Disseminated Infections with Talaromyces marneffei in Non-AIDS Patients Given Monoclonal Antibodies against CD20 and Kinase Inhibitors

Infections with the fungus Talaromyces (formerly Penicillium) marneffei are rare in patients who do not have AIDS. We report disseminated T. marneffei infection in 4 hematology patients without AIDS who received targeted therapy with monoclonal antibodies against CD20 or kinase inhibitors during the past 2 years. Clinicians should be aware of this emerging complication, especially in patients from disease-endemic regions.Talaromyces (formerly Penicillium) marneffei is a pathogenic, thermal dimorphic fungus that causes systemic mycosis in Southeast Asia. T. marneffei infection is characterized by fungal invasion of multiple organ systems, especially blood, bone marrow, skin, lungs, and reticuloendothelial tissues, and is highly fatal, especially when diagnosis and treatment are delayed (1,2). This disease is found predominantly in AIDS patients and occasionally those with cell-mediated immunodeficiencies involving the interleukin-12/interferon-γ (IFN-γ) signaling pathway, such as congenital STAT1 mutations or acquired autoantibodies against IFN-γ (1,3–6). The infection has rarely been reported among hematology patients, including those from disease-endemic regions (7,8). At Queen Mary Hospital in Hong Kong, a 1,600-bed university teaching hospital that has a hematopoietic stem cell transplantation service, where a wide range of invasive fungal infections have been observed (9,10), only 3 cases of T. marneffei infection were encountered in >2,000 hematology patients in the past 20 years, despite the long-standing availability of mycologic culture and serologic testing (7,8,11,12). In contrast, the infection was commonly reported among AIDS patients (13).In the past 2 years, we have been alerted by 4 unprecedented cases of disseminated T. marneffei infection among non-AIDS hematology patients given targeted therapies, including monoclonal antibodies (mAbs) against CD20 and kinase inhibitors, which are being increasingly used in recent years. We report details for these 4 hematology case-patients. The study was approved by the institutional review board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster in Hong Kong.     

Hantavirus Pulmonary Syndrome, United States, 1993�C2009

Hantavirus pulmonary syndrome (HPS) is a severe respiratory illness identified in 1993. Since its identification, the Centers for Disease Control and Prevention has obtained standardized information about and maintained a registry of all laboratory-confirmed HPS cases in the United States. During 1993–2009, a total of 510 HPS cases were identified. Case counts have varied from 11 to 48 per year (case-fatality rate 35%). However, there were no trends suggesting increasing or decreasing case counts or fatality rates. Although cases were reported in 30 states, most cases occurred in the western half of the country; annual case counts varied most in the southwestern United States. Increased hematocrits, leukocyte counts, and creatinine levels were more common in HPS case-patients who died. HPS is a severe disease with a high case-fatality rate, and cases continue to occur. The greatest potential for high annual HPS incidence exists in the southwestern United States.In May 1993, a series of cases of an acute illness associated with rapid development of respiratory failure were noted in the Four Corners region of the United States. Surveillance initiated in the area identified 24 cases of compatible illness that had occurred in New Mexico, Arizona, Colorado, and Utah since December 1992; the case-fatality rate was 50%. Preliminary serologic data for case-patients suggested infection with an unknown virus in the family Bunyaviridae and genus Hantavirus (1). This observation was surprising, given that hantaviruses had not been associated with any human diseases in North or South America at that time, and the only known clinical syndrome associated with hantaviruses, hemorrhagic fever with renal syndrome, did not have a predominantly respiratory involvement. However, nucleic acid sequence from a novel hantavirus was rapidly identified in tissue samples of multiple patients, and similarly from deer mice (Peromyscus maniculatus) trapped near the residence of cases, implicating a novel hantavirus as the cause of the disease (2). Additional serologic and molecular data from case-patients and results of trapping studies in the Four Corners region supported these conclusions (3,4).Since its identification in 1993, hantavirus cardiopulmonary syndrome (HPS) and numerous New World hantavirus species have been described across a wide geographic range of North, Central, and South America (5). In the United States, most HPS cases are likely caused by Sin Nombre virus (6), the virus responsible for the initially identified HPS cases. Other HPS-associated viruses include New York and Monongahela viruses (mice of the genus Peromyscus are reservoirs), associated with HPS in the eastern United States (7–9), Bayou virus, found in the southeastern United States (Oligoryzomys palustris rice rats are reservoirs) (10–12), and Black Creek Canal virus (Sigmodon hispidus cotton rats are reservoirs), which was associated with 1 case of HPS in Florida (13,14).Hantaviruses are believed to be transmitted by inhalation of rodent secretions and excreta, or possibly through direct contact with an infected rodent. Although clusters of human cases have been identified in the United States, no evidence exists of human-to-human or nosocomial transmission of hantaviruses in North America (15,16) Infrequent but clear instances of human-to-human transmission of Andes virus in Argentina and Chile have been documented (17–19).The incubation period of HPS is believed to range from 1 to 5 weeks (20). HPS typically begins with a prodromal syndrome, and common symptoms include fever, myalgias, headache, and nausea/vomiting (21,22). After the prodrome, the hallmark of HPS is rapid onset of a severe pulmonary illness, often involving hypoxia, pulmonary edema, and myocardial depression (22–25). Death typically occurs rapidly after hospitalization (21) and often as the result of cardiogenic shock (25). In this report, we evaluate the epidemiologic and clinical characteristics of all known laboratory-confirmed cases of HPS in the United States during 1993–2009.     

Pneumocystis jirovecii Genotype Associated with Increased Death Rate of HIV-infected Patients with Pneumonia

Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations have been associated with failure of sulfa prophylaxis; their effect on the outcome of patients with P. jirovecii pneumonia (PCP) remains controversial. P. jirovecii DHPS polymorphisms and genotypes were identified in 112 cases of PCP in 110 HIV-infected patients by using PCR single-strand conformation polymorphism. Of the 110 patients observed, 21 died; 18 of those deaths were attributed to PCP. Thirty-three percent of the PCP cases involved a P. jirovecii strain that had 1 or both DHPS mutations. The presence or absence of DHPS mutations had no effect on the PCP mortality rate within 1 month, whereas P.jirovecii type 7 and mechanical ventilation at PCP diagnosis were associated with an increased risk of death caused by PCP. Mechanical ventilation at PCP diagnosis was also associated with an increased risk of sulfa treatment failure at 5 days. Pneumocystis jirovecii causes severe pneumonia in immunocompromised patients, including HIV-infected persons, transplant recipients, patients receiving high-grade chemotherapy for hemato-oncologic diseases, and persons with autoimmune diseases who are treated with immunosuppressive drugs. Cotrimoxazole, the combination of sulfamethoxazole and trimethoprim (SMX/TMP), is the drug of choice for prevention of and treatment for Pneumocystis pneumonia (PCP). SMX/TMP targets enzymes involved in the biosynthesis of folic acid, dihydropteroate synthase (DHPS), and dihydrofolate reductase.Several investigators have reported an association between failure of prophylaxis when using sulfa drugs and substitutions of 2 aa within the putative sulfa binding site of DHPS at positions 55 (Thr to Ala, mutation M1) and 57 (Pro to Ser, M2) (1–4). These mutations were observed either as single (M1 or M2) or double (M3) mutation. This association strongly suggested that P. jirovecii DHPS mutations conferred a level of sulfa resistance sufficient to cause failure of anti-PCP prophylaxis. However, the mutations might have also conferred a clinically substantial resistance to sulfa treatment for overt PCP.To investigate the issue, many studies have analyzed the effect of the mutations on the outcome of PCP. About half of those studies did not detect any association between the mutations and an increased risk of death caused by PCP (5–8) or a decreased response to sulfa drugs (3,9–11). Conversely, other studies detected an association with a poor outcome (12,13): sulfa treatment failure (14,15); more severe symptoms and need of assisted ventilation (13); or a trend for a worse prognosis (16). Thus, the effect of these mutations on PCP outcome is unclear and justifies investigation to improve PCP treatment and prognosis.The possibility of other parameters influencing PCP outcome has also been explored. P. jirovecii genotype Ne of the internal transcribed spacers (ITSs) of the nuclear rRNA operon has been associated with milder disease (17), failure of PCP prophylaxis (18), and failure of PCP treatment (9). One ITS genotype observed in Australia was associated with reduced severity of PCP (13). Specific P. jirovecii genotypes defined by single-nucleotide polymorphisms in 3 loci were associated with low or high burden during the course of PCP (19). In comparison, some studies did not detect any associations between P. jirovecii genotypes, including Ne genotype, and several clinical parameters, such as severity and survival at 3 months (15,20). These observations suggested that some P. jirovecii genotypes might be more virulent or resistant to drugs, but further studies are needed to provide better understanding the issue.We previously examined P. jirovecii DHPS polymorphisms in clinical specimens of 158 immunosuppressed patients from 5 hospitals in the city of Lyon in France (7). We detected an association between DHPS mutation M2 and failure of prophylaxis when pyrimethamine/sulfadoxine was used but not between DHPS mutations and death caused by PCP. In this study, we further observed the proportion of the organisms harboring DHPS mutations (36%) and of death attributed to PCP (20%) among these 158 patients. We investigated in more detail the effect of DHPS mutations on PCP prognoses, taking into account more clinical parameters. Moreover, to test the hypothesis of variable virulence of some P. jirovecii genotypes, we identified those present in the specimens. Because the disease signs and symptoms vary considerably between HIV-infected and HIV-uninfected patients, we limited our analyses to the HIV-infected patients.     

Clostridium difficile Bacteremia, Taiwan1

To determine clinical characteristics and outcome of patients with Clostridium difficile bacteremia (CDB), we identified 12 patients with CDB in 2 medical centers in Taiwan; all had underlying systemic diseases. Five had gastrointestinal diseases or conditions, including pseudomembranous colitis (2 patients); 4 recalled diarrhea, but only 5 had recent exposure to antimicrobial drugs. Ten available isolates were susceptible to metronidazole and vancomycin. Five isolates had C. difficile toxin A or B. Of 5 patients who died, 3 died of CDB. Of 8 patients treated with metronidazole or vancomycin, only 1 died, and all 4 patients treated with other drugs died (12.5% vs. 100%; p = 0.01). C. difficile bacteremia, although uncommon, is thus associated with substaintial illness and death rates.Clostridium difficile is well recognized as the etiologic agent of pseudomembranous colitis and has been implicated as the cause of 10%–25% of cases of antimicrobial drug–associated diarrhea (1). The pathogen has been responsible for numerous recent hospital-based epidemics and is also emerging in the community (2). The clinical features, disease spectrum and pathogenesis, and optimal treatments of C. difficile–associated diarrhea have been well studied. In contrast, reports of the isolation of C. difficile in body sites other than the intestines, or extraintestinal infections, have been anecdotal (3,4). Extracolonic manifestations of C. difficile infections reported were variable, including bacteremia, osteomyelitis, visceral abscess, empyema, reactive arthritis, pyelonephritis, prosthetic joint infection, and skin and soft tissue infection (3–10). Most cases of extracolonic C. difficile infections have been preceded by gastrointestinal events, either C. difficile colitis or surgical and anatomic disruption of the colon (4).Recently, Libby and Bearman reviewed the literature on bacteremia caused by C. difficile (6). Most cases were identified from individual case reports. However, as the incidence of C. difficile infection increases, an increase in cases of C. difficile bacteremia (CDB) is likely (10). Knowledge of the clinical signs and symptoms of these extracolonic manifestations of bloodstream infections will be useful in patient care and could improve clinical outcomes (4). To outline the spectrum and clinical significance of CDB, we report 12 cases of CDB over a recent 10-year period at 2 medical centers in Taiwan and review the literature published in English.     

Confirmed Bacillus anthracis Infection among Persons Who Inject Drugs,Scotland, 2009–2010

In Scotland, the 2009 outbreak of Bacillus anthracis infection among persons who inject drugs resulted in a 28% death rate. To compare nonsurvivors and survivors, we obtained data on 11 nonsurvivors and 16 survivors. Time from B. anthracis exposure to symptoms or hospitalization and skin and limb findings at presentation did not differ between nonsurvivors and survivors. Proportionately more nonsurvivors had histories of excessive alcohol use (p = 0.05) and required vasopressors and/or mechanical ventilation (p<0.01 for each individually). Nonsurvivors also had higher sequential organ failure assessment scores (mean + SEM) (7.3 + 0.9 vs. 1.2 + 0.4, p<0.0001). Antibacterial drug administration, surgery, and anthrax polyclonal immune globulin treatments did not differ between nonsurvivors and survivors. Of the 14 patients who required vasopressors during hospitalization, 11 died. Sequential organ failure assessment score or vasopressor requirement during hospitalization might identify patients with injectional anthrax for whom limited adjunctive therapies might be beneficial.Bacillus anthracis infection in humans has typically been classified as cutaneous, gastrointestinal, or inhalational on the basis of the bacterium’s route of entry (1). However, in Scotland, United Kingdom, during 2009–2010, a total of 47 patients had confirmed B. anthracis soft tissue infection related to injection of contaminated heroin (2,3). This form of B. anthracis infection appears to be distinct from cutaneous disease and has been termed “injectional” anthrax (2–5). In addition to confirmed cases, 35 probable and 37 possible cases in Scotland, 5 confirmed cases in England, and 2 confirmed cases in Germany also were identified. This initial outbreak ended in late 2010, but since the summer of 2012, new cases have been reported in the United Kingdom and Europe (3,4). Although 1 case of injectional anthrax was recognized in Norway in 2001, the patients in 2009–2010 constitute the first large outbreak of this newly recognized and poorly characterized form of anthrax (5).Health Protection Scotland (HPS) has published epidemiologic analyses of the 2009–2010 outbreak (3,6,7). Among other findings, analysis suggested associations between longer injecting histories, opioid substitution therapy, and alcohol use and risk for B. anthracis infection in persons who inject drugs (PWID) (6). Several case reports from the outbreak also have been published (8–12), but they did not include systematic examinations of the physical, laboratory, and surgical findings or of therapies administered. Notably, although 13 of the 47 persons from Scotland who had confirmed cases died, no published report has compared findings in survivors and nonsurvivors. Such a comparison is needed for the prognosis and management of future cases. We therefore sent a questionnaire regarding these issues to clinicians who had treated PWIDs in whom B. anthracis infection was confirmed in Scotland during the outbreak.     

