Immunocompromised Subjects Research Articles

2479. Varicella Zoster Immune Globulin Is Effective up to 10 Days Following Varicella Exposure in Pregnant Women, Immunocompromised Patients, and Infants: Results From a Large, Open-Label Expanded-Access Program

BackgroundThere are more than 300,000 cases of varicella annually; nonimmune individuals exposed to varicella-zoster (VZ) virus have a high likelihood of developing varicella. VZ immune globulin (VARIZIG®) is used for postexposure prophylaxis to prevent or attenuate VZ infection in high-risk individuals. We assessed varicella incidence and severity in high-risk subjects after administration of VZ immune globulin.MethodsThis open-label expanded-access program provided VZ immune globulin to physician-identified, high-risk subjects exposed to varicella. Subjects included immunocompromised children/adults, infants (including preterm infants, newborns whose mothers had VZ infection <5 days before or <2 days after delivery, and infants <1 year of age), and pregnant women. VZ immune globulin (125 IU/10 kg [up to 625 IU]) was administered intramuscularly, ideally ≤96 hours, but up to 10 days, postexposure. Incidence of varicella rash and severity (>100 pox, pneumonia, encephalitis) were assessed up to 42 days after administration.ResultsThe efficacy population (n = 505) included 263 immunocompromised subjects (32 adults, 231 pediatric), 137 pregnant women, and 105 infants. More than 97% of exposures fit the CDC definition. Varicella incidence was low in immunocompromised subjects (4.5%, n = 12/269), pregnant women (7.3%, n = 10/137), and infants (11.4%, n = 12/105) and was similar when comparing administration ≤ 96 hours vs. up to 10 days postexposure (6.2% vs. 9.4%, respectively). Of 34 subjects with varicella, 54% were exposed in the household; 5 were considered severe. Common adverse events were pyrexia (4%), neutropenia (3%), and headache (3%). There were no product-related deaths and only 1 serious adverse event (serum sickness) considered probably related to VZ immune globulin.ConclusionPostexposure administration of VZ immune globulin resulted in low rates of varicella in high-risk subjects, regardless of administration timing within 10 days postexposure. VZ immune globulin—which is FDA-approved, recommended by the CDC, and widely available—was well tolerated and safe in high-risk subjects.Disclosures M. Levin, Merck: Consultant and Scientific Advisor, Consulting fee and Research support. GlaxoSmithKline: Consultant and Scientific Advisor, Consulting fee and Research support. Saol Therapeutics: Consultant and Scientific Advisor, Consulting fee. J. Duchon, Saol Therapeutics: Consultant and Scientific Advisor, Consulting fee. G. K. Swamy, Saol Therapeutics: Consultant and Scientific Advisor, Consulting fee.

In vitro toxicity and efficacy of verdinexor, an exportin 1 inhibitor, on opportunistic viruses affecting immunocompromised individuals.

Infection of immunocompromised individuals with normally benign opportunistic viruses is a major health burden globally. Infections with viruses such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi’s sarcoma virus (KSHV), adenoviruses (AdV), BK virus (BKPyV), John Cunningham virus (JCPyV), and human papillomavirus (HPV) are significant concerns for the immunocompromised, including when these viruses exist as a co-infection with human immunodeficiency virus (HIV). These viral infections are more complicated in patients with a weakened immune system, and often manifest as malignancies resulting in significant morbidity and mortality. Vaccination is not an attractive option for these immune compromised individuals due to defects in their adaptive immune response. Verdinexor is part of a novel class of small molecules known as SINE (Selective Inhibitor of Nuclear Export) compounds. These small molecules demonstrate specificity for the nuclear export protein XPO1, to which they bind and block function, resulting in sequestration of XPO1-dependent proteins in the nucleus of the cell. In antiviral screening, verdinexor demonstrated varying levels of efficacy against all of the aforementioned viruses including previously with HIV. Studies by other labs have discussed likely mechanisms of action for verdinexor (ie. XPO1-dependence) against each virus. GLP toxicology studies suggest that anti-viral activity can be achieved at a tolerable dose range, based on the safety profile of a previous phase 1 clinical trial of verdinexor in healthy human volunteers. Taken together, these results indicate verdinexor has the potential to be a broad spectrum antiviral for immunocompromised subjects for which vaccination is a poor option.

