Unusual cause for intestinal perforation in juvenile dermatomyositis

Abstract

We report a case of juvenile dermatomyositis (JDM) with cytomegalovirus (CMV) colitis which was further complicated with perforation. The patient, a 6-year-old girl, was diagnosed with JDM 1 month prior to the current presentation. After 2 weeks of optimising her treatment with steroid, intravenous Ig and methotrexate, she was readmitted with diffuse abdominal pain. Erect abdominal X-ray revealed gas under diaphragm. An exploratory laparotomy showed perforation of the large intestine. A biopsy showed inclusion bodies of CMV with immunohistochemistry for CMV positive. Strong positive CMV DNA PCR from tissue specimen, positive IgG CMV and negative IgM CMV in blood suggested a reactivation of CMV. The treatment followed included surgery and strategic use of antiviral agents as well as immunomodulators. CMV enteritis with complications should also be suspected in optimally treated autoimmune disease patients, including JDM, when they present with abdominal symptoms.

Background

Cytomegalovirus (CMV) is a form of the Herpes virus. In humans, it is known as human herpesvirus 5 and belongs to the Betaherpesvirinae subfamily of Herpesviridae. Severe complications of CMV can occur in immune compromised patients. CMV infection is not a rare complication in autoimmune diseases under immunosuppressive therapy, and colitis has developed on occasions.^{1 2} It should be suspected when such patients become symptomatic even when optimally treated. Gastrointestinal (GI)symptoms like abdominal pain, diarrhoea, melena and perforation can represent both infections like CMV or GI vasculitis secondary to primary disease.³ Perforation is generally related to primary disease. Therefore, it is important to determine whether symptom aggravation in these patients is due to disease exacerbation or due to infection.⁴ CMV colitis has previously been reported in patients with idiopathic inflammatory myositis (IIM), but to our knowledge, this is the first case of CMV colitis with perforation in a child with IIM, reported in the relevant literature.

Case presentation

A 6 -ear-old girl, on treatment for juvenile dermatomyositis (JDM), was admitted to the emergency department with acute abdominal pain. She had been initially diagnosed with JDM a month previously when she exhibited proximal muscle weakness, typical heliotropic rash with ulcers near medial canthus of both eyes, shawl sign and ulcers over nape of neck. Additional symptoms included intermittent fever with raised muscle enzymes and inflammatory markers. The treatment followed was initially methyl prednisolne (MPSL) pulse then converted to oral high-dose prednisolone and subcutaneous methotrexate.

The patient showed signs of improvement except for the skin ulcers which remained static. Two weeks prior to current admission, she was admitted with worsening weakness and dysphagia and was again pulsed with MPSL. In view of the severity of the disease, intravenous Ig at 2 g/kg was also given, and subcutaneous methorexate and oral prednisolone were continued.

The subsequent and current admission of the patient after 2 weeks was due to diffuse abdominal pain. She denied having nausea, vomiting, dysphagia, diarrhoea, malena, urinary symptoms or fever. On examination, her vitals were found to be stable. Her abdomen was rigid and diffusely tender, with guarding in all quadrants but no rebound tenderness. Other systemic examination proved unremarkable. Her routine investigation at presentation is shown in table 1. Erect X-ray abdomen conducted showed air under diaphragm (figure 1).

Table 1.

Laboratory report at admission

Test	Result
Haemoglobin	104g/L
Total count	4.5×109/L
Lymphocytes	35%
Platelet count	292×109/L
ESR	66 mm/hour
CRP	49.8
AST	20.9 U/L
ALT	19.4 U/L
CPK	70 (0–145) IU/L
LDH	296(110-296) U/L
Creatinine	0.3 mg/dL

ALT, alanine amino transferase; AST, aspartate amino transferase CPK, creatinine phosphokinase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase.

Figure 1.

X-ray abdomen erect showing air under the diaphragm.