Methicillin-Resistant Staphylococcus aureus Sequence Type 239-III, Ohio, USA, 2007�C2009

Methicillin-resistant Staphylococcus aureus (MRSA) is a human pathogen that has diverse molecular heterogeneity. Most MRSA strains in the United States are pulsed-field gel electrophoresis USA100 sequence type (ST) 5 and USA300 ST8. Infections with MRSA ST239-III are common and found during health care–associated outbreaks. However, this strain has been rarely reported in the United States. As part of a study supported by the Prevention Epicenter Program of the Centers for Disease Control and Prevention (Atlanta, GA, USA), which evaluated transmission of MRSA among hospitals in Ohio, molecular typing identified 78 (6%) of 1,286 patients with MRSA ST239-III infections. Ninety-five percent (74/78) of these infections were health care associated, and 65% (51/78) of patients had histories of invasive device use. The crude case-fatality rate was 22% (17/78). Identification of these strains, which belong to a virulent clonal group, emphasizes the need for molecular surveillance.Staphylococcus aureus is a major human pathogen that possesses multiple toxins and virulence mechanisms (1). Antimicrobial drug resistance in S. aureus has added to the complexity of treating serious infections caused by this bacteria, and methicillin-resistant S. aureus (MRSA) appears to have greater virulence than methicillin-susceptible strains (2,3). Most MRSA strains in the United States are pulsed-field gel electrophoresis (PFGE) types USA100 and USA300, corresponding to multilocus sequence typing (MLST) ST5 and ST8, respectively (4). MRSA belonging to MLST ST239 and harboring staphylococcal cassette chromosome mec (SCCmec) type III (MRSA ST239-III) are associated with infections in health care settings, outbreaks, increased resistance to antimicrobial drugs, and capacity for invasive disease (5–7).MRSA ST239-III has a history of successful dissemination in many regions, leading to a diverse array of regionally prevalent clones. These clones include the Brazilian; British Epidemic 1, 4, 7, 9, and 11; Canadian Epidemic 3/Punjab; Czech; Eastern Australian 2 and 3; Georgian; Hungarian; Lublin; Nanjing/Taipei (ST241); Portuguese; and Vienna clones (8,9). Although it is common worldwide, MRSA ST239-III has not played any predominant role in the United States; infections with MRSA ST239-III have been rarely reported in the United States since the 1990s (9–13). Recently, only 2 reports of this strain in the United States involving sporadic nasal colonization and bloodstream infections have been published (13,14).In this study, we describe clinical epidemiologic characteristics and molecular analysis of clinical infections with MRSA ST239-III in the midwestern United States. Identification of a strain from such a virulent clonal group in the United States with wide dissemination in other parts of the world represents a potential public health concern.     

Extensively Drug-Resistant Mycobacterium tuberculosis from Aspirates,Rural South Africa

The yield from aspirating lymph nodes and pleural fluid for diagnosing extensively drug-resistant (XDR) tuberculosis is unknown. Mycobacterium tuberculosis was cultured from lymph node or pleural fluid aspirates of 21 patients; 7 (33%) cultures grew XDR M. tuberculosis. Additive diagnostic yield for XDR M. tuberculosis was found in parallel culture of sputum and fluid aspirate.Tuberculosis (TB) is the leading cause of death among HIV-infected persons in sub-Saharan Africa (1). Drug-resistant TB is an emerging public health threat in HIV-prevalent settings, but diagnosis is challenging because of the severely limited laboratory capacity for culture and drug-susceptibility testing (DST). TB diagnosis for HIV-infected patients is particularly challenging because these patients may be more likely to have smear-negative pulmonary disease or extrapulmonary TB (2,3). Extrapulmonary TB often is diagnosed by clinical findings, indirect measures (e.g., chemistry and cell count of cerebrospinal or pleural fluid, ultrasound of lymph nodes, or pericardial effusions), or smear microscopy for acid-fast bacilli from aspirated extrapulmonary fluid. However, drug-resistant TB is impossible to diagnose by these methods, instead requiring mycobacterial culture and DST (4,5).The prevalence of multidrug-resistant and extensively drug-resistant TB (XDR TB) in South Africa has risen exponentially during the past decade. At our rural study site, ≈10% of all TB cases now are drug resistant, and >90% of TB patients are HIV infected (6). Death from XDR TB exceeds 80%; most infected persons die before sputum culture and DST results are known (6). To improve case detection and decrease diagnostic delay of drug-resistant TB among patients with suspected extrapulmonary TB, we initiated a program to aspirate lymph nodes and pleural fluid for culture and DST. We quantified the yield of these lymph node and pleural fluid aspirates for diagnosing XDR TB.     

Illicit Drug Use and Risk for USA300 Methicillin-Resistant Staphylococcus aureus Infections with Bacteremia

To assess the association of illicit drug use and USA300 methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, a multicenter study was conducted at 4 Veterans Affairs medical centers during 2004–2008. The study showed that users of illicit drugs were more likely to have USA300 MRSA bacteremia (in contrast to bacteremia caused by other S. aureus strains) than were patients who did not use illicit drugs (adjusted relative risk 3.0; 95% confidence interval 1.9–4.4). The association of illicit drug use with USA300 MRSA bacteremia decreased over time (p = 0.23 for trend). Notably, the proportion of patients with USA300 MRSA bacteremia who did not use illicit drugs increased over time. This finding suggests that this strain has spread from users of illicit drugs to other populations.Infections caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are increasing. Outbreaks have been described in a variety of populations, including sports teams, men who have sex with men, prisoners, and children (1–10). The USA300 MRSA clone has been recognized as the most common strain causing CA-MRSA infections (11).CA-MRSA was first reported in illicit drug users in Detroit in 1980 (12). The drug-using population has been identified as a reservoir of CA-MRSA (13). Because of the repeated injection or inhalation of drugs, the opportunity for a person to cause and spread infection with one’s own colonizing strain is multiplied (13,14). Skin and soft tissue infections are the most common infections in illicit drug users; the USA300 MRSA strain is the cause of up to 75% of these infections (13–15). Once this strain colonizes or otherwise infects a person, it can then enter the patient’s bloodstream and become a potentially life-threatening bloodstream infection.If admitted to the hospital, illicit drug–using patients with a USA300 MRSA infection complicated by bacteremia serve as a potential reservoir for transmission to other patient populations. This mechanism may be contributing to the replacement of other MRSA strains typically associated with nosocomial infections by USA300 MRSA and may aid this strain in becoming the predominant isolate causing MRSA infections in both healthcare and community settings (16,17). The objective of this study was to evaluate the association of illicit drug use with USA300 MRSA bacteremia and whether the association is static or has changed over a 5-year period as the USA300 MRSA epidemic has progressed.     

