Rapid Diagnostic Tests for Infectious Diseases
Rapid Diagnostic Tests for Infectious Diseases
In the context of infectious diseases, the term rapid diagnostic test (RDT) most commonly refers to lateral-flow, immunochromatographic tests used to detect certain infections. More generally, such assays may be described as point-of-care (POC) tests. Although there are no accepted criteria for what constitutes an RDT or POC test, published definitions frequently focus on performance time and simplicity. Pathogen-specific or syndrome-based tests are considered RDTs if they meet either or both of the following criteria:
- The test can be incorporated into a POC testing protocol for a given infection or clinical syndrome. Such assays have relatively short performance times, yield results that will affect clinical decision making, and allow management decisions to be made during the same encounter.
- The test can be performed under a certificate of waiver under the Clinical Laboratory Improvement Amendments of 1988, so-called “waived” tests (Table 11-5).
Certain tests that meet this definition may not be used in a manner compatible with POC testing. For instance, an increasing number of waived, sample-to-answer molecular diagnostics (nucleic acid amplification tests, such as PCR or RT-PCR) are becoming available. At a given institution, though, such assays might only be performed in a central laboratory at specific times, thereby limiting their utility in a POC testing protocol. These assays typically require dedicated, bench-top equipment for performance. As such, adding capacity at individual clinical sites may not be feasible.
Lateral-flow immunochromatographic tests and small panels
Systemic febrile illness
Ebola virus 1
Received emergency use authorization by FDA and WHO. May not be appropriate for excluding illness in early infection.
Dengue virus 1
Not FDA-cleared. Highly variable diagnostic performance. Antibodies may cross-react with other flaviviruses.
Best performance characteristics for Plasmodium falciparum infections. Many versions may be available in endemic areas.
Norovirus, rotavirus, adenovirus 1
Available in the United States individually or in combination. Adenovirus rapid tests are approved for ocular specimens.
Group A Streptococcus
Rapid antigen and molecular tests 2 available; both are specific but molecular tests have improved sensitivity.
NP or throat swab
Rapid test sensitivity 50%–70%; negative testing should not direct treatment.
Legionella pneumophila 1
Only detects serogroup 1. Recommended by IDSA for patients with more severe disease.
Respiratory syncytial virus
NP or throat swab
Accurate antigen assays, recommended if results will affect management.
Recommended by IDSA for use in certain patient populations.
Sexually transmitted infections
Chlamydia trachomatis and Neisseria gonorrhea 1
Urine, vaginal swab
Molecular tests remain gold standard; a sample-to-answer molecular assay is available. 1, 2
Whole blood, oral fluids
Antibody and antibody/antigen kits available. Molecular testing preferred for acute infection.
Antibody detection, may not be appropriate for acute infections.
Rapid antigen testing is specific with sensitivity approximately 90%.
Identifies increased sialidase activity, an enzyme associated with BV pathogens.
Multiplex molecular panels
Sensitive, certain positive results may be unrelated to active infection.
Includes common viruses and atypical bacteria 2
Pathogens may have prolonged shedding time; positive results may not rule out infection from other pathogens.
Abbreviations: BV, bacterial vaginosis; FDA, US Food and Drug Administration; IDSA, Infectious Disease Society of America; NP, nasopharyngeal; WHO, World Health Organization.
1 Not waived by Clinical Laboratory Improvement Amendments.
2 Not immunochromatographic assay.
Assays that characterize a host response (such as C-reactive protein and procalcitonin) show promise in limiting unnecessary antibiotic use in certain clinical settings. However, their use and interpretation are complicated and can be confusing in the setting of returning travelers with potentially severe, nonbacterial tropical infectious diseases such as malaria and dengue.
Rapid Diagnostic Testing for Clinical Syndromes
Respiratory infections are among the most common travel-related diseases. Individual and multiplex tests using nasopharyngeal swab samples are widely available for influenza A, influenza B, and respiratory syncytial virus. The sensitivity of rapid antigen tests for influenza is notably poor; negative results should not dictate therapy decisions and should be confirmed with molecular testing. Influenza subtyping is primarily used for public health surveillance and is not commonly available with rapid testing. Subtyping does not affect clinical decision making; however, this may change if certain strains or subtypes become markers for resistance to antiviral medications.
Platforms for multiplex molecular testing are available that identify up to 11 respiratory viruses and 3 atypical bacteria (Table 11-5). These tests are often sensitive and can test for a large number of pathogens in a single sample. However, such multiplex panels are expensive, and results must be interpreted in light of prolonged shedding periods for certain pathogens, the possibility of multiple positive results or coinfections, and variable accuracy for different agents on the panel (such as adenovirus). In addition, currently available waived multiplex assays do not test for common bacterial causes of pneumonia or specific pathogens that may be included in the differential diagnosis for a returning traveler with a respiratory illness (such as Middle East respiratory syndrome coronavirus). Clinicians may prefer to order tests in a tiered approach to limit unnecessary results.
Although many travelers will develop gastrointestinal infections, patients may not present to travel clinics for short illnesses, or they may initiate treatment themselves with antibiotics provided to treat travelers’ diarrhea. Rapid tests for rotavirus and norovirus have received US Food and Drug Administration (FDA) clearance, but not all assays received waived status. These are less sensitive than molecular tests, and for norovirus, rapid antigen testing has only been cleared for use in outbreaks. Multiplex molecular panels, which identify many common viral, bacterial, and parasitic diarrheal pathogens, are available (Table 11-5). These have the same limitations as the multiplex molecular panels described for respiratory pathogens, including the common detection of coinfections.
