Activating de novo monoallelic variants causing inborn errors of immunity in two unrelated children born of HIV-seroconcordant couples.

INTRODUCTION: Around 20% of all inborn errors of immunity (IEI) are autosomal dominant or monoallelic, either by haploinsufficiency, negative dominance, or gain of function (GOF). GOF phenotypes usually include autoinflammation, autoimmunity, lymphoproliferation, allergies, and some infections. CASE SERIES: We describe the cases of two unrelated patients born of HIV-seroconcordant parents. Both patients are HIV-negative but carry de novo GOF missense variants that resulted in inflammatory lymphoproliferative IEI diseases: signal transducer and activator of transcription 3 (STAT3)-GOF and phosphatidylinositol 3-kinase, catalytic delta (PIK3CD)-GOF. Both variants were found through whole-exome sequencing and confirmed by Sanger.An 11-year-old male with recurrent sinopulmonary infections, dysmorphism, growth delay, bronchiectasis, and mild mental retardation, as well as lymphopenia, thrombocytopenia, and high immunoglobulin M. Both his parents were known to be HIV-positive under anti-retroviral treatment. HIV infection was repeatedly ruled out in the patient, whom through whole-exome sequencing was found to have a heterozygous missense variant in exon 24 of PIK3CD, a hotspot transition, and the most reported variant in PIK3CD-GOF patients.A 6-year-old male with autoimmune hemolytic anemia, lymphoproliferation, short stature, and intractable diarrhea. Both his parents were found to be HIV-positive. HIV was repeatedly ruled out in the patient by ELISA and viral load. He was found to have a heterozygous missense/splice variant in exon 22 of STAT3, a hotspot transition, and the most reported variant in STAT3-GOF patients. DISCUSSION: The AID/APOBEC3 A-H family of proteins are cytidine deaminases that induce G>A hypermutation in both the invading viral DNA and the host genome, which results in stop codons inside the endogenized retroviral sequence. Both variants found in our patients are G to A transitions. Retroviral infection might thus have resulted in host genome instability, and our patients' rare congenital diseases are the unfortunate consequence of somatic hypermutation in one of their parents' gametes.

Analysis of Intrahospital Mortality in Patients With Lung Transplant Due to Diffuse Parenchymal Lung Disease.

BACKGROUND: Patients with diffuse parenchymal lung disease (DPLD) have the poorest survival rates both before and after lung transplantation (LT). Early mortality among LT patients as a result of DLPD is estimated at 10% to 20%. The aim of the study was to assess intrahospital mortality after LT procedures for DLPD and to identify factors in the recipient, donor, intra- and postoperative periods that might improve early outcomes. METHODS: A retrospective, observational, cohort, single-hospital study was conducted. Data from 67 patients with LT patients owing to DPLD were recorded between October 2008 to June 2017 in Madrid, Spain. RESULTS: Out of 67 LT recipients with DPLD, 51 had idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), 6 nonspecific interstitial pneumonia (NSIP), and 10 other DPLD. Intrahospital mortality took place in 13.4% of patients, with a median survival time of 34 days (interquartile range [IQR], 27.50-66). In the preoperative period, there were no differences in the recipients' demographic and hemodynamic characteristics, respiratory function, or time spent in the waiting list, except higher doses of systemic steroids in nonsurvivors (prednisone 15 vs 10 mg, P = .046). No differences were reported in the donors' characteristics (age, mechanical ventilation hours, PaO2/FiO2). In the intraoperative and postoperative periods, we found differences statistically significant in longer cold ischemia time and development of primary graft dysfunction (PGD) grade 3 in the nonsurvivor group. CONCLUSIONS: The mortality rate in our series was 13.4%, and the main risk factors for intrahospital mortality were longer cold ischemia time and greater incidence of PGD grade 3.

Diagnosis of metastasis in castration-resistant prostate cancer patients: decision algorithm in imaging tests. / Diagnóstico de metástasis en pacientes con cáncer de próstata resistente a la castración: algoritmo de decisión en pruebas de imagen.

