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Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways

Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways

Our second point is that the clinical phenotype asso- ciated with these mutations is amazingly unpre- dictable. While knockout mice have been useful in pro- viding clues to the importance of a given gene, the clinical significance of the corresponding human mutations vary even within a single family. Thus, more than one gene can cause similar immunodeficiency, and a single gene can have rather variable clinical pres- entation. Given the surprisingly atypical presentations associated with these disorders, mutations may be far more common than we think. Improvements in sequencing technology will permit easier and more rapid analysis of larger numbers of patients. It will be of great interest to determine just how frequent muta- tions and polymorphisms are. It will be important as well to try to determine what modifier genes influence the severity of primary immunodeficiencies.

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Community Acquired Poliovirus Infection in Children with Primary Immunodeficiencies in Tunisia

Community Acquired Poliovirus Infection in Children with Primary Immunodeficiencies in Tunisia

Although immunodeficiencies are listed as a contraindica- tion for receiving OPV, patients with these clinical conditions may occasionally receive the poliovirus live vaccine before their immunodeficiency is diagnosed and/or may be infected with OPV strains excreted by a vaccinee or circulating within the community. When infection with vaccine strains occurs in such patients, protracted virus replication can take place and may last as long as 10 years (19). Beside the risk of developing paralysis due to the emergence of neurovirulent revertants, the issue of long-term excretors was recently raised as a major concern for the polio global eradication program, these pa- tients being a potential reservoir of polioviruses in the poster- adication era (13, 18, 33). Two recent studies reported pro- longed replication of vaccine-derived polioviruses without paralysis in immunodeficient patients after receiving OPV (5, 23). In line with this concern, we explored the potential of community-transmitted polio infection to generate long-term excretors in children with primary immunodeficiencies. FIG. 3. Intratypic differentiation by PCR-RFLP analysis. Ethidium bromide-stained 3% agarose gel showing the RFLP patterns of the different patient isolates and those of Sabin 1 and Sabin 3 strains. The panels show PCR products digested by HaeIII, HpaII, and DdeI. Lanes1 and 19 correspond to the molecular weight marker (PhiX digested with HaeIII); lanes 2 and 4 correspond to nondigested amplification products of Sabin 1 and Sabin 3, respectively; lanes 3 and 5 correspond to the digested amplification products of Sabin 1 and Sabin 3, respectively; and lanes 6 to 18 correspond to the patient poliovirus isolates (7-2, 7-9, 9-2, 9-3, 9-4, 9-5, 9-6, 9-7, 9-8, 9-9, 6-4, 12-4, and 12-5, respectively). The gel image was generated using Adobe Photoshop software.

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Flow Cytometry, a Versatile Tool for Diagnosis and Monitoring of Primary Immunodeficiencies

Flow Cytometry, a Versatile Tool for Diagnosis and Monitoring of Primary Immunodeficiencies

marrow. Flow cytometric assays range from qualitative to quanti- tative (relative and absolute) and phenotyping to functional, be- sides being useful for assessing specific protein expression, cell viability, apoptosis and death, cellular interactions and cell en- richment. These characteristics make it an ideal tool for screening, diagnostic and prognostic assays for PIDs. This minireview is di- vided into four sections, based on the use of flow cytometry in various contexts— disease-specific assessment, functional mea- surements, cellular phenotyping, and other applications, such as flow-FISH (fluorescence in situ hybridization) for telomere length analysis. This minireview is neither methodological nor compre- hensive in scope (there are several other disease-specific, phenotyp- ing, and functional immune-related flow assays that are not covered in this minireview due to space constraints) but rather it provides an overview on the use of flow cytometry in PIDs. The main target au- dience for this minireview is specialty clinicians who see patients with primary immunodeficiencies fairly routinely and diagnostic labora- tory immunologists, who perform and interpret such flow cytom- etry-based assays. To provide basic information for clinicians who do not typically evaluate PID patients,Table 1 and Table 2 contain broad guidelines on clinical contexts where PID should be considered in the differential diagnosis. All of the tests described within this minireview article are available at at least one or more clinical reference laborato- ries (academic medical centers and/or commercial) in the United States and Europe. Some of the more esoteric flow tests are less likely to be easily available in developing countries but with dissemination of knowledge and collaboration, this will hopefully be more broadly accessible throughout the globe in the coming decade.

