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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"2 Diagnosis of SARS-CoV-2 Infection." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

2 Diagnosis of SARS-CoV-2 Infection When Long COVID occurs, it follows an acute infection with SARS-CoV-2, the virus responsible for the COVID-19 pandemic. This chapter addresses the request in the committee’s statement of task (Box 1-1 in Chapter 1) to identify and describe the tests, findings, and signs currently clinically accepted to estab- lish a history of COVID-19, including tests for SARS-CoV-2, findings of other diagnostic tests, and signs consistent with COVID-19. It also addresses the request to identify any methods generally accepted by the medical community for establishing a history of COVID-19 in patients that are not covered by a report of a positive viral test for SARS-CoV-2, a diagnostic test with findings consistent with COVID-19 (e.g., chest x-ray with lung abnormalities), or a diagnosis of COVID-19 based on signs consistent with COVID-19 (e.g., fever, cough). In addressing these tasks, the chapter provides context surrounding the evolution of the diagnosis of COVID-19, beginning with the gold-stan- dard approach of viral testing specifically for SARS-CoV-2. The chapter then reviews the diagnosis of COVID-19 based on signs, symptoms, and diagnostic surrogates prior to the advent of specific testing for SARS-CoV-2 infection. Diagnosis of acute COVID-19 differs from that of Long COVID. Given the absence of a consensus-based definition and the ongoing evidence-based research on best practices for diagnosing Long COVID, this chapter focuses primarily on the early and current diagnostic measures of acute COVID-19. VIRAL TESTING Over the course of the pandemic, diagnostic tests specific to SARS-CoV-2 were developed and became more readily available, although disparities in 39 PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 39 5/21/24 10:49 AM

40 LONG-TERM HEALTH EFFECTS OF COVID-19 socioeconomic status and geographical location still impacted access to such testing (Dalva-Baird et al., 2021; Rentsch et al., 2020; Romero et al., 2020). As of this writing, a viral test is necessary to confirm a diagnosis of SARS-CoV-2 infection. The primary method used today is direct measure- ment through molecular or antigen testing. Early in the pandemic, indi- rect measurement was possible through serological (antibody) studies, but today, viral culture is reserved mainly for research purposes. Nucleic Acid Amplification (Molecular) Tests Nucleic acid amplification tests (NAATs), sometimes called molecular tests, detect nucleic acids (genetic material) from the single-stranded RNA SARS-CoV-2 virus. These tests are now considered the gold-standard for diag- nosis of COVID-19 in the clinical setting because of their high sensitivity and specificity (CDC, 2023d; Hayden et al., 2023; Hellou et al., 2021; Lieberman et al., 2020; NIH, 2023). NAATs can use various methods to amplify and detect virus genes, including reverse transcriptase polymerase chain reaction (PCR) and isothermal amplification (e.g., loop-mediated isothermal ampli- fication [LAMP], clustered regularly interspaced short palindromic repeats [CRISPR]) technologies (CDC, 2023d). Commercial tests generally detect at least two genes’ targets on the virus. Many molecular diagnostic tests for COVID-19 are authorized by the U.S. Food and Drug Administration (FDA); platforms used for the testing can differ around the world (FDA, 2023b). The turnaround time for results ranges from 15 minutes (rapid or some isothermal amplification platforms) to several hours (real-time reverse transcription-PCR [RT-PCR]) (Ganguli et al., 2020; Hayden et al., 2023). It may take up to 5 days following exposure before NAATs can detect viral particles in an infected person (NIH, 2023). A positive test confirms the diagnosis of COVID-19; however, false positives, although rare, can occur (FDA, 2021a). False negatives also have been documented, and repeat testing is indicated if clinically appropriate (CDC, 2023d; FDA, 2023a; Long et al., 2021). An inconclusive or indeterminate result indicates that only one of the two or more genes that the NAAT targets was identified. If the person is early in the disease course, repeat testing can help confirm the result (Hayden et al., 2023). The FDA monitors variants resulting from new mutations that may impact the performance of the NAAT (NIH, 2023). The pooled sensitivity of the SARS-CoV-2 NAAT has been estimated at 97 percent (95% CI 93 to 99); pooled specificity was 100 percent (CI 96 to 100) (Hayden et al., 2023). Viral RNA may be detectable for up to 90 days after initial infection irrespective of active infection; thus, NAATs should not be used to test someone for active infection who has already tested positive in the past 90 days (CDC, 2024b). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 40 5/21/24 10:49 AM