INTRODUCTION: In castration-resistant prostate cancer (CRPC), early detection of metastases is essential for the selection of treatment, and prevention of bone complications. However detecting incipient metastases remains a challenge as the conventional radiological tests (bone scintigraphy or computerised tomography) lack sufficient sensitivity. Diagnostic imaging techniques are currently available that have greater sensitivity and specificity, but are little used due to shortfalls in the recommendations. OBJECTIVE: To create an algorithm that indicates the most suitable diagnostic imaging techniques for the different M0 CRPC patient profiles based on the scientific evidence. EVIDENCE ACQUISITION: Meetings were held with eight experts in Urology, Pathological Anatomy, Radiodiagnostics and Nuclear Medicine organised by the Andalusian Association of Urology, in which the recommendations and scientific evidence on each of the diagnostic imaging techniques were reviewed. SUMMARY OF THE EVIDENCE: We present the current recommendations for the detection of metastasis in M0 CRPC patients, the patients that would benefit from early detection, and summarise the evidence to support the use of each of the new techniques. CONCLUSIONS: Techniques such as 18F-Choline PET/CT or DWWB MRI and probably open MRI have been demonstrated to have good sensitivity and specificity for patients with low PSA (<10ng/ml). Their inclusion in routine clinical practice will help improve the early detection of metastasis in CRPC patients.

Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature.

DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.

Clinical and mutational features of X-linked agammaglobulinemia in Mexico.

X-linked agammaglobulinemia (XLA) is caused by BTK mutations, patients typically show <2% of peripheral B cells and reduced levels of all immunoglobulins; they suffer from recurrent infections of bacterial origin; however, viral infections, autoimmune-like diseases, and an increased risk of developing gastric cancer are also reported. In this work, we report the BTK mutations and clinical features of 12 patients diagnosed with XLA. Furthermore, a clinical revision is also presented for an additional cohort of previously reported patients with XLA. Four novel mutations were identified, one of these located in the previously reported mutation refractory SH3 domain. Clinical data support previous reports accounting for frequent respiratory, gastrointestinal tract infections and other symptoms such as the occurrence of reactive arthritis in 19.2% of the patients. An equal proportion of patients developed septic arthritis; missense mutations and mutations in SH1, SH2 and PH domains predominated in patients who developed arthritis.

Probiotics and autoimmunity: an evolutionary perspective.

Probiotics are microorganisms that have demonstrated beneficial effects on human health. Probiotics are usually isolated from the commensal microflora that inhabits the skin and mucosas. We propose that probiotics represent the species of microorganisms that have established a symbiotic relationship with humans for the longest time. Cultural practices of ancient human societies used to favor that symbiosis and the transmission of probiotics from generation to generation. New practices, introduced as a result of industrialization, such as childbirth by surgical delivery, ingestion of pasteurized and synthetic compounds-supplemented food, cleaner homes, indiscriminate use of antibiotics and so on, have led in recent years to the replacement of probiotics by other microorganisms that are not as well adapted to the microenvironments of the human body. These newly settled microorganisms lack many of the beneficial effects of probiotics. Our hypothesis is that the sudden change (from an evolutive perspective) in human intestinal microflora may importantly contribute to the rise in the incidence of autoimmune diseases, observed in the last half a century.

Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes.

BACKGROUND: Liver biopsy is an invasive technique with associated major complications. There is no information on the validity of five non-invasive indexes based on routinely available parameters, estimated and validated in hepatitis C virus (HCV) monoinfected patients, in human immunodeficiency virus (HIV)/HCV coinfected patients. AIM: To validate these predictive models of liver fibrosis in HIV/HCV coinfected patients. PATIENTS: A total of 357 (90%) of 398 patients from five hospitals were investigated, who underwent liver biopsy and who had complete data to validate all of the models considered. METHODS: The predictive accuracy of the indexes was tested by measuring areas under the receiver operating characteristic curves. Diagnostic accuracy was calculated by estimating sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values. RESULTS: The models performed better when liver biopsies>or=15 mm were used as reference. In this setting, the Forns and Wai indexes, models aimed at discriminating significant fibrosis, showed PPV of 94% and 87%, respectively. Using these models, 27-34% of patients could benefit from exclusion of liver biopsy. If both models were applied sequentially, 41% of liver biopsies could be spared. The indexes aimed at predicting cirrhosis achieved NPV of up to 100%. However, they showed very low PPV. CONCLUSIONS: The diagnostic accuracy of these models was lower in HIV/HCV coinfected patients than in the validation studies performed in HCV monoinfected patients. However, simple fibrosis tests may render liver biopsy unnecessary in deciding anti-HCV treatment in over one third of patients with HIV infection and chronic hepatitis C.

Usefulness of sputum culture for diagnosis of bacterial pneumonia in HIV-infected patients.

