Case report: Relapsed disseminated cutaneous herpes zoster successfully treated with brivudine

Abstract

A 64-year-old man presented with painful rash on the trunk and extremities for more than half a month. Nephrotic syndrome had been diagnosed 2 years ago and had been regularly treated with glucocorticoids and immunosuppressants. He developed herpes zoster 1 year ago. Laboratory investigation demonstrated varicella-zoster virus DNA (VZV-DNA), varicella-zoster virus IgM (VZV-IgM), and varicella-zoster virus antibody IgG (VZV-IgG) were all positive. After the clinical diagnosis of relapsed disseminated cutaneous herpes zoster had been confirmed, systemic therapy with brivudine 125 mg everyday was started.

Introduction

Herpes zoster is caused by the reactivation of the varicella-zoster virus within the nerve roots or ganglia. The rash is mostly distributed along a peripheral nerve, appears on one side of the body. Within a few days after the local rash, the VZV can spread throughout the body in patients with elderly, frail, major medical diseases or chronic lymphoma, developing a chickenpox-like rash, and bullae, blood blisters, and even necrosis, called “disseminated cutaneous herpes zoster”. ¹ Patients with nephrotic syndrome require long-term use of high-dose corticosteroids and immunosuppressants to control disease activity and renal involvement. Long-term use of hormones makes it more prone to diabetes. Diabetes can induce microangiopathy, which can reduce immune levels and cause metabolic disorders that increase the risk of shingles, and are more likely to develop into life-threatening disseminated shingles and recur. ² For such patients, even if they have had shingles, it is necessary to be alert to the occurrence of this disease. Patients with renal insufficiency should be treated with caution with acyclovir, famciclovir, valacyclovir, and foscarnet. On the other hand, brivudine does not require measurement of serum creatinine. ³

Case presentation

A 64-year-old man presented with painful rash on the trunk and extremities for more than half a month. Half a month ago, the patient developed a large of small blisters on right waist, back and abdomen, accompanied by pain. The visual analogue scale (VAS) pain scores is 8. Subsequently, scattered small blisters gradually appeared on the head, face, torso, and limbs (Figure 1). The patient applies the acyclovir cream on his own. The rash didn’t change significantly. As a result, the patient was admitted to hospital on 2 October 2022. Nephrotic syndrome. diabetic nephropathy had been diagnosed 2 years ago and had been regularly treated with prednisone 40 mg everyday and tacrolimus 3 mg everyday for more than half a year. Hypertension, diabetes, and hyperlipidemia have been previously diagnosed. He developed herpes zoster on the right side of the head and face 1 year ago, and was cured by topical acyclovir cream, but he was not vaccinated against shingles.

Figure 1.

(a and b) The full moon face can be seen, the right lower limb and right foot can be seen obvious concave edema. (c and d) Clustered papules, small vesicles, and blood blisters can be seen in the distribution areas of T10, T11, T12, L1 and L2 of the right waist, back and abdomen. More than 20 scattered small blisters can be seen on the head, face, chest and thigh.

Physical examination: The general condition is good, the full moon face can be seen, the right lower limb and right foot can be seen obvious concave edema, and the cardiopulmonary abdominal examination does not show obvious abnormalities. Dermatological examination: Clustered papules, small vesicles, and blood blisters can be seen in the distribution areas of T10, T11, T12, L1 and L2 of the right waist, back and abdomen. The lesions are distributed in bands along the nerve. Several nail cap erosions, ulcers, and blood scabs can be seen on the right abdomen. More than 20 scattered small blisters can be seen on the head, face, chest and thigh.

Laboratory investigation demonstrated varicella-zoster virus DNA (VZV-DNA), varicella-zoster virus IgM (VZV-IgM), and varicella-zoster virus antibody IgG (VZV-IgG) were all positive. The patient has a large amount of proteinuria, urine protein >3.5 g/24 h, hypoproteinemia, blood albumin <30 g/L, accompanied by both lower extremities edema and hyperlipidemia. Renal pathological diagnosis: Combined with light microscopy, immunofluorescence, and electron microscopy, the patient was considered to have stage II membranous nephropathy (PLA2R-related) with acute tubular injury. The patient was diagnosed with recurrent disseminated herpes zoster and membranous nephropathy. The patient was given oral brivudine 125 mg once daily for 7 days. In this patient, CD4+ T lymphocytes, CD4+/CD8+ are low, the percentage of CD8+ T cells is elevated. The patient was given placental polypeptides to improve immunity.

Chest CT showed pneumonia scattered in both lungs, and white blood cell count, C-reactive protein, and procalcitonin were elevated. Piperacillin-tazobactam 4.5 g intravenously every 8 h were started. Double lower extremity arteriovenous ultrasound shows right common femoral vein thrombosis (incomplete occlusion), and right lower extremity superficial femoral vein, popliteal vein, posterior tibial vein thrombosis (complete occlusion). Moreover, the patient’s D-dimer and fibrinogen degradation products were significantly increased. Therefore, the patient is given enoxaparin sodium injected subcutaneously.

After treatment, his procalcitonin, white blood cell count, D dimer, and fibrinogen degradation products returned to normal. His kidney function also did not deteriorate. On the 11th day of admission, the patient’s blisters dried up and scabbed off, leaving pigmentation and mild scarring, and the pain was relieved, the VAS pain scores is 2, and he was transferred to the nephrology department for treatment. Follow-up so far, the patient’s renal function is still acceptable, herpes zoster has not recurred, and there is no postherpetic neuralgia. The patient’s VAS pain scores is 0 and had no impact on work and life.