Current epidemiological situation on Particularly Dangerous Mycoses around the World and Forecast of Its Development

The literature review focuses on epidemiological aspects of the spread of particularly dangerous mycoses across the world (coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis). Forecast of morbidity rates for the next few years is provided too. Out of all endemic mycoses, coccidioidomycosis, endemic for North America regions, poses the most dangerous threat. In case of the infection, complications are most likely to arise, including the dissemination of the process in immunocompromised persons. Histoplasmosis is also classed as particularly dangerous mycosis. It affects both humans and animals. It is endemic for North, Central and South America, as well as Asia and Australia. The most studied endemic areas of infection with blastomycosis are in the territory of North America, while paracoccidioidomycosis is endemic for Latin America countries. Analysis of academic publications on particularly dangerous mycoses over the last three years testifies to the increase in their morbidity rates around the world. This situation is associated, primarily, with the increment in the number of immunocompromised subjects. An important stage in the improvement of the agent diagnostics is introduction of advanced methods for early diagnostics of mycoses, in particular, molecular-genetic and genome sequencing tools. It could also allow for the detection of patients beyond the limits of endemic foci.

Genotyping of Toxoplasma gondii: The advantages of variable number tandem repeats within coding regions

Toxoplasma gondii is an intracellular protozoan which is widely distributed. Infection occurs as a result of ingestion of uncooked meat and exposure to cat feces. Immunocompetent individuals are generally asymptomatic, while severe disease may occur in immunocompromised subjects and in congenital toxoplasmosis, which is caused by transplacental acquisition of T. gondii.Genetic diversity of T. gondii has often been studied using a PCR-RFLP scheme based on nine molecular markers. These studies led to the description of a clonal population structure with three main lineages (I, II and III) in North America and Europe and higher genetic diversity in South America.The aim of this study was to develop molecular markers that could allow the discrimination of genetic variants within each clonal lineage.We analyzed the genome of T. gondii to identify genes containing variable number tandem repeats (VNTRs). The coding sequences of T. gondii ME49 genome were processed with Tandem Repeat Finder software. A panel of candidate markers was selected based on the following parameters: the repeat unit size (>9 bp) and composition (to avoid single and dinucleotide runs), the number of copies (<20), and the absence of introns within the repeat region.The selected panel of eight molecular markers was analyzed in PRU and RH strains. As a first step, the variability of the sequence size allowed us to differentiate PRU from ME49 (two type II strains) and RH from GT1 (two type I strains). Additionally, amplification products from PRU and RH strains were sequenced to study intra-lineage variability. Aside from size polymorphisms in the amplification products we were able to identify sequence variability in polymorphic markers.

Prevalence of hepatitis E in liver transplant recipients in Greece.

Hepatitis E virus (HEV) is a well-known cause of acute hepatitis. Immunocompromised subjects, including liver transplant recipients, are considered to be at risk for HEV infection, which occasionally follows a chronic course. The diagnosis of HEV infection in these patients must be based on HEV RNA testing, as serology has variable performance. The aim of this study was to assess the prevalence of HEV infection in liver transplant recipients in Greece by means of HEV RNA testing. Liver transplant recipients followed in the sole transplant centre in Greece were prospectively included. HEV RNA was detected by real-time RT-PCR. Positive samples were further analysed using a nested reverse transcription RT-PCR kit, which amplifies a 137-nucleotide sequence within the ORF2/ORF3 overlapping region to detect the HEV genotype and perform phylogenetic analysis. The mean age of the included patients (n = 76) was 54 years. The most common indication for liver transplantation was viral hepatitis (57%). The majority of the patients (75%) received a calcineurin inhibitor as part of their immunosuppressive regimen and had normal liver enzymes. HEV RNA was found positive in only 1/76 (1.3%) patient. Phylogenetic analysis showed that the sequence clustered into the HEV genotype 3 clade. This patient experienced an acute hepatitis flare, which nonetheless did not become chronic. The prevalence of HEV infection in liver transplant recipients in Greece is similar (1.3%) to that reported previously in other countries. Transplant physicians should be aware of this condition and its associated consequences.

