From the Cover: Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model

Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen Bordetella pertussis. Pertussis rates in the United States have been rising and reached a 50-y high of 42,000 cases in 2012. Although pertussis resurgence is not completely understood, we hypothesize that current acellular pertussis (aP) vaccines fail to prevent colonization and transmission. To test our hypothesis, infant baboons were vaccinated at 2, 4, and 6 mo of age with aP or whole-cell pertussis (wP) vaccines and challenged with B. pertussis at 7 mo. Infection was followed by quantifying colonization in nasopharyngeal washes and monitoring leukocytosis and symptoms. Baboons vaccinated with aP were protected from severe pertussis-associated symptoms but not from colonization, did not clear the infection faster than naïve animals, and readily transmitted B. pertussis to unvaccinated contacts. Vaccination with wP induced a more rapid clearance compared with naïve and aP-vaccinated animals. By comparison, previously infected animals were not colonized upon secondary infection. Although all vaccinated and previously infected animals had robust serum antibody responses, we found key differences in T-cell immunity. Previously infected animals and wP-vaccinated animals possess strong B. pertussis-specific T helper 17 (Th17) memory and Th1 memory, whereas aP vaccination induced a Th1/Th2 response instead. The observation that aP, which induces an immune response mismatched to that induced by natural infection, fails to prevent colonization or transmission provides a plausible explanation for the resurgence of pertussis and suggests that optimal control of pertussis will require the development of improved vaccines.Pertussis is a highly contagious, acute respiratory illness caused by the bacterial pathogen Bordetella pertussis (1, 2). Infection results in a wide spectrum of clinical manifestations ranging from mild respiratory symptoms to a severe cough illness accompanied by marked leukocytosis and the hallmark inspiratory whoop and posttussive emesis (3). Because acellular pertussis vaccines replaced whole-cell vaccines in the 1990s, pertussis has reemerged at a startling rate in the United States despite nationwide vaccine coverage in excess of 95% (4). With a 50-y high of 42,000 reported cases in the United States in 2012, pertussis is the most common of the vaccine-preventable diseases (5). This resurgence is mirrored throughout the industrial world despite similar high rates of vaccination (6–9). Two common hypotheses for the resurgence have been proposed: i) current acellular pertussis vaccines (aP) vaccines are less effective than the whole-cell pertussis (wP) vaccines they replaced and ii) aP-induced immunity wanes more quickly than anticipated (10–13). However, pertussis resurgence is not completely understood (14, 15).Hampering our ability to counteract this resurgence is the fact that pertussis pathogenesis and immunity to natural infection have not been well studied in humans because typical pertussis is sporadic given high rates of vaccination in developed countries. Human challenge studies have been proposed but never conducted due to a variety of logistical and ethical problems including the potential for severe disease, the lack of an effective therapeutic for established disease, and the highly contagious nature of pertussis. Although a variety of small-animal models have been used to study pertussis, none of them adequately reproduce the human disease (16). To address this gap, we recently developed a nonhuman primate model of pertussis using baboons (Papio anubis) and found the disease is very similar to severe clinical pertussis. Upon challenge, baboons experience 2 wk of heavy respiratory colonization and leukocytosis peaking between 30,000–80,000 cells/mL, similar to the range in pertussis-infected infants (1, 17). In addition, baboons experience a paroxysmal cough illness characterized by repeated fits of 5–10 coughs. The coughing fits last on average >2 wk in the baboon, although this is less than some severely infected children, where the cough can last up to 12 wk (1, 17). We also characterized airborne transmission of B. pertussis from infected to naïve animals, which is the route of transmission postulated to occur between humans (18). Because this is the only model of pertussis to reproduce the cough illness and transmission of the human disease, we believe it provides the unique opportunity to test our hypothesis that aP vaccines fail to prevent B. pertussis colonization, thus enabling transmission among vaccinated individuals.Using this model we have confirmed that, as in humans, aP vaccines provide excellent protection against severe disease in baboons. However, aP vaccines do not prevent colonization following direct challenge or infection by transmission. In addition, aP-vaccinated animals are capable of transmitting disease to naïve contacts. By comparison, wP-vaccinated animals cleared infection significantly more quickly than aP-vaccinated or naïve animals. We also found that aP vaccination induces T helper 2 (Th2) and T helper 1 (Th1) immune memory responses, whereas infection and—to a lesser extent—wP vaccination induce Th17 and Th1 memory. Our results suggest that in addition to the potential contribution of reduced efficacy and waning immunity of aP, the inability of aP to prevent colonization and transmission provides a plausible explanation for pertussis resurgence.     

