Purpura Fulminans Secondary to Varicella-Zoster Virus Infection

The condition now known as purpura fulminans was first described by Guelliot¹ in 1884, with the name coined by Henoch² in 1887. PF is a heterogeneous group of disorders characterized by consumptive coagulopathy and rapidly progressive intravascular thrombosis that causes purpura and necrosis in the skin and soft tissue. This rare, life-threatening condition leads to considerable suffering, including loss of extremities or areas of skin.^3,4 Various clinical conditions cause these clinical and histopathological features described by extensive purpura and dermal vascular thrombosis and hemorrhagic infarction of the surrounding tissues. PF is categorized based on its etiology and pathogenesis. These categories include acute infectious, postinfectious, congenital protein C or S deficiency, acquired protein C or S deficiency, antiphospholipid antibody syndrome, vasculitic disorders, platelet mediated, and toxins/poisons mediated.³ 

“Idiopathic or postinfectious PF” was first described by D’Angelo et al⁵ and Levin et al.⁶ The common presentation of idiopathic or postinfectious PF in young children generally occurs 1 to 3 weeks after an infectious process. Chickenpox and streptococcal infections are the most common causes, with various other childhood diseases rarely resulting in idiopathic or postinfectious PF. The disorder has a biphasic course. After a good recovery from an illness (ie, an uncomplicated childhood disease), affected patients suddenly develop purpura on mainly large anatomic areas, such as the hips and lower limbs. These patients are usually afebrile and hemodynamically stable. The second form of the disease may progress rapidly, causing skin necrosis in large areas and gangrene of the limbs or fingers. Thromboembolic complications may then develop in the internal organs; this is uncommon and may occur in the setting of inadequately treated disease. The fundamental laboratory results are associated with disseminated intravascular coagulation, extended prothrombin time, partial thromboplastin time and thrombin time, hypofibrinogenemia, and elevation of fibrin degradation products.^3,4,7 

Several theories on the etiology of PF have been reported. Nonetheless, there is compelling evidence that the disorder consistently involves an acquired deficiency of protein S caused by autoantibodies against protein S.^6,8-10 It is crucial to identify the special etiology of the problem on a case-by-case basis because treatment options depend on the underlying pathophysiology.³ 

The current case report discusses a 4-year-old Tajik girl with PF secondary to VZV infection. The patient’s protein S level, which was low during the PF attack, improved after replacement therapy and remained within the normal range during the 6-month follow-up period.

A 4-year-old girl with no known disease and of unknown vaccination status was admitted to the hospital in Tajikistan with a report of bruises spreading from her right leg to the gluteal region 3 to 4 days after experiencing chickenpox. She was hospitalized at that time and received meropenem therapy. The patient received replacement therapy in the form of ES and FFP. Her lesions then enlarged to the gluteal region and changed in color from red to black, and she became immobile. Loss of sensation was observed in the right leg, and an arterial thrombosis was detected via Doppler ultrasonography during the hospitalization in Tajikistan. She was later admitted to the hospital of the authors of the present report 10 days after resolution of chickenpox. Physical examination revealed the presence of ecchymotic and purpuric areas on the entire right leg and spreading throughout both gluteal regions, right toe necrosis, and purpura in the left heel at the first admission to the authors’ hospital (Figure 1). Bilateral popliteal and femoral pulses were palpable, but the right dorsalis pedis artery pulse was nonpalpable. The patient had loss of muscle strength and sensation below the right knee. Vesicular lesions were scattered on the trunk; some of these were crusted.

On admission to the authors’ hospital, FFP, thrombolytic, and anticoagulant treatments, as well as meropenem, teicoplanin, and clindamycin were started immediately in the ED. Laboratory results were as follows: anemia (Hb level, 7 g/dL; normal range, 12 g/dL–17 g/dL), hypofibrinogenemia (fibrinogen level, 95 mg/dL; normal range, 200 mg/dL–400 mg/dL), and elevated D-dimer level (8 mg/L; normal range, 0 mg/L–0.5 mg/L), which were compatible with disseminated intravascular coagulation; however, the patient had a normal platelet count (324 × 10³/µL; normal range, 150 × 10³/µL–450 × 10³/µL). VZV immunoglobulin M was positive (203 U/mL; normal range, 0 U/mL–9.99 U/mL).

