Literature review and case report of septic arthritis and purpura fulminans leading to a child limb amputation as chickenpox complications

Introduction and significance: Chickenpox, induced by the varicella-zoster virus (VZV), generally presents with an itchy rash and fluid-filled blisters. While complications such as pneumonia and sepsis are well-documented, occurrences of septic arthritis and purpura fulminans are exceedingly rare. Septic arthritis following varicella infection is infrequently reported and often attributed to Staphylococcus aureus. Purpura fulminans encompasses disorders characterized by rapidly progressing purpuric lesions, often fatal and associated with consumptive coagulopathy. Case presentation: The authors present the case of an 8-year-old boy diagnosed with chickenpox who concurrently developed severe left knee pain, erythema, and swelling indicative of septic arthritis, along with a single pustular lesion on his right foot that progressed to purpura fulminans. Laboratory investigations revealed elevated inflammatory markers. Knee ultrasound findings were consistent with septic arthritis, corroborated by synovial fluid analysis. Immediate initiation of empiric antibiotics was undertaken. Further investigation disclosed unusual coagulation parameters, positive autoantibodies, and reduced protein S levels. Treatment included anticoagulation, immunomodulation, and ultimately, amputation. Clinical discussion: This rare case underscores the complexity of varicella-related complications, representing the first documented instance of simultaneous septic arthritis and purpura fulminans in a pediatric patient. It highlights the necessity of a multidisciplinary approach for accurate diagnosis and management, emphasizing the importance of recognizing rare complications to improve patient outcomes. Conclusion: This case exemplifies the complexity of varicella-associated complications, showcasing a rare simultaneous occurrence of septic arthritis and purpura fulminans in a pediatric patient. It underscores the importance of a thorough understanding and collaborative management approaches for timely intervention and enhanced clinical outcomes.


Introduction
Chickenpox is an infection caused by the varicella-zoster virus (VZV).It causes an itchy rash with small, fluid-filled blisters.Chickenpox is highly contagious to people who haven't had the disease or been vaccinated against it.It could be complicated by pneumonia, sepsis, encephalitis, and with the rarest complication septic arthritis and purpura fulminans [1] .Septic arthritis that develops following varicella is rarely seen.Twenty-nine patients reported in the literature with a 30% frequency of bacterial growth in the synovial fluid cultures of patients (mainly negative growth).The most frequent agent in septic arthritis is Staphylococcus aureus, followed by Group A streptococci, Streptococcus pneumoniae, and Kingella kingae.Although primary viral agent-driven septic arthritis is very rare, they can be seen in the form of an immune-mediated reaction, especially following the live vaccines.Purpura fulminans is a descriptive term depicting a heterogeneous group of disorders characterized by rapidly progressive purpuric lesions, which may develop into extensive areas of skin necrosis and peripheral gangrene.The

HIGHLIGHTS
• Novel results: First documented instance of simultaneous septic arthritis and purpura fulminans in pediatric varicella infection.• New methods: Utilization of multidisciplinary approach for precise diagnosis and management.• Key findings: Unusual coagulation parameters and positive autoantibodies observed in the patient.• Breakthrough insight: Highlighting the complexity and rare complications of varicella infection.• Implications: Emphasizing the need for timely intervention and collaborative management for improved outcomes.
disorder is associated with laboratory evidence of consumptive coagulopathy.The histopathologic features are widespread thrombosis of the dermal capillaries and venules with hemorrhagic infarction of the surrounding tissues.The condition is often fatal, and survivors may have considerable morbidity related to the loss of digits, limbs, or areas of skin [2][3][4] .

