Showing papers in "Mediterranean Journal of Hematology and Infectious Diseases in 2014"

Immunology of Tuberculosis

Abstract: MTB ranks as the first worldwide pathogen latently infecting one third of the population and the second leading cause of death from a single infectious agent, after the human immunodeficiency virus (HIV). The development of vigorous and apparently appropriate immune response upon infection with M.tuberculosis in humans and experimental animals conflict with failure to eradicate the pathogen itself and with its ability to undergo clinical latency from which it may exit. From a clinical standpoint, our views on MTB infection may take advantage from updating the overall perspective, that has quite changed over the last decade, following remarkable advances in our understanding of the manipulation of the immune system by M.tuberculosis and of the role of innate components of the immune response, including macrophages, neutrophils, dendritic cells and NK cells in the initial spread of MTB and in its exit from latency. Scope of this review is to highlight the the major mechanisms of MTB escape from immune control and to provide a supplementary translational perspective for the interpretation of innate immune mechanisms with particular impact on clinical aspects.

Tuberculosis: epidemiology and control

Abstract: Tuberculosis (TB) is a major public health concern worldwide: despite a regular, although slow, decline in incidence over the last decade, as many as 8.6 million new cases and 1.3 million deaths were estimated to have occurred in 2012. TB is by all means a poverty-related disease, mainly affecting the most vulnerable populations in the poorest countries. The presence of multidrug-resistant strains of M. tuberculosis in most countries, with some where prevalence is high, is among the major challenges for TB control, which may hinder recent achievements especially in some settings. Early TB case detection especially in resource-constrained settings and in marginalized groups remains a challenge, and about 3 million people are estimated to remain undiagnosed or not notified and untreated. The World Health Organization (WHO) has recently launched the new global TB strategy for the “post-2015 era” aimed at “ending the global TB epidemic” by 2035, based on the three pillars that emphasize patient-centred TB care and prevention, bold policies and supportive systems, and intensified research and innovation. This paper aims to provide an overview of the global TB epidemiology as well as of the main challenges that must be faced to eliminate the disease as a public health problem everywhere.

Diagnosis and subclassification of acute lymphoblastic leukemia

Abstract: Acute lymphoblastic leukemia (ALL) is a disseminated malignancy of B- or T-lymphoblasts which imposes a rapid and accurate diagnostic process to support an optimal risk-oriented therapy and thus increase the curability rate. The need for a precise diagnostic algorithm is underlined by the awareness that both ALL therapy and related success rates may vary greatly in function of ALL subset, from standard chemotherapy in patients with standard-risk ALL, to allotransplantation (SCT) and targeted therapy in high-risk patients and cases expressing suitable biological targets, respectively. This review offers a glimpse on how best identify ALL and the most relevant ALL subsets.

Tyrosine kinase inhibitors and pregnancy.

Abstract: The management of patients with chronic myeloid leukemia (CML) during pregnancy has became recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients. Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy. This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.

Prognostic factors in hodgkin lymphoma

Abstract: Hodgkin lymphoma (HL) is among the neoplastic diseases that has the best long-term outcome after cytotoxic treatment. Cure rates approach 80-90%, however, 15-20% of patients will be resistant to therapy (primary refractory) or relapse after treatment. Prognostic factors should help to stratify therapy according to the risk profile and identify patients at risk for failure. Significance of prognostic factors partly depends on the efficacy of the treatments administered, since new effective therapies can variably counterbalance the adverse effects of some unfavorable clinical determinants. As a consequence, some prognostic factors thought to be important in the past may become meaningless when modern successful therapies are used. Therefore, the value of prognostic factors has to be updated periodically, and compared to new emerging biomarkers. Besides the prognostic role of PET imaging, tissue and circulating biomarkers, as the number of tumor-infiltrating macrophages, cytokine and chemokine levels and profiling of circulating nucleic acids (DNA and microRNAs) have shown promise.

Central Nervous System Involvement in Adult Acute Lymphoblastic Leukemia: Diagnostic Tools, Prophylaxis, and Therapy

Abstract: In adult patients with acute lymphoblastic leukemia (ALL), Central Nervous System (CNS) involvement is associated with a very poor prognosis. The diagnostic assessment of this condition relies on the use of neuroradiology, conventional cytology (CC) and flow cytometry (FCM) . Among these approaches, which is the gold standard it is still a matter of debate. Neuroradiology and CC have a limited sensitivity with a higher rate of false negative results. FCM demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies of large series of patients are still awaited, a positive finding by FCM appears to anticipate an adverse outcome even if CC shows no infiltration. Current strategies for adult ALL CNS-directed prophylaxis or therapy involve systemic and intrathecal chemotherapy and radiation therapy. Actually, early and frequent intrathecal injection of cytostatic combined with systemic chemotherapy is the most effective strategy to reduce the frequency of CNS involvement. In patients with CNS overt ALL, at diagnosis or upon relapse, allogenic hematopoietic stem cell transplantation might be considered. This review will discuss risk factors, diagnostic techniques for identification of CNS infiltration and modalities of prophylaxis and therapy to manage it.