Rapidly Growing Mycobacterial Infections of the Skin and Soft Tissues Caused by M. fortuitum and M. chelonae

Non-tuberculous mycobacteria (NTM) have emerged as pathogens of clinical importance in human health as etiological agents of opportunist infections. Although NTM are known to cause systemic infections in immunocompromised subjects primarily in HIV patients, yet the growing number of immunosuppressed patients with new therapies and even more recently in non-immunocompromised subjects often localized infections of the lungs or skin and soft tissues (SS resistance to first-line anti-tuberculous drugs is common so therapy should be based on in vitro susceptibility testing. More clinical studies due to a lack of standard guidelines for the treatment of RGM infections are needed.

Micosis sistémicas en pacientes inmunocomprometidos

Despite the availability of new antifungal drugs and more specific and sensitive diagnostic techniques, in recent decades fungal infections have become one of the main causes of morbidity in immunocompromised subjects and continue to cause high mortality rates and social and care costs. The main factor in the acquisition of infections of this type is the increased number of immunocompromised patients. The high mortality of these infections probably relates to their few clinical manifestations until the process is very advanced, and the diagnostic difficulty that results in a delay in starting appropriate antifungal treatment. Very strict clinical and microbiological monitoring is essential to manage these patients successfully, taking an early and aggressive diagnostic and therapeutic approach. If possible, immunological improvement should be achieved either by reducing the immunosuppressant drugs or by pharmacologically stimulating the patient's immunity.

CD4 T-Lymphocytes Count in HIV-&amp;lt;i&amp;gt;Toxoplasma gondii&amp;lt;/i&amp;gt; Co-Infected Pregnant Women Undergoing a Prevention of Mother-to-Child Transmission Program

Toxoplasma gondii (T. gondii) is a parasite responsible of toxoplasmosis, a disease often asymptomatic but with serious consequences in pregnant women and immunocompromised subjects. Objective: This study aimed to investigate the impact of T. gondii infection on CD4+ T lymphocytes count in HIV-infected pregnant women. Methods: This was a cross-sectional study of pregnant women co-infected by HIV and T. gondii. The study was conducted from January to July 2016 at the Prevention of Mother-to-Child Transmission of HIV (PMTCT) sites in the Health District of Lacs in Togo. Diagnosis of HIV was performed by immuno-chromatographic methods with Determine TM HIV-1/2 and immuno-filtration with Tri-Dot HIV-1 and 2 kits. Presence of anti-toxoplasmic IgG and IgM antibodies was established via enzyme immunoassay using ELISA-BIOREX® kit. Flow cytometry was used to count CD4+ T lymphocytes. Results: Our study found that of the 4599 pregnant women, 111 (2.41%) were HIV-positive. Among them, 109 (98.20%) were infected by HIV-1 and 2 (1.98%) by HIV-2. Antibodies against T. gondii were detected in 5.36% (IgM), 25% (IgG) and 3.57% (both IgM and IgG) of HIV 56 infected women. There was no significant difference between CD4 cell count in HIV (+)/T. gondii IgM (-)/IgG (-) infected pregnant women (378.8 ± 222.8 cell//μl) compared to HIV (+)/T. gondii/IgM (+) (457.3 ± 183.3 cell//μl), HIV (+)/T. gondii IgG (+) (419.4 ± 287.3 cell//μl) and HIV (+)/T. gondii IgM/IgG (+) (480.5 ± 252.4 cell/μl). Conclusion: This study showed that intracellular parasite T. gondii did not alter CD4+ T lymphocytes count in HIV/T. gondii co-infected pregnant women.

An unusual case of Rhodotorula mucilaginosa fungaemia in a cancer patient

&lt;em&gt;Rhodotorula&lt;/em&gt; is emerging as a relevant cause of nosocomial and opportunistic infections. Herein, we present a case of fungaemia due to &lt;em&gt;Rhodotorula&lt;/em&gt; &lt;em&gt;mucilaginosa&lt;/em&gt; in a cancer patient with lumbosacral stimulator for herniated disc with unfavourable outcome. The patient was hospitalized for twenty days during which he underwent various diagnostic tests before discovering the presence of colon cancer. At day 16 of hospitalization, a bloodstream infection due to &lt;em&gt;R. mucilaginosa&lt;/em&gt; with an antimycogram profile resistant to fluconazole occurred. It is emphasized the need for the rapid and correct identification of &lt;em&gt;R. mucilaginosa&lt;/em&gt; in order to set up as fast as possible a pathogen driven therapy, in particular in the immunocompromised subjects.

