Non-healing old world cutaneous leishmaniasis caused by L. infantum in a patient from Spain

Background: The prevalence of Old World Cutaneous Leishmaniasis in the Mediterranean region is increasing and in Southern Europe often caused by Leishmania infantum. Spontaneous healing of cutaneous leishmaniasis is commonly observed, especially if caused by L. major, whereas L. infantum associated lesions have been reported with longer disease duration and decreased tendency for self-limitation, however, available information is sparse. Case presentation: We report the case of an otherwise healthy woman from Southern Spain who presented with a seven years persistent, non-healing, painless, central ulcerated, nodular cutaneous lesion with a diameter of 2 cm of the forearm. Cutaneous leishmaniasis was diagnosed by smear and histology, showing large amounts of leishmania amastigotes in subepidermal histiocytes and extensive lymphocyte and plasma cell inflammation. L. infantum as the causative pathogen was confirmed by restriction fragment length polymorphism and microsatellite-PCR. Systemic or visceral involvement was excluded by negative leishmania serology and clinical presentation, relevant concomitant diseases or immunosuppression were excluded including quantification of immunoglobulin levels and lymphocyte phenotyping. Topical and systemic anti-infectious treatment options, often limited in terms of efficacy, tolerability and long lasting treatment duration, were considered. Treatment was successfully performed by surgical extraction in local anaesthesia only. Conclusion: To our knowledge this is the longest reported duration of a L. infantum associated cutaneous leishmaniasis indicating a potential long lasting natural evolution of the disease in an otherwise healthy and immunocompetent patient, however, high parasite density may have reflected a lack of a L. infantum specific immune response. Complete surgical extraction can be successfully performed as treatment

Erregerspezifische Diagnostik tropentypischer Erkrankungen unter dem Einfluss von HIV