Prevention of β Thalassemia in Northern Israel - a Cost-Benefit Analysis

Abstract: Background:β Thalassemia major is characterized by hemolytic anemia, ineffectiveerythropoiesis and hemosiderosis. About 4 % of the world population carries a Thalassemiagene. Management includes blood transfusions and iron chelation, this treatmentis costly and population screening may be significantly more cost benefit. Purpose: Thepurpose of the current study is to analyze the cost of running a preventionprogram for β Thalassemia in Israel and compare it to the actual expensesincurred by treating Thalassemia patients. Methods: Threecost parameters were analyzed and compared: The prevention program, routinetreatment of patients and treatment of complications. An estimation of theexpenses needed to treat patients that present with complications werecalculated based on our ongoing experience in treatment of deterioratingpatients. Results andConclusions: The cost of preventing one affected newborn was $63,660 comparedto $1,971,380 for treatment of a patient during 50 years (mean annual cost: $39,427). Thus, the prevention of 45 affectednewborns over a ten years period represents a net saving of $88.5 million tothe health budget. Even after deducting the cost of the prevention program ($413.795/yr.), the program still represents abenefit of $ 76 million over ten years. Each prevented case could pay thescreening and prevention program for 4.6 ys.

Current knowledge on HIV-associated Plasmablastic Lymphoma

Abstract: HIV-associated PBL is an AIDS-defining cancer, classified by WHO as distinct entity of aggressive DLBCL. To date less than 250 cases have been published, of them17 are pediatric. The pathogenesis of this rare disease is related to immunodefiency, chronic immune stimulation and EBV. Clinically is a rapid growing destructive disease mainly of oral cavity, but frequently involves extraoral and extranodal sites. The diagnosis requires tissue mass or lymph node biopsy, but core needle or fine needle biopsy is acceptable for difficult access sites. Immunophenotype is CD45, CD20, CD79a negative and CD38, CD138, MUM1 positive, EBER and KI67 is >80%. Frequently is diagnosed in patients with low CD4+ and high viral load, however is reported also in patients on effective cART and high CD4. Treatment administered is usually CHOP or CHOP-like regimens, more intensive regimens as CODOX-M/IVAC or DA-EPOCH are possible options. Intensification with ABMT in CR1 may be considered for fit patients. Rituximab is not useful for this CD20- disease. Bortezomib and new drugs were used at case report level, with transient response. CNS prophylaxis is mandatory. Use of cART is recommended during chemotherapy, keeping in mind the possible overlapping toxicities. For refractory/relapsed patients, therapy is usually considered palliative, however in chemosensitive disease intensification + ABMT or new drugs may be considered. Factors affecting outcome are achieving complete remission, PS, clinical stage, MYC , IPI. Reported median PFS ranges between 6-7 months and median OS ranges between 11-13 months. Long term survivor are reported but mostly in pediatric patients. Due to the scarcity of data on this subtype of NHL we suggest that the diagnosis and the management of HIV-positive PBL patients should be performed in specialized centers.

Treatment recommendations for chronic myeloid leukemia

Abstract: The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.

Epidemiological Overview of Hodgkin Lymphoma across the Mediterranean Basin.

Abstract: Hodgkin Lymphoma (HL) is an uncommon neoplasm of B-cell origin with an incidence that varies significantly by age, sex, ethnicity, geographic location and socioeconomic status. This complex pattern was also found to be replicated among Mediterranean basin populations. HL incidence rates progressively decreased from industrialized European countries such as France (ASR=2.61) and Italy (ASR=2.39) to less developed nations such as Albania (ASR=1.34) and Bosnia Herzegovina (ASR=1.1). Regarding HL mortality we have found that countries with the lowest incidence rates show the highest number of deaths from this cancer and viceversa. Finally, a wide gap in terms of survival was showed across the Mediterranean basin with survival rates ranged from 82.3% and 85.1% among Italian men and women, to 53.3 % and 59.3% among Libyan men and women, respectively. Factors such as the degree of socio-economic development, the exposure to risk factors westernization-related, the availability of diagnostic practices along with different genetic susceptibilities to HL may explain its variation across Mediterranean countries. Furthermore, the lack of health resources decisively contribute to the poor prognosis recorded in less developed region. In the future, the introduction of appropriate and accessible treatment facilities along with an adequate number of clinical specialists in the treatment of HL and other cancers are warranted in order to improve the outcomes of affected patients and treat a largely curable type of cancer in disadvantaged regions.