A Mutation in the Progesterone Receptor Is Associated to Hepatitis E Seroprevalence in Liver Transplant Recipients and Correlates With Altered Immune Markers in Serum: 2017 Presidential Poster Award

Introduction: Infection with the hepatitis E virus (HEV) can cause acute hepatitis in immunocompetent hosts as well as liver failure in pregnant women. Recent reports indicate that HEV can lead to chronic infection or acute reactivation in immunocompromised subjects, particularly transplant recipients. A recent study showed that a mutation in the progesterone receptor named PROGINS could confer a higher risk of fulminant hepatic failure by HEV in pregnant women. This mutation is thought to affect the host's immune response to HEV. We have recently shown that the PROGINS mutation is expressed with a higher frequency in individuals with the human immunodeficiency virus who are seropositive for HEV. In this study we studied the frequency of the PROGINS mutations in liver transplant recipients seropositive for HEV. Methods: We evaluated the presence of PROGINS in liver transplant recipients and its relation to HEV infection. Serum samples from 69 individuals who received a liver transplantation were analyzed for the presence of PROGINS through KASP assay. A group of 187 healthy samples were used as controls. Of the 69 transplant recipients, 46 were HEV IgG negative and 23 HEV IgG positive. In a subset of samples, multiplex cytokine assays were performed to compare levels among liver transplant recipients with and without the PROGINS mutation. Results: We found the frequency of PROGINS in transplant recipients HEV-positive to be 35%, compared to 15% in those that were HEV-negative (RR 2.2, CI 0.9-5.5). The frequency of the mutation in the HEV-negative group was similar to that in healthy controls (14%). When we compared serum levels of multiple immune markers among a subgroup of liver transplant recipients with HEV and the presence of PROGINS (N: 7 each group), we found reduced levels of MIG, APRIL and SCF, as well as increased levels of Eotaxin 3 and IL-31, when compared to liver transplant recipients negative for HEV with wild type progesterone receptor. Conclusion: Our results from a small cohort of liver transplant recipients show a strong trend towards an increased frequency of the PROGINS mutations among those that are seropositive for HEV. These patients expressed altered serum levels of multiple immune markers when compared to those without PROGINS. A study with a larger validation cohort is on the way to confirm this finding and examine its implications.

Oxazolidinone Therapy for Recalcitrant Pulmonary Nontuberculous Mycobacterial Infection

