Time between symptom and testing in relation to familial transmission of severe acute respiratory syndrome coronavirus 2 / Tempo entre o início dos sintomas e a testagem está relacionado à maior transmissão de SARS-CoV-2 entre contatos familiares

Abstract Brazil has a huge number of cases and deaths due to coronavirus disease 2019 (COVID-19); however, few studies have dealt with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among familial contacts in Brazil. Here, we report our findings on transmission in a family-based study in Bauru, São Paulo, Brazil. The study, conducted from July to November 2020, comprised 974 individuals with 233 index patients and 741 familial contacts. Familial contacts were evaluated using the rapid COVID-19 Ag ECO and reverse transcription-polymerase chain reaction (RT-PCR) tests immediately after the index patient diagnosis. The antigen-based rapid test was validated in 121 individuals using RT-PCR as the gold standard. Additionally, 30 days later, familial contacts were evaluated for IgM and IgG antibodies against SARS-CoV-2. We found 333 cases of COVID-19 among familial contacts (44.9%). A positive correlation was observed between the time elapsed from the onset of symptoms until the index patient's COVID-19 testing and the number of family contacts infected by SARS-CoV-2. Early SARS-CoV-2 testing and familial contact evaluation are relevant strategies to contain transmission.

Resumo O Brasil apresenta um alto número de casos e óbitos por coronavírus (COVID-19), apesar disso, poucos estudos tratavam da infecção pelo coronavirus-2 causador de síndrome respiratória aguda grave (SARS-CoV-2) entre contatos familiares no Brasil. Relatamos aqui nossos achados sobre a transmissão de SARS-CoV-2 em um estudo de base familiar de Bauru, no estado de São Paulo, Brasil. O estudo foi realizado de julho a novembro de 2020 e compreendeu 974 indivíduos, sendo 233 pacientes índice e 741 contatos familiares. Os contatos familiares foram avaliados por meio do teste rápido COVID-19 Ag ECO Test e RT-PCR imediatamente após o diagnóstico do paciente índice. O uso do teste rápido baseado em antígeno foi validado em 121 indivíduos utilizando RT-PCR como padrão ouro. Adicionalmente, 30 dias após a avaliação inicial, os contatos familiares foram avaliados quanto à presença de anticorpos IgM e IgG contra SARS-CoV-2. Encontramos 333 casos de COVID-19 entre contatos familiares (44,9%). Observamos uma correlação positiva entre o tempo decorrido entre o início dos sintomas e o teste para COVID-19 do paciente índice e o número de contatos familiares infectados por SARS-CoV-2. A testagem precoce da infecção por SARS-CoV-2 e a avaliação de contatos familiares são estratégias relevantes para conter a transmissão.

Perfil sociodemográfico, clínico e geoespacial de casos novos de hanseníase diagnosticados no Instituto Lauro de Souza Lima, Bauru, São Paulo, entre 2015 e 2019 / Sociodemographic, clinical and geospatial profile of new leprosy cases diagnosed at Institute Lauro de Souza Lima, Bauru, São Paulo, between 2015 and 2019

Embora o Brasil venha apresentando uma redução considerável no número de casos novos de hanseníase, alguns estudos têm demonstrado transmissão ativa mesmo em áreas não endêmicas, como o estado de São Paulo. Diante disso, investigamos o perfil sociodemográfico, clínico e geoespacial dos casos novos de hanseníase diagnosticados entre 2015 e 2019 no Instituto Lauro de Souza Lima (ILSL), um centro de referência localizado no município de Bauru, interior do estado de São Paulo. Foram diagnosticados 177 novos casos de hanseníase nesse período, sendo 61,6% dos pacientes naturais do estado. A maioria dos indivíduos era do sexo masculino (59,9%) e a faixa etária mais prevalente foi de 60 a 69 anos; 79,1% se autodeclaravam brancos e 65,6% possuíam pouca ou nenhuma escolaridade. A forma clínica dimorfa foi a mais frequente (42,4%), a baciloscopia foi positiva em 38,4% dos pacientes (49,0% entre o sexo masculino e 22,5% entre o sexo feminino) e 49,0% dos pacientes possuíam incapacidades no diagnóstico. O georreferenciamento, realizado para os casos oriundos do município de Bauru (n = 31), revelou que a maioria dos pacientes residia em regiões com elevado nível de vulnerabilidade social. O perfil dos pacientes atendidos no ILSL apontou para predominância de homens adultos ou idosos com baixa escolaridade, multibacilares, apresentando incapacidades físicas e longo tempo de sintomas. Em conjunto, nossos dados sugerem atraso no diagnóstico que pode contribuir para a manutenção da transmissão da hanseníase mesmo numa região não endêmica.(AU)