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Clinical Epidemiological Pattern of Primary Immunodeficiencies in Malaysia 1987 2006 : A 20 year experience in Four Malaysian Hospitals

Clinical Epidemiological Pattern of Primary Immunodeficiencies in Malaysia 1987 2006 : A 20 year experience in Four Malaysian Hospitals

More primary immunodeficiency cases are being recognized in developing countries such as Malaysia, making it important to develop sufficient tertiary centres equipped with clinical expertise and laboratory facilities for better diagnosis. As PID is still a relative rare but emerging disease in Malaysia, the setting up of a credible registry acting as a tool that provide prospective and retrospective data for the medical community, health authorities, PID patients and families is highly desirable. A registry would improve access to good medical care and promote research and innovation. More clinical epidemiological data on primary immunodeficiencies from developing countries are highly sought. Our data and others support the perception that clinical epidemiological pattern of primary immunodeficiency differs in various population and regions of the world.

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Approach to Primary Immunodeficiencies for the Non Immunologist Physicians

Approach to Primary Immunodeficiencies for the Non Immunologist Physicians

Introduction: Primary immunodeficiencies are a spectrum of diseases that encompasses alteration of the innate and adaptive immune response. Isolated lymphocytopenia may be a manifestation of primary immunodeficiency, which is rarely considered as a diagnostic option by non-immunological phy- sicians. Objectives: To conduct a brief review of the primary immunodefi- ciencies that are most frequently associated with lymphocytopenia in order to provide a resource that will help non-immunological clinicians to recognize and appropriately refer to these cases. Materials and Methods: Review of the literature with scientific articles indexed in English and Spanish. We con- sulted Pubmed database with the keywords: primary immunodeficiencies and severe combined immunodeficiencies. The limit of time was 5 years and only review papers. Results: The search in the database results in 68 papers and we analyzed 35 articles because the objective of the review was Severe Combined Immunodeficiencies. Discussion: Persistent lymphopenia (usually <2500 xmm 3 ) detected in blood cell cytometry that accompanies severe, recurrent

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High Susceptibility for Enterovirus Infection and Virus Excretion Features in Tunisian Patients with Primary Immunodeficiencies

High Susceptibility for Enterovirus Infection and Virus Excretion Features in Tunisian Patients with Primary Immunodeficiencies

To estimate the susceptibility to enterovirus infection and the frequency of long-term poliovirus excreters in Tunisian patients with primary immunodeficiencies (PIDs), enteroviruses were assessed in stool specimens of 82 patients with humoral, com- bined, and other PIDs. Isolated viruses were typed and intratyped by standard molecular techniques, and the whole VP1 region of poliovirus isolates was sequenced. Polioviruses were detected in 6 patients; all isolates were vaccine related. Five patients rap- idly stopped excretion; one excreted a poliovirus type 1 isolate for several months, and the isolate accumulated up to 14 muta- tions in the VP1 region. Nonpolio enteroviruses were identified in 6 patients; 4 of them kept excreting the same strain for more than 6 months. The rate of enterovirus infection was 13.4% of the PID patients and 20.7% of those with an IgG defect; it greatly exceeded the rates generally found in Tunisian supposed-immunocompetent individuals (4.1% during the study period; P ⴝ 0.001 and P < 0.0001, respectively). Interestingly, patients with combined immunodeficiencies were at a higher risk for enterovi- rus infection than those with an exclusively B cell defect. A major histocompatibility complex (MHC) class II antigen expression defect was found in 54% of enterovirus-positive patients and in the unique long-term poliovirus excreter. The study results also suggest that substitutive immunoglobulin therapy may help clearance of a poliovirus infection and that most PID patients have the ability to stop poliovirus excretion within a limited period. However, the high susceptibility of these patients to enterovirus infection reinforces the need for enhanced surveillance of these patients until the use of oral poliovirus vaccine (OPV) is stopped.

