Severe Disseminated Adenovirus Infection After Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report

Abstract

Patient: Male, 52-year-old

Final Diagnosis: Disseminated adenovirus • septic shock

Symptoms: Cough • dyspnea • fever • hematuria • hyponatremia • leukopenia • transaminitis

Clinical Procedure: Bronchoscopy • continuous renal replacement therapy • cystoscopy • HSCT • intubation • lumbar puncture • pericardiocentesis • ureteral stent implantation

Specialty: General and Internal Medicine

Objective: Unusual clinical course

Background

Adenoviruses are double-stranded DNA viruses capable of causing a spectrum of diseases from mild respiratory infections to severe systemic illnesses. Disseminated adenovirus is evidenced by gastrointestinal, pulmonary, genitourinary, neurologic and even cardiac involvement. In immunocompromised individuals, adenovirus infections can become severe and are often associated with significant morbidity and mortality.

Case Report

A 52-year-old man with a history of large granular lymphocytic (LGL) leukemia underwent haploidentical hematopoietic stem cell transplantation (HSCT). His course was complicated by the diagnosis of hemorrhagic cystitis with findings of adenovirus. His condition rapidly declined, necessitating Intensive Care Unit (ICU) admission. Comprehensive workup identified adenovirus in the serum and cerebrospinal fluid (CSF), bronchoalveolar lavage fluid, and positive stool adenovirus. Echocardiographic evaluation revealed a moderate pericardial effusion requiring pericardiocentesis. Unfortunately, adenovirus testing of the aspirate could not be performed. Given the diagnosis of disseminated adenovirus infection, treatment with cidofovir and probenecid was initiated, but despite these interventions, the patient’s status continued to deteriorate complicated by multiorgan failure and refractory shock.

Conclusions

This case underscores the complexity of diagnosing disseminated adenovirus, particularly given the potential for multiorgan system involvement. Early recognition is essential, such as viral polymerase chain reaction (PCR), playing a critical role in the identification and monitoring of infection. The case further emphasizes the pressing need for continued research into novel antiviral therapies and preventive measures to mitigate the risk of adenovirus in this vulnerable population.

Introduction

Adenoviruses are non-enveloped, double-stranded DNA viruses known to cause a broad spectrum of clinical illnesses, ranging from mild upper-respiratory infections to severe, disseminated disease. In immunocompromised patients, particularly hematopoietic stem cell transplant (HSCT) recipients, adenovirus can lead to life-threatening systemic infections with high morbidity and mortality rates [1,2]. Disseminated adenovirus infection can present with respiratory failure, hemorrhagic cystitis, enteritis, encephalitis, and multiorgan dysfunction. Cardiac manifestations, including myocarditis and pericardial effusion, although well documented in pediatric cohorts, remain exceedingly rare in adults [3,4].

Diagnosis is typically confirmed via polymerase chain reaction (PCR) testing of serum or involved body fluids, with high viral loads correlating with worse clinical outcomes. Management is particularly challenging due to the lack of approved, effective antiviral therapies. Cidofovir, a nucleotide analog with known nephrotoxicity, remains the primary treatment option. Brincidofovir, a lipid-conjugated derivative of cidofovir, offers reduced renal toxicity and shows promise but has limited availability [2,5]. Adjunctive therapies, including intravenous immunoglobulin (IVIG) and the co-administration of probenecid, are often used to mitigate adverse effects.

This case highlights the diagnostic and therapeutic challenges of disseminated adenovirus infection in an adult HSCT recipient, particularly focusing on its rare systemic manifestations, including suspected cardiac involvement and central nervous system (CNS) disease.