Bloodstream Infections among HIV-Infected Outpatients, Southeast Asia

Bloodstream infections (BSIs) are a major cause of illness in HIV-infected persons. To evaluate prevalence of and risk factors for BSIs in 2,009 HIV-infected outpatients in Cambodia, Thailand, and Vietnam, we performed a single Myco/F Lytic blood culture. Fifty-eight (2.9%) had a clinically significant BSI (i.e., a blood culture positive for an organism known to be a pathogen). Mycobacterium tuberculosis accounted for 31 (54%) of all BSIs, followed by fungi (13 [22%]) and bacteria (9 [16%]). Of patients for whom data were recorded about antiretroviral therapy, 0 of 119 who had received antiretroviral therapy for >14 days had a BSI, compared with 3% of 1,801 patients who had not. In multivariate analysis, factors consistently associated with BSI were fever, low CD4+ T-lymphocyte count, abnormalities on chest radiograph, and signs or symptoms of abdominal illness. For HIV-infected outpatients with these risk factors, clinicians should place their highest priority on diagnosing tuberculosis.Bloodstream infections (BSIs) are a major cause of illness in HIV-infected persons. A series of studies, most of which were conducted in sub-Saharan Africa during the 1990s, demonstrated a high prevalence of BSIs (ranging from 10% to 63%) among hospitalized HIV-infected persons who had fever (1–17). In studies that measured clinical outcomes, the in-hospital death rate for patients with a BSI was high (19%–47%). A variety of pathogens cause BSIs in febrile, hospitalized persons with HIV, most notably non-Typhi Salmonella spp. (6%–15%) and Mycobacterium tuberculosis (2%–19%). BSI with M. tuberculosis appears to be particularly lethal, causing death during hospitalization in up to 47% of patients (9). Although untreated BSIs are believed to lead rapidly to severe illness, sepsis, and death, patients with BSIs may be able to be identified before they are ill enough to require hospitalization, potentially improving clinical outcomes. Despite the large number of studies that have evaluated BSIs in HIV-infected persons, all previous studies have focused on patients seeking care at hospitals because of fever and did not evaluate infections among outpatients with or without fever.Although overall transmission rates have declined and antiretroviral therapy (ART) has become more widely available, HIV infection remains a major public health problem in Southeast Asia (18). Previous studies of BSI in Southeast Asia enrolled only inpatients, and only 1 evaluated a predominantly HIV-infected population (1,19–21). In this study, we prospectively enrolled patients from multiple HIV testing and treatment clinics in Cambodia, Thailand, and Vietnam to assess BSI prevalence, etiology, and risk factors in outpatients with HIV.     

Recurrent Granulibacter bethesdensis Infections and Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is characterized by frequent infections, most of which are curable. Granulibacter bethesdensis is an emerging pathogen in patients with CGD that causes fever and necrotizing lymphadenitis. However, unlike typical CGD organisms, this organism can cause relapse after clinical quiescence. To better define whether infections were newly acquired or recrudesced, we use comparative bacterial genomic hybridization to characterize 11 isolates obtained from 5 patients with CGD from North and Central America. Genomic typing showed that 3 patients had recurrent infection months to years after apparent clinical cure. Two patients were infected with the same strain as previously isolated, and 1 was infected with a genetically distinct strain. This organism is multidrug resistant, and therapy required surgery and combination antimicrobial drugs, including long-term ceftriaxone. G. bethesdensis causes necrotizing lymphadenitis in CGD, which may recur or relapse.Chronic granulomatous disease (CGD) is a rare genetic disease caused by mutations in any of the 4 structural genes of the NADPH oxidase system and leads to defective production by phagocytes of superoxide and downstream oxygen metabolites (1). Infections in patients with CGD are caused by a narrow spectrum of pathogens, including Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, Nocardia spp., and Aspergillus spp (2–4). Although lymphadenitis is commonly encountered, a pathogen is isolated in only ≈60% of cases (5).Most human bacterial infections, even those that are severe, are transient and curable. Bacteria such as Mycobacterium tuberculosis are unique human pathogens in part because of their ability to persist in a dormant state and reactivate later. The recurrent infections observed in patients with CGD, even when caused by the same species of organism, are the result of reinfection rather than relapse (3,6). Granulibacter bethesdensis is a recently described gram-negative bacterium in the family Acetobacteraceae; it has been isolated from 6 patients with CGD from North and Central America and Spain (7–10). The initial case was in an adult who had prolonged fever, necrotizing lymphadenitis, and multiple disease recurrences culminating in cure 2 years after seeking treatment. Persons with subsequent cases in the Americas had shorter periods before diagnosis and more rapid responses to therapy. A fatal case reported in Spain involved a patient with CGD in whom G. bethesdensis was the only pathogen identified. Given the increasing cases of this emerging pathogen, we present in greater detail the clinical course of these patients and molecular epidemiologic evidence to support the recurrent infections we have diagnosed for some of these patients.Five patients were followed up at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA) under protocol 93-I-0119. Patients 2, 3, and 5 had been actively followed up at NIH for at least 8 years before receiving a diagnosis of G. bethesdensis infection. Patient 1 had been sent to NIH for evaluation of his lymphadenopathy and Granulibacter infection was diagnosed shortly thereafter. Patient 4 was referred to NIH for treatment and follow-up after his Granulibacter infection was diagnosed at an outside hospital (by R.L.W. and D.F.W.).The G. bethesdensis high-density microarray platform, DNA microarray hybridization, and comparative genomic hybridization analysis used for typing of the G. bethesdensis isolates have been described (9). Bacterial DNA was isolated by using the NucliSens Kit (bioMérieux, Durham, NC, USA), and 16S rRNA genes from the 5 patient isolates were sequenced and analyzed as described (8). DNA was isolated from human tissue by using the Maxwell 16 Tissue DNA Purification Kit (Promega, Madison, WI, USA) according to the manufacturer’s protocol. DNA concentrations were measured by using a UV spectrophotometer (NanoDrop, Wilmington, DE, USA).The 16S rRNA and methanol dehydrogenase subunit 1 (GeneID {"type":"entrez-protein","attrs":{"text":"YP_744165.1","term_id":"114327008","term_text":"YP_744165.1"}}YP_744165.1) genes of G. bethesdensis were analyzed by using a PCR and primer sequences 16S-forward: 5′-TCGGGTGGGCACTCTAAAGG-3′, 16S-reverse: 5′-GCATCACTGCCTAGCTTCCC-3′, MDH-forward: 5′-CCGCAATACGGTCAATTCG-3′, and MDH-reverse: 5′-GCCGATCTTCCAGGTTTCTTC-3′. Each reaction mixture contained 47 μL of Platinum Blue PCR SuperMix (Invitrogen, Carlsbad, CA, USA) and 1.5 μL of each primer at a final concentration of 0.75 μmol/L, and the PCR was performed in a thermocycler (Eppendorf, Hauppauge, NY, USA). The PCR amplification conditions were 94°C for 10 min; 40 cycles at 94°C for 30 s, 60°C for 30 s, and 72°C for 30 s; and a final extension at 72°C for 5 min. PCR fragments were visualized by electrophoresis on a 2% agarose gel and showed the expected sizes of 137 bp (16SrRNA) and 63 bp (methanol dehydrogenase subunit 1).     