Differential diagnosis

The differential diagnoses considered initially were perforated peptic ulcer disease secondary to steroid or GI vasculopathy. She had previously received high dose of parenteral steroid and was on divided high dose of oral steroid. GI vasculitis, more common in JDM as compared with adult IIM, was also considered. But it was less likely because primary disease was well controlled, both clinically and laboratory parameters wise showed significant improvement. The third possibility considered was opportunistic infection like CMV though the patient did not exhibit the more common signs such as fever or respiratory symptoms. Nevertheless, since her inflammatory markers were raised, GI vasculopathy and infection were both considered as the cause of perforation.

Treatment

She was kept nil per oral and was started on intravenous fluids, equivalent dose of parenteral MPSL and a broad-spectrum antibiotic. Emergency exploratory laparotomy was conducted. Perforation on anterior antimesenteric surface of transverse colon, of about 5×5 mm, was found. Pus was present in the peritoneal cavity, which on being sent for culture and sensitivity, grew Klebsiella pneumoniae. The perforation was ligated and proximal transverse colon brought out as loop colostomy. Tissue was sent for histopathological examination including CMV DNA PCR and immunohistochemistry (IHC). Immediately after surgery, she was started on parenteral ganciclovir at 5 mg/kg/day. Parenteral antibiotic and steroid was continued.

CMV colitis was diagnosed by both CMV inclusion bodies and positive IHC staining in the colonic tissue histopathological study (figure 2; H&E stain (40×objective)) showed typical intranuclear (owl’s eye) CMV inclusion bodies in some of the endothelial cells (figure 3: IHC stain showed strong focal CMV immunoreactivity with brownish areas; figure 4: colon mucosal ulceration with perforation). There was no evidence of vasculopathy or vasculitis. The CMV DNA PCR result, from the tissue, came high positive (15 924 copies/mL). Her IgG CMV antibody in blood was positive, and IgM CMV antibody was negative. Thus, a reactivation of CMV was considered, and a diagnosis of CMV reactivation with colitis and colonic perforation was made. Ganciclovir was continued. She was given intravenous Ig at 2 g/kg for JDM. After 3 weeks, her repeat CMV PCR in blood was undetectable, and ganciclovir was changed to oral valganciclovir.

Figure 2.

H&E stain (40×objective) of tissue showing typical intranuclear (owl’s eye) cytomegalovirus inclusion bodies in some of the endothelial cells. (Picture courtesy: Dr Roopa Rachel Paulose, Department of Pathology, AIMS.)

Figure 3.

IHC stain showing strong focal CMV immunoreactivity with brownish areas. CMV, cytomegalovirus; IHC, immunohistochemistry. (Picture courtesy: Dr Roopa Rachel Paulose, Department of Pathology, AIMS.)

Figure 4.

Colon mucosal ulceration with perforation. (Picture courtesy: Dr Roopa Rachel Paulose, Department of Pathology, AIMS.)

Outcome and follow-up

The patient was discharged on oral prednisolone and valganciclovir. Colostomy closure was done after 1 month of discharge. Her primary disease remained under control. Valganciclovir was stopped 6 months after surgery. CMV PCR titres repeated at third and sixth month after surgery remained undetectable. Now after 1 year of follow-up, she is off steroid, on weekly methotrexate and is asymptomatic with disease in remission.

Discussion

JDM is the most common of the paediatric IIM). It is a multisystem disease which typically presents with proximal muscle weakness and rash but can frequently affect other organs. Our patient was a 6-year-old girl, who presented with classical features of JDM. Due to disease severity, she required aggressive immunosuppression at the onset with repeat pulses of MPSL and intravenous Ig. She then presented with abdominal pain due to colitis and colonic perforation. Vasculopathy is more associated with JDM than adult DM and can lead to perforation.⁵ As autoimmune diseases are prone for opportunistic infection, CMV colitis causing perforation, though previously not reported in JDM, was also considered.

Data regarding opportunistic infection in JDM is lacking. Previous studies have described infectious complications in around 26% in patients with IIMi.⁶ The most common of which are the infections of the respiratory system.⁶ In 2008, Takizawa et al studied 151 autoimmune disease patients, infected with CMV.⁷ Fifty per cent of the patients had Systemic Lupus Erythematosus (SLE) and 10% had IIM. In that series, GI symptoms were third in frequency after fever and respiratory symptoms.