DIAGNOSIS OF SARS-COV-2 INFECTION 41 Antigen Tests Antigen tests detect certain proteins (antigens) from the virus via immu- noassay. In these tests, synthetic antibodies probe a person’s respiratory sample for evidence of viral proteins, which confirms an active infection (Center for Health Security, 2023). Antigen tests typically provide rapid results (in as little as 15 minutes), allow the patient to test at home and other points of care, and are therefore more accessible and convenient than NAATs (FDA, 2023a; Hayden et al., 2023); they are also less expensive (CDC, 2024). A positive antigen test indicates active COVID infection. Sensitivity is highest in symptomatic individuals within 5 to 7 days of symptom onset (NIH, 2023; Parvu et al., 2021). Although the sensitivity of anti- gen testing is higher in symptomatic than in asymptomatic individuals, it remains lower than that of NAATs (Hayden et al., 2023). Sensitivity is improved with repeated antigen testing (Hayden et al., 2023). A negative antigen test in persons with signs or symptoms of COVID-19 should be confirmed by NAAT (CDC, 2024). False positive antigen tests are rare (CDC, 2023a). Both molecular and antigen tests can be performed by trained personnel in laboratory facilities or in point-of-care settings, such as clinics and hos- pitals, pharmacies, schools, and nursing or rehabilitation facilities (Hayden et al., 2023). Some NAATs can be self-administered by the patient (e.g., at home) and shipped to a laboratory for testing. Antigen tests can be self- administered and performed at home; thus, results may not be officially recorded in a medical record (CDC, 2023c; NIH, 2023). Nasopharyngeal specimens remain the recommended samples for SARS-CoV-2 diagnostic testing; other sampling sites, such as nasal mid- turbinate, anterior nasal, or oropharyngeal swabs, are acceptable alterna- tives (CDC, 2023c; Hayden et al., 2023; Hellou et al., 2021; NIH, 2023). Some tests can be performed on saliva or mouth gargle specimens (FDA, 2023a). With both NAATs and antigen tests, clinical performance, and thus sensitivity and specificity, depends on how well the specimen is collected, the actual site of sampling, and the duration of illness at the time of testing (Brümmer et al., 2021; Dinnes et al., 2022; Hayden et al., 2023; Hellou et al., 2021; Kucirka et al., 2020; Mallett et al., 2020; NIH, 2023; Parvu et al., 2021; Tsang et al., 2021). Because NAATs can detect molecular parts of SARS-CoV-2 for up to 3 months after an infection, even when live virus is no longer present (Rhee et al., 2021), antigen testing is particularly help- ful for individuals with a recent history of COVID infection who need to test following a new exposure to document active infection (CDC, 2022b; Hayden et al., 2023). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 41 5/21/24 10:49 AM

