Discussions and conclusions
We report the case of a patient who had previously been infected with VZV, but probably became re-infected with VZV during immunosuppressive therapy for membranous nephropathy, which led to the development of VDVZV. With careful diagnosis and management, we successfully treated the patient. It is generally considered that people with specific immunity to VZV will not become re-infected, although one study reported that four out of 62 people with VZV-specific antibodies (three of whom were immunologically healthy) who came into contact with a VZV-infected person subsequently developed varicella [
10]. There are also data indicating that 4.15 out of 1000 people with specific immunity are re-infected with VZV per year [
11]. In immunocompromised patients, the disease type at reoccurrence is not limited to herpes zoster; VZV can also present as varicella. Steroid administration generally increases the frequency and severity of VZV infection [
12], and steroid administration of 61 days or longer is a risk factor. Women are reported to have a 25% higher incidence than men [
11], but the reason for this sex-related difference is unknown. Furthermore, varicella is localized to the skin in immunologically healthy people, but the lesions are not similarly limited in immunocompromised patients, who can also develop VDVZV. A report has demonstrated that relapse was an onset factor for VDVZV in three out of four cases [
3]. The patient in the present study developed VDVZV despite testing positive for VZV IgG, which suggests that this was re-infection due to the presence of a patient with herpes zoster in the same hospital room prior to the onset of the condition. Therefore, we conclude that VDVZV can occur in immunocompromised patients through VZV relapse, first-time infection, or re-infection.
The symptoms of the present case were characteristic: a sub-ileus profile with intense abdominal pain but no peritoneal irritation signs or lesions (such as perforations, occlusion, or thrombosis) and extremely mild elevation of leukocytes and inflammatory response, liver dysfunction, and disseminated intravascular coagulation (DIC) test findings. The abdominal pain preceded the skin rash.
Immunocompromised patients, particularly those with underlying blood diseases or kidney transplant recipients, are susceptible to VDVZV. Gastrointestinal symptoms, including abdominal pain, intestinal obstruction, vomiting, and diarrhea, precede the skin rash by a few to 10 days [
13,
14], and the incidence of abdominal pain is high, occurring in 82–100% of cases [
13,
15]. In a report on 15 VDVZV cases in Japan [
15] (mean age was 27.9 years, 14 men and one woman), the underlying diseases were blood diseases (
n = 12), kidney transplant (
n = 2), and kidney disease (
n = 1), and 13 of the patients were using steroids and/or immunosuppressants. The initial symptom was abdominal pain in 14 patients and back pain in one patient, and CT findings were almost completely normal. However, increased CT values of abdominal perivascular adipose tissue were observed in one case, erosion was evident by endoscopy in some cases, and some cases presented with a rash. The mean time from initial symptoms to appearance of the rash was 4.6 days. Narcotics were used for analgesia in five patients, and diagnostic methods included identification of the rash and anti-VZV IgM/IgG, serum VZV-DNA, serum VZV antigens, PCR from lesion site, and Tzanck tests. The mean time from initial symptoms to starting treatment was 4.5 days; all patients were treated with acyclovir and four patients were also treated with gamma globulin. The outcome was reported as death in four cases, and it was reported that the mean time from initial symptoms to starting treatment was 4.2 days for the 11 patients who survived, while a mean time of 5.5 days was reported for those who died. These results reiterate the importance of prompt treatment. In the present case, it was 3 days from the onset of abdominal pain to the appearance of the rash, diagnosis of VDVZV, and initiation of treatment. Until the rash appears, VDVZV is often diagnosed as abdominal pain of unknown etiology. It has been reported that the blood VZV-DNA concentration for herpes zoster is, on average, 1710 copies compared with an average of 214,214 copies for VDVZV. This disparity could be used as a method for diagnosis during the time before the appearance of the rash [
16], and measuring blood VZV-DNA numbers when VDVZV is suspected could be useful. The imaging findings are usually non-specific; increased lipid concentration around the superior mesenteric artery by CT has been reported [
17], and the present case had similar CT findings (Fig.
1).
Since VZV is known to be associated with vasculitis and giant cell arteritis, it is possible that the clinical findings relate to the arteritis accompanying VZV infection [
18,
19]. In the context of autoimmunity or immunodeficiency, VZV vasculitis often occurs in the cerebral blood vessels; [
20] however, it can occur in the abdominal blood vessel, as was observed in the present case.
There have been reports of upper gastrointestinal bleeding or herpes-like lesions on the mucosal or serosal side of the gastrointestinal tract [
21,
22]. Pain management is difficult in such cases and may require opioid analgesics, but there are also reports where even large doses of opioids were not sufficient [
14,
17]. There is a theory that the abdominal pain is caused by proliferation of the VZV on the celiac and mesenteric ganglia [
23], but there are number of different theories [
13,
21] and the details are still unknown. This study had some limitations. Specifically, we did not perform gastroscopy and intestinal endoscopy, and no viral genotyping was available to allow differentiation of disseminated zoster (reactivation) from re-infection.
The prognosis of VDVZV is poor; often becoming much more serious with complications of DIC, encephalitis, pneumonia, and intestinal necrosis; and the mortality rate is reported to be extremely high, at approximately 55% [
24]. Recently, the incidence of VDVZV in Japanese patients receiving allogenic hematopoietic stem cell transplantation was reported to be 0.8%, and the mortality rate was 20% [
4]. Delayed diagnosis has fatal outcomes, sometimes within a few days [
2,
23]. Therefore, awareness of this condition as a severe infection is vital.
Infection prevention is important and measures must be taken to ensure that immunocompromised patients do not come into contact with VZV. In the USA, a live attenuated vaccine is recommended to prevent herpes zoster and postherpetic neuralgia in general patients aged 60 years and older, and there is also a recombinant vaccine recommended for individuals 50 years and older [
25‐
27]. Administration of live vaccines is normally contraindicated as a prophylactic measure for immunocompromised patients, but their use after organ transplant has been reported [
28]. However, pediatricians do not consider the administration of live vaccines to be absolutely contraindicated for transplant recipients, and there are reports that such patients may develop a fever and rash, but do not subsequently develop VZV infection even after exposure to the virus [
29,
30]. Therefore, there is no consensus of opinion.
Prophylactic oral administration of acyclovir has been reported to inhibit VZV activation in hematopoietic stem cell transplantation cases [
31,
32], but the inhibitory effect has been demonstrated to cease once administration is stopped [
33]. Acyclovir is excreted via the kidneys; therefore, ongoing prophylactic administration requires caution in patients with renal insufficiency. The KDIGO guidelines recommend intravenous injection of VZV immunoglobulin or immunoglobulin within 96 h as a preventative measure to counteract exposure of kidney transplant recipients to VZV [
34]. The same guidelines advocate a combination of intravenous administration of acyclovir and temporary reduction of immunosuppressants as a treatment for VZV [
34]. A report of the VZV-related death of a patient during immunosuppressive therapy for kidney disease treatment has been published; however, the acyclovir dose was too low (250 mg/day) and the steroid dose was not reduced [
2]. Awareness of VDVZV must be reiterated not only for patients with blood diseases and kidney transplant recipients, but also for patients with kidney disease undergoing immunosuppressive therapy. It is important to start treatment with a sufficient dose of acyclovir as soon as possible and to reduce the dose of immunosuppressive therapy.
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