Neurognathostomiasis, a Neglected Parasitosis of the Central Nervous System

Gnathostomiasis is a foodborne zoonotic helminthic infection caused by the third-stage larvae of Gnathostoma spp. nematodes. The most severe manifestation involves infection of the central nervous system, neurognathostomiasis. Although gnathostomiasis is endemic to Asia and Latin America, almost all neurognathostomiasis cases are reported from Thailand. Despite high rates of illness and death, neurognathostomiasis has received less attention than the more common cutaneous form of gnathostomiasis, possibly because of the apparent geographic confinement of the neurologic infection to 1 country. Recently, however, the disease has been reported in returned travelers in Europe. We reviewed the English-language literature on neurognathostomiasis and analyzed epidemiology and geographic distribution, mode of central nervous system invasion, pathophysiology, clinical features, neuroimaging data, and treatment options. On the basis of epidemiologic data, clinical signs, neuroimaging, and laboratory findings, we propose diagnostic criteria for neurognathostomiasis.Foodborne parasitic infections are common in the tropics, where many foodborne parasites are endemic and ingestion of raw shellfish and freshwater fish, as well as undercooked meat, is frequent among local populations (1). Increased international travel to areas endemic for these foodborne parasites and migration from tropical areas have led to the emergence of these diseases in temperate climates (2), where such infections are rarely seen by physicians and thus may not be considered in differential diagnoses. Gnathostomiasis is a foodborne zoonotic helminthic infection caused by the third-stage larva of Gnathostoma spp. nematodes (Figure 1, panels A, B). At least 13 species have been identified (3), with 5 recorded in humans. G. spinigerum is the most common of these nematodes in Asia. Human infection with G. hispidum, G. doloresi, and G. nipponicum were found only in Japan (4). In the Americas, G. binucleatum is the only proven pathogenic Gnathostoma nematode in humans. Humans are infected primarily by eating raw or undercooked freshwater fish (Figure 1, panel C), frogs, and chicken. Humans are accidental unsuitable hosts; the parasite rarely develops to an adult worm, and the disease in humans is caused by the migrating larva.Open in a separate windowFigure 1A) Third-stage larva of the nematode Gnathostoma sp. Scale bar = 250 µm. B) Scanning electronic microscopy image depicting head bulb with 4 cephalic hooklet rows. Original magnification ×500. C) Gnathostoma sp. larvae in the flesh of their intermediate host, Eleotris picta fish. Original magnification ×4. Inset: Higher magnification of an encysted larva; original magnification ×100. Larvae photographs courtesy of Dr Diaz-Camacho, Universidad Autónoma de Sinaloa, Sinaloa, Mexico. D) Cross section of a Gnathostoma sp. larva in human skin biopsy sample (hematoxylin and eosin stain). Scale bar = 250 µm.Gnathostomiasis can be divided into cutaneous, visceral, and ocular forms, depending on the site of larval migration and subsequent signs and symptoms (2). The most common clinical presentation is the cutaneous one (Figure 1, panel D), which is characterized by localized, intermittent, migratory swellings of the skin and is often associated with localized pain, pruritus, and erythema (5,6). Visceral involvement can manifest in virtually any organ and any part of the body (3). The most severe manifestation of the visceral disease is involvement of the central nervous system (CNS), i.e., neurognathostomiasis. Neurognathostomiasis has been reported only in G. spinigerum infections (3).We found 24 reports describing a total of 248 patients with neurognathostomiasis published in English-language literature. In this article, we review epidemiology, mode of CNS invasion, pathophysiology, clinical features, neuroimaging data, and treatment options, and we propose diagnostic criteria for this emerging disease.     

Escherichia coli O157 Outbreaks in the United States, 2003–2012

Infections with the Shiga toxin–producing bacterium Escherichia coli O157 can cause severe illness and death. We summarized reported outbreaks of E. coli O157 infections in the United States during 2003–2012, including demographic characteristics of patients and epidemiologic findings by transmission mode and food category. We identified 390 outbreaks, which included 4,928 illnesses, 1,272 hospitalizations, and 33 deaths. Transmission was through food (255 outbreaks, 65%), person-to-person contact (39, 10%), indirect or direct contact with animals (39, 10%), and water (15, 4%); 42 (11%) had a different or unknown mode of transmission. Beef and leafy vegetables, combined, were the source of >25% of all reported E. coli outbreaks and of >40% of related illnesses. Outbreaks attributed to foods generally consumed raw caused higher hospitalization rates than those attributed to foods generally consumed cooked (35% vs. 28%). Most (87%) waterborne E. coli outbreaks occurred in states bordering the Mississippi River.Signs and symptoms of infection with Shiga toxin–producing Escherichia coli O157 can include diarrhea that is often bloody, severe stomach cramps, and vomiting; infection can progress to hemolytic uremic syndrome (HUS) and death (1). In the United States, these infections and related illnesses are estimated to cost >$405 million annually (2).E. coli O157 can be transmitted to humans through contaminated food and water, directly between persons, and through contact with animals or their environment. The most common reservoir is cattle, and ground beef is the most frequently identified vehicle of transmission to humans. E. coli O157 was first recognized as a foodborne pathogen after outbreaks during 1982 were linked to ground beef consumption (1). Since then, many other sources have been identified (3), mostly through outbreak investigations. We describe the epidemiology of E. coli O157 outbreaks during 2003–2012.     

Whole-Genome Characterization of Epidemic Neisseria meningitidis Serogroup C and Resurgence of Serogroup W,Niger, 2015

In 2015, Niger reported the largest epidemic of Neisseria meningitidis serogroup C (NmC) meningitis in sub-Saharan Africa. The NmC epidemic coincided with serogroup W (NmW) cases during the epidemic season, resulting in a total of 9,367 meningococcal cases through June 2015. To clarify the phylogenetic association, genetic evolution, and antibiotic determinants of the meningococcal strains in Niger, we sequenced the genomes of 102 isolates from this epidemic, comprising 81 NmC and 21 NmW isolates. The genomes of 82 isolates were completed, and all 102 were included in the analysis. All NmC isolates had sequence type 10217, which caused the outbreaks in Nigeria during 2013–2014 and for which a clonal complex has not yet been defined. The NmC isolates from Niger were substantially different from other NmC isolates collected globally. All NmW isolates belonged to clonal complex 11 and were closely related to the isolates causing recent outbreaks in Africa.Key words: Meningococcal meningitis, Neisseria meningitidis serogroup C, whole-genome sequencing, Niger, meningitis belt, bacteriaNeisseria meningitidis commonly causes meningitis in the African meningitis belt, where periodic meningococcal epidemics have contributed to the highest reported incidence of meningococcal meningitis in the world (1). Most meningococcal disease historically has been caused by N. meningitidis serogroup A (NmA); however, NmA disease dramatically decreased after the preventative MenAfriVac vaccination campaign was initiated in 2010 (2). Serogroup W (NmW) has been the major cause of meningococcal disease in the region since then (2).N. meningitidis serogroup C (NmC) disease has rarely been reported in the meningitis belt; it has not been detected in many molecular studies of invasive isolates (3,4) and is rarely found in carriage studies (5,6). The last large NmC epidemic in Africa occurred in Burkina Faso (then Upper Volta) in 1979 (7). During 2013 and 2014, NmC outbreaks were reported in Nigeria (8). The Nigerian outbreaks were caused by a novel NmC strain with a previously undescribed sequence type, 10217 (ST-10217), which does not belong to a defined clonal complex. In 2015, an epidemic of 9,367 meningococcal meningitis cases occurred in Niger, with NmC disease comprising most laboratory-confirmed cases (9).NmW disease has been reported in the meningitis belt since the 1980s (10,11), and NmW from clonal complex 11 (CC11) has been a major concern in the region since 2001 (12). The first large epidemic of disease caused by CC11 NmW occurred during 2002 in Burkina Faso (13). Subsequently, NmW disease outbreaks were reported in Niger during 2010 and 2011, both involving CC11 (14). These outbreaks were followed by another large epidemic caused by CC11 NmW in Burkina Faso during 2012 (15). Whole-genome sequencing (WGS) analysis of diverse NmW isolates from around the world has demonstrated that a clone within CC11, commonly associated with NmC, became globally dispersed after it switched to serogroup W (16,17). WGS analyses also provided sufficient resolution to assign isolates from the meningitis belt to a long-standing regional population and to a clone that became globally dispersed after an outbreak during the 2000 Hajj pilgrimage (16,17; A. Retchless, unpub. data).In addition to distinguishing among closely related strains, WGS provides information about allelic variation in genes that may affect antibiotic susceptibility and the coverage of protein-based vaccines. Two vaccines designed for serogroup B meningococcus have been approved for use in the United States and Europe: Trumenba and Bexsero. Trumenba targets the factor H–binding protein (FHbp), and includes components belonging to FHbp subfamilies A and B (18). Bexsero includes 4 different components: an FHbp of variant 1 (subfamily B); a Neisseria adhesion A protein (NadA); a neisserial heparin-binding antigen (NhbA); and outer membrane vesicles from a serogroup B strain containing PorA P1.4 (19). Recognizing the diversity of these genes among strains can aid in evaluating whether these vaccines may provide protection. Likewise, whole-genome sequences can be rapidly screened for indications of antibiotic resistance when the genetic determinants are well characterized, as with genes penA, gyrA, and rpoB, which are involved in reduced susceptibility to penicillin, ciprofloxacin, and rifampin, respectively. To clarify the meningococcal population in Niger during the 2015 epidemic season, we completed genomic analysis on the 102 NmC and NmW invasive isolates collected during this period.     