Cost of Hematopoietic Stem Cell Transplantation in India

Abstract: Hematopoietic stem cell transplantation (HSCT) is the definite cure for many hematological diseases. With the increasing indications for HSCT and its relatively low cost in Indian subcontinent, an increasing number of patients are opting for this procedure. We retrospectively analyzed the cost of one hundred sixty two HSCTs done at our center in the last three years. The median cost of autologous transplant was INR 7,52,294 (USD, $ 12,500) (range INR 6,19,850-14,17,212) and the median cost of allogenic transplant was INR 10,74,881 ($18,000) (range INR 6,49,944-23,82,227). The cost of HSCT is cheaper here compared to that in developed countries and success rates are nearly equivalent. The major factors contributing to the cost are related to the complications post-transplant mainly infections and graft versus host disease, which are also the reasons for the increased stay in the hospital.

Acute Promyelocytic Leukemia (APL): Comparison Between Children and Adults.

Abstract: The outcome of adults and children with Acute Promyelocytic Leukemia (APL) has dramatically changed since the introduction of all trans retinoic acid (ATRA) therapy. Based on the results of several multicenter trials, the current recommendations for the treatment of patients with APL include ATRA and anthracycline-based chemotherapy for the induction of remission and for consolidation, and ATRA combined with low-dose chemotherapy for maintenance. This has improved the prognosis of APL by increasing the complete remission (CR) rate, actually > 90%, decreasing the induction deaths and by reducing the relapse rate, leading to cure rates nowadays exceeding 80% considering both adults and children 1-9 . More recently the combination of ATRA and arsenic trioxide (ATO) as induction and consolidation therapy has been shown to be at least not inferior and possibly superior to ATRA plus chemotherapy in adult patients with APL conventionally defined as non-high risk (Sanz score) 10 . Childhood APL has customarily been treated on adult protocols. Data from several trials have shown that the overall outcome in pediatric APL appears similar to that reported for the adult population, however some clinical and therapeutic aspects differ in the two cohorts which require some important considerations and treatment adjustments.

Tuberculosis in Tropical Areas and Immigrants

Abstract: About 95% of cases and 98% of deaths due to tuberculosis (TB) occurs in tropical countries while in temperate low incidence countries, a disproportionate portion of TB cases is diagnosed in immigrants. Urbanization, poverty, poor housing conditions and ventilation, poor nutritional status, low education level, the HIV co-epidemic, the growing impact of chronic conditions such as diabetes are the main determinants of the current TB epidemiology in tropical areas. TB care in these contests is complicated by several barriers such as geographical accessibility, educational, cultural, socio-psychological and gender issues. High quality microbiological and radiological facilities are not widely available and erratic supply of anti-TB drugs may affects tropical areas from time to time. Nevertheless in recent years, TB control programs reached major achievements in tropical countries as demonstrated by several indicators. Migrants have an high risk of acquire TB before migration. Moreover, after migration, they are exposed to additional risk factors for acquiring new infection or reactivate it such as poverty, stressful living conditions, social inequalities, overcrowded housing, malnutrition, substance abuse, and limited access to health care. TB mass screening programs for migrants have been implemented in low endemic countries, but present several limitations. Screening programs should not represent a stand-alone intervention, but a component of a wider approach integrated with other healthcare activities to ensure the health of migrants.

Pathobiology of Hodgkin Lymphoma

Abstract: Hodgkin's lymphoma is a lymphoid tumour that represents about 1% of all de novo neoplasms occurring every year worldwide. Its diagnosis is based on the identification of characteristic neoplastic cells within an inflammatory milieu. Molecular studies have shown that most, if not all cases, belong to the same clonal population, which is derived from peripheral B-cells. The relevance of Epstein-Barr virus infection at least in a proportion of patients was also demonstrated. The REAL/WHO classification recognizes a basic distinction between nodular lymphocyte predominance HL (NLPHL) and classic HL (CHL), reflecting the differences in clinical presentation, behavior, morphology, phenotype, molecular features as well as in the composition of their cellular background. CHL has been classified into four subtypes: lymphocyte rich, nodular sclerosing, mixed cellularity and lymphocyte depleted. Despite its well known histological and clinical features, Hodgkin's lymphoma (HL) has recently been the object of intense research activity, leading to a better understanding of its phenotype, molecular characteristics and possible mechanisms of lymphomagenesis.