The undifferentiated acute febrile illness presents a diagnostic challenge in returning travelers, requiring prompt evaluation, diagnosis, and management. RDTs alone may not be sufficient in many settings. A commercial RDT for malaria is cleared for use in US hospitals and laboratories but not for individual clinics. Microscopy is still recommended in positive cases to identify the species and calculate parasitemia. Furthermore, patients with malaria can be coinfected with other pathogens contributing to and complicating their diagnosis and management. Rapid tests are not available in the United States for other common or widespread causes of an undifferentiated acute febrile illness in travelers, such as dengue or leptospirosis.
Sexually transmitted infections (STIs) may be acquired locally or abroad. Rapid HIV tests that use blood and cheek swab samples are widely available. These predominantly detect anti-HIV antibodies and perform well for patients with chronic infections, although not those with newly acquired HIV. Antigen/antibody combination tests are available that detect p24 antigen and anti-HIV antibodies. These remain less sensitive than molecular testing to detect acute HIV infection, and in high-risk patients, molecular testing or repeat testing is warranted. Rapid tests for syphilis, trichomonas, and vaginal bacterial infections are available and can help identify other common STIs (Table 11-5).
Diagnostic Testing Performed During Travel
People who become ill while traveling may seek medical care abroad; the development and availability of RDTs for tropical infectious diseases has expanded greatly in recent years. RDTs, in this context, are typically lateral-flow immunochromatographic tests that detect antigen from or antibodies to certain pathogens. Patients may, therefore, return home having received a diagnosis based on results from these tests. As only one such test has been cleared for use in the United States (for malaria), the diagnostic characteristics of these tests are unknown to most providers. Additionally, many different RDTs may be available for certain pathogens (such as dengue), with widely varying or poorly studied performance parameters. Institutions may not have continuous access to a single brand of test; as such, results even within a laboratory can be difficult to interpret.
Following are several common infections for which RDT or POC diagnostics may be available. This is intended to be an illustrative list but by no means exhaustive.
- Malaria. An FDA-cleared RDT for malaria is available, and malaria RDTs are in wide use throughout the endemic world. In general, these perform best in patients with malaria caused by Plasmodium falciparum , with variable or poor performance for other species.
- Dengue. Rapid, lateral-flow assays exist to detect the nonstructural protein 1 (NS1) antigen and anti-dengue IgM and IgG. Tests have widely variable performance, depending on the manufacturer, circulating dengue types in a region, a patient’s past medical history, and duration of symptoms before presentation.
- Emerging infections. These pathogens represent a significant diagnostic challenge. Rapid assays became available after outbreaks of Ebola, chikungunya, and Zika viruses. However, such assays may not be available or well studied at the peak of an outbreak.
- Visceral leishmaniasis. Assays to detect antibodies against the rK39 antigen have demonstrated good performance characteristics in endemic regions.
- Typhoid. Rapid serologic tests have demonstrated only moderate accuracy to diagnose typhoid. Additionally, these are designed to detect Salmonella enterica serotype Typhi only.
- Leptospirosis. Serologic assays have been developed. Their use generally is limited by the large number of pathogenic and intermediate serotypes that result in human disease worldwide.
- Rapid diagnostic tests may require confirmatory or supplementary testing with more complex laboratory techniques.
- Tests are designed for specific targets and may not perform well in the setting of emerging pathogens or strains (such as rapid influenza diagnostics for avian influenza or malaria RDTs for Plasmodium knowlesi ).
- Use of these tests does not provide biological material for additional studies, such as confirmatory testing, laboratory research and development, or strain characterization.
- Multiplex molecular panels may provide test results not requested by the clinician. How to interpret and make intelligent clinical use of such results needs to be clarified.
This designation is specific to the United States. Tests conducted under a certificate of waiver must be simple to perform with a low risk for yielding an incorrect result. Although mandated personnel requirements for waived tests are minimal, testers must be trained and have documented proficiency in assay performance. Additional considerations include the following:
- Waived tests can be performed only on unmodified specimens (saliva, urine, whole blood). Certain tests can be performed as both waived and moderate- or high-complexity tests, depending on the specimen type and protocol.
- Waived tests must be performed according to the most recent manufacturer recommendations. Deviation from the protocol defaults the test to a high-complexity test.
- Test volume and staffing should be considered. Reagents may have specific storage requirements and a relatively short shelf life, which can affect cost effectiveness.
- These tests require oversight and quality assessments to ensure performance.
The number of assays compatible with POC testing will continue to increase, and implementation of these tests outside standard clinical diagnostic laboratories will no doubt expand. In the setting of returning travelers, where the breadth and diversity of infecting pathogens is greater, use of POC testing for nondomestic infectious diseases may not be practical for most centers when factors such as test volume, personnel training, and cost are taken into consideration. However, POC testing for common syndromes such as respiratory tract and gastrointestinal infections, which affect travelers and nontravelers alike, may provide a rapid diagnosis, inform triage decisions, and limit unnecessary laboratory testing.
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- US Food and Drug Administration. CLIA—Clinical Laboratory Improvement Amendments—currently waived analytes. Available from: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfClia/analyteswaived.cfm.
Elizabeth Rabold, Jesse Waggoner