A school-based approach to the control of urinary schistosomiasis and intestinal helminth infections in children in Matuga, Kenya: impact of a two-year chemotherapy programme on prevalence and intensity of infections

A school- and chemotherapy-based urinary schistosomiasis and intestinal helminth infection control programme was conducted in Matuga Division, Kwale District, Coast Province with teachers taking care of diagnosis, treatment and health education. More than 12 000 children in 36 primary schools were included in the 2-year programme. Results for 20 evaluation schools are presented. Children with haematuria were treated with praziquantel (40 mg/kg) once a year. Within 2 years, the prevalence of haematuria in the schools was reduced from 28% (range 8–68%) to 11.4% (range 3–23%). More than 80% of the schoolchildren were infected with one or more intestinal helminths at baseline. After one year with levamisole mass chemotherapy, single dose (2.5 mg/kg) three times a year (once per school term), the prevalence of Ascaris infection was reduced by 83% from 18% to 3%, but there was no change in pretreatment prevalences of hookworm (57%) and Trichuris (56%) infections. In the second year of the programme, albendazole 600 mg once every six months was administered to the children in 10 randomly selected schools. This resulted in 52% and 23% reductions in prevalences of hookworm and Trichuris infections, respectively, in these schools and a reduction in mean intensity of infection of 52.8% and 50.3%, respectively.     

Lymphedema secondary to breast cancer: how choice of measure influences diagnosis, prevalence, and identifiable risk factors

Research on secondary lymphedema primarily uses indirect methods for diagnosis. This paper compares prevalence and cumulative burden following breast cancer surgery, as well as personal, treatment, and behavioral characteristics associated with lymphedema, using different assessment techniques. Lymphedema status was assessed at three-monthly intervals between six- and 18-months post-surgery in a population-based sample of Australian women with recently diagnosed, unilateral, invasive breast cancer, using three methods: bioimpedance spectroscopy (BIS), difference between sum of arm circumferences (SOAC) and self-report. Depending on the method, point prevalence ranged between 8 to 28%, with 1 in 5 to 2 in 5 women experiencing lymphedema at some point in time. Of those with lymphedema defined by BIS, almost 40%-60% went undetected, and 40%-12% were misclassified as having lymphedema, based on self-report and SOAC, respectively. The choice of measure also had significant implications for identified risk factors. Over 10 characteristics were associated with lymphedema, however only one, experiencing other upper-body symptoms at baseline, influenced odds of lymphedema across all three methods. These findings highlight that secondary lymphedema poses a significant public health problem. Utilizing the most accurate and reliable method for assessment is crucial to advance our understanding of preventive and treatment strategies.     

Increasing prevalence of coeliac disease in Swedish children: influence of feeding recommendations, serological screening and small intestinal biopsy activity

BACKGROUND: The prevalence of coeliac disease (CD) in Swedish children has attracted considerable interest over the past few decades, and especially the influence of feeding habits on the increased incidence. A national study has reported a trend towards a decrease in incidence after a change in infant feeding recommendations was introduced in 1996. The aim of this study was to evaluate, in a geographically defined area, the change in incidence with time and the influence of the introduction of antibody analysis. METHODS: Cases of suspected paediatric CD between 1980 and 2003 were studied for prevalence, biopsy findings and antibody analyses. RESULTS: A total of 2029 children were investigated by small intestinal biopsy, yielding 554 CD cases. The area initially showed the same trend as the national study, but the annual incidence rate is now increasing again. Median age at diagnosis has increased significantly since 1997 from less than 2 years of age to above 5 years. Cumulative incidence at 2 years of age is much higher for the birth cohorts 1983-96 than 1980-82 or 1997-2001. Diagnostic accuracy was significantly higher after the introduction of antigliadin (AGA) analysis, and especially after antiendomysium (EMA) analysis. CONCLUSIONS: The incidence rate of CD in small children in our region has varied widely over the 24-year period observed. Feeding practice and methods of investigation have changed during this period. The annual incidence rate for the total child population in 2003 was almost equal to the peak value observed in 1994. There were no conclusive results on whether antibody analysis had an influence on diagnostic activity, but this seems to have increased diagnostic accuracy.     

