The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy.

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

Painful and swollen tongue: mucosal leishmaniasis due to Leishmania infantum.

BACKGROUND: Leishmaniasis is a parasitic disease caused by different Leishmania species. L. infantum is found in the Mediterranean area. It usually causes visceral or cutaneous leishmaniasis, but rarely mucosal leishmaniasis (ML). METHODS: A 62-year-old man with metastatic non-small-cell lung carcinoma visited the outpatient clinic because of a painful and swollen tongue. Initially, oral candidiasis was suspected and patient was unsuccessfully treated accordingly. Subsequently, a biopsy from the tongue was taken. RESULTS: Histology of the tongue biopsy showed an inflammation with histiocytes and Leishmania amastigotes. Molecular analysis determined these parasites as L. donovani complex. Based on the patient's travel history, ML caused by L. infantum was diagnosed. CONCLUSION: ML is an unusual presentation of L. infantum. ML is not only caused by Leishmania species endemic in Latin America, but also should be considered in the differential diagnosis for European patients. A biopsy of the affected location is needed to confirm the diagnosis.

Severity of imported malaria: protective effect of taking malaria chemoprophylaxis.

BACKGROUND: Although chemoprophylaxis remains an important strategy for preventing malaria in travellers, its effectiveness may be compromised by lack of adherence. Inappropriate use of chemoprophylaxis is likely to increase the risk of acquiring malaria, but may probably also worsen the severity of imported cases. The aim of this study was to assess the impact of use of malaria chemoprophylaxis on clinical features and outcome of imported malaria. METHODS: Demographic, clinical and laboratory data of patients included in the Rotterdam Malaria Cohort between 1998 and 2011 were systematically collected and analysed. Patients were classified as self-reported compliant or non-compliant users or as non-users of chemoprophylaxis. Severe malaria was defined using the 2010 WHO criteria. RESULTS: Details on chemoprophylaxis were available for 559 of the 604 patients, of which 64.6% were non-users, 17.9% were inadequate users and 17.5% reported to be adequate users. The group of non-users was predominated by patients with African ethnicity, partial immunity and people visiting friends and relatives. The majority contracted Plasmodium falciparum malaria. In contrast, compliant users acquired non-falciparum malaria more frequently, had significant lower P. falciparum loads on admission, shorter duration of hospitalization and significant lower odds for severe malaria as compared with non-users. Patients with P. falciparum malaria were more likely to have taken their chemoprophylaxis less compliantly than those infected with non-P. falciparum species. Multivariate analysis showed that self-reported adequate prophylaxis and being a partially immune traveller visiting friends and relatives was associated with significantly lower odds ratio of severe malaria. In contrast, age, acquisition of malaria in West-Africa and being a non-immune tourist increased their risk significantly. CONCLUSIONS: Compliant use of malaria chemoprophylaxis was associated with significantly lower odds ratios for severe malaria as compared with non-compliant users and non-users of chemoprophylaxis. After correction for age, gender and immunity, this protective effect of malaria chemoprophylaxis was present only in individuals who adhered compliantly to use of chemoprophylaxis. Patients with P. falciparum malaria were more likely to have used their chemoprophylaxis less compliantly than patients with non-P. falciparum malaria who were more likely to have contracted malaria in spite of compliant use of chemoprophylaxis.

Predictive value of lymphocytopenia and the neutrophil-lymphocyte count ratio for severe imported malaria.

