Clinical presentation and virological assessment of confirmed human monkeypox virus cases in Spain: a prospective observational cohort study.

BACKGROUND: In May, 2022, several European countries reported autochthonous cases of monkeypox, which rapidly spread globally. Early reports suggest atypical presentations. We aimed to investigate clinical and virological characteristics of cases of human monkeypox in Spain. METHODS: This multicentre, prospective, observational cohort study was done in three sexual health clinics in Madrid and Barcelona, Spain. We enrolled all consecutive patients with laboratory-confirmed monkeypox from May 11 to June 29, 2022. Participants were offered lesion, anal, and oropharynx swabs for PCR testing. Participant data were collected by means of interviews conducted by dermatologists or specialists in sexually transmitted infections and were recorded using a standard case report form. Outcomes assessed in all participants with a confirmed diagnosis were demographics, smallpox vaccination, HIV status, exposure to someone with monkeypox, travel, mass gathering attendance, risk factors for sexually transmitted infections, sexual behaviour, signs and symptoms on first presentation, virological results at multiple body sites, co-infection with other sexually transmitted pathogens, and clinical outcomes 14 days after the initial presentation. Clinical outcomes were followed up until July 13, 2022. FINDINGS: 181 patients had a confirmed monkeypox diagnosis and were enrolled in the study. 166 (92%) identified as gay men, bisexual men, or other men who have sex with men (MSM) and 15 (8%) identified as heterosexual men or heterosexual women. Median age was 37·0 years (IQR 31·0-42·0). 32 (18%) patients reported previous smallpox vaccination, 72 (40%) were HIV-positive, eight (11%) had a CD4 cell count less than 500 cells per µL, and 31 (17%) were diagnosed with a concurrent sexually transmitted infection. Median incubation was 7·0 days (IQR 5·0-10·0). All participants presented with skin lesions; 141 (78%) participants had lesions in the anogenital region, and 78 (43%) in the oral and perioral region. 70 (39%) participants had complications requiring treatment: 45 (25%) had a proctitis, 19 (10%) had tonsillitis, 15 (8%) had penile oedema, six (3%) an abscess, and eight (4%) had an exanthem. Three (2%) patients required hospital admission. 178 (99%) of 180 swabs from skin lesions collected tested positive, as did 82 (70%) of 117 throat swabs. Viral load was higher in lesion swabs than in pharyngeal specimens (mean cycle threshold value 23 [SD 4] vs 32 [6], absolute difference 9 [95% CI 8-10]; p<0·0001). 108 (65%) of 166 MSM reported anal-receptive sex. MSM who engaged in anal-receptive sex presented with proctitis (41 [38%] of 108 vs four [7%] of 58, absolute difference 31% [95% CI 19-44]; p<0·0001) and systemic symptoms before the rash (67 [62%] vs 16 [28%], absolute difference 34% [28-62]; p<0·0001) more frequently than MSM who did not engage in anal-receptive sex. 18 (95%) of 19 participants with tonsillitis reported practising oral-receptive sex. The median time from onset of lesions to formation of a dry crust was 10 days (IQR 7-13). INTERPRETATION: In our cohort, monkeypox caused genital, perianal, and oral lesions and complications including proctitis and tonsillitis. Because of the variability of presentations, clinicians should have a low threshold for suspicion of monkeypox. Lesion swabs showed the highest viral loads, which, combined with the history of sexual exposure and the distribution of lesions, suggests close contact is probably the dominant transmission route in the current outbreak. FUNDING: None.

KIT D816V-mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression.

Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P ≤ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome.

Ex vivo identification and characterization of a population of CD13(high) CD105(+) CD45(-) mesenchymal stem cells in human bone marrow.

