Reframing ADHD: New Science, New Treatments, New Perspectives

 

NP CHRONICLES

Clinical Education for NP Students & New Graduates

Reframing ADHD: New Science, New Treatments, New Perspectives

Psychiatry  |  Board Prep  |  Chronic Disease Management

ADHD has a reputation problem in primary care: it's often treated as a straightforward diagnosis with a straightforward fix — confirm inattention or hyperactivity, start a stimulant, done. A recent Pri-Med Institute CE session led by Charles Vega, MD, FAAFP (UC Irvine) and Ajay Shah, MD (Texas Children's Hospital / Baylor College of Medicine) makes the case that this picture is incomplete in ways that matter for real patients. This post distills the session's key clinical content, organized around the case of “Hannah,” a 32-year-old woman whose presentation illustrates most of the diagnostic blind spots the talk addresses.

CASE FROM PRACTICE Hannah, 32, presents with persistent anxiety, excessive worry, and difficulty “shutting off” her mind. She reports trouble sleeping, is easily irritated and frustrated, and is experiencing occupational impairment — missed deadlines, job instability, being passed over for promotion. On the surface, this reads as a generalized anxiety presentation. It's also a textbook example of how adult ADHD frequently presents: not as obvious hyperactivity, but as chronic underperformance, irritability, and what looks like an anxiety or mood disorder.

ADHD Across the Lifespan: How Common, and How Missed

ADHD remains one of the most common neurodevelopmental conditions, and it does not stop at childhood. As of the most recent surveillance data cited in the session:

•     Approximately 15.5 million US adults (6.0%) had a current ADHD diagnosis in 2023 based on self-report — and roughly half of them received that diagnosis at age 18 or older.

•     Approximately 6.5 million US children and adolescents (10.5%) had ADHD in 2022, and 1 in 9 (11.4%) US children have ever received an ADHD diagnosis.

•     An estimated 60% of children with ADHD experience persistence of symptoms into adulthood, and 57% of people with ADHD are diagnosed before age 14.

The gap between those two statistics — 60% of childhood ADHD persisting into adulthood, but only about half of adult diagnoses tracing back to childhood — points to a real problem: a large share of adults living with ADHD were never identified as children, and many still aren't being identified now.

Why Underdiagnosis Happens, and Who It Happens To

NUANCE TO FLAG An estimated 14% of the adult population may meet criteria for undiagnosed ADHD, with women disproportionately affected. Delayed diagnosis is especially common in girls, who typically present with primarily inattentive symptoms and fewer of the disruptive behaviors that tend to trigger evaluation in childhood. Groups at elevated risk for underrecognition also include people who are incarcerated, patients in addiction and mental health treatment settings, and ethnic and racial minorities, including African American and Latino individuals. Many adults with undiagnosed ADHD have simply built coping mechanisms that mask symptoms at work and at home — which is part of why the condition can go unrecognized well into adulthood, often until a life transition (new job, new relationship, parenthood) removes the scaffolding those coping strategies depended on.

Beyond Inattention and Hyperactivity: What Gets Missed

The session emphasized that the formal DSM-5-TR criteria capture only part of the clinical picture. Emotional dysregulation and executive dysfunction — often the most functionally impairing features for adult patients — are not part of the core diagnostic criteria and are not assessed by most standard screening tools, meaning they can go entirely unassessed even in a thorough workup.

•     Emotional dysregulation (low frustration tolerance, irritability, mood lability, disproportionate emotional responses) affects 25–45% of children and 30–70% of adults with ADHD.

•     In a study of 1,500 children, emotional problems had a greater impact on well-being and self-esteem than hyperactivity and inattention did.

•     Executive dysfunction — deficits in working memory, cognitive set-shifting, planning, organization, and time management — was present in at least one domain in 50% of children with ADHD.

•     Notably, stronger working memory skills predict better emotional regulation independent of ADHD symptom severity, suggesting the two domains are mechanistically linked rather than coincidental.

