The Diagnostic Dilemma Under the Tropics
Antibody tests designed to detect SARS-CoV-2 began lighting up positive for people who didn't have COVID-19. This phenomenon of false positivity—where the immune response to one disease mimics another—created a perfect storm for misdiagnosis in areas already burdened by infectious diseases. A pivotal 2022 study from Thailand's front lines revealed how dengue and other tropical infections trick serological tests, forcing scientists to rethink diagnostic strategies in a world of overlapping outbreaks 1 2 .
Antibodies (IgA, IgM, IgG) are the body's molecular "wanted posters"—custom-designed to recognize specific pathogens. Serology tests detect these antibodies to confirm infections. However, viruses from the same family—or even unrelated ones with similar surface proteins—can trigger cross-reactive antibodies. These molecules bind imperfectly to non-target viruses, creating false positives. During the pandemic, this became critical in tropical zones where dengue and COVID-19 cocirculated 1 7 .
Dengue virus emerged as a major offender in false SARS-CoV-2 serology. Studies documented dengue patients testing positive for COVID-19 antibodies despite no SARS-CoV-2 infection. The reverse also occurred: COVID-19 patients showed false-positive dengue rapid tests. This two-way confusion risked misdirected treatments—like prescribing NSAIDs for "dengue" in a COVID-19 patient, potentially worsening outcomes 7 2 .
| Patient Group | Anti-SARS-CoV-2 IgA | Anti-SARS-CoV-2 IgM | Anti-SARS-CoV-2 IgG |
|---|---|---|---|
| All non-COVID samples | 10.6% (18/170) | 5.3% (9/170) | 1.8% (3/170) |
| Adults with dengue | 11.3% | 5.0% | Not reported |
| Adults with other fevers | 16.7% | 13.3% | Not reported |
| Data from the 2022 Thailand cohort study 1 2 | |||
Researchers at Mahidol University's Faculty of Tropical Medicine designed a clever experiment using archived sera from before COVID-19 (2013–2019). This eliminated co-infection doubts. The samples included:
Samples were tested using EUROIMMUN ELISA kits:
Each sample was tested with/without urea dissociation—a technique that breaks weak antibody bonds to reduce false positives 1 2 .
| Sample Type | Standard ELISA | ELISA + Urea | Reduction |
|---|---|---|---|
| False positives | 27/170 | Significantly fewer* | >50% |
| True positives (COVID) | 31/31 | Reduced* | Moderate |
| *Descriptive trends per study data; exact figures not provided in text 1 | |||
The high IgA/IgM false positivity suggests these antibodies bind SARS-CoV-2 proteins with low avidity—a weak, nonspecific attachment. This makes them unreliable in regions with endemic flaviviruses (e.g., dengue, Zika). The study cautioned against using serology alone for COVID-19 diagnosis in acute fever patients in the tropics 1 7 .
| Reagent/Technique | Function | Role in This Study |
|---|---|---|
| ELISA (IgA/IgG anti-S1) | Detects antibodies against spike protein | Primary test for IgA/IgG |
| ELISA (IgM anti-NCP) | Detects IgM against nucleocapsid protein | Primary test for IgM |
| Urea solution (4M) | Disrupts hydrogen bonds in antibody-antigen complexes | Reduced low-avidity false positives |
| RT-PCR assays | Directly detects viral RNA | Confirmed COVID-19/dengue infection |
| Pre-pandemic sera | Biobanked samples from prior outbreaks | Provided true negative controls |
In Singapore, Brazil, and Indonesia, patients with COVID-19 were misdiagnosed with dengue due to false-positive IgM tests—delaying COVID care. Conversely, dengue patients tested "positive" for SARS-CoV-2 antibodies faced unnecessary isolation 7 .
Cross-reactivity isn't unique to COVID-19/dengue. Zika, chikungunya, and even HIV have triggered false alarms. As climate change expands the reach of tropical diseases, diagnostic specificity becomes a critical pillar of global health security 7 .
The Thai study exposed a harsh truth: in regions rife with tropical diseases, our serological tools can become double-edged swords. Yet, it also offered solutions—from urea washes to smarter test deployment.
As pathogens continue to cross borders, understanding immunological mimicry isn't just academic; it's the key to diagnosing accurately, treating swiftly, and preventing needless harm in the world's most vulnerable populations 1 7 .