The use of sputum culture in immunocompetent patients with community-acquired pneumonia is controversial. The usefulness of this technique in HIV-infected patients has not been evaluated. A prospective, observational, multicenter, hospital-based study of bacterial community-acquired pneumonia was carried out to analyze the value of sputum culture in HIV-infected patients. Only good-quality sputum samples were cultured. Altogether, 355 cases of bacterial community-acquired pneumonia were included. An etiological diagnosis was obtained in 190 (53.5%) cases. Sputum was cultured in 313 (88.1%) cases, being diagnostic in 108 (34.5%). The microorganism identified in sputum culture was the same as that identified in sterile samples in 26 of 27 (96.3%) cases in which both cultures were diagnostic. The microbiologic findings in sputum and bronchoscopic cultures were concordant in seven of eight (87.5%) cases in which both were positive. These results suggest that sputum culture is a useful technique, given its availability and ease of performance and its good correlation with culture of sterile samples.

Prognostic evaluation of bacteremia and fungemia in patients with acquired immunodeficiency syndrome.

The incidence of bacterial infections in general and of bacteremia in particular is high among patients with acquired immunodeficiency syndrome (AIDS). The factors influencing the prognosis of bacteremia in these patients are not well known. In order to better define those factors associated with a poor prognosis, all episodes of bacteremia or fungemia in patients with AIDS who were hospitalized in four general hospitals between 1 September 1987 and 31 December 1996 were studied prospectively. Among 1,390 patients diagnosed with AIDS, 238 (17.1%) developed 274 episodes of bacteremia or fungemia. Mortality related to bacteremia was 21.3%. Variables associated with high mortality were fungemia (odds ratio [OR], 6.19; 95% confidence interval [CI], 1.99 - 19.28), hypotension (OR, 19.65; 95%CI, 7.42 - 52.07), inappropriate antimicrobial treatment (OR, 16.94; 95%CI, 4.92 - 58.32), and unknown origin of bacteremia (OR, 3.93; 95%CI, 1.58 - 9.76). The mortality rate among patients with at least one of these factors was 46.7%, whereas in patients without any of these factors, the rate was 4.9% ( P < 0.001). Bacteremic episodes of unknown origin were significantly more frequently associated with community acquisition ( P = 0.001), inappropriate antimicrobial treatment ( P = 0.04), and etiology by gram-negative microorganisms or fungi ( P < 0.001) and were significantly less frequently associated with the presence of a previous intravenous catheter ( P = 0.004), resulting in peculiar etiologic and epidemiological profiles. The factors that influence the outcome of AIDS patients who develop bacteremia are sometimes avoidable or known during the first days after admission. Therefore, knowledge about these factors could improve the prognosis of bloodstream infections in this population.

Community-acquired bacterial pneumonia in human immunodeficiency virus-infected patients: validation of severity criteria. The Grupo Andaluz para el Estudio de las Enfermedades Infecciosas.

Severity criteria for community-acquired pneumonia (CAP) have always excluded patients with human immunodeficiency virus (HIV) infection. A 1-yr, multicenter, prospective observational study of HIV-infected patients with bacterial CAP was done to validate the criteria used in the American Thoracic Society (ATS) guidelines for CAP, and to determine the prognosis-associated factors in the HIV-infected population with bacterial CAP. Overall, 355 cases were included, with an attributable mortality of 9.3%. Patients who met the ATS criteria had a longer hospital stay (p = 0.01), longer duration of fever (p < 0.001), and higher attributable mortality (13.1% versus 3.5%, p = 0.02) than those who did not. Three factors were independently related to mortality: CD4(+) cell count < 100/microl, radiologic progression of disease, and shock. Pleural effusion, cavities, and/or multilobar infiltrates at admission were independently associated with radiologic progression. A prognostic rule based on the five criteria of shock, CD4(+) cell count < 100/microl, pleural effusion, cavities, and multilobar infiltrates had a high negative predictive value for mortality (97.1%). The attributable mortality for severe pneumonia was 11.3%, as compared with 1.3% for nonsevere disease (p = 0.008). The ATS severity criteria are valid in HIV-infected patients with bacterial CAP. Our study provides the basis for identification of patients who may require hospitalization determined by clinical judgment and the five clinical criteria of shock, a CD4(+) cell count < 100/microl, pleural effusion, cavities, and multilobar involvement. These prognostic factors should be validated in independent cohort studies.

Haemophilus influenzae pneumonia in human immunodeficiency virus-infected patients. The Grupo Andaluz para el Estudio de las Enfermedades Infecciosas.