The Disease Burden Goes Well Beyond the Core Symptoms

Untreated or poorly managed ADHD carries measurable downstream consequences across multiple life domains, which is part of why accurate, timely diagnosis matters beyond symptom control alone:

•     Academic: poorer school performance and increased risk of academic failure compared with unaffected peers.

•     Occupational: higher rates of unemployment, lower occupational attainment, more frequent job changes, and reduced earnings.

•     Medical comorbidity: increased rates of obesity, type 2 diabetes, cardiovascular disease, and anxiety/mood disorders.

•     Mortality: higher risk of premature death from accidental injury, motor vehicle accidents, and suicide.

Psychiatric comorbidity specifically is the norm, not the exception. In a nationally representative sample of adults with ADHD: 38% had mood disorders, 47% had anxiety disorders, and 15% had substance use disorders. Roughly 89% of one studied population had clinical depression in adulthood and 50% had anxiety disorders — figures that vary somewhat across studies but consistently point to very high comorbidity burden.

CLINICAL BOTTOM LINE — RECOGNITION Adult ADHD frequently hides behind an anxiety, mood, or substance use presentation — particularly in women, who are more likely to have been missed in childhood. When a patient's history includes long-standing (not new-onset) difficulty with attention and distractibility, ask directly: how long has this been a problem — years or decades, not weeks or months? What would this patient have looked like in a childhood classroom? Emotional dysregulation and executive dysfunction are common, functionally significant, and not captured by most screening tools — they have to be asked about directly.

Diagnosis: A Three-Part Process, Not a Checklist

The DSM-5-TR requires 6 or more symptoms of inattention or hyperactivity/impulsivity (5 or more if age 17+) present for at least 6 months, with several symptoms present before age 12, in two or more settings, causing functional impairment not better explained by another mental disorder.

Inattention	Hyperactivity/Impulsivity
Lack of attention to detail; difficulty sustaining attention	Fidgeting or squirming in seat
Doesn't listen when spoken to directly	Leaves seat when not supposed to; restless/overactive
Trouble completing tasks; poor organization	Difficulty engaging in leisure activities quietly
Avoids sustained mental effort; easily distracted	Always “on the go”; talks excessively
Loses/misplaces things; forgetful in daily activities	Blurts out answers; interrupts others; difficulty waiting turn

 

The American Academy of Family Physicians recommends a 3-part diagnostic approach: clinical history, validated self-report/observer screening tools (e.g., the Adult ADHD Self-Report Scale), and formal assessment against DSM-5-TR criteria. Notably, a survey of 178 clinicians who regularly perform adult ADHD assessments found real gaps in practice: only 31% used a structured or semi-structured interview, and “difficulties concentrating” was the only core feature endorsed as such by a majority of respondents — suggesting many clinicians' working concept of ADHD is narrower than the diagnostic reality.

Screening Tools: Useful, Not Sufficient Alone

Population	Example Validated Tools
Adults	ADHD Rating Scale-IV (with Adult Prompts); Adult ADHD Clinical Diagnostic Scale (ACDS); Adult ADHD Self-Report Scale (ASRS)
Children	ADHD Rating Scale (ADHD-RS); Child Behavior Checklist (CBCL); Vanderbilt scales; Conners' Rating Scale

 

A 2022 meta-analysis found these tools have high diagnostic accuracy overall (pooled AUC 0.82) but insufficient sensitivity and specificity individually (both below 0.8) — the explicit reason screening tools should never be used alone to establish a diagnosis.

CASE FROM PRACTICE Returning to Hannah: she has 5 symptoms from the inattention domain and a childhood history of academic underachievement despite high intelligence — a classic pattern in patients (especially women) who compensated well enough to avoid earlier detection. Beyond the core criteria, DSM-5-TR associated features that support the diagnosis include mild language/motor/social developmental delays, low frustration tolerance, irritability, mood lability, impaired work/academic performance, deficits on memory and executive function testing, and increased risk of suicide attempt in early adulthood — several of which show up directly in Hannah's presentation.

