Identifying childhood leukemia with an excess of hematological malignancies in first-degree relatives in Brazil.

Background: Familial aggregation in childhood leukemia is associated with epidemiological and genomic factors. Albeit epidemiological studies on the familial history of hematological malignancies (FHHMs) are scarce, genome-wide studies have identified inherited gene variants associated with leukemia risk. We revisited a dataset of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients to explore the familial aggregation of malignancies among their relatives. Methods: A series of 5,878 childhood leukemia (≤21 years of age) from the EMiLI study (2000-2019) were assessed. Lack of well-documented familial history of cancer (FHC) and 670 cases associated with genetic phenotypic syndromes were excluded. Leukemia subtypes were established according to World Health Organization recommendations. Logistic regression-derived odds ratios (ORs) and 95% confidence intervals (CIs) were performed and adjusted by age as a continuous variable, where ALL was the reference group for AML and conversely. The pedigree of 18 families with excess hematological malignancy was constructed. Results: FHC was identified in 472 of 3,618 eligible cases (13%). Ninety-six of the 472 patients (20.3%) had an occurrence of FHHMs among relatives. Overall, FHC was significantly associated with AML (OR, 1.36; 95% CI, 1.01-1.82; p = 0.040). Regarding the first-degree relatives, the OR, 2.92 95% CI,1.57-5.42 and the adjOR, 1.16 (1.03-1.30; p0.001) were found for FHC and FHHM, respectively. Conclusion: Our findings confirmed that AML subtypes presented a significant association with hematological malignancies in first-degree relatives. Genomic studies are needed to identify germline mutations that significantly increase the risk of developing myeloid malignancies in Brazil.

A case report of vaccine-induced immune thrombotic thrombocytopenia (VITT) with genetic analysis.

The emergence of the rare syndrome called vaccine-induced immune thrombocytopenia and thrombosis (VITT) after adenoviral vector vaccines, including ChAdOx1 nCov-19, raises concern about one's predisposing risk factors. Here we report the case of a 56-year-old white man who developed VITT leading to death within 9 days of symptom onset. He presented with superior sagittal sinus thrombosis, right frontal intraparenchymal hematoma, frontoparietal subarachnoid and massive ventricular hemorrhage, and right lower extremity arterial and venous thrombosis. His laboratory results showed elevated D-dimer, C-reactive protein, tissue factor, P-selectin (CD62p), and positive anti-platelet factor 4. The patient's plasma promoted higher CD62p expression in healthy donors' platelets than the controls. Genetic investigation on coagulation, thrombophilia, inflammation, and type I interferon-related genes was performed. From rare variants in European or African genomic databases, 68 single-nucleotide polymorphisms (SNPs) in one allele and 11 in two alleles from common SNPs were found in the patient genome. This report highlights the possible relationship between VITT and genetic variants. Additional investigations regarding the genetic predisposition of VITT are needed.

Clinical Presentation of Parvovirus B19 Infection in Adults Living with HIV/AIDS: A Case Series.

Parvovirus B19 (B19V) infection varies clinically depending on the host's immune status. Due to red blood cell precursors tropism, B19V can cause chronic anemia and transient aplastic crisis in patients with immunosuppression or chronic hemolysis. We report three rare cases of Brazilian adults living with human immunodeficiency virus (HIV) with B19V infection. All cases presented severe anemia and required red blood cell transfusions. The first patient had low CD4+ counts and was treated with intravenous immunoglobulin (IVIG). As he remained poorly adherent to antiretroviral therapy (ART), B19V detection persisted. The second patient had sudden pancytopenia despite being on ART with an undetectable HIV viral load. He had historically low CD4+ counts, fully responded to IVIG, and had undiagnosed hereditary spherocytosis. The third individual was recently diagnosed with HIV and tuberculosis (TB). One month after ART initiation, he was hospitalized with anemia aggravation and cholestatic hepatitis. An analysis of his serum revealed B19V DNA and anti-B19V IgG, corroborating bone marrow findings and a persistent B19V infection. The symptoms resolved and B19V became undetectable. In all cases, real time PCR was essential for diagnosing B19V. Our findings showed that adherence to ART was crucial to B19V clearance in HIV-patients and highlighted the importance of the early recognition of B19V disease in unexplained cytopenias.

GATA2 variants in patients with non-tuberculous mycobacterial or fungal infections without known immunodeficiencies.