Our patient had no fever or respiratory complaints at presentation though she became febrile in the night of admission just before surgery. She had abdominal pain but also normal bowel movement until the previous day of admission.

Chen et al studied 192 patients with IIM including 17 with JDM/Juvenile Polymyositis (JPM) and opportunistic infections.⁶ In that series, only four patients had CMV infection. None of them had colitis.

Marie et al studied the characteristics of infection in 279 patients with PM/DM at three medical centres in France from 1996 to 2009.⁸ There were 104 infections (37.3%) of which 33 (11.8%) were opportunistic infections and only 2 patients had CMV infection. There were discrete case reports of CMV infection in the literature of which two patients had colitis and one had rectal ulcer, but none had perforation.

Increased frequency of infections in patients with PM/DM is due to immune system dysfunction, the disease itself and immunosuppressive medications.⁹ It has already been established that the major risk factor for infection in patients with connective tissue disorders is the use of immunosuppressive drugs, mainly steroids. In a meta-analysis of 71 controlled clinical trials, the relative risk of infection was higher (OR 1.6; 95% CI 0.9 to 2.3) for patients receiving steroids, compared with those who did not.¹⁰ The risk of CMV reactivation on steroid administration was primarily demonstrated by a large-scale study in bone marrow transplantation patients.¹¹ Immunodeficiency in steroid use is mainly due to lymphopenia due to redistribution of circulating lymphocytes from the blood to other lymphoid compartments. Also, it causes suppression of IL-2 which also impairs T-cell dependent immunity.^12–14 Our patient had lymphopenia. Other than steroids, CMV reactivation has been seen to cause lymphopenia.¹⁵

Marie et al have observed that infections are common during the first year following PM/DM diagnosis, while receiving high doses of steroids and that most patients who had opportunistic infection in autoimmune disease were on steroids and methotrexate.⁸ Marie et al had only two patients with CMV colitis both of whom were DM/PM patients on methotrexate and steroid, as was our patient. Takizawa et al have found that pulsed MPSL raises the chance of CMV infection and mortality rate significantly when administered additionally to other therapeutic agents.⁷ Lee et al established that patients with high titre of CMV PCR (>60 000 copies/mL) had higher hospital mortality rates.¹⁶ Our patient’s CMV PCR was 15 924 copies/mL. Takizawa et al had also observed that the mortality rate with CMV was higher in patients with IIM in comparison to all autoimmune disease (46.7% vs 29.1%) despite adequate treatment.⁷ They theorised that this could be due to the starting of the treatment once the patient was severely symptomatic and in critical condition. They further proposed to treat CMV infection as soon as suspected. Many studies have also established that antiviral treatment at an early stage of reactivation is beneficial.^17–19

In our case, antiviral agents were started as soon as perforation was found. Alongside, her primary disease was treated with steroid and monthly intravenous Ig. After 3 weeks, her repeat CMV PCR in blood was undetectable, and ganciclovir was converted to oral valganciclovir, and she was discharged. Valganciclovir was stopped 6 months after surgery. CMV PCR titres remained undetectable. Now after 1 year of follow-up, she is off steroid, on weekly methotrexate and is asymptomatic. While CMV colitis causing perforation has been previously reported in autoimmune diseases like SLE,^{20 21} to our knowledge, this is the first case of a child with JDM developing a CMV colitis which was further complicated by a perforation.

learning points.

• Juvenile dermatomyositis (JDM) can be a serious disease causing significant morbidity and mortality. However, aggressive treatment can bring problems of its own.

• Opportunistic infections like cytomegalovirus (CMV) infection with complications should always be considered in the differential diagnosis when patient presents with symptoms even when optimally treated. This is a treatable condition which when untreated is associated with significant mortality and morbidity.

• Prompt action, considerate and optimal management can help to improve the overall outcome for the patient.

• This is possibly the first case report of a child with JDM developing CMV colitis which was further complicated by a perforation.