Lepra Bubalorum, a Potential Reservoir of Mycobacterium leprae.

In 1926, a mycobacterial skin disease was observed in water buffaloes by researchers in Indonesia. The disease was designated as skin tuberculosis, though it was hypothesized that it might be a form of leprosy or a leprosy-like disease. In a follow-up study (Ph.D. thesis Lobel, 1934, Utrecht University, Netherlands) a similar nodular skin disease was described in Indonesian water buffaloes and named "lepra bubalorum" or "nodular leprosy." Two decades later Kraneveld and Roza (1954) reported that, so far, the diagnosis lepra bubalorum had been made in 146 cases in Indonesia. After a final series of research reports by Indonesian veterinarians in 1961, no subsequent cases were published. Based on information from these reports, it can be concluded that, even though evidence of nerve involvement in buffaloes was not reported, similarities exist between lepra bubalorum and Hansen's disease (leprosy), i.e., nodular skin lesions with a chronic course and microscopically granulomatous reactions with AFB in globi in vacuoles. This raises the question as to whether these historical cases might indeed have been caused by Mycobacterium leprae, Mycobacterium lepromatosis or another representative of the M. leprae complex. The future use of state-of-the-art molecular techniques may answer this question and may also help to answer the question whether water buffaloes should be considered as a potential natural reservoir of the causative pathogen of Hansen's disease.

High-Density Blood Transcriptomics Reveals Precision Immune Signatures of SARS-CoV-2 Infection in Hospitalized Individuals.

The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient's clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.

SARS-CoV-2 infection: molecular mechanisms of severe outcomes to suggest therapeutics.

Introduction:The year 2020 was defined by the 29,903 base pairs of RNA that codes for the SARS-CoV-2 genome. SARS-CoV-2 infects humans to cause COVID-19, spreading from patient-to-patient yet impacts patients very divergently.Areas covered: Within this review, we address the known molecular mechanisms and supporting data for COVID-19 clinical course and pathology, clinical risk factors and molecular signatures, therapeutics of severe COVID-19, and reinfection/vaccination. Literature and published datasets were reviewed using PubMed, Google Scholar, and NCBI SRA tools. The combination of exaggerated cytokine signaling, pneumonia, NETosis, pyroptosis, thrombocytopathy, endotheliopathy, multiple organ dysfunction syndrome (MODS), and acute respiratory distress syndrome (ARDS) create a positive feedback loop of severe damage in patients with COVID-19 that impacts the entire body and may persist for months following infection. Understanding the molecular pathways of severe COVID-19 opens the door for novel therapeutic design. We summarize the current insights into pathology, risk factors, secondary infections, genetics, omics, and drugs being tested to treat severe COVID-19.Expert opinion: A growing level of support suggests the need for stronger integration of biomarkers and precision medicine to guide treatment strategies of severe COVID-19, where each patient has unique outcomes and thus require guided treatment.

SARS-CoV2 (COVID-19) Structural/Evolution Dynamicome: Insights into functional evolution and human genomics.

The SARS-CoV-2 pandemic, starting in 2019, has challenged the speed at which labs perform science, ranging from discoveries of the viral composition to handling health outcomes in humans. The small ~30kb single-stranded RNA genome of Coronaviruses makes them adept at cross species spread and drift, increasing their probability to cause pandemics. However, this small genome also allows for a robust understanding of all proteins coded by the virus. We employed protein modeling, molecular dynamic simulations, evolutionary mapping, and 3D printing to gain a full proteome and dynamicome understanding of SARS-CoV-2. The Viral Integrated Structural Evolution Dynamic Database (VIStEDD) has been established (prokoplab.com/vistedd), opening future discoveries and educational usage. In this paper, we highlight VIStEDD usage for nsp6, Nucleocapsid (N), and Spike (S) surface glycoprotein. For both nsp6 and N we reveal highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we have developed a quantitative dynamics cross correlation matrix insight into interaction with the ACE2/SLC6A19 dimer complex. From this quantitative matrix, we elucidated 47 potential functional missense variants from population genomic databases within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Moreover, these variants have ultralow frequency, but can exist as hemizygous in males for ACE2, which falls on the X-chromosome. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2. This powerful database of SARS-CoV-2 can aid in research progress in the ongoing pandemic.

SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.

