Jameson, Andrew MD; Kauffman, Carol A. MD; Cinti, Sandro K. MD; Gandhi, Tejal MD
Cytomegalovirus (CMV) is a common opportunistic infection in patients with human immunodeficiency virus (HIV) infection with advanced immunosuppression, especially those who have a CD4 cell count of less than 50 cells/μL. Retinitis, colitis, pneumonia, hepatitis, and CMV viremia without end-organ disease are well described.1,2 Cytomegalovirus appendicitis is a rare manifestation of CMV disease. Eight cases with available clinical data, most of whom were seen before the availability of combination antiretroviral therapy (ART), have been reported.3–10 We present 2 recent cases of CMV appendicitis treated at our medical center and review the characteristics of the 8 cases previously reported.
We performed a PubMed search of the English-language literature for cases of CMV appendicitis in persons with HIV infection using the key terms human immunodeficiency virus, cytomegalovirus, CMV, appendicitis, AIDS, and acquired immunodeficiency syndrome (AIDS) and cross referenced all of the articles to include missed cases. We only included cases in which the following criteria were met: clinical picture compatible with appendicitis, diagnosis of HIV infection, and CMV infection documented by histopathologic examination of the appendix.
A 49-year-old woman presented in November 2010 with 3 days of nonproductive cough, hypoxia, and fever; she described a 50-lb weight loss over the previous 9 months. She had numerous episodes of thrush noted in the past, and myelodysplastic syndrome had been previously diagnosed based on bone marrow biopsy results. The patient underwent bronchoscopy, and the diagnosis of Pneumocystis jiroveci pneumonia was made. Laboratory studies revealed a positive HIV antibody, 80 CD4 cells/μL, and 4,430,000 HIV copies/mL by polymerase chain reaction (PCR) testing. Plasma CMV PCR value was 11,000 copies/mL. The patient was treated with oral primaquine/clindamycin without corticosteroids for Pneumocystis jiroveci pneumonia with resolution of the pneumonia and a twice-daily dosage of 900 mg oral valganciclovir for CMV viremia. Antiretroviral therapy was not initiated at this point.
One month later, the patient developed fevers and severe abdominal pain. Urgent appendectomy finding revealed a phlegmonous mass in the right lower quadrant consistent with acute appendicitis. Histopathologic examination finding revealed intranuclear inclusions consistent with CMV, and the plasma CMV PCR value had increased to 80,500 copies/mL. The patient was treated with a twice-daily dosage of 275 mg intravenous ganciclovir for a total of 4 weeks with an excellent response; the plasma CMV PCR value was undetectable at the end of therapy. Therapy was changed to oral valganciclovir treatment of another 6 weeks followed by secondary prophylaxis for a total of 6 months. The patient subsequently responded well to treatment of HIV infection with recovery of CD4 cell counts and undetectable HIV-1 plasma RNA levels by PCR.
A 63-year-old man presented in May 2012 with 2 weeks of fever, night sweats, 10-lb weight loss, dysphagia, and frequent diarrhea. The diarrhea was described as watery without pain or hematochezia. Physical examination showed a chronically ill-appearing man who had thrush and perianal ulcerations likely due to herpes simplex. Laboratory studies revealed antibodies to HIV, white blood cell (WBC) count of 2900 cells/μL, 72 CD4 cells/μL, and HIV-1 RNA viral load of 9,720,000 copies/mL.
The patient was started on emtricitabine/tenofovir/efavirenz (Atripla; Bristol-Myers Squibb, New York, NY), acyclovir, and fluconazole. Nine days after starting Atripla, the perianal herpetic lesions and oral thrush had resolved but dysphagia and diarrhea continued. Plasma CMV PCR value was noted to be 290,000 copies/mL, and a twice-daily dosage of 900 mg oral valganciclovir was initiated. Ten days later, he developed acute right lower quadrant abdominal pain, fever, and anorexia. Abdominal computed tomographic scan finding revealed an inflamed appendix, and the patient immediately underwent an appendectomy. Histopathologic examination finding revealed appendicitis and periappendiceal abscess with fat necrosis; immunoperoxidase staining was positive for CMV virocytes (Fig. 1). The patient was treated with 30 days of induction therapy with a twice-daily dosage of 900 mg valganciclovir followed by 6 months of maintenance therapy with a twice-daily dosage of 450 mg valganciclovir.
Three weeks after appendectomy and 5 weeks after initiation of ART, the patient’s repeated CD4 cell count was 138 cells/μL. Repeated HIV-1 RNA viral load was 1580 copies/mL. The patient’s repeated CMV PCR was undectable on treatment dosing of valganciclovir. The patient continued to improve with weight gain, suppression of HIV replication, and improvement of CD4 cell count up to 249 cells/μL by 12 weeks after initial presentation.
A total of 10 patients, including the 2 patients presented herein, met our case definition for HIV-associated CMV appendicitis (Table 1). Among the 8 patients for whom CD4 cell counts were reported, all had a CD4 cell count of below 100 cells/μL. Only 3 cases were identified after the introduction of combination ART, and all 3 were patients with a new diagnosis of AIDS within weeks of the diagnosis of CMV appendicitis.
The mean duration of symptoms of acute appendicitis was 5.1 days (range, 1–10 days). All patients had abdominal pain, but only 8 of the 10 patients were febrile. Diarrhea occurred in 3 patients, and peritoneal signs were present in 6 of the 10 patients. In regards to laboratory evaluation, the mean WBC count at presentation was 5700 cells/μL (range, 2900–14,000 cells/μL), and the mean CD4 cell count was 48.7 cells/μL (range, 2–84 cells/μL). Appendectomy was often delayed by an average of 3.3 days (range, 6 hours–11 days) from the time of presentation.