Neighborhood psychosocial hazards and cardiovascular disease: the Baltimore Memory Study

Objectives. We examined associations between cardiovascular disease and neighborhood psychosocial hazards, such as violent crime, abandoned buildings, and signs of incivility, to evaluate whether features of place are associated with older adult health.Methods. We analyzed first-visit data from the Baltimore Memory Study of randomly selected residents aged 50 to 70 years (n=1140) of 65 contiguous neighborhoods in Baltimore, Maryland. We looked for associations between self-reports of history of selected cardiovascular diseases and scores on the 12-item neighborhood psychosocial hazards scale.Results. After adjustment for established individual risk factors for cardiovascular disease, residents in neighborhoods with scores in the highest quartile of the psychosocial hazards scale had more than 4 times higher odds of a history of myocardial infarction and more than 3 times higher odds of myocardial infarction, stroke, transient ischemic attack, or intermittent claudication compared with residents living in neighborhoods scoring in the lowest quartile.Conclusions. Neighborhood psychosocial hazards were significantly associated with self-reported cardiovascular disease after adjustment for individual-level risk factors. This is consistent with the hypothesis that environmental stress plays a role in the etiology of cardiovascular disease.The effect on health of the places in which people live—apart from individual, genetic, or lifestyle characteristics—is of increasing interest to researchers.1 A new wave of research is examining the health consequences of various aspects of residential neighborhoods. Moving beyond the study of individual risk factors to the study of neighborhoods may be a key to understanding widening health disparities across racial/ethnic and sociodemographic groups.2^,3Many aspects of neighborhoods are hypothesized to influence cardiovascular disease (CVD) risk through several different and potentially interrelated mechanisms.4^–6 Health behavior has received significant attention. Some data suggest that residents of socioeconomically deprived neighborhoods are more likely to engage in high-risk health behaviors, including inactivity,7^,8 poor diet,9 illicit drug use,10^,11 and smoking.12 However, studies that found an association between neighborhood of residence and CVD after adjustment for many of these health behaviors raised doubts that behavior was the sole mechanism.13^,14Several studies have examined the relationship between neighborhood socioeconomic characteristics (such as percentage of residents living in poverty) and CVD. Living in disadvantaged neighborhoods was found to be independently associated with increased risk of subclinical CVD,15 coronary heart disease,13^,16 and stroke,17 as well as poorer prognosis and decreased survival after myocardial infarction.18 Several explanations have been suggested for this association.4Psychosocial hazards in the neighborhood may be an important link between neighborhood socioeconomic disadvantage and adverse health outcomes.5^,19 Psychosocial hazards are visible characteristics of neighborhoods—such as violent crime, abandoned buildings, and signs of incivility—that give rise to a heightened state of vigilance, alarm, or threat.6^,20 Daily exposure to psychosocial hazards in the neighborhood is known to activate a physiological stress response.21^,22 Chronic stress may in turn lead to dysregulation of either the autonomic nervous system23 or the hypothalamic–pituitary–adrenal axis, or both. Dysregulation of the latter has been linked to key CVD risk factors, including the deposition of abdominal fat,24^,25 acute and chronic elevations in blood pressure,26 and various inflammatory processes.27We tested the hypothesis that a higher level of neighborhood psychosocial hazards is associated with increased odds of self-reported myocardial infarction, stroke, transient ischemic attack, and intermittent claudication, independent of individual-level risk factors.     

Childhood socioeconomic position, gender, adult body mass index, and incidence of type 2 diabetes mellitus over 34 years in the Alameda County Study

Objectives. We examined the association between childhood socioeconomic position and incidence of type 2 diabetes and the effects of gender and adult body mass index (BMI).Methods. We studied 5913 participants in the Alameda County Study from 1965 to 1999 who were diabetes free at baseline (1965). Cox proportional hazards models estimated diabetes risk associated with childhood socioeconomic position and combined childhood socioeconomic position–adult BMI categories in pooled and gender-stratified samples. Demographic confounders and potential pathway components (physical inactivity, smoking, alcohol consumption, hypertension, depression, health care access) were included as covariates.Results. Low childhood socioeconomic position was associated with excess diabetes risk, especially among women. Race and body composition accounted for some of this excess risk. The association between childhood socioeconomic position and diabetes incidence differed by adult BMI category in the pooled and women-only groups. Adjustment for race and behaviors attenuated the risk attributable to low childhood socioeconomic position among the obese group only.Conclusions. Childhood socioeconomic position was a robust predictor of incident diabetes, especially among women. A cumulative risk effect was observed for both childhood socioeconomic position and adult BMI, especially among women.In recent years, much effort has gone into characterizing biological and social exposures during gestation and childhood that may lead to adult chronic diseases. Childhood socioeconomic disadvantage has been associated with mortality1^–4 and several adult physical5^–7 and mental health5^,7^–9 outcomes.Studies investigating the relationship between childhood socioeconomic disadvantage and diabetes have shown inconsistent results. Childhood socioeconomic position (SEP) was linked to prevalent type 2 diabetes,10^–14 insulin resistance,15 higher glucose levels,16^,17 and metabolic syndrome18^,19 in some studies, yet showed no association with impaired glucose tolerance20^,21 or metabolic syndrome22 in others. Three studies investigated the association between childhood SEP and incident diabetes in adulthood and reported either modest11^,23 or no effects.12Although the evidence thus far is insufficient to establish a causal link between childhood SEP and incident type 2 diabetes, the hypothesis is plausible. Childhood disadvantage has been linked to illnesses, such as cardiovascular diseases,24 that have overlapping pathologies with diabetes. Persons exposed to socioeconomic disadvantage in childhood are more likely to be of lower socioeconomic means as adults.25^,26 Several studies have shown inverse, graded associations between different measures of adult SEP and the prevalence11^,13^,22^,27^,28 and incidence11^,12^,23^,29^–34 of type 2 diabetes. Childhood SEP also influences adult body composition35^–41 and several behaviors20^,42^–45 that are risk factors for type 2 diabetes.Obesity is a strong predictor of type 2 diabetes.46^–48 Therefore, the effect of childhood SEP on diabetes incidence may differ by body mass index (BMI; weight in kilograms divided my height in meters squared) in adulthood. For example, low childhood SEP and adult obesity together may impart a greater risk of type 2 diabetes than the risk imparted by low childhood SEP alone. Such exposure patterns may represent an accumulation of risk over time or a risk pathway. In addition, several studies have shown that the effects of childhood circumstances on adult health and risk behaviors differ by gender.37^,38^,40^,49^–52 The question remains whether childhood SEP differentially influences diabetes risk for women and men.Previous studies of childhood SEP and incident diabetes had short follow-up periods,11^,12^,23 and one was limited to women.23 Our approach complemented these studies by using 5 waves of data collected in a population-based sample from 1965 to 1999 to examine the association between childhood SEP and the incidence of type 2 diabetes and how this association may differ by gender or adult BMI.     

