Low Platelet Level May be a Predictor for Mortality in Adult Patients with Common Variable Immune Deficiency

Comparison of clinical and immunological features and mortality in common variable immunodeficiency and agammaglobulinemia patients

Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency in adults. This study assessed the utility of using the C-reactive protein (CRP)/albumin ratio (CAR) at diagnosis to predict mortality in CVID patients. Between 2010 and 2022, hospital records and follow-up cards of patients with CVID were reviewed retrospectively. Seventy-five patients were included in the study. CRP 0–5 mg/L and albumin 3.5–5.5 g/dL were taken as references. The CAR was obtained by dividing the CRP value by the albumin value. Of the included patients, 41 (55%) were male and 34 (35%) were female. The median age was 38 (21–77) years. The mortality rate of the patients during the follow-up time was 20%. Of the patients, 41% had splenomegaly, 10.6% had malignancy, and 39% had bronchiectasis. The cut-off value of CAR to predict mortality was >2.18 (sensitivity: 88.4%, specificity: 90.1%). When the patients were classified according to the CAR, the mortality rate in the patient group with a CAR > 2.18 was statistically significantly higher than the patient group with a CAR ≤ 2.18. The CAR is a cheap, simple, and easily calculated parameter that can predict mortality in CVID patients.

IntroductionInterstitial lung disease (ILD) is a prevalent complication in patients with common variable immunodeficiency (CVID) and is often related to other characteristics such as bronchiectasis and autoimmunity. Because the term ILD encompasses a variety of acute and chronic pulmonary conditions, diagnosis is usually based on imaging features. Histopathology is less available. This study was conducted with the aim of investigating the ILD in patients with CVID.Materials and methodsIn this retrospective cross-sectional study, sixty CVID patients who referred to the pulmonology and immunodeficiency clinics of Mofid Children’s Hospital between 2013 and 2022 were included. The diagnosis of ILD were based on transbronchial lung biopsy (TBB) or clinical and radiological symptoms. The prevalence of ILD in CVID patients was determined. Also, the CVID patients with and without ILD were compared in terms of demographic characteristics, clinical, laboratory and radiologic findings.ResultsAmong all patients, ten patients had ILD (16.6%). In terms of laboratory parameters, there was a significant difference between platelets in the two groups of CVID patients with and without ILD, and the level of platelets was higher in the group of patients with ILD. Moreover, in terms of clinical symptoms, pneumonia, diarrhea and hepatomegaly were significantly different between the two groups and were statistically higher in the group of patients with ILD (P < 0.05). Autoimmunity and malignancy were not significantly different in two groups. There was a significant difference in, hyperinflation between the two groups of CVID patients with and without ILD, and the frequency of, hyperinflation was higher in the patients without ILD (P = 0.040).ConclusionUnderstanding the pathogenesis of ILD plays an essential role in revealing non-infectious pulmonary complications that occur in CVID patients. Increasing efforts to understand ILD not only shed light on its hidden pathogenesis and clinical features, but also enhance our understanding of CVID in a broader sense.

