When a ‘Clean’ Spinal Tap Deceives: Adenovirus Strikes Toddlers’ Brains and Bodies

Human adenovirus is usually thought of as a mundane pathogen of childhood, responsible for red eyes, sore throats, and the occasional bout of gastroenteritis that sweeps through day-care centers. In children with healthy immune systems, severe disease is rare, and involvement of the central nervous system is rarer still. A new case series from Vietnam National Children’s Hospital, published in BMC Pediatrics, now documents a striking exception: four previously healthy toddlers who developed fulminant, multiorgan illness in which adenovirus genetic material was detected in the cerebrospinal fluid, despite spinal fluid cell counts that were almost entirely normal. Three of the four children died. The report is a sobering reminder that a reassuring-looking lumbar puncture can mask a devastating viral process, and that molecular testing of spinal fluid may be critical when neurological dysfunction accompanies systemic adenoviral infection.

The retrospective study reviewed four consecutive children aged between 13 and 26 months who were admitted to Vietnam National Children’s Hospital between June and December 2022. To be included, each child had to show acute neurological dysfunction together with adenovirus detected by real-time polymerase chain reaction, or PCR, in both the cerebrospinal fluid and a nasopharyngeal specimen. This dual requirement is important: it demonstrates that the virus was circulating systemically and that viral DNA had also reached the compartment surrounding the brain and spinal cord. All four children were previously healthy, with no known immunodeficiency that would predispose them to overwhelming viral infection, which makes the severity of their presentations all the more unusual and clinically significant.

The cerebrospinal fluid findings are the technical heart of the paper. In classical viral encephalitis or meningitis, clinicians expect a pleocytosis, an elevated number of white blood cells in the spinal fluid, typically accompanied by raised protein. In these four toddlers, leukocyte counts ranged from just 1 to 3 cells per microliter, values that would generally be considered within or barely above the normal range, and protein concentrations ranged from 0.38 to 0.62 grams per liter, likewise unremarkable. Yet real-time PCR returned positive results for adenovirus in every sample. The authors argue that such near-normal indices do not exclude clinically important adenovirus-associated central nervous system disease, and that clinicians should not be falsely reassured by a clean-looking spinal tap when a child is neurologically deteriorating in the context of systemic adenoviral illness.

Neuroimaging added further complexity. Brain magnetic resonance imaging was performed in two of the four children. One scan showed bilateral frontoparietal cortical lesions compatible with encephalitic involvement, providing objective evidence that the brain parenchyma itself was affected. The other showed nonspecific widening of the frontoparietal subarachnoid spaces, a finding that could reflect cerebral volume loss or atrophy but is not diagnostic of any single process. The limited imaging data reflect the realities of retrospective case series in an intensive care setting, where the sickest children may be too unstable for transport to the scanner. Even so, the images underscore that adenovirus can produce structural brain injury in immunocompetent toddlers, not merely self-limited meningitic symptoms.

The systemic component of the illness was equally severe. All four children required invasive mechanical ventilation, and one additionally needed extracorporeal membrane oxygenation, a heart-lung bypass technique reserved for patients whose respiratory or circulatory failure cannot be managed by a ventilator alone, as well as renal replacement therapy for kidney failure. The combination of respiratory failure, circulatory collapse, renal injury, and neurological dysfunction in previously healthy toddlers illustrates the fulminant, multisystem character of the syndrome. Adenovirus is capable of infecting respiratory epithelium, gastrointestinal tract, liver, and other organs, and in these cases the infection appears to have triggered a cascade of organ dysfunction that outpaced the children’s physiological reserves.

A particularly notable laboratory feature was marked hyperferritinemia, an extremely elevated blood level of ferritin, the iron-storage protein. Very high ferritin values are a hallmark of systemic hyperinflammation and are seen in conditions such as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, disorders in which the immune system’s scavenger cells become pathologically activated and release a storm of inflammatory cytokines. In this series, two children received a clinical diagnosis of macrophage activation syndrome during their admission, although the authors note that a complete evaluation according to the HLH-2004 criteria was not performed. This raises the possibility that at least part of the tissue damage in these children was driven not by direct viral cytopathic effect but by a runaway inflammatory response to the infection, a mechanism with important implications for treatment.