Zusätzlich zu den tropentypischen Erkrankungen werden die afrikanischen Länder südlich der Sahara von einer disproportionalen Ausbreitung des Human Immunodeficiency Virus (HIV) geplagt. In einer Region, die ohnehin mehr als andere unter Infektionserkrankungen leidet, wurde schon lange diskutiert, ob chronische Wurmerkrankungen zu einer erhöhten Suszeptibilität für HIV führen könnten. Helmintheninfektionen werden häufig bereits in der Kindheit erworben und können unbehandelt über Jahre im menschlichen Körper verbleiben. Da Helmintheninfektionen somit zeitlich der Lebensphase mit erhöhtem Risiko für den Erwerb einer HIV-Infektion vorausgehen, könnten sie für die HIV Epidemiologie eine Rolle spielen. Trotz vieler Hinweise, die diese Hypothese unterstützen, blieb der Beweis über lange Jahre aus. In der vorliegenden Habilitationsarbeit werden Daten einer großen prospektiven Studie in der Normalbevölkerung Süd-West-Tansanias ausgewertet und der Einfluss verschiedener Helminthen auf die Empfänglichkeit für eine HIV-Infektion untersucht. Die Infektion mit W. bancrofti, dem Erreger der lymphatischen Filariose (LF), die trotz adäquater Behandlung lange im menschlichen Körper bleibt, zeigte einen signifikanten Einfluss auf die HIV Inzidenz. Der Vergleich von Filarien-Infizierten mit nicht-Infizierten zeigt ein 3,2-fach erhöhtes Risiko für die HIV-Ansteckung bei den 14 bis 25-Jährigen, ein 2,4-fach erhöhtes Risiko für die 25 bis 45-Jährigen, und ein 1,2-fach erhöhtes Risiko für die über 45-Jährigen. Mehrere Konsequenzen können aus den Ergebnissen gezogen werden: Das erhöhte Risiko für den Erwerb einer HIV-Infektion kann sehr wahrscheinlich reduziert werden durch schnellere Elimination des Wurmes aus dem befallenen menschlichen Körper mit bereits verfügbaren moderneren Therapieschemata. Damit könnte ein erheblicher Beitrag zur HIV Prävention geleistet werden, der bislang nicht propagiert wurde. Die weiteren Untersuchungen zu HIV-Risikofaktoren in der Studienpopulation deckten auf, dass die verschiedenen Altersgruppen unterschiedlich empfänglich für diese Faktoren sind. Dies sollte bei Präventionsmaßnahmen berücksichtigt werden, die auf Zielgruppen zurechtgeschnitten werden. Es wurden innerhalb der großen prospektiven Studie auch intestinale Nematoden untersucht, die keinen signifikanten Einfluss auf die HIV Inzidenz zeigten. Interessant sind auch weitere Analysen, die versuchen die Hintergründe für die gesteigerte HIV Inzidenz zu beleuchten. Es wurden Veränderungen der Immunaktivierung und der Rezeptorbeladung der T-Helferzellen gefunden, die insbesondere bei Patienten infiziert mit W. bancrofti, aber nicht bei den mit intestinalen Helminthen Infizierten auftraten. Die extreme Verbreitung des HI-Virus in den Ländern im südlichen Afrika hat zur Folge, dass andere Infektionen aber auch bösartige Erkrankungen in diesen Regionen an Häufigkeit zunehmen. Eine der häufigsten Ko-Infektionen in diesen Ländern ist die Tuberkulose (TB). Eine zügige und korrekte Diagnose und Therapie ist erschwert durch die paucibazilläre Natur, in der TB bei den HIV-Ko-infizierten vorliegt. Mit zwei neueren diagnostischen Methoden, den Interferon-gamma-Release Assays (IGRA) sowie wie der Untersuchung des Lipoarabinomannan (LAM) habe ich mich näher befasst. LAM ist ein Teil der Zellwand von Mykobakterien und im Urin von Tuberkulosepatienten nachweisbar Die Verfügbarkeit von Urin und der unkomplizierte Testablauf machen diesen Test attraktiv. Die Studien der letzten Jahre hatten aber sehr schwankende Spezifitäten und recht niedrige Sensitivitäten gezeigt, was die Begeisterung über diese neue Testmethode dann doch begrenzt hat. Wir konnten in den hier beigelegten Studien in Tansania einiges zur Klärung der wechselhaften Spezifität beitragen. Die Sensitivität dieses Tests ist sehr unterschiedlich bei Personen mit bzw. ohne HIV-Infektion. Bei stark immunkompromittierten HIV-Infizierten werden tolerable Sensitivitäten erreicht, die diesen Test sinnvoll erscheinen lassen. Ebenfalls interessant als alternative diagnostische Möglichkeit für Tuberkulose sind die sogenannten Interferon-gamma Release Assays (IGRA). Wie der Tuberkulin-Haut-Test (TST) messen die IGRAs die spezifische Immunantwort gegen M. tuberculosis und zeigen eine aktive oder latente Tuberkulose an. Im Gegensatz zum Tuberkulin-Haut-Test reagieren die IGRAs nicht falsch positiv, bei Personen die mit dem BCG- Impfstoff geimpft wurden, oder die mit anderen (nicht-tuberkulösen) Mykobakterien (NTM) Kontakt hatten und sind somit erheblich spezifischer. Sie haben im Vergleich mit dem TST ebenfalls den großen Vorteil, dass sie korrekt negative Befunde unterscheiden können von einer immunkompromittierten Situation in denen die Tests nicht aussagefähig sind. Die HIV-Infektion führt sehr früh bereits zu einem Verlust der TB-spezifischen Gedächtniszellen. Dies beeinflusst die Interpretation eines positiven IGRAs bei den HIV/TB-Ko-infizierten und kann diagnostisch benutzt werden

Evidence for significant influence of host immunity on changes in differential blood count during malaria