Although Brazil has shown a considerable reduction in the number of new cases of leprosy, some studies have shown active transmission even in non-endemic areas, such as São Paulo state. Considering this, we investigated the sociodemographic, clinical and geospatial profile of new cases of leprosy diagnosed between 2015 and 2019 at the Lauro de Souza Lima Institute (ILSL) a reference center localized in Bauru, a municipality in the interior of São Paulo state. A total of 177 new cases of leprosy were diagnosed in this period, with 61.6% of the patients born in the state. The majority of the individuals was male (59.9%), the most prevalent age group was 60 to 69 years old, 79.1% declared themselves white color/race and 65.6% had little or no schooling. The borderline form of leprosy was the most frequent (42.4%), slit skin smear was positive in 38.4% of patients (49.0% among men and 22.5% among women) and 49.0% had disabilities at diagnosis. Georeferencing, performed for cases from the municipality of Bauru (n = 31), revealed that most patients lived in regions with a high level of social vulnerability. The profile of leprosy new cases found at ILSL pointed to a predominance of adult or elderly men with low education, multibacillary, presenting physical disabilities and a long time of symptoms. Altogether, our data suggests a delay in diagnosis that may contribute to the maintenance of leprosy transmission even in a non-endemic region.(AU)

High rate of sensitization to Kathon CG, detected by patch tests in patients with suspected allergic contact dermatitis

Abstract Background: Kathon CG, a combination of methylchloroisothiazolinone and methylisothiazolinone, is widely used as preservative in cosmetics, as well in household cleaning products, industrial products such as paints and glues. It has emerged as an important sensitizing agent in allergic contact dermatitis. Objectives: This study evaluated the reactivity to this substance in patients subjected to patch tests at the Dermatology Institute in Bauru, São Paulo from 2015 to 2017 and its correlation with other preservatives, the professional activity and location of the lesions. Methods: The patients were submitted to standard series of epicutaneous tests, standardized by the Brazilian Group Studies on Contact Dermatitis. Results: Out the 267 patients tested, 192 presented positivity to at least one substance and 29 of the patients (15.10%) presented reaction to Kathon CG, with predominance of the female gender (n = 27); main professional activity associated with Kathon CG sensibilization was cleaning (17.24%), followed by aesthetic areas (13.79%) and health care (10.34%). The most prevalent sensitizations among the substances tested were nickel sulphate (56.3%), followed by cobalt chloride (23.4%), neomycin (18.2%), potassium dichromate (17.7%), thimerosal (14.5%), formaldehyde (13.2%), paraphenylenediamine (9.3%), and fragrance mix (8.3%). Study limitations: We do not have data from patients that were submitted to patch test a decade ago in order to confront to current data and establish whether or no sensitization to Kathon CG has increased. Conclusion: High positivity to Kathon CG corroborates the recent findings in the literature, suggesting more attention to concentration of this substance, used in cosmetics and products for domestic use.

Desempenho dos antígenos PGL-I, LID-1e NDO-LID para diagnóstico sorológico de hanseníase em pacientes e contatos domiciliares: revisão de literatura / Performance of PGL-I, LID-1 and NDO-LID antigens for leprosy serological diagnosis in patients and household contacts: a review of the literature