INTRODUCTION: Mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and multilineage differentiation. Their multipotential capacity and immunomodulatory properties have led to an increasing interest in their biological properties and therapeutic applications. Currently, the definition of MSCs relies on a combination of phenotypic, morphological and functional characteristics which are typically evaluated upon in vitro expansion, a process that may ultimately lead to modulation of the immunophenotypic, functional and/or genetic features of these cells. Therefore, at present there is great interest in providing markers and phenotypes for direct in vivo and ex vivo identification and isolation of MSCs. METHODS: Multiparameter flow cytometry immunophenotypic studies were performed on 65 bone marrow (BM) samples for characterization of CD13(high) CD105(+) CD45(-) cells. Isolation and expansion of these cells was performed in a subset of samples in parallel to the expansion of MSCs from mononuclear cells following currently established procedures. The protein expression profile of these cells was further assessed on (paired) primary and in vitro expanded BM MSCs, and their adipogenic, chondrogenic and osteogenic differentiation potential was also determined. RESULTS: Our results show that the CD13(high) CD105(+) CD45(-) immunophenotype defines a minor subset of cells that are systematically present ex vivo in normal/reactive BM (n = 65) and that display immunophenotypic features, plastic adherence ability, and osteogenic, adipogenic and chondrogenic differentiation capacities fully compatible with those of MSCs. In addition, we also show that in vitro expansion of these cells modulates their immunophenotypic characteristics, including changes in the expression of markers currently used for the definition of MSCs, such as CD105, CD146 and HLA-DR. CONCLUSIONS: BM MSCs can be identified ex vivo in normal/reactive BM, based on a robust CD13(high) CD105(+) and CD45(-) immunophenotypic profile. Furthermore, in vitro expansion of these cells is associated with significant changes in the immunophenotypic profile of MSCs.

Detection and outcome of occult leptomeningeal disease in diffuse large B-cell lymphoma and Burkitt lymphoma.

The benefit of intrathecal therapy and systemic rituximab on the outcome of diffuse large B-cell lymphoma at risk of central nervous system disease is controversial. Furthermore, the effect of intrathecal treatment and rituximab in diffuse large B-cell and Burkitt lymphoma with occult leptomeningeal disease detected by flow cytometry at diagnosis is unknown. Untreated diffuse large B-cell (n=246) and Burkitt (n=80) lymphoma at clinical risk of central nervous system disease and having had pre-treatment cerebrospinal fluid were analyzed by flow cytometry and cytology. Spinal fluid involvement was detected by flow cytometry alone (occult) in 33 (13%) diffuse large B-cell and 9 (11%) Burkitt lymphoma patients, and detected by cytology in 11 (4.5%) and 5 (6%) patients, respectively. Diffuse large B-cell lymphoma with occult spinal fluid involvement had poorer survival (P=0.0001) and freedom from central nervous system relapse (P<0.0001) compared to negative cases. Burkitt lymphoma with occult spinal fluid involvement had an inferior freedom from central nervous system relapse (P=0.026) but not survival. The amount of intrathecal chemotherapy was quantitatively associated with survival in diffuse large B-cell lymphoma with (P=0.02) and without (P=0.001) occult spinal fluid involvement. However, progression of systemic disease and not control of central nervous system disease was the principal cause of treatment failure. In diffuse large B-cell lymphoma, systemic rituximab was associated with improved freedom from central nervous system relapse (P=0.003) but not with survival. Our results suggest that patients at risk of central nervous system disease should be evaluated by flow cytometry and that intrathecal prophylaxis/therapy is beneficial.

Contribution of cerebrospinal fluid sCD19 levels to the detection of CNS lymphoma and its impact on disease outcome.