Because ADHD symptoms overlap substantially with depression, anxiety, bipolar disorder, substance use disorders, and personality disorders (poor concentration, distractibility, mood swings, irritability, restlessness are common to several of these), guidelines recommend treating the most impairing condition first when ADHD coexists with other psychopathology. Three practical questions can help surface ADHD in a complicated presentation: Have these attention/distractibility problems been long-standing and consistent? Have current complaints been present for 10–20 years, not just recently? What would this patient have looked like in a childhood classroom?

The Neurobiology, in Plain Terms

ADHD involves dysregulation across three interacting neurotransmitter systems, and understanding this framework has direct treatment implications.

System	Primary Roles
Dopaminergic	Movement regulation, mood, attention, learning/memory, novelty and reward processing
Noradrenergic	Attention and arousal, signal-to-noise processing, mood regulation, stress response
Serotonergic	Modulates both dopamine and norepinephrine pathways; implicated in impulsivity, emotional dysregulation, and cognitive inflexibility

 

The relative contribution of each pathway varies by individual and across the lifespan — part of why ADHD is increasingly understood as a highly heterogeneous disorder requiring a multifactorial, dimensional view rather than a single unifying mechanism. Current pharmacotherapy targets dopaminergic and noradrenergic pathways almost exclusively. That matters clinically: while these medications often improve core inattention and hyperactivity-impulsivity symptoms, many patients continue to struggle with organization, emotion regulation, motivation, or functional performance despite adequate adherence — domains more closely tied to serotonergic and executive-network function than to dopamine/norepinephrine alone.

CLINICAL BOTTOM LINE — NEUROBIOLOGY If a patient on an adequately dosed, adherently taken stimulant or nonstimulant still reports significant executive dysfunction, emotional dysregulation, or functional impairment, that is not necessarily a sign of inadequate dosing — it may reflect that current medications primarily target dopamine/norepinephrine pathways and leave serotonergic and broader executive-network contributions to the disorder comparatively unaddressed.

Current Medications: Strengths and Real Limitations

Class	Examples	Key Advantages	Key Limitations
Stimulants	Methylphenidate, amphetamines (lisdexamfetamine, dextroamphetamine)	Large effect size; rapid onset; helps comorbid ODD/conduct issues	Appetite/sleep/CV effects; limited daily duration; rebound; Schedule II
NRIs	Atomoxetine, viloxazine ER	Around-the-clock effect; not controlled; option in comorbid SUD	Smaller effect size; 6–12 wks to effect; black box suicidality warning
Alpha-2 agonists	Clonidine ER, guanfacine ER	Around-the-clock; option in comorbid tics/anxiety/CV disease	Sedation; smaller effect size; 2–4 wks to effect
Bupropion (off-label)	Bupropion XL	Once-daily; may help comorbid depression/anxiety/SUD	Seizure risk; smaller effect size; suicidality warning under age 25

 

Clinical factors that specifically favor a nonstimulant: concern for stimulant misuse or diversion, comorbid anxiety that stimulants might worsen (favoring atomoxetine/viloxazine), cardiovascular contraindications, or comorbid tics/Tourette syndrome — which occurs in 8–10% of patients with ADHD (favoring alpha-2 agonists).

Pediatric guidance from the AAP/AAFP: behavioral therapy first-line for ages 4–5, with methylphenidate reserved for cases with continued moderate-to-severe functional disability; FDA-approved medication and/or behavioral therapy for ages 6–11; medication with patient assent (plus optional behavioral therapy) for ages 12–18. None of the nonstimulants currently carry FDA approval for preschool-age children. Notably, no formal adult ADHD management guidelines currently exist in the US, though the American Professional Society of ADHD and Related Disorders (APSARD) is working to develop them.