Tuberculosis in patients with haematological malignancies

Abstract: Tuberculosis (TB) is an infectious disease that causes more than 1 million deaths worldwide every year. In addition, it is estimated that one third of the world population is infected with M. tuberculosis in a latent state, which involves an eventual risk of progressing to active TB disease. Patients with immunodeficiencies, such as those suffering from haematological malignancies, have a greater risk of progressing to TB disease once infected. It is estimated that the Relative Risk of TB disease in patients with hematologic malignancies is 2-40 times that of the general population. The diagnosis of TB in these patients is often challenging as they often present clinical characteristics that are distinct to those of patients without any other underlying disease. Mortality due to TB is higher. Therefore, it is recommended to diagnose latent TB infection and consider preventive therapy that could avoid the progression from a latent state to active TB disease. There are currently two methods for diagnosing latent TB infection: the Tuberculin Skin Test (TST) and the Interferon-Gamma Release Assays (IGRA). Due to the lack of sensitivity in patients with immunodeficient conditions, a combined TST-IGRA testing is probably the best way for latent TB diagnosis in order to gain sensitivity. Treatment of latent TB infection and TB disease should follow the general principles to that in the general population.

Longitudinal Study on Liver Functions in Patients with Thalassemia Major before and after Deferasirox (DFX) Therapy.

Abstract: With regular blood transfusion and iron chelation therapy, most patients with thalassemia major (BTM) now survive beyond the third decade of life . Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are important causes of liver pathology. Iron chelation with desferrioxamine (Desferal) reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox (Exjade- DFX ), an oral single dose therapy has improved the compliance to chelation therapy. Aims: To study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX therapy in relation to ferritin level and IGF-I level. Methods: Liver function tests including: serum bilirubin, alanine transferase (ALT), aspartate transferase (AST) , albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every 6 months in 40 patients with BTM, with hepatitis negative screening (checked every year), for at least five years of DFO therapy and 4-5 years of DFX therapy . Results: DFX therapy (20 mg/kg/day) significantly decreased serum ferritin level in patients with BTM, this was associated with significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum ferritin concentrations ( r = 0.45 and 0.33 respectively , p < 0.05) . IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels. The negative correlation between serum ferritin concentrations and ALT suggests that impairment of hepatic function negatively affects IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis. Conclusions : Some impairment of liver function can occur in hepatitis negative BMT patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients.

Association of Mycobacterium Tuberculosis Lineages with IFN-γ and TNF-α Gene Polymorphisms among Pulmonary Tuberculosis Patient.

Abstract: The six major lineages of Mycobacterium tuberculosis [MTB] are found to be strongly associated with specific geographical outbreaks. But whether these bacterial lineages influence the host genetic polymorphism is uncertain. The present study was designed to evaluate the relevance of strain diversity and host genetic polymorphisms in susceptibility to pulmonary tuberculosis [PTB]. For this reason, single –nucleotide polymorphisms [SNPs] in interferon- γ [IFN-γ] receptor-1[G-611A], IFNG [G+ 2109A] and tumor necrosis factors [TNF-α] genes [at -238, 308,-857position] in patients [n=151] were analyzed and compared with controls [n=83]. The genetic diversity of M. tuberculosis isolates were performed using spacer oligonucleotide typing. Thereafter, the profile of IFN-γ and TNF-α allele frequency were investigated in each subtype of M .tuberculosis. The results showed C allele of TNF 857 and A allele of TNF 238 were more frequent in PTB cases [[TNF 857 C allele OR [CI95%] 0.6[0.4-0.9], p= 0.02] for TNF 238 A allele OR [CI95%] 5.5[3.4-9.0], p= 0.00]]. Similarly, G allele in IFNG+ 2109 A/G polymorphism were significantly more in patients than control subject[OR[CI95%] 0.3; p< 0.05]. The major identified clinical isolates of M. tuberculosis were EAI[42; 27.8% ], Haarlem[ 31; 20.5% ], CAS [ 23;15.2% ], Beijing[14; 9.2%], and T [11; 7.2% ] lineages. No correction was observed between strains diversity and frequency of SNPs in studied PTB cases. In conclusions, we exclude the possibility of genetic mutation in IFN-γ and TNF-α gene by different subtypes of M .tuberculosis. Although, our results supports a positive correlation between host SNPs and susceptibility to PTB.

