Author(s): Elizabeth Rabold, Jesse Waggoner

Rapid diagnostic tests (RDTs) refer to a group of diagnostics categorized by performance characteristics rather than the specific analyte or test platform. Such assays have relatively short performance times, provide results to inform clinical decision making, and enable management at the point-of-care (POC). RDTs are available in a variety of test formats and platforms and for various detection targets. RDTs are designed for detecting pathogen-specific antigens or nucleic acid sequences, as well as host antibody responses against certain pathogens (Table 11-05).

To select an appropriate RDT, factor in the pros and cons of the different analytes, timing of patient presentation, and specifics of the disease or syndrome under investigation (e.g., acute versus chronic infection). RDTs described here include any pathogen-specific or syndrome-based test that can be incorporated into a POC testing protocol for a given infection or clinical syndrome.

Tests that meet the definition of an RDT may be performed under a certificate of waiver (so-called “waived” tests) indicating they are simple to perform with a low risk for yielding an incorrect result. The certificate of waiver is specific to the United States. Nevertheless, some of its requirements are useful when considering using RDTs in international settings. For example, although mandated personnel requirements for such tests are minimal, testers must be trained and document proficiency on use of the assay. Waived tests can only be performed on unmodified specimens (whole blood, saliva, urine) according to the most recent manufacturer recommendations. Deviations from the specimen type or manufacturer protocol make the test high-complexity and require that it be performed in a dedicated laboratory setting. Finally, RDT reagents might have specific storage requirements and a limited shelf life. These factors impact accuracy of the test and necessitate oversight and quality assessments to ensure proper performance.

Some tests with performance characteristics of an RDT might not be readily compatible with POC testing. For instance, an increasing number of waived, sample-to-answer molecular diagnostics (nucleic acid amplification tests) are becoming available. At a given institution, these assays might only be performed in a central laboratory at specific times, thereby limiting their applicability at the POC. These assays typically must be performed with dedicated bench-top equipment; adding this capacity at clinical sites, therefore, might not be feasible.

Rapid Diagnostic Tests for Clinical Syndromes

RDTs, including multiplex molecular panels (Table 11-06 and Table 11-07), are available for many common clinical syndromes among travelers, the etiologies of which can overlap substantially with those of non-travel–associated syndromes. Thus, clinics might augment RDT diagnosis of common pathogens with specialized or follow-up testing for rare pathogens or positive results.

In general, RDTs for antigen and antibody detection are less sensitive than standard laboratory assays. Rapid HIV tests that use blood and cheek swab samples are widely available and perform well in identifying individuals with chronic infections. Even later-generation antigen/antibody tests remain less sensitive than molecular testing for acute HIV infection, however, and in high-risk patients, molecular testing or repeat testing is warranted. The sensitivity of rapid antigen tests for influenza and certain gastrointestinal pathogens (e.g., norovirus, rotavirus) are notably poor. Negative results should not dictate therapy decisions, and positive results should be confirmed with molecular testing.

Multiplex molecular panels are becoming more common for central nervous system (CNS), gastrointestinal, and respiratory infections, and new panels are under evaluation for febrile returning travelers. These panels often are very sensitive and can test for many pathogens in a single sample. These tests are expensive, however, and results must be interpreted in the clinical context; certain pathogens might require additional testing when there is high clinical suspicion. Notably, available multiplex assays do not test for common bacterial causes of pneumonia. Also, detection of emerging or novel pathogens is not feasible with large, preconstructed testing panels. When interpreting results provided by multiplex molecular panels, consider the prolonged shedding periods of certain pathogens, the possibility of multiple positive results or co-infections, the detection of asymptomatic carriage, and the variable accuracy for different agents on the panel (e.g., cryptococcus in CNS panels, adenovirus in respiratory panels).