The Real-World Gap

NUANCE TO FLAG Real-world outcomes data cited in the session are sobering: an estimated 95% of adults and roughly 60% of children experience at least one treatment-related adverse event, and two-thirds of individuals change their ADHD medication within the first 12 months. A 2025 component network meta-analysis (N=14,887) found that while stimulants and atomoxetine show consistent short-term efficacy for core symptoms in adults, ADHD medications were not shown to be efficacious for quality-of-life outcomes, with little long-term evidence either way. Non-pharmacologic strategies (CBT, cognitive remediation, mindfulness, psychoeducation, tDCS) showed inconsistent results, and — notably — neither medications nor cognitive training were effective at improving executive dysfunction in adults in this analysis. This is a meaningful treatment gap, not a reason to withhold first-line therapy, but a reason to set realistic expectations with patients about what medication will and won't fix.

CASE FROM PRACTICE After a full discussion of stimulant, nonstimulant, and nonpharmacologic options, Hannah chooses a stimulant. After 3 months of treatment, her core symptoms have overall improved — but she is still having significant frustration and irritability. This is exactly the residual-symptom pattern the neurobiology framework predicts: dopaminergic/noradrenergic-targeted treatment often does not fully resolve emotional dysregulation, which may have a stronger serotonergic component.

Emerging Treatments: Targeting a Third Pathway

Two investigational agents highlighted in the session take a different mechanistic approach by adding serotonergic activity to the more traditional dopamine/norepinephrine targets.

Centanafadine — Triple Reuptake Inhibitor

Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin simultaneously. Across 4 completed phase 3 trials (N=2,477) in children, adolescents, and adults, centanafadine showed statistically significant improvement in ADHD symptom scores versus placebo, with open-label extension data suggesting sustained efficacy. Preliminary analyses suggest possible additional benefit in executive functioning, mood/anxiety symptoms, and emotional dysregulation — domains current medications often leave unaddressed. A phase 3b trial (N=315) specifically in adults with ADHD and comorbid generalized or social anxiety disorder found a statistically significant 18.5-point reduction in ADHD symptom scores (vs. 12.6 for placebo) and a significant reduction on the Hamilton Anxiety Rating Scale as well, with effects seen as early as week 1. Common adverse events were insomnia, decreased appetite, nausea, headache, and rash, most mild-to-moderate.

Solriamfetol — Dopamine-Norepinephrine Reuptake Inhibitor

Solriamfetol is already FDA-approved for narcolepsy and obstructive sleep apnea, and is being studied for ADHD via its dopamine/norepinephrine reuptake inhibition plus additional TAAR1 and 5-HT1A receptor activity. In the phase 3 FOCUS trial (N=516), once-daily solriamfetol produced a statistically significant 17.7-point reduction in ADHD symptom scores (vs. 14.3 for placebo) over 6 months, with a 53.5% clinical response rate versus 41.3% for placebo. Onset of effect was observed as early as week 1, with no serious adverse events reported; pediatric trials are planned.

NUANCE TO FLAG Both centanafadine and solriamfetol are investigational for ADHD and not yet FDA-approved for this indication — they are not currently prescribable for ADHD. This CE activity was supported by an educational grant from Otsuka America Pharmaceutical, which has a commercial interest in centanafadine; Axsome Therapeutics, developer of solriamfetol, was also cited via company and industry-conference sources for some of the data presented. None of this invalidates the underlying trial data, but it's worth reading efficacy figures from company press releases and conference posters with the same scrutiny you'd apply to any pharma-sourced data — awaiting independent peer-reviewed publication and, eventually, FDA review, before treating these as established options.

Key Takeaways

•     ADHD is a highly prevalent, heterogeneous, chronic neurodevelopmental disorder; roughly 60% of children have symptoms that persist into adulthood, and adult presentations — especially in women — are frequently missed for years.

•     Psychiatric comorbidity is the norm: roughly half of adults with ADHD have a mood disorder and nearly half have an anxiety disorder.

•     Executive dysfunction and emotional dysregulation are common, functionally significant, and not reliably captured by core DSM-5-TR criteria or standard screening tools — ask about them directly.

•     The neurobiology involves dopamine, norepinephrine, and serotonin pathways; current first-line medications target only the first two, which may explain persistent residual symptoms in appropriately treated patients.