42 LONG-TERM HEALTH EFFECTS OF COVID-19 Antibody Tests (Serology) Antibody (immunoglobulin) tests, or serology, are an indirect method of demonstrating recent exposure to SARS-CoV-2. Early in the pandemic, prior to the availability of at-home antigen tests and the facility of molecu- lar testing, antibody tests were used to help diagnose SARS-CoV-2 infection. Several types of antibodies are produced after infection, including IgM, a short-term immunoglobulin that becomes undetectable weeks to months following infection, and IgG, which is usually produced after two or more weeks and may confer long-term protection and/or remain positive for a long time even if not offering protection. Antibody tests can be used to detect prior SARS-CoV-2 infection and/ or prior vaccination. Different tests target different protein parts of the virus, such as the spike protein or the nucleocapsid protein (CDC, 2022a). Because COVID-19 vaccines are engineered using the viral spike protein, vaccinated persons will test positive for the IgG antibody. Individuals with previous infection may also mount a positive serum IgM or IgG spike pro- tein response. Antibodies to the nucleocapsid protein are generated only by infection, so a specific antibody test (IgG or IgM) against the nucleocapsid protein can be used to document prior infection in a vaccinated individual as long as the antibodies are still positive (CDC, 2022a). Antibodies (IgG or IgM) against the SARS-CoV-2 virus are typically measurable two or more weeks after the onset of symptoms. Hence, negative antibody testing during the acute phase of the disease cannot rule out the disease, and convalescent titers may be helpful (CDC, 2022a). An IgG response to the spike protein has been reported to remain stable over 6+ months (Dan et al., 2021). For diagnostic or epidemiological purposes, the grade of evidence for the use of antibody tests is very low to moderate (Hayden et al., 2024). Both serum IgM and IgG tests have variable levels of sensitivity and specificity depending on the timeline of evaluation, and the predictive value of a diag- nostic test depends not only on the characteristics of the test but also on the prevalence of the disease, which varies greatly depending on fluctuations of SARS-CoV-2 prevalence in different geographic locations and points in time. The method used to quantify antibodies can also impact accu- racy, with a large systematic review and meta-analysis performed in 2022 showing better performance with respect to sensitivity for tests performed through ELISA (enzyme-linked immunosorbent assays) (81–82 percent) or CLIA (chemiluminescent immunoassays) (77–79 percent) than through LFIA (lateral flow immunoassays) (69–70 percent) (Zheng et al., 2022). Seroprevalence data from November 2022 show that 96.7 percent of the U.S. population aged 16 and older had been vaccinated for or infected with SARS-CoV-2. Therefore, serological testing is not currently indicated to establish an active infection (CDC, 2024a). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 42 5/21/24 10:49 AM

DIAGNOSIS OF SARS-COV-2 INFECTION 43 One important topic with regard to the accuracy of serologic testing is recognition of patients worldwide who have primary and secondary immu- nodeficiencies. Those conditions may result in an inability to produce, or propensity to lose, antibodies, which may lead to false negatives on serology testing and/or require immunoglobulin replacement therapies, which may lead to false positives on serology testing. Assessment of serologic testing performed on patients with humoral defects indicates that vaccination is safe and cellular immunity is stimulated, but with an inadequate response in terms of production of antibodies and low-quality antibodies in a large number of the patients who do produce them (Arroyo-Sánchez et al., 2022; Connolly and Paik, 2022; Pham et al., 2022; Van Leeuwen et al., 2022). Other Tests Newer tests, such as interferon-γ (IFN-γ) release assays (IGRAs), aimed at identifying the adaptive T cell immune response (“memory T cells”) to SARS-CoV-2, are in development and may have potential as a more long- term marker of active/past infection compared with antibody response. More robust data are needed to determine how long the T cell immune response remains following infection and what level of protection may be provided by the presence of that response (Binayke et al., 2024; Fernández- González et al., 2022). BEFORE VIRAL DIAGNOSTIC TESTNG Signs and Symptoms SARS-CoV-2 was first identified in Wuhan City, China, in December 2019. It is unclear whether, and for how long, the virus may have been in circulation prior to that time (Pekar et al., 2021, 2022). It quickly spread worldwide, and COVID-19 was officially declared a pandemic on March 11, 2020. Viral diagnostic tests were limited at the onset of the pandemic until clinical laboratories began to offer viral testing for SARS-CoV-2 in March 2020 (Greninger and Jerome, 2020), and clinicians therefore had to rely on the presenting symptoms to make a diagnosis of COVID-19. The most frequently reported symptoms at that time, for both adults and children, included fever, cough, shortness of breath, sore throat, muscle soreness, diarrhea, headache, and fever (Irfan et al., 2021; Kadirvelu et al., 2022; Kaye et al., 2021). It is noteworthy that many infected individu- als experienced a loss, or disturbance, of taste and smell. The loss of taste (ageusia) and smell (anosmia) were two of the more distinctive symptoms of SARS-CoV-2 infection (Dixon et al., 2021; Mizrahi et al., 2020), particu- larly with earlier variants (Von Bartheld and Wang, 2023). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 43 5/21/24 10:49 AM

