Cytomegalovirus-induced severe enterocolitis associated with ANCA-associated vasculitis and diffuse alveolar haemorrhage in a child: a diagnostic and therapeutic dilemma

Abstract

Background

ANCA-associated vasculitis (AAV) is rare in children and may be triggered by infections. Cytomegalovirus (CMV), a common pathogen, can rarely cause severe gastrointestinal complications like stricture, obstruction, and perforation. While adult cases suggest a potential association between CMV and AAV, reports of severe intestinal complications leading to AAV in immunocompetent children are scarce.

Case presentation

A previously healthy 12-year-old boy presented with fever, abdominal pain, and vomiting. Abdominal CT revealed intestinal obstruction and perforation. Emergency surgery confirmed acute hemorrhagic necrotizing enterocolitis, and metagenomic next-generation sequencing (mNGS) diagnosed CMV viremia. His condition deteriorated rapidly, culminating in acute respiratory failure and acute kidney injury requiring continuous renal replacement therapy. Serological testing using indirect immunofluorescence was positive for cytoplasmic-ANCA (C-ANCA). Confirmatory ELISA testing confirmed positivity for anti-proteinase 3 (PR3) antibodies at a titer of 1:51; anti-myeloperoxidase (MPO) antibodies were negative. Chest CT and bronchoscopy confirmed diffuse alveolar haemorrhage. AAV was diagnosed per the 2022 ACR/EULAR criteria. The central management challenge was the co-occurrence of active CMV infection and fulminant vasculitis. Immunosuppressive therapy was withheld until sepsis parameters normalized. A life-threatening bleeding event on day 13 prompted initiation of high-dose methylprednisolone and cyclophosphamide, leading to rapid clinical improvement. A subsequent renal biopsy showed subacute tubulointerstitial injury without crescents.

Conclusion

Severe CMV enterocolitis may be temporally associated with fulminant AAV in children. In pediatric cases of severe CMV infection with multi-organ dysfunction, a high index of suspicion for AAV and ANCA serology testing is warranted. Furthermore, multidisciplinary team input is crucial for guiding optimal timing of immunosuppression in the context of concurrent active infection, which is pivotal for improving patient outcomes.

Background

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases characterised by necrotising inflammation of small- to medium-sized vessels. The global prevalence of childhood-onset AAV is estimated at 3.41–4.28 cases per million children [1]. Although rare in this population, the disease often presents with complex clinical manifestations and frequently leads to multi-organ damage [2]. Its aetiology remains elusive; however, the prevailing hypothesis suggests that environmental factors, particularly infections, may be associated with disease onset in genetically susceptible individuals [3]. Cytomegalovirus (CMV) infection is ubiquitous and typically asymptomatic or self-limited in the general population. Nevertheless, severe complications, including enterocolitis with potential progression to obstruction or perforation can occur in immunocompetent hosts [4, 5]. Although CMV infection has been reported in association with AAV in adults [6], this link predominantly reflects viral reactivation following immunosuppression. In contrast, our pediatric case suggests a reversed temporal sequence, in which active CMV infection may have acted as a precipitating trigger for the disease. Despite these documented associations, no systematic reports of severe CMV enterocolitis acting as a precursor to AAV, culminating in life-threatening multi-organ involvement in a child. Herein, we present a rare case to illustrate this diagnostic and therapeutic challenge, explore potential pathogenesis through a literature review, and share our clinical experience in balancing immunosuppressive therapy with active infection.

Case presentation

A previously healthy 12-year-old boy was admitted with a 2-day history of fever, abdominal pain, and vomiting. Prior to this acute illness, the child had a complete vaccination history and no history of recurrent infections. Upon admission, HIV serology was negative, and serum immunoglobulin (IgG, IgA, IgM) levels, as well as lymphocyte subset counts were within normal limits for age, supporting an immunocompetent status before the acute infection. Abdominal computed tomography (CT) revealed intestinal perforation (Fig. 1A) and obstruction (Fig. 1B). An emergency laparotomy identified intestinal necrosis, which necessitated segmental bowel resection and anastomosis. Histopathological examination of the resected specimen confirmed acute hemorrhagic necrotising enterocolitis (Fig. 2). Broad-spectrum antibiotics were administered postoperatively. Concurrently, metagenomic next-generation sequencing (mNGS)—a culture-independent, unbiased approach for comprehensive pathogen detection—performed on blood collected upon admission was positive for CMV, prompting the immediate initiation of intravenous ganciclovir.

Fig. 1.