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The Genetic, Molecular, And Cellular Bases Of Unidentified Primary Immunodeficiencies

The Genetic, Molecular, And Cellular Bases Of Unidentified Primary Immunodeficiencies

genetically analyzed three patient families with unidentified primary immunodeficiencies. Using whole exome sequencing coupled with in vitro and in vivo biochemical and cellular assays, I identified two novel genetic etiologies of primary immunodeficiency. I first identified de novo missense mutations in GNAI2, the gene encoding the ubiquitously expressed heterotrimeric G-protein Gαi2, in 2 families with life-threating multi- organ system autoimmunity and immunodeficiency to mucocutaneous infections. Gαi2 is essential for chemokine mediated leukocyte migration as well as regulating development, inflammation, and metabolism in the immune system and beyond. The heterozygous dominant gain-of-function patient proteins impaired chemokine signaling and chemotaxis in addition to augmenting T cell activation by constitutively activating costimulatory pathways and reducing the requirement for T cell costimulation. I also identified homozygous missense mutations in IFIH1, the gene encoding the cytosolic pattern recognition receptor of dsRNA MDA5, in the third family of study. The affected individual presented with recurrent severe respiratory infections with RNA viruses including human rhinovirus, coronaviruses (HKU1, OC43, NL63), influenza virus, and respiratory syncytial virus. The mutant protein lost the ability to bind dsRNA and failed to initiate antiviral interferon-β and pro-inflammatory NF-κB responses. Using gene knockdown and gene editing in

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What is the burden of immunoglobulin replacement therapy in adult patients with primary immunodeficiencies? A systematic review

What is the burden of immunoglobulin replacement therapy in adult patients with primary immunodeficiencies? A systematic review

The choice of which route to use for Ig administration usually depends upon personal preference of the patient, ease of intra- venous access, dose of Ig required, tolerability of any previous Ig products, patient lifestyle, and it can be reviewed regularly and adjusted throughout the period of treatment as patient’s circumstances change. However, it is worth mentioning that one study found IVIg treatment to be associated with higher levels of anxiety and depression. For example Heath et al. (42) specifically investigated anxiety and depression in adults with primary immunodeficiencies, and how their experiences of mental health relate to their illnesses. They assessed depression as well as anxiety with the Hamilton-Depression (HAM-D) and Hamilton-Anxiety (HAM-A) questionnaires. Their participants included adults who had either received IV IG, either at home or hospital, and patients receiving home-SC. While this was not intended as a direct comparison of treatment burden for both groups, the authors report some relevant findings: in regards to depression, it was found that patients receiving IVIg (home or hospital) scored significantly higher on the HAM-D scale than SC patients, and thus were significantly more depressed than SC patients (p = 0.0004). The authors concluded that receiving IVIg treatment may, therefore, be a risk factor for PID patients for developing depression. For the HAM-A, the relevant finding to this review is that IVIg patients attributed higher percentages of their anxiety to their PID diagnoses compared to patients receiv- ing SCIg (p = 0.030). Monitoring the psychological well-being of PID patients receiving IVIg therapy especially may, therefore, be needed although more research is warranted to investigate this possible relationship further.

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What Is the Burden of Immunoglobulin Replacement Therapy in Adult Patients With Primary Immunodeficiencies? A Systematic Review

What Is the Burden of Immunoglobulin Replacement Therapy in Adult Patients With Primary Immunodeficiencies? A Systematic Review

he choice of which route to use for Ig administration usually depends upon personal preference of the patient, ease of intra- venous access, dose of Ig required, tolerability of any previous Ig products, patient lifestyle, and it can be reviewed regularly and adjusted throughout the period of treatment as patient’s circumstances change. However, it is worth mentioning that one study found IVIg treatment to be associated with higher levels of anxiety and depression. For example Heath et  al. (42) speciically investigated anxiety and depression in adults with primary immunodeiciencies, and how their experiences of mental health relate to their illnesses. hey assessed depression as well as anxiety with the Hamilton-Depression (HAM-D) and Hamilton-Anxiety (HAM-A) questionnaires. heir participants included adults who had either received IV IG, either at home or hospital, and patients receiving home-SC. While this was not intended as a direct comparison of treatment burden for both groups, the authors report some relevant indings: in regards to depression, it was found that patients receiving IVIg (home or hospital) scored signiicantly higher on the HAM-D scale than SC patients, and thus were signiicantly more depressed than SC patients (p = 0.0004). he authors concluded that receiving IVIg treatment may, therefore, be a risk factor for PID patients for developing depression. For the HAM-A, the relevant inding to this review is that IVIg patients attributed higher percentages of their anxiety to their PID diagnoses compared to patients receiv- ing SCIg (p = 0.030). Monitoring the psychological well-being of PID patients receiving IVIg therapy especially may, therefore, be needed although more research is warranted to investigate this possible relationship further.