44 LONG-TERM HEALTH EFFECTS OF COVID-19 Infected adults and children may be asymptomatic or have mild, moderate, or severe illness (Shang et al., 2022). The severity of COVID-19 symptoms depends on the presence of underlying premorbid conditions and chronic disease, age, vaccination status, health status, and the vari- ant causing the infection. Signs and symptoms have changed throughout the course of the pandemic and through variant mutations. Omicron variants, for example, are less associated with anosmia compared with the Delta variant (Von Bartheld and Wang, 2023; Butowt et al., 2022), and patients infected with an Omicron variant more frequently report runny nose, headache, sneezing, and sore throat relative to those with earlier variants (Public Health Agency of Canada, 2022). By October 2022, fewer than 20 percent of cases included reports of anosmia (ZOE, 2022); symptoms experienced at that time differ from those reported early in the pandemic (Public Health Agency of Canada, 2022; Whitaker et al., 2022). Even among Omicron variants, Omicron BA.2 was found more likely to be symptomatic compared with BA.1. People infected with the Delta variant experienced a longer duration of acute symptoms relative to those infected with the Omicron variant. However, symptom duration with any variant was found to be shorter among those who had received three doses of the COVID-19 vaccine (Public Health Agency of Canada, 2022). Individual signs and symptoms alone have poor diagnostic accuracy for SARS-CoV2 infection given their overlap with those of other viral syndromes, and the presence or absence of specific signs and symptoms is not sufficient to confirm or rule out infection (Struyf et al., 2022). For this reason, and given the lack of access to and availability of viral testing, a variety of nonviral diagnostic tests were utilized early in the pandemic to help with diagnosis. Supporting Diagnostic Testing Although the tests described in this section are not specific to COVID-19, the consistent prevalence of certain abnormalities seen in hospitalized COVID-19 patients fostered their use in diagnosing the disease early in the pandemic. Imaging studies, pulmonary function tests, and laboratory tests are among the ancillary tests used in the diagnosis of COVID-19 (Silva et al., 2021). Imaging Studies Typical chest X-ray (CXR) findings for COVID-19 include bilateral peripheral and basal multifocal airspace opacities (ground-glass opac- ity and consolidation); however, various patterns of CXR findings may PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 44 5/21/24 10:49 AM

DIAGNOSIS OF SARS-COV-2 INFECTION 45 be observed (Rousan et al., 2020). Because of the higher sensitivity of chest computed tomography (CT) compared with CXR in the detection of early lung disease, disease progression, and alternative diagnosis, high-resolution CT was also used in the clinical evaluation of suspected COVID-19 pneumonia cases (Silva et al., 2021; Wiersinga et al., 2020). CT hallmarks of COVID-19 are bilateral distribution of ground glass opacities with or without consolidation in the posterior and peripheral lung, but the predominant findings in later phases include consolida- tions, linear opacities, “crazy-paving” pattern, “reversed halo” sign, and vascular enlargement. The CT findings for COVID-19 can overlap with the findings of other diseases, including other causes of viral pneumonia, but were considered additional support for the diagnosis given the epidemiological context (Carotti et al., 2020). Less common findings, termed “ancillary findings,” have also been seen on radiography in patients with COVID-19, reflecting the heterogeneity of this disease. These ancillary findings include intra- pulmonary vessel enlargement, subpleural curvilinear lines, centrilobular solid nodules, and pleural and pericardial effusion, among others (Silva et al., 2021). A systematic review and meta-analysis of 94 studies aimed at detecting the accuracy of chest CT, CXR, and lung ultrasound in sus- pected COVID-19 cases showed that both chest CT (69 studies) and lung ultrasound (15 studies) correctly diagnosed COVID-19 in 87 percent of cases, and CXR (17 studies) correctly diagnosed it in 73 percent of cases (Ebrahimzadeh et al., 2022). Compared with the COVID-specific viral tests that are now available, these imaging studies are not as sensitive or specific to COVID. Pulmonary Function Tests Abnormal results on pulmonary function tests, called “lung diffusion capacity of carbon monoxide” or DLCO, may also be seen as a result of destruction of the alveolar air sacs or thickening of the alveolar–capillary basement membrane, which then leads to impaired gas exchange. This phenomenon has been well described in cases of COVID-19 pneumonia (Cortes-Telles et al., 2021; Lee et al., 2022; Steinbeis et al., 2022; Torres- Castro et al., 2021). Laboratory Tests Common laboratory abnormalities seen in COVID-19 include abnormal complete blood count (e.g., lymphopenia), abnormal coagulation (e.g., elevated D-dimer), elevated inflammatory markers (e.g., C-reactive protein), elevated serum lactate dehydrogenase, and reduced serum albumin (Greco et al., 2021). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 45 5/21/24 10:49 AM