The pandemic of COVID-19 raised many questions about the impact of comorbidities on susceptibility, severity, and outcome in these patients. Hypertension and diabetes are considered as the most prevalent comorbidities in COVID-19 patients.1, 2 It is not fully clarified whether hypertension and diabetes are independent predictors of severity and outcome in COVID-19 patients or they have synergistic negative effect in this population.3, 4 In the current issue, Sun et al5 reported that neither hypertension nor elevated blood pressure was an independent risk factor for mortality or acute respiratory distress syndrome (ARDS) and respiratory failure. Hypertension was associated only with increased risk of severe COVID-19 infection. On the other hand, diabetes alone or in combination with hypertension was independent predictor of mortality.5 The investigators divided all participants into 4 groups: (i) patients without hypertension and diabetes, (ii) patients with hypertension alone, (iii) patients with diabetes alone, and (iv) patients with concomitant diabetes and hypertension. Cardio- and cerebrovascular diseases were more prevalent in patients with hypertension and diabetes alone than in those without these conditions, and the highest prevalence was reported in patients with both conditions.5 Chronic kidney disease was more prevalent in patients with diabetes with or without hypertension, as well as in patients with diabetes and hypertension in comparison with hypertensive patients. Analyses restricted to hypertensive patients and those with neither hypertension nor diabetes showed no elevation of risk associated with hypertension, independent of whether other comorbidities were or were not included in the analysis. Even when patients were grouped according to blood pressure values and glucose levels, only glucose level, but not blood pressure, was risk factor for mortality in COVID-19 patients. Diabetes alone or in combination with hypertension increased the risk of ARDS and respiratory failure. Diabetes and elevated glucose level, but not arterial hypertension and elevated blood pressure, were independent predictors of ARDS and respiratory failure in COVID-19 patients.5 The multivariable analysis showed the diabetes alone or in combination with hypertension increased the risk of severe COVID-19 infection. Nevertheless, hypertension was also associated with a mild increase in risk of severe infection. Elevated fasting blood glucose, but not elevated blood pressure, was a risk factor for the development of severe COVID-19 infection independently of other comorbid conditions. Recent meta-analysis included 18 012 COVID-19 patients and revealed that diabetes mellitus and hypertension were moderately associated with severity and mortality for COVID-19, whereas the existence of cardiovascular disease was strongly related to both severity and mortality.6 However, the authors did not have possibility to investigate the influence of each of these comorbidities in the same model, which did not allow us to conclude whether hypertension and diabetes were independently associated with severity and outcome in COVID-19 patients.6 Systematic review that involved 15 794 COVID-19 participants showed that hypertension and diabetes were associated with admission in intensive care and mortality in unadjusted model.7 However, neither hypertension nor diabetes or their combination was not related to COVID-19 severity. Meta-analysis included 310 494 patients and analyzed the relationship between large number of variables and mortality.3 These parameters included demographics, signs, and symptoms and related morbidities, vital signs, laboratory findings, imaging studies, and underlying diseases. The authors reported that older age, hypertension, and diabetes significantly increased risk of mortality among patients with COVID-19. However, the multivariate analysis showed that only diabetes was independently associated with increased mortality.3 The main question that arises is whether hypertension and diabetes independently of sex, age, and other comorbidities are associated with severity and adverse outcome of COVID-19. In the current study, Sun et5 al tried to overcome this problem by separating patients with diabetes and hypertension from other cardiovascular and cerebrovascular diseases, chronic lung, liver, and kidney diseases, endocrine and immune system disorders, or cancer. In these circumstances, hypertension or elevated blood pressure was not recognized as an independent predictor of severity or mortality in COVID-19 patients. Recently published study that included large number of patients with type 1 and type 2 diabetes in England revealed that hypertension was not related to mortality in patients with type 1 diabetes.8 Interestingly, hypertension was weakly associated with lower COVID-19–related mortality in patients with type 2 diabetes.8 Furthermore, the use of antihypertensive drugs was related to increased mortality and the use of statins was associated with lower mortality in type 2 diabetes, whereas the relationship with type 1 diabetes was insignificant.8 The authors stated that drawing conclusions about the possible effects of antihypertensive drugs or statins on COVID-19–related mortality was not possible due to potential confounding factors. Nevertheless, these medications reduce cardiovascular and renal disease, which is why their use can help to decrease not only non-COVID-19–related mortality, but could contribute to the reduction in COVID-19–related mortality, because these findings also revealed that a history of cardiovascular disease and impaired renal function was related to COVID-19–associated mortality.8 There are some important limitations of the current study that deserve further discussion. Therapeutic approach in hypertension and diabetes could interfere with final results. Namely, the authors provided information regarding main antihypertensive classes and reported significant differences between groups.5 Angiotensin-converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB) were used more frequently in patients with hypertension and diabetes than in participants with only one of these conditions. Similar differences were found in the use of beta-blockers and diuretics between patients with both conditions and those with only hypertension or diabetes.5 ACEI were used significantly less frequently than CCB in the present population that differs from common clinical practice in Western countries, which should be considered during the analysis of obtained findings. Hypoglycemic drugs except insulin were more frequently used in patients with both conditions than in patients with isolated diabetes.5 Medications, except ACEI, were not included in multivariable analysis and therefore it is not possible to exclude them as a potential confounding factor in this analysis. Furthermore, the influence of obesity was not investigated and body mass index (BMI), as the main parameter of obesity, was not provided in this investigation. This is a very important point because previous studies showed that underweight and obese patients (BMI <20 kg/m2 and BMI >30 kg/m2) were under increased risk of mortality in type 2 diabetes.8 The investigators included only type 2 diabetic patients and excluded patients with type 1 diabetes, and therefore, obtained results do not have to be necessarily applied to type 2 diabetic patients. Underweight and obesity potentially could be a significant confounding factor in this study group. One should also notice that Asian and black races were important predictors of COVID-related mortality in patients with type 2 diabetes in previous studies.8 Considering the fact that current study is performed in the Asian population, the obtained findings should be interpreted with caution and possibly could not be fully applied worldwide. The persisting problem present also in the current study is lack of information about the percentage of patients with hypertension and diabetes prior to hospitalization for COVID-19. Patients with persistent hypertension and diabetes have significantly more pronounced endothelial damage, which is essential in pathogenesis of complications related to COVID-19. On the other hand, chronic patients have more prevalent target organ damage, which increases susceptibility for COVID-19 and risk of adverse outcome in these patients. Data regarding the impact of chronic and newly diagnosed hypertension in COVID-19 patients are scarce. Ran et al recently investigated only chronic hypertensive COVID-19 patients and reported that poor blood pressure control was independently associated with adverse outcome in these patients.9 Another study showed that stage I pre-diagnosed hypertension existed in only 37% of hospitalized COVID-19 patients, while the percentage of pre-diagnosed stage II and stage III hypertension was significantly higher among these patients (61% and 70%, respectively).10 This confirms our hypothesis that hypertension is diagnosed concomitantly with COVID-19 in significant portion of these patients. Nevertheless, the authors showed that adverse outcomes (septic shock, respiratory failure, ARDS, ICU admission) and mortality gradually increased with blood pressure elevation, despite the fact that hypertension was diagnosed and treated before hospitalization due to COVID-19.10 It is even more complicated relationship between pre-existing and new onset of diabetes among COVID-19 patients. Pre-existing diabetes increases risk of severe COVID-19. However, COVID-19 could also induce new onset of diabetes with metabolic complications and necessity for insulin therapy. Li et al11 reported that newly diagnosed diabetes was related to higher mortality than known diabetes or hyperglycemia in hospitalized patients with COVID-19. Similar findings were revealed from the Italian group of authors.12 These studies raised many questions that remained unanswered. It seems that the role of antihypertensive and anti-diabetic therapy, whenever it has been initiated—before or during COVID-19–related hospitalization, is clearer. The influence of acute and chronic therapy could also impact final results. Ran et al9 did not find any influence of chronic use of RAAS inhibitors on outcome in hypertensive COVID-19 patients. Findings from diabetic population showed that adequate blood glucose regulation was essential in this population, irrespective of when anti-diabetic therapy was initiated.13 However, differences between various antihypertensive medications remain to be determined. There is a consensus about high prevalence of hypertension and diabetes among (i) all COVID-19 patients, (ii) COVID-19 patients who were admitted in intensive care unit due to complicated course of disease, and (iii) COVID-19 patients with lethal outcome. However, there is no agreement about the role of hypertension and diabetes as independent predictors of outcome in COVID-19 patients. Current study reported independent role of diabetes, but not hypertension, on mortality in COVID-19 patients. This emphasizes the importance of glucose regulation in chronic and newly diagnosed diabetic patients. Interestingly patients with diabetes demonstrated higher risk of mortality than those with concomitant diabetes and hypertension, which is not expected due to negative influence of both conditions in COVID-19 patients. There was no difference in insulin therapy between these two groups of patients, but all antihypertensive classes (ACEI, ARB, CCB, and BB) were used significantly more frequently in patients with both conditions. The latter might be responsible for lower mortality risk in patients with hypertension and diabetes, and therefore, beneficial influence of antihypertensive agents should not be forgotten in COVID-19 patients. Even though the present study did not reveal independent effect of hypertension on severity and mortality of COVID-19, one should be careful in interpretation of obtained results and should not neglect the importance of hypertension and antihypertensive medications in these patients. Longitudinal multicenter studies with larger number of COVID-19 patients of different races and more detailed information regarding duration of hypertension and diabetes are necessary to investigate isolated and joined effect of hypertension and diabetes irrespective of other common comorbidities and therapy. No conflict of interest. Marijana Tadic wrote the review paper. Cesare Cuspidi contributed to detailed review with constructive remarks that substantially changed the review paper.