A hanseníase afeta os nervos periféri-cos e a pele levando a ocorrência de incapacidades na ausência de tratamento específico oportuno. Portanto, parâmetros sorológicos são necessários para intervenções terapêuticas precoces. A detecção de anticorpos contra o glicolipídio fenólico I (PGL-I) é amplamente empregada no diagnóstico e classificação clínica, enquanto a proteína Leprosy IDRI Diagnostic (LID)-1 foi desenhada com a intenção de melhorar o diagnóstico de pacien-tes paucibacilares. Posteriormente, este antígeno foi conjugado com o na-tural dissacarídeo ligado ao radical oc-til (ND-O) do PGL-I, originando o NDO--LID, para aumentar sua sensibilidade. Nesta revisão, avaliamos 16 estudos, comparando a performance desses três antígenos (PGL-I, LID-1 e NDO--LID) para diagnóstico da hanseníase e avaliação de contatos domiciliares. Verificamos grande variação quanto às populações envolvidas, tamanho das amostras, classificação clínica dos pacientes e metodologia utilizada, dificultando a comparação. Entre os pacientes multibacilares, a positividade anti-PGL-I variou de 54,0 a 96,0%, en-quanto para LID-1 foi de 47,4 a 94,8% e para NDO-LID apresentou níveis de 60,0 a 98,9%. Nos pacientes paucibacilares, a positividade variou de 6,4 a 52,9% quando PGL-I foi utilizado, 4,0 a 60% contra LID-1 e 16,0 a 63,6% frente ao NDO-LID. Para os contatos domiciliares, as respostas anti-PGL-I, LID-1 e NDO-LID foram 13,2%, 21,7% e 22,9%, respectivamente. O antígeno NDO-LID apresentou maior sensibilidade na maioria dos estudos refletindo seu potencial como ferramenta para o diagnóstico da hanseníase, principalmente em pacientes MB, entretanto, o reconhecimento desse antígeno por contatos domiciliares saudáveis reforça o valor da avaliação clínica para o diagnóstico da hanseníase.(au)

Leprosy affects skin and peripheral nerves bringing several disabilities in absence of specific treatment. So that, effective diagnostic tools are required for early therapeutic interventions. Detection of antibodies against phenolic glycolipid I (PGL-I) is widely employed in the diagnosis and clinical classification while the leprosy IDRI diagnostic (LID-1) protein was designed to improve the diagnosis of paucibacillary patients. More recently, this synthetic antigen was conjugated with the natural octyl disaccharide (ND-O) of PGL-I, originating the NDO-LID in order to increase its sensitivity. Here, we evaluate 16 studies, comparing the performance of these three antigens (PGL-I, LID-1 and NDO-LID) for leprosy diagnosis and evaluation of the household contacts. We verified among the different studies high variation regarding to population involved, sample size, clinical classification of patients and methodology used, making difficult the comparison. Among multibacillary patients, anti-PGL-I positivity ranged from 54.0 to 96.0%, while for LID-1 it was between 47.4 to 94.8% and for NDO-LID presented levels from 60 to 98.9%. In paucibacillary patients, responsiveness ranged from 6.4 to 52.9% when PGL-I was used, 4.0 to 60% against LID-1 and 16.0 to 63.6% if NDO-LID was employed. For household contacts, the responseanti-PGL-I, LID-1 and NDO-LID was13.2%, 21.7% and 22.9%, respectively.NDO-LID antigen showed higher sensitivity in most studies reflecting its potential as tool for leprosy diagnosis, mainly of MB patients, however, the recognition of this antigen by healthy household contact reinforces the value of the clinical evaluation to leprosy diagnosis.(au)

Activation and cytokine profile of monocyte derived dendritic cells in leprosy: in vitro stimulation by sonicated Mycobacterium leprae induces decreased level of IL-12p70 in lepromatous leprosy

Dendritic cells (DCs) play a pivotal role in the connection of innate and adaptive immunity of hosts to mycobacterial infection. Studies on the interaction of monocyte-derived DCs (MO-DCs) using Mycobacterium leprae in leprosy patients are rare. The present study demonstrated that the differentiation of MOs to DCs was similar in all forms of leprosy compared to normal healthy individuals. In vitro stimulation of immature MO-DCs with sonicated M. leprae induced variable degrees of DC maturation as determined by the increased expression of HLA-DR, CD40, CD80 and CD86, but not CD83, in all studied groups. The production of different cytokines by the MO-DCs appeared similar in all of the studied groups under similar conditions. However, the production of interleukin (IL)-12p70 by MO-DCs from lepromatous (LL) leprosy patients after in vitro stimulation with M. lepraewas lower than tuberculoid leprosy patients and healthy individuals, even after CD40 ligation with CD40 ligand-transfected cells. The present cumulative findings suggest that the MO-DCs of LL patients are generally a weak producer of IL-12p70 despite the moderate activating properties ofM. leprae. These results may explain the poor M. leprae-specific cell-mediated immunity in the LL type of leprosy.