Abdominal CT at admission. A Axial view showing retroperitoneal free air (arrow), highly suggestive of gastrointestinal perforation. B Coronal view demonstrating dilated, gas-filled intestinal loops with disordered arrangement, consistent with intestinal obstruction

Fig. 2.

Histopathology of the resected ileum specimen (Hematoxylin and Eosin staining, ×100). Acute hemorrhagic necrotising enterocolitis is seen, characterised by transmural necrosis, interstitial haemorrhage, and inflammatory cell infiltration

A rapid clinical deterioration complicated the patient’s early postoperative course. He developed acute respiratory failure, requiring reintubation and mechanical ventilation. Chest CT demonstrated diffuse exudative opacities in both lungs (Fig. 3). Concurrently, he became anuric, with serum creatinine escalating to 772 µmol/L, necessitating continuous renal replacement therapy (CRRT). Urinalysis showed proteinuria (2+) and microscopic hematuria (3+). Subcutaneous hemorrhagic spots were also noted in the axillary region.

Fig. 3.

Chest CT during clinical deterioration. Bilateral, extensive patchy consolidations are evident, which developed concurrently with the onset of acute respiratory failure

Serological testing was pivotal in establishing the diagnosis. ANCA testing was performed using standard indirect immunofluorescence, which revealed a cytoplasmic (C-ANCA) pattern. Confirmatory antigen-specific ELISA testing was positive for anti-proteinase 3 (PR3) antibodies at a titer of 1:51, while testing for anti-myeloperoxidase (MPO) antibodies was negative. Antinuclear and anticardiolipin antibodies were also negative. Based on the clinical presentation, serological findings (PR3-ANCA positivity), and radiological evidence of diffuse alveolar haemorrhage, the patient met the classification criteria for granulomatosis with polyangiitis (GPA) according to the 2022 ACR/EULAR framework. Accordingly, a diagnosis of AAV (GPA) was made based on the integrated clinical and paraclinical evidence.

The central therapeutic challenge was the coexistence of life-threatening AAV and active CMV infection. Immunosuppressive therapy was initially withheld due to uncontrolled sepsis, with management focused on organ support. Over the following week, markers of infection (white blood cell count, C-reactive protein, procalcitonin) normalised. However, on hospital day 13, he experienced a dramatic flare of vasculitis, manifested by hemoptysis and worsening subcutaneous haemorrhage. Bronchoscopy confirmed diffuse alveolar haemorrhage, which was corroborated by subsequent imaging (Figs. 4 and 5).

Fig. 4.

Histopathology of lung tissue (Hematoxylin and Eosin staining, ×100). Diffuse alveolar damage with prominent alveolar haemorrhage is observed

Fig. 5.

Chest radiograph suggestive of diffuse alveolar haemorrhage (DAH). The image shows an increasing confluence of bilateral patchy opacities. In the context of hemoptysis and active vasculitis, these findings are highly consistent with DAH

Faced with controlled infection but life-threatening vasculitis, high-dose methylprednisolone pulse therapy combined with cyclophosphamide was initiated. The clinical response was rapid; subcutaneous and pulmonary haemorrhage began to resolve within 24 h. The patient was successfully extubated on hospital day 35, and CRRT was discontinued as renal function recovered (Fig. 6). A renal biopsy was not performed during the acute phase due to the patient’s instability and family concerns.

Fig. 6.

Disease course and management timeline. This schematic illustrates the progression from cytomegalovirus (CMV) enterocolitis complicated by intestinal perforation to the development of ANCA-associated vasculitis with diffuse alveolar haemorrhage and acute kidney injury in a 12-year-old boy. The critical temporal relationship between CMV infection control and the subsequent vasculitis flare is highlighted, demonstrating the therapeutic challenge in timing immunosuppressive initiation. (CMV: cytomegalovirus; AAV: ANCA-associated vasculitis; DAH: diffuse alveolar haemorrhage; AKI: acute kidney injury)

The patient was discharged in a stable condition on hospital day 47. A follow-up renal biopsy one month later primarily showed subacute tubulointerstitial injury (Fig. 7), with no evidence of active crescentic glomerulonephritis.

Fig. 7.