Case Report

A 52-year-old man with a history of large granular lymphocytic (LGL) leukemia underwent an allogeneic haploidentical hematopoietic stem cell transplant (HSCT) from a first-degree relative. His conditioning regimen included fludarabine, thiotepa, and 4 Gy total body irradiation (TBI). The patient’s Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) score was 1, reflecting mild comorbidity due to a prior infection. He received post-transplant graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy), tacrolimus, mycophenolate mofetil (MMF), and budesonide. In addition, prophylactic acyclovir, atovaquone, posaconazole, and letermovir were administered. His early post-transplant course was complicated by cytomegalovirus (CMV) reactivation and BK viruria, which was initially treated with foscarnet before transitioning back to letermovir.

At post-transplant week 14, he developed high fever, a productive cough, and dyspnea, leading to hospitalization. Upon admission, he was febrile (39.2°C), tachycardic (HR 124 bpm), and hypoxic (SpO₂ 92% on room air). Laboratory tests showed severe leukopenia (WBC=0.7 K/μL). Respiratory panel results were positive for influenza A, and sputum and blood cultures were positive for Pseudomonas aeruginosa. Sputum cultures also grew Candida guilliermondii. Chest imaging revealed multifocal pneumonia (Figure 1), and he was treated with cefepime and ciprofloxacin for double Pseudomonas coverage and micafungin for fungal pneumonia, later switched to posaconazole. After 3 weeks of hospitalization, he was discharged to an acute rehabilitation facility for deconditioning, presenting with bilateral lower-extremity weakness and neuropathy.

Figure 1.

Computed tomography angiography of the chest with contrast revealing patchy and confluent non-enhancing consolidative opacities in both lungs, compatible with multifocal pneumonia, as indicated by the black arrows.

Approximately 3 weeks after discharge, he was readmitted with persistent hematuria, hyponatremia, and transaminitis. On admission, he was afebrile (36.5°C), tachycardic (HR 112 bpm), and without hypoxia (SpO₂ 95%). Laboratory tests revealed WBC 6.6 K/μL, hemoglobin 9.5 g/dL, platelets 20 K/μL, sodium 129 mEq/L, BUN 44 mg/dL, Cr 1.0 mg/dL, and transaminitis (AST 180 IU/L, ALT 48 IU/L, total bilirubin 1.5 mg/dL). Posaconazole was held due to hepatotoxicity, and micafungin was restarted.

A workup for hematuria, including renal and bladder ultrasound, urine cultures, and urine eosinophils, was unremarkable. Given the patient’s immunocompromised status and history of elevated BK virus levels, BK virus PCR was performed, revealing 15 952 copies/mL. He was managed supportively with hydration, bladder irrigation, and pain control. Despite these interventions, hematuria persisted with worsening blood clots. An immunoglobulin panel revealed hypogammaglobulinemia (IgG 283 mg/dL), prompting the administration of IVIG (0.5 g/kg) to assist with BK viruria clearance.

During hospitalization, he developed chills and a febrile episode (38.2°C). A respiratory panel detected adenovirus, although blood and sputum cultures remained negative. By hospital day 10, his respiratory status deteriorated, with chest CT revealing bilateral ground-glass opacities and new focal consolidations. He was started on cefepime, as repeat sputum cultures grew gram-negative rods.

A Karius panel detected adenovirus B and D, and serum adenoviral PCR was 4.9 million copies/mL. In response, cidofovir with probenecid was initiated, and antibiotics were escalated from cefepime to meropenem. Shortly after, he developed acute kidney injury (Cr 2.3 mg/dL) and worsening hemorrhagic cystitis. Urology performed cystoscopy with clot evacuation and bilateral ureteral stent placement.

Postoperatively, he developed acute hypoxic respiratory failure, requiring high-flow nasal cannula and ICU admission. His clinical course was further complicated by hypotension and persistent altered mental status. Given ongoing encephalopathy, a lumbar puncture was performed, revealing CSF-positive adenovirus PCR, confirming central nervous system (CNS) involvement.