Increased hepcidin expression in multibacillary leprosy

Iron is essential for all organisms and its availability can control the growth of microorganisms; therefore, we examined the role of iron metabolism in multibacillary (MB) leprosy, focusing on the involvement of hepcidin. Erythrograms, iron metabolism parameters, pro-inflammatory cytokines and urinary hepcidin levels were evaluated in patients with MB and matched control subjects. Hepcidin expression in MB lesions was evaluated by quantitative polymerase chain reaction. The expression of ferroportin and hepcidin was evaluated by immunofluorescence in paucibacillary and MB lesions. Analysis of hepcidin protein levels in urine and of hepcidin mRNA and protein levels in leprosy lesions and skin biopsies from healthy control subjects showed elevated hepcidin levels in MB patients. Decreases in haematologic parameters and total iron binding capacity were observed in patients with MB leprosy. Moreover, interleukin-1 beta, ferritin, soluble transferrin receptor and soluble transferrin receptor/log ferritin index values were increased in leprosy patients. Hepcidin was elevated in lepromatous lesions, whereas ferroportin was more abundant in tuberculoid lesions. In addition, hepcidin and ferroportin were not colocalised in the biopsies from leprosy lesions. Anaemia was not commonly observed in patients with MB; however, the observed changes in haematologic parameters indicating altered iron metabolism appeared to result from a mixture of anaemia of inflammation and iron deficiency. Thus, iron sequestration inside host cells might play a role in leprosy by providing an optimal environment for the bacillus.

Seroreactivity to new Mycobacterium leprae protein antigens in different leprosy-endemic regions in Brazil

New Mycobacterium leprae protein antigens can contribute to improved serologic tests for leprosy diagnosis/classification and multidrug therapy (MDT) monitoring. This study describes seroreactivity to M. leprae proteins among participants from three highly endemic leprosy areas in Brazil: central-western Goiânia/Goiás (GO) (n = 225), Rondonópolis/Mato Grosso (MT) (n = 764) and northern Prata Village/Pará (PA) (n = 93). ELISA was performed to detect IgG to proteins (92f, 46f, leprosy IDRI diagnostic-1, ML0405, ML1213) and IgM to phenolic glycolipid-I (PGL-I). Multibacillary (MB) leprosy had positive rates for PGL-I that were similar to those for proteins; however, some anti-PGL-I-negative subjects were positive for proteins, suggesting that adding protein antigen to PGL-I can enhance the sensitivity of MB leprosy detection. In MT, different degrees of seroreactivity were observed and ranked for MB, former patients after MDT, paucibacillary (PB) leprosy, household contact (HHC) and endemic control (EC) groups. The seroreactivity of PB patients was low in GO and MT. HHCs from different endemic sites had similar IgG antibody responses to proteins. 46f and 92f were not recognised by most tuberculosis patients, ECs or HHCs within GO, an area with high BCG vaccination coverage. Low positivity in EC and HHC was observed in PA and MT. Our results provide evidence for the development of an improved serologic test that could be widely applicable for MB leprosy testing in Brazil.

Leprosy patients: neurotrophic factors and axonal markers in skin lesions / Pacientes com hanseníase: fatores neurotróficos e marcadores axonais em lesões de pele

Neurotrophins are growth factors with crucial roles in neural pathophysiology. These mediators functionally modulate nociceptive fibers, and changes in neurotrophins expression have been correlated with early loss of nociception in leprosy. This study investigated the expression of NGF, BDNF, and NT3 in dermal nerves of leprosy patients. Characterization of Remak bundles was achieved by p75NTR, and axonal markers NF-L and PGP 9.5 immunostaining. Clinical parameters of neural impairment have been evaluated by Semmes-Wenstein monofilaments. Our findings demonstrated decrease of NGF in borderline leprosy, when compared to control specimens. Similar results were observed in PGP 9.5 expression (borderline: p<0.001 and lepromatous: p<0.05) and NF-L (lepromatous: p<0.05), suggesting advanced Remak bundles degeneration in multibacillary leprosy. It has also been observed positive correlation between p75NTR and PGP 9.5, indicating association between Schwann cells and axons in Remak bundles. Present data indicate that neurotrophins imbalance may participate in the establishment of peripheral nerve damage.