Tacrolimus Associated Posterior Reversible Encephalopathy Syndrome – A Case Series and Review

Abstract: Tacrolimus is an immunosuppressive drug mainly used to lower the risk of transplant rejection in individuals who are post solid organ or hematopoietic transplantation. It is a macrolide which reduces peptidyl-propyl isomerase activity and inhibits calcineurin, thus inhibiting T-lymphocyte signal transduction and interleukin-2 (IL-2) transcription. It has been associated with Posterior Reversible Encephalopathy Syndrome (PRES), a disease of sudden onset that can present as a host of different symptoms, depending on the affected area of the brain. While infectious causes of encephalopathy must always be entertained, the differential diagnosis should also include PRES in the appropriate context. We report three cases of PRES in patients with acute myeloid leukemia (AML) placed on tacrolimus after receiving a bone marrow transplant (BMT). The focus of this review is to enhance clinical recognition of PRES as it is related to an adverse effect of Tacrolimus in the setting of hematopoietic transplantation.

Insulin-like growth factor-1 (igf-1): demographic, clinical and laboratory data in 120 consecutive adult patients with thalassaemia major

Abstract: Introduction : Insulin-like growth factor 1 (IGF-1) is a key peptide involved in cell growth and protein turnover, acting as the primary mediator of many of the responses regulated by growth hormone (GH) in tissues. Signs and symptoms of adult GH deficiency (AGHD) in patients with β-thalassaemia major (TM) may be subtle and overlap with those of the disease itself; therefore, the diagnosis may be missed or delayed, with potentially serious consequences. The diagnosis of AGHD requires an appropriate clinical setting and is confirmed through biochemical testing. The aim of this study was to measure IGF-1 values and other clinical data in a large number of adult patients with TM and to evaluate whether an IGF-1 concentration 2 SDs below normative values could be used as an effective index supporting the probable presence of AGHD. Patients and Methods: A cohort of 120 adult patients with TM was studied for plasma levels of IGF-1. Plasma total IGF-1 was determined by chemiluminescent immunometric assay (CLIA) method. In eleven patients (4 males) the GH response during glucagon stimulation test (GST) was also evaluated. Results: Fifty percent of patients (33 males and 27 females) had IGF-1 levels -2SDs. In multivariate regression analyses, height, weight, BMI, serum ferritin, ALT, HCV serology and left ventricular ejection fraction (LVEF) were not significantly related to IGF-1, but a significant correlation was found in females between HCV-RNA positivity and IGF-1, ALT and serum ferritin (p= 0.043). AGHD was diagnosed in 6 (4 males) out of 11 patients (54.5%) who had glucagon stimulation tests and in 5 out of 8 (62.5%) with IGF-1 <-2SD. The mean age of patients with GHD was 39.3 years (range: 25-49 years) versus 35.8 years (range: 27-45 years) in non-GHD patients. A positive correlation between GH peak after GST and IGF-1 level was found (r: 0.6409; p: < 0.05). Conclusions: On the basis of the present results and data from the literature, the Inter national Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) recommends a GH stimulation test in adults with TM in the presence of very low IGF-1 levels (<-2SDs of normative values for healthy individuals matched for age and sex) especially in patients with childhood onset of GHD with pituitary iron deposition and/or atrophy. In addition the presence of short stature (HtSDS <-2.5), severe and/or prolonged iron overload, and severe osteoporosis strengthens the indications for a GH stimulation test in adult patients with TM.

A Prospective, Observational Study of Adverse Reactions to Drug Regimen for Multi-Drug Resistant Pulmonary Tuberculosis in Central India

Abstract: Objective: 1) To assess the adverse drug reactions of second line anti-tubercular drugs used to treat Multi-drug resistant Tuberculosis (MDR TB) in central India on the basis of causality, severity and avoidability scales. 2) To study the relationship of type of MDR TB (primary or secondary) and presence of diabetes mellitus (DM) with mean smear conversion time. Material and Methods: A prospective, observational study was carried out on diagnosed multidrug resistant tuberculosis patients enrolled for DOTS‑Plus regimen at TB and Chest Disease Department from January to December 2012. They were followed for 9 months thereafter and encountered adverse drug reactions (ADRs) were noted along with the time of sputum conversion. The data were analysed by Chi-square or Fisher’s exact test and unpaired student’s‘t’ test. Results: Total 64 ADRs were reported in 55 patients out of total 110 patients (n = 110). As per the Naranjo causality assessment of ADRs, 7 patients had “definite” causal relation, 45 had “probable” causal relation and 3 had “possible” causal relation with drugs of DOTS Plus regime. As per the Hartwig’s severity assessment scale, there were total 7 ADRs in Level 1, 6 in Level 2, 33 in Level 3 and 9 in Level 4. Hallas avoidability assessment scale divided the ADRs as 3 being “Definitely avoidable”, 26 “Possibly avoidable”, 23 “Not avoidable” and 3 “unevaluable”. ). Mean sputum smear conversion time is significantly higher in patients with secondary type than that of primary type of MDR TB (p = 0.0001) and in patients with DM than those without DM (p <0.0001). Conclusion: ADRs were common in patients of MDR TB on DOTs-Plus drug regime. It was due to lack of availability of safer and equally potent drugs in DOTs-Plus drug regime compared to DOTS regime in non-resistant TB. The frequency and severity of ADRs can be reduced by strict vigilance about known and unknown ADRs, monitoring their laboratory and clinical parameters and instituting appropriate measures. Keywords: Adverse drug reactions, Avoidability, Causality, DOTs-Plus, MDR TB, Severity.

