Herpes simplex virus 2-associated symmetrical peripheral gangrene in an immunocompetent fourteen-year-old girl: a case report

Introduction

Symmetrical peripheral gangrene (SPG) is a rare but life-threatening condition with mortality rates of as high as 35% (1). This syndrome is characterized by symmetrical distal ischemic necrosis affecting two or more sites, without large vessel obstruction or vasculitis (2). Among survivors, more than 70% require amputations, often of multiple limbs, markedly affecting their quality of life (1,3). The causes of SPG remain incompletely understood but are broadly categorized into infectious and noninfectious causes (4). Noninfectious factors include cardiovascular diseases, medications, malignancies, connective tissue disorders, and miscellaneous factors. Infectious etiologies predominantly involve bacterial, parasitic, and viral pathogens (2,5). Notably, sepsis secondary to infection represents the most significant pathogenic mechanism in SPG development (1,3,6).

Although no standardized treatment guidelines exist for SPG, management generally focuses on halting progression, treating the underlying cause, stabilizing hemodynamics, preventing secondary infection, and removing necrotic tissue (2). Current practice relies on a multimodal approach, including etiological treatment, correction of disseminated intravascular coagulation (DIC), wound care, skin grafting and surgical intervention, etc. (4). Despite these strategies, SPG remains challenging, with rapid deterioration and high risks of disability or death. This report presents a rare case of SPG in a young female patient following herpes simplex virus 2 (HSV-2) infection complicated by sepsis, shock, DIC, and hemophagocytic lymphohistiocytosis (HLH). Fortunately, through early recognition, aggressive resuscitation, and targeted therapy, the patient achieved a remarkable recovery, with only minor residual cutaneous pigmentation on her extremities. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-638/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s legal guardians for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Initial presentation

A 14-year-old girl was admitted to Tongji Hospital of Huazhong University of Science and Technology with a 5-day history of persistent fever and black discoloration of the distal extremities that appeared one day before admission. The illness initially presented with high fever, peaking at 39.8 ℃. On the second day, she developed herpes lesions on the right lip, followed by widespread erythematous rash with small blisters on the trunk and extremities, accompanied by noticeable limb edema (Figure 1). Then she visited a local hospital, where tests revealed thrombocytopenia (86×10⁹/L) and elevated inflammatory markers, including C-reactive protein (CRP, 43.83 mg/L) and procalcitonin (0.59 ng/mL). Despite receiving antibiotic and supportive treatment, her condition failed to improve. By the fourth day, she developed concerning black discoloration of fingers and toes (Figure 1), prompting urgent referral to the hospital where authors are based for further treatment.

Figure 1 Clinical presentation of bilateral hand and foot lesions in the patient. (A) The left hand showed edematous fingers with widely distributed dusky macules, gangrene, and blisters. (B) Several ruptures were observed after blister rupture, and the gangrene extended to the back of the left hand. (C,D) Similar findings were observed symmetrically on the right hand. (E,F) The toes showed blisters and gangrene, accompanied by patches of erythema on the dorsum of the feet. (G,H) Erythema and gangrene were widely distributed on the soles. And ruptures were observed after blister rupture. (I) The same symptoms extended to the lower leg.

Physical examination and initial management

The initial physical examination revealed high fever (39.0 ℃) and widespread skin lesions including erythema, papules, maculopapular rash, and herpetic eruptions. Multiple blisters of varying sizes on erythematous bases were observed on the extremities, with developing blackening and necrosis at the fingertips and toes. Vital signs showed blood pressure 95/55 mmHg and respiratory rate 20 breaths/min. Electrocardiogram demonstrated sinus tachycardia (128 beats/min). Antibiotic therapy with teicoplanin (400 mg/day) was promptly initiated. On the following day, the patient developed progressive dyspnea despite nasal oxygen supplementation, with evident suprasternal, supraclavicular, and intercostal retractions. Physical examination revealed tachycardia (168 beats/min) and tachypnea (46 breaths/min), with bilateral pulmonary rales. The patient subsequently lost consciousness and developed cold extremities with prolonged capillary refill time (>3 s). These findings indicated a critical condition with severe respiratory distress and impending shock. Consequently, the patient was urgently transferred to the pediatric intensive care unit (PICU), where immediate endotracheal intubation and mechanical ventilation were performed. Antibiotic therapy was intensified with ceftriaxone and tazobactam (50 mg/kg/day), accompanied by aggressive fluid resuscitation and vasopressor support (dopamine and norepinephrine).

