Chronic exposure to cigarette smoke transiently worsens the disease course in a mouse model of pulmonary paracoccidioidomycosis

ABSTRACT Paracoccidioidomycosis (PCM) may present as an acute/subacute clinical form, characterized by a progressive disease arising from the airborne initial infection, or, most often, as an asymptomatic or subclinical infection that may manifest later during an individual's life, the chronic form. Epidemiological studies show the existence of a strong association between smoking and the development of the chronic form. Current evidence demonstrates that cigarette smoke (CS) has immunosuppressive properties that could be implicated in the increasing susceptibility to the chronic form of PCM. To address this issue, we developed a murine model of a non-progressive pulmonary form of PCM that was exposed to CS at a magnitude that mimicked a moderate smoker. The chronic CS exposure started after 2 weeks and lasted up until 20 weeks post-infection, with the aim of mimicking human natural history, since it is estimated that individuals from endemic areas are infected early in life. The control group consisted of infected but not CS-exposed mice. We assessed the lung fungal burden (colony forming units [CFU]) and the area affected by the granulomatous inflammatory response, fungal dissemination to spleen and liver, and, by immunohistochemistry, the presence of CD4 and CD8 lymphocytes, CD68 and MAC-2 macrophages, and IFN-γ, IL-10 and TNF expressing cells within the granulomatous response. We detected a CS effect as early as 2 weeks after exposure (four weeks post-infection) when the lung CFU of exposed animals was significantly higher than in their non-exposed counterparts. At 12 weeks, the CS-exposed animals presented a more severe disease, as witnessed by the persistent higher lung fungal load (although it did not reach statistical significance [ p = 0.054]), greater dissemination to other organs, greater affected area of the lung, decreased IFN-γ/IL-10 ratio, and higher TNF expression within the granulomas, compared with CS-non-exposed mice. The number of CD4 and CD8 lymphocytes infiltrating the granulomas was similar between both mice groups, but there was a decrease in the number of MAC-2+ macrophages. No difference was noted in the CD68+ macrophage number. However, the follow-up in week 20 showed that the immunological effects of exposure to CS ceased, with both CS and NCS mice showing the same infectious features, i.e., a trend for resolution of the infection. In conclusion, we show that chronic CS-exposure alters the course of the disease in an experimental model of subclinical pulmonary PCM, confirming the epidemiological link between CS-exposure and the chronic form of PCM. However, we also show that this effect is transitory, being detected between 4- and 12-weeks post-infection but not thereafter. The possible immune mechanisms that mediate this effect and the reasons for its transitory effect are discussed.

Fatal disseminated cytomegalovirus infection with necrotizing oophoritis in a patient with acquired immunodeficiency syndrome

Disseminated human cytomegalovirus (CMV) disease occurs mainly as a congenital infection and among immunocompromised hosts. Patients with acquired immunodeficiency syndrome (AIDS) are at increased risk for CMV infection, and the most prevalent clinical manifestation is retinitis, followed by colitis, esophagitis, pneumonitis, and encephalitis. CMV oophoritis is poorly described in the literature with some cases reported in patients with hematological or solid malignancies, bone marrow or solid organ transplantation, immunosuppressive therapy, and advanced AIDS cases. We report the case of a 61-year-old woman with a recent diagnosis of AIDS, which was associated with a wasting syndrome. The patient presented with abdominal pain, headache, cutaneous vesicular lesions on the abdomen, anemia, lymphopenia, and hyponatremia; she died suddenly on the fourth day of hospitalization. The autopsy was performed and demonstrated disseminated CMV infection with hemorrhagic encephalitis as the immediate cause of death. Additionally, pneumonitis, extensive adrenalitis, ulcerated enteritis, focal hepatitis, and necrotizing oophoritis were found.

CHAGASIC MENINGOENCEPHALITIS IN AN HIV INFECTED PATIENT WITH MODERATE IMMUNOSUPPRESSION: PROLONGED SURVIVAL AND CHALLENGES IN THE HAART ERA / Meningoencefalite chagásica em paciente infectada pelo HIV com imunodepressão moderada: desafios na era HAART e sobrevida prolongada

The reactivation of Chagas disease in HIV infected patients presents high mortality and morbidity. We present the case of a female patient with confirmed Chagasic meningoencephalitis as AIDS-defining illness. Interestingly, her TCD4+ lymphocyte cell count was 318 cells/mm3. After two months of induction therapy, one year of maintenance with benznidazol, and early introduction of highly active antiretroviral therapy (HAART), the patient had good clinical, parasitological and radiological evolution. We used a qualitative polymerase chain reaction for the monitoring of T. cruzi parasitemia during and after the treatment. We emphasize the potential value of molecular techniques along with clinical and radiological parameters in the follow-up of patients with Chagas disease and HIV infection. Early introduction of HAART, prolonged induction and maintenance of antiparasitic therapy, and its discontinuation are feasible, in the current management of reactivation of Chagas disease.

A reativação da doença de Chagas em pacientes com a infecção pelo HIV apresenta uma alta morbidade e mortalidade. Neste relato, apresentamos caso confirmado de meningoencefalite chagásica, como doença definidora de aids, em paciente com 318 linfócitos T-CD4+/mm3. Após 2 meses de tratamento seguido de um ano de profilaxia secundária com benzonidazol e início precoce de terapia antirretroviral (HAART), a paciente apresentou boa evolução clínica, parasitológica e radiológica. Utilizamos a reação em cadeia da polimerase qualitativa do T. cruzi, para monitorização da parasitemia por T. cruzi durante e após o tratamento. Ressaltamos o valor potencial das técnicas moleculares associadas aos parâmetros clínicos e radiológicos nos pacientes com doença de Chagas e infecção pelo HIV. A introdução precoce da terapia antirretroviral, a terapia antiparasitária prolongada, manutenção e descontinuação da mesma, são desafios atuais, embora possíveis, no manejo da reativação da doença de Chagas na era das terapias antirretrovirais de alta eficácia.