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Pulmonary Manifestations of Primary Immunodeficiencies in Children - A Review

Pulmonary Manifestations of Primary Immunodeficiencies in Children - A Review

Primary immunodeficiency diseases (PIDs) are inherited defects of the innate or adaptive arms of the immune system that differs from secondary immunodeficiencies. Respiratory disorders are significant causes of morbidity and the leading causes of death (30% -65%) in both children and adults with PIDs. The spectrum of respiratory manifestations is extremely wide due to PIDs. PIDs are broadly classified according to the components of the immune system that is primarily disrupted. Predominant antibody deficiency disorders are the most frequent and comprise approximately 70-75% of all PIDs. The most common clinical manifestations are infections involving the respiratory tract e.g. rhinosinusitis, otitis media, bronchitis, bronchiectasis and recurrent pneumonia (30% -65%). Recurrent respiratory infections are often the first warning sign. Timely diagnosis and appropriate therapy can improve or at least decelerate the progression of these complications. Infectious and non-infectious respiratory complications determinate the patient’s prognosis. These complications are associated with significant morbidity and mortality in PID patients. Appropriate awareness of these manifestations is essential, especially for the pulmonologist to reduce morbidity and mortality in PID patients.

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Cost-effectiveness analysis of subcutaneous immunoglobulin replacement therapy in Iranian patients with primary immunodeficiencies

Cost-effectiveness analysis of subcutaneous immunoglobulin replacement therapy in Iranian patients with primary immunodeficiencies

This research provided a cost-effectiveness analysis of IVIG and SCIG, with an emphasis on changes in serum immunoglobulin (Ig) levels and adverse effects following therapy. The epidemiological model included PID pa- tients, who received IVIG at Children’s Medical Center of Tehran during 2014 and 2015, and costing was done from the perspective of the health care providers. Effectiveness of interventions was measured based on the results of a systematic review and meta-analysis of 24 primary studies (randomized control trials and cohort studies). IVIG costs were determined through field studies, and cost items were identified based on IVIG treatment protocol and hospital bills. While SCIG method has not yet been ad- ministered in Iran, we used previous studies to find the cost items of SCIG administration (11, 15). In this re- search, IVIG was compared to rapid push SCIG. Rapid push SCIG is a more common technique than pump infu- sion, and the patient can administer it directly with a sy- ringe (17). To calculate the costs in one-year time horizon, we used average number of therapy sessions (12-16 ses- sions per year/4-6 hours per session for IVIG therapy and 48-64 sessions per year/1-2 hours per session for SCIG therapy). Finally, the total direct medical costs (cost of hospital, personnel, and medical supplies) were calculated for each method. Moreover, due to similar level of Ig dos- es in both therapies (the difference is in the number of

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Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies

Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies

Crohn’s disease at the age of 13 years when she had abdominal pain, fatigue and hematochezia. She under- went exploratory endoscopy and colonoscopy and her biopsy showed evidence of mild to active small bowel and colonic colitis with non-necrotizing granulomas. Her prior history was significant for skin abscesses, at least once per year, on the upper arm, gluteal region, thighs, vulvar and vaginal areas. There was no evidence of pneumonia, sinusitis, osteomyelitis, cellulitis or meningitis. She was treated almost continuously with immunosuppressive and biological therapies along with steroids since the initial diagnosis of Crohn’s disease. Her family history was remarkable for XL-CGD and ocular complications of CGD. Flow cytometric testing for neutrophil oxidative burst revealed 2 populations for DHR fluorescence with a larger negative and smaller positive population (Figure 3E). Genetic testing revealed a heterozygous deletion of 16 nucleotides (c.360- 375del16). The patient ’ s mother and two maternal aunts carried the same deletion mutation (one of these mater- nal aunts also had ulcerative colitis and primary biliary cirrhosis), and one maternal uncle died at the age of 18 months with recurrent neck abscesses. The family his- tory also revealed two maternal great-uncles who died in childhood of unknown causes, but presumed CGD.