Increasing prevalence of coeliac disease in Swedish children: influence of feeding recommendations,serological screening and small intestinal biopsy activity

Background: The prevalence of coeliac disease (CD) in Swedish children has attracted considerable interest over the past few decades, and especially the influence of feeding habits on the increased incidence. A national study has reported a trend towards a decrease in incidence after a change in infant feeding recommendations was introduced in 1996. The aim of this study was to evaluate, in a geographically defined area, the change in incidence with time and the influence of the introduction of antibody analysis. Methods: Cases of suspected paediatric CD between 1980 and 2003 were studied for prevalence, biopsy findings and antibody analyses. Results: A total of 2029 children were investigated by small intestinal biopsy, yielding 554 CD cases. The area initially showed the same trend as the national study, but the annual incidence rate is now increasing again. Median age at diagnosis has increased significantly since 1997 from less than 2 years of age to above 5 years. Cumulative incidence at 2 years of age is much higher for the birth cohorts 1983–96 than 1980–82 or 1997–2001. Diagnostic accuracy was significantly higher after the introduction of antigliadin (AGA) analysis, and especially after antiendomysium (EMA) analysis. Conclusions: The incidence rate of CD in small children in our region has varied widely over the 24‐year period observed. Feeding practice and methods of investigation have changed during this period. The annual incidence rate for the total child population in 2003 was almost equal to the peak value observed in 1994. There were no conclusive results on whether antibody analysis had an influence on diagnostic activity, but this seems to have increased diagnostic accuracy.     

Longitudinal study of young children in Kenya: intestinal parasitic infection with special reference to Giardia lamblia, its prevalence, incidence and duration, and its association with diarrhoea and with other parasites.

84 young children from a rural community, Nderu, in Kenya, were each followed for up to 10 months, from January to November 1987. Their ages ranged from 10 to 28 months over the period of study. Stools were obtained once a week, as were reports from the mothers about presence of abdominal complaints, including diarrhoea. A total of 2258 stools and 1873 reports were collected. 9 parasites were commonly encountered of which Giardia lamblia was the most frequent at 44.7%. The overall estimated number of new Giardia episodes per year per child was 2.77 +/- 2.22 SD and the mean estimated duration of infection was 75.25 +/- 73.84 SD days per child. The mean proportion of positive visits per child was 0.42 +/- 0.25 SD. Giardia trophozoites, Trichomonas hominis, Chilomastix mesnili, Entamoeba histolytica, Blastocystis hominis and Hymenolepis nana were all significantly associated with unformed stools and reports of diarrhoea. There was a significant probability of finding Giardia in stool within +/- 2 weeks of a report of diarrhoea. Poly-parasitism was common and several paired associations were significantly positive, particularly between species of amoebae. Quantity of Giardia in stool (expressed as a 0 to 5+ score) was suppressed both by type and number of other parasites present.     

Asymptomatic intestinal colonization by pathogenic Entamoeba histolytica in amebic liver abscess: prevalence, response to therapy, and pathogenic potential.

Since the application of isoenzyme electrophoresis to the study of Entamoeba histolytica, the prevalence and natural history of asymptomatic intestinal colonization in patients with amebic liver abscess (ALA) has not been addressed. We prospectively evaluated this enteric phase in 50 patients with ALA, using two dosage regimens of metronidazole. The overall prevalence of asymptomatic colonization was 72% (36/50). All these isolates, without exception, proved to express pathogenic zymodemes. Despite a 100% clinical response of the hepatic lesions, failure to eradicate the organism from the bowel occurred in 20 of these 36 subjects. During longitudinal posttreatment surveillance, three carriers returned with second bouts of invasive disease: one with dysentery and two with liver abscesses. Thus, in patients with ALA, there is a high prevalence of intestinal colonization with exclusively pathogenic strains, and treatment with metronidazole frequently results in a continued carrier state. These carriers have a propensity for developing recurrent invasive disease and constitute a public health hazard.     

Geographical influences on the association between adherence to the Mediterranean diet and the prevalence of acute coronary syndromes, in Greece: the CARDIO2000 study