By day 22, renal function continued to decline despite urological interventions, necessitating the initiation of hemodialysis, which was later transitioned to continuous renal replacement therapy (CRRT). On day 26, he developed progressive respiratory failure requiring intubation and mechanical ventilation. A comprehensive infectious workup for aspergillosis, Pneumocystis jirovecii (PJP), Legionella, Cryptococcus, and Coccidioides was negative, but sputum cultures grew Stenotrophomonas maltophilia. After discussion with Infectious Disease, antibiotics were switched to levofloxacin and minocycline, but his condition continued to worsen, with hypotension requiring norepinephrine and vasopressin, necessitating stress-dose steroids.

Despite these interventions, adenoviral PCR levels remained elevated, and multiorgan dysfunction progressed. Bronchoscopy with bronchoalveolar lavage (BAL) confirmed the presence of adenovirus and Stenotrophomonas, with negative fungal and tuberculosis studies. Respiratory failure continued to worsen, requiring up to 100% FiO₂. The patient’s condition was further complicated by a gastrointestinal bleed, with melena requiring transfusions. Stool studies were PCR-positive for adenovirus, indicating gastrointestinal involvement.

On day 28, transthoracic echocardiography (TTE) and CT chest were performed due to persistent tachycardia and hypotension, revealing a moderate pericardial effusion (Figure 2), suggestive of adenoviral myocarditis with pericardial involvement – an exceedingly rare manifestation in adult HSCT recipients. Despite renal replacement therapy, broad-spectrum antimicrobials, and antiviral therapy, the patient’s condition continued to deteriorate. On hospital day 29, goals-of-care discussions were held, and after shared decision-making with the family, care was transitioned to comfort measures. The patient died later that day.

Figure 2.

Computed tomography angiography of the chest with contrast showing moderate-sized pericardial effusion, as indicated by the white arrow.

Discussion

This case highlights the severe and often life-threatening nature of disseminated adenovirus infection in immunocompromised post-hematopoietic stem cell transplant (HSCT) patients.

Mortality can reach 83% in this population compared to approximately 60% in immunocompetent hosts, highlighting the devastating impact of adenoviral infections in the setting of prolonged immunosuppression [2,6]. Such disparities underscore the heightened vulnerability of transplant recipients to aggressive viral infections, particularly those with extended immunosuppression [2]. Disseminated adenovirus infection in post-HSCT patients remains a rare but devastating complication, often affecting multiple organ systems, including the respiratory, gastrointestinal, renal, neurological, and cardiac systems (Table 1). This case exemplifies multiorgan involvement [7]. While adenoviral infections commonly affect the respiratory and gastrointestinal systems in HSCT recipients, CNS and cardiac involvement is very rare in adult patients [7]. The presence of a new pericardial effusion raised concern for disseminated adenovirus, a diagnosis supported by the clinical context but unconfirmed due to insufficient pericardial fluid for PCR testing. Our inability to confirm adenoviral DNA in the pericardial fluid due to insufficient sample volume does not diminish the suspicion that adenovirus contributed to the effusion, reinforcing the complexity of diagnosing disseminated infections in immunocompromised hosts. Although adenoviral pericardial effusion is well documented in children [4], reports in adult HSCT recipients are sparse. Furthermore, the patient’s CNS involvement was confirmed by a positive adenoviral PCR in cerebrospinal fluid – a complication more commonly reported in pediatric patients [6], but rarely described in adults, underscoring the rarity of this manifestation.

Table 1.

Adenovirus PCR results in multiorgan systems.

	Organ systems involved
	Blood (serum)	Renal (urine)	Neurologic (CSF)	Pulmonary (Bronchoalveolar lavage fluid)	Gastrointestinal (stool)	Cardiac (pericardial fluid)
Adenovirus result (qPCR)	4 600 000 H copies/mL	460 000 H copies/mL	Positive	4.00 E+ 0.9 H copies/mL	4 700 000 H copies/mL	Insufficient volume

Despite early recognition and initiation of cidofovir with probenecid, the patient developed acute kidney injury and continued rapid clinical deterioration. This highlights the aggressive nature of adenoviral infection in immunocompromised adults, especially in those with persistent viremia.