Background: Malaria has been shown to change blood counts. Recently, a few studies have investigated the alteration of the peripheral blood monocyte-to-lymphocyte count ratio (MLCR) and the neutrophil-to-lymphocyte count ratio (NLCR) during infection with Plasmodium falciparum. Based on these findings this study investigates the predictive values of blood count alterations during malaria across different sub-populations. Methods: Cases and controls admitted to the Department of Infectious Diseases and Tropical Medicine from January 2000 through December 2010 were included in this comparative analysis. Blood count values and other variables at admission controlled for age, gender and immune status were statistically investigated. Results: The study population comprised 210 malaria patients, infected with P. falciparum (68%), Plasmodium vivax (21%), Plasmodium ovale (7%) and Plasmodium malariae (4%), and 210 controls. A positive correlation of parasite density with NLCR and neutrophil counts, and a negative correlation of parasite density with thrombocyte, leucocyte and lymphocyte counts were found. An interaction with semi-immunity was observed; ratios were significantly different in semi-immune compared to non-immune patients (P <0.001). The MLCR discriminated best between malaria cases and controls (AUC = 0.691; AUC = 0.741 in non-immune travellers), whereas the NLCR better predicted severe malaria, especially in semi-immune patients (AUC = 0.788). Conclusion: Malaria causes typical but non-specific alterations of the differential blood count. The predictive value of the ratios was fair but limited. However, these changes were less pronounced in patients with semi-immunity. The ratios might constitute easily applicable surrogate biomarkers for immunity

High Seroprevalence for Typhus Group rickettsiae, southwestern Tanzania.

Rickettsioses caused by typhus group rickettsiae have been reported in various African regions. We conducted a cross-sectional survey of 1,227 participants from 9 different sites in the Mbeya region, Tanzania; overall seroprevalence of typhus group rickettsiae was 9.3%. Risk factors identified in multivariable analysis included low vegetation density and highway proximity

Low specificity of determine HIV1/2 RDT using whole blood in south west Tanzania

Objective: To evaluate the diagnostic performance of two rapid detection tests (RDTs) for HIV 1/2 in plasma and in whole blood samples. Methods: More than 15,000 study subjects above the age of two years participated in two rounds of a cohort study to determine the prevalence of HIV. HIV testing was performed using the Determine HIV 1/2 test (Abbott) in the first (2006/2007) and the HIV 1/2 STAT-PAK Dipstick Assay (Chembio) in the second round (2007/2008) of the survey. Positive results were classified into faint and strong bands depending on the visual appearance of the test strip and confirmed by ELISA and Western blot. Results: The sensitivity and specificity of the Determine RDT were 100% (95% confidence interval = 86.8 to 100%) and 96.8% (95.9 to 97.6%) in whole blood and 100% (99.7 to 100%) and 97.9% (97.6 to 98.1%) in plasma respectively. Specificity was highly dependent on the tested sample type: when using whole blood, 67.1% of positive results were false positive, as opposed to 17.4% in plasma. Test strips with only faint positive bands were more often false positive than strips showing strong bands and were more common in whole blood than in plasma. Evaluation of the STAT-PAK RDT in plasma during the second year resulted in a sensitivity of 99.7% (99.1 to 99.9%) and a specificity of 99.3% (99.1 to 99.4%) with 6.9% of the positive results being false. Conclusions: Our study shows that the Determine HIV 1/2 strip test with its high sensitivity is an excellent tool to screen for HIV infection, but that – at least in our setting – it can not be recommended as a confirmatory test in VCT campaigns where whole blood is used

Wuchereria bancrofti infection is linked to systemic activation of CD4 and CD8 T cells