46 LONG-TERM HEALTH EFFECTS OF COVID-19 Again, these abnormalities are not unique to SARS-CoV-2 infection, but they gained relevance in the adequate epidemiological context. Surveillance case definitions have changed over time based on the avail- ability of SARS-CoV2 specific diagnostic testing (CDC, 2023b). Clinical diagnosis is one of exclusion, meaning symptoms are not explained by any other probable disease. Initially, clinical criteria included at least two of the following symptoms: fever (measured or subjective), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s) OR at least one of the following symptoms: cough, shortness of breath, or difficulty breathing OR Severe respiratory illness with at least one of the following: • Clinical or radiographic evidence of pneumonia, OR • Acute respiratory distress syndrome (ARDS). AND No alternative more likely diagnosis. (CDC, 2023b, 2020 Interim Case Definition, Approved April 5, 2020) Case definitions have incorporated other clinical data, laboratory/ microbiological data, and/or epidemiological linkages or exposure history— for example, travel to areas with sustained transmission, occupation as a health care worker, or a contact with a positive test. Since August 2020, case definitions have been further classified as “suspect,” “probable,” or “confirmed” (CDC, 2023b). Epidemiological linkage for a SARS-CoV-2 diagnosis was defined by the Centers for Disease Control and Preven- tion (CDC) in 2021 as “close contact—being within 6 feet for at least 15 minutes (cumulative over 24 hours) with a confirmed or probable case of COVID-19 disease” or “member of an exposed risk cohort as defined by public health authorities during an outbreak or during high commu- nity transmission” (CDC, 2023b). The presence of epidemiological link- age and meeting clinical criteria allows a case to be classified at most as “probable,” but does not require confirmatory or presumptive laboratory evidence of SARS-CoV-2 infection when that evidence is not available. Of note, given the eventual expansion of viral testing, the 2023 update of the PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 46 5/21/24 10:49 AM

DIAGNOSIS OF SARS-COV-2 INFECTION 47 case definition for COVID-19 no longer includes epidemiological linkage (CDC, 2023b). ESTABLISHING A HISTORY OF PRIOR COVID-19 Prior COVID-19 During the early days of the COVID-19 pandemic, testing capacity was significantly constrained in the United States (Mercer and Salit, 2021). Con- sequently, many people with signs and symptoms of SARS-CoV-2 infection lacked access to testing and were not formally diagnosed. As the pandemic unfolded, testing constraints eased, at-home testing kits became widely available, and testing behavior changed. As a result, many people with signs and symptoms of SARS-CoV-2 infection either did not undergo testing or self-tested at home without formal reporting to a health care system. These realities underscore that reliance on testing to diagnose COVID-19 and sub- sequently its long-term health effects will necessarily miss these individuals and therefore should not be used as the sole approach to ascertaining a history of SARS-CoV-2 infection. In the absence of objective laboratory testing, signs and symptoms of COVID-19 or a self-report should be con- sidered sufficient. Among patients without positive laboratory test results, the use of non-SARS-CoV-2 specific ICD codes (e.g., generic coronavirus infection, SARS [the prior disease] utilized prior to SARS-CoV-2 specific ICD codes), alone or in combination with signs/symptoms, may be an alter- native approach to support a history of prior COVID-19, combined with all the other clinical findings described above. Future Directions Rapid advances in biomedical research and technology make the manu- facturing of a newer generation of diagnostic tools and tests for COVID-19 likely. Host DNA methylation patterns have been studied to differentiate between COVID-19–infected and –uninfected persons, and these patterns may help predict disease progression and outcomes even before the onset of symptoms (Konigsberg et al., 2021). DNA methylation entails the addition of a methyl group to the DNA molecule in the cells, which plays a crucial role in silencing gene expression, preventing DNA synthesis (Moore et al., 2013). Although neither widely used nor generally recognized presently, specific DNA methylation patterns have been shown to aid in the diagnosis of SARS- CoV-2 infection, to predict disease severity, and to establish a history of prior infection (Konigsberg et al., 2021; Pang et al., 2022). This and many novel techniques are expected to emerge. Several studies are evaluating biomark- ers of both COVID-19 and Long COVID, but results are not yet conclusive. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 47 5/21/24 10:49 AM

