First Reported Case of Upadacitinib-Associated Cytomegalovirus Viremia and Suspected Pneumonitis in Ulcerative Colitis

Abstract

Cytomegalovirus (CMV) reactivation is a clinically important risk in patients with inflammatory bowel disease, particularly those receiving systemic immunosuppression or Janus kinase (JAK) inhibitor therapy, which can impair immunity. JAK inhibitors, including upadacitinib, may predispose patients to opportunistic viral infections. We report a patient with moderate ulcerative colitis who developed CMV viremia with suspected CMV pneumonitis 4 weeks after starting upadacitinib. Antiviral therapy led to clinical and virologic resolution. This case broadens the spectrum of CMV-related complications associated with JAK inhibition and underscores the importance of maintaining vigilance for systemic viral reactivation in inflammatory bowel disease patients receiving immunosuppressive therapy.

INTRODUCTION

Upadacitinib is a Janus kinase 1 (JAK1)-selective inhibitor effective in ulcerative colitis (UC) with primary nonresponse.¹ Upadacitinib increases the risk of opportunistic infections, with rare reports of cytomegalovirus (CMV) colitis and viremia.² CMV colitis has been reported with upadacitinib in UC, and CMV retinitis in rheumatoid arthritis.^3,4 To date, CMV viremia or pneumonitis associated with upadacitinib has not been reported.

CASE REPORT

A 59-year-old man with UC presented 4 weeks after initiating upadacitinib 30 mg daily. His medical history included primary sclerosing cholangitis on ursodiol 300 mg twice daily, polymyalgia rheumatica on a stable, chronic low-dose prednisone 2 mg twice daily since 2021, and previous prostate cancer treated with brachytherapy. He presented with 9 days of fever, chills, night sweats, shortness of breath, and a nonproductive cough. On admission, temperature was 101.5°F. Laboratory evaluation revealed a white blood cell count of 9.9 × 10³/µL. Comprehensive metabolic panel revealed hyponatremia and elevated liver enzymes; urinalysis and chest X-ray were unremarkable.

A computed tomography (CT) angiogram of the chest (Figure 1) revealed bilateral pneumatoceles, pulmonary densities, and a right-sided posterior subpleural density. Gastroenterology was consulted, and magnetic resonance cholangiopancreatography demonstrated diffuse irregular intrahepatic bile ducts, more prominent in the left lobe than the right, consistent with primary sclerosing cholangitis. In addition, there was colonic wall thickening, most prominent in the ascending colon, hepatic flexure, and proximal transverse colon, consistent with UC.

Figure 1.

(A and B) CTA of the chest with bilateral pneumatoceles, findings consistent with an ongoing infectious process. (C) CTA of the chest revealing a posterior subpleural linear density in the superior segment of the right lower lobe. Bilateral pneumatoceles are also noted. CTA, computed tomography angiogram.

Infectious disease was consulted for fever of unknown origin. A white blood cell scan revealed atypical infection in the bilateral lung bases (Figure 2). Owing to worsening leukocytosis and rising liver function tests, empiric piperacillin-tazobactam was initiated. However, a subsequent complete blood count with differential revealed 59% lymphocytes, suggesting a viral etiology, prompting discontinuation of antibiotics.

Figure 2.

White blood cell scan showing abnormal diffuse bilateral lung activity, findings consistent with an occult atypical infection. The remainder of the tracer distribution is physiologic.

An extensive infectious workup including viral panels, HIV, hepatitis, and blood cultures was negative. Varicella zoster virus serology showed positive IgG with negative IgM. Previous shingles vaccination made active varicella zoster virus unlikely. Inflammatory markers included an erythrocyte sedimentation rate of 40 mm/hr, C-reactive protein of 4.8 mg/dL, and stool calprotectin of 734 μg/g.

CMV DNA PCR was elevated at 119,000 IU/mL, confirming CMV viremia. The patient was started on valganciclovir, leading to significant improvement in respiratory symptoms, making Pneumocystis jirovecii pneumonia (PJP) less likely. Pulmonology was consulted for suspected pneumonitis. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was performed for PJP staining and CMV cytology. Bronchoscopy revealed oral candidiasis (thrush) and chronic bronchitic changes. BAL culture grew Candida albicans, and cytology from the right lower lobe showed rare cells with cytopathic changes (Figure 3) suggestive but not diagnostic of CMV pneumonitis.

Figure 3.

(Papanicolaou stain, magnification 400×) Cytohistopathology of bronchial washing from the right lower lobe. One cell exhibits characteristics of a degenerated epithelial cell, including a large inclusion-like nucleolus and a washed-out, homogeneous chromatin pattern. Another cell displays macrophage-like cytoplasm with multiple nuclei, each containing large nucleolus-like inclusions. No other ciliated bronchial columnar cells with enlarged nuclei or possible cytoplasmic inclusions were identified. The slide shows rare cells with features suggestive of, but not diagnostic for, cytomegalovirus viral cytopathic effect (white arrow).

Symptoms continued to improve on valganciclovir without PJP treatment, supporting CMV as the primary etiology. The patient was discharged with a regimen of valganciclovir, nystatin, and ipratropium bromide/albuterol inhaler.

At 3 weeks, CMV DNA was undetectable in plasma and BAL, and chest CT was normal. Upadacitinib was resumed at 15 mg daily. Mirikizumab was discussed, but the patient chose to continue upadacitinib. At 3 months, colonoscopy revealed crypt cell–type dysplasia in the mid to ascending colon, prompting colectomy. Chromoendoscopy and CT enterography were planned to assess extent and small bowel involvement. Total proctocolectomy and total abdominal colectomy (TAC) with ileorectal anastomosis (IRA) were discussed, with surgery scheduled based on these results.