In coagulation cascade protein assays to investigate the etiology of thrombosis, a low protein S level was detected (7%; normal range, 60%–140%); however, levels of antithrombin III, factor V, protein C, homocysteine, and anticardiolipin were in the normal range, and the patient was lupus anticoagulant negative. A defect of the arterial current was noted on arterial Doppler ultrasonography and computed tomography angiography, which was compatible with ischemia of the right leg below the knee. Venous Doppler ultrasonography demonstrated no evidence of deep vein thrombosis. Echocardiography was normal. 

The patient was transferred to the pediatric intensive care unit due to clinical deterioration. Tissue plasminogen activator was started as a thrombolytic therapy, but this was discontinued on the second day due to lack of response. Anticoagulant and antimicrobial therapies were continued. FFP and ES were administered according to coagulation parameters and Hb level. Embolectomy and hyperbaric oxygen therapy could not be performed in the setting of tissue necrosis.

After clinical stabilization was achieved, the patient was transferred to the pediatric hematology inpatient service on day 10 of hospitalization. FFP, ES, and anticoagulant treatments were continued.

The patient was transferred to the plastic, reconstructive, and aesthetic surgery inpatient service after the fourth week of hospitalization. Forty surgical debridements were performed to manage necrotic tissues, and 8 of these debridements involved grafting as well (Figure 2). All debridements were performed in the operating room with the patient under sedation or general anesthesia. These debridements were mostly minor, including scrubbing with a chlorhexidine solution and vacuum-assisted closure dressing changes every 2 to 3 days. However, 3 major debridement procedures were performed, such as below-knee amputation and debridement of large areas of necrotic skin. For each debridement, the wounds were assessed, and clean areas deemed suitable for grafting were grafted. Daily decolonization with 2% chlorhexidine solution was performed. Surgical debridement specimens were positive for Acinetobacter baumannii, Enterococcus spp, Candida spp, Stenotrophomonas maltophilia, Escherichia coli, Bacteroides fragilis, Corynebacterium striatum, methicillin-sensitive Staphylococcus epidermidis, and Streptococcus salivarius. Antimicrobial and antifungal therapies were given according to antibiotic and antifungal susceptibilities of the isolated microorganisms. In week 16 of hospitalization, the patient’s right leg was amputated below the knee (Figure 3). Histopathological examination of tissues revealed diffuse coagulative necrosis. 

Additional tests were performed to investigate the etiology of thrombosis, with the patient found to be a heterozygous carrier of factor V Leiden and MTHFR A1298C polymorphism on analysis of the hereditary thrombophilia panel. Because the repeated protein S level was within the normal range, the patient was diagnosed with acquired protein S deficiency.

The patient remained in the plastic, reconstructive, and aesthetic surgery inpatient service for 26 weeks. She was discharged with a stable outcome and after all wounds were closed. After the patient was discharged from the hospital, she received follow-up care in the pediatric hematology and plastic, reconstructive, and aesthetic surgery outpatient clinic. However, she developed a knee contracture due to skin grafts and inadequate mobilization during follow-up. The patient was readmitted to the hospital, and the knee contracture was successfully released with a free parascapular flap.

This case report discusses a 4-year-old girl diagnosed with PF due to acquired protein S deficiency 10 days after resolution of chickenpox. Although PF secondary to chickenpox is rare, there are reported cases in pediatric patients.^11,12

As noted previously, the laboratory findings of the patient in the current case report (anemia, hypofibrinogenemia, and an elevated D-dimer level) were in line with the diagnosis of PF. These findings were compatible with disseminated intravascular coagulation, although prothrombin time, activated partial thromboplastin time, and platelet count were normal. These 3 normal findings may have been the result of the replacement therapy the patient received in Tajikistan.

In the patient in this case report, the possible mechanisms of PF were believed to be acquired protein S deficiency as well as heterozygous carrier of factor V Leiden and MTHFR A1298C polymorphism status. Evidence indicates that autoantibodies against protein S consistently lead to an acquired deficiency of protein S. Antibody levels decrease within a few weeks.^6,8-10 Additionally, heterozygous carrier of factor V Leiden status has been shown to increase the risk of developing PF.^13,14 

The authors of the current case report immediately started FFP, thrombolytic, and anticoagulant treatments in the ED in the 4-year-old patient. Early recognition and management of PF are important to prevent hemostatic abnormalities and rapid progression to sepsis. Therefore, it is crucial to identify the specific cause of a case to determine appropriate treatment options based on the underlying pathophysiology. Until the underlying condition is determined and sepsis is ruled out, it is necessary to provide supportive therapies such as replacement of blood and blood products such as FFP and ES, thrombolytic and anticoagulant treatments, and broad-spectrum antimicrobial therapies.^3,4,7 In the multicenter case series and literature review by Theron et al,¹⁵ which included 52 cases of idiopathic PF, anticoagulant treatment was used in almost all patients and FFP was used in 79% of the cases.