Concurrent or preceding opportunistic infections were common in these patients. Pneumocystis jiroveci pneumonia was most common; other infections included Mycobacterium tuberculosis lymphadenitis, disseminated Mycobacterium avium complex disease, disseminated varicella, herpes proctitis, and oropharyngeal candidiasis.
Cytomegalovirus inclusions were present in all histopathologic specimens. Histopathologic findings alone were the sole means of identifying CMV infection in 2 cases. In situ hybridization tests using probes for CMV DNA were positive in 2 cases, and immunohistochemical staining was positive in an additional 4 cases. Cytomegalovirus IgG was positive in 5 cases. Quantitative plasma PCR value for CMV DNA was positive in our patients, and another patient had CMV DNA detected qualitatively in peripheral WBC count, urine, and appendiceal tissue. Cytomegalovirus was successfully cultured from appendiceal tissue in 1 patient.
Computed tomographic scans were performed in 7 of the 10 patients, and 6 of the scan findings revealed inflammatory changes involving the appendix. No evidence of perforation was present on computed tomographic scan. Appendiceal perforation and/or abscess were found during the operation in 2 patients.
Treatment and Outcome
Five patients were treated with appendectomy alone. Of these, 1 patient died 3 months after presentation. It is unclear whether the cause of death was related to CMV disease. The remaining 5 patients were treated with appendectomy combined with either valganciclovir or ganciclovir. The duration of antiviral therapy was not discussed in the previous case reports.
Appendicitis associated with CMV infection is a rare occurrence among individuals with HIV infection.11–13 Cytomegalovirus appendicitis in persons with HIV infection has a similar clinical presentation to appendicitis in the normal host. The common signs and symptoms, including fever, right lower quadrant abdominal pain, and peritoneal signs, are similar to those seen in immunocompetent individuals. The radiographic appearance and gross inflammatory changes noted at surgery also are similar among CMV-associated cases and what are described in typical cases of appendicitis.14
However, there are some notable differences in appendicitis between patients with HIV infection and normal hosts. The mean age of the patients in the current review is nearly 2 decades older than the peak incidence of acute appendicitis in the general population, which are 10 to 14 years in males and 15 to 19 years in females.14 The duration of symptoms preceding presentation is several days longer in patients with HIV infection than the usual presentation within 24 hours of symptom onset in most cases of acute appendicitis.14 Patients with HIV infection with CMV appendicitis have advanced HIV infection, and thus, other concurrent opportunistic infections are common. These other infections may have led to a delay in diagnosis because the patient and the physician attributed the symptoms to another known opportunistic infection.
In addition to the acute symptoms, several of the patients with HIV in the current review had chronic symptoms, such as diarrhea and abdominal cramping that were consistent with gastrointestinal CMV infection before the development of appendicitis. In patients with advanced HIV infection, the development of acute onset right lower quadrant pain in the setting of chronic diarrhea, fever, and weight loss and known CMV viremia should raise the suspicion for CMV appendicitis.
Acute appendicitis in the general population is associated with leukocytosis, neutrophilia, and elevated inflammatory markers. Leukocytosis correlates most closely with acute appendicitis; in 1 study, the likelihood ratio that acute appendicitis was present ranged from 0.1 in patients with WBC count of 4000 to 7000 cells/μL up to 2.8 in patients with WBC count of 11,000 to 13,000 cells/μL.15 In the 10 cases reported herein, only 1 patient had a WBC count of greater than 10,000 cells/μL. This relative leukopenia likely reflects the suppressive effects on the bone marrow of HIV and CMV infections.16,17
Cytomegalovirus appendicitis was documented in every case by identification of the typical CMV “owl’s eye” or intranuclear viral inclusions noted within the appendicular tissue.18 Immunohistochemistry and in situ hybridization are useful confirmatory tests for CMV infection. It is noteworthy that the conditions of our patients were diagnosed only after the pathologists were asked to reevaluate the specimens for possible CMV infection. Both of our patients had CMV viremia documented before they developed appendicitis.
The standard treatment of CMV gastrointestinal disease is intravenous ganciclovir or oral valganciclovir, depending on the severity of illness. The conditions of 5 of the patients were diagnosed before ganciclovir was widely available and were treated with appendectomy alone. Four of the 5 patients had a full recovery, and the remaining patient died 3 months later of unknown causes. All of the patients treated with ganciclovir or valganciclovir had a complete recovery without relapse.
Cytomegalovirus appendicitis may be a more frequent event than documented among persons with HIV/AIDS because patients are treated for other CMV-associated end-organ disease before appendiceal infection is clinically apparent. In addition, CMV inclusions may be missed on histopathologic examination of appendectomy specimens.
Our second case possibly represents immune reconstitution inflammatory syndrome manifesting as CMV appendicitis. The patient had CMV viremia with appropriate treatment initiated 10 to 14 days before symptom onset, and ART was begun 21 days before appendicitis was manifested. His CD4 cell count rapidly improved, and the viral load decreased dramatically over the first month of ART. Cytomegalovirus retinitis has been described as a manifestation of immune reconstitution inflammatory syndrome in persons with AIDS.19 Our patient’s clear worsening condition while on appropriate therapy for CMV is consistent with this complication.
We describe 2 cases and review an additional 8 cases of CMV appendicitis in patients with AIDS. The clinical course and acute symptoms were similar when these patients were compared with immunocompetent patients who had appendicitis. However, laboratory findings and concomitant opportunistic infections set this disease process apart in patients with HIV infection. Treatment was primarily surgery with adjunctive antiviral therapy. Accurate and timely diagnosis requires a high index of suspicion on the part of clinician.
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