SESSION TITLE: Chest Infections SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Non-tuberculous mycobacteria (NTM) are emerging pathogens that affect immunocompromised and immunocompetent subjects. The incidence and prevalence of NTM lung disease is increasing and treatment options are lengthy and fraught with toxicities and poor outcome. The decision to start treatment requires individualized assessment and analysis of antimicrobial resistance patterns. Use of linezolid in NTM patients was recently reported for the first time in a multicenter non-randomized study (Winthrop et al, ERJ, 2015). Here we report the use of linezolid and tidezolid in eleven subjects with recalcitrant pulmonary NTM infection. METHODS: The study was a retrospective analysis of the outcome of oxazolidinone therapy in subjects with a diagnosis of NTM. We identified eleven patients during a 3 year study period. Radiology, microbiology, prior NTM therapy, macrolide sensitivity, oxazolidinone regimen and drug toxicities were noted for all subjects. RESULTS: The majority of patients were female (90%) and caucasian. The median age was 65 years (range 26-77). Common comorbidities were asthma, COPD, bronchiectasis, GERD and depression. Six of the eleven subjects had cavitary disease and the remaining had significant bronchiectasis with a nodular or cystic component on radiology. Ten subjects (90%) grew Mycobacterium avium intracellulare. Other subjects grew M abscessus (55%), and M kansasii. Macrolide resistance (erm gene) was confirmed in 6 subjects (55%). Prior to the institution of oxazolidinone therapy, all subjects had been on complex antimicrobial regimens which included amikacin, augmentin, clofazimine, cefoxitin, ethambutol, macrolides, meropenem, moxifloxacin, rifampin and tigecycline. Ten subjects (90%) were treated with oral linezolid. Five patients (45%) had to be transitioned from linezolid to tidezolid due to adverse effects. The most commonly used regimen for linezolid was 600mg once daily (72.7%). This dose was decreased to 300 mg once daily in one patient due to nausea. The most commonly used regimen for tidezolid was 200mg once daily (83%). Average duration of therapy was 10.2 months for linezolid and 6 months for tidezolid. Patients were routinely monitored for symptoms, blood counts and peripheral neuropathy. The most common side effects observed were peripheral neuropathy (three patients), nausea (three patients), thrombocytopenia (one patient) and anemia (one patient). In one case, linezolid was stopped due to drug interaction with an antidepressant. Therapy was discontinued in one patient due to cost considerations. Three patients continue on oxazolidinone therapy without any complications. Vitamin B6 was prescribed for every patient to prevent hematological complications and peripheral neuropathy. CONCLUSIONS: In summary, we have demonstrated that both linezolid and tidezolid can be used for longer durations in the treatment of recalcitrant NTM disease. Adverse events requiring cessation of therapy are common but some of these could be due to other therapies or coexistent comorbidities. Larger studies are required to ascertain efficacy and tolerability. CLINICAL IMPLICATIONS: Oxazolinidone antimicrobials could be considered in the treatment regimen of patients with difficult NTM infection. DISCLOSURE: The following authors have nothing to disclose: Kelsey Luoma, Shivani Singh, Doreen Addrizzo-Harris No Product/Research Disclosure Information

Clinical Yield of Routine Use of Molecular Testing for Adult Outpatients with Diarrhea

BackgroundMolecular diagnostics for enteropathogens increase yield while reducing turnaround time. However, many pathogens do not require specific therapy, and the cost is substantial.MethodsWe reviewed the use of the FilmArray GI Panel (BioFire Diagnostics, Salt Lake City, Utah) in adult outpatients at the University of Virginia and identified clinical features that could limit testing without reducing yield. We defined yield as (a) detection of a pathogen, (b) detection of a pathogen for which antimicrobial therapy is indicated, or (c) detection of a pathogen that can change management, which additionally included viral pathogens in immunocompromised patients.ResultsBetween March 23, 2015 and February 25, 2016, we reviewed 452 tests from adult outpatients with diarrhea. A pathogen was detected in 88/452 (19.5%). The most common pathogens were: enteropathogenic E. coli (36; 8.0%), norovirus (17; 3.8%), Campylobacter (7, 1.5%), enteroaggregative E. coli (6, 1.3%), Giardia (6; 1.3%), and sapovirus (5; 1.1%). Based on clinical guidelines, antimicrobial treatment was clearly indicated for 19/452 subjects (4.2%). Limiting testing to patients with an additional enteric symptom (abdominal pain, nausea, vomiting, fecal urgency, tenesmus, or flatulence), a travel history, or an immunocompromising condition would reduce testing by 25.9%, with a treatable pathogen identified in 18/331 (5.4%) (sensitivity 94.7%, specificity 27.7%). Further modifying testing criteria to exclude subjects with vomiting, 18/288 (6.3%) had a treatable pathogen (sensitivity 94.7%, specificity 37.3%), and a pathogen which could change management was detected in 28/288 (9.7%) (sensitivity 96.6%, specificity 38.5%). Excluding immunocompromised subjects or those with a travel history, American College of Gastroenterology guidelines for testing were met by 293/348 (84.2%) with a documented duration of diarrhea, and a treatable pathogen was detected in 8/293 (2.7%) vs. 3/55 (5.5%) who did not meet testing guidelines.ConclusionTesting could be reduced by 36.3% without decreasing clinical yield by limiting testing to patients with diarrhea with an additional enteric symptom and no history of vomiting, a travel history, or an immunocompromising condition. ACG guidelines did not improve testing efficiency.Disclosures All authors: No reported disclosures.

Clinicopathologic features and survival in immunocompromised vs. immunocompetent patients with Merkel cell carcinoma: An exploratory analysis of a series of consecutive patients.

