Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach.

Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.

Co-Infection between Dengue Virus and SARS-CoV-2 in Cali, Colombia.

The co-occurrence of COVID-19 with endemic diseases is a public health concern that may affect patient prognosis and outcomes. The objective of this study was to describe the clinical characteristics of patients with dengue virus (DENV) and SARS-CoV-2 co-infections and compare their outcomes against those of COVID-19 patients without dengue. A cross-sectional study was conducted in patients with SARS-CoV-2 infection who attended a single center in Cali, Colombia, from March 2020 to March 2021. All patients who were tested by both real-time polymerase chain reaction for SARS-CoV-2 and IgM/NS1 for DENV were included. Dengue was diagnosed as having either an IgM- or an NS1- positive test. A total of 90 patients were included (72 with COVID-19 only and 18 with co-infection). Patients with co-infection had more dyspnea (61.1% versus 22.2%; P = 0.003) as well as higher oxygen desaturation (53.3% versus 13.4%; P = 0.002) and neutrophil-to-lymphocyte ratio (5.59 versus 3.84; P = 0.038) than patients with COVID-19 alone. The proportion of patients classified with moderate to severe COVID-19 was higher in the co-infection group (88.3% versus 47.8%; P = 0.002). Also, co-infection was associated with an increased need for mechanical ventilation (P = 0.06), intensive care unit (ICU) initial management (P = 0.02), and ICU admission during hospitalization (P = 0.04) compared with COVID-19 only. The ICU mortality rate was 66.6% in patients with co-infection versus 29.4% in patients infected with only SARS-CoV-2 (P < 0.05). The possibility of DENV and SARS-CoV2 co-infection occurred in the convergence of both epidemic waves. Co-infection was associated with worse clinical outcomes and higher mortality in ICU-admitted patients than in patients with the COVID-19 only.

Cutaneous tuberculosis as a manifestation of Pott's Disease: A diagnostic challenge in patients with Non-HIV immunosuppression.

Tuberculosis (TB) is one of the most important public health issues in developing countries. The World Health Organization estimates that approximately 20%-40% of the world's population is infected. Pulmonary forms account for the majority of cases; however, it can manifest as extrapulmonary disease in 8.4%-13.7% of cases. Of these extrapulmonary forms of TB, only 1%-2% may have skin manifestations. Cutaneous tuberculosis (CTB) is relatively uncommon and is not a well-defined disease, which complicates diagnosis. We present two patients with Pott's disease that manifested as CTB, one with tuberculous gumma and the other with scrofuloderma. Both patients with non-HIV immunosuppression. The diagnosis of CTB was made by detecting Mycobacterium tuberculosis in skin samples by real-time polymerase chain reaction (Xpert MTB/RIF test) and Ziehl-Neelsen staining. The histologic findings described in these two forms of TB may vary or be absent in immunosuppressed patients, making diagnosis difficult.

Magnitude and kinetics of the human immune cell response associated with severe dengue progression by single-cell proteomics.

Approximately 5 million dengue virus-infected patients progress to a potentially life-threatening severe dengue (SD) infection annually. To identify the immune features and temporal dynamics underlying SD progression, we performed deep immune profiling by mass cytometry of PBMCs collected longitudinally from SD progressors (SDp) and uncomplicated dengue (D) patients. While D is characterized by early activation of innate immune responses, in SDp there is rapid expansion and activation of IgG-secreting plasma cells and memory and regulatory T cells. Concurrently, SDp, particularly children, demonstrate increased proinflammatory NK cells, inadequate expansion of CD16+ monocytes, and high expression of the FcγR CD64 on myeloid cells, yet a signature of diminished antigen presentation. Syndrome-specific determinants include suppressed dendritic cell abundance in shock/hemorrhage versus enriched plasma cell expansion in organ impairment. This study reveals uncoordinated immune responses in SDp and provides insights into SD pathogenesis in humans with potential implications for prediction and treatment.

An 8-gene machine learning model improves clinical prediction of severe dengue progression.