Flow cytometry (FCM) is more sensitive than conventional cytology for detection of occult leptomeningeal lymphoma; however, some FCM-negative patients show central nervous system (CNS) recurrence. Here, we evaluated the cerebrospinal fluid (CSF) levels of 13 B-cell-associated markers and their contribution to the diagnosis of CNS lymphoma in 91 diffuse large B-cell lymphomas (DLBCL) and 22 Burkitt lymphomas (BLs). From all markers tested, CD19 was the most informative. Thus, higher soluble CD19 (sCD19) levels were associated with a greater frequency of neurological symptoms in DLBCL and BL and with parenchymal CNS lymphoma in DLBCL; sCD19 emerged as a powerful predictor of event-free and overall survival in DLBCL and BL, particularly when combined with FCM detection of CNS disease. These results support the utility of combined FCM detection of lymphoma cells and assessment of sCD19 levels in CSF, for more accurate identification of CNS disease in DLBCL and BL patients.

Epiteliopatía pigmentaria placoide multifocal posterior aguda. Una rara causa de ictus isquémico / Acute posterior multifocal placoid pigment epitheliopathy. A rare cause of ischaemic stroke

Introducción. La epiteliopatía pigmentaria placoide multifocal posterior aguda (EPPMPA) es una enfermedad inflamatoria rara, generalmente de etiología indeterminada, de la coriocapilar, el epitelio pigmentario y la retina externa. Afecta predominantemente a pacientes jóvenes y en algunos casos puede involucrar al sistema nervioso central en forma de ictus o de meningoencefalitis. Presentamos el caso clínico de una mujer joven con EPPMPA complicada con ictus e hipertensión intracraneal. Caso clínico. Mujer de 16 años que comienza con cefalea intensa sugestiva de hipertensión intracraneal, así como con un déficit agudo hemisférico izquierdo. La resonancia magnética craneal ponía de manifiesto lesiones embólicas o vasculíticas en diferentes territorios. No se evidenciaron datos de meningoencefalitis en el estudio del líquido cefalorraquídeo, pero sí de hipertensión intracraneal asociada. La presencia de lesiones muy específicas en el polo ocular posterior permitió el diagnóstico de EPPMPA complicada con ictus isquémico, probablemente por mecanismo vasculítico. Un amplio estudio etiológico fue negativo para identificar un factor desencadenante claro del proceso. Se inició tratamiento corticoideo con buena evolución clínica y radiológica. Conclusiones. La EPPMPA es una entidad rara que generalmente entraña buen pronóstico; sin embargo, en algunos casos puede complicarse con afectación del sistema nervioso central, y el ictus isquémico secundario a vasculitis es la complicación más grave. Ante un paciente joven con ictus que presente sintomatología visual y lesiones coriorretinianas, debe considerarse la EPPMPA en su diagnóstico etiológico (AU)

Introduction. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a rare inflammatory disease, generally of unknown aetiology, affecting the choriocapillaris, the pigment epithelium and the outer retina. It predominantly affects young patients and in some cases may involve the central nervous system in the form of strokes or meningoencephalitis. We report the clinical case of a young female with APMPPE that was complicated by stroke and intracranial hypertension. Case report. Our patient was a 16-year-old female who began with intense headaches suggesting intracranial hypertension, as well as with an acute deficit in the left hemisphere. A magnetic resonance scan of the head revealed embolic or vasculitic lesions in different territories. No evidence of meningoencephalitis was found in the cerebrospinal fluid analysis, but signs of associated intracranial hypertension were observed. The presence of very specific lesions in the posterior pole of the eye led to a diagnosis of APMPPE complicated by ischaemic stroke, probably caused by a vasculitic mechanism. An extensive aetiological study failed to identify a clear precipitating factor underlying the process. Treatment with corticoids was established, with good clinical and radiological progression. Conclusions. APMPPE is an infrequent condition that generally has a good prognosis. In some cases, however, complications may arise owing to involvement of the central nervous system, and ischaemic stroke secondary to vasculitis is the most severe complication. In young patients with stroke who present visual symptoms and chorioretinital lesions, APMPPE must be considered in the aetiological diagnosis (AU)

[Acute posterior multifocal placoid pigment epitheliopathy. A rare cause of ischaemic stroke]. / Epiteliopatía pigmentaria placoide multifocal posterior aguda. Una rara causa de ictus isquémico.