•     Emerging triple- and dual-reuptake inhibitors (centanafadine, solriamfetol) aim to address that gap, but remain investigational for this indication as of this writing.

 

Reference

Vega, C., & Shah, A. (2026). Reframing ADHD: New science, new treatments, new perspectives. Pri-Med Institute CE activity, supported by an educational grant from Otsuka America Pharmaceutical, Inc.

Making Sense of Serologies: HIV, Lyme, Hepatitis, and TB Testing in Primary Care

 

NP CHRONICLES

Clinical Education for NP Students & New Graduates

Making Sense of Serologies: HIV, Lyme, Hepatitis, and TB Testing in Primary Care

Infectious Disease  |  Board Prep  |  Test Interpretation

Serologic testing looks straightforward until you're staring at a reactive HIV screen in a low-risk patient, a Lyme ELISA drawn three days after a rash appeared, or an isolated hepatitis B core antibody before an infusion. This post distills a CE lecture from Daniel A. Solomon, MD, FIDSA, of the Division of Infectious Diseases at Brigham and Women's Hospital, covering four serologies that come up constantly in primary care: HIV, Lyme disease, hepatitis B/C, and latent TB. The focus is interpretation — not just what to order, but what the result actually means once it's back.

HIV: The Algorithm Matters as Much as the Result

Modern HIV screening uses a 4th-generation antigen/antibody (Ag/Ab) combination assay, which detects both HIV antibody and the p24 antigen — meaningfully shortening the “window period” compared to older antibody-only assays. But a reactive screen is never a diagnosis on its own. It triggers a defined confirmatory sequence.

Step	Test	Purpose
1	HIV Ag/Ab combination assay (screen)	Initial screen; detects antibody and p24 antigen
2	HIV-1/2 differentiation assay	Confirms and distinguishes HIV-1 vs. HIV-2 if the screen is reactive
3	HIV RNA PCR (viral load)	Resolves discordant results; confirms diagnosis in suspected acute infection

 

CASE FROM PRACTICE A 26-year-old pregnant woman, mutually monogamous and asymptomatic, has a reactive HIV Ag/Ab screen on routine prenatal testing. The HIV-1/2 differentiation assay comes back negative, and HIV viral load is undetectable. Interpretation: false-positive screen, possibly related to cross-reactive antibodies that can occur during pregnancy. In low-prevalence populations, a false-positive screening result is genuinely more common than acute HIV — but a false positive on both the screen AND the differentiation assay is rare, occurring in roughly 1 in 200,000 cases.

That case illustrates a core teaching point: as HIV prevalence in the tested population drops, the proportion of reactive screens that are false positives rises, even with a highly specific test (99.4% specificity in the example used). At 10% prevalence, most reactive screens are true positives; at 0.4% prevalence, false positives become common. This is Bayesian reasoning applied directly to a test result NPs order constantly.

When Acute HIV Is the Real Concern

CASE FROM PRACTICE A 22-year-old man who has sex with both men and women presents with fever, myalgias, pharyngitis, diarrhea, and cervical lymphadenopathy. His last HIV test, one month prior, was negative, and he has had one new partner since. HIV Ag/Ab is reactive, but the differentiation assay is negative — a pattern that would normally suggest a false positive. Because acute infection was clinically suspected, viral load was sent anyway: >10,000,000 copies/mL, with a CD4 count of 256 (13%). Diagnosis: acute HIV. He was started on ART at diagnosis and has since achieved an undetectable viral load with excellent adherence.

The clinical lesson: a reactive screen with a negative differentiation assay is not automatically a false positive if acute infection is on the differential. Antibody hasn't yet fully developed during the acute window, so the differentiation assay can be falsely negative even as the patient is acutely, highly infectious. Any time acute HIV is a real possibility — a compatible “mononucleosis-like” syndrome, recent high-risk exposure, or a discordant result in a symptomatic patient — send the viral load.

•     Acute HIV syndrome is highly variable: approximately 40% of cases are asymptomatic. Among those who are symptomatic, the most common features are fever (75%), fatigue (68%), myalgia (49%), rash (48%), headache (45%), pharyngitis (40%), and cervical adenopathy (39%).

