Introduction
Diagnostic testing has changed dramatically over the last few decades. Molecular techniques such as polymerase chain reaction (PCR) and next-generation sequencing have transformed the way infectious diseases are detected, offering high levels of sensitivity and speed. Despite these advances, traditional laboratory methods continue to play an important role. One of these is haemagglutination—the visible clumping of red blood cells caused by interactions with antibodies, antigens or certain microbial proteins. Although the principle has been known for many years, it continues to underpin a range of diagnostic applications. [5, 3]
Rather than being replaced entirely by newer technologies, haemagglutination has found a place alongside them. Its relatively simple workflow, low equipment requirements and ability to produce rapid visual results have made it particularly valuable in serology, blood testing and point-of-care diagnostics. Interest in the technique grew again during the COVID-19 pandemic, when researchers adapted it for rapid antibody testing. [2, 3]
What is Haemagglutination?
Haemagglutination is the process by which red blood cells clump together after being cross-linked by antibodies or other binding molecules. Because the reaction is visible to the naked eye, it provides a straightforward way of detecting specific biological interactions without the need for complex instrumentation. This simplicity is one of the reasons the technique has remained useful for decades. [5, 3]
Depending on the assay design, laboratories may look either for the presence of agglutination or for its inhibition. In haemagglutination inhibition assays, antibodies present in a patient’s sample prevent red blood cells from clumping together. This allows previous exposure to a pathogen—or immunity following vaccination—to be assessed and has made the technique particularly valuable in infectious disease serology. [1, 3]
A Long History in Infectious Disease Testing
Long before automated immunoassays became routine, haemagglutination formed the basis of many infectious disease tests. One of the best-known examples is rubella serology, where haemagglutination inhibition became the standard method for assessing immunity and supporting national surveillance programmes. The technique was widely adopted because it was relatively easy to perform, reproducible and suitable for testing large numbers of samples. [1]
Many of the concepts that are now taken for granted in serology—such as measuring antibody titres and assessing immune responses after infection or vaccination—were established through these early haemagglutination assays. Although enzyme immunoassays and molecular diagnostics have now become more common, haemagglutination played an important role in shaping modern diagnostic microbiology. [1, 2]
Renewed Interest During COVID-19
The COVID-19 pandemic showed that haemagglutination is far from being just a historical laboratory technique. Researchers rapidly developed assays that used red blood cell agglutination to detect antibodies against SARS-CoV-2, providing an alternative to conventional laboratory-based serology. [2, 3]
One of the main advantages of these assays was their accessibility. They required very little specialised equipment and, in many cases, could be interpreted visually within minutes. Studies reported encouraging levels of sensitivity and specificity while also demonstrating that the tests could provide an indication of antibody levels rather than simply a positive or negative result. [2, 3]
These developments illustrated how a well-established laboratory principle could be adapted quickly to meet an emerging global healthcare need.
Point-of-Care Testing
As healthcare increasingly moves towards faster and more accessible testing, haemagglutination has attracted renewed attention as a platform for point-of-care diagnostics. Researchers have developed new formats using dried reagents, paper-based devices and passive microfluidic systems that simplify testing while maintaining reliable performance. [4, 2]
These approaches have particular advantages in outbreak situations, rural healthcare settings and regions where laboratory infrastructure is limited. By combining traditional immunological principles with modern engineering, developers have been able to produce tests that are inexpensive, portable and relatively easy to perform. [4, 5]
Advantages and Limitations
One reason haemagglutination has remained relevant is that it offers several practical advantages. The assays are generally inexpensive, require minimal laboratory equipment and can often be performed by trained personnel without highly specialised instrumentation. These characteristics make them especially useful where resources are limited. [5]
Like any diagnostic method, haemagglutination also has its limitations. Results interpretation can sometimes be subjective, particularly when reactions are weak, and the analytical sensitivity is generally lower than that achieved by molecular methods such as PCR. For this reason, haemagglutination is now more commonly used alongside other diagnostic techniques rather than replacing them altogether. [5, 2]
Conclusion
Haemagglutination may be one of the oldest techniques in diagnostic microbiology, but it has continued to adapt as diagnostic science has evolved. From its early use in infectious disease serology to its more recent application in SARS-CoV-2 antibody testing and point-of-care diagnostics, the technique has repeatedly demonstrated its ability to meet changing clinical needs. [2, 4]
As demand grows for rapid, affordable and accessible diagnostic tests, haemagglutination is likely to remain a valuable part of the diagnostic toolbox. While it is unlikely to replace molecular technologies, its simplicity and flexibility mean it will continue to complement newer approaches in both established and emerging areas of infectious disease testing.
References
1. Centers for Disease Control and Prevention (CDC). Standard Rubella Haemagglutination-Inhibition Test. 1970. Available at: https://stacks.cdc.gov/view/cdc/82196/cdc_82196_DS1.pdf
2. Kruse RL, Huang Y, Lee A, et al. A Haemagglutination-Based Semiquantitative Test for Point-of-Care Determination of SARS-CoV-2 Antibody Levels. Journal of Clinical Microbiology. 2021;59(12):e01186-21. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC8601214/
3. Townsend A, Rijal P, Xiao J, et al. A Haemagglutination Test for Rapid Detection of Antibodies to SARS-CoV-2. Nature Communications. 2021;12:1951. Available at: https://www.nature.com/articles/s41467-021-22045-y
4. Samae M, Chatpun S, Chirasatitsin S. Haemagglutination Detection with Paper–Plastic Hybrid Passive Microfluidic Chip. Micromachines. 2021;12(12):1533. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC8708700/
5. Qian Q, Fan G, Yang W, et al. Advances in Diagnostic Techniques for Infectious Diseases: A Review of Current and Emerging Technologies. Tropical Medicine and Infectious Disease. 2025;10(6):152. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC12197469/