Laboratory findings, diagnoses and systemic treatment

Initial laboratory (Table 1) and imaging investigations revealed significant abnormalities. Systemic inflammation was evident, with elevated CRP (75.4 mg/L), procalcitonin (0.92 ng/mL), and ferritin (4,988 µg/L). These inflammatory markers showed a progressive upward trend, strongly suggesting severe sepsis. Hematological evaluation demonstrated neutropenia (neutrophil 1.57×10⁹/L), anemia (hemoglobin 10.3 g/dL), and profound thrombocytopenia (platelet 41×10⁹/L). Coagulation studies showed prolonged activated partial thromboplastin time (51.8 s) and prothrombin time (17.3 s), markedly elevated D-dimer (11.48 µg/mL), and increased fibrinogen degradation products (93.8 µg/mL), consistent with DIC. Fibrinogen level was at the lower limit of normal (2.00 g/L). Hepatic function tests indicated mild liver injury with elevated transaminases. Notably, cardiac biomarkers (high-sensitivity troponin I and N-terminal pro B-type natriuretic peptide) remained normal, excluding myocardial injury. Hypoalbuminemia (26.9 g/L) and significant lactic acidosis (4.0 mmol/L) were observed. Imaging studies demonstrated splenomegaly (splenic thickness 4.1 cm) on ultrasound, bilateral peribronchial infiltrates on chest radiography, and no large vessel occlusion in the major arteries of the upper and lower limbs on Doppler ultrasound. The constellation of clinical findings (bilateral acral gangrene and septic shock), laboratory evidence of coagulopathy and lactic acidosis, and Doppler findings strongly supported the preliminary diagnosis of SPG (4), after considering and excluding other gangrenous conditions such as Fournier’s gangrene (7) and purpura fulminans based on lesion location and clinical features.

Following the initial diagnosis and laboratory findings, additional investigations were conducted (Table 1). All key inflammatory cytokines involved in sepsis and SPG were markedly elevated, with interleukin 2 receptor exceeding the detection limit. Along with hyperferritinemia (peaking at 11,237 µg/L) and hypofibrinogenemia (nadir 1.34 g/L), these findings raised suspicion of HLH and supported the diagnosis (8), prompting bone marrow aspiration, which showed granulocytic hyperplasia, diminished erythropoiesis, lymphopenia, reduced platelet distribution, and dysplastic megakaryocyte maturation without evidence of hemophagocytosis. Given the association between SPG and DIC, coagulation profiling was performed, revealing depletion of the natural anticoagulants: antithrombin activity was reduced to 78%, protein C levels remained normal, and protein S activity was markedly decreased to 28%. Thromboelastography revealed markedly prolonged reaction time and reduced maximum amplitude, indicative of impaired coagulation factor activity and platelet dysfunction. As a factor associated with intravascular microthrombosis, the activity of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) was decreased to 51%. Subsequently, anti-DIC therapies were administered, including replacement of coagulation factors (platelets, plasma, fibrinogen), anticoagulation with heparin, and thrombolysis with urokinase. Thereafter, she received high-dose methylprednisolone (20 mg/kg/d) for 3 days and then routine doses (40 mg/d) were administered for 7 days of maintenance. Oral cyclosporine (6 mg/kg/d for 10 days) was also added to inhibit the excessive inflammatory response. In addition, intravenous immunoglobulin was given for 3 days (25 g/day), and 2 sessions of plasma exchange (1.6 L/1.45 L plasma was replaced by 1 L/1.25 L fresh plasma, 0.15 L/0.05 L albumin and 0.45 L/0.15 L normal saline, respectively) were performed to facilitate clearance of inflammatory mediators.

