Post Transplant Lymphoproliferative Disease Isolated to Kidney Allograft / Doença Linfo Proliferativa Pós-Transplante Isolada ao Enxerto Renal

ABSTRACT Post-transplantation lymphoproliferative disease (PTLD) comprises a heterogeneous group of hematolymphoid proliferations resulting from a monoclonal or polyclonal proliferation of lymphoid cells. The clinical presentation varies according to the affected sites. The gastrointestinal tract and the central nervous system are the most common, and constitutional symptoms are frequent. Isolated allograft involvement is rare. We report a case of polyclonal PTLD isolated in the kidney allograft in a patient who received an HLA-identical living donor seven years before. Noteworthy, this patient did not present constitutional symptoms, and his only clinical manifestation was graft dysfunction, expressed by an increase in serum creatinine and mild proteinuria. The diagnosis was performed through renal biopsy, which showed dense lymphoid interstitial infiltrate. The PTLD was polyclonal, unrelated to Epstein-Bar virus (EBV), and it was successfully treated with chemotherapy, reduced immunosuppression, and sirolimus.

RESUMO A doença linfoproliferativa pós-transplante (DLPT) é formada por um grupo heterogêneo de proliferações hematolinfóides resultantes da proliferação mono ou policlonal das células linfoides. O quadro clínico é variado e dependente dos sítios envolvidos, sendo o trato gastrintestinal e o sistema nervoso central os mais comuns, e sintomas constitucionais são frequentes. O envolvimento isolado do enxerto é raro. Relatamos aqui um caso de DLPT policlonal isolada do enxerto em um receptor de transplante renal com doador vivo HLA idêntico, ocorrido sete anos após o transplante. Digno de nota, o paciente não apresentou sintomas constitucionais e sua única manifestação clínica foi disfunção do enxerto, expressa através da elevação da creatinina e discreta proteinuria, sendo o diagnóstico realizado através de biópsia renal, que evidenciou infiltrado intersticial linfoide denso. Tratava-se de DLPT policlonal não relacionada ao vírus Epstein-Bar (EBV) e foi tratado com sucesso com quimioterapia, redução da imunossupressão e sirolimo.

A Brazilian university hospital position regarding transplantation criteria for HIV-positive patients according to the current literature

Human immunodeficiency virus (HIV) infection was considered a contraindication for solid organ transplantation (SOT) in the past. However, HIV management has improved since highly active antiretroviral therapy (HAART) became available in 1996, and the long-term survival of patients living with HIV has led many transplant programs to reevaluate their policies regarding the exclusion of patients with HIV infection. Based on the available data in the medical literature and the cumulative experience of transplantation in HIV-positive patients at our hospital, the aim of the present article is to outline the criteria for transplantation in HIV-positive patients as recommended by the Immunocompromised Host Committee of the Hospital das Clínicas of the University of São Paulo.

Chikungunya in kidney transplant recipients: A series of cases.

Chikungunya (CHIK) is a mosquito-borne virus (CHIKV) infection that recently appeared in the Americas and thousands of confirmed cases have been reported in Brazil since the first autochthonous cases were reported in September 2014. We reported four cases of CHIK in kidney transplant recipients. The diagnosis was confirmed by positive CHIKV real-time polymerase chain reaction in two cases and positive CHIKV-IgM serology in two patients. The time between transplantation and CHIKV infection ranged from 2 to 11 years. All of them had arthralgia, and 3 of them had fever. Other symptoms were mild conjunctivitis, rash, and retro-orbital pain. Kidney function remained stable in all cases. In three patients prednisone doses were temporally increased and the symptoms disappeared concurrently with the increase of the dose. As for the fourth patient, the prednisone dose remained unchanged and yet she improved. Other immunosuppressive drugs were not changed for the four cases. As far as we know, there are only two previously reported cases of CHIK among solid organ transplant recipients besides the four cases reported here. Despite the small number of cases, we can speculate that the use of immunosuppression might have played a role in the paucity of symptoms and the gradual complete recovery with no complication.