BACKGROUND: Each year 3-6 million people develop life-threatening severe dengue (SD). Clinical warning signs for SD manifest late in the disease course and are nonspecific, leading to missed cases and excess hospital burden. Better SD prognostics are urgently needed. METHODS: We integrated 11 public datasets profiling the blood transcriptome of 365 dengue patients of all ages and from seven countries, encompassing biological, clinical, and technical heterogeneity. We performed an iterative multi-cohort analysis to identify differentially expressed genes (DEGs) between non-severe patients and SD progressors. Using only these DEGs, we trained an XGBoost machine learning model on public data to predict progression to SD. All model parameters were "locked" prior to validation in an independent, prospectively enrolled cohort of 377 dengue patients in Colombia. We measured expression of the DEGs in whole blood samples collected upon presentation, prior to SD progression. We then compared the accuracy of the locked XGBoost model and clinical warning signs in predicting SD. RESULTS: We identified eight SD-associated DEGs in the public datasets and built an 8-gene XGBoost model that accurately predicted SD progression in the independent validation cohort with 86.4% (95% CI 68.2-100) sensitivity and 79.7% (95% CI 75.5-83.9) specificity. Given the 5.8% proportion of SD cases in this cohort, the 8-gene model had a positive and negative predictive value (PPV and NPV) of 20.9% (95% CI 16.7-25.6) and 99.0% (95% CI 97.7-100.0), respectively. Compared to clinical warning signs at presentation, which had 77.3% (95% CI 58.3-94.1) sensitivity and 39.7% (95% CI 34.7-44.9) specificity, the 8-gene model led to an 80% reduction in the number needed to predict (NNP) from 25.4 to 5.0. Importantly, the 8-gene model accurately predicted subsequent SD in the first three days post-fever onset and up to three days prior to SD progression. CONCLUSIONS: The 8-gene XGBoost model, trained on heterogeneous public datasets, accurately predicted progression to SD in a large, independent, prospective cohort, including during the early febrile stage when SD prediction remains clinically difficult. The model has potential to be translated to a point-of-care prognostic assay to reduce dengue morbidity and mortality without overwhelming limited healthcare resources.

Challenges of dengue and coronavirus disease 2019 coinfection: two case reports.

BACKGROUND: Dengue fever and coronavirus disease 2019 have now begun to overlap within tropical and subtropical regions. This is due to the high prevalence of dengue fever in these regions and the current severe acute respiratory syndrome coronavirus 2 pandemic situation. The similarity of symptoms between the two diseases can confuse diagnoses, but coinfection can also occur. CASE PRESENTATION: We present two cases of patients with dengue and severe acute respiratory syndrome coronavirus 2 coinfection. The first case is that of a 24-year-old Hispanic woman with acute fever, odynophagia, and diarrhea, without respiratory symptoms and with positive molecular tests for both dengue and severe acute respiratory syndrome coronavirus 2. The second case is that of a 59-year-old Hispanic male patient with fever and respiratory symptoms of 2 weeks duration, negative molecular tests, and positive serological tests for both viruses. The clinical and epidemiological characteristics of both viral infections can help elucidate diagnoses and prognoses. CONCLUSIONS: Severe dengue infection is common in young adults, while coronavirus disease 2019 is generally asymptomatic. In older people, the severity of dengue fever will depend on their comorbidities or the infectious serotype, but coronavirus disease 2019 is consistently more severe in this group. The accurate diagnosis of both infections can better guide clinical management, as well as public health actions in transmission control, now especially important during the coronavirus disease 2019 pandemic.

Fatal Brucellosis Infection in a Liver Transplant Patient: A Case Report and Review of the Literature.