Bordetella Bronchiseptica in the Immunosuppressed Population – A Case Series and Review.

Abstract: Organisms that are not known to cause serious infection in the immunocompetent population can in fact cause devastating illness in immunosupressed neutropenic populations especially those who are undergoing hematopoietic stem cell transplantation (HSCT), and solid organ transplantation or a history of malignancy. One organism of interest isolated from immunosupressed patients at our institution was Bordetella bronchiseptica. B. bronchiseptica is a Gram-negative, rod shaped bacterium, primary respiratory tract organism known to cause respiratory tract disease in the animal population which include dogs, cats, and rabbits. This organism rarely causes serious infection in the immunocompetent population. However; in immunosupressed patients, it can cause serious pulmonary disease. We present three cases of B. bronchiseptica isolated from patients with a history of malignancy a serious pulmonary infection.

SECOND-GENERATION TYROSINE KINASE INHIBITORS (TKI) AS SALVAGE THERAPY FOR RESISTANT OR INTOLERANT PATIENTS TO PRIOR TKIs

Abstract: With the advent of target therapies, imatinib became the mainstay for treatment of chronic myeloid leukemia. However, despite the brilliant results obtained with this drug, more than 30% of patients discontinue therapy in long-term due to several reasons, including failure and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) are more potent drugs and have expanded inhibition against a broad spectrum of mutations resistant to imatinib. Both nilotinib and dasatinib have demonstrated in vitro and in vivo clinical activity against different types of mutations and various forms of resistance. However, patients with T315I mutation do not obtain an advantage from these drugs and a third generation inhibitor ponatinib, a pan-BCR drug, was tested with significant results. In this review, we report the results of second- and third-generation TKIs tested as second or third line therapy in patients resistant and/or intolerant to previous inhibitors.

Spectrum of Beta Globin Gene Mutations in Egyptian Children with β-Thalassemia.

Abstract: Background: The molecular defects resulting in β-thalassemia phenotype, in the Egyptian population show a clear heterogenic mutations pattern. PCR based techniques, including direct DNA sequencing are effective on the molecular detection and characterization of these mutations. The molecular characterization of β-thalassemia is absolutely necessary for carrier screening, for genetic counseling, and to offer prenatal diagnosis.The aim of the work: was to evaluate the different β-globin gene mutations in one hundred Egyptian children with β-thalassemia. Patients and Methods: One hundred of β-thalassemic Egyptian children, covering most Egyptian Governorates. All patients were subjected to meticulous history taking, clinical examinations, complete blood count, complete blood count, hemoglobin electrophoresis, serum ferritin and direct fluorescent DNA sequencing of β-globin gene to detect the frequency of different mutations in studied patients. Results: The most common mutations among patients were IVS I-110(G>A) 48%, IVS I-6(T>C) 40%, IVS I-1(G>A)19%,IVS I-5(G>C)10%, IVS II-848 (C>A) 9%, IVS II-745(C>G) 8%, IVS II-1(G>A) 7%, codon"Cd"39(C> T) 4%,-87(C>G) 3% and the rare mutations were: Cd37 (G>A), Cd8 (-AA), Cd29(-G), Cd5 (-CT), Cd6(-A), Cd8/9(+G), Cd 106/107(+G), Cd27(C>T), IVS II-16(G> C), Cd 28 (-C), Cap+1(A>C), -88(C>A), all of these rare mutations were present in 1%. There was considerable variation in phenotypic severity among patients resulting from interaction of different β° and β+mutations, 79(79%) patients were thalassemia major (TM) and 21(21%) were thassemia intermedia (TI), without genotype phenotype association. Conclusion: Direct DNA sequencing provides insights for the frequency of different mutations in β- thalassemic patients including rare and /or unknown ones.