48 LONG-TERM HEALTH EFFECTS OF COVID-19 DIAGNOSIS OF LONG COVID There currently are no consensus-based diagnostic criteria for Long COVID. The condition is generally diagnosed on the basis of presumed history of acute SARS-CoV-2 infection (as indicated by a positive viral test or patient self-report; as of this writing, no diagnostic test for Long COVID is available), the presence of Long COVID health effects and symptoms, and consideration of other conditions that could be causing the symptoms. Continued research on and discussion of Long COVID will help inform a case definition and standardized diagnosis (Srikanth et al., 2023). There are several definitions of Long COVID that include varying time since acute SARS-CoV-2 infection, and the definitions in the literature are subject to change as research and data progress. SUMMARY AND CONCLUSIONS Testing to diagnose acute SARS-CoV-2 infection, as well as testing capacity and behaviors, has changed dramatically over the course of the COVID-19 pandemic. Testing was constrained during the early phase of the pandemic, but subsequently became increasingly available. The intro- duction of at-home testing means that many people may not have reported their positive results to health care systems. As viral infections fluctuate, as insurance coverage for at-home tests change, and as society returns to prepandemic activities, some individuals may not even be testing for SARS- CoV-2 with at-home tests when ill. As a result of these two drivers, the diagnosis of many individuals with SARS-CoV-2 infection was not formally documented. Reliance on a documented history of SARS-CoV-2 infection when diagnosing Long COVID will miss individuals whose infection was not documented and therefore should not be used as the sole approach to establishing a diagnosis. The presence of signs and symptoms and self- reported prior infection is generally sufficient to establish a diagnosis of SARS-CoV-2 infection. REFERENCES Arroyo-Sánchez, D., O. Cabrera-Marante, R. Laguna-Goya, P. Almendro-Vázquez, O. Carretero, F. J. Gil-Etayo, P. Suàrez-Fernández, P. Pérez-Romero, E. Rodríguez De Frías, A. Serrano, L. M. Allende, D. Pleguezuelo, and E. Paz-Artal. 2022. Immunogenicity of anti-SARS-CoV-2 vaccines in common variable immunodeficiency. Journal of Clinical Immunology 42(2): 240–252. Binayke, A., A. Zaheer, S. Vishwakarma, S. Singh, P. Sharma, R. Chandwaskar, M. Gosain, S. Raghavan, D. R. Murugesan, P. Kshetrapal, R. Thiruvengadam, S. Bhatnagar, A. K. Pandey, P. K. Garg, and A. Awasthi. 2024. A quest for universal anti-SARS-CoV-2 T-cell assay: Systematic review, meta-analysis, and experimental validation. npj Vaccines 9:3. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch02.indd 48 5/21/24 10:49 AM

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Since the onset of the coronavirus disease 2019 (COVID-19) pandemic in early 2020, many individuals infected with the virus that causes COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have continued to experience lingering symptoms for months or even years following infection. Some symptoms can affect a person's ability to work or attend school for an extended period of time. Consequently, in 2022, the Social Security Administration requested that the National Academies convene a committee of relevant experts to investigate and provide an overview of the current status of diagnosis, treatment, and prognosis of long-term health effects related to Long COVID. This report presents the committee conclusions.

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