Brucellosis is the most common zoonosis, particularly in developing countries. The true incidence of human brucellosis is unknown. The WHO points out that 500,000 cases of brucellosis are reported each year from around the world. In Colombia, there is currently no regular surveillance of the event in humans and its prevalence is low due a low clinical suspicion. We report a case of a 66-year-old man, an urban merchant, who had received a liver transplant 11 years ago. The patient presented to the emergency department for two months of fatigue, severe myalgia, paresis of the extremities, loss of muscle strength, and progressive deterioration of functional class. In the emergency room, he became disoriented and was transferred to the intensive-care unit. He had a white blood cell count of 18990/uL and creatine phosphokinase 10302 U/L. Routine blood cultures were positive for Brucella melitensis. The patient reported consumption of unpasteurized bovine milk. He was treated with doxycycline and ciprofloxacin. Despite antibiotic management, after one month of hospitalization and in the context of septic shock with multiorgan failure, the patient died. Brucellosis is an unsuspected and underdiagnosed disease. It can occur in people with or without risk factors. Although the mortality is low, immunocompromised patients can develop fatal infections. A presumptive diagnosis can be established through the correlation of patient history and classic laboratory findings, which include transaminitis, anemia, and leukopenia with relative lymphocytosis; however, other findings can help us to guide the diagnosis, such as rhabdomyolysis, which appears as a complication in different infections; however, it had not been described before in brucellosis. A partnership between clinical suspicion laboratory diagnostic tests and improved disease surveillance systems is necessary to fight the disease.

Transmission of malaria from donors to solid organ transplant recipients: A case report and literature review.

Malaria is a febrile and potentially fatal infection. It is typically transmitted to humans through the bite of Anopheles mosquitoes and less frequently can be contracted through blood transfusions, sharing contaminated needles and syringes, mother-to-child transmission, or after solid organ transplantation. Posttransplant malaria has rarely been reported in the literature, even in endemic areas. We report the cases of three solid organ recipients in which Plasmodium vivax infection was documented during postsurgical evaluation 30 days after transplant surgery. The diagnosis of donor-derived malaria was confirmed in all patients by demonstrating Plasmodium in a peripheral blood smear and by polymerase chain reaction (PCR). All recipients had symptoms. The liver transplant recipient had myalgia, arthralgia, and thrombocytopenia; the kidney transplant recipient developed acute renal failure; and the heart transplant recipient had fever, cephalalgia, and tonic-clonic seizures. Pre-transplant screening of donors and recipients from endemic regions may not be sufficient to safely rule out persistent malaria. In Colombia, according to legislation, no mandatory testing is required for the diagnosis of malaria in organ donors in nonendemic areas. Therefore, donor screening by questionnaire is the only tool for preventing transplant-borne malaria. The migratory trend from Venezuela to Colombia has increased the number of imported cases of malaria, and the infection may be present in endemic and nonendemic regions. Although donor evaluation is not standardized in current guidelines, we suggest that donors be tested for malaria with a peripheral blood smear, detection of specific IgG antibodies against Plasmodium, and techniques such as PCR, if possible.

Disseminated bronchiectasis in an adult with common variable immunodeficiency.

Primary immunodeficiencies (PID) are traditionally considered childhood diseases; however, adults account for 35% of all patients with PID. Antibody deficiencies, especially Common Variable Immunodeficiency (CVID), which have their peak incidence in adulthood, require a high suspicion index. Even though the estimated frequency of CVID is not high (1:25,000), high rates of under diagnosis and under reporting are very likely. The delay in diagnosis increases the morbidity and mortality; therefore, adult physicians should be able to suspect, identify and initiate management of individuals with PID. Here we report the case of a 37 year-old man presenting to the emergency room with dyspnea, fever and cough; he developed respiratory failure requiring mechanical ventilation. He complained of recurring pneumonia associated with widespread bronchiectasis since he was 18 years old. Serum immunoglobulins quantification showed severe hypogammaglobulinemia (total IgG <140 mg/dL; total IgA, 2.9 mg/dL; and total IgM <5 mg/dL). Treatment with Human Intravenous Immunoglobulin (IVIG) 10% was started, and with antibiotic treatment for severe pneumonia (during 14 days) was also prescribed. His clinical evolution has been favorable after one year follow-up. Common Variable Immunodeficiency (CVID) diagnosis was made.