In the early stages of PF, surgical intervention other than fasciotomy is rarely needed. Debridement and skin grafting should be delayed until the demarcation line is clear and the underlying disease is under control.³ No deaths were reported in Theron et al.¹⁵ However, those authors reported distal amputation in 14 patients (27%), skin necrosis with grafting in 15 patients (29%), and the need for both treatments in 4 patients.¹⁵ The patient in the current case report did not need a fasciotomy. She had undergone multiple skin grafting operations, and ultimately she underwent below-knee amputation of the right leg.

A surgical site infection is one that occurs within 30 days after a surgical procedure or within 90 days if an implant is used.¹⁶ As noted previously, surgical debridement specimens from the patient in the current case report yielded A baumannii, Enterococcus spp, Candida spp, S maltophilia, E coli, B fragilis, C striatum, methicillin-sensitive S epidermidis, and S salivarius. Antimicrobial and antifungal therapies were given according to antibiotic and antifungal susceptibilities of the isolated microorganisms. In the other case and in previously published case series, microbial growth due to microorganisms in the wound area has not been reported.^6,8,15 

PF is a devastating condition that can lead to mortality if it is not properly managed, or to long-term morbidity such as skin necrosis in large areas and amputation of the extremities. The underlying condition generally determines the prognosis.^3,4 Published reports indicate a mortality rate of postinfectious PF of approximately 20% to 30%.^17,18 The patient in the current report underwent below-knee amputation. As of this writing, she is alive and healthy. 

This case report has limitations. It presents a single case of a rare condition in a pediatric patient. The photographs of the patient’s first rash of chickenpox and detailed medical records from the prior institution at which she received treatment were unavailable as she travelled from abroad. 

PF is a rare, life-threatening condition caused by various etiologies. It is vital to identify the specific cause on a case-by-case basis, because specific treatment options are available based on the underlying pathophysiology. 

Although VZV infections mostly cause mild and self-limiting eruptive disease, they can progress to life-threatening complications, including PF. To prevent VZV infections and their complications, immunization with live attenuated vaccines and maintaining population immunity above a certain threshold are the most important strategies. For this reason, efforts to facilitate children’s access to vaccines and to increase parents’ or caregivers’ knowledge and awareness of this issue should be supported and strengthened worldwide.

Authors: Aylin Dizi Işık, MD¹; Ahmet Hamdi Sakarya, MD²; Pınar Canizci Erdemli, MD¹; Zeynep Ergenc¹; Seyhan Yılmaz, MD¹; Sevgi Aslan Tuncay, MD¹; Burcu Parlak, MD¹; Ömer Doğru, MD³; Ahmet Koç, MD³; Feyza İnceköy Girgin, MD⁴; and Eda Kepenekli, MD⁵

Affiliations: ¹Marmara University Faculty of Medicine, Division of Pediatric Infectious Diseases, Department of Pediatrics, Istanbul, Turkey; ²Marmara University Faculty of Medicine, Department of Plastic, Reconstructive and Aesthetic Surgery, Istanbul, Turkey; ³Marmara University Faculty of Medicine, Division of Pediatric Hematology and Oncology, Department of Pediatrics, Istanbul, Turkey; ⁴Marmara University Faculty of Medicine, Division of Pediatric Intensive Care Unit, Department of Pediatrics, Istanbul, Turkey; ⁵Bahçeşehir University Faculty of Medicine, Division of Pediatric Infectious Diseases, Department of Pediatrics, Istanbul, Turkey

ORCID: Dizi Işık, 0000-0002-5420-3706; Sakarya, 0000-0001-5551-4218; Canizci Erdemli, 0000-0002-6200-3173; Ergenc, 0000-0002-4547-6489; Yılmaz, 0000-0001-6873-0745; Aslan Tuncay, 0000-0002-2626-0316; Parlak, 0000-0002-1222-8761; Doğru, 0000-0002-2528-2409; Koç, 0000-0001-7940-2640; İnceköy Girgin, 0000-0003-4324-0488; Kepenekli, 0000-0003-1886-5224

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence:  Eda Kepenekli, MD; Bahçeşehir University Faculty of Medicine, Division of Pediatric Infectious Diseases, Department of Pediatrics, Sahrayı Cedid District, Batman St No: 66-68 Yenisahra/Kadıköy, Istanbul, Turkey; ekepenekli@yahoo.com

Manuscript Accepted: May 8, 2024