To identify the underlying cause, further laboratory (Table 1) and imaging investigations were conducted. The patient’s erythrocyte sedimentation rate was normal, and autoimmune tests, including anti-neutrophil cytoplasmic antibody (ANCA), rheumatoid factor, and cardiolipin antibodies, were all negative. Physical examination revealed normal peripheral pulses, and Doppler ultrasonography of the extremities demonstrated no thrombosis, thus effectively ruling out vasculitis, connective tissue disorders, and thromboangiitis obliterans. A thorough medication review excluded pharmaceutical causes, as no potentially causative agents were administered before SPG onset. Microbiological investigations, including bacterial cultures of blood, sputum, and vesicular fluid, showed no growth. The key diagnostic finding emerged from metagenomic next-generation sequencing (mNGS) of vesicular fluid, which identified HSV-2 as the sole pathogen. This was subsequently confirmed by positive HSV-2 immunoglobulin M (IgM) serology. Consequently, HSV-2 was established as the probable etiology, prompting initiation of acyclovir therapy (10 mg/kg every 8 hours for 7 days). Regrettably, HSV-2 nucleic acid testing was not available in the hospital at that time. Given that HSV-2 is primarily sexually transmitted, a detailed social history was obtained, which revealed no history of sexual activity or abuse. The precise source of HSV-2 infection in this patient remains undetermined.

Topical therapy and wound management

To facilitate rapid recovery of the affected limbs, meticulous wound care was performed, including daily warm (≤38 ℃) compound potassium permanganate (PP) solution soaks, followed by gentle wrapping with sterile towels and covering with clean protective pads. A properly adjusted limb thermal insulation device was then secured over these pads to maintain distal extremity warmth. This thermal therapy, administered three times daily for 30 minutes, likely contributed significantly to microcirculatory improvement. The wound care protocol was tailored to lesion characteristics: open lesions were treated sequentially with mupirocin ointment and acyclovir cream followed by petrolatum-impregnated gauze, intact skin with moist exposed burn ointment (MEBO), and re-epithelialized areas with epidermal growth factor gel to promote epidermal regeneration. Interdigital separation was maintained using sterile cotton spacers to prevent syndactyly (Figure 2A-2F).

Figure 2 Treatment procedures and subsequent improvement of the lesions. (A) The right hand was bathed in compound PP solution. (B,C) Sterile cotton balls were placed between the limbs to prevent adhesion. (D) Sterile towels soaked in PP solution were applied to the lesions. (E) Clean protective pads were wrapped around the towels. (F) A thermal apparatus was fixed outside to warm lower limbs with the aim of improving microcirculation. (G-I) The blackened hands and toes returned to normal, leaving only mild pigmentation. PP, potassium permanganate.

Outcome and follow-up

Following treatment, the patient demonstrated significant clinical improvement. Her body temperature normalized by the eighth hospital day, allowing for successful ventilator weaning on day nine as vital signs stabilized. Serial laboratory monitoring revealed complete normalization of previously deranged parameters by day 29, including transaminases, inflammatory markers, hematologic indices, coagulation profiles, natural anticoagulants, and ferritin level (detailed data not shown). The distal gangrenous changes resolved remarkably, leaving only minimal residual pigmentation (Figure 2G-2I). Three-month follow-up documented complete nail regeneration following the physiologic shedding of affected nails. The clinical course is summarized in the treatment timeline (Figure 3).

Figure 3 Timeline of the patient from admission to follow-up. ADAMTS13, a disintegrin and metalloproteinase with thrombospondin motifs 13; APTT, activated partial thromboplastin time; CRP, C-reactive protein; DIC, disseminated intravascular coagulation; FDP, fibrinogen degradation products; HSV-2, herpes simplex virus 2; IgM, immunoglobulin M; IL-2R, interleukin 2 receptor; IVIG, intravenous immunoglobulins; mNGS, metagenomics next generation sequencing; PT, prothrombin time.

Discussion

Epidemiology

First described by Hutchinson in 1891 as symmetrical gangrene of the distal extremities (9), SPG remains a rare but life-threatening condition that has received insufficient clinical attention. The exact incidence of SPG is unknown; it affects both sexes at all ages, but pediatric cases are particularly rare, with fewer than 10 reported. The 14-year-old patient presented in this report represents the first pediatric case at this institution.

Etiology and pathogenesis

The etiology of SPG includes infectious and non-infectious causes (2,4). In the present case, before gangrene of the extremities, vasoactive drugs and heparin were not administered, and no cardiovascular disease was observed. Laboratory and imaging tests also ruled out malignancy and connective tissue disorders. Therefore, non-infectious causes were not considered. Among infectious causes, bacteria, viruses, and parasites have been reported. So far, viruses associated with SPG include viral gastroenteritis (10), rubeola, varicella zoster, human immunodeficiency virus (HIV) (4), coronavirus disease 2019 (COVID-19) (11,12), West Nile virus (13), dengue virus (14) and influenza (5). However, HSV-2 has not been reported. Here, excluding other possible pathogens, HSV-2 was confirmed by mNGS of herpes fluid and serology as the probable pathogen. This represents the first documented case of HSV-2-associated SPG to date.