9568 Background: Clinicopathologic characteristics and outcomes between immunocompromised and immunocompetent Merkel cell carcinoma (MCC) patients may differ. Methods: With approval of IRB, we conducted retrospective analysis in 40 consecutive patients with MCC treated at our institution in 2006-2016. 10 patients were immunocompromised and 30 immunocompetent. Immunosuppressed patients included patients with organ transplantation (n = 3), chronic lympocytic leukemia (n = 2), metastatic skin cancer post chemotherapy (n = 1), rheumatoid arthritis on azathioprine (n = 1), myasthenia gravis on mycophenolate mofetil (n = 1), follicular lymphoma post chemotherapy (n = 1) and human immunodeficiency virus infection (n = 1). Clinicopathologic features, therapy and survival were compared between two cohorts. Significance of associations was assessed via Fishers' exact test. Survival analysis was performed via Cox proportional model and 95% confidence intervals (CI). Results: Compared to immunocompetent MCC patients, the immunocompromised had an absolute male predominance (100% vs. 67%; p &lt; 0.01), more TNM stage III disease (40% vs. 33%; p = 0.021) but less lymphovascular invasion (30% vs. 7%; p &lt; 0.01). They received more chemotherapy (50% vs. 30%; p &lt; 0.01) and radiation therapy (80% vs 57%; p &lt; 0.01). Survival was worse in immunocompromised subjects (average time to death 290.13 days vs. 618.2 days (p &lt; 0.001), and they were 5 times more likely to die (RR = 5.01, 95% CI = 1.49-16.86). Conclusions: Immunocompromised MCC patients displayed significantly shorter survival than their immunocompetent counterparts. They were all male, with more advanced disease but less lymphovascular invasion. They received more chemo- and radiotherapy presumably due to a more advanced stage. As our study is limited by sample size, larger studies are needed to confirm the significance of our findings.

Cardiothoracic Transplant Recipient Mycoplasma hominis: An Uncommon Infection with Probable Donor Transmission

The role of infection with Mycoplasma hominis following cardiothoracic organ transplantation and its source of transmission have not been well-defined. Here, we identify and describe infection with M. hominis in patients following cardiothoracic organ transplantation after reviewing all cardiothoracic transplantations performed at our center between 1998 and July 2015. We found seven previously unreported cases of M. hominis culture positive infection all of whom presented with pleuritis, surgical site infection, and/or mediastinitis. PCR was used to establish the diagnosis in four cases. In two instances, paired single lung transplant recipients manifested infection, and in one of these pairs, isolates were indistinguishable by multilocus sequence typing (MLST). To investigate the prevalence of M. hominis in the lower respiratory tract, we tested 178 bronchoalveolar lavage (BAL) fluids collected from immunocompromised subjects for M. hominis by PCR; all were negative. Review of the literature revealed an additional 15 cases of M. hominis in lung transplant recipients, most with similar clinical presentations to our cases. We recommend that M. hominis should be considered in post-cardiothoracic transplant infections presenting with pleuritis, surgical site infection, or mediastinitis. M. hominis PCR may facilitate early diagnosis and prompt therapy. Evaluation for possible donor transmission should be considered.

Disseminated nocardiosis in an immunocompetent adult with retinal abscess and endocardial mass

Nocardiosis is an opportunistic infection reported among immunocompromised subjects. Endophthalmitis secondary to hematogenous spread is a well-known sequel in such cases. In healthy individuals, ocular manifestations are limited to surface infections like keratitis. We report a case of endogenous endophthalmitis due to dissemination from cutaneous nocardiosis in a healthy adult who also had evidence of the right atrial nocardial mass.

Effect of donor STAT4 polymorphism rs7574865 on clinical outcomes of pediatric acute leukemia patients after hematopoietic stem cell transplant

STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post-hematopoietic stem cell transplantation (post-HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post-HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno-occlusive disease, acute graft-vs-host disease, chronic graft-vs-host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P=0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P=0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post-transplant outcomes.