Patients with cancer are at risk for severe COVID-19. Previous studies examining mortality in cancer patients with COVID-19 have produced inconclusive results. Several published meta-analyses have aimed to estimate this association; however, because of methodological limitations in study selection and data aggregation, these studies do not reliably estimate the independent association between cancer and COVID-19 mortality. We conducted this systematic review and meta-analysis to determine whether cancer is an independent risk factor for COVID-19 mortality. A literature search was performed in PubMed to identify studies that compared COVID-19 mortality in adult patients with and without cancer. Selection criteria included polymerase chain reaction-confirmed COVID-19, multivariate adjustment and/or matching for mortality risk estimates, and inclusion of hospitalized noncancer controls. Adjusted odds ratios and/or hazard ratios for mortality based on cancer status were extracted. Odds ratio and hazard ratio estimates were pooled using a random effects model. The analysis included 42 studies comprising 129 840 patients: 8612 cancer patients and 121 228 noncancer patients. Of these studies, 18 showed a null difference in survival between cancer and noncancer patients with COVID-19, and 24 studies showed statistically significantly worse survival in cancer patients with COVID-19. Meta-analysis revealed an increased risk of mortality in patients with cancer compared with noncancer patients with COVID-19 (odds ratio = 1.93, 95% confidence interval = 1.55 to 2.41; hazard ratio = 1.54, 95% confidence interval = 1.29 to 1.84). We conclude that cancer is an independent risk factor for mortality in unvaccinated patients admitted for or diagnosed with COVID-19 during hospitalization.