Life-Course Socioeconomic Position and Incidence of Diabetes Mellitus Among Blacks and Whites: The Alameda County Study, 1965�C1999

Objectives. We examined associations between several life-course socioeconomic position (SEP) measures (childhood SEP, education, income, occupation) and diabetes incidence from 1965 to 1999 in a sample of 5422 diabetes-free Black and White participants in the Alameda County Study.Methods. Race-specific Cox proportional hazard models estimated diabetes risk associated with each SEP measure. Demographic confounders (age, gender, marital status) and potential pathway components (physical inactivity, body composition, smoking, alcohol consumption, hypertension, depression, access to health care) were included as covariates.Results. Diabetes incidence was twice as high for Blacks as for Whites. Diabetes risk factors independently increased risk, but effect sizes were greater among Whites. Low childhood SEP elevated risk for both racial groups. Protective effects were suggested for low education and blue-collar occupation among Blacks, but these factors increased risk for Whites. Income was protective for Whites but not Blacks. Covariate adjustment had negligible effects on associations between each SEP measure and diabetes incidence for both racial groups.Conclusions. These findings suggest an important role for life-course SEP measures in determining risk of diabetes, regardless of race and after adjustment for factors that may confound or mediate these associations.Diabetes mellitus is a major cause of morbidity and mortality in the United States.^1,2 Type 2 diabetes disproportionately affects Hispanics, as well as non-Hispanic Black Americans, American Indians/Alaska Natives, and some Asian/Pacific Islander groups. In the United States, members of racial and ethnic minority groups are almost twice as likely to develop or have type 2 diabetes than are non-Hispanic Whites.^2–5 Significant racial and ethnic differences also exist in the rates of diabetes-related preventive services, quality of care, and disease outcomes.^6–10Researchers have attempted to determine why, relative to Whites, members of racial and ethnic minority groups are disproportionately affected by diabetes. For example, compared with White Americans, Black Americans are presumed to have stronger genetic^5,11 or physiological^11–13 susceptibility to diabetes, or greater frequency or intensity of known diabetes risk factors, such as obesity, physical inactivity, and hypertension.^14–17Black Americans also are more likely than are White Americans to occupy lower socioeconomic positions.¹⁸ Low socioeconomic position (SEP) across the life course is known to influence the prevalence^19–24 and incidence^3,19,25–30 of type 2 diabetes. The risk of diabetes also is greater for people who are obese,^3,17,31 physically inactive,^3,32 or have hypertension,^33,34 all of which are conditions more common among people with lower SEP.^16,35–37Several studies have focused on the extent to which socioeconomic factors, body composition (i.e., weight, height, body mass index, and waist circumference), and behaviors explain the excess risk of diabetes attributed to race.^4,12,19,30 For example, 2 separate studies, one with data from the Health and Retirement Study¹⁹ and the other with data from the Atherosclerosis Risk in Communities Study,³⁰ used race to predict diabetes incidence. Attempting to separate the direct and indirect effects of race on diabetes,³⁸ these studies assessed, via statistical adjustment, which socioeconomic measures and diabetes-related risk factors, when adjusted, could account for the excess risk among Black participants relative to White participants.^19,30 Adjustment for education lessened the effect of Black race on diabetes incidence in the Atherosclerosis Risk in Communities Study.³⁰ In the Health and Retirement Study, excess risk attributed to Black race was not explained by early-life socioeconomic disadvantage, but it was reduced after adjustment for education and later-life economic resources.¹⁹ The validity of this analytic approach has been challenged, however, because the socioeconomic measures used were assumed to have the same meaning across all racial/ethnic groups, a questionable assumption³⁸ in the United States, especially in 1965.We sought to explore the predictive effects of several life-course socioeconomic factors on the incidence of diabetes among both Black and White Americans. We examined demographic confounders (age, gender, marital status) and diabetes risk factors (obesity, large waist circumference, physical inactivity, high blood pressure, depression, access to health care) as possible mediators of the observed associations between SEP and incident diabetes (i.e., the development of new cases of diabetes over time).     

The association between perceived discrimination and obesity in a population-based multiracial and multiethnic adult sample