Hepatite E crônica - relato de um caso brasileiro / Chronic hepatitis E - a brazilian case report

Hepatite é a quinta forma conhecida de hepatites humanas virais. Apesar de ser muito incomum em nossa prática clínica, a incidência em países ocidentais vem aumentando. O vírus da Hepatite E (HVE) pode estar relacionado à doença aguda, falência hepática, hepatite crônica e cirrose. O HVE é um RNA vírus, com 5 genótipos descritos (1, 2, 3, 4 e 5), sendo que quatro deles podem afetar humanos. Além das manifestações hepáticas, o genótipo 3 pode também levar a manifestações extra-hepáticas, como alterações neurológicas, renais e reumatológicas. O diagnóstico pode ser difícil porque existem poucos testes validados e ainda com baixa sensibilidade e especificidade. A hepatite aguda não precisa ser tratada, já a hepatite E crônica deve ser tratada. Relatamos aqui um caso brasileiro de Hepatite E crônica em um paciente imunossuprimido.

Hepatitis E is the fifth known form of human viral hepatitis. Although not very common in our clinical practice, the incidence in Western countries is increasing. Hepatitis E virus (HEV) may be related to acute illness, liver failure, chronic hepatitis and cirrhosis. HEV is an RNA virus, with 5 described genotypes (1,2,3,4,5), 4 of them can affect humans. Besides liver manifestations, genotype 3 is also related to extra-hepatic manifestations, such as neurological, renal and rheumatological. The diagnosis may be difficult because of the low availability of tests and due to low sensibility and specificity. The acute illness does not have to be treated, but the chronic one does. We presente here a Brazilian case of chronic hepatitis E in an immunosuppressed patient.

Synthesis and Immunosuppressive Activity of New Mycophenolic Acid Derivatives.

BACKGROUND: Immunosuppressive drugs are widely used to prevent and treat allograft rejection and autoimmune diseases. Mycophenolic acid (MPA) and its derivatives are currently one of the most prescribed immunosuppressive drugs; however, metabolic drawbacks and variable interand intrapatient responses limit their use. OBJECTIVE: In order to find out new safe and effective immunosuppressive compounds, we report here the synthesis and pharmacological evaluation of hybrid MPA derivatives containing the thalidomide/ phthalimide subunits. RESULTS: All compounds 3a-d exhibited an enhanced ability to reduce the levels of pro-inflammatory cytokines compared to the parental drugs MPA and thalidomide. The mixed lymphocyte reaction assay has demonstrated that compound 3d - (E)-(3-(1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1- yl)methyl-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enoate - has superior activity compared to that of MPA. In addition, compound 3d was less cytotoxic against Jurkat cells than MPA and did not demonstrate in vivo genotoxic effect. CONCLUSION: All these data have shown that compound 3d is a promising lead compound useful in the immunosuppressive therapy.

Immunoblotting using Strongyloides venezuelensis larvae, parthenogenetic females or eggs extracts for the diagnosis of experimentally infected immunosuppressed rats.

The nematode Strongyloides stercoralis is responsible for strongyloidiasis in humans. Diagnosis of infection occurs through detection of larvae in feces, but low elimination of larvae often hampers the detection of disease, particularly in cases of patient immunosuppression. Immunodiagnostic tests have been developed; however obtaining S. stercoralis larvae for the production of homologous antigen extract is technically difficult. Thus, the use different developmental forms of Strongyloides venezuelensis has become an alternative method for the production of antigen extracts. The aim of this study was to evaluate immunoblotting using alkaline extracts from S. venezuelensis L3 larvae, parthenogenetic females or eggs to test detection of experimental strongyloidiasis associated with immunosuppression. Immunocompetent and immunosuppressed male rats were experimentally infected, and serum sample from all animals were obtained at 0, 5, 8 13, and 21 days post infection (d.p.i.). Immunoblotting was evaluated for use in detection of anti-S. venezuelensis IgG in both experimental rat groups. The larval extract immunoblotting profile had the most immunoreactive fractions in the immunosuppressed group beginning at 5 d.p.i., while the immunocompetent group reactivity began on 8 d.p.i. Immunoreactive protein fractions of 17 kDa present in larval alkaline extract presented as possible markers of infection in immunosuppressed rats. It is concluded that all extracts using immunoblotting have diagnostic potential in experimental strongyloidiasis, particularly larval extract in immunosuppressed individuals.