Subclinical infection and dosing in primary immunodeficiencies.

Chronic lung disease is the most common cause of morbidity and mortality in patients with common variable immunodeficiency (CVID). While biomarkers exist to predict non-infectious complications, the unique features that define CVID patients with chronic lung disease are not well understood. We analyzed data from CVID patients from the retrospective USIDNET (United States Immunodeficiency Network) patient database. Patients were categorized into 3 phenotypes for comparison: (1) CVID without chronic lung disease, (2) CVID with bronchiectasis only, and (3) CVID with interstitial lung disease (ILD) with or without bronchiectasis. Among these groups, differences were assessed in demographics, comorbidities, infections, treatments, and peripheral blood immune measures. We analyzed 1518 CVID patients which included 1233 (81.2%) without chronic lung disease, 147 (9.7%) with bronchiectasis only, and 138 (9.1%) with interstitial lung disease. Patients with ILD had lower CD3+ cell counts (P = .001), CD4+ cell counts (P < .05), and CD8+ cell counts (P < .001) compared with patients without lung disease. Additionally, there was significantly more CVID patients with ILD with pneumonia (P < .001), herpes viruses (P = .01) and fungal infections (P < .001) compared with patients with CVID without chronic lung disease. This analysis suggests that patients with chronic lung disease may be more likely to have lower peripheral T cell counts and complications of those defects compared with CVID patients without chronic lung disease.

Cellular and humoral influenza-specific immune response upon vaccination in patients with common variable immunodeficiency and unclassified antibody deficiency

Common variable immunodeficiency (CVID) and immunoglobulin (Ig) G subclass deficiency (IgGSD) are heterogeneous disorders characterized by respiratory tract infections, selective Ig isotype deficiencies, and impaired antibody responses to polysaccharide antigens. Using univariable analyses, we compared observations in 34 CVID and 398 IgGSD adult index patients (81.9% women) referred to a hematology/oncology practice. Similarities included specialties of referring physicians, mean ages, proportions of women, reactivity to Pneumovax, median serum IgG3 and IgG4 levels, median blood CD56+/CD16+ lymphocyte levels, positivity for HLA-A and -B types, and frequencies of selected HLA-A, -B haplotypes. Dissimilarities included greater prevalence of autoimmune conditions, lower median IgG, IgA, and IgM, and lower median CD19+, CD3+/CD4+, and CD3+/CD8+ blood lymphocytes in CVID patients. Prevalence of Sjögren's syndrome and hypothyroidism was significantly greater in CVID patients. Combined subnormal IgG1/IgG3 occurred in 59% and 29% of CVID and IgGSD patients, respectively. Isolated subnormal IgG3 occurred in 121 IgGSD patients (88% women). Logistic regression on CVID (versus IgGSD) revealed a significant positive association with autoimmune conditions and significant negative associations with IgG1, IgG3, and IgA and CD56+/CD16+ lymphocyte levels, but the odds ratio was increased for autoimmune conditions alone (6.9 (95% CI 1.3, 35.5)).