Background Susceptibility to HIV has been linked to systemic CD4+ T cell activation in cohorts of seronegative individuals with high HIV-exposure risk. We recently described an increased risk of HIV transmission in individuals infected with Wuchereria bancrofti, the causative agent for lymphatic filariasis, in a prospective cohort study. However, the reason for this phenomenon needs further investigation. Methodology/Principal findings Two-hundred and thirty-five HIV negative adults were tested using Trop Bio ELISA for detection of W. bancrofti infection and Kato Katz urine filtration and stool based RT-PCR for detection of soil transmitted helminths and schistosomiasis. FACS analysis of the fresh peripheral whole blood was used to measure T cell activation markers (HLA-DR, CD38), differentiation markers (CD45, CD27), markers for regulatory T cells (FoxP3, CD25) and the HIV entry receptor CCR5. Frequencies of activated HLA-DRpos CD4 T cells were significantly increased in subjects with W. bancrofti infection (n = 33 median: 10.71%) compared to subjects without any helminth infection (n = 42, median 6.97%, p = 0.011) or those with other helminths (Schistosoma haematobium, S. mansoni, Trichuris trichiura, Ascaris lumbricoides, hookworm) (n = 151, median 7.38%, p = 0.009). Similarly, a significant increase in HLA-DR(pos)CD38(pos) CD4 T cells and effector memory cells CD4 T cells (CD45RO(pos)CD27(neg)) was observed in filarial infected participants. Multivariable analyses further confirmed a link between W. bancrofti infection and systemic activation of CD4 T cells independent of age, fever, gender or other helminth infections. Conclusions/Significance W. bancrofti infection is linked to systemic CD4 T cell activation, which may contribute to the increased susceptibility of W. bancrofti infected individuals to HIV infection

Distinct Immune Profiles of Exhausted Effector and Memory CD8+ T Cells in Individuals With Filarial Lymphedema

CD8+ T cells are crucial for the clearance of viral infections, and current research begins to highlight their importance in parasitic diseases too. In-depth research about characteristics of CD8+ T-cell subsets and exhaustion remains uncertain, especially during filariasis, a chronic helminth infection. Lymphatic filariasis, elicited by Wuchereria bancrofti, remains a serious health problem in endemic areas in Ghana, especially in those suffering from morbidity due to lymphedema (LE). In this observational study, the characteristics and profiles of CD8+ T cells were compared between asymptomatic Wuchereria bancrofti-infected individuals, uninfected endemic normals, and those with LE (grades 2–6). Focusing on exhausted memory (CD8+exmem: CD8+ T-betdimEomeshi) and effector (CD8+exeff: CD8+T-bethiEomesdim) CD8+ T-cell subsets, advanced flow cytometry revealed that LE individuals presented reduced frequencies of IFN-γ+CD8+exmem T cells expressing Tim-3 or LAG-3 which negatively correlated to the presence of LE. Moreover, the LE cohort further showed significantly higher frequencies of IL-10+CD8+exeff T cells expressing either Tim-3, LAG-3, CD39, KLRG-1, or PD-1, all associated markers of exhaustion, and that these frequencies positively correlated with the presence of LE. In summary, this study shows that distinct exhausted CD8+ T-cell subsets are prominent in individuals suffering from LE, suggesting that enhanced inflammation and constant immune activation might drive exhaustion of CD8+ T cells. Since T-cell exhaustion is known to be associated with insufficient control of persisting antigen, the data presented here reveals that these CD8+ T-cell exhaustion patterns in filarial LE should be taken into consideration for prevention and control management of LE

Ascaris lumbricoides Infection and Its Relation to Environmental Factors in the Mbeya Region of Tanzania, a Cross-Sectional, Population-Based Study

Background: With one quarter of the world population infected, the intestinal nematode Ascaris lumbricoides is one of the most common infectious agents, especially in the tropics and sub-tropics. Infection is caused by oral intake of eggs and can cause respiratory and gastrointestinal problems. To identify high risk areas for intervention, it is necessary to understand the effects of climatic, environmental and socio-demographic conditions on A. lumbricoides infection. Methodology: Cross-sectional survey data of 6, 366 study participants in the Mbeya region of South-Western Tanzania were used to analyze associations between remotely sensed environmental data and A. lumbricoides infection. Non-linear associations were accounted for by using fractional polynomial regression, and socio-demographic and sanitary data were included as potential confounders. Principal Findings: The overall prevalence of A. lumbricoides infection was 6.8%. Our final multivariable model revealed a significant non-linear association between rainfall and A. lumbricoides infection with peak prevalences at 1740 mm of mean annual rainfall. Mean annual land surface temperature during the day was linearly modeled and negatively associated with A. lumbricoides infection (odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.78-0.97). Furthermore, age, which also showed a significant non-linear association (infection maximum at 7.7 years),socio-economic status (OR = 0.82, CI = 0.68-0.97),and latrine coverage around the house (OR = 0.80, CI = 0.67-0.96) remained in the final model. Conclusions: A. lumbricoides infection was associated with environmental, socio-demographic and sanitary factors both in uni-and multivariable analysis. Non-linear analysis with fractional polynomials can improve model fit, resulting in a better understanding of the relationship between environmental conditions and helminth infection, and more precise predictions of high prevalence areas. However, socio-demographic determinants and sanitary conditions should also be considered, especially when planning public health interventions on a smaller scale, such as the community level

