Mehdi Mirsaeidi

Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations

Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNγR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNγ. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations (∼1.4%) in 77 genes (∼13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.

Acute Myocardial Infarction in Hospitalized Patients with Community-Acquired Pneumonia

BACKGROUND An epidemiological link between respiratory infection and acute myocardial infarction (AMI) has been suggested, and recent data indicate that there is an association between AMI and pneumococcal community-acquired pneumonia (CAP) in hospitalized patients. The objective of this study was to investigate the association of AMI with the severity of pneumonia at hospitalization and clinical failure during hospitalization among patients with CAP. METHODS An observational, retrospective study involving consecutive patients hospitalized with CAP was performed at the Veterans Hospital of Louisville, Kentucky. Patients admitted to the intensive care unit were defined as having severe CAP. Clinical failure was defined as the development of respiratory failure or shock. AMI was diagnosed on the basis of abnormal troponin levels and electrocardiogram findings. Propensity-adjusted models that controlled for clinical and nonclinical factors were used to investigate the association between AMI and pneumonia severity index and between AMI and clinical failure. RESULTS Data for a total of 500 patients were studied. At hospital admission, AMI was present in 13 (15%) of 86 patients with severe CAP. During hospitalization, AMI was present in 13 (20%) of 65 patients who experienced clinical failure. Following risk adjustment, significant associations were discovered between AMI and the pneumonia severity index score (modeled with a restricted cubic spline) (P = .05) and between AMI and clinical failure (P = .04). CONCLUSIONS A combined diagnosis of CAP and AMI is common among hospitalized patients with severe CAP. In cases in which the clinical course of a hospitalized patient with CAP is complicated by clinical failure, AMI should be considered as a possible etiology.

Incidence, Etiology, Timing, and Risk Factors for Clinical Failure in Hospitalized Patients With Community-Acquired Pneumonia

BACKGROUND The etiology of clinical failure in hospitalized patients with community-acquired pneumonia (CAP) may be related or unrelated to pulmonary infection. The objective of this study was to define the incidence, etiology, timing, and risk factors associated with clinical failures related to CAP vs those unrelated to CAP. METHODS Observational retrospective study of consecutive CAP patients. All patients who experienced clinical failure were identified. Cases were presented to a review committee that defined, by consensus, etiology, timing, and risk factors for clinical failures related to CAP. RESULTS Among 500 patients who were enrolled in the study, clinical failure was identified in 67 (13%). Clinical failure was related to CAP in 54 patients (81%). The most common etiologies for clinical failure related to CAP were severe sepsis (33%), acute myocardial infarction (28%), and progressive pneumonia (19%). All cases of severe sepsis occurred in the first 72 h of hospitalization. The most common etiology for clinical failure unrelated to CAP was the development of hospital-acquired pneumonia (45%). At the time of hospital admission, factors associated with clinical failure related to CAP were advanced age, congestive heart failure, hypotension, abnormal gas exchange, acidosis, hypothermia, thrombocytopenia, and pleural effusion. CONCLUSIONS The development of severe sepsis early during hospitalization is the primary etiology for clinical failure related to CAP. To achieve early treatment intervention, physicians should maintain a high index of suspicion for severe sepsis in hospitalized patients with CAP. To decrease the number of clinical failures unrelated to CAP, interventions need to be developed at the local level to improve the processes of care for patients with pneumonia.

Thrombocytopenia and Thrombocytosis at Time of Hospitalization Predict Mortality in Patients With Community-Acquired Pneumonia

BACKGROUND Platelets are inflammatory cells with an important role in antimicrobial host defenses. We speculate that an abnormal platelet count may be a marker of severity in patients with community-acquired pneumonia (CAP). The objectives of this study were to evaluate if abnormal platelet count in hospitalized patients with CAP was associated with 30-day mortality and to compare platelet count and leukocyte count as predictors of 30-day mortality. METHODS We performed a retrospective cohort study of 500 consecutive patients hospitalized with CAP at the Veterans Hospital of Louisville, Kentucky, between June 2001 and March 2006 to investigate the association of platelet count and leukocyte count with 30-day mortality. Predictor variables were platelet count and leukocyte count. Abnormal platelet count was < 100,000/L (thrombocytopenia) and > 400,000/L (thrombocytosis). The outcome variable was 30-day mortality. To control for potential confounding, a propensity score that incorporated 33 variables was used. RESULTS Platelet count was strongly associated (P = .0009) with 30-day mortality, whereas no association was observed for leukocyte count (P = .5114). High platelet counts resulted in a significantly increased risk of mortality. CONCLUSIONS Thrombocytopenia and thrombocytosis are associated with mortality in patients hospitalized with CAP. When evaluating an initial CBC test in patients with CAP, an abnormal platelet count is a better predictor of outcome than an abnormal leukocyte count.