Low percentages of regulatory T cells in common variable immunodeficiency (CVID) patients with autoimmune diseases and its association with increased numbers of CD4+CD45RO+ T and CD21low B cells

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. The homeostatic chemokines CCL19 and CCL21 and their receptor CCR7 are associated with modulation of inflammatory responses. CVID patients have decreased proportions of CCR7(+) T cells in peripheral blood and we hypothesized a further dysregulation of CCL19/CCL21/CCR7 in CVID. Serum levels of CCL19 and CCL21 were compared in CVID patients and controls. T cell expression of CCR7 was related to clinical characteristics in CVID patients. Spleens extirpated from CVID patients were analysed for expression of CCL19, CCL21 and CCR7. Peripheral blood mononuclear cells (PBMC) from CVID patients and controls were analysed for cytokine response on stimulation with CCL19 and CCL21. The main findings were: (i) CVID patients have raised serum levels of CCL19 and CCL21 independently of features of chronic inflammation; (ii) CCL19 and CCR7 have similar expression in spleens from CVID patients and controls, while CCL21 is variably down-regulated in spleens from patients; (iii) T cell expression of CCR7 is particularly low in patients characterized by chronic inflammation in vivo; and (iv) PBMC from CVID patients had attenuated cytokine response to stimulation with CCL19 and CCL21. CVID patients have raised circulatory levels of CCL19 and CCL21, and an attenuated cytokine response to stimulation with these chemokines. Because CCR7, CCL19 and CCL21 are key mediators balancing immunity and tolerance in the immune system, the abnormalities of these mediators might contribute to the profound immune dysregulation seen in CVID.

Nodular regenerative hyperplasia (NRH) is associated with high morbidity and mortality in patients with common variable immunodeficiency (CVID). While liver biopsy is the gold standard for NRH diagnosis, a non-invasive technique could facilitate early disease recognition, monitoring, and/or immune intervention. We performed a cross-sectional analysis of ultrasound-based transient elastography (TE) in patients with CVID to evaluate liver stiffness and compared this between patients with (N = 12) and without (N = 6) biopsy-proven NRH. Additionally, these data were compared to a cohort followed at our institution for non-alcoholic fatty liver disease (NAFLD) (N = 527), a disease for which TE has routine diagnostic use. Clinical and pathologic features of NRH were evaluated as correlates of liver stiffness, and receiver operating characteristic curves were used to define a liver stiffness cutoff with diagnostic utility for NRH among CVID patients. CVID patients with NRH had a more severe disease presentation compared to those without. This included increased autoinflammatory disease comorbidities, combined B-cell and T-cell dysfunction, and abnormal liver biochemistries (specifically an increased mean alkaline phosphatase level [proximal to TE, 250 vs. 100 U/L; p = 0.03; peak, 314 vs. 114 U/L; p = 0.02). Results of TE demonstrated a significantly elevated liver stiffness in CVID patients with NRH (mean 13.2 ± 6.2 kPa) as compared to both CVID patients without NRH (mean 4.6 ± 0.9 kPa) and non-CVID patients with NAFLD (mean 6.9 ± 5.5 kPa) (p < 0.01). No single or composite histopathologic feature of NRH correlated with liver stiffness including nodule size, nodule density, sinusoidal dilation, fibrosis, and/or lymphocytosis. In contrast, liver stiffness by TE was significantly correlated with clinical parameters of portal hypertension, including an elevated hepatic venous pressure gradient, an increased splenic longitudinal diameter, presence of varices, and presence of peripheral edema. A liver stiffness of greater than or equal to 6.2 kPa was a clinically significant cutoff for NRH in CVID patients. We propose that TE has diagnostic utility in CVID, particularly in the presence of immunophenotypic features such as combined B-cell and T-cell dysfunction, autoinflammatory comorbidities, and/or abnormal liver tests. Elevated liver stiffness by TE should raise suspicion for NRH in patients with CVID and prompt expedited evaluation by hepatology.