•     Diagnosing acute HIV matters because the window period, while small, still exists; the syndrome resolves spontaneously (creating real risk of loss to follow-up if missed); acute infection is a period of maximum infectiousness; and early treatment reduces transmission risk, preserves CD4 counts, targets a less diverse viral population, and reduces the size of the HIV reservoir.

NUANCE TO FLAG Lifetime HIV risk is not evenly distributed, and the data are worth knowing for both clinical index of suspicion and for framing risk discussions without bias. Estimated lifetime risk in heterosexual men: 1 in 2,713 (White), 1 in 437 (Latinx), 1 in 97 (Black/African American). Among men who have sex with men: 1 in 11 (White), 1 in 5 (Latinx), 1 in 2–3 (Black/African American). These disparities reflect structural and systemic factors, not individual behavior differences, and should inform equitable testing practices — offering testing broadly rather than only to patients who disclose risk factors.

CLINICAL BOTTOM LINE — HIV False-positive HIV screens are common in low-prevalence populations. The standard confirmatory test is the HIV-1/2 differentiation assay, but any positive screen — and any case where acute infection is clinically suspected, regardless of differentiation assay result — should be confirmed or clarified with an HIV RNA viral load.

Lyme Disease: Match the Test to the Stage

Lyme testing performance depends heavily on how long the infection has been present, which is why clinical staging should drive both diagnosis and test selection rather than reflexively ordering serology on every rash or joint complaint.

Stage	Time from Bite	Key Features	Diagnostic Approach
Early localized	7–28 days	Erythema migrans; fatigue, headache, myalgias, fever	Clinical diagnosis preferred — serology often still negative
Early disseminated	Weeks to months	Meningitis, CN palsy, radiculopathy, peripheral neuropathy; Lyme carditis, AV block	Antibody test with reflex to confirmatory testing
Late disease	Months to years	Knee arthritis, acrodermatitis chronica atrophicans, encephalopathy	Antibody test with reflex to confirmatory testing
Post-treatment Lyme disease syndrome	3–12 months post-treatment	Headache, fatigue, arthralgias	Clinical diagnosis; no antibiotics indicated

 

Standard two-tier testing (an ELISA with reflex to Western blot, or a modified two-tier approach using two sequential EIAs) is designed to be used in early disseminated or late disease — not early localized disease, where sensitivity is genuinely poor.

Stage	Sensitivity	Specificity
Early localized	14–17%	>99%
Early disseminated	89.7%	>99%
Late disseminated	99.4%	>99%

 

CLINICAL BOTTOM LINE — LYME In early localized disease (classic erythema migrans, 7–28 days post-bite), diagnose clinically — serology sensitivity is only 14–17% at this stage and a negative result should not delay treatment. Reserve two-tier serologic testing for early disseminated or late disease, where sensitivity exceeds 89%. Don't use antibody testing as a “test of cure” — many patients remain seropositive long after successful treatment, and diagnosing reinfection serologically can be genuinely difficult.

Hepatitis B: The Triple Screen, Explained

CASE FROM PRACTICE A 37-year-old woman with no past medical history, born in Ho Chi Minh City and living in the US since 2007, presents for a routine visit. Should she be screened for hepatitis B? Yes — and per current CDC guidance, so should essentially every adult.

CDC now recommends universal hepatitis B screening: every adult aged 18 and older should be screened at least once in their lifetime, regardless of disclosed risk factors. Pregnant patients should be screened for HBsAg during every pregnancy, regardless of vaccination history or prior testing. Periodic risk-based testing should additionally cover incarcerated individuals, people with a history of STIs or multiple partners, people with hepatitis C, and anyone who simply requests testing.

The “triple screen” — HBsAg, HBsAb, and HBcAb — accomplishes three distinct goals at once, and understanding what each component tells you is the key to interpreting the panel correctly.