Persistence of hepatitis A virus antibodies after primary immunization and response to revaccination in children and adolescents with perinatal HIV exposure / Persistência de anticorpos contra o vírus da hepatite A após imunização primária e resposta à revacinação em crianças e adolescentes com exposição perinatal ao HIV

OBJECTIVE: To assess possible factors associated with the loss of antibodies to hepatitis A 7 years after the primary immunization in children of HIV-infected mothers and the response to revaccination in patients seronegative for hepatitis A. METHODS: Quantification of HAV antibodies by electrochemiluminescence was performed in 39 adolescents followed up at the Pediatric Aids Clinic of Federal University of São Paulo (Unifesp): 29 HIV-infected (HIV group) (median age: 12.8 years) and 10 HIV-exposed but non-infected (ENI group) (median age: 13.4 years). All of them received two doses of HAV vaccine (Havrix(r)) in 2002. RESULTS: The median age at primary immunization (PI) was 5.4 years for HIV group and 6.5 years for ENI group. All children, from both groups, had antibodies to HAV >20 mIU/mL after PI. Seven years later, the ENI group showed a median concentration of antibodies = 253.5 mIU/mL, while the HIV group = 113.0 mIU/mL (Mann-Whitney test, p=0.085). All ENI group and 23/29 (79.3%) from HIV group mantained HAV antibodies 7 years after PI. The levels of hepatitis A antibodies in the primary vaccination were the only factor independently associated with maintaining these antibodies for 7 years. The group that lost HAV seropositivity was revaccinated and 83.3% (5/6) responded with antibodies >20 mUI/mL. CONCLUSIONS: The antibodies levels acquired in the primary vaccination in the HIV group were the main factor associated with antibodies loss after HAV immunization.

OBJETIVO: Avaliar possíveis fatores associados à perda de anticorpos para o vírus da hepatite A (VHA) sete anos após a imunização primária e resposta à revacinação em crianças nascidas de mães soropositivas para HIV nos pacientes soronegativos para Hepatite A. MÉTODOS: Quantificação de anticorpos para o VHA por meio da eletroquimioluminescência foi feita em 39 adolescentes acompanhados no Ambulatório de Aids Pediátrica da Universidade Federal de São Paulo (Unifesp): 29 infectados pelo HIV e 10 expostos e não infectados (ENI) pelo HIV, com mediana de idade, respectivamente, de 12,8 e 13,4 anos. Todos receberam duas doses da vacina VHA (Havrix(r)) em 2002. RESULTADOS: A mediana da idade na época da imunização primária (IP) era de 5,4 anos para o grupo HIV e 6,5 anos para o grupo ENI. As crianças dos dois grupos apresentaram anticorpos para o VHA > 20 mUI/mL após a IP. Sete anos após, o grupo ENI apresentava mediana de anticorpos = 253,5 mUI/mL e o grupo HIV = 113,0 mUI/mL (Mann-Whitney; p=0,085). Todo grupo ENI e 23/29 (79,3%) do grupo HIV mantiveram anticorpos contra o VHA sete anos após IP. Os níveis de anticorpos para hepatite A na primovacinação foram o único fator independentemente associado à manutenção desses anticorpos decorridos sete anos. O grupo que perdeu soropositividade para VHA foi revacinado e 83,3% (5/6) responderam com anticorpos >20 mUI/mL. CONCLUSÕES: Os níveis de anticorpos obtidos na primovacinação no grupo HIV foram o principal fator associado à perda de anticorpos após imunização VHA.