Differences Between Pediatric Extra-Pulmonary and Pulmonary Tuberculosis: a Warning Sign for the Future

Abstract: Introduction: Tuberculosis (TB) remains a major global health problem affecting millions of people annually. Tuberculosis in children has unique features different from adults which makes the diagnosis to be more difficult. The spectrum of the symptoms of TB in children could vary from non-specific symptoms to severe clinical presentations. In this study, we reviewed our experience at pediatric patients with active TB admitted in a tertiary hospital and aimed to compare the epide­miological, clinical and microbiological features of children with the extra-pulmonary tuberculosis(EPTB) and pulmonary tuberculosis(PTB). Material and methods: Patients under 14 years of age diagnosed with active TB in our unit between December 2008 and September 2013 were included in the study. Data including demographic characteristics, clinical history, microbiology, imaging studies, medications and outcomes of the patients were collected from medical records. Results: A total of 129 cases of active TB were identified. Ninety-two (78.6%) of the cases had Pulmonary Tuberculosis and 25 (21.4%) of the cases had Extra-pulmonary tuberculosis. The most common signs and symptoms on admission were fever in 40 cases (34.2%) and cough in 81 cases (69.2%). The number of patients without symptoms including fever, cough, malaise and weight loss were significantly higher in EXPTB (72.0%) group when compared with patients in PTB group (13.0%) (p 0.05). The detection rate of source in PTB group (42.4%) was significantly higher than the rate in EPTB group (20.0%)( p=0.04). In the drug-resistant group, no source of infection could be established in 5 of 9 patients (55.5%). Conclusions: Extra-pulmonary tuberculosis diagnosis is more difficult than Pulmonary tuberculosis in children due to the various problems such as absence of associated pulmonary involvement, lack of constitutional symptoms and negative tuberculosis exposure history compared to Pulmonary Tuberculosis. New strategies are required for improving the diagnosis of Extra-pulmonary tuberculosis in children

Treatment of adolescent and young adults with acute lymphoblastic leukemia.

Abstract: The primary objective of this review was to update and discuss the current concepts andthe results of the treatment of acute lymphoblastic leukemia (ALL) in adolescents and young adults(AYA). After a brief consideration of the epidemiologic and clinicobiologic characteristics of ALLin the AYA population, the main retrospective comparative studies stating the superiority ofpediatric over adult-based protocols were reviewed. The most important prospective studies inyoung adults using pediatric inspired or pediatric unmodified protocols were also reviewedemphasizing their feasibility at least up to the age of 40 yr and their promising results, with eventfreesurvival rates of 60-65% or greater. Results of trials from pediatric groups have shown that theunfavourable prognosis of adolescents is no more adequate. The majority of the older adolescentswith ALL can be cured with risk-adjusted and minimal residual disease-guided intensivechemotherapy, without stem cell transplantation. However, some specific subgroups, which aremore frequent in adolescents than in children (e.g., early pre-T, iAMP21, and BCR-ABL-like),deserve particular attention. In summary, the advances in treatment of ALL in adolescents havebeen translated to young adults, and that explains the significant improvement in survival of thesepatients in recent years.

Acute lung injury complicating blood transfusion in post-partum hemorrhage: incidence and risk factors.

Abstract: Background. We retrospectively investigated the incidence and risk factors for transfusion-related acute lung injury (TRALI) among patients transfused for post-partum hemorrhage (PPH). Methods. We identified a series of 71 consecutive patients with PPH requiring the urgent transfusion of three or more red blood cell (RBC) units, with or without fresh frozen plasma (FFP) and platelet (PLT) transfusion. Clinical records were then retrieved and examined for respiratory distress events. According to the 2004 consensus definition, cases of new-onset hypoxemia within 6 hours after transfusion, with bilateral pulmonary changes in the absence of cardiogenic pulmonary edema were identified as TRALI; if an alternative risk factor for acute lung injury was present, possible TRALI was diagnosed. Results. Thirteen cases of TRALI and 1 case of possible TRALI were identified (overall incidence 19.7%). At univariate analysis, patients with TRALI received higher number of RBC, PLT and FFP units and had a longer post-partum hospitalization. Among several pregnancy-related diseases (including hypertensive disorders, anemia, intrahepatic cholestasis, gestational diabetes) and various pre-existing comorbidities, only gestational hypertension and pre-eclampsia significantly increased the risk to develop TRALI (p = 0.006). At multivariate analysis, including both transfusion- and patient-related risk factors, pregnancy-related hypertensive disorders were confirmed to be the only predictors for TRALI, with an odds ratio of 27.7 ( 95% CI 1.27-604.3, p=0.034). Conclusions. Patients suffering from PPH represent a high-risk population for TRALI. In particular, patients with gestational hypertension and pre-eclampsia have the highest risk, particularly if they are not receiving anti-hypertensive therapy. A careful monitoring of these patients after transfusions is therefore recommended.