Objectives. We examined whether perceived chronic discrimination was related to excess body fat accumulation in a random, multiethnic, population-based sample of US adults.Methods. We used multivariate multinomial logistic regression and logistic regression analyses to examine the relationship between interpersonal experiences of perceived chronic discrimination and body mass index and high-risk waist circumference.Results. Consistent with other studies, our analyses showed that perceived unfair treatment was associated with increased abdominal obesity. Compared with Irish, Jewish, Polish, and Italian Whites who did not experience perceived chronic discrimination, Irish, Jewish, Polish, and Italian Whites who perceived chronic discrimination were 2 to 6 times more likely to have a high-risk waist circumference. No significant relationship between perceived discrimination and the obesity measures was found among the other Whites, Blacks, or Hispanics.Conclusions. These findings are not completely unsupported. White ethnic groups including Polish, Italians, Jews, and Irish have historically been discriminated against in the United States, and other recent research suggests that they experience higher levels of perceived discrimination than do other Whites and that these experiences adversely affect their health.It is estimated that 2 of every 3 adults in the United States are overweight or obese.^1,2 Obesity is a major risk factor for chronic health conditions, such as type 2 diabetes, coronary heart disease, hypertension, stroke, some forms of cancer, and osteoarthritis.³ Although it is widely accepted that high-fat diets and physical inactivity are preventable risk factors,⁴ obesity continues to increase.^1,2,5There is a growing interest in the relationship between psychosocial risk factors and excess body fat accumulation.^6–16 In particular, some evidence suggests that psychosocial stressors may play a role in disease progression in general and in excess body fat in particular.^7,8,17 The key factors underlying physiological reactions to psychosocial stress have not been completely elucidated, but McEwen and Seeman¹⁷ and others^7,18,19 posit that the continued adaptation of the physiological system to external challenges alters the normal physiological stress reaction pathways and that these changes are related to adverse health outcomes.^8,17,18,20 For example, in examining the association between psychosocial stress and excess body fat accumulation, Björntorp and others have suggested that psychosocial stress is linked to obesity, especially in the abdominal area.^7,8Perceived discrimination, as a psychosocial stressor, is now receiving increased attention in the empirical health literature.^21–24 Such studies suggest perceived discrimination is inversely related to poor mental and physical health outcomes and risk factors, including hypertension,^24,25 depressive symptoms,^26–28 smoking,^29–31 alcohol drinking,^32,33 low birthweight,^34,35 and cardiovascular outcomes.^36–38Internalized racism, the acceptance of negative stereotypes by the stigmatized group,³⁹ has also been recognized as a race-related psychosocial risk factor.⁴⁰ Recent studies have also suggested that race-related beliefs and experiences including perceived discrimination might be potentially related to excess body fat accumulation. Three of these studies^9,13,41 showed that internalized racism was associated with an increased likelihood of overweight or abdominal obesity among Black Caribbean women in Dominica⁴¹ and Barbados¹³ and adolescent girls in Barbados.⁹ These researchers posit that individuals with relatively high levels of internalized racism have adopted a defeatist mindset, which is believed to be related to the physiological pathway associated with excess body fat accumulation. However, Vines et al.¹⁶ found that perceived racism was associated with lower waist-to-hip ratios among Black women in the United States. Although the assessment of race-related risk factors varied across these studies, the findings suggest that the salience of race-related beliefs and experiences may be related to excess body fat accumulation.Collectively, the results of these studies are limited. First, because they examined the relationship between race-related beliefs and experiences and excess body fat only among women, we do not know if this relationship is generalizable to men.^13,16,41 Second, these studies only examined this relationship among Blacks, even though perceived unfair treatment because of race/ethnicity has been shown to be adversely related to the health of multiple racial/ethnic population groups in the United States^42–49 and internationally.^27,50–55 Third, none of the studies have examined the relationship between excess body fat accumulation and perceived nonracial/nonethnic experiences of interpersonal discrimination. Some evidence suggests that the generic perception of unfair treatment or bias is adversely related to health, regardless of whether it is attributed to race, ethnicity, or some other reason.^45,55,56 Fourth, none of these studies included other measures of stress. We do not know if the association between race-related risk factors and obesity is independent of other traditional indicators of stress.Using a multiethnic, population-based sample of adults, we examined the association of perceived discrimination and obesity independent of other known risk factors for obesity, including stressful major life events. Additionally, because reports of perceived racial/ethnic discrimination and non-racial/ethnic discrimination vary by racial/ethnic groups^24,45,46,57 and because Whites tend to have less excess body fat than do Blacks and Hispanics,^1,3 we examined the relationships between perceived discrimination and excess body fat accumulation among Hispanics, non-Hispanic Whites, and non-Hispanic Blacks.     

Minimal Diversity of Drug-Resistant Mycobacterium tuberculosis Strains,South Africa

Multidrug- (MDR) and extensively drug-resistant tuberculosis (XDR TB) are commonly associated with Beijing strains. However, in KwaZulu-Natal, South Africa, which has among the highest incidence and mortality for MDR and XDR TB, data suggest that non-Beijing strains are driving the epidemic. We conducted a retrospective study to characterize the strain prevalence among drug-susceptible, MDR, and XDR TB cases and determine associations between strain type and survival. Among 297 isolates from 2005–2006, 49 spoligotype patterns were found. Predominant strains were Beijing (ST1) among drug-susceptible isolates (27%), S/Quebec (ST34) in MDR TB (34%) and LAM4/KZN (ST60) in XDR TB (89%). More than 90% of patients were HIV co-infected. MDR TB and XDR TB were independently associated with mortality, but TB strain type was not. We conclude that, although Beijing strain was common among drug-susceptible TB, other strains predominated among MDR TB and XDR TB cases. Drug-resistance was a stronger predictor of survival than strain type. Key words: Mycobacterium tuberculosis, drug resistance, transmission, genotype, South Africa, HIV, bacteria, tuberculosis, tuberculosis and other mycobacteria, antimicrobial resistanceDrug-resistant tuberculosis (TB) has emerged as a substantial threat to advances in global TB control over the past several decades (1). Worldwide, an estimated 630,000 cases of multidrug-resistant (MDR) TB occurred in 2011, and extensively drug-resistant (XDR) TB has now been reported in 84 countries (2). MDR TB and XDR TB are each associated with very high mortality rates (3), and their transmission—both in community and health care settings—remains an ongoing challenge in resource-limited settings and in countries with high rates of HIV co-infection.In South Africa, the incidence of MDR TB has increased 5-fold since 2002 (2,4). MDR TB treatment is now estimated to consume more than half of the budget allocated for TB control in South Africa (5). The emergence of XDR TB, and its associated high mortality rates, have further underscored the need for clarifying the factors driving the drug-resistant TB epidemic to better focus control efforts (3,6,7).Drug-resistant TB is generally considered a human-made phenomenon that occurs when inadequate TB treatment creates selection pressure for the emergence of drug-resistant Mycobacterium tuberculosis subpopulations (acquired resistance) (1). Researchers initially believed that the mutations causing drug resistance would exert a “fitness cost,” rendering those strains too weak to be transmitted (8,9). Nonetheless, transmission of drug-resistant TB strains has now been well-documented (10–13), and laboratory studies have shown that clinical strains may have minimal fitness costs or even none (14). Emerging data suggest that most MDR TB and XDR TB cases in South Africa and worldwide are likely caused by primary transmission of drug-resistant strains (2,15–19).Although the M. tuberculosis W/Beijing strain family has been described among cases of drug-susceptible, MDR TB, and XDR TB in South Africa, numerous other strain types have also been identified (20,21). Little is known about the transmissibility and virulence of M. tuberculosis strains aside from the W/Beijing strain family (22,23). In the Eastern Cape and Western Cape Provinces of South Africa, strains from the W/Beijing family have most often been associated with transmission of drug-resistant TB (24–27). At our study site in KwaZulu-Natal Province, however, the LAM4/KZN strain type has predominated among MDR TB and XDR TB cases and has been linked to nosocomial transmission and high mortality rates (3,16,17,28,29). This strain is a member of the Euro-American strain family and was first described in this region in 1994, evolving into an increasingly resistant phenotype over time (29).The reasons for why the LAM4/KZN strain is prominent in KwaZulu-Natal Province, rather than the Beijing strain, which is seen globally and in other parts of South Africa, is unclear. Moreover, it is unknown whether the higher mortality among patients with MDR TB and XDR TB in KwaZulu-Natal can be explained, in part, by a difference in genotypic prevalence and associated differences in strain virulence (3,6,7,28). In this study, we sought to characterize the genotypic diversity of M. tuberculosis strains among isolates causing drug-susceptible TB, MDR TB, and XDR TB in KwaZulu-Natal Province, South Africa. We also examined the relationship between M. tuberculosis strain, drug resistance, and patient survival.