The therapeutic implications are considerable. If hyperinflammation contributes substantially to the deterioration of these patients, then immunomodulatory strategies, such as those used in macrophage activation syndrome or hemophagocytic lymphohistiocytosis, might theoretically be considered alongside antiviral therapy and organ support. At the same time, the authors are careful to draw a boundary around what their data can support. They conclude that escalation of respiratory, circulatory, renal, or extracorporeal support should be guided by the child’s physiological deterioration and objective measures of organ dysfunction, rather than by cerebrospinal fluid PCR positivity alone. In other words, finding adenoviral DNA in the spinal fluid is a diagnostic clue, not a treatment algorithm, and clinical judgment anchored in the patient’s trajectory remains paramount.

Why adenovirus reached the central nervous system in these children, and why the spinal fluid showed so little inflammation, remains unresolved. Several mechanisms are plausible: direct viral invasion of neural tissue, infection of the meninges, or a post-infectious inflammatory process. The paucity of pleocytosis could reflect very early sampling in the disease course, before the inflammatory cascade had spilled into the cerebrospinal fluid, or a pattern of parenchymal rather than meningeal involvement. It is also possible that the profound systemic hyperinflammation altered the usual immunology of the central nervous system compartment. The authors of the series do not claim to have settled these questions; their contribution is to document that the dissociation between positive PCR results and normal routine indices can occur, and that it matters for clinical practice.

The study’s design imposes limits that readers should keep in view. It is a retrospective case series of four children at a single hospital over a six-month period, without a comparison group, and the authors did not perform a complete HLH-2004 workup, so the diagnoses of macrophage activation syndrome rest on clinical assessment. Case series cannot establish incidence, cannot prove causation between adenovirus and the neurological syndrome, and cannot determine whether the outcomes would have differed under alternative management strategies. Nevertheless, the consistency of the pattern, four previously healthy toddlers, all with dual respiratory and cerebrospinal fluid PCR positivity, all requiring mechanical ventilation, and three deaths, is difficult to dismiss as coincidence, and the ethical review board of Vietnam National Children’s Hospital approved the study under the Declaration of Helsinki with consent requirements waived for its retrospective design.

For clinicians caring for young children, the practical message is one of heightened vigilance rather than alarm. Adenovirus remains a common and usually benign pathogen of early childhood. But when a toddler with confirmed or suspected adenoviral infection develops new neurological dysfunction, whether seizures, altered consciousness, or focal signs, the new data suggest that cerebrospinal fluid PCR testing for adenovirus deserves a place in the etiological assessment, even when cell counts and protein are normal or nearly so. Equally, the presence of marked hyperferritinemia and other signs of systemic hyperinflammation should prompt consideration of macrophage activation syndrome in the differential diagnosis. As molecular diagnostics become faster and more widely available, the challenge will be to integrate these sensitive tools with sound physiological reasoning, so that detection of viral genetic material informs, rather than dictates, the care of the sickest children.

Subject of Research: Severe multisystem adenovirus infection with central nervous system involvement in immunocompetent toddlers

Article Title: Fulminant multisystem adenovirus-associated illness with cerebrospinal fluid PCR positivity and minimal pleocytosis in previously healthy toddlers: a case series

Article References: Do, T. H., Van, A. V., Trong, H. D., Thi, H. T. N., & Nguyen, S. D. (2026). Fulminant multisystem adenovirus-associated illness with cerebrospinal fluid PCR positivity and minimal pleocytosis in previously healthy toddlers: a case series. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07691-9

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07691-9

Keywords: adenovirus, cerebrospinal fluid, PCR, encephalitis, hyperinflammation, macrophage activation syndrome, pediatric critical care, toddlers, central nervous system, mechanical ventilation, ECMO, BMC Pediatrics