[Persistence of hepatitis A virus antibodies after primary immunization and response to revaccination in children and adolescents with perinatal HIV exposure]. / Persistência de anticorpos contra o vírus da hepatite A após imunização primária e resposta à revacinação em crianças e adolescentes com exposição perinatal ao HIV.

OBJECTIVE: To assess possible factors associated with the loss of antibodies to hepatitis A 7 years after the primary immunization in children of HIV-infected mothers and the response to revaccination in patients seronegative for hepatitis A. METHODS: Quantification of HAV antibodies by electrochemiluminescence was performed in 39 adolescents followed up at the Pediatric Aids Clinic of Federal University of São Paulo (Unifesp): 29 HIV-infected (HIVgroup) (median age: 12.8 years) and 10 HIV-exposed but non-infected (ENI group) (median age: 13.4 years). All of them received two doses of HAV vaccine (Havrix(®)) in 2002. RESULTS: The median age at primary immunization (PI) was 5.4 years for HIV group and 6.5 years for ENI group. All children, from both groups, had antibodies to HAV >20 mIU/mL after PI. Seven years later, the ENI group showed a median concentration of antibodies = 253.5 mIU/mL, while the HIV group = 113.0 mIU/mL (Mann-Whitney test, p=0.085). All ENI group and 23/29 (79.3%) from HIV group mantained HAV antibodies 7 years after PI. The levels of hepatitis A antibodies in the primary vaccination were the only factor independently associated with maintaining these antibodies for 7 years. The group that lost HAV seropositivity was revaccinated and 83.3% (5/6) responded with antibodies >20 mUI/mL. CONCLUSIONS: The antibodies levels acquired in the primary vaccination in the HIV group were the main factor associated with antibodies loss after HAV immunization.

Resposta humoral, carga parasitária e avaliação histopatológica na infecção experimental por Leishmania (Leishmania) chagasi em camundongos BALB/c imunossuprimidos / Humoral response, parasite load and histopathological evaluation in immunossuppressed BALB/c mice experimentally infected by Leishmania (Leishmania) chagasi

O objetivo do estudo foi avaliar a resposta humoral, a carga parasitária e os aspectos histopatológicos presentes no fígado em camundongos BALB/c experimentalmente infectados por L. (L.) chagasi e imunossuprimidos. 96 camundongos foram subdivididos em quatro grupos: controle (I) – sem tratamento; imunossuprimidos (II) – tratamento com dexametasona (DXM) e pentoxifilina (PTX); infectado (III) – infecção por L (L.) chagasi e infectados e imunossuprimidos (IV) - infecção por L (L.) chagasi e tratados com DXM e PTX. O dia de infecção foi considerado como o dia zero e a imunossupressão ocorreu 60 dias pós-infecção. As amostras foram obtidas de cada grupo, em momentos distintos 15, 30, 60, 75 e 90 dias pós-infecção, em que se coletou sangue total, para detecção de IgG1 e IgG2a pelo ensaio imunoenzimático (ELISA), fragmentos de baço e fígado, para detecção da carga parasitária pela técnica de microtitulação em cultura e fragmentos de fígado para o exame histopatológico. Houve diferença significativa na produção das imunoglobulinas e IgG1 foi à subclasse de imunoglobulina mais produzida pelos grupos (P < 0,0001). Quando comparadas a subclasses de imunoglobulinas dentro do mesmo grupo, IgG1 também apresentou médias maiores de produção nos grupos III e IV (P = 0,014 e P = 0,009). E quando se considera o momento, não houve diferenças significativas entre IgG1 e IgG2a. Aos 90 dias pós-infecção foram encontradas diferenças significativas entre as médias de produção de IgG1 e IgG2a, entre os grupos III e IV e o grupo III produziu mais as duas subclasses (P = 0,02). Nos momentos 75 e 90 dias pós-infecção houve produção maior de IgG1 e IgG2a. O Grupo IV apresentou maior carga parasitária (P < 0,005).(...)