Case report
We report the case of an 8-year-old boy admitted to our hospital due to severe progressive left knee pain for 2 days, following three days of multiple crusted vesicular lesions distributed across his body, diagnosed as chickenpox.The pain was associated with erythema, warmth, swelling, and resistance to knee flexion or extension.Physical examination revealed an irritable patient with notable crusted vesicular lesions and a high fever of 38.5°C as documented by the doctor.Laboratory tests demonstrated elevated WBC of 14 000, neutrophils at 71.4%, lymphocytes at 14%, hemoglobin at 10 g/dl, CRP at 212 mg/l, ESR at 83 mm/h two hours after admission, uric acid at 2.6 mg/dl, with platelet and coagulation profiles within normal ranges, and a negative Brucella test.Ultrasound of the knee revealed a large effusion of 40 ml with internal echoes extending into the suprapatellar bursa with medial suprapatellar plica, consistent with septic arthritis.Aspiration was performed, followed by empiric antibiotics (ceftriaxone 75 mg/kg/day IV for 4 days and vancomycin 20 mg/kg/ day IV for 7 days).Chemical and cytological analysis of synovial fluid showed a turbid yellow color, no crystals, pH 7, WBC 14 × 10 9 /l, neutrophils at 80%, lymphocytes at 20%, and culture returned negative (no growth).During his hospital stay for septic arthritis treatment, on the sixth day, he suddenly developed a single pustular lesion on a dark base on the dorsum of his right foot (Fig. 1).The lesion was surrounded by an area of bluish discoloration that progressively enlarged, involving the ankle and the proximal third of the tibia, accompanied by extreme pain (Fig. 2).His vital signs were stable with a temperature of 37.5°C.Upon examination, the right foot became cold and edematous over time, with palpable peripheral pulses.Coagulation profile showed D-dimer at 70 000 ng/ml FEU (normal range for his age 100-560 ng/dl FEU), fibrinogen at 114 mg/dl (normal range 200-400 mg/dl), platelets at 225 mcl, and PT/PTT/INR within normal ranges.Inflammatory markers showed ESR at 65 mm/h, CRP at 162 mg/l, and WBC at 16.4 × 10 9 .Doppler ultrasound and multiphase CT angiography of the lower limb revealed no abnormalities with patent blood flow.The patient was started on heparin infusion (25 IU/kg/hr) and gentamicin (2 mg/kg/dose every eight hours) with no improvement.Contrarily, symptoms worsened, and the foot   became more edematous with tense tenderness and darker lesions (Figs.3,4).The following day, the patient was transferred to a more advanced tertiary center where further investigations revealed: Protein S at 12.7% (normal range 70-140%), Anti-Xa levels at 0.2 (0.6-1.0 units/ml).Antinuclear antibody (ANA), anti-DNA antibody, and antiphospholipid antibody were positive, but there was no evidence of rheumatological disease based on his normal history and current symptoms.Notably, both parents had normal protein S levels.
The child was treated with daily fresh frozen plasma, Enoxaparin IM 40 mg twice daily titrated against Anti-Xa levels, 3 units of vitamin K, and 2 courses of synthetic PG analog (Iloprost), each for 5 days.The patient experienced severe pain with a VAS score of 10/10, managed by patient-controlled analgesia (PCA) with morphine throughout his hospital stay.Over time, calcium and phosphate levels (previously normal) increased: Ca at 3.82 mmol/l (normal range 2.2-2.7 mmol/l), phosphate at 2.1 mmol/l (normal range 1.12-1.45mmol/l), with normal kidney function (Cr at 31 umol/l, normal range 25-42 umol/l), indicating necrosis.Consequently, surgical debridement to clear necrotic tissue was performed.Despite this, the purpuric lesion progressed, leading to extensive toe necrosis with dry gangrene, necessitating a below-knee amputation based on orthopedic consultation.The surgery was completed without complications.Protein S levels improved to 56% U/dl and Anti-Xa to 0.7 units/ml after 5 weeks of treatment.Fortunately, the child was fitted with an artificial limb and was able to walk.

Review of literature
We initiated our work by conducting a bibliographic search in the Medline database (1946 to 1 July 2021) using the following keywords: VZV, chickenpox, varicella, varicella zoster virus, arthritis, "idiopathic purpura fulminans," "acquired protein S deficiency," and "anti-protein S antibodies."The search was limited to publications in English, and the references in the articles were reviewed for all cases of varicella arthritis and purpura fulminans.Missing information was obtained from the authors.All articles that met the inclusion criteria and presented sufficient data were included.The same data were collected as would be in a retrospective case series.The demographic, clinical, and biological characteristics of patients with varicella arthritis are presented in Table 1 [6] .
The median age was 5.5 years (interquartile range: 1-11), with a predominance of girls (71.4%).All patients were immunocompetent.Joint involvement was confined to a single joint in 27 cases (93%), while 2 cases presented with involvement of more than one joint.The knee was the most commonly affected joint (18/29 cases, 62%), followed by the ankle (4/29 cases, 13.7%), the shoulder (1/29 cases, 3.4%), and the foot (3/29 cases, 10.3%).The median time to onset of arthritis was 2 days (interquartile range: 6 days before the onset of varicella infection up to 10 days after).VZV DNA was isolated by polymerase chain reaction (PCR) from synovial fluid in 3 cases.No positive viral cultures were reported.The median ESR rate was 43 mm/1st h (interquartile range: 3-83), and the median leukocyte count in synovial fluid was 7250/l (interquartile range: 1650-73 500) with a lymphocyte count of 81% (interquartile range: 2-100).Clinically, all symptoms and signs of arthritis resolved within one month in 79.3% of cases (23/29), within two months in 6.8% (2/29), and within six months in 3.4% (1/29).Finally, one child presented with chronic arthritis, and one child with intermittent arthritis in the context of a moderate varicella rash.
We analyzed the relationship between several factors and the occurrence of severe complications in the overall cohort.At the time of diagnosis, the median AT activity level (79% vs. 101%; P < .001)and the median platelet count (51.5 × 10 9 /l vs. 188.5 × 10 9 /l; P < .001)were significantly lower in patients with severe complications.Univariable analyses confirmed these results with odds ratios (ORs) of 1.08 (95% CI, 1.03-1.14;P = .003)for the median AT activity level and 1.02 (95% CI, 1.01-1.02;P = .001)for the median platelet count.In multivariable analysis, a correlation was found between severe complications and the median AT activity level, with an OR of 1.07 (95% CI, 1.01-1.14;P = .03),and the median platelet count with an OR of 1.01 (95% CI, 1.00-1.02;P = .04).All results are presented in Figure 2 and Table 2.

