Cytomegalovirus infection in heart transplant patient presenting as appendicitis

Abstract

Cytomegalovirus (CMV) may manifest in various ways. While immunocompetent hosts may be asymptomatic or present with a mononucleosis-like illness, immunocompromised patients can have organ-specific disease capable of significant morbidity and mortality. CMV appendicitis is a particularly rare presentation. A 22-year-old female with a history of orthotopic heart transplantation presented to our hospital with a three-day history of worsening abdominal pain. A computed tomography scan of her abdomen was consistent with acute uncomplicated appendicitis, and she underwent laparoscopic appendectomy. Pathology revealed acute appendicitis with numerous large cells with intranuclear “owl's eye” inclusions characteristic of CMV. Her CMV viral load was elevated at 327,018 IU/ml. She was started on ganciclovir which resulted in improvement of her CMV level to 30,118 IU/ml within three weeks. CMV is a frequent cause of opportunistic infection in solid organ transplant patients and commonly involves the gastrointestinal tract. Acute appendicitis is a rarely reported complication to consider in the differential diagnosis of abdominal pain in immunocompromised patients.

Learning objective

Heart transplant recipients are at increased risk for opportunistic infections. Cytomegalovirus (CMV) is a frequent culprit and can present with a broad range of disease. A particularly rare presentation is that of acute appendicitis. We describe a case of a young woman with CMV appendicitis following orthotopic heart transplant.

Introduction

Cytomegalovirus (CMV) infections may manifest in various ways, and the clinical presentations vary between immunocompetent and immunocompromised hosts. For immunocompetent patients, the most common presentation is an illness resembling infectious mononucleosis. While infectious mononucleosis is mostly caused by Epstein-Barr virus, approximately 5–7 % of time it is due to CMV [1]. Among immunocompromised patients, CMV infection can manifest as tissue-invasive disease with specific organ involvement and cause significant morbidity and mortality. CMV is a common infectious complication for patients with hematopoietic stem cell transplant (HSCT) or solid organ transplant [2].

Prevention strategies include screening transplant recipients and donors using CMV serology for risk stratification. Transplant recipients who lack preexisting CMV-specific immunity and receive an organ from a CMV seropositive donor (D+/R−) are deemed high-risk, with an incidence of CMV infection up to 24 % [3]. If the recipient is seropositive and the donor is either seropositive or seronegative (D+/R+ or D−/R+) they are at moderate risk; and if both are CMV-seronegative (D−/R−), they are at low risk for developing CMV infection. The CMV serostatus provides guidance for antiviral prophylaxis and viral surveillance using serial CMV quantitative nucleic acid testing (QNAT) [4].

The increased morbidity associated with CMV infections in transplant recipients is in part due to the potential for organ-specific disease, frequently involving the gastrointestinal tract. While CMV colitis is a well-known complication, CMV infection may also present as esophagitis, gastritis, duodenitis, ileitis, or proctitis. An unusual presentation of CMV is that of acute appendicitis, which has mainly been reported in patients infected with human immunodeficiency virus (HIV) and rarely in solid organ transplant recipients [5]. We present a case of a young woman with CMV appendicitis following orthotopic heart transplant.

Case report

A 22-year-old female with a history of orthotopic heart transplantation one month previously for end-stage hypertrophic cardiomyopathy presented to our hospital with a three-day history of worsening shortness of breath, lightheadedness, abdominal pain, dysuria, and fever. Her immunosuppressive regimen at the time of presentation included prednisone 15 mg daily, mycophenolate 360 mg three times a day, and tacrolimus 6 mg every morning and 5 mg nightly. Her tacrolimus level was 4.5 (goal: 10–12). She was taking acyclovir, trimethoprim/sulfamethoxazole, and nystatin for prophylaxis of herpes simplex virus, Pneumocystis jiroveci pneumonia, and oropharyngeal fungal infections, respectively. She had no history of transplant rejection, which was monitored with endomyocardial biopsies. She had no prior history of CMV infection (serostatus D−/R−).

Upon presentation to the hospital, she was afebrile and hemodynamically stable. Examination was notable for mild, diffuse abdominal tenderness. Laboratory studies showed white blood cell (WBC) count 3000 cells/mm3, absolute lymphocyte count 600 cells/mm3, lactic acid 1.3 mmol/l, creatinine 1.12 mg/dl, and urinalysis was negative for nitrites and leukocyte esterase. Peripheral blood cultures were drawn at the time of admission and showed no growth. A computed tomography scan of the abdomen revealed acute uncomplicated appendicitis (Fig. 1). The surgery team was consulted, and she was taken to the operating room for laparoscopic appendectomy. Her post-operative course was complicated by hemoperitoneum, necessitating exploratory laparoscopy. Two days post-operatively, she was experiencing moderate abdominal pain but was able to tolerate solid foods.

Fig. 1.

Computed tomography scan of the abdomen showing a 5-mm appendicolith with mild dilatation and wall thickening of the appendix (blue arrows), consistent with acute appendicitis.

On post-operative day 3, microscopic examination of the appendix revealed acute appendicitis with numerous large cells with intranuclear “owl's eye” inclusions (Fig. 2A) characteristic of CMV, which was confirmed by immunohistochemistry (Fig. 2B). She was found to have an elevated CMV DNA level in peripheral blood of 327,018 IU/ml (ref < 50). She was treated with intravenous (IV) ganciclovir 5 mg/kg every 12 h and acyclovir was stopped. By post-operative day 5, her abdominal pain had improved and she was ambulating without assistance. She was discharged home on IV ganciclovir on post-operative day 8 after having a central venous catheter placed with interventional radiology. Due to CMV infection with low WBC count, her mycophenolate was discontinued. At 3-week follow up, her CMV level had improved to 30,118 and IV ganciclovir was transitioned to oral valganciclovir 900 mg twice daily. The infectious disease team scheduled weekly CMV level monitoring with plans to decrease valganciclovir to a maintenance dose after two consecutive weeks of CMV levels <50.