The precise pathogenesis of SPG remains incompletely elucidated, but three hallmark features are consistently observed: shock, DIC, and natural anticoagulant depletion (15). In this case, the patient developed severe sepsis with impending shock shortly after admission, accompanied by concurrent DIC. This coagulation disorder results in systemic fibrin formation and deposition, leading to widespread microvascular thrombosis. Furthermore, the patient showed a marked inflammatory response with elevated interleukin 6 and tumor necrosis factor-α, which may upregulate plasminogen activator inhibitor-1 in endothelial cells and impair fibrinolysis (2,16). These mechanisms collectively promote persistent thrombus formation in small to medium-sized vessels, consistent with current SPG pathogenesis theories. Natural anticoagulant depletion typically manifests as severe reductions in protein C and antithrombin activity, driving uncontrolled thrombin generation—a phenomenon well-documented in meningococcal sepsis-induced Shwartzman reactions (15). This case exhibited an atypical profile: protein C activity was normal, antithrombin mildly decreased, and protein S markedly reduced (28%). This deficiency, likely secondary to sepsis-induced consumption, may have contributed to the prothrombotic state and microvascular occlusion.

Treatment

Currently, no standardized treatment guidelines exist for SPG. Given the critical condition and poor prognosis, the patient was immediately admitted to the PICU. Upon confirmation of HSV-2, immediate targeted antiviral therapy with acyclovir was initiated alongside empirical broad-spectrum antibiotics to prevent secondary bacterial infections. Comprehensive hemodynamic support was provided for the evolving septic shock. As a common complication of SPG (15), DIC was managed with coagulation factor supplementation, anticoagulation to prevent thrombosis, and judicious thrombolysis of microvascular occlusions, all aimed at restoring coagulation homeostasis. Furthermore, laboratory tests demonstrated persistently elevated CRP, cytokines, and ferritin, indicating a systemic hyperinflammatory response consistent with sepsis. Cyclosporine was therefore added to suppress cytokine transcription and plasma exchange was performed to remove pro-inflammatory cytokines and replenish coagulation factors.

Therapeutic plasma exchange, reported to rapidly improve hemodynamics and modulate cytokines (17,18), is a potential adjunct in septic shock and has been considered in SPG (15), though its efficacy remains unreported due to the condition’s rarity. In this case, two sessions of plasma exchange significantly reduced inflammatory cytokines and improved coagulation. Hemoadsorption, an alternative extracorporeal cytokine removal method using specialized filters, also benefited a reported SPG case in a Hodgkin lymphoma patient following hematopoietic stem cell transplantation (19). Although their efficacy needs validation in controlled studies, plasma exchange and hemoadsorption showed benefit in these cases, achieving full tissue recovery without amputation. Additional cases and studies are needed to confirm their relevance.

Other therapeutic options such as hyperbaric oxygen (20) and sildenafil citrate (21) have also been reported to have some efficacy. In addition, wound care involving meticulous debridement, targeted antimicrobials, and staged skin grafting may significantly improve outcomes (2,6). The choice of solution for necrotic skin care is also important, with topical nitroglycerin reported to be effective (22). In this case, comprehensive nursing measures were implemented, including compound PP liquid for cleansing, topical acyclovir cream for antiviral therapy, mupirocin ointment for bacterial prophylaxis, and MEBO with epidermal growth factor gel to promote skin healing. The treatment and intensive care described above resulted in significant clinical improvement, with complete resolution of cutaneous lesions, saving the patient’s life and avoiding skin grafts or amputations.

