Management of Resistant Herpetic Whitlow: A Case of Recurrent Herpetic Whitlow Resistant to Standard Therapy

Abstract

Introduction

Herpetic whitlow, due to herpes simplex virus (HSV) type 1 or 2, typically presents with vesicles that may coalesce into bullae. Herpetic whitlow often resolves without intervention but can be treated with antiviral medications.

Case Presentation

Herein is a report of a 68-year-old female patient with a history of well-controlled human immunodeficiency virus (HIV) infection and a 4-year history of recurrent HSV-2 herpes genitalis who failed multiple trials of standard antiviral therapy clinically confirming a case of resistant HSV-2 infection, with recurrent tender lesions on her digits. Physical examination showed bullae involving the nail folds of her right thumb and left index finger. Initial PCR was negative for HSV-1 and HSV-2, but repeat PCR was positive for HSV-2. Treatment with foscarnet resulted in clinical improvement of both herpetic whitlow and herpes genitalis.

Conclusion

Though herpetic whitlow typically resolves without intervention, a case is described of recurrent lesions in an HIV-positive patient unresponsive to multiple first-line antiviral treatment regimens and an interdisciplinary approach to treatment in a challenging case.

Introduction

Herpetic whitlow is an infection of the distal fingertip, first described in 1959 as a hospital cross-infection in a case series of healthcare workers [1–3]. Herpetic whitlow is uncommon, with estimated prevalence of 2.4–5.0 per 100,000 individuals [4]. It is caused by inoculation with herpes simplex virus (HSV) type 1, which causes gingivostomatitis, or HSV-2, which causes herpes genitalis [5]. HSV is spread by direct contact with broken epidermis or mucous membranes [2]. Herpetic whitlow may develop exogenously through contact with another HSV-shedding person or autogenously through contact with another affected skin area [1].

Herpetic whitlow often presents after a 3–4-day prodromal period of burning, with paronychial inflammation and tenderness. Development of vesicles on an erythematous base, which often coalesce into bullae, is typical. Vesicular liquid may be clear, purulent, or hemorrhagic. If vesicles develop within the nail bed, painful onycholysis may ensue. Herpetic whitlow is often mistaken for bacterial felon or paronychia. Diagnosis is rendered based on clinical examination, with PCR, viral culture, serological tests, or Tzank smear used for confirmation [1, 2].

Most cases of herpetic whitlow resolve within a few weeks without intervention. Therapeutic options include antiviral medications starting with oral acyclovir (400 mg 3×/day for 10 days), valacyclovir (1,000 mg 2×/day for 10 days), or famciclovir (250 mg 3×/day for 10 days) [1, 6]. HSV strains are typically highly susceptible to these first-line antiviral medications, but resistant strains have been identified, requiring alternative forms of therapy [7]. In this report, there is a description of a patient with well controlled human immunodeficiency virus (HIV) and persistent herpes genitalis unresponsive to multiple first-line antiviral treatment regimens, who developed recurrent herpetic whitlow. This case demonstrates treatment challenges, including recurrence and drug resistance, and highlights the importance of multidisciplinary approach to therapy in atypical presentations of herpetic whitlow.

Case Report

A 68-year-old female patient with a history of HIV infection (most recent HIV viral load of <30 copies/mL and CD4+ count of 283/12%), autoimmune hemolytic anemia, and herpes genitalis presented to our practice with recurrent tender lesions on her digits despite standard oral and intravenous (IV) antiviral therapies. Physical examination was significant for bullae involving the nail folds of the left index finger and right thumb (Figs. 1a, b, 2a, 2b). Initial bacterial cultures, viral cultures, and HSV PCR of the left 2nd digit were negative for HSV-1, HSV-2, and varicella zoster virus DNA. X-ray of the left 2nd digit was negative for osteomyelitis. Six weeks later, she had recurrence of the digital bullae and repeat PCR was positive for HSV-2. The patient concurrently saw her infectious disease (ID) doctor, who started foscarnet infusions. Three weeks later, the patient reported significant improvement on a follow-up visit (Fig. 3).

Fig. 1.

a Herpetic whitlow involving the proximal and lateral nail folds of the left 2nd digit on initial presentation. b Herpetic whitlow involving the proximal and lateral nail folds of the left 2nd digit on initial presentation.

Fig. 2.

a Herpetic whitlow involving the distal fingertip and hyponychium of the right first digit on initial presentation. b Herpetic whitlow involving the distal fingertip and hyponychium of the right first digit on initial presentation.

Fig. 3.

Bulla involving the right first digit 6 weeks after initial presentation.

Four years prior, the patient presented to ID clinic with extensive anogenital lesions and was diagnosed with HSV-2 herpes genitalis. She was initially treated with oral valacyclovir at 1,000 mg twice daily, but lesions persisted. HSV resistance was suspected, and patient was placed on famciclovir 500 mg twice daily with resolution of her lesions. One year later, the patient was diagnosed with recurrent autoimmune hemolytic anemia and immune thrombocytopenic purpura and was treated with a course of prednisone and rituximab. Since starting rituximab, the patient had recurrence of anogenital herpetic lesions despite compliance with famiciclovir suppression therapy. Thus, famciclovir dose was increased to 500 mg three times daily with improvement.

