, resistance to tuberculosis drugs and HIV prevalence, significant problems in many European countries, have not caused problems in tuberculosis control in Croatia. This favourable epidemiological situation must be kept and improved through strengthened tuberculosis control measures.

[Childhood tuberculosis: an ancient disease in the youngest generation in the 21st century from epidemiological point of view]. / Epidemioloski aspekti tuberkuloze--stare bolesti u djece 21. stoljeca danas.

Childhood tuberculosis (TB) has distinct epidemiological and clinical features. TB burden in children worldwide and in Croatia, the risk of infection and disease, as well as disease characteristics, sources of infection in children, diagnostic difficulties, impact of HIV on pediatric tuberculosis, limits of BCG-vaccine and program implications are discussed in this paper. Children younger than 15 years account for 15%-20% of global TB burden, which is often associated with severe TB-related morbidity and mortality. Childhood TB is rarely sputum-smear positive on microscopy. That is probably the reason for the lower priority traditionally given to children by TB control programs compared to that of adult disease. Young children are at a high risk of rapid progression from infection to disease, reflecting recent transmission rather than secondary reactivation. Therefore, the pediatric burden potentially provides a useful measure of current transmission within a community and it is a good indicator of the efficacy of TB control achieved in a particular community. Strict contact tracing and use of preventive chemotherapy is important to reduce TB-related suffering of children. Untreated latent TB infection in children provides the seed of the epidemic for the next generation. Evidence of an adult TB index case is a clue for diagnosis of childhood TB in low-endemic countries. Prognosis of early detected and properly treated TB is excellent. Consequently, new diagnostic methods and treatment options are an imperative. Among HIV-coinfected children, the optimal timing for highly active antiretroviral therapy initiation and drug combinations that have minimal interactions with anti-TB drugs need to be further explored. The most effective vaccine, suitable even for HIV-infected children, remains the need for successful prevention at the global level. The Stop TB Strategy, which builds on the previous Directly Observed Treatment Short-Course Strategy (DOTS) developed by the World Health Organization, has a critical role in reducing the worldwide burden of the disease and thus in protecting children from infection and disease. The management of children with TB should be in line with the Stop TB Strategy, taking into consideration the particular epidemiology and clinical presentation of TB in children. In addition to reducing the burden of adult TB, attention to childhood nutrition and improvement of socioeconomic conditions of communities is likely to have an impact on TB transmission to children.

[Significance of laboratory statistics in tuberculosis control in Medimurje County]. / Znacenje laboratorijskih podataka u nadzoru nad tuberkulozom u Medimurskoj zupaniji.

UNLABELLED: Microbiological diagnosis of tuberculosis is the axis of any national tuberculosis control program. Tuberculosis notification rate in Medimurje County has been equivalent to the national average, except in 2009 when it (23/100,000) surpassed the national rate of 19.3/100,000. The aim of this study was to analyze laboratory results (age, sex, site of the disease, drug susceptibility test results, and genotyping results) in tuberculosis control in Medimurje County. MATERIAL, METHODS AND RESULTS: A prospective study of genotyping all newly isolated Mycobacterium tuberculosis strains is currently conducted at the Croatian National Institute of Public Health, Tuberculosis Diagnostic Department. The genotyping method used is determining variable number of tandem repeats of mycobacterial repetitive interspersed unit. Between 2007 and 2009, a total of 59 strains from patients coming from Medimurje County were genotyped, 27 (45.8%) of which had a unique genotype in the national database, while 32 (54.2%) were grouped in 22 clusters with 2 to 22 pertaining strains. Two of 22 clusters, one with two and one with five members each, were made up from strains isolated solely in Medimurje County. These strains are not only characteristic of the County, but the patients they originated from had most likely been exposed to the same route of transmission. The remaining 25 strains were grouped in 20 clusters. The patients they came from were from different parts of Croatia, while the number of Medimurje natives in these clusters varied between 1 and 3. A relatively high percentage of strains of unique genotype pointed to a relatively low degree of recent transmission. The results of molecular epidemiology analysis as part of monitoring the routes of tuberculosis transmission, showed the efficiency of counter epidemic measures by detection of unexpected routes of transmission and by identification of strains present in a given community, which more often than others cause disease.

[Comparison of new and old tests for the diagnosis of latent tuberculosis infection (quantiferon and TST)]. / Usporedba nove i stare dijagnostike latentne tuberkulozne infekcije (quantiferon i PPD).

Tuberculosis (TB) is the second most common contagious disease, caused by Mycobacterium tuberculosis (M. tuberculosis). Besides a rare laryngeal tuberculosis, pulmonary tuberculosis is the only one contagious form of the disease, although it can affect any organ of the human body. TB represents a new challenge to the doctors because it appears with numerous chronic diseases, affects immunocompromised hosts, elderly people and because nonadequate therapy could create drug resistant tuberculosis. Early diagnosis of TB is fundamental for every tuberculosis control program. Before 2001 when QuantiFERON test was approved, tuberculin skin test (TST) was the only diagnostic test for detection of latent M. tuberculosis infection. In contrast of TST, which is in vivo test, the novel whole blood tests in vitro, so-called IGRA tests (QuantiFERON, Elispot.T-SPOT.TB) now exist. This paper presents advantages and disadvantages of both methods. IGRA tests are considered to have higher specifity and sensitivity than TST.