Necrotizing Otitis Externa: A Disease Barely Known to Neurosurgeons

AbstractNecrotizing otitis externa (NOE), also known as malignant otitis externa (MOE), is a severe and rare infectious disease of the external auditory canal (EAC). Without treatment, it may progress to skull base involvement. The bacteria Pseudomonas aeruginosa is the most common causative agent (∼ 90% of the cases), and affects immunocompromised subjects, particularly diabetic patients. Severe chronic otalgia, otorrhea, and cranial nerve palsy are the most common clinical presentations. Patients with NOE are frequently referred to neurosurgery because of the neurological impairment and skull base compromise. The definitive diagnosis is frequently elusive, requiring a high index of suspicion. Several laboratorial tests, imaging modalities, and the histologic exclusion of malignancy may be required. An early diagnosis and aggressive treatment reduce morbidity and mortality. We present four NOE cases to illustrate the spectrum of clinical presentation and complementary exams. According to the literature, more effort for early diagnosis and treatment is required, and neurosurgeons play an important role in this task.

Brincidofovir Is Not a Substrate for the Human Organic Anion Transporter 1: A Mechanistic Explanation for the Lack of Nephrotoxicity Observed in Clinical Studies.

Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir (CDV) with increased in vitro potency relative to CDV against all 5 families of double-stranded DNA viruses that cause human disease. After intravenous (IV) administration of CDV, the organic anion transporter 1 (OAT1) transports CDV from the blood into the renal proximal tubule epithelial cells with resulting dose-limiting nephrotoxicity. To study whether OAT1 transports BCV and to evaluate the pharmacokinetic and renal safety profile of oral BCV compared with IV CDV. The cellular uptake of BCV and its major metabolites was assessed in vitro. Renal function at baseline and during and after treatment in subjects in BCV clinical studies was examined. In OAT1-expressing cells, uptake of BCV and its 2 major metabolites (CMX103 and CMX064) was the same as in mock-transfected control cells and was not inhibited by the OAT inhibitor probenecid. In human pharmacokinetic studies, BCV administration at therapeutic doses resulted in detection of CDV as a circulating metabolite; peak CDV plasma concentrations after oral BCV administration in humans were <1% of those observed after IV CDV administration at therapeutic doses. Analysis of renal function and adverse events from 3 BCV clinical studies in immunocompromised adult and pediatric subjects indicated little to no evidence of associated nephrotoxicity. Over 80% of subjects who switched from CDV or foscarnet to BCV experienced an improvement in renal function as measured by maximum on-treatment estimated glomerular filtration rate. The lack of BCV uptake through OAT1, together with lower CDV concentrations after oral BCV compared with IV CDV administration, likely explains the superior renal safety profile observed in immunocompromised subjects receiving BCV compared with CDV.

Occasional Observation of Acanthamoeba in the Pharynx. A Case Report

Acanthamoeba is an opportunistic protozoan free-living widely distributed in nature and is a potential pathogen for Man. It is responsible for pathologies inherent in the CNS, the cornea , the skin, especially in immunocompromised subjects. An adult subject of 70 years old, suffering from acute pharyngitis, was subjected to a cytological sampling of the pharyngeal mucosa by means of the modified Ayre spatula type A from Armone Caruso, to perform either a coloring method according to the May-Grunwald - Giemsa, and observed under the microscope optical with oil immersion at 100 x of fifty fields, that a preparation for observation under the SEM.( Scanning Electron Microscope,). In both observations it was highlighted in the form of trophozoite some rare Acanthamoeba. The subject was observed without that have appeared due to protozoan diseases: in practice it was a casual observation. The clinical case, described occasionally, it shows how the distribution in the environment of these amoebae is very extensive and mainly related to water and become of interest about the health, for the human use of the latter for purposes such as hygiene care, bathing, medical and health applications. The objective of this paper is to provide a starting point to discuss the potential pathogenicity associated with the presence of Acanthamoeba in the water ecosystems. This is for raise the awareness the scientific community and promote environmental control initiatives of this pathogen in both outdoor and indoor environments.