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Primary immunodeficiency associated with chromosomal aberration – an ESID survey

Primary immunodeficiency associated with chromosomal aberration – an ESID survey

This retrospective survey demonstrates that patients with chromosomal aberrations and recurrent infections may harbor underlying primary immunodeficiencies. By specifically excluding the syndromic immunodeficiencies associated with Down and DiGeorge syndromes, we showed that a diverse spectrum of chromosomal aberra- tions can be associated with immunological abnormal- ities. In our cohort antibody deficiency was the most prevalent; this is important because infectious complica- tions can be prevented with early interventions like anti- biotic prophylaxis or immunoglobulin replacement treatment in these patients. To assess whether this asso- ciation is a truly causal relation, a large case–control study would be needed; this is not really feasible. And of course, our survey results do not negate other contribut- ing factors (e.g. aspiration; abnormal anatomy) in the development of recurrent ENT and airway infections in these patients. Nonetheless, our findings suggest it is

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Use of V(D)J recombination excision circles to identify T  and B cell defects and to monitor the treatment in primary and acquired immunodeficiencies

Use of V(D)J recombination excision circles to identify T and B cell defects and to monitor the treatment in primary and acquired immunodeficiencies

T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) are circular DNA segments generated in T and B cells during their maturation in the thymus and bone marrow. These circularized DNA elements persist in the cells, are unable to replicate, and are diluted as a result of cell division, thus are considered markers of new lymphocyte output. The quantification of TRECs and KRECs, which can be reliably performed using singleplex or duplex real-time quantitative PCR, provides novel information in the management of T- and B-cell immunity-related diseases. In primary immunodeficiencies, when combined with flow cytometric analysis of T- and B-cell subpopulations, the measure of TRECs and KRECs has contributed to an improved characterization of the diseases, to the identification of patients ’ subgroups, and to the monitoring of stem cell transplantation and enzyme replacement therapy. For the same diseases, the TREC and KREC assays, introduced in the newborn screening program, allow early disease identification and may lead to discovery of new genetic defects. TREC and KREC levels can also been used as a surrogate marker of lymphocyte output in acquired immunodeficiencies. The low number of TRECs, which has in fact been extensively documented in untreated HIV-infected subjects, has been shown to increase following antiretroviral therapy. Differently, KREC number, which is in the normal range in these patients, has been shown to decrease following long-lasting therapy. Whether changes of KREC levels have relevance in the biology and in the clinical aspects of primary and acquired immunodeficiencies remains to be firmly established.

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Non-Canonical Roles for RAG1 in Lymphocyte Development

Non-Canonical Roles for RAG1 in Lymphocyte Development

The RAG1/RAG2 (RAG) endonuclease recombines accessible antigen receptor (AgR) genes through DNA double strand break (DSB) intermediates to generate a diverse AgR repertoire. RAG-mediated DSBs signal changes in expression of genes encoding proteins involved in cellular survival, lymphocyte differentiation, and AgR selection. RAG proteins are each comprised of "core" endonuclease domains and dispensable "non-core" regions. Humans with mutations in non-core RAG1 regions exhibit fatal primary immunodeficiencies, and mice expressing truncated core, but not full-length, Rag1 protein (Rag1C/C mice) exhibit impaired early lymphocyte development associated with reduced levels of AgR gene rearrangements. In addition to serving with RAG2 as the V(D)J endonuclease, the RAG1 protein has been proposed to utilize non-core regions to regulate V(D)J recombination by enhancing AgR locus accessibility, promoting efficient RAG endonuclease activity, and/or generating RAG DSB-induced survival and differentiation signals. The experiments described in this thesis use a variety of mouse genetic models to investigate how mutations in RAG1 protein that preserve RAG endonuclease activity impair V(D)J recombination efficiency and lymphocyte development. First, these studies have identified roles for non-core Rag1 regions in regulating normal Alpha/Beta T cell development and TCRB recombination by promoting VB rearrangements and diverse usage of VB gene segments in both primary and secondary VB rearrangements. Second, these studies show that non-core Rag1 regulates normal B cell development by inducing transcriptional activation of the pro-survival kinase Pim2 in response to RAG cleavage and by promoting the survival of developing IgKappa+ and IgLambda+ B cells. These studies have also identified roles for Rag1 in enhancing IgKappa and IgLambda locus accessibility in pre-B cells prior to RAG cleavage. Collectively, the data presented in this thesis demonstrate that RAG1 has critical functions outside of V(D)J recombination that enhance AgR gene segment accessibility, promote V(D)J recombination at multiple AgR loci, and transduce pro-survival signals during AgR recombination to establish a broad AgR repertoire and thereby foster normal lymphocyte development.