Hemophagocytic Lymphohistiocytosis: an Unusual Complication of Orientia tsutsugamushi Disease (Scrub Typhus).

Abstract: Background: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, potentially fatal, hyperinflammatory syndrome that may rarely complicate the clinical course of Orientia tsutsugamushi disease (scrub typhus). Methods: We describe here the clinicopathological features, laboratory parameters, management, and outcome data of three adult patients (1 female, 2 males) with scrub typhus associated HLH from a tertiary center with a brief and concise review of international literature. Results: All three patients satisfied the HLH-2004 diagnostic criteria; one had multi organ dysfunction with “sky high” ferritin level; and all had a dramatic recovery following doxycyclin therapy. Literature review from January 1990 to March 2014 revealed that scrub typhus associated HLH were reported in 21 patients, mostly from the scrub endemic countries of the world. These included 11 females and 10 males with mean age of 35 years (range; 8 months to 81 years). Fifteen of 17 patients (where data was available) had a favorable outcome following early serological diagnosis and initiation of definitive antibiotic therapy with (N=6) or without (N=9) immunosuppressive/immunomodulator therapy. Mutation analysis for primary HLH was performed in one patient only, and HLH-2004 protocol was used in two patients. Conclusion: We suggest that HLH should be considered in severe cases of scrub typhus especially if associated with cytopenia (s), liver dysfunction, and coagulation abnormalities. Further studies are required to understand whether an immunosuppressive and/or immunomodulator therapy could be beneficial in those patients who remain unresponsive to definitive antibiotic therapy.

Antifungal susceptibility testing: current role from the clinical laboratory perspective

Abstract: Despite availability of many antifungal agents, antifungal clinical resistance occurs, perhaps as a consequence of an infecting organism found to be resistant in vitro to one or more antifungals tested. From what derives the important current role of the in vitro antifungal susceptibility testing (AFST), that is to determine which agents are like to be scarcely effective for a given infection. Thus, AFST results, if timely generated by the clinical microbiology laboratory and communicated to clinicians, can aid them in the therapeutic decision making, especially for difficult-to-treat invasive candidiasis and aspergillosis. Although recently refined AFST methods are commercially available for allowing a close antifungal resistance surveillance in many clinical setting, novel assays such as flow cytometry or MALDI-TOF mass spectrometry are upcoming tools for AFST. Based on short-time antifungal drug exposure of fungal isolates, these assays could provide a reliable means for quicker and sensitive assessment of AFST.

Hodgkin’s Lymphoma in Older Patients: an Orphan Disease?

Abstract: Hodgkin Lymphoma HL ica be cured in the large majority of younger patients, but prognosis for older patients, especially those with advanced-stage disease, has not improved substantially. The percentage of HL patients aged over 60 ranges between 15% and 35%.A minority of them is enrolled into clinical trials. HL in the elderly have some specificities: more frequent male sex, B-symptoms, advanced stage, sub diaphragmatic presentation, higher percentage of mixed cellularity, up to 50% of advanced cases associated to EBV. Very old age (>70) and comorbidities are factor of further worsening prognosis. Like in younger patients, ABVD is the most used protocol, but treatment outcome remains much inferior with more frequent, severe and sometimes specific toxicities. Few prospective studies with specific protocols are available. The main data have been published by the Italian Lymphoma Group with the VEPEMB schedule and the German Hodgkin Study Group with the PVAG regimen. Recently, the Scotland and Newcastle Lymphoma Study Group published the SHIELD program associating a prospective phase 2 trial with VEPEMB and a prospective registration of others patients. Patients over 60y with early-stage disease received three cycles plus radiotherapy and had 81% of 3-year overall survival (OS).Those with advanced-stage disease received six cycles, with 3-year OS of 66%.The role of geriatric and comorbidity assessment in the treatment’s choice for HL in the elderly is a major challenge. The combination of loss of activities of daily living combined with the age stratification more or less 70y has been shown as a simple and effective survival model. Hopes come from promising new agents like brentuximab-vedotin (BV) a novel antibody-drug conjugate. The use of TEP to adapt the combination of chemotherapy and radiotherapy according to the metabolic response could also be way for prospective studies.

Immunological deregulation in classic hodgkin lymphoma.

Abstract: Hodgkin’s Disease (HD) has a unique histology since only a few neoplastic cells are surrounded by inflammatory accessory cells that in the last years have emerged as crucial players in sustaining the course of disease. In addition, recent studies suggest that the abnormal activity of these inflammatory cells (such as deregulation in Tregsignaling, expansion of myeloid derived suppressor cells, HLA-G signaling and NK dysfunction) may have prognostic significance. This review is focused on summarizing recent advanced in immunological defects in HD with translational implications.