BACKGROUND: Lymphocytopenia has frequently been described in patients with malaria, but studies on its association with disease severity have yielded conflicting results. The neutrophil/lymphocyte count ratio (NLCR) has been introduced as a parameter for systemic inflammation in critically ill patients and was found, together with lymphocytopenia, to be a better predictor of bacteraemia than routine parameters like C-reactive protein and total leukocyte count. In the present study, the predictive value of the NLCR and lymphocytopenia for severe disease was evaluated in patients with imported malaria. METHODS: All patients diagnosed with malaria at the Harbour Hospital between January 1st 1999 and January 1st 2012 with differential white cell counts determined within the first 24 hours after admission were included in this retrospective study. Severe malaria was defined according to the WHO criteria. The performance of the NLCR and lymphocytopenia as a marker of severe malarial disease was compared back-to-back with that of C-reactive protein as a reference biomarker. RESULTS: A total of 440 patients (severe falciparum malaria n = 61, non-severe falciparum malaria n = 259, non-falciparum malaria n=120) were included in the study. Lymphocytopenia was present in 52% of all patients and the median NLCR of all patients was 3.2. Total lymphocyte counts and NLCR did not differ significantly between groups. A significant correlation of total leukocyte count and NLCR, but not lymphocyte count, with parasitaemia was found. ROC analysis revealed a good negative predictive value but a poor positive predictive value of both lymphocytopenia and NLCR and performance was inferior to that of C-reactive protein. After complete parasite clearance a significant rise in total leukocyte count and lymphocyte count and a significant decrease in NLCR was observed. CONCLUSION: The NLCR was found to correlate with parasitaemia, but both lymphocytopenia and the NLCR were inferior to C-reactive protein as markers for severe disease in patients with imported malaria. The NLCR and lymphocytopenia are not useful as predictive markers for severe disease in imported malaria in the acute care setting.

Imported scrub typhus in The Netherlands.

Two cases of travel-acquired scrub typhus imported in the Netherlands are described. The characteristic eschar was absent in both cases. One case acquired scrub typhus in non-rural surroundings in India, highlighting that scrub typhus must also be considered a (sub) urban zoonosis.

The prognostic value of schizontaemia in imported Plasmodium falciparum malaria.

BACKGROUND: In Plasmodium falciparum infection, peripheral parasite counts do not always correlate well with the sequestered parasite burden. As erythrocytes parasitized with mature trophozoites and schizonts have a high tendency to adhere to the microvascular endothelium, they are often absent in peripheral blood samples. The appearance of schizonts in peripheral blood smears is thought to be a marker of high sequestered parasite burden and severe disease. In the present study, the value of schizontaemia as an early marker for severe disease in non-immune individuals with imported malaria was evaluated. METHODS: All patients in the Rotterdam Malaria Cohort diagnosed with P. falciparum malaria between 1 January 1999 and 1 January 2012 were included. Thick and thin blood films were examined for the presence of schizontaemia. The occurrence of WHO defined severe malaria was the primary endpoint. The diagnostic performance of schizontaemia was compared with previously evaluated biomarkers C-reactive protein and lactate. RESULTS: Schizonts were present on admission in 49 of 401 (12.2%) patients. Patients with schizontaemia were more likely to present with severe malaria, a more complicated course and had longer duration of admission in hospital. Schizontaemia had a specificity of 0.95, a sensitivity of 0.53, a negative predictive value of 0.92 and a positive predictive value of 0.67 for severe malaria. The presence of schizonts was an independent predictor for severe malaria. CONCLUSION: Absence of schizonts was found to be a specific marker for exclusion of severe malaria. Presence of schizonts on admission was associated with a high positive predictive value for severe malaria. This may be of help to identify patients who are at risk of a more severe course than would be expected when considering peripheral parasitaemia alone.

[Tick-borne encephalitis after a holiday in Southern Germany]. / Teken-encefalitis na een vakantie in Zuid-Duitsland.

A 56-year-old man was admitted to hospital with complaints of headache, fever and photophobia, 3 weeks after being bitten by ticks in Southern Germany. Two weeks before admission he had experienced a short period of a flu-like illness, from which he spontaneously recovered. Based on the tick bites in Southern Germany and the biphasic course of the illness shortly afterwards, we made the diagnosis tick-borne encephalitis, Frühsommer-Meningoenzephalitis in German (FSME). The diagnosis was confirmed serologically. FSME is caused by a flavivirus, which is transmitted via tick bites. In 72-87% of cases the course is biphasic. The virus subtype and the degree of central nervous system involvement determine the prognosis. The patient may experience residual symptoms. The treatment is symptomatic. Active immunisation offers protection, but is only recommended to those who stay frequently or for a long period in areas where the virus is endemic.