BackgroundInfections caused by bacteria or viruses are frequent in common variable immunodeficiency (CVID) patients due to antibody deficiencies, which may be associated with altered T cell function. CVID patients are frequently in contact with pathogen-associated molecular patterns (PAMPs), leading to the activation of innate immunity through Toll-like receptors (TLR) affecting T cell activation. We evaluated the effect of TLR activation on T cells in CVID patients undergoing intravenous immunoglobulin (IVIg) replacement using synthetic ligands.MethodsExpression of exhaustion, activation and maturation markers on T cells from peripheral blood as well as regulatory T cells and follicular T cells in peripheral blood mononuclear cells (PBMCs) from CVID and healthy individuals were evaluated by flow cytometry. PBMCs cultured with TLR agonists were assessed for intracellular IFN-γ, TNF, IL-10, IL-17a or IL-22 secretion as monofunctional or polyfunctional T cells (simultaneous cytokine secretion) by flow cytometry.ResultsWe found increased expression of the exhaustion marker PD-1 on effector memory CD4+ T cells (CD45RA−CCR7−) in the peripheral blood and increased expression of CD38 in terminally differentiated CD8+ T cells (CD45RA+CCR7−). Furthermore, a decreased frequency of naïve regulatory T cells (CD45RA+Foxp3low), but not of activated regulatory T cells (CD45RA−Foxp3high) was detected in CVID patients with splenomegaly, the non-infectious manifestation in this CVID cohort (43.7 %). Moreover, the frequency of peripheral blood follicular helper T cells (CD3+CD4+CXCR5+PD-1+ICOS+) was similar between the CVID and control groups. Upon in vitro TLR3 activation, a decreased frequency of CD8+ T cells secreting IFN-γ, IL-17a or IL-22 was detected in the CVID group compared to the control group. However, a TLR7/TLR8 agonist and staphylococcal enterotoxin B induced an increased Th22/Tc22 (IL-22+, IFN-γ−, IL-17a−) response in CVID patients. Both TLR2 and TLR7/8/CL097 activation induced an increased response of CD4+ T cells secreting three cytokines (IL-17a, IL-22 and TNF)in CVID patients, whereas CD8+ T cells were unresponsive to these stimuli.ConclusionThe data show that despite the unresponsive profile of CD8+ T cells to TLR activation, CD4+ T cells and Tc22/Th22 cells are responsive, suggesting that activation of innate immunity by TLRs could be a strategy to stimulate CD4+ T cells in CVID.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0900-2) contains supplementary material, which is available to authorized users.

Primary antibody deficiency (PAD) is the most common group of primary immunodeficiency disorders, resulting from different defects in the development and function of B cell lineage. Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are two of the major types of PADs. Optimal growth and subsequently bone health could potentially compromise due to the interference of several factors in PAD with childhood onset. In the present study, our aim was to evaluate bone mineral density (BMD) of patients with CVID and XLA. BMD of 37 CVID and 19 XLA patients was examined. Total BMD was determined by dual-energy X-ray absorptiometry and the calculated scores were compared internally and externally with age-sex matched and ethnic-specific reference. Related factors associated with bone density including immune-related complications, serum calcium, phosphate, total alkaline phosphatase, 25(OH) vitamin D and parathyroid hormone levels were recorded. The median age at the time of study was 20 years among all patients and was not statistically different between CVID and XLA groups and the mean of body mass index (BMI) was 19.4±4.6 kg/cm². Thirty-eight (67.9%) of total patients had normal BMD and 18 (32.1%) patients had a low BMD. BMI was positively correlated with BMD at lumbar spine and femoral neck. The number of low BMD patients in CVID (40.5%) group was more than the XLA (15.8%). Beside nutritional, gastrointestinal and infectious complications which are shared in both groups of patients, CVID patients are more prone to alteration of BMD due to association with lymphoproliferative and endocrine diseases. Therefore routine evaluation of bone density and treatment adjustment should be considered in all PAD patients particularly in CVID patients.

A recent meta-analysis has suggested that nesiritide (NES), a new agent for the treatment of congestive heart failure (CHF), is associated with an increased risk of short-term mortality. We retrospectively examined this issue among 1407 consecutive elderly CHF patients by Pearson's chi-squared test, and determined independent risk factors for 60-day mortality by multivariate analysis in a cohort of 682 patients for whom we had sufficient clinical and laboratory data. Univariate analysis revealed that NES usage was associated with increased mortality (n=1407, 10 vs 6%, P=0.011; n=682, 19 vs 12.5%, P=0.046). However, by forward stepwise regression analysis, NES usage did not survive as an independent predictor of mortality. The following variables were independent predictors of mortality: development of acute renal failure (ARF) defined as an increase of serum creatinine (SCr) >or= 0.5 mg/dl; lack of beta-adrenergic blockade; increased admission blood urea nitrogen; digoxin use; and increased admission brain natriuretic peptide. When patients were stratified according to NES usage, ARF emerged as an independent risk factor for mortality only among patients who received NES. Strikingly, among CHF patients who developed ARF (n=102), NES usage emerged as the only independent predictor of mortality (P=0.006, OR=3.73, 95% CI 1.45-9.56). We conclude that, while NES per se is not independently associated with an increased risk for mortality, the development of ARF in association with NES use may confer an increased risk of mortality.