Neurotrofinas são fatores de crescimento com papel fundamental na fisiopatologia neural. Esses mediadores modulam funcionalmente fibras nociceptivas. Mudanças em sua expressão têm sido relacionadas à perda precoce da nocicepção na hanseníase. Este estudo investigou a expressão de NGF, BDNF e NT3 em nervos dérmicos de pacientes hansenianos. A caracterização de fibras nervosas não mielinizadas foi feita por p75NTR e marcadores axonais NF-L e PGP 9.5. Os parâmetros clínicos de dano neural foram avaliados por monofilamentos Semmes-Wenstein. Nossos achados demonstram diminuição de NGF nos pacientes dimorfos em comparação aos controles. Resultados similares foram observados para PGP 9.5 (dimorfos: p<0,001; virchowianos: p<0,05) e NF-L (virchowianos: p<0.05), sugerindo degeneração avançada das terminações nervosas na hanseníase multibacilar. Foi observada correlação positiva entre p75NTR e PGP 9.5, indicando associação entre células de Schwann e axônios em fibras nervosas não mielinizadas. Os resultados indicam que o desequilíbrio na expressão das neurotrofinas pode participar do dano neural periférico.

Quantificação dos níveis séricos de leptina na Hanseníase / Quantification of serum leptin levels in leprosy

A leptina é uma adipocina com semelhanças estruturais e funcionais às citocinas pró-inflamatórias, contribuindo para a diferenciação de células Th1, e parece estar envolvida na resposta imune a agentes infecciosos. Na hanseníase, doença infecciosa crônica causada pelo Mycobacterium leprae, cujas manifestações clínicas dependem da resposta imune do hospedeiro, não há relatos sobre o papel da leptina. Neste estudo piloto foram quantificados os níveis séricos de leptina em pacientes recém-diagnosticados com as diferentes formas clínicas da doença, pacientes hansenianos em reação tipo 1 e 2,contatos de pacientes hansenianos e controles saudá-veis (237 amostras de soros: 165 homens e 72 mulheres).No sexo masculino, as formas TT e BB apresentaram concentrações próximas àquelas observadas nos controles enquanto os grupos I, BT, BV, VV, reação do tipo1 e 2 apresentaram médias inferiores à observada nos controles e contatos, sendo que nos BV e VV foram observados os menores níveis de leptina. No sexo feminino verificamos uma grande variação entre os valores observados nos diferentes grupos. O grupo BV apresentou níveis maiores de leptina enquanto os grupos I, TT, BT e BB apresentaram média próxima àquela observada nos contatos e controles. Pacientes do grupo VV e em reação tipo 1 e 2 apresentaram médias inferiores ao observado nos contatos e controles. As diferenças observadas tanto em homens quanto em mulheres não foram estatisticamente significantes. Em nossos achados há uma tendência a níveis mais baixos de leptina nas formas multibacilares, contudo, estes resultados não permitem associação desses níveis com qualquer forma clínica da hanseníase.

Leptin, an adipokine with structural and functional similaritiesto proinflammatory cytokines that contributesto the differentiation of T helper-1 cells, seems to beinvolved in the immune response to infectious agents.In leprosy, a chronic infectious disease caused by Mycobacteriumleprae, whose clinical manifestations depend on the host immune response, there are no reports onthe role of leptin. In this pilot study the serum leptin levelswere quantified in newly diagnosed patients withdifferent clinical forms of leprosy, patients with type 1and 2 reaction, contacts of leprosy patients and healthycontrols (237 serum samples:165 men and 72 women).In males, TT and BB patients showed concentrations closeto those observed in controls while groups I, BT, BV,VV, type 1 and 2 reactional patients had lower means incomparison to controls and contacts, whereas in BV andVV patients it were observed the lowest levels of leptin.In females, we found a wide variation between the valuesobserved in the different groups. The BV group hadhigher levels of leptin while groups I, TT, BT and BB hadaverages closed to that observed in contacts and controls.The differences observed in both men and womenwere not statistically significant. Our findings show atendency to lower levels of leptin in multibacillary patients,however, these results do not allow any associationof leptin with leprosy clinical forms.