Undifferentiated acute febrile illness is a common and potentially life-threating clinical presentation among returning travelers that poses a diagnostic challenge and requires prompt evaluation, diagnosis, and management. RDTs might be unavailable or insufficient to diagnose the many possible causes of febrile illness. For example, a commercial RDT for malaria has been cleared for use in hospitals and laboratories but not for individual clinics; microscopy is still the diagnostic tool of choice in malaria cases to identify the species and calculate the level of parasitemia (see Sec. 5, Part 3, Ch. 16, Malaria). Furthermore, patients with malaria can be co-infected with other pathogens that can contribute to and complicate diagnosis and management. RDTs are not available in the United States for other common causes of undifferentiated acute febrile illness in travelers (e.g., dengue, leptospirosis).

Coronavirus Disease 2019

High demand for diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), combined with an emphasis on decreasing exposures to people infected with the virus, led the US Food and Drug Administration (FDA) to issue an Emergency Use Authorization for several RDTs and multiplex panels that include SARS-CoV-2. RDTs include rapid antigen diagnostics and the first molecular diagnostic for home use. These can be performed with self- or caregiver-collected samples. Some home test kits require that users download a smartphone application that provides test interpretation for the user and reports de-identified data for public health surveillance. These diagnostic kits perform best in symptomatic people; results in asymptomatic people should be interpreted with caution.

Diagnostic Testing Performed During Travel

People who become ill while traveling might seek medical care abroad; development and availability of RDTs for diagnosis of tropical infectious diseases has expanded greatly in recent years, and travelers might return home having been diagnosed based on results from these tests. RDTs for tropical infections typically are lateral-flow immunochromatographic tests that detect antigens from or antibodies to certain pathogens. Because only 1 such test (for malaria) is cleared for use in the United States, the diagnostic characteristics of RDTs used overseas are unfamiliar to most providers. Additionally, a variety of RDTs might be available for certain pathogens (e.g., dengue) in other countries, with widely varying or poorly studied performance characteristics. Institutions that do not have continuous access to a single brand of test further complicates interpretation of results provided by the laboratory.

The following is an illustrative, though by no means exhaustive, list of several common infections for which RDTs are available.

Dengue. Rapid, lateral-flow assays are available to detect the dengue nonstructural protein 1 (NS1) antigen, and IgM and IgG. Dengue tests have widely variable performance characteristics depending on the manufacturer, circulating dengue types, a patient’s past medical history, and symptom duration.

Emerging Infections. Emerging pathogens represent a diagnostic challenge. Rapid assays became available after outbreaks of chikungunya, Ebola, and Zika. Such assays might not be available or well-studied at the peak of an outbreak, however.

Leishmaniasis. Assays to detect antibodies against the rK39 antigen (visceral leishmaniasis) have demonstrated good specificity in endemic regions, and highest sensitivity for detecting disease in South Asia.

Leptospirosis. Because of the many pathogenic and intermediate Leptospira serotypes that result in human disease worldwide, the usefulness of serologic assays for diagnosing leptospirosis is limited.

Malaria. An FDA-cleared RDT for malaria is available, and malaria RDTs are widely used throughout the world. In general, these tests perform best for Plasmodium falciparum, with variable or poor performance for other Plasmodium species.

Typhoid. Rapid serologic tests have demonstrated only moderate accuracy to diagnose typhoid. Additionally, these tests are designed to detect Salmonella enterica serotype Typhi only.

Future Directions

The number of assays compatible with POC testing will undoubtedly continue to increase. Building upon testing milestones achieved during the COVID-19 pandemic, “at home” testing, including molecular testing, is expected to increase in the coming years for both respiratory viruses and other pathogens. Because of the wide breadth and diversity of infecting pathogens in returned travelers, use of POC testing for nondomestic infectious diseases might not be practical for most centers once test volume, personnel training, and cost are taken into consideration. POC testing for common syndromes that affect travelers and nontravelers alike (e.g., respiratory tract and gastrointestinal infections) could provide rapid diagnosis, inform triage decisions, and limit unnecessary laboratory testing.