Nontuberculous Mycobacterial Disease Mortality in the United States, 1999–2010: A Population-Based Comparative Study

Background Environmental nontuberculous mycobacteria (NTM) are ubiquitous organisms with which humans commonly interact. The epidemiologic characteristics of NTM diseases including mortality rate and its associated factors remain largely unknown. In this study, we explored the geographical area of exposure and mortality and comorbid conditions of affected persons to determine environment, host, and host-pathogen interactive factors. Methods We analyzed mortality related to nontuberculous mycobacterial infections from 1999 through 2010 by examining multiple-cause-of-death data from the National Center for Health Statistics. Among those who died with these diseases, we analyzed age-adjusted mortality rates, trends, associations with demographic variables, and comorbid conditions and correlated this information with similar data for tuberculosis-related mortality during the same time. Measurements and Mean Results From 1999 through 2010, nontuberculous mycobacterial disease was reported as an immediate cause of death in 2,990 people in the United States with a combined overall mean age-adjusted mortality rate of 0.1 per 100,000 person-years. A significant increase in the number of NTM related deaths was seen from 1999 through 2010 (R2 = 0.72, p<0.0001), but it was not significant after adjustment for age. Persons aged 55 years and older, women, those living in Hawaii and Louisiana, and those of non-Hispanic, white ethnicity had higher mortality rates. Compared to tuberculosis-related mortality, chronic obstructive pulmonary disease, bronchiectasis, HIV, interstitial lung diseases, and tobacco use were significantly more common in persons with nontuberculous mycobacteria-related deaths. Conclusions Nontuberculous mycobacteria-related death numbers are rising and are unevenly distributed. The strong association of nontuberculous mycobacterial disease with age suggests that its prevalence will increase as the United States population ages.

Non-tuberculous mycobacterial disease is common in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms. Cystic fibrosis (CF) patients are susceptible to NTM, but data about NTM in patients with non-CF bronchiectasis are limited. METHODS We conducted a retrospective, descriptive study at the University of Illinois Medical Center. All patients diagnosed with bronchiectasis (code 494) using the International Classification of Diseases, ninth revision (ICD-9), between 1999 and 2006, were identified. Clinical data including lung function, radiology studies, and presence of NTM in sputum were abstracted for those who met the study criteria. RESULTS One hundred eighty-two patients were enrolled in the study. Patients were divided into two groups: bronchiectasis with NTM isolates (n = 68) and bronchiectasis without isolates (n =114), and compared for clinical characteristics and underlying diseases. Mycobacterium avium complex (MAC) was the most common isolate. Fifty-five patients (30%) met the American Thoracic Society criteria for diagnosis of NTM disease. Gram-negative rods were commonly co-isolated. The probability of NTM isolation was significantly higher in elderly female patients (p = 0.04). Moreover, the probability of NTM isolation was significantly higher in the female group with low body mass index (BMI) (p = 0.002). CONCLUSIONS NTM infections are common in non-CF bronchiectasis. MAC is the most frequently isolated NTM in these patients. There is also great variability in age and sex characteristics for NTM in non-CF bronchiectasis patients. Female patients with a low BMI are a high risk group for NTM infection in non-CF bronchiectasis. Routine screening for NTM is strongly recommended in this patient population.

