Severe dengue in the intensive care unit

Abstract

Dengue fever is considered the most prolific vector-borne disease in the world, with its transmission rate increasing more than eight times in the last two decades. While most cases present mild to moderate symptoms, 5% of patients can develop severe disease. Although the mechanisms are yet not fully comprehended, immune-mediated activation leading to excessive cytokine expression is suggested as a cause of the two main findings in critical patients: increased vascular permeability that may shock and thrombocytopenia, and coagulopathy that can induce hemorrhage. The risk factors of severe disease include previous infection by a different serotype, specific genotypes associated with more efficient replication, certain genetic polymorphisms, and comorbidities such as diabetes, obesity, and cardiovascular disease. The World Health Organization recommends careful monitoring and prompt hospitalization of patients with warning signs or propensity for severe disease to reduce mortality. This review aims to update the diagnosis and management of patients with severe dengue in the intensive care unit.

Keywords: Diagnosis; Intensive care units; Management; Pathogenesis; Severe dengue; Shock.

Figure 1

Pathophysiology of severe dengue. Infection: (1) After inoculating into the skin, the virus infects macrophages, dendritic cells, and Langerhans cells, which migrate to the lymph nodes and start the viremia. (2) Into the bloodstream, DENV and complexes formed between the virus and non-neutralizing immunoglobulin (from previous infections by different serotypes) infect macrophages and neutrophils. (3) Infected cells start releasing virions, non-structural proteins (especially NS1), and pro-inflammatory cytokines. Plasma leakage: (4) DENV directly infects endothelial cells, causing its rupture. (5) Pro-inflammatory cytokines, such as TNF-α and ILs, act in the endothelial cells, increasing permeability. (6) NS1 protein binds to endothelial cells and triggers dysfunction of the EGL by the degradation of the sialic acid and the shedding of heparan sulfate proteoglycans from the EGL, which culminates in the loss of its integrity. (7) DENV infects mast cells, which release tryptases, disrupting the tight junctions, and bradykinins, causing the rash. (8) DENV induces the secretion of IL-1β by platelets, leading to the release of NO, a potent vasodilator. Hemorrhage: (9) DENV infects stem cells, hematopoietic stromal cells, and megakaryocytes in the bone marrow, reducing the production of platelets. (10) Endothelial cells infected by DENV mark platelets throw their rolling process, causing their destruction in the liver. (11) The virus directly infects platelets, activating them and leading to their apoptosis. (12) Immuno-mediated complexes between antibodies and the virus or NS1 cross-react with surface platelet antigens, inducing their destruction. (13) DENV activates the complement system, by the MBL complex, triggering the cleavage of C4 and initiating the lectin pathway. Additionally, the classical complement cascade can be activated by immunocomplex, formed by antibodies linked to antigen proteins. NS1 protein can interact with the complement proteins, promoting the degradation of C4 and halting both the classical and lectin pathways. These mechanisms lead to complement consumption and platelet opsonization and destruction. DENV: Dengue virus; EGL: Endothelial glycocalyx layer; IL: Interleukin; MBL: Mannose-binding lectin; NO: Nitric oxide; NS1: Non-structural 1; TNF: Tumor necrosis factor.

Figure 2

Factors associated with severe dengue. CTLA-4: Cytotoxic T-lymphocyte antigen 4; DENV: Dengue virus; HLA: Human leukocyte antigen; JAK1: Janus kinase 1; TGF: Transforming growth factor; TNF: Tumor necrosis factor.

Figure 3

Clinical phases of dengue infection and the relation with clinical and laboratory finds. IgG: Immunoglobulin G; IgM: Immunoglobulin M; NS1: Non-structural 1.

Figure 4

Dengue severity classification according to WHO.^[92] ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; DSS: Dengue shock syndrome; WHO: World Health Organization.

Figure 5

Management of severe dengue, according to WHO.^[101] WHO: World Health Organization.