Discussion

Disseminated cutaneous herpes zoster is defined as a lesion involving more than two dermatomes, or more than 20 blisters outside the primary dermatome, or systemic involvement.^1,4 The patient was diagnosed with recurrent disseminated herpes zoster as a result of clusters of blisters, distributed along nerves, arranged in bands, unilateral, and marked neuralgia, positive for varicella-zoster virus DNA, lesions involving more than two dermatomes, more than 20 blisters outside the dermatomes, and having had facial shingles in the past 1 year ago. However, it is still necessary to distinguish it from contact dermatitis and herpes simplex. Herpes simplex tends to occur at the mucocutaneous junction and has a history of recurrent attacks, generally not distributed along nerves. Contact dermatitis has a history of exposure before the onset, and acute dermatitis with a clear boundary occurs at the site of contact, and the rash is mostly a single form, and the lesions quickly resolve after removing the cause.

After healing from HZ, long-lasting immunity is obtained. However, some studies have found a lower rate of recurrence within 12 months of the first onset of HZ, and subsequently comparable to the incidence of the first HZ.^5,6 Recurrence of HZ may be associated with immunosenescence. ¹ The level of herpes zoster specific cell-mediated immunity (CMI) gradually decreases with age. However, the amount of anti-herpes zoster virus antibody did not change significantly. Some scholars believe that a history of HZ is a protective factor for recurrence. Compared with the first-onset, the relapsed patients had small skin lesions, mild pain, a smaller proportion of postherpetic neuralgia, and a stronger VZV skin test antigen response, while the intensity of humoral immune response was similar. ⁷ However, some studies believe that the body is not adequately protected after the initial herpes zoster, ⁸ and there is no significant difference in the skin lesion area, location, pain time, degree and treatment effect between the initial and recurrent patients. Therefore, the mechanism of HZ recurrence requires further study.

The patient has nephrotic syndrome, long-term glucocorticoids combined with immunosuppressant therapy, which can result in impaired immune function. ⁹ The patient’s CD4+ T lymphocytes were low, the percentage of CD8+ T cells was increased, and CD4+/CD8+ was low, which indicating that T cell immunity was significantly suppressed. ¹⁰ As a result, the patient is immunosuppressed. CD4+ T lymphocytes are helper T cells that play a major role in cellular immunity. They are also the main cause of VZV activation and replication, and the main immunological changes in the early stages of HZ. And their reduction can cause autoimmune dysfunction. CD8+ T lymphocytes are cytotoxic T cells, which are effector cells with killing activity, and their elevation exerts immunosuppressive effects. A low CD4+/CD8+ ratio reflects decreased immune function ¹¹

Diabetes promotes viral infections. Some scholars have found that VZV-CMI in diabetic patients is significantly reduced. ¹² Short-term elevated blood glucose levels also affect the immune response, which suggesting that poor glycemic control favors the spread of VZV. ¹³ In addition, hypertension, hyperlipidemia, untimely treatment, and statins are also risk factors for HZ recurrence, which can lead to VZV reactivation. ¹⁴

Drugs approved in Europe for the systemic treatment of herpes zoster are acyclovir, penciclovir, valacyclovir, famciclovir, brivudine. Valacyclovir has high oral bioavailability and is more convenient to administer, and is generally the first choice for oral antivirals. For immunocompromised patients, intravenous acyclovir should be an option as appropriate. famciclovir or other antiviral agents should be considered for patients resistant to acyclovir; for immunocompromised patients resistant to acyclovir, intravenous drips of foscarnet sodium can be an option. ¹⁵ Compared to other drugs, ¹⁶ brivudine is a non-nephrotoxic drug. In elderly patients and patients with moderate or severe renal dysfunction, the main pharmacokinetic parameters of brivudine did not change. In addition, studies have confirmed that brivudine has a stronger antiviral effect and more effective in relieving pain than other antiviral drugs, which can be used as the first choice for severe herpes zoster cases. ¹⁷ The patient is an older man with significant body, severe pain, severe lesions, a long time from onset to initiation of treatment, nephrotic syndrome, immunosuppression, and rash progressing despite oral corticosteroids. Disseminated shingles is critically ill. Acyclovir, penciclovir, valacyclovir and famciclovir are metabolized by the kidneys and are nephrotoxic and require strict monitoring of renal function. Brivudine is non-nephrotoxic and has a stronger antiviral effect. Therefore, brivudine is chosen for treatment after consultation with the patient. After treatment, the patient’s pain was significantly reduced and the rash improved significantly.

In summary, a variety of risk factors can contribute to HZ recurrence. Some scholars support that people who have been infected with HZ inoculated against herpes zoster vaccine can prevent recurrence, and shows that vaccination is beneficial within 12 months of the first illness.^8,18 The recommendation for patients taking glucocorticoids is that the herpes zoster vaccine is safe when using low-doses or short-course glucocorticoids (prednisone <20 mg/day <14 days), while high-dose glucocorticoids (prednisone≥ 20 mg/day ≥14 days) or immunosuppressants should be discontinued for at least 4 weeks before vaccination. ¹⁹

Conclusion

Patients with nephrotic syndrome are immunocompromised due to long-term glucocorticoid or immunosuppressive use. Even patients with previous herpes zoster need to be alert to the development of shingles. Because brivudine does not impair renal function and does not require creatinine monitoring, brivudine is recommended for patients with herpes zoster and nephrotic syndrome.