Reservoirs and transmission routes of leprosy; A systematic review.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae) and the more recently discovered Mycobacterium lepromatosis (M. lepromatosis). The two leprosy bacilli cause similar pathologic conditions. They primarily target the skin and the peripheral nervous system. Currently it is considered a Neglected Tropical Disease, being endemic in specific locations within countries of the Americas, Asia, and Africa, while in Europe it is only rarely reported. The reason for a spatial inequality in the prevalence of leprosy in so-called endemic pockets within a country is still largely unexplained. A systematic review was conducted targeting leprosy transmission research data, using PubMed and Scopus as sources. Publications between January 1, 1945 and July 1, 2019 were included. The transmission pathways of M. leprae are not fully understood. Solid evidence exists of an increased risk for individuals living in close contact with leprosy patients, most likely through infectious aerosols, created by coughing and sneezing, but possibly also through direct contact. However, this systematic review underscores that human-to-human transmission is not the only way leprosy can be acquired. The transmission of this disease is probably much more complicated than was thought before. In the Americas, the nine-banded armadillo (Dasypus novemcinctus) has been established as another natural host and reservoir of M. leprae. Anthroponotic and zoonotic transmission have both been proposed as modes of contracting the disease, based on data showing identical M. leprae strains shared between humans and armadillos. More recently, in red squirrels (Sciurus vulgaris) with leprosy-like lesions in the British Isles M. leprae and M. lepromatosis DNA was detected. This finding was unexpected, because leprosy is considered a disease of humans (with the exception of the armadillo), and because it was thought that leprosy (and M. leprae) had disappeared from the United Kingdom. Furthermore, animals can be affected by other leprosy-like diseases, caused by pathogens phylogenetically closely related to M. leprae. These mycobacteria have been proposed to be grouped as a M. leprae-complex. We argue that insights from the transmission and reservoirs of members of the M. leprae-complex might be relevant for leprosy research. A better understanding of possible animal or environmental reservoirs is needed, because transmission from such reservoirs may partly explain the steady global incidence of leprosy despite effective and widespread multidrug therapy. A reduction in transmission cannot be expected to be accomplished by actions or interventions from the human healthcare domain alone, as the mechanisms involved are complex. Therefore, to increase our understanding of the intricate picture of leprosy transmission, we propose a One Health transdisciplinary research approach.

Biologics in Leprosy: A Systematic Review and Case Report.

Tumor necrosis factor (TNF)-α inhibitors increase susceptibility to tuberculosis, but the effect of biologics on susceptibility to leprosy has not been described. Moreover, biologics may play a role in treating erythema nodosum leprosum (ENL). The objectives of this systematic review were to determine whether the development of clinical leprosy is increased in patients being treated with biologics and to assess the use of biologics in treating leprosy reactions. A systematic literature review was completed of patients with leprosy who received treatment with biologics either before or after a diagnosis of leprosy was confirmed. All studies and case reports were included for qualitative evaluation. The search yielded 10 cases (including one duplicate publication) of leprosy diagnosed after initiation of TNF-α inhibitors and four case reports of refractory ENL successfully treated with infliximab or etanercept. An unpublished case of persistent ENL responsive to infliximab is also presented. These data demonstrate that the use of TNF-α inhibitors may be a risk factor for developing leprosy or reactivating subclinical infections. Leprosy can present with skin lesions and arthritis, so leprosy should be considered in patients presenting with these signs before starting treatment with these agents. Leprosy should be considered in patients who develop worsening eruptions and neurologic symptoms during treatment with TNF-α inhibitors. Finally, TNF-α inhibitors appear effective in some cases of refractory ENL.

Detection of Mycobacterium leprae DNA in soil: multiple needles in the haystack.

Leprosy is an infectious disease caused by Mycobacterium leprae affecting the skin and nerves. Despite decades of availability of adequate treatment, transmission is unabated and transmission routes are not completely understood. Despite the general assumption that untreated M. leprae infected humans represent the major source of transmission, scarce reports indicate that environmental sources could also play a role as a reservoir. We investigated whether M. leprae DNA is present in soil of regions where leprosy is endemic or areas with possible animal reservoirs (armadillos and red squirrels). Soil samples (n = 73) were collected in Bangladesh, Suriname and the British Isles. Presence of M. leprae DNA was determined by RLEP PCR and genotypes were further identified by Sanger sequencing. M. leprae DNA was identified in 16.0% of soil from houses of leprosy patients (Bangladesh), in 10.7% from armadillos' holes (Suriname) and in 5% from the habitat of lepromatous red squirrels (British Isles). Genotype 1 was found in Bangladesh whilst in Suriname the genotype was 1 or 2. M. leprae DNA can be detected in soil near human and animal sources, suggesting that environmental sources represent (temporary) reservoirs for M. leprae.

Diagnostic Accuracy of Clinical and Microbiological Signs in Patients With Skin Lesions Resembling Buruli Ulcer in an Endemic Region.