Conclusions

Despite its rarity, SPG is a life-threatening condition with poor outcomes, necessitating a high index of clinical suspicion. While its pathogenesis is multifactorial, prompt identification of underlying causes is crucial for targeted therapy. Early diagnosis and aggressive treatment, including removing causative factors, preventing secondary infections, managing complications, and providing appropriate care, can improve prognosis and help avoid amputation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-638/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-638/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-638/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s legal guardians for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ghosh SK, Bandyopadhyay D, Ghosh A. Symmetrical peripheral gangrene: a prospective study of 14 consecutive cases in a tertiary-care hospital in eastern India. J Eur Acad Dermatol Venereol 2010;24:214-8. [Crossref] [PubMed]
2. Foead AI, Mathialagan A, Varadarajan R, et al. Management of Symmetrical Peripheral Gangrene. Indian J Crit Care Med 2018;22:870-4. [Crossref] [PubMed]
3. Davis MD, Dy KM, Nelson S. Presentation and outcome of purpura fulminans associated with peripheral gangrene in 12 patients at Mayo Clinic. J Am Acad Dermatol 2007;57:944-56. [Crossref] [PubMed]
4. Ghosh SK, Bandyopadhyay D. Symmetrical peripheral gangrene. Indian J Dermatol Venereol Leprol 2011;77:244-8. [Crossref] [PubMed]
5. Kaulgud RS, Kamath V, Patil V, et al. Symmetric Peripheral Gangrene Associated with H1N1 Infection. Int J Prev Med 2013;4:1206-9.
6. Macheka KT, Masamha T, Mungani H, et al. Symmetrical peripheral gangrene: A rare clinical entity. Clin Case Rep 2020;8:2914-7. [Crossref] [PubMed]
7. Susini P, Marcaccini G, Efica J, et al. Fournier's Gangrene Surgical Reconstruction: A Systematic Review. J Clin Med 2024;13:4085. [Crossref] [PubMed]
8. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. [Crossref] [PubMed]
9. Hutchinson J. Notes of Uncommon Cases. Br Med J 1891;2:8-9. [Crossref] [PubMed]
10. Kashyap R, Behl RK, Mahajan S, et al. Symmetrical peripheral gangrene due to viral gastroenteritis. J Assoc Physicians India 2004;52:500-1.
11. Sil A, Chakraborty U, Chandra A, et al. COVID-19 associated symmetrical peripheral gangrene: A case series. Diabetes Metab Syndr 2022;16:102356. [Crossref] [PubMed]
12. Wang M, Sun T, Dong L, et al. Symmetrical peripheral gangrene: potential mechanisms and therapeutic approaches in severe COVID-19. Front Cardiovasc Med 2023;10:1280625. [Crossref] [PubMed]
13. Shah S, Fite LP, Lane N, et al. Purpura fulminans associated with acute West Nile virus encephalitis. J Clin Virol 2016;75:1-4. [Crossref] [PubMed]
14. Patel ML, Sachan R, Verma A, et al. Symmetrical peripheral gangrene: Unusual complication of dengue fever. Adv Biomed Res 2016;5:154. [Crossref] [PubMed]
15. Warkentin TE, Ning S. Symmetrical peripheral gangrene in critical illness. Transfus Apher Sci 2021;60:103094. [Crossref] [PubMed]
16. Ikezoe T. Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation. J Intensive Care 2015;3:1. [Crossref] [PubMed]
17. Knaup H, Stahl K, Schmidt BMW, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care 2018;22:285. [Crossref] [PubMed]
18. David S, Bode C, Putensen C, et al. Adjuvant therapeutic plasma exchange in septic shock. Intensive Care Med 2021;47:352-4. [Crossref] [PubMed]
19. Uncu Ulu B, Yiğenoğlu TN, Hacıbekiroğlu T, et al. Recovery of Symmetrical Peripheral Gangrene of Limbs in a Patient After Performing Hemoadsorption in Septic Shock. J Clin Apher 2021;36:649-53. [Crossref] [PubMed]
20. Stewart S. Symmetrical peripheral gangrene and the use of systemic hyperbaric oxygen therapy. J Wound Care 2012;21:615-6, 618-9. [Crossref] [PubMed]
21. Gandhi V, Sharma R, Raizada A, et al. Peripheral symmetrical gangrene treated with sildenafil citrate. J Cutan Aesthet Surg 2012;5:57-8. [Crossref] [PubMed]
22. Alfraij A, Elseadawy M, Alghounaim M. The effect of topical nitroglycerin on symmetrical peripheral gangrene in a pediatric patient. Clin Case Rep 2021;9:e04213. [Crossref] [PubMed]