This study aimed to evaluate the humoral response, the parasite load and liver histopathological features in BALB/c experimentally infected by L. (L.) chagasi and immunosuppressed Ninety-six mice divided into four groups: control (I) - no treatment; immunosuppressed (II) - Treatment with dexamethasone (DXM) and pentoxifylline (PTX), infected (III) - infection by L. (L.) chagasi and infected and immunosuppressed (IV) - infection by L (L.) chagasi and treated with PTX and DXM. The days of infection was considered as day zero and immunosuppression occurred 60 days post-infection. Samples were obtained from each group at different times 15, 30, 60, 75 and 90 days post-infection, which collected whole blood for detection of IgG1 and IgG2a by test immunoassay (ELISA), fragments of spleen and liver, to detect the parasite load in the technique microtiter culture and fragments of liver for histopathology. Significant differences in production of immunoglobulins, IgG1 was the subclass immunoglobulin produced by most groups (P<0.0001). When comparing the immunoglobulin subclasses within the same group, IgG1 also showed higher average production in groups III and IV (P=0.014 and P=0.009). When one considers the time, there were no significant differences between IgG1 and IgG2a. At 90 days post-infection were significant differences between the means of production of IgG1 and IgG2a between group III and IV and group III produced over the two subclasses (P=0.02). In periods of 75 and 90 days post-infection there was increased production of IgG1 and IgG2a. Group IV showed a higher parasite load (P <0.005).(...)

Mucormicose rino-órbito-cerebral associada com trombose do seio cavernoso: relato de caso / Rhino-orbitocerebral mucormycosis associated with cavernous sinus thrombosis: case report

Introdução: A Mucormicose é uma infecção oportunista rara causada por fungos da ordem dos Mucorales, sendo o Rhizopus o gênero mais comum (70% dos casos). Esta é uma infecção fúngica invasiva aguda que pode apresentar-se na forma disseminada, cutânea, pulmonar, gastrointestinal e rino-órbito-cerebral (forma mais comum). Nesta última, as queixas mais comuns são de rinorréia unilateral, febre e cefaléia. Quando há envolvimento orbitário as queixas podem ser de quemose, diplopia e diminuição da acuidade visual. A infecção pode disseminar-se para o Sistema Nervoso Central através do ápice orbitário, da placa cribiforme ou causar trombose em artérias que irrigam o Sistema Nervoso Central. A Mucormicose é uma emergência médica e o tratamento consiste na cirurgia para debridamento agressivo e no uso de antifúngicos sistêmicos. Mesmo com a terapêutica adequada à taxa de mortalidade chega a até 40% dos casos. Uma possível complicação intracraniana da Mucormicose é a Trombose de Seio Cavernoso que é uma infecção rara e com alta taxa de mortalidade. Na Trombose de Seio Cavernoso as queixas iniciais são de cefaléia, dor retro-orbital, edema periorbitário, proptose, diplopia e diminuição da acuidade visual. Relato do Caso: Nós relatamos o caso de uma paciente com 43 anos de idade com antecedentes de diabetes mellitus e uso drogas imunossupressoras para transplante renal, que desenvolveu quadro de Rinossinusite Bacteriana Aguda e Rinossinusite Fúngica Invasiva Aguda associada à Trombose de Seio Cavernoso.