OBJECTIVE: We evaluated the interaction between adherence to the Mediterranean diet and region of Greece on the likelihood of having acute coronary syndromes (ACS). METHODS: During 2000-2001, a random sample of 848 patients (61+/-10 years) with their first coronary heart disease event, and 1078 frequency matched (by age-sex) controls with no cardiovascular disease in their medical history, from all the country, entered into the study. Among several factors, adherence to the Mediterranean diet was assessed by a diet-score that incorporated the inherent characteristics of this diet. RESULTS: The multi-adjusted analysis showed that a 10-unit increase in the diet score was associated with a 27% (95% CI 0.66 to 0.89) decrease of the odds of having ACS. Moreover, a highly significant interaction was observed between region and diet score (p<0.001). The odds ratios varied from roughly 0.5 in Southern to 1.2 or more in Northern Greek regions (p for heterogeneity<0.05). Differences in food patterns consumed did not explain the previous findings. In addition, when we stratified our analysis by rural and urban areas we found significant differences in the estimated odds ratios (p for interaction between diet score and area=0.01), since a 10-unit increase in the diet score was associated with 22% (95% CI 0.63 to 0.96) lower odds n urban areas and 31% (95% CI 0.48 to 0.98) lower odds in rural areas. CONCLUSION: Our findings underline the significance of the Mediterranean diet on the primary prevention of ACS. Moreover, we revealed a geographical variation in the importance of this dietary pattern on coronary risk, independent from the composition of food patterns followed and the prevalence of the common cardiovascular risk factors.     

Relationship of prevalence and intensity of infection to morbidity in schistosomiasis japonica: a study of three communities in Leyte, Philippines

To determine whether prevalence and intensity of infection are factors in morbidity in schistosomiasis japonica, a cross-sectional study was undertaken in three villages in Leyte, Philippines, namely, Santol (A), Santa Rosa (B), and Macanip (C). Kato thick-smear fecal examination and egg counts were made on 289 of 341 residents in Village A (85%), 824 of 1,008 in Village B (82%), and 1,113 of 1,241 in Village C (90%). Prevalences of 26%, 39%, and 44%, respectively, were found in the three villages, the majority of their populations (56-74%) remaining uninfected. Most of the infected persons (17-30% of the total population) had light infections (10-100 eggs/g feces). Moderately infected persons (101-400 eggs/g) comprised a smaller segment (7-14%), while a very small proportion (2-7%) had heavy infections (greater than or equal to 401 eggs/g). Age prevalence and egg excretion peaked earlier in the areas with higher prevalence (B and C) than in the area with the lowest prevalence (A). There was no relationship between area prevalence and mean egg count. Symptoms of inability to work, weakness, abdominal pain, and diarrhea correlated with the presence of infection in the area with the highest prevalence (C), but not in the area with the lowest prevalence (A). Except for diarrhea, there was no relationship between symptoms and intensity of infection. Very few persons presented with hepatomegaly and/or splenomegaly (1-5%). The frequency of liver enlargement on the midsternal (measuring 3-6 cm and 6 cm or more) and midclavicular line (2-4 cm), as well as spleen enlargement (Hackett 2 or greater), correlated with the presence but not with the intensity of infection. Hepatomegaly was sex- and age-related, being most common among males and among adolescents aged 10-14 years.     

Human infection with Wuchereria bancrofti in Matara,Sri Lanka: the use,in parallel,of an ELISA to detect filaria-specific IgG4 in urine and of ICT card tests to detect filarial antigen in whole blood

The ICT card test to detect circulating filarial antigen and an ELISA that detects filaria-specific urinary IgG(4) were each used to screen 473 subjects from a community in Sri Lanka where Wuchereria bancrofti is endemic. When the ICT test was used as the gold standard, the ELISA was found to have a sensitivity of 91.2%. However, far more of the subjects were found ELISA-positive than ICT-positive (76.5% v. 31.1%). The youngest children studied (aged 1-10 years) were similar to the adult subjects in terms of the prevalence of antigenaemia (33.8%) and the prevalence (72.1%) and concentration of filaria-specific IgG(4) in their urine. Therefore, especially as urine samples are easier, less painful and safer to collect than blood samples, the ELISA may be particularly useful to screen very young and school-age children, to estimate current levels of transmission in a particular area.     

Nutrition, immunity and helminth infection: effect of dietary protein on the dynamics of the primary antibody response to Trichuris muris (Nematoda) in CBA/Ca mice

The effect of dietary protein on the specific antibody responses (total immunoglobulins, IgG1 and IgA) to the intestinal nematode Trichuris muris was studied in CBA/Ca mice fed isocaloric diets containing 16% or 4% protein. Mice fed the 16% diet and given a high infection dose of 650 eggs expelled almost their entire primary infection by day 21 post infection. In similarly infected animals fed the 4% protein diet, there was prolonged survival of adult worms. At a low infection dose of 10 eggs, there was no evidence of an expulsion response in either dietary group. The primary antibody response to parasite excretory/secretory (E/S) antigen was time-dependent, regardless of dietary protein or infection dose, and was predominantly an IgG1 response. Within each dietary group, antibody production and antigen recognition occurred earlier and the antibody responses were more intense in mice given the higher infection dose. The principal finding was that the specific antibody response was more vigorous, both quantitatively (serum titres) and qualitatively (antigen recognition by IgG1), in mice on a low protein diet, even though worm expulsion did not occur in these hosts. This result suggests that serum antibody level or antigen recognition is not related simply to protective immunity against T. muris in CBA/Ca mice.     