DISCUSSION

Upadacitinib is an oral, reversible JAK1-selective inhibitor that modulates the JAK-STAT pathway by disrupting interleukin-6 (IL-6) and interferon-gamma (IFN-γ) signaling.⁵ Its immunosuppressive effects increase the risk of opportunistic infections, with higher rates at 30 mg and 45 mg compared with 15 mg.⁶

CMV reactivation in UC is multifactorial, driven by inflammation, immunosuppression, and patient-specific factors.⁷ Corticosteroids pose the greatest pharmacologic risk, with studies showing a dose-dependent and duration-dependent risk. Higher doses ≥20 mg/d substantially increase the risk. However, the risk at lower doses (eg, 4 mg/d) is unclear.^8,9 Concomitant JAK inhibitor use may increase immunosuppressive burden, although clinical trials have not demonstrated a significant increase in CMV infection.^10,11

The plasma CMV viral load in this patient was markedly elevated at 119,000 IU/mL, well above the median of 41,939 IU/mL in confirmed CMV pneumonitis, indicating active systemic CMV replication.¹² However, these cohorts included heterogeneous immunocompromised populations, and extrapolation to inflammatory bowel disease (IBD) patients receiving JAK inhibitors is limited. Despite nondiagnostic BAL cytology, the clinical presentation, elevated CMV DNA, imaging findings, and response to antivirals support CMV pneumonitis. Higher viral loads are associated with worse outcomes; however, CMV DNA level alone is not independently prognostic and must be interpreted in clinical context; here, the absence of respiratory failure or multiorgan involvement suggested a favorable short-term prognosis.^13–15

In our patient, following resolution of CMV, therapy was resumed at 15 mg daily through multidisciplinary consensus, balancing inflammation control with the risks of further immunosuppression, particularly in the setting of refractory dysplasia. Upadacitinib 15 mg daily was selected as the lowest FDA-approved maintenance dose with proven clinical and endoscopic efficacy in moderate-to-severe UC.¹⁶ Post-marketing and long-term safety data demonstrate modest, dose-dependent infection risks.¹¹ There is no published evidence supporting dose reduction from 30 to 15 mg after serious infection, as pivotal trials did not permit dose adjustment, nor are outcomes of de-escalation after CMV viremia or pneumonitis addressed in current guidelines.¹⁶ Nevertheless, dose minimization aligns with clinical consensus emphasizing the lowest effective immunosuppressive dose, as both 15 and 30 mg are approved for maintenance therapy.¹⁷

Alternative biologics including mirikizumab (anti-IL23) were considered given the patient's previous secondary loss of response to vedolizumab (anti-integrin). Network meta-analyses suggest superior efficacy of upadacitinib compared with mirikizumab in moderate-to-severe UC, particularly in biologic-exposed patients.^18,19 Upadacitinib was resumed at a reduced dose after individualized risk-benefit assessment, while mirikizumab was discussed but declined by the patient.

CMV viremia and pneumonitis are rare and poorly characterized among patients with IBD receiving JAK inhibitors. Postmarketing data are limited, and upadacitinib remains relatively new in this population. This case highlights a novel presentation, underscoring the need for further study of incidence, risk factors, and mechanisms of CMV reactivation with upadacitinib in patients with IBD. Heightened clinical awareness is essential for early recognition and management of these rare but serious complications.

DISCLOSURES

Author contributions: WJ Javier-Rojas: Provided direct patient care; conducted comprehensive literature searches and critical reviews; organized and managed references; extracted and systematically organized data from the patient's medical records; drafted and edited the manuscript; verified factual accuracy and performed final proofreading; and created the figures with accompanying legends. Served as the guarantor of the article and accepts full responsibility for the accuracy and integrity of the study. AB Newman-Caro: Conducted literature searches and critical reviews; and contributed to drafting and revising the manuscript. M. Ghellai: Conducted literature searches and contributed to manuscript drafting and revision. V. Mupparaju: Conducted a critical review of the manuscript for key intellectual and conceptual content. S. Chandrupatla: Conducted a critical review of the manuscript for key intellectual and conceptual content. S. Mathur: Conducted a critical review of the manuscript for key intellectual and conceptual content. Y. Lin: Conducted a critical review of the manuscript for key intellectual and conceptual content.

Acknowledgments: We extend our sincere gratitude to Dr. Joanna Kosko of the Pathology Department at HCA Florida Blake Hospital for generously providing the histopathological image along with her expert interpretation.

Financial disclosure: None to report.

Previous presentation: This case report was presented at the American College of Gastroenterology (ACG) 2025 Annual Scientific Meeting; October 27, 2025; Phoenix, Arizona.

Informed written and verbal consent were obtained for this case report.

ABBREVIATIONS:

µg/g

Micrograms per gram

anti-IL23

Anti-interleukin-23

BAL

Bronchoalveolar lavage

CMV DNA PCR

Cytomegalovirus Deoxyribonucleic Acid Polymerase Chain Reaction

CMV

Cytomegalovirus

CT

Computed tomography

F

Fahrenheit

FDA

Food and Drug Administration

HIV

Human immunodeficiency virus

IBD

Inflammatory bowel disease

IFN-γ

Interferon-gamma

IgG

Immunoglobulin G

IgM

mmunoglobulin M

IL-6

Interleukin-6

IRA

ileorectal anastomosis

IU/mL

International Units per Milliliter

JAK

Janus kinase

JAK1

Janus kinase1

mg

Milligram

mg/d

Milligrams per day

mg/dL

Milligrams per deciliter

mm/hr

Millimeters per hour

PJP

Pneumocystis jirovecii pneumonia

STAT

Signal Transducer and Activator of Transcription

TAC

Total abdominal colectomy

UC

Ulcerative Colitis

uL

Microliter