Six months later, the patient developed a left index finger abscess, which was initially suspected to be bacterial. The patient underwent incision and drainage and was given several courses of oral antibiotics (1 week of oral doxycycline, 1 week of oral cephalexin, 1 month of amoxicillin and ciprofloxacin), as well as debridement were attempted without improvement. She was then admitted to the hospital for management with IV antibiotics. During hospitalization, HSV cultures of the left index finger were positive, and she received IV foscarnet therapy as twice-daily infusion with clinical improvement. The patient was then discharged on IV cidofovir 345 mg in 100 mL sodium chloride 0.9% once weekly at an infusion clinic for HSV suppression due to recurrent HSV infection. However, cidofovir therapy was discontinued about a month later due to reactive transaminitis, nausea, hypertension, and tachycardia. After cidofovir discontinuation, the patient presented with recurrence of anogenital lesions and a new right index finger ulceration and was sent to the emergency department for evaluation of severe cutaneous HSV infections. During hospitalization, she received IV foscarnet 2,400 mg in 5% at 200 mL/h twice daily for 5 weeks with significant improvement and clearance of almost 99% of lesions. Foscarnet therapy was discontinued prior to discharge and the patient was started on oral valaciclovir 1 g twice daily with overall improvement but persistence of cutaneous HSV lesions.

Her HIV infection remained well controlled with an undetectable viral load, and in an effort to avoid recurrent hospital admissions, she was initiated on IV foscarnet 2,400 mg in 5% dextrose IV at 200 mL/h daily at an infusion clinic for HSV suppression. However, a month into the new regimen, the patient developed neutropenia requiring discontinuation of therapy. Two weeks after treatment discontinuation, absolute neutrophil count recovered, but the patient developed new right index finger bulla with purulent drainage. The patient was restarted on foscarnet at the same dose, once daily for 5 days, then transitioned to once weekly with excellent response (Fig. 4). Of note, HSV culture was performed three times, with lack of growth on culture and thus inability to assess drug sensitivities or perform genetic analysis of the HSV strain. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546664).

Fig. 4.

Clinical course.

Discussion

A case of recurrent herpetic whitlow infection is described in a patient with a known diagnosis of well-controlled HIV, history of recurrent herpes genitalis, recurrent autoimmune hemolytic anemia, and immune thrombocytopenic purpura, who was unresponsive to several first-line HSV therapies, suggesting a resistant strain of HSV-2. The herpetic whitlow and herpes genitalis infections resolved following treatment and suppression with foscarnet.

Diagnosis of herpetic whitlow can be challenging in immunosuppressed and HIV patients, who may present atypically with severe ulcerations, bacterial or fungal superinfection, or recurrent infections [8–11]. For example, in an observational study of 3,900 isolated HSV-1 and HSV-2 strains from 3,357 hospitalized patients (45% immunocompromised), isolates from immunocompromised versus immunocompetent patients were more often acyclovir resistant (3.5% vs. 0.32%, p < 0.001) using genotypic assays for identification of antiviral resistance mutations. Among HIV patients, 4.2% of isolates demonstrated acyclovir resistance, suggesting that immunocompromised and HIV patients may be more likely to be infected with resistant HSV strains [12]. An open-label drug trial in 4 patients with acquired immunodeficiency syndrome and acyclovir-resistant strains of HSV-2, treatment with 60 mg/kg of IV foscarnet every 8 h for 12–50 days, resulted in eradication of HSV from mucosal surfaces and dramatic improvement of clinical findings in all patients [7]. Of note, our patient developed autoimmune hemolytic anemia. This, in combination with her positive HIV status, may have contributed to ineffective immune response and possibly resulted in selection of resistant HSV strains [13]. Taken together, these studies and our case report suggest that immunocompromised and HIV patients with herpetic whitlow may be more susceptible to drug resistance and that foscarnet treatment may be a viable therapeutic option in these cases.

In conclusion, the present case highlights the challenges in diagnosis and treatment of herpetic whitlow in HIV-positive patients unresponsive to first-line HSV treatment options. For these patients, ID consultation should be considered, with shared decision-making regarding the use of foscarnet. Our case highlights the importance of confirmatory testing, including culture and PCR, and an interdisciplinary approach to treatment of atypical or challenging presentations of herpetic whitlow.

Statement of Ethics

Ethics approval was not required in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflict of Interest Statement

Dr. Lipner has received research funding from BelleTorus Corporation and Moberg Pharmaceuticals. Other authors have no conflicts of interest to declare.

Funding Sources

This article was not supported by any sponsor or funder.

Author Contributions

S.R.L. conceived the presented idea. A.S., T.T.W., and S.R.L. contributed to the conception, plan, and design of this project. A.S. wrote the initial first draft of the manuscript. T.T.W. and S.R.L. contributed to critical feedback editing of the manuscript. T.T.W. acquired patient consent.

Funding Statement

This article was not supported by any sponsor or funder.

Data Availability Statement

All data discussed in this case are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.