Goal	Test	Action if Positive/Result
Identify chronic HBV	HBsAg	Monitoring and/or antiviral treatment
Identify susceptibility	HBsAb (anti-HBs)	If negative — vaccinate
Identify reactivation risk	HBcAb (anti-HBc)	If positive and patient becomes immunosuppressed — monitor or give prophylaxis

 

The reactivation risk identified by an isolated positive HBcAb is not theoretical. HBV flares can occur even in patients who appear to have fully resolved infection, are often preceded by a rise in viral DNA, and classically occur at the start or withdrawal of immunosuppressive therapy. The 2025 AGA Clinical Practice Guidelines stratify management by reactivation risk category:

•     High risk: antiviral prophylaxis is recommended over monitoring alone (strong recommendation, moderate-certainty evidence).

•     Moderate risk: antiviral prophylaxis is suggested over monitoring alone (conditional recommendation, moderate-certainty evidence).

•     Low risk: monitoring alone is suggested over antiviral prophylaxis (conditional recommendation, moderate-certainty evidence).

CASE FROM PRACTICE A 42-year-old woman with newly diagnosed multiple sclerosis is about to start ocrelizumab, an anti-CD20 agent. Her hepatitis B panel: HBsAg negative, HBsAb negative, HBcAb positive. Interpretation: this is an isolated core antibody pattern — no current active infection, no protective surface antibody, but evidence of past exposure with a real risk of reactivation on B-cell-depleting therapy. Recommended action: preventive antiviral therapy for roughly one month before starting ocrelizumab, then continuing through the full treatment course.

Hepatitis C: One Antibody Test, Different Meanings Over Time

Hepatitis C follows a different logic than hepatitis B, and it trips people up for a specific reason: the antibody result doesn't change even after the virus is long gone.

•     HCV antibody remains positive for life once a person has been infected — whether they spontaneously cleared the virus, were successfully treated, or have ongoing chronic infection.

•     A positive HCV antibody does not confer immunity to reinfection. Patients with ongoing risk factors need periodic screening for reinfection using an HCV viral load, not repeat antibody testing.

•     If HCV antibody is positive, the next step is an HCV viral load (RNA). A negative viral load in an antibody-positive patient indicates either spontaneous clearance or prior successful treatment — not an active infection needing treatment now, but a patient who should be counseled on reinfection risk and re-screened as needed.

•     A positive viral load confirms current infection requiring further workup and treatment consideration.

Left untreated, chronic HCV follows a long natural history: roughly 20–25 years from infection to cirrhosis in a subset of patients, and 25–30 years to hepatocellular carcinoma, end-stage liver disease, or death in those who progress — underscoring why identifying chronic infection early, even in asymptomatic patients, changes the trajectory.

CLINICAL BOTTOM LINE — HEPATITIS B & C For hepatitis B, order the triple screen (HBsAg, HBsAb, HBcAb) to simultaneously assess for active infection, immunity, and reactivation risk — an isolated positive HBcAb before immunosuppressive therapy is a common, clinically important finding that changes management. For hepatitis C, remember the antibody is lifelong and does not indicate current infection or immunity; use HCV viral load to determine current infection status and to screen for reinfection in patients with ongoing risk factors.

Latent TB: TST vs. IGRA, and Why Pre-Test Probability Matters

TB has not disappeared from US practice — cases in foreign-born individuals have exceeded those in US-born individuals every year since 2001, and globally TB remains a major cause of morbidity and mortality. Age at immigration matters because it affects the likelihood of prior BCG vaccination and the duration and context of potential TB exposure, both of which shape how test results should be interpreted.

Tuberculin Skin Test (TST)

The TST involves an intradermal injection of purified protein derivative (PPD), read at 48–72 hours and measured in millimeters of induration — never simply recorded as positive or negative. The cutoff for a positive result depends on the patient's individual risk profile:

Induration Cutoff	Applies To
≥5 mm	HIV or other immunosuppression, close contacts of active TB cases, fibrotic changes on chest x-ray
≥10 mm	Other high-risk groups (e.g., recent immigrants from high-burden countries, congregate settings, certain comorbidities)
≥15 mm	Everyone else (no known risk factors)

 

TST has real limitations in both directions. False positives can result from non-TB mycobacteria exposure or prior BCG vaccination (more likely to cause persistent false positives with older age at vaccination) or simple misinterpretation. False negatives can occur with poor technique, the two-visit requirement (loss to follow-up), very recent infection, active TB disease itself, immunosuppression or anergy, very young age (under 6 months), live virus vaccination, or recent viral infection — measles being the classically described culprit.