INTRODUCTION: Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a rare inflammatory disease, generally of unknown aetiology, affecting the choriocapillaris, the pigment epithelium and the outer retina. It predominantly affects young patients and in some cases may involve the central nervous system in the form of strokes or meningoencephalitis. We report the clinical case of a young female with APMPPE that was complicated by stroke and intracranial hypertension. CASE REPORT: Our patient was a 16-year-old female who began with intense headaches suggesting intracranial hyper-tension, as well as with an acute deficit in the left hemisphere. A magnetic resonance scan of the head revealed embolic or vasculitic lesions in different territories. No evidence of meningoencephalitis was found in the cerebrospinal fluid analysis, but signs of associated intracranial hypertension were observed. The presence of very specific lesions in the posterior pole of the eye led to a diagnosis of APMPPE complicated by ischaemic stroke, probably caused by a vasculitic mechanism. An extensive aetiological study failed to identify a clear precipitating factor underlying the process. Treatment with corticoids was established, with good clinical and radiological progression. CONCLUSIONS: APMPPE is an infrequent condition that generally has a good prognosis. In some cases, however, complications may arise owing to involvement of the central nervous system, and ischaemic stroke secondary to vasculitis is the most severe complication. In young patients with stroke who present visual symptoms and chorioretinital lesions, APMPPE must be considered in the aetiological diagnosis.

TITLE: Epiteliopatia pigmentaria placoide multifocal posterior aguda. Una rara causa de ictus isquemico.Introduccion. La epiteliopatia pigmentaria placoide multifocal posterior aguda (EPPMPA) es una enfermedad inflamatoria rara, generalmente de etiologia indeterminada, de la coriocapilar, el epitelio pigmentario y la retina externa. Afecta predominantemente a pacientes jovenes y en algunos casos puede involucrar al sistema nervioso central en forma de ictus o de meningoencefalitis. Presentamos el caso clinico de una mujer joven con EPPMPA complicada con ictus e hipertension intracraneal. Caso clinico. Mujer de 16 anos que comienza con cefalea intensa sugestiva de hipertension intracraneal, asi como con un deficit agudo hemisferico izquierdo. La resonancia magnetica craneal ponia de manifiesto lesiones embolicas o vasculiticas en diferentes territorios. No se evidenciaron datos de meningoencefalitis en el estudio del liquido cefalorraquideo, pero si de hipertension intracraneal asociada. La presencia de lesiones muy especificas en el polo ocular posterior permitio el diagnostico de EPPMPA complicada con ictus isquemico, probablemente por mecanismo vasculitico. Un amplio estudio etiologico fue negativo para identificar un factor desencadenante claro del proceso. Se inicio tratamiento corticoideo con buena evolucion clinica y radiologica. Conclusiones. La EPPMPA es una entidad rara que generalmente entrana buen pronostico; sin embargo, en algunos casos puede complicarse con afectacion del sistema nervioso central, y el ictus isquemico secundario a vasculitis es la complicacion mas grave. Ante un paciente joven con ictus que presente sintomatologia visual y lesiones coriorretinianas, debe considerarse la EPPMPA en su diagnostico etiologico.

Radiation-induced osteochondroma of the T4 vertebra causing spinal cord compression.

A case of a radiation-induced osteochondroma arising from the vertebral body of T4 in an 18-year-old man is reported. The patient presented with a history of progressive left lower extremity weakness. At 7 years of age, he had undergone resection of a cerebellar medulloblastoma and received adjunctive craniospinal irradiation and systemic chemotherapy. Both CT and MR imaging revealed an extradural mass contiguous with the posteroinferior endplate of the T4 vertebral body. This case indicates that radiation-induced osteochondroma should be considered in the differential diagnosis of patients with symptoms of myelopathy or nerve root compression and a history of radiation therapy involving the spine in childhood.