Protocol of a population-based prospective COVID-19 cohort study Munich, Germany (KoCo19)

Background: Due to the SARS-CoV-2 pandemic, public health interventions have been introduced globally in order to prevent the spread of the virus and avoid the overload of health care systems, especially for the most severely affected patients. Scientific studies to date have focused primarily on describing the clinical course of patients, identifying treatment options and developing vaccines. In Germany, as in many other regions, current tests for SARS-CoV2 are not conducted on a representative basis and in a longitudinal design. Furthermore, knowledge about the immune status of the population is lacking. Nonetheless, these data are needed to understand the dynamics of the pandemic and hence to appropriately design and evaluate interventions. For this purpose, we recently started a prospective population-based cohort in Munich, Germany, with the aim to develop a better understanding of the state and dynamics of the pandemic. Methods: In 100 out of 755 randomly selected constituencies, 3000 Munich households are identified via random route and offered enrollment into the study. All household members are asked to complete a baseline questionnaire and subjects ≥14 years of age are asked to provide a venous blood sample of ≤3 ml for the determination of SARS-CoV-2 IgG/IgA status. The residual plasma and the blood pellet are preserved for later genetic and molecular biological investigations. For twelve months, each household member is asked to keep a diary of daily symptoms, whereabouts and contacts via WebApp. If symptoms suggestive for COVID-19 are reported, family members, including children < 14 years, are offered a pharyngeal swab taken at the Division of Infectious Diseases and Tropical Medicine, LMU University Hospital Munich, for molecular testing for SARS-CoV-2. In case of severe symptoms, participants will be transferred to a Munich hospital. For one year, the study teams re-visits the households for blood sampling every six weeks. Discussion: With the planned study we will establish a reliable epidemiological tool to improve the understanding of the spread of SARS-CoV-2 and to better assess the effectiveness of public health measures as well as their socio-economic effects. This will support policy makers in managing the epidemic based on scientific evidence

Reduction of malaria prevalence after introduction of artemisinin-combination-therapy in Mbeya Region, Tanzania: results from a cohort study with 6773 participants

Background: A marked decline in malaria morbidity and mortality has been reported after the introduction of artemisinin-based combination therapy (ACT) in high malaria prevalence countries in Africa. Data on the impact of ACT and on the prevalence of malaria has so far been scarce for Southwest Tanzania. Methods: Between 2005 and 2011, a large general population cohort in the Mbeya Region in the south-west of Tanzania has been surveyed within the EMINI-study (Evaluation and Monitoring of the Impact of New Interventions). Participants were examined once per year, including rapid diagnostic testing for malaria. ACT was introduced in the region according to national guidelines in the time period 2006/2007, replacing sulfadoxine/pyrimethamine as first-line therapy. In four study sites, 6773 individuals who participated in the first two of three consecutive survey visits in the period from 2006 to 2009 were included in this analysis. The prevalence of Plasmodium infection prior to and after the introduction of ACT was compared by logistic regression, with consideration of climatic variability, age, sex, socioeconomic status and bed net use as potential confounders. Results: A significant reduction over time in the prevalence of Plasmodium falciparum infection from 2.5 to 0.3% was shown across the four study sites. The decline was not explained by other factors included in the analysis, therefore, the decline over time most likely reflects the impact of introduction of ACT in the study area. Conclusions: The longitudinal study showed a significant and relevant decline in the prevalence of P. falciparum infection after introduction of ACT, which could not be explained by potential confounders. The data suggests that artemisinin-based combinations are not only an effective instrument for reduction of immediate morbidity and mortality, but also for reduction of transmission rates