Interferon-Gamma Release Assays (IGRAs)

IGRAs (QuantiFERON-TB Gold and T-SPOT.TB are the two commercially available options) measure interferon-gamma production after incubating whole blood with M. tuberculosis-specific antigens. Advantages over TST include requiring only one visit, more objective interpretation, and no confusion from prior BCG vaccination. Downsides include higher cost, the need for whole blood processing, variable availability, and cross-reactivity with M. marinum and M. kansasii.

Test	Sensitivity	Specificity	Negative Predictive Value
TST	90–100%	29–39%	99–100%
IGRA	80–90%	56–83%	99–100%

 

Note the specificity gap: TST has meaningfully lower specificity than IGRA, largely driven by BCG cross-reactivity, which is precisely why IGRA is often preferred in BCG-vaccinated populations. TST and IGRA can be discordant in either direction, and when they disagree, incorporating pre-test probability — not just picking whichever result you trust more — is the correct approach. The Online TST/IGRA Interpreter (tstin3d.com, or search “Online IGRA Interpreter”) is a free calculator designed for exactly this scenario, incorporating risk factors like HIV status, immunosuppression, chest x-ray findings, and age at TB exposure to estimate active TB risk from a discordant or borderline result.

Why Biologics Change the Calculus

TNF-alpha is critical to both in vitro and in vivo control of TB, which is why anti-TNF biologics carry a well-documented TB reactivation risk. Compiled data cited in the lecture found active TB rates of roughly 10.9 per 100,000 in the general population versus 1,503 per 100,000 in patients on biologics during the pre-screening era — a more than 100-fold difference. Among patients on TNF inhibitors who develop active TB, median time to onset is 3–6 months (closer to 12 months for etanercept specifically), disseminated disease occurs in roughly a third of cases (versus ~6% in the general population), and fatality is 12–18% (versus under 5% in patients not on biologics).

CASE FROM PRACTICE A patient with a positive TST, a borderline IGRA, and a history of BCG vaccination is being considered for etanercept. Using the online TST/IGRA interpreter with the patient's specific risk profile (including planned TNF-alpha inhibitor use) to estimate active TB risk, the recommended answer was: give preventive (latent TB) therapy for approximately one month before starting etanercept, then continue the full course of treatment concurrently. This reflects the standard approach of treating LTBI before or concurrent with initiating anti-TNF therapy rather than withholding the biologic indefinitely.

CLINICAL BOTTOM LINE — LATENT TB TST and IGRA measure different things and can legitimately disagree — TST's main weakness is lower specificity (BCG cross-reactivity), while IGRA trades some sensitivity for improved specificity and single-visit convenience. Interpret either test using the patient's pre-test probability, not in isolation. Before starting any anti-TNF biologic, screen for LTBI and treat it — reactivation risk on these agents is dramatically elevated and carries higher rates of disseminated disease and fatality than TB in the general population.

Putting It All Together

The thread connecting all four serologies is the same: a single test result rarely stands on its own. It has to be read against the pre-test probability the clinical picture creates — prevalence and exposure history for HIV, time since tick bite for Lyme, immunosuppression status for hepatitis B, and TB exposure risk for TST/IGRA interpretation. Ordering the right test, at the right time, for the right stage of disease is most of the battle; the rest is resisting the urge to treat a lab value as a verdict rather than one more piece of the clinical picture.

 

Reference

Solomon, D.A. (2026). Making sense of serologies: Ordering and interpreting HIV, hepatitis, Lyme, and TB tests in primary care. Pri-Med Institute CE activity.