Although Haemophilus influenzae is a common etiologic agent of pneumonia in patients infected with human immunodeficiency virus (HIV), the characteristics of this pneumonia have not been adequately assessed. We have prospectively studied features of H. influenzae pneumonia in 26 consecutive HIV-infected inpatients. Most of these patients were severely immunosuppressed; 73.1% had a CD4+ cell count <100/microL. A subacute clinical presentation was observed in 27% of the patients and was associated with a higher degree of immunosuppression (P=.04). Bilateral lung infiltrates were noted radiographically in 57.7% of the cases. The mortality attributable to H. influenzae pneumonia was 11.5%. Thus, pneumonia caused by H. influenzae affects mainly patients with advanced HIV disease, and since its clinical and radiological features may be diverse, this etiology should be considered when pneumonia occurs in patients with advanced HIV infection. The mortality rate associated with H. influenzae pneumonia is not higher than that occurring in the general population.

Prospective evaluation of a two-week course of intravenous antibiotics in intravenous drug addicts with infective endocarditis. Grupo de Estudio de Enfermedades Infecciosas de la Provincia de Cádiz.

In a prospective study, a two-week course of antibiotics (cloxacillin 2 g/4 h plus amikacin 7.5 mg/kg/12 h) was evaluated in the therapy of right-sided infective endocarditis in intravenous drug users (IVDU). All IVDU admitted to hospital during the study period who fulfilled the strict criteria for diagnosis of infective endocarditis were analysed. A subgroup of patients with right-sided endocarditis caused by Staphylococcus aureus who had a good prognosis were selected as being eligible for the two-week course of treatment. In a total of 139 episodes of infective endocarditis in IVDU, 72 (51.8%) cases were eligible for the two-week treatment. Of this group, 67 were cured, 4 needed prolongation of treatment to cure the infection and 1 died in hospital of respiratory distress syndrome on day 10 of treatment. In patients not eligible for the two-week treatment, the mortality was higher (24.2% versus 0.7%; p = 0.00015). Drug toxicity in the treated group was low. It can be concluded that administration of cloxacillin and amikacin parenterally for 14 consecutive days was successful in the therapy of right-sided endocarditis in IVDU.

[Infective endocarditis in heroin addicts in the province of Cádiz. A multicenter study of 150 cases]. / Endocarditis infecciosa en heroinómanos en la provincia de Cádiz. Un estudio multicéntrico sobre 150 episodios.

BACKGROUND: Given the progressive increase in infectious endocarditis (IE) in intravenous drug addicts (IVDA) in the province of Cadiz the present study was designed with the aim of studying the epidemiologic and clinical characteristics of this disease in our environment. METHODS: One hundred fifty episodes of IE occurring in 133 IVDA admitted to 6 hospitals in the province of Cadiz were studied in an open, multicentric study with a protocol of gathering of common data. Well known diagnostic criteria were used for this process and a univariant technique was employed in the analysis of prognostic factors. RESULTS: Fifty-three percent of the episodes occurred in the county of Campo de Gibraltar and 32% in the area of the Bay of Cadiz. The increase of the disease has been progressive since 1984 and marked over the last two years. All the patients presented fever, abnormal chest radiography in 90% and the process was produced by Staphylococcus aureus in 88%. Echography was abnormal in 85% of the episodes and vegetation was identified in 75%. The IE was located as right in 90%, mixed in 5% and left in 5%. Surgical treatment was required in 4 patients. Mortality was of 9%. Mixed or left location (p = 0.00003) and the development of the respiratory distress syndrome of the adult (p = 0.00001) were significantly associated with greater mortality. CONCLUSIONS: Infectious endocarditis in intravenous drug addicts maintains a well defined pattern of clinical expressivity and presents identifiable factors of prognostic influence. The increase in its prevalence in the province of Cadiz is probably due to a parallel increase in the addiction to intravenous heroin in this area.

[Prevalence of hepatitis B virus in a sample of healthy children in Madrid]. / Prevalencia del virus de la hepatitis B en una muestra de la población infantil sana de Madrid.

In order to determine the prevalence of hepatitis B virus (HBV) markers, we studied 375 healthy children, 242 males and 113 females, with age ranged between 6 to 14 years, from different schools at the Tetuán district (Madrid). We sent a questionnaire to the parents to investigate the presence of risk factor in the children and/or their parents. All children were screened for hepatitis B markers in serum. Our results shown the existence of HBV markers in 22 (5.9%) children. No major incidence of risk factors was found in the children with serologic evidence of HBV infection.