Background: The diagnosis of the neglected tropical skin and soft tissue disease Buruli ulcer (BU) is made on clinical and epidemiological grounds, after which treatment with BU-specific antibiotics is initiated empirically. Given the current decline in BU incidence, clinical expertise in the recognition of BU is likely to wane and laboratory confirmation of BU becomes increasingly important. We therefore aimed to determine the diagnostic accuracy of clinical signs and microbiological tests in patients presenting with lesions clinically compatible with BU. Methods: A total of 227 consecutive patients were recruited in southern Benin and evaluated by clinical diagnosis, direct smear examination (DSE), polymerase chain reaction (PCR), culture, and histopathology. In the absence of a gold standard, the final diagnosis in each patient was made using an expert panel approach. We estimated the accuracy of each test in comparison to the final diagnosis and evaluated the performance of 3 diagnostic algorithms. Results: Among the 205 patients with complete data, the attending clinicians recognized BU with a sensitivity of 92% (95% confidence interval [CI], 85%-96%), which was higher than the sensitivity of any of the laboratory tests. However, 14% (95% CI, 7%-24%) of patients not suspected to have BU at diagnosis were classified as BU by the expert panel. The specificities of all diagnostics were high (≥91%). All diagnostic algorithms had similar performances. Conclusions: A broader clinical suspicion should be recommended to reduce missed BU diagnoses. Taking into consideration diagnostic accuracy, time to results, cost-effectiveness, and clinical generalizability, a stepwise diagnostic approach reserving PCR to DSE-negative patients performed best.

Buruli ulcer in traveler from Suriname, South America, to the Netherlands.

We report Buruli ulcer in a man in the Netherlands. Phenotyping of samples indicate the Buruli pathogen was acquired in Suriname and activated by trauma on return to the Netherlands. Awareness of this disease by clinicians in non-Buruli ulcer-endemic areas is critical for identification.

Patient access innovations: integrating patients within the system of care.

Clinically integrated networks seeking to ensure in-network access and strengthen patient engagement should adopt five strategic areas of focus: Extend access beyond traditional models. Manage out-migration. Make it easy for patients to stay in the network. Build patient engagement into clinical care models. Explore innovative methods to engage patients.

Plantar pressure and daily cumulative stress in persons affected by leprosy with current, previous and no previous foot ulceration.

Not only plantar pressure but also weight-bearing activity affects accumulated mechanical stress to the foot and may be related to foot ulceration. To date, activity has not been accounted for in leprosy. The purpose was to compare barefoot pressure, in-shoe pressure and daily cumulative stress between persons affected by leprosy with and without previous or current foot ulceration. Nine persons with current plantar ulceration were compared to 15 with previous and 15 without previous ulceration. Barefoot peak pressure (EMED-X), in-shoe peak pressure (Pedar-X) and daily cumulative stress (in-shoe forefoot pressure time integral×mean daily strides (Stepwatch™ Activity Monitor)) were measured. Barefoot peak pressure was increased in persons with current and previous compared to no previous foot ulceration (mean±SD=888±222 and 763±335 vs 465±262kPa, p<0.05). In-shoe peak pressure was only increased in persons with current compared to without previous ulceration (mean±SD=412±145 vs 269±70kPa, p<0.05). Daily cumulative stress was not different between groups, although persons with current and previous foot ulceration were less active. Although barefoot peak pressure was increased in people with current and previous plantar ulceration, it did not discriminate between these groups. While in-shoe peak pressure was increased in persons with current ulceration, they were less active, resulting in no difference in daily cumulative stress. Increased in-shoe peak pressure suggests insufficient pressure reducing footwear in persons with current ulceration, highlighting the importance of pressure reducing qualities of footwear.

[A woman with periocular swelling]. / Een vrouw met peri-orbitale zwelling.

We present a 37-year-old woman with an 8-year history of rosacea, who developed persistent swelling of the right lower eyelid, diagnosed as Morbihan's disease. Morbihan's disease is considered a rare complication of rosacea.

Increased plantar foot pressure in persons affected by leprosy.

Although foot pressure has been reported to be increased in people affected by leprosy, studies on foot pressure and its determinants are limited. Therefore, the aim was to assess barefoot plantar foot pressure and to identify clinical determinants of increased plantar foot pressure in leprosy affected persons. Plantar pressure in both feet was assessed using the Novel EMED-X platform in 39 persons affected by leprosy. Peak pressure was determined for the total foot and four regions: hallux, metatarsal heads, midfoot and heel. Potential determinants were: age, weight, nerve function (Neuropathy Disability Score, Pressure Perception Threshold and Vibration Perception Threshold), toe and foot deformities, joint mobility, ankle muscle strength and callus. Increased peak pressure (>600kPa) was observed in 46% of the participants. The highest peak pressure (mean) was found in the metatarsal heads region (right 549 (SD 321)kPa; left 530 (SD 298)kPa). Multilevel regression analysis showed that Neuropathy Disability Score, amputation/absorption of toes and hallux valgus independently contributed to metatarsal heads peak pressure in persons affected with leprosy. To conclude, peak pressure is increased in people affected by leprosy. The highest peak pressure is found in the forefoot region and is significantly associated to Neuropathy Disability Score, toe amputation/absorption and hallux valgus. Screening for clinical characteristics can be used to identify individual persons affected by leprosy at risk of excessive pressure.