Cidofovir, a nucleotide analog known to inhibit adenoviral replication, is the standard treatment for severe adenovirus infections in immunocompromised patients, particularly those who underwent HSCT [8,9]. However, the nephrotoxic potential of cidofovir poses a significant challenge, especially in patients with pre-existing renal issues. In this case, the decision to co-administer probenecid was aimed at minimizing nephrotoxicity, with prior studies observing reduced renal complications with this approach [3]. Despite this, the patient’s renal function continued to decline, and the clinical course rapidly worsened, which highlights the limitations of current antiviral agents in controlling adenoviral infections in HSCT recipients [10].

One alternative treatment to cidofovir is brincidofovir, a lipid-conjugated derivative with reduced nephrotoxicity. However, the clinical efficacy of brincidofovir remains under investigation [5], and was not available for this patient. The continued focus on antiviral therapies, including adoptive T cell therapies, presents a promising future direction in managing adenoviral infections. The application of genetic engineering for more targeted antiviral T cell therapies is a novel approach that may improve outcomes for these high-risk patients [11].

This patient’s clinical deterioration due to multiorgan adenoviral involvement, including suspected cardiac involvement with pericardial effusion and CNS involvement, presents several diagnostic and management challenges. The rapid onset of pericardial effusion required a thorough differential diagnosis, which included bacterial infections, graft-versus-host disease (GVHD), and post-transplant lymphoproliferative disorder (PTLD), all of which were ruled out. However, given the patient’s history of HSCT, immunosuppression, and the systemic nature of the infection, adenovirus was considered the most likely etiology. This case emphasizes the need for heightened awareness of disseminated adenovirus infections in HSCT recipients. As demonstrated, the virus can lead to extensive multiorgan failure, including rare complications like pericardial effusion, which has not been widely reported in adult transplant recipients. The findings of this case align with recent literature that underscores the poor prognosis of disseminated adenovirus infections in post-HSCT patients. Despite antiviral treatment, mortality remains high due to the rapid progression of the disease and the limited therapeutic options. There is a pressing need for novel therapeutic strategies, such as adoptive T cell therapy, to address adenoviral infections in these vulnerable populations. Engineered antiviral T cells could offer a more targeted and effective approach to managing these infections [5,11]. However, further research is required to determine the efficacy and safety of these novel treatments in clinical practice.

This case underscores the significant challenges in diagnosing and managing disseminated adenovirus infection, particularly in immunocompromised post-HSCT patients [7]. The multiorgan involvement observed in this case – spanning the respiratory, renal, gastrointestinal, neurological, and potentially cardiac systems – emphasizes the need for heightened clinical suspicion and early recognition. A high index of suspicion, rapid diagnostic workup, and timely initiation of therapy are critical but may still be insufficient, reflecting the need for better therapeutic options.

Conclusions

The case illustrates the aggressive and multiorgan nature of disseminated adenovirus infection in an immunocompromised post-HSCT patient. Despite early antiviral intervention with cidofovir and adjunctive therapy, the patient developed multiorgan failure, including rare cardiac and CNS involvement, ultimately leading to death. This case report shows the limitations of current antiviral therapies, specifically the use of cidofovir, which, despite early initiation, did not prevent the patient’s rapid clinical deterioration. This outcome illustrates the urgent need for continued research into novel antiviral treatments and preventive strategies. While the prognosis for disseminated adenovirus remains poor, there is potential for improved outcomes through early identification, timely antiviral interventions, and a multidisciplinary care approach. Collaboration among infectious disease specialists, transplant teams, nephrologists, and critical care providers is essential for managing the complex needs of these patients. Additionally, the integration of novel diagnostic tools and therapeutic options could further enhance survival rates and quality of life for post-transplant patients.

In conclusion, the case serves as a reminder of the complexity of managing adenovirus infections in immunocompromised patients and highlights the need for ongoing innovation in both diagnostic and therapeutic approaches to improve outcomes in this vulnerable population.