INTRODUCTION: Haploinsufficiency of the hematopoietic transcription factor GATA2 is associated with a broad spectrum of diseases, including infection susceptibility and neoplasms. We aimed to investigate GATA2 variants in patients with non-tuberculous mycobacterial (NTM) and/or fungal infections (FI) without known immunodeficiencies. METHOD: We performed GATA2 genotyping in patients with NTM and/or FI. RESULTS: Twenty-two patients were enrolled (seventeen FI, four NTM and one with both infections). The pathogenic variant NG_029334.1:g.16287C>T was found in one patient (4.5%) and two asymptomatic offsprings. We also found the likely-benign variant NG_029334.1:g.12080G>A (rs2335052), the benign variant NG_029334.1:g.16225C>T (rs11708606) and the variant of uncertain significance NG_029334.1:g.16201G>A (rs369850507) in 18.2%, 27.3%, and 4.5% of the cases, respectively. Malignant diseases were additionally diagnosed in six patients. CONCLUSION: Although detected in 45.4% of the patients, most GATA2 variants were benign or likely benign. Identifying a pathogenic variant was essential for driving both the patient's treatment and familial counseling. Pathogenic variants carriers should receive genetic counseling, subsequent infection prevention measures and malignancies surveillance. Additionally, case-control genotyping should be carried out in Brazil to investigate whether the observed variants may be associated with susceptibility to opportunistic infections and/or concurrent neoplasms.

Vaccine-induced immune thrombotic thrombocytopenia post COVID-19 booster vaccination in Brazil: a case series.

Background: The emergence of new variants of SARS-CoV-2 has led to the administration of different booster vaccines to mitigate COVID-19. Vaccines with adenoviral vectors have been rarely associated with vaccine-induced immune thrombotic thrombocytopenia (VITT). Objectives: This study aimed to describe 15 cases of VITT after the third and fourth doses of the COVID-19 vaccine in Brazil. Methods: Cases were reported after all kinds of anti-SARS-CoV-2 booster vaccinations between October 17, 2021, and September 4, 2022. Results: Of the 26 suspected cases, 15 cases of VITT were analyzed. Of these, 10 were classified as definite VITT, 2 as probable, 1 as possible, and 2 as unlikely. The estimated frequency of definite, probable, or possible VITT was 0.33 cases per million. Cases were assigned to ChAdOx1 (13 cases), Ad26.COV2.S (1 case), and BNT162b2 (1 case). None of the patients received an adenoviral vaccine as a primary vaccination. The average age of participants was 34 years, and symptoms usually appeared 8 days after vaccination. Headache was the most common symptom, and cerebral veins were the most affected thrombotic site. The overall mortality risk was 53%. Anti-platelet factor 4 enzyme-linked immunosorbent assay serology was positive in 11 out of 15 patients (73.3%), negative in 2 (13.3%), and missing in 2 (13.3%). Conclusion: The study confirms that VITT is linked to the first exposure to adenoviral vector vaccines. Since January 2023, Brazil has recommended preferably COVID-19 messenger RNA vaccines for individuals aged 18 to 39 years. We suggest that, in the current disease scenario, COVID-19 adenovirus vaccines should not be the first choice for individuals aged <50 years who have not received a previous dose of this type of vaccine.

GATA2 variants in patients with non-tuberculous mycobacterial or fungal infections without known immunodeficiencies

ABSTRACT Introduction Haploinsufficiency of the hematopoietic transcription factor GATA2 is associated with a broad spectrum of diseases, including infection susceptibility and neoplasms. We aimed to investigate GATA2 variants in patients with non-tuberculous mycobacterial (NTM) and/or fungal infections (FI) without known immunodeficiencies. Method We performed GATA2 genotyping in patients with NTM and/or FI. Results Twenty-two patients were enrolled (seventeen FI, four NTM and one with both infections). The pathogenic variant NG_029334.1:g.16287C>T was found in one patient (4.5%) and two asymptomatic offsprings. We also found the likely-benign variant NG_029334.1:g.12080G>A (rs2335052), the benign variant NG_029334.1:g.16225C>T (rs11708606) and the variant of uncertain significance NG_029334.1:g.16201G>A (rs369850507) in 18.2%, 27.3%, and 4.5% of the cases, respectively. Malignant diseases were additionally diagnosed in six patients. Conclusion Although detected in 45.4% of the patients, most GATA2 variants were benign or likely benign. Identifying a pathogenic variant was essential for driving both the patient's treatment and familial counseling. Pathogenic variants carriers should receive genetic counseling, subsequent infection prevention measures and malignancies surveillance. Additionally, case-control genotyping should be carried out in Brazil to investigate whether the observed variants may be associated with susceptibility to opportunistic infections and/or concurrent neoplasms.

Acute promyelocytic leukemia in a long-standing HIV-positive patient: Case report and literature review.

The use of antiretroviral therapy has drastically improved the life quality and prognosis of people living with the human immunodeficiency virus (HIV). The risk of acute myeloid leukemia (AML) currently does not appear to be significantly increased compared to the general population. Acute promyelocytic leukemia (APL), infrequent in people with HIV, is a distinct subtype of AML with unique molecular pathogenesis, clinical manifestations, and treatment. Herein we describe a fatal case of APL hypogranular variant in an HIV-positive patient presenting with hyperleukocytosis. Also, we conducted a literature review of the ten cases reported so far.