Trying to Understand NK Cell Function in vivo Points towards a Severity Score for CVID Patients

Natural Killer (NK) cells were described 40 years ago as lymphoid cells exerting cytolytic activity against tumor cell lines in vitro (Herberman et al., 1975) and are accounted to the group of innate lymphoid cells. Functionally, they have been associated with anti-viral immunity (esp. herpesviridae) and tumor surveillance. However, NK cells have been less in the research focus compared to other components of the immune system (citations in Pubmed in 2015: ~ 2600 for NK cells compared to ~ 7100, ~ 14,600 and ~ 12,100 for B, T cells and macrophages, respectively). An isolated reduction of NK cells in humans has been suggested to be asymptomatic. Whether this notion somewhat reflects the inattentiveness towards NK cells or if NK cells in humans have only redundant functions in the immune system is still a matter of debate. Eric Vivier and colleagues hypothesized that the function of NK cells in humans might be revealed in immunocompromised subjects and report on a large cohort of patients with common variable immunodeficiency (CVID) registered in the French Registry (DEFI) (Ebbo et al., 2016). They stratified 457 CVID patients according to their NK cell numbers at study inclusion: roughly half of the patients had normal NK cell counts (> 100/μl), one quarter of the patients had slightly reduced NK cell counts (50–99/μl) and almost one quarter had severely reduced NK cell numbers (< 50/μl). CVID patients with severe NK cell lymphopenia exhibited a statistically significant increased rate of invasive bacterial infections defined as septicemia, pneumonia or meningitis: the frequency of invasive infections was 68.7% in severe NK lymphopenia, 60.2% in mild NK lymphopenia and 48.8% in patients with normal NK cell counts. However, there was no correlation of NK cell number and viral infections or malignancies. These results rely on prospectively collected registry data that might be skewed by reporting bias and correlations do not necessarily prove causality. Nonetheless, this observation fits well into the increasingly recognized role of NK cells in adaptive immunity. Apart from insights into NK cell biology the paper by Ebbo et al. reveals interesting aspects of NK cells in CVID. On a clinical basis CVID patients can be separated into patients who suffer from infectious complications as only complaint (“infection-only group”) and those who additionally suffer from non-infectious complications/immune dysregulation with e.g. lymphoproliferation, lung disease, enteropathy and malignancies. Whilst the infection-only group has a close to normal life expectancy when treated with immunoglobulin replacement, patients with immune dysregulation have an elevated mortality (Resnick et al., 2012). It is therefore of crucial interest to identify these patients early in the course of the disease and multiple groups have attempted to identify biomarkers in CVID by different approaches targeting B and/or T cells in the majority of cases (Piqueras et al., 2003, Giovannetti et al., 2007, Moratto et al., 2006, Driessen et al., 2011, Kamae et al., 2013, Wehr et al., 2008, Chapel et al., 2012). Ebbo and co-workers now add NK cells as a potential biomarker to the list as they showed that CVID patients with non-infectious complications are overrepresented amongst the patients with severe NK lymphopenia. This was significant for patients with granulomatous complications (NK cells severely reduced vs mildly reduced vs normal: 25.3% vs 13.6% vs 8.8%, p < 0.001) but there was also a trend towards higher frequencies of lymphoid hyperplasia (35.4% vs 24.6% and 19.2%), enteropathies (41.4% vs 28% vs 24.2%) and autoimmune cytopenia (25.3% vs 12.7% vs 14.6%). The authors also report that severely reduced NK cell counts in CVID are associated with lymphopenia i.e. CD4 + lymphopenia (median 415/μl vs 568 and 691/μl, p = 0.003), reduction of naive CD4 + cells (median 63/μl vs 135 and 183/μl, p = 0.003), CD8 lymphopenia (310/μl vs 431/μl vs 479/μl, p = 0.003) and B lymphopenia (median: 59/μl vs 99/μl and 122/μl, p = 0.003). CVID patients with severe NK lymphopenia also had lower levels of IgG, A and M at initial diagnosis compared to the two other groups. Mortality was higher in CVID with low T cell numbers (T cells < 200/μl) but not in patients with isolated low NK lymphopenia. Whilst other groups have associated low naive CD4 cell counts and expansion of CD21low B cells with a more severe CVID phenotype, Ebbo et al. show a weak, positive correlation between NK cell counts and CD21low B cells (r = 0.13, p = 0.05). Considering the large CVID cohort investigated by Ebbo et al., NK cells will have to be considered in future attempts to stratify CVID patients. Ideally the topic will be approached by a multinational team to unify the multiple attempts and dissect predictive biomarkers in CVID helping to early identify patients at risk from severe manifestations.