In a 47‑year‑old woman with systemic lupus erythematosus, past infectious mononucleosis, and ADHD who has persistent intra‑labial lesions despite valacyclovir and a newly enlarged cervical lymph node, what is the most likely diagnosis and recommended management?

Persistent Intra-Labial Lesions with Cervical Lymphadenopathy in a Lupus Patient

This patient most likely has either acyclovir-resistant HSV-1 or a lupus-related mucocutaneous flare, and you should immediately obtain viral culture with susceptibility testing from the lesions while simultaneously checking lupus serologies (anti-dsDNA, complement levels) to distinguish between these two diagnoses. 1, 2

Diagnostic Algorithm

Step 1: Recognize Treatment Failure

• Persistent or progressive HSV lesions that have not begun to resolve after 7–10 days of appropriate valacyclovir therapy are the primary sign of antiviral resistance, especially in immunocompromised hosts like lupus patients 2
• Your patient has received valacyclovir with only partial improvement ("lips are improving but has not resolved"), suggesting either inadequate treatment duration, resistant virus, or an alternative diagnosis 2
• The newly swollen cervical lymph node is a red flag—this could represent either persistent viral replication, secondary bacterial infection, or lupus lymphadenopathy 3, 4

Step 2: Assess Immunocompromised Status

• SLE patients are functionally immunocompromised due to both the disease itself and typical immunosuppressive therapy (hydroxychloroquine is standard, often with additional agents like azathioprine or mycophenolate) 3, 4
• Immunocompromised patients experience substantially higher rates of acyclovir-resistant HSV (approximately 7%) compared with immunocompetent hosts (≤0.5%) 5
• In immunocompromised individuals, HSV lesions are typically more severe, painful, atypical, and prolonged, potentially involving extensive oral cavity or facial spread 5

Step 3: Obtain Definitive Diagnosis

• When resistance is suspected, obtain a viral culture from the lesion with susceptibility testing before changing therapy—this step directs appropriate alternative treatment 2
• Simultaneously check lupus activity markers: anti-dsDNA antibodies, complement levels (C3, C4), complete blood count, and urinalysis to assess for lupus flare 3, 4
• It can be notoriously difficult to differentiate between infection and lupus flare, and they may co-exist 6

Management Based on Diagnosis

If Acyclovir-Resistant HSV is Confirmed:

• Intravenous foscarnet 40 mg/kg every 8 hours until clinical resolution is the treatment of choice for confirmed resistance 2
• All acyclovir-resistant HSV strains are also resistant to valacyclovir (valacyclovir is a pro-drug of acyclovir), and most are cross-resistant to famciclovir—do not switch to these agents 2
• For external mucocutaneous disease, topical cidofovir 1% gel applied daily for 5 days may be used as adjunctive therapy 2
• Consult an infectious disease specialist when managing confirmed valacyclovir-resistant HSV 2

If Lupus Flare is Confirmed:

• Mucocutaneous manifestations are common in SLE and can present as oral ulcers or cheilitis 3, 4
• Lymphadenopathy occurs frequently during lupus flares 3, 4
• Treatment would involve optimizing immunosuppression (hydroxychloroquine dose verification, possible addition of low-dose glucocorticoids or other immunosuppressants) in coordination with rheumatology 3, 4

If Both Conditions Co-Exist:

• Treat the resistant HSV with foscarnet while coordinating with rheumatology regarding immunosuppression adjustment 2, 3
• In patients with disseminated or invasive herpes infections, consider temporary reduction or discontinuation of immunosuppressive medications if clinically feasible 1

Critical Monitoring During Treatment

For Foscarnet Therapy:

• Monitor renal function closely—foscarnet is nephrotoxic 2
• Ensure adequate hydration to minimize nephrotoxicity 1
• Watch for electrolyte disturbances (hypocalcemia, hypomagnesemia, hypokalemia) 2

For Lupus Management:

• Regular platelet count measurement should be considered in SLE patients on antiviral agents—acyclovir-induced thrombocytopenia has been reported in lupus patients 7
• Monitor for signs of lupus nephritis (proteinuria, hematuria, rising creatinine) 3, 4

Common Pitfalls to Avoid

• Do not switch to famciclovir for suspected acyclovir/valacyclovir resistance because of common cross-resistance 2
• Do not delay viral culture with susceptibility testing once resistance is suspected—timely testing guides definitive therapy 2
• Do not assume this is purely a lupus flare without ruling out resistant HSV—the history of recent valacyclovir treatment makes resistant virus a strong possibility 2, 6
• Do not continue valacyclovir indefinitely without reassessment—lesions that persist beyond 7–10 days despite appropriate therapy demand investigation 1, 2

Additional Considerations

• Once the acute infection resolves, the recombinant zoster vaccine (Shingrix) should be considered for all adults ≥50 years with SLE to prevent future VZV reactivation, though this patient's current presentation is more consistent with HSV than VZV 1
• Hydroxychloroquine is the cornerstone of SLE treatment and reduces disease flares—verify the patient is taking this medication as prescribed 3, 4
• The patient's history of infectious mononucleosis at age 16 is notable, as EBV has been proposed as a trigger for new-onset SLE, though this is not directly relevant to the current acute presentation 8