Introduction: Mucormycosis is a rare opportunistic infection caused by Mucorales fungi, and the Rhizopus is the most common one (70% of the cases). It is an acute invasive fungal disease whose form is disseminated, cutaneous, pulmonary, gastrointestinal and rhino-orbitocerebral. The latter is the most common form and its symptoms comprise of unilateral sinusitis, fever and headache. Once established in the orbit the symptoms can be chemosis, diplopia and reduced vision. The infection can spread to the brain via the orbital apex, orbital arteries or via the cribriform plate. Mucormycosis is a medical emergency and the treatment consists of a surgery to an aggressive debridement and in the use of antifungal therapy. Despite the appropriate management, the mortality rate can reach 40% of the cases. One possible intracranial complication of Mucormycosis is the Cavernous Sinus Thrombosis which is a rare and fatal infective disease. The initial symptoms of Cavernous Sinus Thrombosis are headache, retro-orbital pain, periorbital edema, proptosis, diplopia and reduced vision. Case Report: We describe the case of 43-year-old woman with medical history of diabetes mellitus and use of immunosuppressant drugs after kidney transplantation. The patient developed Acute Bacterial Sinusitis and Rhino-orbitocerebral Mucormycosis associated with Cavernous Sinus Thrombosis.

Alteraçoes anatomopatológicas renais em indivíduos com a síndrome da imunodeficiência adquirida / Renal anatomopathological changes in patients with acquired immunodeficiency deficiency syndrome

Renal anatomopathological lesions were studied among 119 AIDS patients from Faculdade de Medicina do Triângulo Mineiro's University Hospital (Uberaba, MG, Brazil). From formalin-fixed blocks, slides were obtained and studied by light microscopy. Of 119 patients, 67 presented tubulointerstitial nephritis (TIN), 18 inespecific, 2 xantogranulomatous and infections agents were found in 48 as follows: mycosis in 28 (16 Cryptococcus sp; 9 Histoplasma sp, 1 Candida sp e 2 Paracoccidioides brasiliensis); bacteria in 18 (9 Mycobacterium sp), virus in 6 (Cytomegalovirus). Acute tubular necrosis was found in 43 cases (36.1%). Other diagnosis were: nefrocalcinosis (15.1%), arteriolar hyalinosis (22.7%), two cases of focal segmental glomerulosclerosis (1.7%) and one case of diffuse mesangial hyperplasia (0.8%). We conclude that the renal involvement in patients with AIDS, presents a wide spectrum of pathologies, secondary to complications related to opportunistic infections, therapeutic and diagnostic management, and the nephropathies associated to HIV.

As alterações anatomopatológicas renais foram estudadas em 119 casos de indivíduos com a síndrome da imunodeficiência humana adquirida (SIDA) no Hospital Escola da Faculdade de Medicina do Triângulo Mineiro, Uberaba MG. A partir das amostras de rim fixadas em formol, foram confeccionadas lâminas e analisadas ao microscópio de luz. Dos 119 casos estudados, 67 tiveram diagnóstico de nefrite túbulo intersticial (NTI), sendo 18 inespecíficas, 2 xantogranulomatosas e encontrou-se agente infeccioso em 48: fungos em 28 (16 Cryptococcus sp, 9 Histoplasma sp, 1 Candida sp e 2 Paracoccidioides brasiliensis); bactérias em 18 (9 Mycobacterium sp); vírus em 6, Citomegalovírus. Em 43 havia necrose tubular aguda (NTA). Outros diagnósticos foram: nefrocalcinose (15,1%) e hialinose arteriolar (22,7%). Encontrou-se também 2 casos com glomeruloesclerose segmentar focal (GESF) e um caso de hiperplasia mesangial difusa. Houve predomínio da NTI, que pode ser devido às infecções oportunistas, predominando as fúngicas; a toxicidade por drogas ou ainda devido a possível ação direta do próprio vírus. A necrose tubular aguda (NTA), foi a segunda causa em freqüência, de acometimento renal da amostra. Concluiu-se que o envolvimento renal nos pacientes com SIDA apresenta um espectro variado de processos patológicos, principalmente relacionados com infecções oportunistas, o tratamento e os procedimentos para diagnósticos, e ainda as nefropatias associadas ao vírus da imunodeficiência humana (VIH).