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Immunoglobulins and Their Use in Children

Immunoglobulins and Their Use in Children

Immunoglobulin preparations are one of the products of human plasma fractionation. These drugs are concentrates of all IgG subclasses. In ac- cordance with WHO guidelines, the plasma used for the production of immunoglobulins should be obtained from at least 1,000 donors. This ensures a  variety of antibodies in the final product, pro- viding its clinical universality [1]. In clinical prac- tice, intravenous human immunoglobulin prep- arations (IVIG) are mostly used as replacement therapy in patients with primary and secondary immunodeficiencies, such as congenital hypo- and agammaglobulinaemia, Common Variable Immu- nodeficiency (CVID), severe combined immuno- deficiency, Wiskott-Aldrich syndrome, recurrent infections in patients with AIDS or severe infec- tions. IVIG are also very useful in haematology, especially paediatric haematology, neurology and rheumatology.

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Modulatory effects on immunoglobulin synthesis and secretion by lymphocytes from immunodeficient patients

Modulatory effects on immunoglobulin synthesis and secretion by lymphocytes from immunodeficient patients

immunodeficiencies, including infantile sex-linked agammaglobulinemia. Immunoregulatory activities were noted to vary with the normal donor used in co-culture experiments and with time. Cell populations that were active in influencing B-cell differentiation to functional plasma cells did not have an appreciable modulatory effect on T-lymphocyte responses to mitogens. These observations may provide a functional subclassifications for

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Molecular heterogeneity of a lymphocyte glycoprotein in immunodeficient patients

Molecular heterogeneity of a lymphocyte glycoprotein in immunodeficient patients

Previous evaluation of lymphocytes taken from patients with Wiskott-Aldrich syndrome (WAS) and other X-linked immunodeficiencies has revealed deficiencies of a lymphocyte sialoglycoprotein with a relative molecular mass of 115 kD (designated gpL-115) found in normal lymphocytes. The development of monoclonal antibodies to gpL-115 has permitted the detection of molecular heterogeneity in gpL-115 from the lymphocytes of

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The Repertoire of Adenovirus in Human Disease: the Innocuous to the Deadly

The Repertoire of Adenovirus in Human Disease: the Innocuous to the Deadly

In the immunocompromised [56] population, adenovirus is implicated in a wider spectrum of disease. Factors conferring high risk of invasive infection and disseminated disease include stem cell or solid organ transplantation [57, 58], congenital immunodeficiencies like severe combined immunodeficiency (SCID) syndrome [59] and acquired immunodeficiencies like human immunodeficiency virus (HIV) [60, 61] which can predispose patients to more severe adenoviral disease. Patients undergoing chemotherapy [62], bone marrow transplantation, severe lymphopenia and those suffering from graft-verusus-host disease are also predisposed to disseminated adenoviral infections. Interestingly, life-threatening disease currently appears to be relatively rare in acquired immunodeficiency associated with HIV infection which is attributable to the advent of effective antiretroviral therapies, but the mortality rate of adenoviral infection can be as high as 55% in SCID [59-61]. In solid organ transplant recipients, adenoviral infections can range from asymptomatic to severe with increased morbidity, graft loss and mortality [63]. Adenoviral infections can be acquired de novo or with reactivation of latent virus from the recipient or the transplanted organ [64]. The symptoms of infection are variable but severe and even fatal courses have also been described [65]. However, invasive adenoviral infection usually does not correlate with organ rejection [64]. Adenoviral diseases are well characterized in hematopoietic stem cell transplant recipients. A wide range of clinical syndromes including pneumonia, colitis, hepatitis, hemorrhagic cystitis, tubulointerstitial nephritis, encephalitis, and disseminated disease have been frequently described. According to studies, allogenic stem cell transplantation seems to be a major risk factor for adenoviral infection while infections in patients with autologous stem cell transplantation is rare [66]. Workup: In the past, adenovirus infections were difficult to diagnose and some infections were inappropriately treated with antibacterial agents. Direct fluorescent assay (DFA), as part of a viral respiratory panel, revolutionized prompt diagnosis of adenoviral infection [67]. After development of DFA, viral cultures were less often utilized in clinical decision making [68]. The sample collection process is largely noninvasive as a number of different samples including peripheral blood, stool, urine, bronchoalveolar fluid, nasopharyngeal aspirates or swabs can be readily used [52, 54, 59]. Low sensitivity was one of the major issues with DFA and viral cultures remained notoriously time consuming to impact clinical judgment and management. Thus, these methods are less commonly utilized in routine clinical screening in favor of PCR-based techniques, which are rapid and more reliable [69-71].

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