[A white woman with white skin spots]. / Een blanke vrouw met lichte vlekken.

A 26-year-old white woman came to the clinic because of white spots. The spots were confluent in the midline, non-scaly and localized on trunk and proximal parts of the arms. Biopsy showed loss of pigment in the epidermis. The diagnosis was: progressive macular hypomelanosis.

Variation in clinical presentation and genotype of causative Leishmania major strain in cutaneous leishmaniasis in north and south Afghanistan.

A different clinical picture and therapeutic response were observed when data from Leishmania major-infected Dutch military personnel stationed in southern (N = 8) and northern (N = 169) Afghanistan were analyzed. Clinical presentation of cutaneous leishmaniasis in personnel in the south was milder and seemed to respond better to antileishmanial treatment; molecular analyses of parasite isolates seem to indicate that these differences may be genetic.

Foot impairments and limitations in walking activities in people affected by leprosy.

OBJECTIVE: To explore the relationships between perceived limitations in walking-related daily activities, walking ability (capacity), and the amount of daily walking (performance) in persons affected by leprosy and to identify their determinants. DESIGN: A cross-sectional study. SUBJECTS: Thirty-nine persons affected by leprosy. METHODS: Perceived limitations were assessed with the World Health Organization Disability Schedule II, domain "getting around". Walking capacity was assessed as covered distance in 6 min. Walking performance was recorded as mean strides/day with the Stepwatch(TM) 3 Activity Monitor. Potential determinants were sensory function, foot deformities, joint mobility, ankle muscle strength and co-morbidity. RESULTS: Perceived limitations in walking-related activities were significantly correlated with walking capacity (r = -0.47; p < 0.01) but not with walking performance, although walking capacity significantly correlated with walking performance (r = 0.38; p < 0.05). Various foot impairments independently contributed to reduced walking capacity and, to a lower degree, to perceived limitations in activities and performance. CONCLUSION: People affected by leprosy perceive limitations in walking-related activities that are determined by a reduced walking ability and the severity of foot impairments. Since perceived limitations in walking-related activities were not related to walking performance, perceived limitations are apparently weighted against the individual's needs.

Cutaneous leishmaniasis (Leishmania major infection) in Dutch troops deployed in northern Afghanistan: epidemiology, clinical aspects, and treatment.

Cutaneous leishmaniasis caused by Leishmania major infection affected 172 (18.3%) of 938 Dutch military troops deployed in northern Afghanistan in 2005. The high attack rate was a result of initial insufficient availability of means of prevention and insufficient adherence to preventive measures. At presentation, the lymphatic system was involved in 24.8%. Treatment with intralesional injections of antimony with or without cryotherapy was satisfactory, but 19.5% of patients received secondary treatment with miltefosine. Six months after treatment, 128 (77.1%) of 166 treated patients were cured, 16 (9.6%) were lost to follow-up, and 22 (13.3%) already experienced cure at six weeks but were not seen at six months. Natural evolution played a role in this observational study, which showed cure of all patients seen at six months. In general, management of cutaneous leishmaniasis was feasible under field conditions.

Effects of impairments on activities and participation in people affected by leprosy in The Netherlands.

OBJECTIVE: To assess the prevalence of impairments and evaluate the relationships between impairments, activity limitations and participation restrictions in people affected by leprosy living in The Netherlands. DESIGN: A cross-sectional study. SUBJECTS: Eighty-two people affected by leprosy living in The Netherlands. METHODS: A postal questionnaire was performed. Impairments were inventoried with the Total Impairment Score. Activity limitations were assessed with the World Health Organization Disability Schedule II (WHODAS-II) and participation restrictions with the Impact on Participation and Autonomy (IPA) questionnaire. RESULTS: A high prevalence of impairments was found (83%), mostly in hands and feet. Activity limitations were substantial, and highest for the WHODAS-II domains "household/work" and "getting around". The severity of impairments correlated significantly with activity limitations. Eye and foot impairments independently contributed to the domains "household/work" and "getting around", explaining 34% and 40% of variance. Poor or very poor participation (IPA) was reported by 13-32% of persons, mostly in the "autonomy outdoors" and "family role" domains. These domains were associated with activity limitations and hand impairments CONCLUSIONS: People affected by leprosy in The Netherlands encounter limitations in activities and participation restrictions, which are related to the severity of impairments. The high prevalence of disability suggests rehabilitation care should be considered for a substantial proportion of people affected by leprosy.