Renal pathological findings at one-month post-discharge. A Light microscopy (Hematoxylin and Eosin staining, ×400) reveals mild glomerular mesangial hypercellularity, periglomerular fibrosis, and severe vacuolar degeneration of tubular epithelial cells with luminal dilation and brush border loss. B PAS staining (×400) shows no thickening of the glomerular basement membrane and no significant eosinophilic deposits in the mesangial, subepithelial, or subendothelial areas. C, D Electron microscopy demonstrates segmental foot process effacement and shedding of tubular microvilli. Interstitial oedema with infiltration of lymphocytes and monocytes is also present

Discussion

Clinical cases of cytomegalovirus (CMV) infection complicated by intestinal perforation are rare in immunocompetent individuals, with previous reports focusing on immunosuppressed patients, such as those infected with human immunodeficiency virus (HIV) or organ transplant recipients [7, 8]. Studies on the clinical features of CMV infection associated with intestinal necrosis and perforation in infants have shown that these complications are infrequent in this population [9, 10]. Arnold et al., in a systematic review of gastrointestinal manifestations of CMV in children, found that intestinal perforation occurred in 18% of cases; notably, all children who developed perforations had underlying risk factors for impaired immune function [11]. Thus, reports of intestinal perforation following CMV infection in immunocompetent children remain scarce.

The mechanism of injury may be related to CMV’s ability to infect both epithelial and smooth muscle cells, potentially triggering a lysogenic infection that leads to necrosis and perforation. CMV impairs gap junction function by down-regulating connexin 43 [12], disrupting intestinal barrier integrity. In this case, CMV inclusion bodies were not detected on pathologic examination, which may be related to sampling limitations. As Arnold et al. also indicated, CMV inclusion bodies are not necessarily visible on histologic examination of affected organs in children with CMV-associated gastrointestinal complications [11].

While the clear temporal sequence in our case is consistent with a potential triggering role of CMV in the development of AAV, we acknowledge that definitive causality cannot be established from a single observation. The following discussion outlines plausible pathophysiological hypotheses that may explain this association. Although the aetiology of AAV remains incompletely elucidated, a widely accepted pathogenic model involves a breakdown of immune tolerance in genetically susceptible individuals triggered by specific environmental factors, among which viral infections are considered pivotal. The association between cytomegalovirus (CMV) infection and the onset of AAV, while supported by clinical observations, remains incompletely characterized, with the underlying mechanisms yet to be fully defined. CMV infection does not appear to stimulate ANCA production directly, but may instead induce vasculitis through indirect immunomodulatory effects.

A key mechanism may involve the expansion of CD4 + CD28– T cells, a population typically expanded in response to CMV infection [13–15]. These lymphocytes exhibit a pro-inflammatory, cytotoxic phenotype, characterized by the expression of CD57, granzyme B, and perforin [16]. In patients with AAV, CD4 + CD28– T cells are biased toward a Th1 phenotype and have been identified as a significant source of interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) upon stimulation with CMV antigens [13, 17].

As endothelial cells are a primary target of CMV [18], the local release of IFN-γ and TNF-α plays a critical role in disrupting endothelial integrity. These cytokines compromise endothelial cell-to-cell junctions and upregulate the expression of adhesion molecules and chemokines on the vascular surface [19]. This process promotes the recruitment, adhesion, and transendothelial migration of leukocytes, thereby amplifying vascular inflammation. Furthermore, aberrant neutrophil activation and apoptosis are central to AAV pathogenesis, a process that the CMV-fostered inflammatory milieu may exacerbate. Additionally, CMV may contribute to vascular injury through other pathways, including direct induction of endothelial apoptosis and stimulation of smooth muscle cell proliferation [20]. These mechanisms likely act in concert, synergistically aggravating the severity of vascular lesions in AAV.

This case underscores the diagnostic and therapeutic complexities inherent in ANCA-associated vasculitis (AAV). The development of diffuse alveolar haemorrhage (DAH), while highly suggestive of pulmonary vasculitis, is not pathognomonic for AAV and can occur in other conditions, including severe infections, acute respiratory distress syndrome, or coagulopathies. However, in our patient, the temporal association of DAH with ANCA seropositivity, the absence of alternative explanations for pulmonary haemorrhage (coagulation parameters were within normal limits, and there was no evidence of fluid overload), and most importantly, the dramatic response to immunosuppressive therapy all strongly support a vasculitic etiology rather than a purely infectious or critical illness-related complication.

This diagnostic reasoning, however, unfolded progressively as clinical manifestations evolved. Consistent with this, it is estimated that approximately 60% of AAV patients experience diagnostic delays [21], a challenge that was particularly pronounced in our patient. The initial presentation of intestinal obstruction, perforation, and CMV infection, coupled with a positive ANCA serology, necessitated a critical differentiation from inflammatory bowel disease (IBD), given that atypical P-ANCA is strongly associated with colonic lesions [22, 23] and PR3-ANCA can be present in juvenile ulcerative colitis [24]. Consequently, in the absence of classic renal or pulmonary symptoms early on, distinguishing AAV from IBD became a central diagnostic challenge.