Las inmunodeficiencias primarias (IDP) son patologías que tradicionalmente se consideran de la niñez sin embargo los adultos representan el 35% del total de pacientes con IDP. Las deficiencias de anticuerpos, en especial la Inmunodeficiencia Común Variable (IDCV) tienen su pico de incidencia en la edad adulta, requiere un alto índice de sospecha y si bien su frecuencia estimada no es alta (1:25,000), es muy posible que el subregistro y subdiagnóstico si lo sean. El retraso en el diagnóstico aumenta la morbi-mortalidad razón por la cual los médicos de adultos deben estar en capacidad de sospechar, identificar e iniciar el manejo de las personas con IPD. Presentamos el caso de un hombre de 37 años de edad atendido en la sala de urgencias con disnea, fiebre y tos, desarrolla falla respiratoria requiriendo ventilación mecánica. Refería neumonías a repetición desde los 18 años de edad asociadas con bronquiectasias generalizadas. La cuantificación de inmunoglobulinas séricas evidenció hipogammaglobulinemia severa (IgG total <140 mg/dL, IgA total 2.9 mg/dL, IgM total <5 mg/dL), se inició inmunoglobulina humana endovenosa (IGIV) al 10%, y recibió tratamiento antibiótico por 14 días para neumonía severa, su evolución clínica ha sido favorable hasta ahora (un año de seguimiento), se estableció el diagnostico de Inmunodeficiencia Común Variable (IDCV).

Disseminated bronchiectasis in an adult with common variable immunodeficiency / Bronquiectasias diseminada en un adulto con inmunodeficiencia común variable

Primary immunodeficiencies (PID) are traditionally considered childhood diseases; however, adults account for 35% of all patients with PID. Antibody deficiencies, especially Common Variable Immunodeficiency (CVID), which have their peak incidence in adulthood, require a high suspicion index. Even though the estimated frequency of CVID is not high (1:25,000), high rates of under diagnosis and under reporting are very likely. The delay in diagnosis increases the morbidity and mortality; therefore, adult physicians should be able to suspect, identify and initiate management of individuals with PID. Here we report the case of a 37 year-old man presenting to the emergency room with dyspnea, fever and cough; he developed respiratory failure requiring mechanical ventilation. He complained of recurring pneumonia associated with widespread bronchiectasis since he was 18 years old. Serum immunoglobulins quantification showed severe hypogammaglobulinemia (total IgG <140 mg/dL; total IgA, 2.9 mg/dL; and total IgM <5 mg/dL). Treatment with Human Intravenous Immunoglobulin (IVIG) 10% was started, and with antibiotic treatment for severe pneumonia (during 14 days) was also prescribed. His clinical evolution has been favorable after one year follow-up. Common Variable Immunodeficiency (CVID) diagnosis was made.

Las inmunodeficiencias primarias (IDP) son patologías que tradicionalmente se consideran de la niñez sin embargo los adultos representan el 35% del total de pacientes con IDP. Las deficiencias de anticuerpos, en especial la Inmunodeficiencia Común Variable (IDCV) tienen su pico de incidencia en la edad adulta, requiere un alto índice de sospecha y si bien su frecuencia estimada no es alta (1:25,000), es muy posible que el subregistro y subdiagnóstico si lo sean. El retraso en el diagnóstico aumenta la morbi-mortalidad razón por la cual los médicos de adultos deben estar en capacidad de sospechar, identificar e iniciar el manejo de las personas con IPD. Presentamos el caso de un hombre de 37 años de edad atendido en la sala de urgencias con disnea, fiebre y tos, desarrolla falla respiratoria requiriendo ventilación mecánica. Refería neumonías a repetición desde los 18 años de edad asociadas con bronquiectasias generalizadas. La cuantificación de inmunoglobulinas séricas evidenció hipogammaglobulinemia severa (IgG total <140 mg/dL, IgA total 2.9 mg/dL, IgM total <5 mg/dL), se inició inmunoglobulina humana endovenosa (IGIV) al 10%, y recibió tratamiento antibiótico por 14 dias para neumonía severa, su evolución clínica ha sido favorable hasta ahora (un año de seguimiento), se estableció el diagnostico de Inmunodeficiencia Común Variable (IDCV).