Fig. 2.

(A) Cytomegalic cells with intranuclear “owl's eye” inclusions (400× magnification, hematoxylin and eosin stain). (B) Immunostain for cytomegalovirus highlights numerous viral inclusions (200× magnification).

Due to concern that valganciclovir was contributing to the patient's leukopenia, therapy was switched to letermovir for continued treatment of CMV approximately four months post-transplant. At subsequent follow-up visits, the patient's tacrolimus levels fluctuated widely. This was concerning for nonadherence to her immunosuppressive medications, placing her at increased risk for transplant rejection. Five months after discontinuation of mycophenolate, endomyocardial biopsy showed Grade 2R acute cellular rejection. She was treated with prednisone 100 mg daily for three days and repeat biopsy was negative for rejection.

Discussion

Appendicitis is a very rare presentation of CMV and has previously been reported in one other heart transplant recipient to our knowledge [5]. Our patient and donor were both CMV seronegative (D−/R−), categorizing her as low risk for CMV infection; therefore, she did not receive prophylaxis with valganciclovir. She developed CMV appendicitis 1 month after transplant. In comparison, the other previously reported case was a 42-year-old man with CMV serostatus D+/R+ at moderate risk for CMV infection [5]. He received 6 months of valganciclovir for CMV prophylaxis and subsequently developed CMV appendicitis 2 months after ganciclovir was stopped, consistent with post prophylaxis delayed-onset CMV disease. The immunosuppression induction regimens also differed between these two cases: our patient had induction with methylprednisolone, while the other patient's induction regimen included basiliximab. Both patients were on the same immunosuppressive maintenance (prednisone, mycophenolate, and tacrolimus) at the time of developing appendicitis. Both patients similarly presented with abdominal pain, underwent appendectomies, and saw rapid improvement in CMV polymerase chain reaction (PCR) levels after initiation of IV ganciclovir.

In addition to serostatus, other risk factors for CMV infection in solid organ transplant recipients include prior episodes of allograft rejection, severe lymphopenia, and intense immunosuppression. An additional risk factor relevant to our patient is exposure to day care centers, where rates of CMV infection in children are notably higher compared to children not attending day care [6]. Our patient's home also functioned as a day care center, which is the likely etiology of her CMV infection.

Antiviral prophylaxis against CMV has led to a reduction in potentially detrimental effects on solid organ transplant recipients. One pitfall of antiviral prophylaxis is “post prophylaxis delayed-onset CMV disease,” which typically occurs within 3–6 months of stopping antivirals. This terminology is used to differentiate true “late-onset CMV,” which may occur many years after transplant [4]. In one study, CMV D+/R− liver transplant patients were monitored for the incidence of CMV while on antiviral prophylaxis and no breakthrough cases were observed [7]. However, once prophylaxis was stopped, 25 % developed primary CMV within 3 months. Of note, no significant association was seen between CMV disease and patient or allograft survival [7]. The increased awareness of post prophylaxis delayed-onset CMV disease has brought about a new wave of strategies to counter the disease. These focus on the first 3–6 months after stopping prophylaxis and include counseling patients to have a low threshold to seek medical care at the first sign of symptoms as well as viral surveillance with CMV QNAT. Additionally, some centers have extended the duration of antiviral prophylaxis, although it is important to note the associated increased risk of myelotoxicity [4]. Despite the advances in CMV prevention, CMV infection continues to be a concern for solid organ transplant patients, with the gastrointestinal tract being frequently involved. Various studies in transplant recipients have found CMV to be the underlying etiology of oral and esophageal ulcers, gastro-duodenal ulceration, and colitis presenting with an array of symptoms from watery diarrhea to hemorrhagic ulcers [5].

The diagnosis of tissue-invasive disease ultimately requires biopsy with identification of CMV inclusions and/or positive CMV-specific immunohistochemistry staining on histopathology. In addition, CMV QNAT should be obtained as it will be used to monitor an individual's response to treatment, while also supporting evidence of infection [8]. Of note, quantitative PCR (qPCR) for CMV DNA in plasma can be negative even when biopsy-proven disease has been identified [9]. One study, which included kidney and liver transplant patients, showed CMV qPCR had a sensitivity of 85 % and specificity of 95 % for diagnosing CMV disease in the gastrointestinal tract [9]. Therefore, both CMV QNAT and histopathological testing should be performed to accurately diagnose CMV tissue-invasive disease.

For patients with confirmed or presumptive CMV disease, first-line treatments include intravenous ganciclovir and oral valganciclovir, with cidofovir and foscarnet being second line due to an elevated risk for nephrotoxicity [10]. Letermovir, a newer medication without significant myelotoxicity, is currently approved for prophylaxis in HSCT recipients and is being studied as a possible treatment option for CMV [8]. Treatment duration varies and is influenced by disease severity and the clinical and virologic response to treatment. If viral loads do not improve with antiviral therapy, drug-resistant CMV should be suspected and followed up with testing for resistance mutations. Primary risk factors for developing resistance include previous or prolonged (>3 months) antiviral CMV drug exposure, high levels of immunosuppression, and inadequate viral drug delivery [8].

Conclusion

CMV can rarely present as acute appendicitis in immunocompromised patients. CMV appendicitis should be considered in the differential diagnosis of abdominal pain in immunocompromised patients.

Consent statement

Written informed consent was obtained from the patient for publication of this case report.

Declaration of competing interest

The authors declare that there is no conflict of interest.