Racial Difference in Sarcoidosis Mortality in the United States

BACKGROUND The clinical presentation and outcome of sarcoidosis varies by race. However, the race difference in mortality outcome remains largely unknown. METHODS We studied mortality related to sarcoidosis from 1999 through 2010 by examining data on multiple causes of death from the National Center for Health Statistics. We compared the comorbid conditions between sarcoidosis-related deaths with deaths caused by car accidents (previously healthy control subjects) and rheumatoid arthritis (chronic disease control subjects) in both African Americans and Caucasians. RESULTS From 1999 through 2010, sarcoidosis was reported as an immediate cause of death in 10,348 people in the United States with a combined overall mean age-adjusted mortality rate of 2.8 per 1 million person-years. Of these, 6,285 were African American and 3,984 Caucasian. The age-adjusted mortality rate for African Americans was 12 times higher than for Caucasians. African Americans died at an earlier age than Caucasians. African Americans living in the District of Columbia and North Carolina and Caucasians living in Vermont had higher mortality rates. Although the total sarcoidosis age-adjusted mortality rate had not changed over the 12 year period studied, this rate increased for Caucasians (R = 0.747, P = .005) but not for African Americans. Compared with the control groups, pulmonary hypertension was significantly more common in individuals with sarcoidosis. CONCLUSIONS This nationwide population-based study exposes a significant difference in ethnicity and sex among people dying of sarcoidosis in the United States. Pulmonary hypertension investigation should be considered in all patients with sarcoidosis, especially African Americans.

Inherited disorders of the IL-12-IFN-γ axis in patients with disseminated BCG infection

Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN-γ axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN-γ circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN-γ receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12Rβ1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN-γ circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN-γ circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.

Rituximab in the treatment of refractory pulmonary sarcoidosis

To the Editor: Sarcoidosis is a chronic disease characterised by granulomatous depositions that can occur in virtually any organ system [1]. Currently, there is no US Food and Drug Administration (FDA)-approved therapy for sarcoidosis; however, corticosteroids have proven efficacious and are a commonly used treatment [2]. In patients with chronic or pulmonary disease who do not respond to corticosteroids, or in whom steroid use is contraindicated, agents such as methotrexate, azathioprine and tumour necrosis factor (TNF)-α antagonists may be effective [3, 4]. However, a need persists for patients who fail to respond to current options. Sarcoidosis is a T-cell-mediated disease; however, humoral mechanisms may play a role in its pathogenesis [5]. Sarcoidosis is often associated with hypergammaglobulinaemia, autoantibody production and circulating immune complexes [6]. B-cell-targeted therapies have shown positive results in many T-cell-mediated autoimmune diseases. Rituximab is a chimeric monoclonal antibody that causes depletion of CD20+ B-cells [7]. Rituximab is FDA approved for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis, and is also being studied in Sjogren’s syndrome, systemic lupus erythematosus and vasculitis [8]. There have been case reports of the effectiveness of rituximab for sarcoidosis [9–11]. Given the evidence for humoral involvement in sarcoidosis pathogenesis, this study sought to evaluate the utility of B-cell depletion using rituximab in patients with refractory pulmonary sarcoidosis. This was a prospective, open-label, phase I/II trial. The study was approved by the …

First-line anti-tuberculosis drug resistance patterns and trends at the national TB referral center in Iran—eight years of surveillance

OBJECTIVE Resistance to anti-tuberculosis (anti-TB) drugs is becoming a major and alarming threat in most regions worldwide. METHODS This was a descriptive cross-sectional study at a tertiary hospital in Iran, using patient medical records for 2000-2003. The findings were analyzed following the same framework as that used for previous reports from this center. RESULTS Among 1556 TB patients, drug susceptibility testing (DST) was performed for 548 culture-positive cases. Anti-TB drug resistance to both isoniazid and rifampin was identified in 10 (2.8%) of the new TB cases (multidrug-resistant TB; MDR-TB). Any resistance was detected in 228 (41.6%), showing an increasing trend in both new and retreatment cases. The data analysis revealed that drug-resistant TB had a statistically significant association with Afghan ethnicity, age>65 years, and the type of disease (retreatment vs. new TB case) (p<0.05). Also, assessment of the drug resistance trends showed a significant increase in resistance to any anti-TB agent, to isoniazid, and to streptomycin in new cases, and to all of the first-line anti-TB drugs in retreatment patients. CONCLUSIONS There has been an increasing trend in drug resistance in recent years, particularly in retreatment cases. Hence, revision of the national TB control program, reevaluation of the role of the World Health Organization category II (CAT II) regimen, as well as the conducting of a nationwide drug resistance survey, are recommended.