Mycobacterium xenopi pulmonary disease - epidemiology and clinical features in non-immunocompromised patients.

OBJECTIVES: The genus Mycobacterium has more than 120 well-characterized species. Although the incidence of tuberculosis has decreased over the studied period, other, non-tuberculous mycobacteria (NTM) are isolated more often. Since, Mycobacterium xenopi is the most frequent NTM isolate in Croatia we studied its epidemiology and clinical relevance. METHODS: We performed a retrospective study over a 25-year period determining epidemiology, radiological findings and clinical importance of M. xenopi infection, obtaining data from archives in health care institutions from all over the country. RESULTS: We detected 40 patients with a positive isolate of M. xenopi. Twenty-four patients met American Thoracic Society criteria for pulmonary disease. Eighteen (90%) of treated patients were male, on average 61.7 years old. Nineteen (95%) patients lived in towns. Most of them had comorbid disease, 18 (90%), with chronic obstructive pulmonary disease (COPD) being the most frequent, found in 11 (55%) patients. All patients were immunocompetent. We found COPD as the most frequent comorbid disease in the group of patients with worse treatment response (n=8; 80%), while in patients with good treatment response COPD was less frequent (n=3; 30%). Differences in the proportions of patients with COPD were significant (p=0.037). CONCLUSION: In patients with M. xenopi pulmonary infection, COPD is a predisposing condition, and as a comorbid disease, is an important prognostic factor for treatment response.

[Infections due to nontuberculous mycobacteria]. / Infekcije izazvane netuberkuloznim mikobakterijama.

The best known members of genus Mycobacterium belong to M. tuberculosis complex. Other mycobacteria are known as nontuberculous mycobacteria (NTM). NTM less commonly cause a disease (mycobacteriosis), more often colonising respiratory tract. The presence of NTM is more common in immunocompromised patients and in those with a previous lung disease. The decrease in the incidence of tuberculosis is followed by increased incidence of NTM. Since tuberculosis has been declining in Croatia over the last 50 years, increasing incidence of NTM is expected. Growing incidence of chronic obstructive pulmonary disease (COPB) is contributing to this increase. NTM are ubiquitous and inhaling of aerosol particles constitutes the dominant route of infection. They are not transmitted via interhuman contact. In addition to pulmonary and skin infections, disseminated infections are also described. The treatment of mycobacteriosis is difficult and long. Besides using antituberculotic drugs such as rifampin and ethambutol, the therapies use fluoroquinolones; the introduction of macrolides has significantly improved the outcome of treatment.

Mycobacterial infection of pigs in Croatia.

During a five-year period (2000 to 2004) 74,342 pigs were tested by the intradermal tuberculin test in Croatia. Of them, 248 (0.33%) pigs were positive and 91 (0.12%) were found to be suspicious in 7 out of the 13 farms included in the study. Gross pathological changes characteristic of tuberculosis were observed in tuberculin-positive and/or suspicious swine. Mycobacterium was isolated from the lymph nodes of 183 out of 234 swine (78.2%). For better epidemiological understanding, isolates were typed by conventional methods, PCR and hybridisation. The results show that most of the isolates belonged to the Mycobacterium avium complex (175 isolates, 95.7%). Other isolates belonged to M. fortuitum (6 isolates, 3.3%), M. chelonae (1 isolate, 0.5%), and M. peregrinum (1 isolate, 0.5%). Isolated strains of the M. avium complex were identified as M a. avium (37 isolates, 21.1%) and M. a. hominissuis (138 isolates, 78.9%).

[Drug resistant tuberculosis: ten years of surveillance in Croatia]. / Rezultati desetogodisnjeg laboratorijskog pracenja rezistentne tuberkuloze u Hrvatskoj.

Drug resistant and multidrug resistant tuberculosis is a consequence of human activity. Resistant strains of M. tuberculosis are mainly prevalent in regions with weak national TB programs or poor socioeconomic environment. Therefore an effective surveillance of the resistance patterns of TB bacilli is an essential tool for the quality of tuberculosis control programs and a demanding task in all countries. Surveillance of tuberculosis in Croatia is based on individual notifications of every newly diagnosed patient by the physicians, followed by laboratory notifications. Data are collected at the Epidemiology Service, National Institute of Public Health Tuberculosis Register (TR). TR is part of the World Health Organization informational system and Surveillance of Tuberculosis in Europe (EuroTB). The results of the ten-year surveillance of the prevalence of drug resistant (5.7%) and multidrug resistant (1.6%) tuberculosis show that Croatia has a favorable situation which should be kept up strictly following the measures of the national TB program.