Age-specific prevalence of antibodies to hepatitis A in Santiago,Chile: risk factors and shift in age of infection among children and young adults

Transition from high to lower endemicity of hepatitis A virus (HAV) infection may portend increased public health burden with the shift of infection to older ages and increasing morbidity and mortality. This report describes age-specific prevalence of antibodies to HAV (anti-HAV) among children and young adults in Santiago, Chile, compared with previous prevalence data and assesses factors predictive for anti-HAV. In 1998, a serosurvey was performed in Metropolitan Santiago, designed to enroll a representative, age-stratified population on the basis of area of residence. A total of 784 individuals (age range, 1-24 years) were enrolled. Anti-HAV prevalence by year of life was as follows: ages 1 to 4, 12.5%; 5 to 9, 26.2%; 10 to 14, 43.4%; 15 to 19, 57.4%; 20 to 24, 73.9%. Adjusting for age, factors associated (inversely) with anti-HAV included residential areas of higher socioeconomic status (SES), parental education, and household characteristics of potable water, municipal sewage system, and the presence of a toilet or refrigerator in the house. In logistic regression analysis, only maternal years of education and residence in areas of higher SES remained independently associated with anti-HAV. Excluding those from higher SES areas, comparison of the age-specific anti-HAV prevalence data from previous studies of similar methodology in areas of lower SES revealed consistent decreases across all age groups; the age-standardized prevalence for this age range (1-24 years) dropped from 53.7% in 1990 to 40.6% in 1998. In light of the growing pool of susceptible individuals at older ages, with HAV continuing to circulate in the communities, evaluation of the feasibility of vaccination programs would be judicious.     

Contribution of Interferon gamma release assays testing to the diagnosis of latent tuberculosis infection in HIV-infected patients: A comparison of QuantiFERON-TB gold in tube, T-SPOT.TB and tuberculin skin test

ABSTRACT: BACKGROUND: Diagnosis and treatment of latent tuberculosis infection (LTBI) is the most effective strategy to control tuberculosis (TB) among patients with HIV infection. The tuberculin skin test (TST) was the only available method to identify LTBI. The aim of the present work was to evaluate the usefulness of the interferon-gamma release assays (IGRAs): QuantiFERONtuberculosis (TB) Gold-In-Tube test (QFG) and T-SPOT.TB for the diagnosis of LTBI in a diverse cohort of HIV-infected patients. METHODS: A prospective study was carried out in consecutive patients cared for in a single institution in Spain from January 2009 to October 2010. IGRAS and tuberculin skin test (TST) were performed simultaneously. TST induration [greater than or equal to] 5 mm was considered positive. RESULTS: QFG, T-SPOT.TB and TST were performed in 373 subjects. Median CD4 cell count was 470/mul with a median nadir of 150/mul. TST, QFG and T-SPOT.TB were positive in 13.3%, 7.5% and 18.5% cases respectively. Among 277 patients with neither past or current TB nor previous treatment for LTBI and who had TST results, a positive TST result was obtained in 20 (7.2%) cases. When adding QFG results to TST, there were a total of 26 (8.6%) diagnoses of LTBI. When the results of both IGRAs were added, the number of diagnoses increased to 54 (17.9%) (incremental difference: 10.7% [95% confidence interval [CI]:5.3-16.2%] [p <0.001]), and when both IGRAs were added, the number of diagnoses reached 56 (18.5%) (incremental difference: 11.3% [95% CI:5.7%-16.9%] [p < 0.001]). Patients with a CD4 cell count greater than 500 cells/mul and prior stay in prison were more likely to have a diagnosis of LTBI by TST and/or QFG and/or T-SPOT.TB (adjusted odds ratio [aOR]: 3.76; 95% CI, 1.4 - 9.89; and aOR: 3.3; 95% CI, 1.3 - 8.3, respectively). CONCLUSIONS: IGRAs were more sensitive than TST for diagnosis of M. tuberculosis infection in HIVinfected patients. Dual sequential testing with TST and IGRAs may be the optimal approach for LTBI screening in this population.