The renal pathological findings in our case warrant in-depth consideration. The absence of crescentic glomerulonephritis on follow-up biopsy makes less likely a classic vasculitic etiology for the acute kidney injury (AKI) [25, 26]. Notably, the biopsy was performed on follow-up, and histopathology may have been influenced by the clinical course and treatment. This necessitates a careful evaluation of alternative etiologies. In the context of the patient’s critical illness, the following non-vasculitic causes are highly plausible and likely predominated: 1) sepsis-associated acute tubular necrosis, strongly supported by documented hemodynamic instability; 2) ischemic injury secondary to intestinal perforation and major surgery; and 3) possible direct CMV-mediated renal tubular injury, given the active systemic infection and the virus’s known renal tropism. While the observed limited-glomerular histological pattern—characterized by predominant tubulointerstitial injury without crescents—has been described in approximately 20–25% of ANCA-associated glomerulonephritis cases and is generally associated with a more favorable prognosis [25–27], its presence in this case does not exclude the crucial role of the aforementioned non-vasculitic insults. The patient’s renal recovery aligns with the resolution of these primary septic, ischemic, and potential viral injuries. Therefore, the overall evidence suggests that the AKI likely had a multifactorial origin, with critical illness-related factors constituting the principal drivers, rather than a definitive primary vasculitis.

Therapeutically, this case exemplifies the profound dilemma of initiating immunosuppression in the context of active infection. While CMV reactivation is a recognised complication following immunosuppressive therapy for AAV [3, 28, 29], our case is distinctive because fulminant CMV enterocolitis and subsequent sepsis preceded the diagnosis of AAV. This sequence created a critical juncture: early immunosuppression risked exacerbating the infection, while delayed treatment risked irreversible organ damage from escalating vasculitis. The decision to initiate high-dose immunosuppression was therefore carefully timed, guided by the resolution of sepsis markers and the life-threatening progression of diffuse alveolar haemorrhage. The patient’s favourable outcome validates this judicious, monitored approach.

Conclusion

In summary, this case highlights a critical clinical consideration: severe cytomegalovirus infection, particularly with gastrointestinal involvement, may precede fulminant ANCA-associated vasculitis in children. Consequently, we recommend a high index of suspicion and early ANCA serology testing in pediatric patients with severe CMV who develop persistent systemic inflammation or unexplained multi-organ dysfunction. It is important to acknowledge the limitations of deriving causal inferences from a single case report; the proposed sequence and management approach require confirmation through larger, prospective studies. The successful navigation of the ensuing therapeutic paradox—balancing aggressive immunosuppression against active infection—mandates a multidisciplinary collaboration among pediatric rheumatology, intensive care, and infectious disease specialists from the outset. This collaborative framework is essential for tailoring therapeutic strategies that optimally manage the competing risks of uncontrolled autoimmunity and overwhelming infection.

Abbreviations

AAV

ANCA-associated vasculitis

ACR

American College of Rheumatology

AKI

Acute kidney injury

ANCA

Antineutrophil cytoplasmic antibody

C-ANCA

Cytoplasmic antineutrophil cytoplasmic antibody

CMV

Cytomegalovirus

CRRT

Continuous renal replacement therapy

CT

Computed tomography

DAH

Diffuse alveolar haemorrhage

EULAR

European Alliance of Associations for Rheumatology

GPA

Granulomatosis with polyangiitis

IBD

Inflammatory bowel disease

IFN-γ

Interferon-gamma

mNGS

Metagenomic next-generation sequencing

MPO

Myeloperoxidase

P-ANCA

Perinuclear antineutrophil cytoplasmic antibody

PR3

Proteinase 3

TNF-α

Tumor necrosis factor-alpha

Authors’ contributions

DW Ma, SH Xu, and DP Yu are co-first authors. DW Ma conceived the study, designed the overall methodology, and supervised the entire project. SH Xu led patient recruitment and clinical data interpretation. DP Yu led the pathological analysis and interpretation. The initial manuscript was drafted by DW Ma and critically revised by SH Xu and DP Yu. LY Yang, Y Li, and QP Yuan managed critical care aspects and data collection. AK Peng and HH Yang performed and analysed cardiological evaluations. DW Ma, as the corresponding author, is the guarantor of the work. All authors reviewed and approved the final manuscript.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

The publication of this case report was approved by the Ethics Committee of the People’s Hospital of Pu’er City. Written informed consent for publication was obtained from the patient’s parent. The authors hold the consent form, which is available for review if requested.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare no competing interests.