Seroreactivity to new Mycobacterium leprae protein antigens in different leprosy-endemic regions in Brazil

New Mycobacterium leprae protein antigens can contribute to improved serologic tests for leprosy diagnosis/classification and multidrug therapy (MDT) monitoring. This study describes seroreactivity to M. leprae proteins among participants from three highly endemic leprosy areas in Brazil: central-western Goiânia/Goiás (GO) (n = 225), Rondonópolis/Mato Grosso (MT) (n = 764) and northern Prata Village/Pará (PA) (n = 93). ELISA was performed to detect IgG to proteins (92f, 46f, leprosy IDRI diagnostic-1, ML0405, ML1213) and IgM to phenolic glycolipid-I (PGL-I). Multibacillary (MB) leprosy had positive rates for PGL-I that were similar to those for proteins; however, some anti-PGL-I-negative subjects were positive for proteins, suggesting that adding protein antigen to PGL-I can enhance the sensitivity of MB leprosy detection. In MT, different degrees of seroreactivity were observed and ranked for MB, former patients after MDT, paucibacillary (PB) leprosy, household contact (HHC) and endemic control (EC) groups. The seroreactivity of PB patients was low in GO and MT. HHCs from different endemic sites had similar IgG antibody responses to proteins. 46f and 92f were not recognised by most tuberculosis patients, ECs or HHCs within GO, an area with high BCG vaccination coverage. Low positivity in EC and HHC was observed in PA and MT. Our results provide evidence for the development of an improved serologic test that could be widely applicable for MB leprosy testing in Brazil

Genética humana na susceptibilidade a hanseníase / Human genetic in leprosy susceptibility

Dados de investigações familiares, de estudos comgêmeos e da genômica do Mycobacterium leprae, bemcomo observações sobre a epidemiologia da hanseníase,têm apontado a importância da genética humanacomo determinante do curso da doença desde a resistênciaà dicotomia imunológica que definem os pólostuberculóide e virchowiano. Nesse contexto, estudosde varredura genômica e de associação têm apontadoalgumas regiões genômicas cujas variações são candidatasa fatores de risco para a doença. Entretanto, asassociações já descritas são discretas e não se replicamem todos os estudos, o que evidencia a distinção entreos fatores de risco para diferentes populações, alémde divergências nos desenhos destes estudos, comocausadores destas controvérsias. Assim, esta revisão temo propósito de compilação dos dados já descritos paraas diversas regiões genômicas humanas que devemparticipar do controle genético da hanseníase

Data from familiar investigations, studies involving twins and from Mycobacterium leprae genomic, as well epidemiological observations of leprosy have shown the importance of the human genetic as determinant of the disease’s course, from the resistance, to the immunological dichotomy which defines tuberculoid and lepromatous poles. Thus, studies using genome-wide scan and association methods have shown some genomic regions whose alterations are candidates to risk factors for leprosy. However, these associations are weak and are not repeated in all different studies, which put in evidence the divergence in risk factors for different populations as well in design studies as causatives of this controversial data. In this manner, this review has as purpose the data collection which have already been described about human genomic regions that must participate in the genetic control of leprosy.

Early histopathological changes in bone marrow of Paracoccidioides brasiliensis-infected mice

The involvement of bone marrow in the pathology of experimental P. brasiliensis infection in BALB/c mice was investigated. The histopathological features of bone marrow induced by the fungus were correlated with hematological changes in peripheral blood from 1 to 28 days post-infection. Intense lymphopenia and moderate neutrophilia were detected. The early changes in bone marrow included (i) maturation arrest characterized by an increase immature blood cell precursors, mainly of granulocytic origin, (ii) intense vascular congestion when compared with the vessels of normal marrow, and (iii) an increased number of megakaryocytes. The normal histological pattern of bone marrow was restored by 28 days post-infection. No histologically recognizable lesion, such as granuloma formation or an abnormal cellular infiltrate, which could indicate the presence of the P. brasiliensis in bone marrow, was observed. In addition, special stains were unable to detect the fungus. The mechanisms responsible for the alterations described here are still unclear but are probably related to more general phenomena affecting the host rather than the direct damage of the precursors cells by P. brasiliensis.