Varicella complications: septic arthritis and purpura fulminans
Varicella, commonly seen in childhood, is generally a benign disease.However, its most frequent complications include skin and soft tissue infections, neurological complications, and pneumonia.Septic arthritis following varicella is rare, as is purpura fulminans; this is the first documented case in which both conditions occur in the same patient according to the literature.

Septic arthritis
There have been 29 reported cases of joint involvement due to varicella (Fig. 5).This involvement can occur due to direct viral invasion, resulting in aseptic arthritis, or as a secondary bacterial infection.Differentiating between the two can be aided by detecting viral DNA in the joint fluid and identifying bacterial growth in joint fluid or blood cultures, along with high levels of LDH, protein, and acute phase reactants.Literature indicates that bacterial growth is detected in 30% of blood cultures and around 70% of joint fluid cultures in septic arthritis cases.The most frequent causative agent is S. aureus, followed by Group A streptococci, Streptococcus pneumoniae, and Kingella kingae.

Purpura fulminans
Purpura fulminans is a rapidly progressing condition characterized by dermal hemorrhage resulting from intracapillary thrombus formation without histological vascular wall involvement.preceding infections, occurring in 30% and 20% of patients, respectively.

Case comparison
In comparison to the literature, our case involves a 7-year-old male, which fits within the reported age range of 1.5-11 years.The affected joint, the left knee, is consistent with the most frequently reported joint (31%).Onset occurred two days after the varicella rash, within the reported range.The arthritis duration was less than one month, similar to 79% of reported cases.Laboratory values were within the reported ranges: WBCs at 14K (range 3.5K-16.7K),ESR at 20 (22% of reported values were less than 21), and synovial fluid WBCs at 14K (range 1.65K-73.5K)with lymphocytes at 20% (range 2-100%).
Regarding purpura fulminans, our case is unique in its spread pattern from the dorsum of the feet to the ankle and proximal tibia, whereas the most common locations in literature are the lower limbs (89-97%).PS activity levels were reduced, consistent with recent case series and literature.Treatment included heparin and FFP, similar to 100% and 97% of cases, respectively.Despite using iloprost, the outcome was amputation, the third most frequently reported outcome in the literature.Other outcomes included skin necrosis with grafting (28-29%) and venous thromboembolism (33-32%).Extensive lab tests indicated an acquired protein S deficiency caused by anti-protein-S antibodies.The improvement in protein S levels after receiving FFP, and normal protein S levels in the patient's parents, support this diagnosis.
The presence of antiphospholipid antibodies in patients with purpura fulminans following varicella infection may explain the severity of clinical manifestations.This suggests that transient autoimmune-mediated protein S deficiency, potentially due to a cross-immune reaction between protein S and Varicella-Zoster virus, led to a hypercoagulable state.Prompt heparinization and large volumes of FFP were effective in halting disease progression, though protein S concentrate was ultimately needed to restore normal levels [26,27] .

Conclusion
This case underscores the intricacies associated with varicellarelated complications, exemplifying the unusual presentation of both septic arthritis and purpura fulminans in a pediatric patient.It underscores the significance of comprehensive comprehension and collaborative management strategies for prompt intervention and enhanced clinical results.Regrettably, in numerous countries where there is no vaccination against the chickenpox virus, we advocate for the administration of this vaccine to all infants to avert the devastating consequences of chickenpox, as witnessed in our patient.

Figure 1 .
Figure 1.Single pustular lesion with a dark base on the right foot.

Figure 2 .
Figure 2. Bluish discoloration spreading from the lesion, involving the ankle and proximal tibia, with severe pain.

Figure 3 .
Figure 3. Increased edema and tense tenderness in the foot, with darker lesions as symptoms progressed.

Figure 4 .
Figure 4. Increased edema and tense tenderness in the foot, with darker lesions as symptoms progressed.
sedimentation rate; F, female; lymphs, lymphocytes; M, male; ND, not determined; WBC, white blood cell.a (-) means days before the onset of Varicella infection clinical symptoms.

Figure 5 .
Figure 5. Literature-reported locations of septic arthritis post-varicella infection (Y = number of reported events).

Table 2
Patient characteristics, clinical presentation, type of virus, biology at diagnosis, treatment and outcomes of recent case series in comparison to literature.
PC, protein C; PS, protein S.