A Brazilian examination of tissue from four people who died with confirmed dengue virus serotype 4, or DENV-4, found visible damage in the liver, lungs and kidneys, while the hearts studied were largely preserved. The researchers also detected staining for the cytokines TNF-α and IFN-γ in liver, lung and kidney samples.
The findings provide a detailed view of organ changes in fatal DENV-4 cases, but they do not establish that the virus itself caused each lesion or immune-marker pattern. The evidence comes from a small, qualitative tissue investigation rather than a study designed to estimate risk or test treatment effects.
What the tissue showed
In the liver, the main injury was necrosis, or tissue death, concentrated largely in the centrilobular zone. The sections also showed ballooning degeneration, in which cells become swollen, along with widened sinusoidal capillaries and steatosis, the buildup of fat in liver cells.
The lung samples showed several forms of structural disruption: oedema, vascular congestion, thickening and bleeding in the alveolar walls, and ruptured septa. The researchers also described bronchitis and bronchiolitis, inflammation affecting the larger and smaller airways.
The kidney findings included congestion and atrophy of glomerular capillaries, enlargement of Bowman’s space and thickening of the capsule lining around the glomerulus. Tubular necrosis was seen in both the proximal and distal convoluted tubules.
Other kidney changes included partial shedding of tubular cells, tubular atrophy, regularly observed hyaline casts and sparse inflammatory-cell infiltration near areas of tubular necrosis and oedema. These were tissue-level observations; renal functional measurements were not reported.
The heart was different from the other organs examined. The researchers described normal morphology without noteworthy pathological alterations. Very few heart-muscle cells stained for TNF-α, and only a few inflammatory cells stained for IFN-γ.
Signals seen across organs
TNF-α-stained mononuclear inflammatory cells were detected in the liver, lungs and kidneys. IFN-γ-stained inflammatory cells were found in those same organs, and lung endothelial cells—the cells lining blood vessels—also stained for IFN-γ.
The staining was reported as a qualitative observation. The researchers did not provide cell counts or estimates of staining intensity, so the study cannot show how much of either marker was present or whether the levels differed between organs.
A small, focused case series
The material came from four fatal cases during the 2012 Ceará epidemic. The case table listed ages of 17, 47, 70 and 71. One patient had hypertension; the other three were listed as having no comorbidities.
DENV-4 confirmation relied on immunohistochemistry for cases 1, 2 and 3. For case 4, the researchers used immunohistochemistry together with viral isolation. The tissue samples were received through spontaneous demand, according to the study’s methods.
For the tissue review, paraffin blocks were cut into 4-micrometre sections, stained with haematoxylin and eosin and examined under bright-field microscopy. The team used immunohistochemistry to look for TNF-α and IFN-γ, applying the primary antibodies overnight at a 1:200 dilution and incubating the secondary antibody for 15 minutes.
A patient who was not infected with DENV-4 was also described as a morphology comparator. However, the comparator’s selection, matching and sample size were not reported in the supplied analysis, so it cannot serve as a formal comparison group for estimating differences between infections.
What remains uncertain
The authors interpreted the liver, lung and kidney changes as consistent with fatal dengue pathology. They also said the fatal cases showed that DENV-4 infection was not confined to a milder clinical presentation. Those interpretations describe the cases; they do not establish that DENV-4 is milder or more severe than other dengue serotypes.
For the heart, the authors suggested that the absence of major alterations could reflect the rarity of cardiac involvement or reduced tropism of this serotype for heart cells. The study cannot determine which explanation, if either, is correct, and preserved heart morphology was not shown to be specific to DENV-4.
The renal findings were discussed alongside systemic dengue manifestations, while the authors stated that the kidney is supposedly not a site of viral replication. The tissue observations alone cannot establish that claim or determine whether the kidney and lung lesions reflect direct viral involvement, systemic illness or treatment-related processes.
The study analyzed only four fatal cases, reported no statistical analysis and provided no denominator for calculating how often any lesion occurred. Clinical information and detailed laboratory data were limited, and the authors said missing information could not be retrieved. They also noted that pulmonary oedema may result from fluid replacement rather than a specific histopathological effect of DENV infection.
The next questions are whether these organ patterns recur in other fatal DENV-4 cases, whether they also appear with other serotypes or in nonfatal disease, and how much of the lung and kidney injury comes from direct viral involvement, systemic illness or treatment. Further cardiac tissue studies would also be needed to test whether the preserved morphology is reproducible.
Publication details
The article was published in 2026 in Memórias do Instituto Oswaldo Cruz, volume 121, as article e250248. Funding was reported from FAPERJ, CNPq grants 302462/2018-0 and 301992/2017-7, and CNPq student fellowships. The authors declared no conflicts of interest.
The study reported approval from the Oswaldo Cruz Institute and Federal University of Ceará ethics committees, compliance with the Declaration of Helsinki, and informed consent from all subjects and/or their legal guardians.
Paper data and sources
Original title: Dengue virus serotype 4 infection in human fatal cases: histopathological investigation
Authors: Rasinhas A, Caldas G, de Almeida A et al.
Journal/Repository: Memorias do Instituto Oswaldo Cruz
Status: Peer-reviewed
First online: 2026-08-19
DOI: Not available
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