Vaccine-induced immune thrombotic thrombocytopenia after COVID-19 vaccination: Description of a series of 39 cases in Brazil.

OBJECTIVE: Describe a case series of vaccine-induced immune thrombotic thrombocytopenia (VITT) after COVID-19 vaccination in Brazil that included ChAdOx1 nCoV-19, Ad26.COV2.S and BNT162b2 vaccines, describing their clinical and laboratory characteristics. METHODOLOGY: Descriptive case series study using Bio-Manguinhos/Fiocruz/AstraZeneca Brazil and National Immunization Program/Ministry of Health (NIP/MoH) data on COVID-19 AEFI surveillance. We obtained patient-level data from pharmacovigilance for AEFI surveillance and used both the NIP/MoH and Bio-Manguinhos/Fiocruz pharmacovigilance databases to create the study database. Thirty-nine cases of suspect VITT were included, 36 after ChAdOx1 nCoV-19, one after BNT162b2 and two after Ad26.COV2.S vaccine. All cases were based on meeting the Brighton Collaboration criteria for VITT. The primary outcomes were clinical and laboratory features, site of thrombosis, and anti-PF4 ELISA, when available. RESULTS: Thirty-nine cases met the criteria, 38 of which were classified as level 1 and one as level 3 according to Brighton Collaboration. Most cases had the central nervous system (CNS) as the main site of thrombosis (21/39) and happened after the vaccine first dose (34/39). The median age of the cases was 41 years old (23 to 86 yo). Most of the cases (61.5%) occurred in women. The median interval between vaccination and onset of symptoms was 8 days (0-37 days). The platelet count and D-dimer count had median values of 34,000/µL and 19,235 µg FEU/L, respectively. The ELISA anti-PF4 antibody was positive in 18 samples. The overall mortality rate was 51% and was higher in cases of CNS thrombosis with intracerebral bleeding. CONCLUSION: Our case series shows that Brazilian VITT cases have similar clinical and laboratory profiles as demonstrated in the literature. Brazil has administered more than 300 million doses of COVID-19 vaccines (more than 110 million from ChAdOx1 nCoV-19). VITT seems to be a very rare but serious adverse event following COVID-19 immunization, especially adenoviral vector immunization.

Generalized Edema and Pseudothrombocytopenia After ChAdOx1 nCoV-19 COVID-19 Vaccination: A Case Report.

Reports of side effects of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasing worldwide. Capillary leak syndrome and vaccine-induced immune thrombotic thrombocytopenia are very rare but life-threatening adverse events that should be identified early and treated. However, isolated thrombocytopenia can indicate pseudothrombocytopenia. In certain people, ethylenediaminetetraacetic acid (EDTA) induces an in vitro platelet aggregation, resulting in misleading underestimation of platelet counts. It is essential to recognize pseudothrombocytopenia to prevent diagnostic errors, overtreatment, anxiety, and unnecessary invasive procedures. We present a case who developed generalized edema and persistent pseudothrombocytopenia after the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca).

The Prenatal Origin of Childhood Leukemia: Potential Applications for Epidemiology and Newborn Screening.

Childhood leukemias are heterogeneous diseases with widely differing incident rates worldwide. As circulating tumors, childhood acute leukemias are uniquely accessible, and their natural history has been described in greater detail than for solid tumors. For several decades, it has been apparent that most cases of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) initiate in utero. Circumstantial evidence in support of this contention includes the young age of onset and high rate of concordance among identical twins. "Backtracking" of leukemic somatic mutations, particularly gene translocations, to cord blood and dried blood spots collected during the perinatal period has provided molecular proof of prenatal leukemogenesis. Detection of a patient's leukemia translocation in easily accessible birth samples, such as dried blood spots, is straightforward with the knowledge of their idiosyncratic breakpoints. However, to translate these findings into population-based screening and leukemia prevention requires novel methods able to detect translocations at all possible breakpoints when present in a low frequency of cells. Several studies have attempted to screen for leukemic translocations, mainly the common ETV6-RUNX1 translocation, in cord blood samples from healthy children. Most studies have reported finding translocations in healthy children, but estimates of prevalence have varied widely and greatly exceed the incidence of leukemia, leading to concerns that technical artifact or contamination produced an artificially inflated estimate of translocation prevalence at birth. New generation techniques that capture the presence of these translocations at birth have the potential to vastly increase our understanding of the epidemiology of acute leukemias. For instance, if leukemic translocations are present at birth in a far higher proportion of children than eventually develop acute leukemia, what are the exposures and somatic molecular events that lead to disease? And could children with translocations present at birth be targeted for prevention of disease? These questions must be answered before large-scale newborn screening for leukemia can occur as a public health initiative. Here, we review the literature regarding backtracking of acute leukemias and the prevalence of leukemic translocations at birth. We further suggest an agenda for epidemiologic research using new tools for population screening of leukemic translocations.